STRESS & ADJUSTMENT DISORDERS (SITUATIONAL DISORDERS)
ESSENTIALS OF DIAGNOSIS
Anxiety or depression in reaction to an identifiable stress.
Subsequent symptoms of anxiety or depression commonly elicited by similar stress of lesser magnitude.
Alcohol and other drugs are commonly used in self-treatment.
An individual experiences stress when the adaptive capacity of the individual is overwhelmed by events. The event may be an insignificant one when objectively considered, and even favorable changes (eg, promotion and transfer) requiring adaptive behavior can produce stress. For each individual, stress is subjectively defined, and the response to stress is a function of each person’s personality and physiologic endowment.
Opinion differs about what events are most apt to produce stress reactions. The causes of stress are different at different ages—eg, in young adulthood, the sources of stress are found in the marriage or parent-child relationship, the employment relationship, and the struggle to achieve financial stability; in the middle years, the focus shifts to changing spousal relationships, problems with aging parents, and problems associated with having young adult offspring who themselves are encountering stressful situations; in old age, the principal concerns are apt to be retirement, loss of physical and mental capacity, major personal losses, and thoughts of death.
An individual may react to stress by becoming anxious or depressed, by developing a physical symptom, by running away, drinking alcohol, overeating, starting an affair, or in limitless other ways. Common subjective responses are anxiety, sadness, fear, rage, guilt, and shame. Acute and reactivated stress may be manifested by restlessness, irritability, fatigue, increased startle reaction, and a feeling of tension. Inability to concentrate, sleep disturbances (insomnia, bad dreams), and somatic preoccupations often lead to self-medication, most commonly with alcohol or other central nervous system depressants. Maladaptive behavior in response to stress is called adjustment disorder, with the major symptom specified (eg, “adjustment disorder with depressed mood”). Even with an identifiable stressor, if the patient meets syndromal criteria for another disorder such as major depression, then the convention would be to diagnose a major depression and not an adjustment disorder with depressed mood.
Adjustment disorders are distinguished from anxiety disorders, mood disorders, bereavement, other stress disorders such as posttraumatic stress disorder (PTSD), and personality disorders exacerbated by stress and from somatic disorders with psychic overlay. Unlike many other psychiatric disorders, such as bipolar disorder or schizophrenia, adjustment disorders are wholly situational and usually resolve when the stressor resolves or the individual effectively adapts to the situation. Adjustment disorders may have symptoms that overlap with other disorders, such as anxiety symptoms, but they occur in reaction to an identifiable life stressor such as a difficult work situation or romantic breakup. An adjustment disorder that persists and worsens can potentially evolve into another psychiatric disorder such as major depression or generalized anxiety disorder (GAD). However, that is not the case for most patients. Patients with adjustment disorders have marked distress after a stressor and significant impairment in social or occupational functioning but not to the degree experienced by patients with a more severe disorder such as major depressive disorder or PTSD. By definition, an adjustment disorder occurs within 3 months of an identifiable stressor.
Stress reduction techniques include immediate symptom reduction (eg, rebreathing in a bag for hyperventilation) or early recognition and removal from a stress source before full-blown symptoms appear. It is often helpful for the patient to keep a daily log of stress precipitators, responses, and alleviators. Relaxation, mindfulness-based stress reduction, and exercise techniques are also helpful in reducing the reaction to stressful events.
The stress reactions of life crisis problems are a function of psychosocial upheaval, and patients frequently present with somatic symptoms. While it is not easy for the patient to make necessary changes (or they would have been made long ago), it is important for the clinician to establish the framework of the problem, since the patient’s denial system may obscure the issues. Clarifying the problem allows the patient to begin viewing it within the proper context and facilitates the difficult decisions the patient eventually must make (eg, change of job).
Prolonged in-depth psychotherapy is seldom necessary in cases of isolated stress response or adjustment disorder. Supportive psychotherapy (see above) with an emphasis on the here and now and strengthening of existing coping mechanisms is a helpful approach so that time and the patient’s own resiliency can restore the previous level of function. In addition, cognitive behavioral therapy has long been established to treat acute stress and facilitate recovery in patients with an adjustment disorder.
Judicious use of sedatives (eg, lorazepam, 0.5–1 mg two or three times daily orally) for a limited time and as part of an overall treatment plan can provide relief from acute anxiety symptoms. Problems arise when the situation becomes chronic through inappropriate treatment or when the treatment approach supports the development of chronicity. There are occasions where the short-term use of selective serotonin reuptake inhibitors (SSRIs) targeting dysphoria and anxiety may be useful.
Return to satisfactory function after a short period is part of the clinical picture of this syndrome. Resolution may be delayed if others’ responses to the patient’s difficulties are thoughtlessly harmful or if the secondary gains outweigh the advantages of recovery. The longer the symptoms persist, the worse the prognosis.
et al. Psychological benefits for cancer patients and their partners participating in mindfulness-based stress reduction (MBSR). Psychooncology. 2010 Sep;19(9):1004–9.
TRAUMA & STRESSOR-RELATED DISORDERS
ESSENTIALS OF DIAGNOSIS
Exposure to a traumatic or life-threatening event.
Symptoms, such as flashbacks, intrusive images, and nightmares, often represent reexperiencing the event.
Avoidance symptoms, including numbing, social withdrawal, and avoidance of stimuli associated with the event.
Increased vigilance, such as startle reactions and difficulty falling asleep.
Symptoms impair functioning.
Posttraumatic stress disorder (PTSD) has been reclassified from an anxiety disorder to a trauma and stressor-related disorder in the DSM-5. PTSD is a syndrome characterized by “reexperiencing” a traumatic event (eg, sexual assault, severe burns, military combat) and decreased responsiveness and avoidance of current events when associated with the trauma. The National Veterans Vietnam Readjustment Survey indicated that 53.4% of male and 48.1% of female Vietnam War veterans experienced some symptoms of PTSD, with approximately 60% of these affected veterans experiencing the full syndrome. Of the male veterans with PTSD, 44.7% experienced a lifetime prevalence of alcohol or drug abuse, with 13% experiencing current abuse or dependence. Data indicate that 13% of veterans who served in Iraq and 6% of those who served in Afghanistan have experienced PTSD. The 2005 National Comorbidity Survey Report estimated the lifetime prevalence of PTSD among adult Americans at 6.8% with a point prevalence of 3.6% and with women having rates twice as high as men. PTSD is more common when the event is associated with physical injury than when it is not. Many individuals with PTSD (20–40%) have experienced other associated problems, including divorce, parenting problems, difficulties with the law, and substance abuse. Since the terrorist attacks in the United States on September 11, 2001, estimates of PTSD have ranged from 4.7% to 10.2% in those witnessing the live attacks and have been associated with functional impairment as well as increased rates of substance use.
The key to establishing the diagnosis of PTSD lies in the history of exposure to a life-threatening event followed by intrusive (eg, flashbacks, nightmares) or avoidance (eg, withdrawal) symptoms. Patients with PTSD experience physiologic hyperarousal, including startle reactions, intrusive thoughts, illusions, overgeneralized associations, sleep problems, nightmares, dreams about the precipitating event, impulsivity, difficulties in concentration, and hyperalertness. The symptoms may be precipitated or exacerbated by events that are a reminder of the original traumatic event. Symptoms frequently arise after a long latency period (eg, child abuse can result in later-onset PTSD). DSM-5 includes the requirement that the symptoms persist for at least 1 month. In some individuals, the symptoms fade over months or years, and in others it may persist for a lifetime.
In 75% of cases, PTSD occurs with comorbid depression or panic disorder, and there is considerable overlap in the symptom complexes of all three conditions. Acute stress disorder occurs during or shortly after a traumatic event and has many of the same symptoms as PTSD but lasts between 2 and 28 days. Some individuals with dissociative features, such as borderline personality disorders, may mimic some of the symptoms of PTSD, but those disorders are typically more related to chronic childhood maltreatment not a specific traumatic event. The other major comorbidity is alcohol and substance abuse.
Psychotherapy should be initiated as soon as possible after the traumatic event, and it should be brief (typically 8–12 sessions), once the individual is in a safe environment. Cognitive behavior therapy, exposure therapy, and eye-movement desensitization reprocessing have been effective in significantly reducing the duration of symptoms. In all of these approaches, the individual confronts the traumatic situation and learns to view it with less reactivity. Psychological debriefing in a single session, once a mainstay in prevention of PTSD, is now considered to be ineffective and possibly harmful. Posttraumatic stress syndromes respond to interventions that help patients integrate the event in an adaptive way with some sense of mastery in having survived the trauma. Partner relationship problems are a major area of concern, and it is important that the clinician have available a dependable referral source when marriage counseling is indicated.
Treatment initiated later, when symptoms have crystallized, includes programs for cessation of alcohol and other drug use, group and individual psychotherapy, and improved social support systems. The therapeutic approach is to facilitate the normal recovery that was blocked at the time of the trauma.
Treatment of any comorbid substance abuse is an essential part of the recovery process for patients with PTSD. Support groups and 12-step programs such as Alcoholic Anonymous are often very helpful.
SSRIs in full dosage are helpful in ameliorating depression, panic attacks, sleep disruption, and startle responses in chronic PTSD. Sertraline and paroxetine are approved by the US Food and Drug Administration (FDA) for this purpose, and the SSRIs are the only class of medications approved for the treatment of PTSD. They are, therefore, considered the pharmacotherapy of choice for PTSD. Early treatment of anxious arousal with beta-blockers (eg, propranolol, 80–160 mg orally daily) may lessen the peripheral symptoms of anxiety (eg, tremors, palpitations) but has not been shown to help prevent PTSD. Similarly, noradrenergic agents such as clonidine (titrated from 0.1 mg orally at bedtime to 0.2 mg three times a day) have been shown to help with the hyperarousal symptoms of PTSD. The alpha-adrenergic blocking agent prazosin (2–10 mg orally at bedtime) decreases nightmares and improves quality of sleep in PTSD. Antiseizure medications such as carbamazepine (400–800 mg orally daily) will often mitigate impulsivity and difficulty with anger management. Benzodiazepines, such as clonazepam (1–4 mg orally daily, divided into one or two doses), will reduce anxiety and panic attacks when used in adequate dosage, but dependency problems are a concern, particularly when the patient has had such problems in the past. Trazodone (25–100 mg orally at bedtime) is commonly prescribed as a non–habit forming hypnotic agent. Second-generation antipsychotics have not demonstrated significant utility in the the treatment of PTSD but agents such as quetiapine 50–300 mg/day may have a limited role in treating agitation and sleep disturbance in PTSD patients.
The sooner therapy is initiated after the trauma, the better the prognosis. Approximately half of patients experience chronic symptoms. Prognosis is best in those with good premorbid psychiatric functioning. Individuals experiencing an acute stress disorder typically do better than those experiencing a delayed posttraumatic disorder. Individuals who experience trauma resulting from a natural disaster (eg, earthquake or hurricane) tend to do better than those who experience a traumatic interpersonal encounter (eg, rape or combat).
et al. Treatment of complex PTSD: results of the ISTSS expert clinician survey on best practices. J Trauma Stress. 2011 Dec;24(6):615–27.
et al. Treatment of posttraumatic stress disorder in U.S. combat veterans: a meta-analytic review. Psychol Rep. 2011 Oct;109(2):573–99.
et al. Combined pharmacotherapy and psychological therapies for posttraumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2010 Jul 7;(7):CD007316.
et al. Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry. 2015 Feb;206(2):93–100.
ESSENTIALS OF DIAGNOSIS
Overt anxiety or an overt manifestation of a coping mechanism (such as a phobia), or both.
Not limited to an adjustment disorder.
Somatic symptoms referable to the autonomic nervous system or to a specific organ system (eg, dyspnea, palpitations, paresthesias).
Not a result of physical disorders, psychiatric conditions (eg, schizophrenia), or drug abuse (eg, cocaine).
Stress, fear, and anxiety all tend to be interactive. The principal components of anxiety are psychological (tension, fears, difficulty in concentration, apprehension) and somatic (tachycardia, hyperventilation, shortness of breath, palpitations, tremor, sweating). Other organ systems (eg, gastrointestinal) may be involved in multiple-system complaints. Fatigue and sleep disturbances are common. Sympathomimetic symptoms of anxiety are both a response to a central nervous system state and a reinforcement of further anxiety. Anxiety can become self-generating, since the symptoms reinforce the reaction, causing it to spiral. This is often the case when the anxiety is an epiphenomenon of other medical or psychiatric disorders.
Anxiety may be free-floating, resulting in acute anxiety attacks, occasionally becoming chronic. When coping mechanisms for stress management are not functioning, the consequences are problems such as phobias, conversion reactions, and dissociative states. Lack of structure is frequently a contributing factor, as noted in those people who have “Sunday neuroses.” They do well during the week with a planned work schedule but cannot tolerate the unstructured weekend. Planned-time activities tend to bind anxiety, and many people have increased difficulties when this is lost, as in retirement.
Some believe that various manifestations of anxiety are not a result of unconscious conflicts but are “habits”—persistent patterns of nonadaptive behavior acquired by learning. The “habits,” being nonadaptive, are unsatisfactory ways of dealing with life’s problems—hence the resultant anxiety. Help is sought only when the anxiety becomes too painful. Exogenous factors such as stimulants (eg, caffeine, cocaine) must be considered as a contributing factor.
A. Generalized Anxiety Disorder
This is among the most common of the clinically significant anxiety disorders. Initial manifestations appear at age 20–35 years, and the rate appears to increase with age. GAD becomes chronic in many patients with over half of patients having the disorder for longer than 2 years. About 7% of women and 4% of men will meet criteria for GAD over a lifetime. The anxiety symptoms of apprehension, worry, irritability, difficulty in concentrating, insomnia, and somatic complaints are present more days than not for at least 6 months. Manifestations can include cardiac (eg, tachycardia, increased blood pressure), gastrointestinal (eg, increased acidity, nausea, epigastric pain), and neurologic (eg, headache, near-syncope) systems. The focus of the anxiety may be a number of everyday activities.
This is characterized by recurrent, unpredictable episodes of intense anxiety accompanied by marked physiologic manifestations. Agoraphobia, fear of being in places where escape is difficult, such as open spaces or public places where one cannot easily hide, may be present and may lead the individual to confine his or her life to the home environment. Distressing symptoms and signs such as dyspnea, tachycardia, palpitations, headaches, dizziness, paresthesias, choking, smothering feelings, nausea, and bloating are associated with feelings of impending doom (alarm response). Although these symptoms may lead to overlap with some of the same bodily complaints found in the somatic symptom disorders, the key to the diagnosis of panic disorder is the psychic pain and suffering the individual expresses. Recurrent sleep panic attacks (not nightmares) occur in about 30% of panic disorders. Anticipatory anxiety develops in all these patients and further constricts their daily lives. Panic disorder tends to be familial, with onset usually under age 25; it affects 3–5% of the population, and the female-to-male ratio is 2:1. The premenstrual period is one of heightened vulnerability. Patients frequently undergo emergency medical evaluations (eg, for “heart attacks” or “hypoglycemia”) before the correct diagnosis is made. Gastrointestinal symptoms (eg, stomach pain, heartburn, diarrhea, constipation, nausea and vomiting) are especially common, occurring in about one-third of cases. Myocardial infarction, pheochromocytoma, hyperthyroidism, and various recreational drug reactions can mimic panic disorder. Mitral valve prolapse may be present but is not usually a significant factor. Patients who have recurrent panic disorder often become demoralized, hypochondriacal, agoraphobic, and depressed. These individuals are at increased risk for major depression and the suicide attempts associated with that disorder. Alcohol abuse (in about 20%) results from self-treatment and is frequently combined with dependence on sedatives. Some patients have atypical panic attacks associated with seizure-like symptoms that often include psychosensory phenomena (a history of stimulant abuse often emerges). About 25% of panic disorder patients also have obsessive-compulsive disorder (OCD).
Phobias are fears of a specific object or situation (eg, spiders, height) that are out of proportion to the danger posed and they tend to be chronic. Social phobias are global or specific; in the former, all social situations are poorly tolerated, while the latter group includes performance anxiety (eg, fear of public speaking). Agoraphobia is frequently associated with severe panic attacks, and it often develops in early adult life, making a normal lifestyle difficult. Patients with agoraphobia experience intense fear about common situations, such as being in open spaces (eg, marketplaces), enclosed spaces (eg, theaters), standing in line, or being alone outside of their homes. While patients with simple phobias such as fear of heights may function as long as they do not have to be in tall buildings or airplanes, a patient with agoraphobia may not be able to function vocationally or interpersonally. Thus, patients with agoraphobia are much more likely to seek treatment than those with simple or even social phobia.
In all cases, underlying medical disorders must be ruled out (eg, cardiovascular, endocrine, respiratory, and neurologic disorders and substance-related syndromes, both intoxication and withdrawal states). These and other disorders can coexist with panic disorder.
Antidepressants including the SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) are safe and effective in the long-term management of GAD. The antidepressants appear to be as effective as the benzodiazepines without the risks of tolerance or dependence. However, benzodiazepines are the anxiolytics of choice in the acute management of generalized anxiety (Table 25–1). They are almost immediately effective.
Table 25–1.Commonly used antianxiety and hypnotic agents. |Favorite Table|Download (.pdf) Table 25–1. Commonly used antianxiety and hypnotic agents.
|Drug ||Usual Daily Oral Doses ||Usual Daily Maximum Doses ||Cost for 30 Days Treatment Based on Maximum Dosage1 |
|Benzodiazepines (used for anxiety) |
|Alprazolam (Xanax)2 ||0.5 mg ||4 mg ||$223.80 |
|Chlordiazepoxide (Librium)3 ||10–20 mg ||100 mg ||$37.20 |
|Clonazepam (Klonopin)3 ||1–2 mg ||10 mg ||$122.40 |
|Clorazepate (Tranxene)3 ||15–30 mg ||60 mg ||$260.40 |
|Diazepam (Valium)3 ||5–15 mg ||30 mg ||$30.60 |
|Lorazepam (Ativan)2 ||2–4 mg ||4 mg ||$69.00 |
|Oxazepam (Serax)2 ||10–30 mg ||60 mg ||$95.40 |
|Benzodiazepines (used for sleep) |
|Estazolam (Prosom)2 ||1 mg ||2 mg ||$29.70 |
|Flurazepam (Dalmane)3 ||15 mg ||30 mg ||$11.40 |
|Midazolam (Versed)4 ||5 mg || ||$1.00/dose |
|Quazepam (Doral)3 ||7.5 mg ||15 mg ||$138.00 |
|Temazepam (Restoril)2 ||15 mg ||30 mg ||$26.40 |
|Triazolam (Halcion)5 ||0.125 mg ||0.25 mg ||$82.20 |
|Miscellaneous (used for anxiety) |
|Buspirone (Buspar)2 ||10–30 mg ||60 mg ||$217.80 |
|Phenobarbital3 ||15–30 mg ||90 mg ||$37.80 |
|Miscellaneous (used for sleep) |
|Eszopiclone (Lunesta)5 ||2–3 mg ||3 mg ||$349.80 |
|Hydroxyzine (Vistaril)2 ||50 mg ||100 mg ||$62.40 |
|Suvorexant (Belsomra) ||5–10 mg ||20 mg ||$341.10 |
|Ramelteon (Rozerem) ||8 mg ||8 mg ||$367.04 |
|Zaleplon (Sonata)6 ||5–10 mg ||10 mg ||$108.30 |
|Zolpidem (Ambien)5 ||5–10 mg ||10 mg ||$138.60 |
All of the benzodiazepines may be given orally, and several are available in parenteral formulations. Benzodiazepines such as lorazepam are absorbed rapidly when given intramuscularly. In psychiatric disorders, the benzodiazepines are usually given orally; in controlled medical environments (eg, the ICU), where the rapid onset of respiratory depression can be assessed, they are often given intravenously. Diazepam and clorazepate are the most rapidly absorbed oral benzodiazepines, which may explain the popularity of diazepam. In the average case of anxiety, diazepam, 5–10 mg orally twice daily as needed, is a reasonable starting regimen.
Benzodiazepines such as lorazepam do not produce active metabolites and have intermediate half-lives of 10–20 hours, characteristics useful in treating elderly patients. Ultra-short-acting agents such as triazolam have half-lives of 1–3 hours and may lead to rebound withdrawal anxiety. Longer-acting benzodiazepines such as flurazepam and diazepam produce active metabolites, have half-lives of 20–120 hours, and should be avoided in the elderly. Since people vary widely in their response and since the medications are long lasting, the dosage must be individualized. Once this is established, an adequate dose early in the course of symptom development will obviate the need for “pill popping,” which contributes to dependency problems.
Antidepressants are the first-line medications for sustained treatment of GAD, having the advantage of not causing physiologic dependency problems. Antidepressants can themselves be anxiogenic—thus, at the initiation of treatment, concomitant short-term treatment with a benzodiazepine is often indicated. Venlafaxine and duloxetine are FDA-approved for the treatment of GAD in usual antidepressant doses. Initial daily dosing should start low (37.5–75 mg for venlafaxine and 30 mg for duloxetine) and be titrated upward as needed. SSRIs, such as paroxetine, are also used. While most antidepressants including tricyclic antidepressants (TCAs) and monoamine oxidase (MAO) inhibitors are often effective in the treatment of anxiety disorders, their side effects and drug interactions make them second- or third-line agents. Bupropion may be the most anxiogenic antidepressant and has no clear usefulness in treatment of anxiety disorders. Buspirone, sometimes used as an augmenting agent in the treatment of depression and compulsive behaviors, is also effective for generalized anxiety. Buspirone is usually given in a total dose of 15–60 mg/day in three divided doses. Higher doses tend to be counterproductive and produce gastrointestinal symptoms and dizziness. There is a 2- to 4-week delay before antidepressants and buspirone take effect, and patients require education regarding this lag. Sleep is sometimes negatively affected. Gabapentin (titrated to doses of 900–1800 mg orally daily) appears effective and lacks the habit-forming potential of the benzodiazepines. Unfortunately, like buspirone, many patients find gabapentin less effective than benzodiazepines in the management of acute anxiety. Beta-blockers, such as propranolol, may help reduce peripheral somatic symptoms. Alcohol is the most frequently self-administered drug and should be interdicted.
Antidepressants are the first-line pharmacotherapy for panic disorder. Several SSRIs, including fluoxetine, paroxetine, and sertraline, are approved for the treatment of panic disorder. The SNRI venlafaxine is FDA approved for treatment of panic disorder. As with GAD, panic disorder is often a chronic condition; the long-term use of high-dose benzodiazepines can result in benzodiazepine dependence. While, panic disorder often responds to high-potency benzodiazepines such as clonazepam and alprazolam, the best use of these agents is generally early in the course of treatment concurrently with an antidepressant. Once the antidepressant has begun working after 4 or more weeks, the benzodiazepine may be tapered. Thus, those benzodiazepines and the antidepressants are the most commonly used agents for panic disorder.
Whether the indications for benzodiazepines are anxiety or insomnia, the medications should be used judiciously. The longer-acting benzodiazepines are used for the treatment of alcohol withdrawal and anxiety symptoms; the intermediate medications are useful as sedatives for insomnia (eg, lorazepam), while short-acting agents (eg, midazolam) are used for medical procedures such as endoscopy.
The side effects of all the benzodiazepine antianxiety agents are patient and dose dependent. As the dosage exceeds the levels necessary for sedation, the side effects include disinhibition, ataxia, dysarthria, nystagmus, and delirium. (The patient should be told not to operate machinery and drive with caution until he or she is well stabilized without side effects.)
Paradoxical agitation, anxiety, psychosis, confusion, mood lability, and anterograde amnesia have been reported, particularly with the shorter-acting benzodiazepines. These agents produce cumulative clinical effects with repeated dosage (especially if the patient has not had time to metabolize the previous dose), additive effects when given with other classes of sedatives or alcohol (many apparently “accidental” deaths are the result of concomitant use of sedatives and alcohol), and residual effects after termination of treatment (particularly in the case of medications that undergo slow biotransformation).
Overdosage results in respiratory depression, hypotension, shock syndrome, coma, and death. Flumazenil, a benzodiazepine antagonist, is effective in overdosage. Overdosage (see Chapter 38) and withdrawal states are medical emergencies. Serious side effects of chronic excessive dosage are development of tolerance, resulting in increasing dose requirements, and physiologic dependence, resulting in withdrawal symptoms similar in appearance to alcohol and barbiturate withdrawal (withdrawal effects must be distinguished from reemergent anxiety). Abrupt withdrawal of sedative medications may cause serious and even fatal convulsive seizures. Psychosis, delirium, and autonomic dysfunction have also been described. Both duration of action and duration of exposure are major factors related to likelihood of withdrawal.
Common withdrawal symptoms after low to moderate daily use of benzodiazepines are classified as somatic (disturbed sleep, tremor, nausea, muscle aches), psychological (anxiety, poor concentration, irritability, mild depression), or perceptual (poor coordination, mild paranoia, mild confusion). The presentation of symptoms will vary depending on the half-life of the drug. There are no significant side effects on organ systems other than the brain, and the medications are safe in most medical conditions. Benzodiazepine interactions with other medications are listed in Table 25–2.
Table 25–2.Benzodiazepine interactions with other medications. |Favorite Table|Download (.pdf) Table 25–2. Benzodiazepine interactions with other medications.
|Drug ||Effects |
|Antacids ||Decreased absorption of benzodiazepines |
|Cimetidine ||Increased half-life of diazepam and triazolam |
|Contraceptives ||Increased levels of diazepam and triazolam |
|Digoxin ||Alprazolam and diazepam raise digoxin level |
|Disulfiram ||Increased duration of action of sedatives |
|Isoniazid ||Increased plasma diazepam |
|Levodopa ||Inhibition of antiparkinsonism effect |
|Propoxyphene ||Impaired clearance of diazepam |
|Rifampin ||Decreased plasma diazepam |
|Warfarin ||Decreased prothrombin time |
Panic attacks may be treated in several ways. A sublingual dose of alprazolam (0.5–1 mg) or clonazepam (0.5–1 mg) is often effective for urgent treatment. For sustained treatment, SSRIs are the initial medications of choice (adequate blood levels will require dosages similar to those used in the treatment of depression). For example, sertraline starting at 25 mg/day and increased after 1 week to 50 mg/day may be effective. Because of initial agitation in response to antidepressants, doses should start low and be very gradually increased. High-potency benzodiazepines may be used for symptomatic treatment as the antidepressant dose is titrated upward. Clonazepam (1–6 mg/day orally) and alprazolam (0.5–6 mg/day orally) are effective alternatives to antidepressants. Both medications may produce marked withdrawal if stopped abruptly and should always be tapered. Because of chronicity of the disorders and the problem of dependency with benzodiazepine medications, it is generally desirable to use antidepressant medications as the principal pharmacologic approach. Antidepressants have been used in conjunction with beta-blockers in resistant cases. Propranolol (40–160 mg/day orally) can mute the peripheral symptoms of anxiety without significantly affecting motor and cognitive performance. They block symptoms mediated by sympathetic stimulation (eg, palpitations, tremulousness) but not nonadrenergic symptoms (eg, diarrhea, muscle tension). Contrary to common belief, they usually do not cause depression as a side effect and can be used cautiously in patients with depression. The most effective long-term pharmacotherapy for panic disorder is treatment with an antidepressant. While not as rapidly acting as the benzodiazepines, the antidepressants are not habit forming. The SSRIs are known to be effective in the management of panic disorder and several are FDA approved for the treatment of panic disorder including sertraline, paroxetine, and fluoxetine. In addition, the SNRI venlafaxine is approved by the FDA for the treatment of panic disorder. Other antidepressants, including the TCAs and MAO inhibitors, are often effective when safer and easier to use medications prove ineffective.
A phobic disorder may be part of the panic disorder or may occur independently. Social phobias and agoraphobia may be treated with SSRIs, such as paroxetine, sertraline, and fluvoxamine. In addition, phobic disorders often respond to SNRIs such as venlafaxine. Gabapentin, an antiseizure medication with anxiolytic properties, is an alternative to antidepressants in the treatment of social phobia in a dosage of 300–3600 mg/day, depending on response versus sedation. Specific phobias such as performance or test anxiety may respond to moderate doses of beta-blockers, such as propranolol, 20–40 mg 1 hour prior to exposure. Specific phobias tend to respond to behavioral therapies such as systematic desensitization, which is when the patient is gradually exposed to the feared object or situation in a controlled setting. A meta-analysis has demonstrated that the antituberculous drug D-cycloserine (DCS) enhances extinction of fear responses with exposures. Importantly, such medications must be used in combination with cognitive behavioral exposure strategies.
Behavioral approaches are widely used in various anxiety disorders, often in conjunction with medication. Any of the behavioral techniques can be used beneficially in altering the contingencies (precipitating factors or rewards) supporting any anxiety-provoking behavior. Relaxation techniques can sometimes be helpful in reducing anxiety. Desensitization, by exposing the patient to graded doses of a phobic object or situation, is an effective technique and one that the patient can practice outside the therapy session. Emotive imagery, wherein the patient imagines the anxiety-provoking situation while at the same time learning to relax, helps decrease the anxiety when the patient faces the real-life situation. Physiologic symptoms in panic attacks respond well to relaxation training. Both GAD and panic disorder appear to respond as well to cognitive behavioral therapy as they do to medications.
Cognitive behavioral approaches have been effective in treatment of panic disorder, GAD, and phobias when erroneous beliefs need correction. These approaches share a common behavioral technique of exposing the individual to the feared object or situation. The combination of medical and cognitive behavioral therapy is more effective than either alone. Group therapy is the treatment of choice when the anxiety is clearly a function of the patient’s difficulties in dealing with social settings. Acceptance and commitment therapy has been used with some success in anxiety disorders. It encourages individuals to keep focused on life goals while they “accept” the presence of anxiety in their lives.
Peer support groups for panic disorder and agoraphobia have been particularly helpful. Social modification may require measures such as family counseling to aid acceptance of the patient’s symptoms and avoid counterproductive behavior in behavioral training. Any help in maintaining the social structure is anxiety-alleviating, and work, school, and social activities should be maintained. School and vocational counseling may be provided by professionals, who often need help from the clinician in defining the patient’s limitations.
Anxiety disorders are usually long-standing and may be difficult to treat. All can be relieved to varying degrees with medications and behavioral techniques. The prognosis is better if the commonly observed anxiety-panic-phobia-depression cycle can be broken with a combination of the therapeutic interventions discussed above.
et al. D-cycloserine augmentation of behavioral therapy for the treatment of anxiety disorders: a meta-analysis. J Clin Psychiatry. 2012 Apr;73(4):533–7.
et al. New approaches to the pharmacological management of generalized anxiety disorder. Expert Opin Pharmacother. 2013 Feb;14(2):175–84.
et al; Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada and McGill University. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1.
et al. A systematic review of predictors and moderators of improvement in cognitive-behavioral therapy for panic disorder and agoraphobia. Clin Psychol Rev. 2015 Dec;42:179–92.
et al. Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. JAMA. 2010 May 19;303(19):1921–8.
OBSESSIVE-COMPULSIVE DISORDER & RELATED DISORDERS
ESSENTIALS OF DIAGNOSIS
Anxiety is alleviated only by ritualistic performance of the action or by deliberate contemplation of the intruding idea or emotion.
Other behaviors may overlap with OCD resulting in “OCD spectrum.”
Neurologic abnormalities of fine motor coordination and involuntary movements are common.
Obsessive compulsive disorder (OCD), classified as an anxiety disorder in the DSM-IV, now is part of a separate category of Obsessive-Compulsive Disorder and Related Disorders in DSM-5. The new category includes such disorders as trichotillomania and compulsive gambling in addition to OCD. In OCD, the irrational idea or the impulse persistently intrudes into awareness. Obsessions (recurring anxiety provoking thoughts such as fears of exposure to germs) and compulsions (repetitive actions such as washing the hands many times or cognitions such as counting rituals) are recognized by the individual as absurd and are resisted, but anxiety is alleviated only by ritualistic performance of the action or by deliberate contemplation of the intruding idea or emotion. Many patients do not mention the symptoms and must be asked about them. These patients are often predictable, orderly, conscientious, and intelligent—traits that are seen in many compulsive behaviors such as food binging and purging and compulsive exercise. There is an overlapping of OCD and other behaviors (“OCD spectrum”), including tics, trichotillomania (hair pulling), excoriation disorder (skin picking), hoarding, onychophagia (nail biting), Tourette syndrome, and eating disorders (see Chapter 29). The incidence of OCD in the general population is 2–3% and there is a high comorbidity with major depression: major depression will develop in two-thirds of OCD patients during their lifetime. Male to female ratios are similar, with the highest rates occurring in the young, divorced, separated, and unemployed (all high-stress categories). Neurologic abnormalities of fine motor coordination and involuntary movements are common. Under extreme stress, these patients sometimes exhibit paranoid and delusional behaviors, often associated with depression, and can mimic schizophrenia.
OCD responds to serotonergic antidepressants including the SSRIs and clomipramine in about 60% of cases and usually requires a longer response time than for depression (up to 12 weeks). Clomipramine has proved effective in doses equivalent to those used for depression. Fluoxetine has been widely used in this disorder but in doses higher than those used in depression (up to 60–80 mg orally daily). The other SSRI medications, such as sertraline, paroxetine, and fluvoxamine, are used with comparable efficacy each with its own side-effect profile. Buspirone in doses of 15–60 mg orally daily appears to be effective primarily as an anti-obsessional augmenting agent for the SSRI medications. There is some evidence that antipsychotics may be helpful as adjuncts to the SSRIs in treatment-resistant cases. Alternatively, low-dose clomipramine may be an effective adjunct to an SSRI in some patients. Psychosurgery has a limited place in selected cases of severe unremitting OCD. Experimental work has suggested a role for deep brain stimulation in OCD and it is FDA approved on a compassionate basis for refractory OCD patients.
OCD may respond to a variety of behavioral techniques. One common strategy is systematic desensitization. As in the treatment of simple phobias, systematic desensitization involves gradually exposing the OCD spectrum patient to situations that the patient fears, such as perceived germs or situations that a hoarder must part with things they are hoarding. By gradually exposing the patient to increasingly stressful situations and helping them manage their anxiety, OCD spectrum patients are often able to develop some mastery over the compulsions.
A technique used to help quell obsessive thoughts is “thought stopping.” In this technique, the patient is taught to identify an obsessive thought and then to derail it. For example, the patient may be taught to say STOP any time an obsessive thought is present. In time, thought stopping can mitigate some of the obsessive thoughts.
In addition to behavioral techniques, OCD may respond to psychological therapies including cognitive behavioral therapy in which the patient learns to identify maladaptive cognitions associated with obsessive thoughts and challenge those cognitions. For example, an OCD patient may fear that if he does not wash his hands 50 times after shaking hands he or someone close to him might develop a serious disease. These cognitions can be identified and gradually replaced with more rational thoughts.
OCD can have devastating effects on the ability of a patient to lead a normal life. Educating both the patient and family about the course of illness and treatment options is extremely useful in setting appropriate expectations. Severe OCD is commonly associated with vocational disability, and the clinician may sometimes need to facilitate a leave of absence from work or encourage vocational rehabilitation to get the patient back to work.
OCD is usually a chronic disorder with a waxing and waning course. As many as 40% of patients in whom OCD problems develop in childhood will experience remission as adults. However, it is less common for OCD to remit without treatment when it develops during adulthood.
SOMATIC SYMPTOM DISORDERS (ABNORMAL ILLNESS BEHAVIORS)
ESSENTIALS OF DIAGNOSIS
Physical symptoms may involve one or more organ systems and are not intentional.
Subjective complaints exceed objective findings.
Correlations of symptom development and psychosocial stresses.
Combination of biogenetic and developmental patterns.
Any organ system can be affected in somatic symptom disorders. In DSM-5, somatic symptom disorders encompass disorders that were listed under somatic disorders in DSM-IV, including conversion disorder, hypochondriasis, somatization disorder, and pain disorder secondary to psychological factors. Vulnerability in one or more organ systems and exposure to family members with somatization problems plays a major role in the development of particular symptoms, and the “functional” versus “organic” dichotomy is a hindrance to good treatment. Clinicians should suspect psychiatric disorders in a number of conditions. For example, 45% of patients complaining of palpitations had lifetime psychiatric diagnoses including generalized anxiety, depression, panic, and somatization disorders. Similarly, 33–44% of patients who undergo coronary angiography for chest pain but have negative results have been found to have panic disorder.
In any patient presenting with a condition judged to be somatic symptom disorder, depression must be considered in the diagnosis.
“Conversion” of psychic conflict into physical symptoms in parts of the body innervated by the sensorimotor system (eg, paralysis, aphonic) is a disorder that is more common in individuals from lower socioeconomic classes and certain cultures. The somatic manifestation that takes the place of anxiety is often paralysis, and in some instances the organ dysfunction may have symbolic meaning (eg, arm paralysis in marked anger so the individual cannot use the arm to strike someone). Pseudoepileptic (“hysterical”) seizures are often difficult to differentiate from intoxication states or panic attacks and commonly occur in patients who also have seizures of organic etiology. Retention of consciousness, random flailing with asynchronous movements of the right and left sides, and resistance to having the nose and mouth pinched closed during the attack, all point toward a pseudoepileptic event. Electroencephalography, particularly in a video-electroencephalography assessment unit, during the attack is the most helpful diagnostic aid in excluding genuine seizure states. Serum prolactin levels rise abruptly in the postictal state only in true epilepsy. La belle indifférence (an unconcerned affect) is not a significant identifying characteristic, as commonly believed, since individuals even with genuine medical illness may exhibit a high level of denial. Important conversion disorder criteria include a history of conversion or somatization disorder, modeling the symptom after someone else who had a similar presentation, a serious precipitating emotional event, associated psychopathology (eg, depression, schizophrenia, personality disorders), a temporal correlation between the precipitating event and the symptom, and a temporary “solving of the problem” by the conversion. It is important to identify physical disorders with unusual presentations (eg, multiple sclerosis, systemic lupus erythematosus).
B. Somatic Symptom Disorder
Somatic symptom disorder is characterized by one or more somatic symptoms that are associated with significant distress or disability. The somatic symptoms may be associated with persistent thoughts about the seriousness of the symptoms, a high level of anxiety about health, or excessive time and energy devoted to these symptoms. The patient’s focus on somatic symptoms is usually chronic. Panic, anxiety, and depression are often present, and major depression is an important consideration in the differential diagnosis. There is a significant relationship (20%) to a lifetime history of panic-agoraphobia-depression. It usually occurs before age 30 and is ten times more common in women. Polysurgery is often a feature of the history. Preoccupation with medical and surgical therapy becomes a lifestyle that may exclude other activities. The symptoms indicate maladaptive coping techniques and there is often evidence of longstanding somatic complaints, including multiple pain and gastrointestinal symptoms (such as dyspareunia, dysmenorrhea, headache, backache, abdominal pain, vomiting, bloating) and pseudoneurologic symptoms (such as amnesia or pseudoepileptic seizures), often with a history of similar organ system involvement in other family members. Multiple symptoms that constantly change and the inability of more than three doctors to make a diagnosis are strong clues to the problem.
C. Somatic Symptom Disorder with Predominant Pain
This involves a long history of complaints of severe pain out of proportion to biomedical findings that are present. This diagnosis must be one of exclusion and should be made only after extended evaluation has established a clear correlation of psychogenic factors with exacerbations and remissions of complaints.
These disorders, in which symptom production is intentional, are not somatic symptom conditions in that symptoms are produced consciously, in contrast to the unconscious process of the other somatic symptom disorders. They are characterized by self-induced symptoms or false physical and laboratory findings for the purpose of deceiving clinicians or other health care personnel. The deceptions may involve self-mutilation, fever, hemorrhage, hypoglycemia, seizures, and an almost endless variety of manifestations—often presented in an exaggerated and dramatic fashion (Munchausen syndrome). “Munchausen by proxy” is the term used when a parent creates an illness in a child so the adult (usually the mother) can maintain a relationship with clinicians. The duplicity may be either simple or extremely complex and difficult to recognize. The patients are frequently connected in some way with the health professions and there is no apparent external motivation other than achieving the patient role. A poor clinician-patient relationship and “doctor shopping” tend to exacerbate the problem. The only secondary gain of inducing symptoms in Munchausen syndrome is being the focus of medical attention rather than obtaining disability benefits or being excused from work or school in malingering situations.
Sedative and analgesic dependency is the most common iatrogenic complication. Patients may pursue medical or surgical treatments that induce iatrogenic problems. Thus, identifying patients with a potential somatic symptom disorder and attempting to limit tests, procedures, and medications that may lead to harm is quite important.
Medical support with careful attention to building a therapeutic clinician-patient relationship is the mainstay of treatment. It must be accepted that the patient’s distress is real. Every problem not found to have an organic basis is not necessarily a mental disease. Diligent attempts should be made to relate symptoms to adverse developments in the patient’s life. It may be useful to have the patient keep a meticulous diary, paying particular attention to various pertinent factors evident in the history. Regular, frequent, short appointments that are not symptom-contingent may be helpful. Medications (frequently abused) should not be prescribed to replace appointments. One person should be the primary clinician, and consultants should be used mainly for evaluation. An empathic, realistic, optimistic approach must be maintained in the face of the expected ups and downs. Ongoing reevaluation is necessary, since somatization can coexist with a concurrent physical illness.
The primary clinician can use psychological approaches when it is clear that the patient is ready to make some changes in lifestyle in order to achieve symptomatic relief. This is often best approached on a here-and-now basis and oriented toward pragmatic changes rather than an exploration of early experiences that the patient frequently fails to relate to current distress. Group therapy with other individuals who have similar problems is sometimes of value to improve coping, allow ventilation, and focus on interpersonal adjustment. Hypnosis or lorazepam interviews used early are helpful in resolving conversion disorders. If the primary clinician has been working with the patient on psychological problems related to the physical illness, the groundwork is often laid for successful psychiatric referral.
For patients who have been identified as having a factitious disorder, early psychiatric consultation is indicated. There are two main treatment strategies for these patients. One consists of a conjoint confrontation of the patient by both the primary clinician and the psychiatrist. The patient’s disorder is portrayed as a cry for help, and psychiatric treatment is recommended. The second approach avoids direct confrontation and attempts to provide a face-saving way to relinquish the symptom without overt disclosure of the disorder’s origin. Techniques such as biofeedback and self-hypnosis may foster recovery using this strategy. Another face-saving approach is to use a double bind with the patient. For example, the patient is told there are two possible diagnoses: (1) an organic disease that should respond to the next medical intervention (usually modest and noninvasive), or (2) factitious disorder for which the patient will need psychiatric treatment. Given these options, many patients will choose to recover and not have to admit the origin of their problem.
Behavioral therapy is probably best exemplified by biofeedback techniques. In biofeedback, the particular abnormality (eg, increased peristalsis) must be recognized and monitored by the patient and therapist (eg, by an electronic stethoscope to amplify the sounds). This is immediate feedback, and after learning to recognize it, the patient can then learn to identify any change thus produced (eg, a decrease in bowel sounds) and so become a conscious originator of the feedback instead of a passive recipient. Relief of the symptom operantly conditions the patient to utilize the maneuver that relieves symptoms (eg, relaxation causing a decrease in bowel sounds). With emphasis on this type of learning, the patient is able to identify symptoms early and initiate the countermaneuvers, thus decreasing the symptomatic problem. Migraine and tension headaches have been particularly responsive to biofeedback methods.
Social endeavors include family, work, and other interpersonal activity. Family members should come for some appointments with the patient so they can learn how best to live with the patient. This is particularly important in treatment of somatization and pain disorders. Peer support groups provide a climate for encouraging the patient to accept and live with the problem. Ongoing communication with the employer may be necessary to encourage long-term continued interest in the employee. Employers can become just as discouraged as clinicians in dealing with employees who have chronic problems.
The prognosis is better if the primary clinician is able to intervene early before the situation has deteriorated. After the problem has crystallized into chronicity, it is difficult to effect change.
et al. An approach to the patient with multiple physical symptoms or chronic disease. Med Clin North Am. 2010 Nov;94(6):1207–16.
et al. Chronic pain, psychopathology, and DSM-5 somatic symptom disorder. Can J Psychiatry. 2015 Apr;60(4):160–7.
ME. Somatic symptom disorders without known physical causes: one disease with many names? Am J Med. 2015 Oct;128(10):1054–8.
ESSENTIALS OF DIAGNOSIS
Chronic complaints of pain.
Symptoms frequently exceed signs.
Minimal relief with standard treatment.
History of having seen many clinicians.
Frequent use of several nonspecific medications.
A problem in the management of pain is the lack of distinction between acute and chronic pain syndromes. Most clinicians are adept at dealing with acute pain problems but have difficulty treating the patient with a chronic pain disorder. This type of patient frequently takes too many medications, stays in bed a great deal, has seen many clinicians, has lost skills, and experiences little joy in either work or play. All relationships suffer (including those with clinicians), and life becomes a constant search for relief. The search results in complex clinician-patient relationships that usually include many drug trials, particularly sedatives, with adverse consequences (eg, irritability, depressed mood) related to long-term use. Treatment failures provoke angry responses and depression from both the patient and the clinician, and the pain syndrome is exacerbated. When frustration becomes too great, a new clinician is found, and the cycle is repeated. The longer the existence of the pain disorder, the more important become the psychological factors of anxiety and depression. As with all other conditions, it is counterproductive to speculate about whether the pain is “real.” It is real to the patient, and acceptance of the problem must precede a mutual endeavor to alleviate the disturbance.
Components of the chronic pain syndrome consist of anatomic changes, chronic anxiety and depression, anger, and changed lifestyle. Usually, the anatomic problem is irreversible, since it has already been subjected to many interventions with increasingly unsatisfactory results. An algorithm for assessing chronic pain and differentiating it from other psychiatric conditions is illustrated in Figure 25–1.
Algorithm for assessing psychiatric component of chronic pain. (Adapted and reproduced, with permission, from Eisendrath SJ. Psychiatric aspects of chronic pain. Neurology. 1995 Dec;45(12 Suppl 9):S26–34.)
Chronic anxiety and depression produce heightened irritability and overreaction to stimuli. A marked decrease in pain threshold is apparent. This pattern develops into a hypochondriacal preoccupation with the body and a constant need for reassurance. The pressure on the clinician becomes wearing and often leads to covert rejection of the patient, such as not being available or making referrals to other clinicians.
This is perceived by the patient, who then intensifies the effort to find help, and the typical cycle is repeated. Anxiety and depression are seldom discussed, almost as if there is a tacit agreement not to deal with these issues.
Changes in lifestyle involve some of the pain behaviors. These usually take the form of a family script in which the patient accepts the role of being sick, and this role then becomes the focus of most family interactions and may become important in maintaining the family, so that neither the patient nor the family wants the patient’s role to change. Demands for attention and efforts to control the behavior of others revolve around the central issue of control of other people (including clinicians). Cultural factors frequently play a role in the behavior of the patient and how the significant people around the patient cope with the problem. Some cultures encourage demonstrative behavior, while others value the stoic role.
Another secondary gain that frequently maintains the patient in the sick role is financial compensation or other benefits. Frequently, such systems are structured so that they reinforce the maintenance of sickness and discourage any attempts to give up the role. Clinicians unwittingly reinforce this role because of the very nature of the practice of medicine, which is to respond to complaints of illness. Helpful suggestions from the clinician are often met with responses like, “Yes, but….” Medications then become the principal approach, and drug dependency problems may develop.
The cornerstone of a unified approach to chronic pain syndromes is a comprehensive behavioral program. This is necessary to identify and eliminate pain reinforcers, to decrease drug use, and to use effectively those positive reinforcers that shift the focus from the pain. It is critical that the patient be made a partner in the effort to manage and function better in the setting of ongoing pain symptoms. The clinician must shift from the idea of biomedical cure to ongoing care of the patient. The patient should agree to discuss the pain only with the clinician and not with family members; this tends to stabilize the patient’s personal life, since the family is usually tired of the subject. At the beginning of treatment, the patient should be assigned self-help tasks graded up to maximal activity as a means of positive reinforcement. The tasks should not exceed capability. The patient can also be asked to keep a self-rating chart to log accomplishments, so that progress can be measured and remembered. Instruct the patient to record degrees of pain on a self-rating scale in relation to various situations and mental attitudes so that similar circumstances can be avoided or modified.
Avoid positive reinforcers for pain such as marked sympathy and attention to pain. Emphasize a positive response to productive activities, which remove the focus of attention from the pain. Activity is also desensitizing, since the patient learns to tolerate increasing activity levels.
Biofeedback techniques (see Somatic Symptom Disorders, above) and hypnosis have been successful in ameliorating some pain syndromes. Hypnosis tends to be most effective in patients with a high level of denial, who are more responsive to suggestion. Hypnosis can be used to lessen anxiety, alter perception of the length of time that pain is experienced, and encourage relaxation. Mindfulness-based stress reduction programs have been useful in helping individuals develop an enhanced capacity to live a higher quality life with persistent pain.
A single clinician in charge of the comprehensive treatment approach is the highest priority. Consultations as indicated and technical procedures done by others are appropriate, but the care of the patient should remain in the hands of the primary clinician. Referrals should not be allowed to raise the patient’s hopes unrealistically or to become a way for the clinician to reject the case. The attitude of the clinician should be one of honesty, interest, and hopefulness—not for a cure but for control of pain and improved function. If the patient manifests opioid addiction, detoxification may be an early treatment goal.
Medication management of chronic pain is addressed in Chapter 5. A fixed schedule lessens the conditioning effects of these medications. SNRIs (eg, venlafaxine, milnacipran, and duloxetine) and TCAs (eg, nortriptyline), in doses up to those used in depression may be helpful, particularly in neuropathic pain syndromes. Both duloxetine and milnacipran are approved for the treatment of fibromyalgia; duloxetine is also indicated in chronic pain conditions. The antidepressants impact the endogenous analgesic pathways independent of their effects on depression. In general, the SNRIs tend to be safer in overdose than the TCAs. Suicidality is often an important consideration in treating patients with chronic pain syndromes. Gabapentin and pregabalin, anticonvulsants with possible applications in the treatment of anxiety disorders, have been shown to be useful in somatic symptom disorders and fibromyalgia.
In addition to medications, a variety of nonpharmacologic strategies may be offered, including physical therapy and acupuncture.
Involvement of family members and other significant persons in the patient’s life should be an early priority. The best efforts of both patient and therapists can be unwittingly sabotaged by other persons who may feel that they are “helping” the patient. They frequently tend to reinforce the negative aspects of the chronic pain disorder. The patient becomes more dependent and less active, and the pain syndrome becomes an immutable way of life. The more destructive pain behaviors described by many experts in chronic pain disorders are the results of well-meaning but misguided efforts of family members. Ongoing therapy with the family can be helpful in the early identification and elimination of these behavior patterns.
In addition to group therapy with family members and others, groups of patients can be helpful if properly led. The major goal, whether of individual or group therapy, is to gain patient involvement. A group can be a powerful instrument for achieving this goal, with the development of group loyalties and cooperation. People will frequently make efforts with group encouragement that they would never make alone. Individual therapy should be directed toward strengthening existing coping mechanisms and improving self-esteem. For example, teaching patients to challenge expectations induced by chronic pain may lead to improved functioning. As an illustration, many chronic pain patients, making assumptions more derived from acute injuries, incorrectly believe they will damage themselves by attempting to function. The rapport between patient and clinician, as in all psychotherapeutic efforts, is the major factor in therapeutic success.
et al. An overview of pharmacologic management of chronic pain. Med Clin North Am. 2016 Jan;100(1):65–79.
et al. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015 Jan 8;1:CD011209.
S. Efficacy and effectiveness of cognitive behaviour therapy for chronic pain: progress and some challenges. Pain. 2011 Mar;152(3 Suppl):S99–106.
The stages of sexual activity include excitement (arousal), orgasm, and resolution. The precipitating excitement or arousal is psychologically determined. Arousal response leading to orgasm is a physiologic and psychological phenomenon of vasocongestion, a parasympathetic reaction causing erection in men and labial-clitoral congestion in women. The orgasmic response includes emission in men and clonic contractions of the analogous striated perineal muscles of both men and women. Resolution is a gradual return to normal physiologic status.
While the arousal stimuli—vasocongestive and orgasmic responses—constitute a single response in a well-adjusted person, they can be considered as separate stages that can produce different syndromes responding to different treatment procedures.
There are three major groups of sexual disorders.
A. Paraphilias (Sexual Arousal Disorders)
In these conditions, formerly called “deviations” or “variations,” the excitement stage of sexual activity is associated with sexual objects or orientations different from those usually associated with adult sexual stimulation. The stimulus may be a woman’s shoe, a child, animals, instruments of torture, or incidents of aggression. The pattern of sexual stimulation is usually one that has early psychological roots. Poor experiences with sexual activity frequently reinforce this pattern over time. Paraphilias include exhibitionism, transvestism, voyeurism, pedophilia, incest, sexual sadism, and sexual masochism.
Exhibitionism is the impulsive behavior of exposing the genitalia to unsuspecting strangers in order to achieve sexual excitation. It is a childhood sexual behavior carried into adult life.
Transvestism in a heterosexual man consists of recurrent cross-dressing behavior for the purpose of sexual excitation. Such fetishistic behavior can be part of masturbation foreplay. Transvestism in homosexuality and transsexualism is not for the purpose of sexual excitement but is a function of preference or gender identity disorder.
Voyeurism involves the achievement of sexual arousal by watching the activities of an unsuspecting person, usually in various stages of undress or sexual activity. In both exhibitionism and voyeurism, excitation leads to masturbation as a replacement for sexual activity.
Pedophilia is the use of a child of either sex to achieve sexual arousal and, in many cases, gratification. Contact is frequently oral, with either participant being dominant, but pedophilia includes intercourse of any type. Adults of both sexes engage in this behavior, but because of social and cultural factors it is more commonly identified with men.
Incest involves a sexual relationship with a person in the immediate family, most frequently a child. In many ways it is similar to pedophilia (intrafamilial pedophilia). Incestuous feelings are fairly common, but cultural mores are usually sufficiently strong to act as a barrier to the expression of sexual feelings.
Sexual sadism is the attainment of sexual arousal by inflicting pain upon the sexual object. Much sexual activity has aggressive components (eg, biting, scratching). However, forced sexual acquiescence (eg, rape) is an act of aggression.
Sexual masochism is the achievement of erotic pleasure by being humiliated, enslaved, physically bound, and restrained. It may be life-threatening, since neck binding or partial asphyxiation usually forms part of the ritual. The practice is much more common in men than in women.
B. Gender Identity Disorder
Core gender identity reflects a biologic self-image—the conviction that “I am a boy” or “I am a girl” that is usually well developed by age 3 or 4. Gender dysphoria refers to the development of a sexual identity that is the opposite of the biologic one.
Transsexualism is an attempt to deny and reverse biologic sex by maintaining sexual identity with the opposite gender. Transsexuals do not alternate between gender roles; rather, they assume a fixed role of attitudes, feelings, fantasies, and choices consonant with those of the opposite sex, all of which clearly date back to early development. For example, male to female transsexuals in early childhood behave, talk, and fantasize as if they were girls. They do not grow out of feminine patterns; they do not work in professions traditionally considered to be masculine; and they have no interest in their own penises either as evidence of maleness or as organs for erotic behavior. The desire for sex change starts early and may culminate in assumption of a feminine lifestyle, hormonal treatment, and use of surgical procedures, eg, castration and vaginoplasty.
C. Psychosexual Dysfunction
This category includes a large group of vasocongestive and orgasmic disorders. Often, they involve problems of sexual adaptation, education, and technique that are often initially discussed with, diagnosed by, and treated by the primary care provider.
There are two conditions common in men: erectile dysfunction and ejaculation disturbances.
Erectile dysfunction is inability to achieve or maintain an erection firm enough for satisfactory intercourse; patients sometimes use the term to mean premature ejaculation. Careful questioning is necessary, since causes of this vasocongestive disorder can be psychological, physiologic, or both. The majority are pathophysiologic and, to varying degrees, treatable. After onset of the problem, a history of occasional erections—especially nocturnal penile tumescence, which may be evaluated by a simple monitoring device, or a sleep study in the sleep laboratory—is usually evidence that the dysfunction is psychological in origin. Decreased nocturnal penile tumescence occurs in some depressed patients. Psychological erectile dysfunction is caused by interpersonal or intrapsychic factors (eg, partner disharmony, depression). Organic factors are discussed in Chapter 23.
Ejaculation disturbances include premature ejaculation, inability to ejaculate, and retrograde ejaculation. (Ejaculation is possible in patients with erectile dysfunction.) Ejaculation is usually connected with orgasm, and ejaculatory control is an acquired behavior that is minimal in adolescence and increases with experience. Pathogenic factors are those that interfere with learning control, most frequently sexual ignorance. Intrapsychic factors (anxiety, guilt, depression) and interpersonal maladaptation (partner problems, unresponsiveness of mate, power struggles) are also common. Organic causes include interference with sympathetic nerve distribution (often due to surgery or radiation) and the effects of pharmacologic agents (eg, SSRIs or sympatholytics).
In women, the most common forms of sexual dysfunction are orgasmic disorder and hyposexual desire disorder (see Chapter 18).
Orgasmic disorder is a complex condition in which there is a general lack of sexual responsiveness. The woman has difficulty in experiencing erotic sensation and does not have the vasocongestive response. Sexual activity varies from active avoidance of sex to an occasional orgasm. Orgasmic dysfunction—in which a woman has a vasocongestive response but varying degrees of difficulty in reaching orgasm—is sometimes differentiated from anorgasmia. Causes for the dysfunctions include poor sexual techniques, early traumatic sexual experiences, interpersonal disharmony (partner struggles, use of sex as a means of control), and intrapsychic problems (anxiety, fear, guilt). Organic causes include any conditions that might cause pain in intercourse, pelvic pathology, mechanical obstruction, and neurologic deficits.
Hyposexual desire disorder consists of diminished or absent libido in either sex and may be a function of organic or psychological difficulties (eg, anxiety, phobic avoidance). Any chronic illness can reduce desire as can aging. Hormonal disorders, including hypogonadism or use of antiandrogen compounds such as cyproterone acetate, and chronic kidney disease contribute to deterioration in sexual desire. Although menopause may lead to diminution of sexual desire in some women, the relationship between menopause and libido is complicated and may be influenced by sociocultural factors. Alcohol, sedatives, opioids, marijuana, and some medications may affect sexual drive and performance.
A. Paraphilias and Gender Identity Disorders
Sexual arousal disorders involving variant sexual activity (paraphilia), particularly those of a more superficial nature (eg, voyeurism) and those of recent onset, are responsive to psychotherapy in some cases. The prognosis is much better if the motivation comes from the individual rather than the legal system; unfortunately, judicial intervention is frequently the only stimulus to treatment because the condition persists and is reinforced until conflict with the law occurs. Therapies frequently focus on barriers to normal arousal response; the expectation is that the variant behavior will decrease as normal behavior increases.
Aversive and operant conditioning techniques have been tried frequently in gender role disorders but have only occasionally been successful. In some cases, the sexual arousal disorders improve with modeling, role-playing, and conditioning procedures. Emotive imagery is occasionally helpful in lessening anxiety in fetish problems.
Although they do not produce a change in sexual arousal patterns or gender role, self-help groups have facilitated adjustment to an often hostile society. Attention to the family is particularly important in helping persons in such groups to accept their situation and alleviate their guilt about the role they think they had in creating the problem.
Medroxyprogesterone acetate, a suppressor of libidinal drive, is used to mute disruptive sexual behavior in men of all ages. Onset of action is usually within 3 weeks, and the effects are generally reversible. Fluoxetine or other SSRIs at depression doses may reduce some of the compulsive sexual behaviors including the paraphilias. A focus of study in the treatment of severe paraphilia has been agonists of luteinizing hormone–releasing hormone (LHRH). Case reports and open label studies suggest that LHRH-agonists may play a role in preventing relapse in some patients with paraphilia. While some transsexuals are treated with genital reconstructive surgery, many others are screened out by trial periods of living as the other sex prior to operation.
B. Psychosexual Dysfunction
Even if the condition is not reversible, identification of the specific cause helps the patient to accept the condition. Partner disharmony, with its exacerbating effects, may thus be avoided. Of all the sexual dysfunctions, erectile dysfunction is the condition most likely to have an organic basis. Sildenafil, tadalafil, and vardenafil are phosphodiesterase type 5 inhibitors that are effective oral agents for the treatment of penile erectile dysfunction (eg, sildenafil 25–100 mg orally 1 hour prior to intercourse). These agents are effective for SSRI-induced erectile dysfunction in men and in some cases for SSRI-associated sexual dysfunction in women. Use of the medications in conjunction with any nitrates can have significant hypotensive effects leading to death in rare cases. Because of their common effect in delaying ejaculation, the SSRIs have been effective in premature ejaculation.
Flibanserin is a 5-HT1A-agonist/5-HT2-antagonist that is FDA approved for the treatment of female hyposexual desire disorder. This is the first drug marketed to improve sexual desire in women. The data suggest that compared to placebo, women treated flibanserin have somewhat higher number of sexual events. The drug interacts with alcohol, causing hypotensive events, so patients need to be educated about this risk. Flibanserin is taken 100 mg orally at bedtime to circumvent the side effects of dizzinesss, sleepiness, and nausea.
Syndromes resulting from conditioned responses have been treated by conditioning techniques, with excellent results. Masters and Johnson have used behavioral approaches in all of the sexual dysfunctions, with concomitant supportive psychotherapy and with improvement of the communication patterns of the couple.
The use of psychotherapy by itself is best suited for those cases in which interpersonal difficulties or intrapsychic problems predominate. Anxiety and guilt about parental injunctions against sex may contribute to sexual dysfunction. Even in these cases, however, a combined behavioral-psychological approach usually produces results most quickly.
The proximity of other people (eg, a mother-in-law) in a household is frequently an inhibiting factor in sexual relationships. In such cases, some social engineering may alleviate the problem.
J. JAMA patient page. Flibanserin for treating low sexual desire in women. JAMA. 2015 Sep 22–29;314(12):1312.
et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012 Aug;87(8):766–78.
et al. First pharmacological therapy for hypoactive sexual desire disorder in premenopausal women: flibanserin. Ann Pharmacother. 2016 Feb;50(2):125–32.
et al. Male erectile dysfunction: integrating psychopharmacology and psychotherapy. Gen Hosp Psychiatry. 2013 Jan;35(1):33–8.
ESSENTIALS OF DIAGNOSIS
Long history dating back to childhood.
Recurrent maladaptive behavior.
Minimal introspective ability with a tendency to blame others for all problems.
Major difficulties with interpersonal relationships or society.
Depression with anxiety when maladaptive behavior fails.
An individual’s personality structure, or character, is an integral part of self-image. It reflects genetics, interpersonal influences, and recurring patterns of behavior adopted in order to cope with the environment. The classification of subtypes of personality disorders depends on the predominant symptoms and their severity. The most severe disorders—those that bring the patient into greatest conflict with society—tend to be classified as antisocial (psychopathic) or borderline.
Personality disorders can be considered a matrix for some of the more severe psychiatric problems (eg, schizotypal, relating to schizophrenia, and avoidance types, relating to some anxiety disorders).
Classification & Clinical Findings
Table 25–3.Personality disorders: Classification and clinical findings. |Favorite Table|Download (.pdf) Table 25–3. Personality disorders: Classification and clinical findings.
|Personality Disorder ||Clinical Findings |
|Antisocial ||Selfish, callous, promiscuous, impulsive, unable to learn from experience, often has legal problems. |
|Avoidant ||Fears rejection, hyperreacts to rejection and failure, with poor social endeavors and low self-esteem. |
|Borderline ||Impulsive; has unstable and intense interpersonal relationships; is suffused with anger, fear, and guilt; lacks self-control and self-fulfillment; has identity problems and affective instability; is suicidal (a serious problem—up to 80% of hospitalized borderline patients make an attempt at some time during treatment, and the incidence of completed suicide is as high as 5%); aggressive behavior, feelings of emptiness, and occasional psychotic decompensation. This group has a high drug abuse rate, which plays a role in symptoms. There is extensive overlap with other diagnostic categories, particularly mood disorders and posttraumatic stress disorder. |
|Dependent ||Passive, overaccepting, unable to make decisions, lacks confidence, with poor self-esteem. |
|Histrionic (hysterical) ||Dependent, immature, seductive, egocentric, vain, emotionally labile. |
|Narcissistic ||Exhibitionist, grandiose, preoccupied with power, lacks interest in others, with excessive demands for attention. |
|Obsessive compulsive ||Perfectionist, egocentric, indecisive, with rigid thought patterns and need for control. |
|Paranoid ||Defensive, oversensitive, secretive, suspicious, hyperalert, with limited emotional response. |
|Schizoid ||Shy, introverted, withdrawn, avoids close relationships. |
|Schizotypal ||Superstitious, socially isolated, suspicious, with limited interpersonal ability, eccentric behaviors, and odd speech. |
Patients with personality disorders tend to show anxiety and depression when pathologic coping mechanisms fail, and their symptoms can be similar to those disorders. Occasionally, the more severe cases may decompensate into psychosis under stress and mimic other psychotic disorders.
Social and therapeutic environments such as day hospitals, halfway houses, and self-help communities utilize peer pressure to modify the self-destructive behavior. The patient with a personality disorder often has failed to profit from experience, and difficulties with authority impair the learning experience. The use of peer relationships and the repetition possible in a structured setting of a helpful community enhance the behavioral treatment opportunities and increase learning. When problems are detected early, both the school and the home can serve as foci of intensified social pressure to change the behavior, particularly with the use of behavioral techniques.
The behavioral techniques used are principally operant conditioning and aversive conditioning. The former simply emphasizes the recognition of acceptable behavior and its reinforcement with praise or other tangible rewards. Aversive responses usually mean punishment, although this can range from a mild rebuke to some specific punitive responses such as deprivation of privileges. Extinction plays a role in that an attempt is made not to respond to inappropriate behavior, and the lack of response eventually causes the person to abandon that type of behavior. Pouting and tantrums, for example, diminish quickly when such behavior elicits no reaction. Dialectical behavioral therapy is a program of individual and group therapy specifically designed for patients with chronic suicidality and borderline personality disorder. It blends mindfulness and a cognitive-behavioral model to address self-awareness, interpersonal functioning, affective lability, and reactions to stress.
Psychological interventions can be conducted in group and individual settings. Group therapy is helpful when specific interpersonal behavior needs to be improved. This mode of treatment also has a place with so-called “acting-out” patients, ie, those who frequently act in an impulsive and inappropriate way. The peer pressure in the group tends to impose restraints on rash behavior. The group also quickly identifies the patient’s types of behavior and helps improve the validity of the patient’s self-assessment, so that the antecedents of the unacceptable behavior can be effectively handled, thus decreasing its frequency. Individual therapy should initially be supportive, ie, helping the patient to restabilize and mobilize coping mechanisms. If the individual has the ability to observe his or her own behavior, a longer-term and more introspective therapy may be warranted. The therapist must be able to handle countertransference feelings (which are frequently negative), maintain appropriate boundaries in the relationship (no physical contact, however well-meaning), and refrain from premature confrontations and interpretations.
Hospitalization is indicated in the case of serious suicidal or homicidal danger. In most cases, treatment can be accomplished in the day treatment center or self-help community. Pharmacotherapy should be directed to specific symptom clusters. Antidepressants have improved anxiety, depression, and sensitivity to rejection in some patients with borderline personality disorder. SSRIs also have a role in reducing aggressive behavior in impulsive aggressive patients (eg, fluoxetine 20–60 mg orally daily or sertraline 50–200 mg orally daily). Antipsychotics may be helpful in targeting hostility, agitation, and as adjuncts to antidepressant therapy (eg, olanzapine [2.5–10 mg/day orally], risperidone [0.5–2 mg/day orally], or haloperidol [0.5–2 mg/day orally, split into two doses]). In some cases, these medications are required only for several days and can be discontinued after the patient has regained a previously established level of adjustment; they can also provide ongoing support. Anticonvulsants including, carbamazepine, 400–800 mg orally daily in divided doses, lamotrigine, 50–200 mg/day and valproate 500–2000 mg/day have been shown to decrease the severity of behavioral dyscontrol in some personality disorder patients.
Antisocial and borderline categories generally have a guarded prognosis. Those patients with a history of parental abuse and a family history of mood disorder tend to have the most challenging treatments. Patients with a schizotypal personality often improve with antipsychotics, while those with avoidant personality may benefit from strategies that reduce anxiety, including the use of SSRIs and benzodiazepines.
et al. Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials. J Clin Psychiatry. 2010 Jan;71(1):14–25.
et al. Pharmacotherapy for borderline personality disorder—current evidence and recent trends. Curr Psychiatry Rep. 2015 Jan;17(1):534.
et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. 2012 Aug 15;8:CD005652.
SCHIZOPHRENIA SPECTRUM DISORDERS
ESSENTIALS OF DIAGNOSIS
Social withdrawal, usually slowly progressive; deterioration in personal care.
Loose thought associations; often slowed thinking and rapid shifting from topic to topic.
Autistic absorption in inner thoughts; frequent sexual or religious preoccupations.
Auditory hallucinations, often of a derogatory nature.
Delusions, frequently of a persecutory nature.
Symptoms of at least 6 months’ duration.
Frequent additional signs:
Flat affect and rapidly alternating mood shifts irrespective of circumstances.
Hypersensitivity to environmental stimuli, with a feeling of enhanced sensory awareness.
Variability or changeable behavior incongruent with the external environment.
Concrete thinking with inability to abstract; inappropriate symbolism.
Impaired concentration worsened by hallucinations and delusions.
Depersonalization, wherein one behaves like a detached observer of one's own actions.
Schizophrenia is manifested by a massive disruption of thinking, mood, and overall behavior as well as poor filtering of stimuli. The characterization and nomenclature of the disorders are quite arbitrary and are influenced by sociocultural factors and schools of psychiatric thought.
The cause of schizophrenia is believed to be multifactorial, with genetic, environmental, and neurotransmitter pathophysiologic components. Studies have demonstrated that schizophrenia is at least eight distinct disorders. At present, there is no laboratory method for confirming the diagnosis of schizophrenia. There may or may not be a history of a major disruption in the individual’s life (failure, loss, physical illness) before gross psychotic deterioration is evident.
“Other psychotic disorders” are conditions that are similar to schizophrenic disorders in their acute symptoms but have a less pervasive influence over the long term. The patient usually attains higher levels of functioning. The acute psychotic episodes tend to be less disruptive of the person’s lifestyle, with a fairly quick return to previous levels of functioning.
A. Schizophrenic Disorders
Schizophrenia is the most common of the psychotic disorders that are all characterized by a loss of contact with reality. While about 1% if the population suffers from schizophrenia, those with the diagnosis account for up to 50% of all long-term psychiatric hospitalizations. Schizophrenia is a chronic disorder that is characterized by increasing social and vocational disability that begins in late adolescence or early adulthood and tends to continue through life. Schizophrenic symptoms have been classified into positive and negative categories. Positive symptoms include hallucinations, delusions, disorganized speech and behavior; these symptoms appear to be related to increased dopaminergic (D2) activity in the mesolimbic region. Negative symptoms include diminished sociability, restricted affect, and poverty of speech; these symptoms appear to be related to decreased D2 activity in the mesocortical system.
Delusional disorders are psychoses in which the predominant symptoms are persistent delusions with minimal impairment of daily functioning. (The schizophrenic disorders show significant impairment.) Intellectual and occupational activities are little affected, whereas social and partner functioning tends to be markedly involved. Hallucinations are not usually present. Common delusional themes include paranoid delusions of persecution, delusions of being related to or loved by a well-known person, and delusions that one’s partner is unfaithful.
C. Schizoaffective Disorder
Schizoaffective disorders are those cases that fail to fit comfortably either in the schizophrenic or in the affective categories. They are usually cases with affective symptoms (either a major depressive episode, manic episode, or hypomanic episode) that precede or develop concurrently with psychotic manifestations and the psychotic symptoms occur in the absence of any mood symptoms. There has been increasing interest in studying prodromal schizophrenia with a goal of prevention or early treatment.
D. Schizophreniform Disorders
Schizophreniform disorders are similar in their symptoms to schizophrenic disorders except that the duration of prodromal, acute, and residual symptoms is longer than 1 week but less than 6 months.
E. Brief Psychotic Disorders
These disorders last less than 1 week. They are the result of psychological stress. The shorter duration is significant and correlates with a more acute onset and resolution as well as a much better prognosis.
The symptoms and signs of schizophrenia vary markedly among individuals as well as in the same person at different times. The patient’s appearance may be bizarre, although the usual finding is a mild to moderate unkempt blandness. Motor activity is generally reduced, although extremes ranging from catatonic stupor to frenzied excitement occur. Social behavior is characterized by marked withdrawal coupled with disturbed interpersonal relationships and a reduced ability to experience pleasure. Dependency and a poor self-image are common. Verbal utterances are variable, the language being concrete yet symbolic, with unassociated rambling statements (at times interspersed with mutism) during an acute episode. Neologisms (made-up words or phrases), echolalia (repetition of words spoken by others), and verbigeration (repetition of senseless words or phrases) are occasionally present. Affect is usually flattened, with occasional inappropriateness. Depression is present in almost all cases but may be less apparent during the acute psychotic episode and more obvious during recovery. Depression is sometimes confused with akinetic side effects of antipsychotic medications. It is also related to boredom, which increases symptoms and decreases the response to treatment. Work is generally unavailable and time unfilled, providing opportunities for counterproductive activities such as drug abuse, withdrawal, and increased psychotic symptoms.
Thought content may vary from a paucity of ideas to a rich complex of delusional fantasy with archaic thinking. One frequently notes after a period of conversation that little if any information has actually been conveyed. Incoming stimuli produce varied responses. In some cases a simple question may trigger explosive outbursts, whereas at other times there may be no overt response whatsoever (catatonia). When paranoid ideation is present, the patient is often irritable and less cooperative. Delusions (false beliefs) are characteristic of paranoid thinking, and they usually take the form of a preoccupation with the supposedly threatening behavior exhibited by other individuals. This ideation may cause the patient to adopt active countermeasures such as locking doors and windows, taking up weapons, covering the ceiling with aluminum foil to counteract radar waves, and other bizarre efforts. Somatic delusions revolve around issues of bodily decay or infestation. Perceptual distortions usually include auditory hallucinations—visual hallucinations are more commonly associated with organic mental states—and may include illusions (distortions of reality) such as figures changing in size or lights varying in intensity. Cenesthetic hallucinations (eg, a burning sensation in the brain, feeling blood flowing in blood vessels) occasionally occur. Lack of humor, feelings of dread, depersonalization (a feeling of being apart from the self), and fears of annihilation may be present. Any of the above symptoms generate higher anxiety levels, with heightened arousal and occasional panic and suicidal ideation, as the individual fails to cope.
The development of the acute episode in schizophrenia frequently is the end product of a gradual decompensation. Frustration and anxiety appear early, followed by depression and alienation, along with progressive ineffectiveness in day-to-day coping. This often leads to feelings of panic and increasing disorganization, with loss of the ability to test and evaluate the reality of perceptions. The stage of so-called psychotic resolution includes delusions, autistic preoccupations, and psychotic insight, with acceptance of the decompensated state. The process is frequently complicated by the use of caffeine, alcohol, and other recreational drugs. Life expectancy of schizophrenic patients is as much as 20% shorter than that of cohorts in the general population and is often associated with comorbid conditions such as the metabolic syndrome, which may be induced or exacerbated by the atypical antipsychotic agents.
Polydipsia may produce water intoxication with hyponatremia—characterized by symptoms of confusion, lethargy, psychosis, seizures, and occasionally death—in any psychiatric disorder, but most commonly in schizophrenia. These problems exacerbate the schizophrenic symptoms and can be confused with them. Possible pathogenetic factors in polydipsia include a hypothalamic defect, inappropriate antidiuretic hormone (ADH) secretion, antipsychotic medications (anticholinergic effects, stimulation of hypothalamic thirst center, effect on ADH), smoking (nicotine and syndrome of inappropriate antidiuretic hormone [SIADH]), psychotic thought processes (delusions), and other medications (eg, diuretics, antidepressants, lithium, alcohol) (see Chapter 21). Other causes of polydipsia must be ruled out (eg, diabetes mellitus, diabetes insipidus, kidney disease).
Ventricular enlargement and cortical atrophy, as seen on CT scan, have been correlated with chronic course, severe cognitive impairment, and nonresponsiveness to antipsychotic medications. Decreased frontal lobe activity seen on PET scan has been associated with negative symptoms.
The diagnosis of schizophrenia is best made over time because repeated observations increase the reliability of the diagnosis. One should not hesitate to reconsider the diagnosis of schizophrenia in any person who has received that diagnosis in the past, particularly when the clinical course has been atypical. A number of these patients have been found to actually have bipolar disorder, which has responded well to lithium. Manic episodes often mimic schizophrenia. However, schizophrenia is less likely to be associated with the decreased need for sleep, increase in goal directed activity, and overconfidence, symptoms that are typical of mania. However, thought disorder, auditory hallucinations, and delusions are commonly seen in manic psychosis.
Psychotic depressions, brief reactive psychosis, delusional disorder, and any illness with psychotic ideation tend to be confused with schizophrenia, partly because of the regrettable tendency to use the terms interchangeably.
Medical disorders such as thyroid dysfunction, adrenal and pituitary disorders, reactions to toxic materials (eg, mercury, PCBs), and almost all of the organic mental states in the early stages must be ruled out. Postpartum psychosis is discussed under Mood Disorders. Complex partial seizures, especially when psychosensory phenomena are present, are an important differential consideration. Toxic drug states arising from prescription, over-the-counter, herbal and street drugs may mimic all of the psychotic disorders. The chronic use of amphetamines, cocaine, and other stimulants frequently produces a psychosis that is almost identical to the acute paranoid schizophrenic episode. Drug-induced psychoses can have all the positive symptoms of schizophrenia but less commonly have the negative symptoms. The presence of formication (sensation of insects crawling on or under the skin) and stereotypy suggests the possibility of stimulant abuse. Phencyclidine, a common street drug, may cause a reaction that is difficult to distinguish from other psychotic disorders. Cerebellar signs, excessive salivation, dilated pupils, and increased deep tendon reflexes should alert the clinician to the possibility of a toxic psychosis. Industrial chemical toxicity (both organic and metallic), degenerative disorders, and metabolic deficiencies must be considered in the differential diagnosis.
Catatonia, frequently assumed to exist solely as a component of schizophrenic disorders, is actually the end product of a number of illnesses, including a number of organic conditions as well as other psychiatric disorders such as bipolar disorder. Neoplasms, viral and bacterial encephalopathies, central nervous system hemorrhage, metabolic derangements such as diabetic ketoacidosis, sedative withdrawal, and liver and kidney malfunction have all been implicated. It is particularly important to realize that drug toxicity (eg, overdoses of antipsychotic medications such as fluphenazine or haloperidol) can cause catatonic syndrome, which may be misdiagnosed as a catatonic schizophrenic disorder and inappropriately treated with more antipsychotic medication. Catatonia is also seen in other major psychiatric disorders, including bipolar disorder and major depression.
Hospitalization is often necessary, particularly when the patient’s behavior shows gross disorganization. The presence of competent family members lessens the need for hospitalization, and each case should be judged individually. The major considerations are to prevent self-inflicted harm or harm to others and to provide the patient’s basic needs. A full medical evaluation and CT scan or MRI of the brain should be considered in first episodes of schizophreniform disorder and other psychotic episodes of unknown cause.
Antipsychotic medications are the treatment of choice. The relapse rate can be reduced by 50% with proper maintenance antipsychotic therapy. Long-acting, injectable depot antipsychotics are used in nonadherant patients or nonresponders to oral medication.
Antipsychotic medications include the “typical or first-generation” antipsychotics (phenothiazines, thioxanthenes, butyrophenones, dihydroindolones, dibenzoxazepines, and benzisoxazoles) and the newer “atypical or second-generation” antipsychotics (clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, asenapine, iloperidone, lurasidone, and cariprazine) (Tables 25–4 and 25–5). Generally, increasing milligram potency of the typical antipsychotics is associated with decreasing anticholinergic and adrenergic side effects and increasing extrapyramidal symptoms. For example, chlorpromazine has lower potency and more severe anticholinergic and adrenergic side effects. The increased anticholinergic effect of chlorpromazine, however, lowers the risk of extrapyramidal symptoms. Data suggest similar antipsychotic efficacy for both classes and a tendency for the second-generation antipsychotics being better tolerated leading to enhanced compliance. One study also highlighted lack of patient adherence as a major factor in treatments effectiveness.
Table 25–4.Commonly used antipsychotics and medications. |Favorite Table|Download (.pdf) Table 25–4. Commonly used antipsychotics and medications.
|Drug ||Usual Daily Oral Dose ||Usual Daily Maximum Dose1 ||Cost per Unit ||Cost for 30 Days Treatment Based on Maximum Dosage2 |
|Aripiprazole (Abilify) ||10–15 mg ||30 mg ||$45.41/30 mg ||$1362.30 |
|Asenapine (Saphris) ||10–20 mg ||20 mg ||$13.79/10 mg ||$827.40 |
|Cariprazine (Vraylar) ||1.5–6 mg ||6 mg ||$40.24/6 mg ||$1207.30 |
|Chlorpromazine (Thorazine; others) ||100–400 mg ||1 g ||$13.74/200 mg ||$2061.00 |
|Clozapine (Clozaril) ||300–450 mg ||900 mg ||$8.17/100 mg ||$2205.90 |
|Fluphenazine (Permitil, Prolixin)3 ||2–10 mg ||60 mg ||$1.15/10 mg ||$207.00 |
|Haloperidol (Haldol) ||2–5 mg ||60 mg ||$2.76/20 mg ||$248.40 |
|Iloperidone (Fanapt) ||12–24 mg ||24 mg ||$36.49/12 mg ||$2189.40 |
|Loxapine (Loxitane) ||20–60 mg ||200 mg ||$2.57/50 mg ||$308.40 |
|Lurasidone (Latuda) ||40–80 mg ||80 mg ||$36.88/80 mg ||$1106.40 |
|Olanzapine (Zyprexa) ||5–10 mg ||20 mg ||$39.83/20 mg ||$1194.90 |
|Paliperidone (Invega) ||6–12 mg ||12 mg ||$30.53/6 mg ||$1831.80 |
|Perphenazine (Trilafon)3 ||16–32 mg ||64 mg ||$3.90/16 mg ||$468.00 |
|Quetiapine (Seroquel) ||200–400 mg ||800 mg ||$19.93/400 mg ||$1195.80 |
|Risperidone (Risperdal)4 ||2–6 mg ||10 mg ||$7.59/2 mg ||$946.16 |
|Thiothixene (Navane)3 ||5–10 mg ||80 mg ||$0.65/10 mg ||$156.00 |
|Trifluoperazine (Stelazine) ||5–15 mg ||60 mg ||$2.45/10 mg ||$441.00 |
|Ziprasidone (Geodon) ||40–160 mg ||160 mg ||$10.76/80 mg ||$645.60 |
Table 25–5.Relative potency and side effects of antipsychotic medications. |Favorite Table|Download (.pdf) Table 25–5. Relative potency and side effects of antipsychotic medications.
|Drug ||Chlorpromazine: Drug Potency Ratio ||Anticholinergic Effects1 ||Extrapyramidal Effect1 |
|Aripiprazole ||1:20 ||1 ||1 |
|Chlorpromazine ||1:1 ||4 ||1 |
|Clozapine ||1:1 ||4 ||— |
|Fluphenazine ||1:50 ||1 ||4 |
|Haloperidol ||1:50 ||1 ||4 |
|Iloperidone ||1:25 ||1 ||1 |
|Loxapine ||1:10 ||2 ||3 |
|Lurasidone ||1:5 ||1 ||2 |
|Olanzapine ||1:20 ||1 ||1 |
|Perphenazine ||1:10 ||2 ||3 |
|Quetiapine ||1:1 ||1 ||1 |
|Risperidone ||1:50 ||1 ||3 |
|Thiothixene ||1:20 ||1 ||4 |
|Trifluoperazine ||1:20 ||1 ||4 |
|Ziprasidone ||1:1 ||1 ||1 |
The phenothiazines comprise the bulk of the currently used “typical” antipsychotic medications. The only butyrophenone commonly used in psychiatry is haloperidol, which is different in structure but similar in action and side effects to the piperazine phenothiazines such as fluphenazine, perphenazine, and trifluoperazine. These medications and haloperidol (dopamine [D2] receptor blockers) have high potency and a paucity of autonomic side effects and act to markedly lower arousal levels. Loxapine, while less potent, is similar in action, side effects, and safety to the piperazine phenothiazines.
Clozapine, the first “atypical” (novel) antipsychotic drug developed, has dopamine (D4) receptor-blocking activity as well as central serotonergic, histaminergic, and alpha-noradrenergic receptor-blocking activity. It is effective in the treatment of about 30% of psychoses resistant to other antipsychotic medications, and it may have specific efficacy in decreasing suicidality in patients with schizophrenia. Risperidone is an antipsychotic that blocks some serotonin receptors (5-HT2) and dopamine receptors (D2). Risperidone causes fewer extrapyramidal side effects than the typical antipsychotics at doses less than 6 mg. It appears to be as effective as haloperidol and possibly as effective as clozapine in treatment-resistant patients without necessitating weekly white cell counts, as required with clozapine therapy. Risperidone-induced hyperprolactinemia, even on low doses, has been reported, and that effect is thought to be more common with risperidone than with other atypical antipsychotics. Risperidone is available in a long-acting injectable preparation.
Olanzapine is a potent blocker of 5-HT2 and dopamine D1, D2, and D4 receptors. High doses of olanzapine (10–20 mg daily) appear to be more effective than lower doses. The drug is somewhat more effective than haloperidol in the treatment of negative symptoms, such as withdrawal, psychomotor retardation, and poor interpersonal relationships. It is available in an orally disintegrating form for patients who are unable to tolerate standard oral dosing and in an injectable form for the management of acute agitation associated with schizophrenia and bipolar disorder. Olanzapine tends to result in elevations of serum alanine aminotransferase more commonly than does haloperidol. Olanzapine is associated with a much lower incidence of dystonic reaction than haloperidol and is less likely to induce tardive dyskinesia. Its most common side effects include somnolence, agitation, nervousness, headache, insomnia, dizziness, and significant weight gain. Multiple case reports have linked olanzapine and clozapine to new-onset type 2 diabetes, and all atypical medications should be monitored for this adverse effect as well. Both atypical and typical agents have been associated with a significantly higher risk of stroke and death in elderly patients. Olanzapine is available in a long-term injectable preparation but this formulation tends to be used less commonly than other depot formulations because some patients experience severe sedation and delirium.
Quetiapine is an antipsychotic with greater 5-HT2 relative to D2 receptor blockade as well as a relatively high affinity for alpha-1- and alpha-2-adrenergic receptors. It appears to be as efficacious as haloperidol in treating positive and negative symptoms of schizophrenia, with fewer extrapyramidal side effects even at high doses. More common side effects include somnolence, dizziness, and postural hypotension. Because of an association with lens changes seen in patients on long-term treatment, an eye examination to detect cataract formation is recommended at initiation of treatment and then at 6-month intervals during treatment. Quetiapine may cause QT prolongation particularly when prescribed with other medications that effect the QT interval and in overdose.
Ziprasidone has both anti-dopamine receptor and anti-serotonin receptor effects, with good efficacy for both positive and negative symptoms of schizophrenia. Ziprasidone is not associated with significant weight gain, hyperlipidemia, or new-onset diabetes and offers a good alternative for some patients. It has been implicated in QTc interval delay of greater than 500 ms in some patients, although in several cases of overdose there were no incidents of torsades de pointes or sudden death. Patients taking ziprasidone should be screened for cardiac risk factors. Aripiprazole is a partial agonist at the dopamine D2 and serotonin 5-HT1 receptors and an antagonist at 5-HT2 receptors, it is effective against positive and negative symptoms of schizophrenia. It functions as an antagonist or agonist, depending on the dopaminergic activity at the dopamine receptors. This may help decrease side effects. More activating than sedating, aripiprazole is thought to impose a low risk of extrapyramidal symptoms (except for akathisia), weight gain, hyperprolactinemia, and delayed QT interval. Aripiprazole is approved as an augmentation agent for treatment-resistant depression, even when psychosis is not present, and as a maintenance treatment for bipolar disorder. Aripiprazole is available as an acute injectable preparation as well as a long-term injectable preparation that is given once monthly in patients who are not able to adhere to daily oral dosing. Asenapine, approved for the treatment of schizophrenia and bipolar disorder (mixed or manic state), appears to be particularly helpful in treating negative symptoms of schizophrenia. Asenapine can cause hyperprolactinemia and weight gain. It carries a warning for possible serious allergic reactions, which can occur even after the first dose, including anaphylaxis, hypotension, and difficulty breathing. Patients should be appropriately cautioned. Paliperidone, the active metabolite of risperidone, is available as a capsule and a monthly injection. It has the advantage of low associations with diabetes mellitus, weight gain, and dyslipidemia. Both asenapine and paliperidone increase the risk of QT interval prolongation and should be avoided in patients with risk factors for this ECG finding. Iloperidone has low incidence of extrapyramidal side effects that is similar to the other atypical agents but requires careful initial titration due to the risk of orthostatic hypotension and possibility of lengthening the QT interval. When coadministered with paroxetine or clarithromycin, the dose of iloperidone must be halved because of decreased hepatic metabolism by the cytochrome P450 CYP2D6 and CYP3A4 isozymes. Lurasidone is FDA-approved and has been shown to be effective in treating acute decompensation in patients with chronic schizophrenia. This medication is distinguished by low incidence of weight gain, increased lipids or prolonged QT interval, but clinicians should be mindful of side effects of akathisia, elevated prolactin and in higher doses, somnolence. Cariprazine is a partial agonist of the D2 and D3 receptor and is approved by the FDA for the treatment of schizophrenia and bipolar disorder. Akithisia, weight gain, and insomnia are among the more commonly reported side effects with cariprazine. Because cariprazine is not a potent D2-antagonist, it is less likely to increase prolactin levels than most antipsychotics. None of the antipsychotics produce true physical dependency. All decrease adrenergic responses. Despite higher costs, atypical antipsychotics are often considered preferable to traditional antipsychotics because they are thought to be associated with reduced extrapyramidal symptoms and a lesser risk of tardive dyskinesia.
The antipsychotics are used to treat all forms of the schizophrenias as well as psychotic ideation in delirium, drug-induced psychoses, psychotic depression, augmentation of unipolar depression, acute mania, and the prevention of mood cycles in bipolar disorder. They are also effective in Tourette syndrome and behavioral dyscontrol in autistic patients. While frequently used to treat agitation in dementia patients, no antipsychotic has been shown to be reliably effective in this population and may increase the risk of early mortality in elderly dementia patients. Antipsychotics quickly lower the arousal (activity) level and, perhaps indirectly, gradually improve socialization and thinking. The improvement rate for treating positive symptoms is about 80%. Patients whose behavioral symptoms worsen with use of antipsychotic medications may have an undiagnosed organic condition such as anticholinergic toxicity.
Symptoms that are ameliorated by these medications include hyperactivity, hostility, aggression, delusions, hallucinations, irritability, and poor sleep. Individuals with acute psychosis and good premorbid function respond quite well. The most common cause of failure in the treatment of acute psychosis is inadequate dosage, and the most common cause of relapse is noncompliance.
Although first-generation antipsychotics are efficacious in the treatment of positive symptoms of schizophrenia, such as hallucinations and delusions, second-generation antipsychotics are thought to have efficacy in reducing positive symptoms and some efficacy in treating negative symptoms. Antidepressant medications may be used in conjunction with antipsychotics if significant depression is present. Resistant cases may require concomitant use of lithium, carbamazepine, or valproic acid. The addition of a benzodiazepine drug to the antipsychotic regimen may prove helpful in treating the agitated or catatonic psychotic patient who has not responded to antipsychotics alone—lorazepam, 1–2 mg orally, can produce a rapid resolution of catatonic symptoms and may allow maintenance with a lower antipsychotic dose. Electroconvulsive therapy (ECT) has also been effective in treating catatonia.
The dosage range is quite broad (Table 25–4). For example, risperidone, 0.25–1 mg orally at bedtime, may be sufficient for the elderly person with mild dementia with psychosis (especially in view of the increased risk of stroke and death in the elderly), whereas up to 6 mg/day may be used in a young patient with acute schizophrenia. For quick response, an atypical antipsychotic may be started in combination with a benzodiazepine (eg, risperidone oral solution, 2 mg, or olanzapine, 10 mg orally, and lorazepam, 2 mg orally, every 2–4 hours as needed). In an acutely distressed, psychotic patient one might use haloperidol, 10 mg intramuscularly, which is absorbed rapidly and achieves an initial tenfold plasma level advantage over equal oral doses. Psychomotor agitation, racing thoughts, and general arousal are quickly reduced. The dose can be repeated every 3–4 hours; when the patient is less symptomatic, oral doses can replace parenteral administration in most cases. In the elderly, both atypical (eg, risperidone 0.25 mg–0.5 mg daily or olanzapine 1.25 mg daily) and typical (eg, haloperidol 0.5 mg daily or perphenazine 2 mg daily) antipsychotics, often used effectively in small doses for behavioral control, have been linked to premature death in some cases.
Absorption of oral medications may be increased or decreased by concomitant administration of other medications (eg, antacids tend to decrease the absorption of antidepressants). Previous gastrointestinal surgery may alter pH, motility, and surface areas available for drug absorption. There are racial differences in metabolizing the antipsychotic medications—eg, many Asians require only about half the usual dosage. Bioavailability is influenced by other factors such as smoking or hepatic microsomal enzyme stimulation with alcohol or barbiturates and enzyme-altering medications such as carbamazepine or methylphenidate. Antipsychotic plasma drug level determinations are not currently of major clinical assistance.
Divided daily doses are not necessary after a maintenance dose has been established, and most patients can then be maintained on a single daily dose, usually taken at bedtime. This is particularly appropriate in a case where the sedative effect of the drug is desired for nighttime sleep, and undesirable sedative effects can be avoided during the day. Risperidone is an exception, being given twice daily. First-episode patients especially should be tapered off medications after about 6 months of stability and carefully monitored; their rate of relapse is lower than that of multiple-episode patients.
Psychiatric patients—particularly paranoid individuals— often neglect to take their medication. In these cases and in nonresponders to oral medication, the enanthate and decanoate (the latter is slightly longer-lasting and has fewer extrapyramidal side effects) forms of fluphenazine or the decanoate form of haloperidol may be given by deep subcutaneous injection or intramuscularly to achieve an effect that will usually last 7–28 days. A patient who cannot be depended on to take oral medication (or who overdoses on minimal provocation) will generally agree to come to the clinician’s office for a “shot.” The usual dose of the fluphenazine long-acting preparations is 25 mg every 2 weeks. Dosage and frequency of administration vary from about 100 mg weekly to 12.5 mg monthly. Use the smallest effective amount as infrequently as possible. A monthly injection of 25 mg of fluphenazine decanoate is equivalent to about 15–20 mg of oral fluphenazine daily. Risperidone was the first atypical antipsychotic available in a long-acting injectable form (25–50 mg intramuscularly every 2 weeks). Concomitant use of a benzodiazepine (eg, lorazepam, 2 mg orally twice daily) may permit reduction of the required dosage of oral or parenteral antipsychotic drug. Long-acting injectables are now available for risperidone, paliperidone, aripiprazole, and olanzapine.
Intravenous haloperidol, the antipsychotic most commonly used by this route, is often used in critical care units in the management of agitated, delirious patients. Intravenous haloperidol should be given no faster than 1 mg/min to reduce cardiovascular side effects, such as torsades de pointes. Current practice indicates that ECG monitoring should be used whenever haloperidol is being administered intravenously.
Some antipsychotic agents are available for intranasal administration. The intranasal form of loxapine has a more rapid onset of action for the treatment of agitation (about 10 minutes) than either intramuscular or oral antipsychotic agents. Also, intranasal administration tends to be less traumatic to patients than getting an injection. However, intranasal loxapine requires the cooperation of the patient and is more expensive than generic antipsychotic injectable preparations.
For both typical and atypical antipsychotic agents, a range of side effects has been reported. The most common anticholinergic side effects include dry mouth (which can lead to ingestion of caloric liquids and weight gain or hyponatremia), blurred near vision, urinary retention (particularly in elderly men with enlarged prostates), delayed gastric emptying, esophageal reflux, ileus, delirium, and precipitation of acute glaucoma in patients with narrow anterior chamber angles. Other autonomic effects include orthostatic hypotension and sexual dysfunction—problems in achieving erection, ejaculation (including retrograde ejaculation), and orgasm in men (approximately 50% of cases) and women (approximately 30%). Delay in achieving orgasm is often a factor in medication noncompliance. Electrocardiographic changes occur frequently, but clinically significant arrhythmias are much less common. Elderly patients and those with preexisting cardiac disease are at greater risk. The most frequently seen electrocardiographic changes include diminution of the T wave amplitude, appearance of prominent U waves, depression of the ST segment, and prolongation of the QT interval (Table 25–6). Ziprasidone can produce QTc prolongation. A pretreatment ECG is indicated for patients at risk for cardiac sequelae (including patients taking other medications that might prolong the QTc interval). In some critical care patients, torsades de pointes has been associated with the use of high-dose intravenous haloperidol (usually greater than 30 mg/24 h).
Table 25–6.Adverse factors associated with atypical antipsychotic medications. |Favorite Table|Download (.pdf) Table 25–6. Adverse factors associated with atypical antipsychotic medications.
| ||Weight Gain ||Hyperlipidemia ||New-Onset Diabetes Mellitus ||QTc Prolongation1 |
|Asenapine ||+/– ||+/– ||+/– ||+++ |
|Aripiprazole ||+/– ||– ||– ||++ |
|Clozapine ||+++ ||+++ ||+++ ||+/– |
|Lurasidone ||– ||– ||– ||– |
|Olanzapine ||+++ ||+++ ||+++ ||+/– |
|Paliperidone ||+ ||+/— ||+/– ||+++ |
|Quetiapine ||++ ||++ ||++ ||+++ |
|Risperidone ||++ ||++ ||++ ||+ |
|Ziprasidone ||+/– ||— ||– ||+++ |
Associations have been suggested between the atypical antipsychotics and new-onset diabetes, hyperlipidemia, and weight gain (Table 25–6). The FDA has particularly noted the risk of hyperglycemia and new-onset diabetes in this class of medication that is not related to weight gain. The risk of diabetes mellitus is increased in patients taking clozapine and olanzapine. Monitoring of weight, fasting blood sugar and lipids prior to initiation of treatment and at regular intervals thereafter is an important part of medication monitoring. The addition of metformin to olanzapine may improve drug-induced weight gain in patients with drug-naïve, first-episode schizophrenia. Antipsychotic medications in general may have metabolic and endocrine effects, including weight gain, hyperglycemia, impaired temperature regulation in hot weather, and water intoxication, that may be due to inappropriate ADH secretion. Lactation and menstrual irregularities are common (antipsychotic medications should be avoided, if possible, in breast cancer patients because of potential trophic effects of elevated prolactin levels on the breast). Both antipsychotic and antidepressant medications inhibit sperm motility. Bone marrow depression and cholestatic jaundice occur rarely; these are hypersensitivity reactions, and they usually appear in the first 2 months of treatment. They subside on discontinuance of the drug. There is cross-sensitivity among all of the phenothiazines, and a drug from a different group should be used when allergic reactions occur.
Clozapine is associated with a 1.6% risk of agranulocytosis (higher in persons of Ashkenazi Jewish ancestry), and its use must be strictly monitored with weekly blood counts during the first 6 months of treatment, with monitoring every other week thereafter. The risk of developing agranulocytosis is approximately 2.5 times higher in patients with a polymorphism for HLADQB1 gene. Thus, this genetic test may be worthwhile to perform before initiating clozapine. Discontinuation of the medication requires weekly monitoring of the white blood cell count for 1 month. Clozapine has been associated with fatal myocarditis and is contraindicated in patients with severe heart disease. In addition, clozapine lowers the seizure threshold and has many side effects, including sedation, hypotension, increased liver enzyme levels, hypersalivation, respiratory arrest, weight gain, and changes in both the ECG and the electroencephalogram. Notably, adynamic ileus is a rare side effect of clozapine that can be fatal.
Photosensitivity, retinopathy, and hyperpigmentation are associated with use of fairly high dosages of chlorpromazine. The appearance of particulate melanin deposits in the lens of the eye is related to the total dose given, and patients on long-term medication should have periodic eye examinations. Teratogenicity has not been causally related to these medications, but prudence is indicated particularly in the first trimester of pregnancy. The seizure threshold is lowered, but it is safe to use these medications in epileptics who take anticonvulsants.
The neuroleptic malignant syndrome (NMS) is a catatonia-like state manifested by extrapyramidal signs, blood pressure changes, altered consciousness, and hyperpyrexia; it is an uncommon but serious complication of antipsychotic treatment. Muscle rigidity, involuntary movements, confusion, dysarthria, and dysphagia are accompanied by pallor, cardiovascular instability, fever, pulmonary congestion, and diaphoresis and may result in stupor, coma, and death. The cause may be related to a number of factors, including poor dosage control of antipsychotic medication, affective illness, decreased serum iron, dehydration, and increased sensitivity of dopamine receptor sites. Lithium in combination with an antipsychotic drug may increase vulnerability, which is already increased in patients with an affective disorder. In most cases, the symptoms develop within the first 2 weeks of antipsychotic drug treatment. The syndrome may occur with small doses of the medications. Intramuscular administration is a risk factor. Elevated creatine kinase and leukocytosis with a shift to the left are present early in about half of cases. Treatment includes controlling fever and providing fluid support. Dopamine agonists such as bromocriptine, 2.5–10 mg orally three times a day, and amantadine, 100–200 mg orally twice a day, have also been useful. Dantrolene, 50 mg intravenously as needed, is used to alleviate rigidity (do not exceed 10 mg/kg/day due to hepatotoxicity risk). There is ongoing controversy about the efficacy of these three agents as well as the use of calcium channel blockers and benzodiazepines. ECT has been used effectively in resistant cases. Clozapine has been used with relative safety and fair success as an antipsychotic drug for patients who have had NMS. The syndrome must be differentiated from malignant catatonia, malignant hyperthermia, neurotoxic syndromes (including AIDS), and a variety of other conditions such as viral encephalitis, Wilson disease, central anticholinergic syndrome, and hypertonic states (eg, tetany, strychnine poisoning).
Akathisia is the most common (about 20%) extrapyramidal symptom. It usually occurs early in treatment (but may persist after antipsychotics are discontinued) and is frequently mistaken for anxiety or exacerbation of psychosis. It is characterized by a subjective desire to be in constant motion followed by an inability to sit or stand still and consequent pacing. It may induce suicidality or feelings of fright, rage, terror, or sexual torment. Insomnia is often present. It is crucial to educate patients in advance about these potential side effects so that the patients do not misinterpret them as signs of increased illness. In all cases, reevaluate the dosage requirement or the type of antipsychotic drug. One should inquire also about cigarette smoking, which in women has been associated with an increased incidence of akathisia. Antiparkinsonism medications (such as trihexyphenidyl, 2–5 mg orally three times daily) may be helpful, but first-line treatment often includes a benzodiazepine (such as clonazepam 0.5–1 mg orally three times daily). In resistant cases, symptoms may be alleviated by propranolol, 30–80 mg/day orally, diazepam, 5 mg orally three times daily, or amantadine, 100 mg orally three times daily.
Acute dystonias usually occur early, although a late (tardive) occurrence is reported in patients (mostly men after several years of therapy) who previously had early severe dystonic reactions and a mood disorder. Younger patients are at higher risk for acute dystonias. The most common signs are bizarre muscle spasms of the head, neck, and tongue. Frequently present are torticollis, oculogyric crises, swallowing or chewing difficulties, and masseter spasms. Laryngospasm is particularly dangerous. Back, arm, or leg muscle spasms are occasionally reported. Diphenhydramine, 50 mg intramuscularly, is effective for the acute crisis; one should then give benztropine mesylate, 2 mg orally twice daily, for several weeks, and then discontinue gradually, since few of the extrapyramidal symptoms require long-term use of the antiparkinsonism medications (all of which are about equally efficacious—though trihexyphenidyl tends to be mildly stimulating and benztropine mildly sedating).
Drug-induced parkinsonism is indistinguishable from idiopathic parkinsonism, but it is reversible, occurs later in treatment than the preceding extrapyramidal symptoms, and in some cases appears after antipsychotic withdrawal. The condition includes the typical signs of apathy and reduction of facial and arm movements (akinesia, which can mimic depression), festinating gait, rigidity, loss of postural reflexes, and pill-rolling tremor. AIDS patients seem particularly vulnerable to extrapyramidal side effects. High-potency antipsychotics often require antiparkinsonism medications (see Table 24–6). The antipsychotic dosage should be reduced, and immediate relief can be achieved with antiparkinsonism medications in the same dosages as above. After 4–6 weeks, these antiparkinsonism medications can often be discontinued with no recurrent symptoms. In any of the extrapyramidal symptoms, amantadine, 100–400 mg orally daily, may be used instead of the antiparkinsonism medications. Antipsychotic-induced catatonia is similar to catatonic stupor with rigidity, drooling, urinary incontinence, and cogwheeling. It usually responds slowly to withdrawal of the offending medication and use of antiparkinsonism agents.
Tardive dyskinesia is a syndrome of abnormal involuntary stereotyped movements of the face, mouth, tongue, trunk, and limbs that may occur after months or (usually) years of treatment with antipsychotic agents. The syndrome affects 20–35% of patients who have undergone long-term antipsychotic therapy. Predisposing factors include older age, many years of treatment, cigarette smoking, and diabetes mellitus. Pineal calcification is higher in this condition by a margin of 3:1. There are no clearcut differences among the antipsychotic medications in the development of tardive dyskinesia. (Although the atypical antipsychotics appear to offer a lower risk of tardive dyskinesia, long-term effects have not been investigated.) Early manifestations of tardive dyskinesia include fine worm-like movements of the tongue at rest, difficulty in sticking out the tongue, facial tics, increased blink frequency, or jaw movements of recent onset. Later manifestations may include bucco-linguo-masticatory movements, lip smacking, chewing motions, mouth opening and closing, disturbed gag reflex, puffing of the cheeks, disrupted speech, respiratory distress, or choreoathetoid movements of the extremities (the last being more prevalent in younger patients). The symptoms do not necessarily worsen and in rare cases may lessen even though antipsychotic medications are continued. The dyskinesias do not occur during sleep and can be voluntarily suppressed for short periods. Stress and movements in other parts of the body will often aggravate the condition.
Early signs of dyskinesia must be differentiated from those reversible signs produced by ill-fitting dentures or nonantipsychotic medications such as levodopa, TCAs, antiparkinsonism agents, anticonvulsants, and antihistamines. Other neurologic conditions such as Huntington chorea can be differentiated by history and examination.
The emphasis should be on prevention of side effects. Use the least amount of antipsychotic drug necessary to mute the psychotic symptoms, and use atypical antipsychotics as first-line agents. Detect early manifestations of dyskinesias. When these occur, stop anticholinergic medications and gradually discontinue antipsychotic medications, if clinically feasible. Weight loss and cachexia sometimes appear on withdrawal of antipsychotics. In an indeterminate number of cases, the dyskinesias will remit. Keep the patient off the medications until reemergent psychotic symptoms dictate their resumption, at which point they are restarted in low doses and gradually increased until there is clinical improvement. If antipsychotic medications are restarted, clozapine and olanzapine appear to offer less risk of recurrence. The use of adjunctive agents such as benzodiazepines or lithium may help directly or indirectly by allowing control of psychotic symptoms with a low dosage of antipsychotics. If the dyskinesic syndrome recurs and it is necessary to continue antipsychotic medications to control psychotic symptoms, informed consent should be obtained. Benzodiazepines, buspirone (in doses of 15–60 mg/day orally), phosphatidylcholine, clonidine, calcium channel blockers, vitamin E, omega-3 fatty acids, and propranolol all have had limited usefulness in treating the dyskinetic side effects.
Environmental considerations are most important in the individual with a chronic illness, who usually has a history of repeated hospitalizations, a continued low level of functioning, and symptoms that never completely remit. Family rejection and work failure are common. In these cases, board and care homes staffed by personnel experienced in caring for psychiatric patients are most important. There is frequently an inverse relationship between stability of the living situation and the amounts of required antipsychotic medications, since the most salutary environment is one that reduces stimuli. Nonresidential self-help groups such as Recovery, Inc., should be utilized whenever possible. They provide a setting for sharing, learning, and mutual support and are frequently the only social involvement with which this type of patient is comfortable. Vocational rehabilitation and work agencies (eg, Goodwill Industries, Inc.) provide assessment, training, and job opportunities at a level commensurate with the person’s clinical condition.
The need for psychotherapy varies markedly depending on the patient’s current status and history. In a person with a single psychotic episode and a previously good level of adjustment, supportive psychotherapy may help the patient reintegrate the experience, gain some insight into antecedent problems, and become a more self-observant individual who can recognize early signs of stress. Insight-oriented psychotherapy is often counterproductive in this type of disorder. Research suggests that cognitive behavioral therapy—in conjunction with medication management—may have some efficacy in the treatment of symptoms of schizophrenia. Cognitive behavioral therapy for schizophrenia involves helping the individual challenge psychotic thinking and alters response to hallucinations. Similarly, a form of psychotherapy called acceptance and commitment therapy has shown value in helping prevent hospitalizations in schizophrenia. Cognitive remediation therapy is another approach to treatment that may help patients with schizophrenia become better able to focus their disorganized thinking. Family therapy may also help alleviate the patient’s stress and to assist relatives in coping with the patient.
Behavioral techniques (see above) are most frequently used in therapeutic settings such as day treatment centers, but they can also be incorporated into family situations or any therapeutic setting. Many behavioral techniques (eg, positive reinforcement—whether it be a word of praise or an approving nod—after some positive behavior), can be a powerful instrument for helping a person learn behaviors that will facilitate social acceptance. Music from portable digital players with earphones is one of many ways to divert the patient’s attention from auditory hallucinations.
For most patients with any psychosis, the prognosis is good for alleviation of positive symptoms such as hallucinations or delusions treated with medication. Negative symptoms such as diminished affect and sociability are much more difficult to treat but appear mildly responsive to atypical antipsychotics. Cognitive deficits, such as the executive dysfunction that is common to schizophrenia, also do not appear as responsive to antipsychotics as do positive symptoms. Unfortunately, both negative symptoms and cognitive deficits appear to contribute more to long-term disability in schizophrenic patients than do positive symptoms. Unavailability of structured work situations and lack of family therapy are two other reasons why the prognosis is so guarded in such a large percentage of schizophrenic patients. Psychosis connected with a history of serious drug abuse has a guarded prognosis because of the central nervous system damage, usually from the medications themselves and associated medical illnesses.
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MOOD DISORDERS (DEPRESSION & MANIA)
ESSENTIALS OF DIAGNOSIS
Present in most depressions
Mood varies from mild sadness to intense despondency and feelings of guilt, worthlessness, and hopelessness.
Difficulty in thinking, including inability to concentrate, ruminations, and lack of decisiveness.
Loss of interest, with diminished involvement in work and recreation.
Somatic complaints such as headache; disrupted, lessened, or excessive sleep; loss of energy; change in appetite; decreased sexual drive.
Present in some severe depressions
Psychomotor retardation or agitation.
Delusions of a somatic or persecutory nature.
Withdrawal from activities.
Physical symptoms of major severity, eg, anorexia, insomnia, reduced sexual drive, weight loss, and various somatic complaints.
Present in mania
Mood ranging from euphoria to irritability.
Grandiosity or extreme overconfidence.
Variable psychotic symptoms.
Depression is extremely common, with up to 30% of primary care patients having depressive symptoms. Depression may be the final expression of (1) genetic factors (neurotransmitter dysfunction), (2) developmental problems (personality problems, childhood events), or (3) psychosocial stresses (divorce, unemployment). It frequently presents in the form of somatic complaints with negative medical workups. Although sadness and grief are normal responses to loss, depression is not. Patients experiencing normal grief tend to produce sympathy and sadness in the clinician caregiver; depression often produces frustration and irritation in the clinician. Grief is usually accompanied by intact self-esteem, whereas depression is marked by a sense of guilt and worthlessness.
Mania is often combined with depression and may occur alone, together with depression in a mixed episode, or in cyclic fashion with depression.
In general, there are four major types of depression, with similar symptoms in each group.
A. Adjustment Disorder with Depressed Mood
Depression may occur in reaction to some identifiable stressor or adverse life situation, usually loss of a person by death (grief reaction), divorce, etc; financial reversal (crisis); or loss of an established role, such as being needed. Anger is frequently associated with the loss, and this in turn often produces a feeling of guilt. The disorder occurs within 3 months of the stressor and causes significant impairment in social or occupational functioning. The symptoms range from mild sadness, anxiety, irritability, worry, and lack of concentration, discouragement, and somatic complaints to the more severe symptoms of frank depression. When the full criteria for major depressive disorder are present, then that diagnosis should be made and treatment instituted even when there is a known stressor. The presence of a stressor is not the determining diagnostic driver, it is the resultant syndromal complex. One should not neglect treatment for major depression simply because it may appear to be an understandable reaction to a particular stress or difficulty.
The subclassifications include major depressive disorder and dysthymia.
1. Major depressive disorder
A major depressive disorder consists of a syndrome of mood, physical and cognitive symptoms that occurs at any time of life. Many consider a physiologic or metabolic aberration to be causative. Complaints vary widely but most frequently include a loss of interest and pleasure (anhedonia), withdrawal from activities, and feelings of guilt. Also included are inability to concentrate, some cognitive dysfunction, anxiety, chronic fatigue, feelings of worthlessness, somatic complaints (unexplained somatic complaints frequently indicate depression), loss of sexual drive, and thoughts of death. Unemployment has been associated with increase in depression risk. Diurnal variation with improvement as the day progresses is common. Vegetative signs that frequently occur are insomnia, anorexia with weight loss, and constipation. Occasionally, severe agitation and psychotic ideation are present. Psychotic major depression occurs up to 14% of all patients with major depression and 25% of patients who are hospitalized with depression. Psychotic symptoms (delusions, paranoia) are more common in depressed persons who are older than 50 years. Paranoid symptoms may range from general suspiciousness to ideas of reference with delusions. The somatic delusions frequently revolve around feelings of impending annihilation or somatic concerns (eg, that the body is rotting away with cancer). Hallucinations are less common than unusual beliefs and tend not to occur independent of delusions.
In addition to psychotic major depression, other subcategories include major depression with atypical features that is characterized by hypersomnia, overeating, lethargy, and mood reactivity in which the mood brightens in response to positive events or news. Melancholic major depression is characterized by a lack of mood reactivity seen in atypical depression, the presence of a prominent anhedonia and more severe vegetative symptoms. Major depression with a seasonal onset (seasonal affective disorder) is a dysfunction of circadian rhythms that occurs more commonly in the fall and winter months and is believed to be due to decreased exposure to full-spectrum light. Common symptoms include carbohydrate craving, lethargy, hyperphagia, and hypersomnia. Major depression with postpartum onset usually occurs 2 weeks to 6 months postpartum.
Most women (up to 80%) experience some mild letdown of mood in the postpartum period. For some of these (10–15%), the symptoms are more severe and similar to those usually seen in serious depression, with an increased emphasis on concerns related to the baby (obsessive thoughts about harming it or inability to care for it). When psychotic symptoms occur, there is frequently associated sleep deprivation, volatility of behavior, and manic-like symptoms. Postpartum psychosis is much less common (less than 2%), often occurs within the first 2 weeks, and requires early and aggressive management. Biologic vulnerability with hormonal changes and psychosocial stressors all play a role. The chances of a second episode are about 25% and may be reduced with prophylactic treatment.
Dysthymia is a chronic depressive disturbance. Sadness, loss of interest, and withdrawal from activities over a period of 2 or more years with a relatively persistent course is necessary for this diagnosis. Generally, the symptoms are milder but longer-lasting than those in a major depressive episode.
3. Premenstrual dysphoric disorder
Depressive symptoms occur during the late luteal phase (last 2 weeks) of the menstrual cycle. (See also Chapter 18.)
Bipolar disorder consists of episodic mood shifts into mania, major depression, hypomania, and mixed mood states. The ability of bipolar disorder to mimic aspects of many other coincident major mental health disorders and a high comorbidity with substance abuse can make the initial diagnosis of bipolar disorder difficult. Bipolar I is diagnosed when an individual has both depressive and manic episodes. For individuals who experience depressive and hypomanic episodes without frank mania, the diagnosis is Bipolar II.
A manic episode is a mood state characterized by elation with hyperactivity, overinvolvement in life activities, increased irritability, flight of ideas, easy distractibility, and little need for sleep. The overenthusiastic quality of the mood and the expansive behavior initially attract others, but the irritability, mood lability with swings into depression, aggressive behavior, and grandiosity usually lead to marked interpersonal difficulties. Activities may occur that are later regretted, eg, excessive spending, resignation from a job, a hasty marriage, sexual acting out, and exhibitionistic behavior, with alienation of friends and family. Atypical manic episodes can include gross delusions, paranoid ideation of severe proportions, and auditory hallucinations usually related to some grandiose perception. The episodes begin abruptly (sometimes precipitated by life stresses) and may last from several days to months. Spring and summer tend to be the peak periods. Generally, the manic episodes are of shorter duration than the depressive episodes. In almost all cases, the manic episode is part of a broader bipolar (manic-depressive) disorder. Patients with four or more discrete episodes of a mood disturbance in 1 year are called “rapid cyclers.” (Substance abuse, particularly cocaine, can mimic rapid cycling.) These patients have a higher incidence of hypothyroidism. Manic patients differ from patients with schizophrenia in that the former use more effective interpersonal maneuvers, are more sensitive to the social maneuvers of others, and are more able to utilize weakness and vulnerability in others to their own advantage. Creativity has been positively correlated with mood disorders, but the best work done is between episodes of mania and depression.
These are chronic mood disturbances with episodes of subsyndromal depression and hypomania. The symptoms must have at least a 2-year duration and are milder than those that occur in depressive or manic episodes. Occasionally, the symptoms will escalate into a full-blown manic or depressive episode, in which case reclassification as bipolar I or II would be warranted.
D. Mood Disorders Secondary to Illness and Medications
Any illness, severe or mild, can cause significant depression. Conditions such as rheumatoid arthritis, multiple sclerosis, stroke, and chronic heart disease are particularly likely to be associated with depression, as are other chronic illnesses. Depression is common in cancer, as well, with a particularly high degree of comorbidity in pancreatic cancer. Hormonal variations clearly play a role in some depressions. Varying degrees of depression occur at various times in schizophrenic disorders, central nervous system disease, and organic mental states. Alcohol dependency frequently coexists with serious depression.
The classic model of drug-induced depression occurred with the use of reserpine, both in clinical settings and as a pharmacologic probe in research settings. Corticosteroids and oral contraceptives are commonly associated with mood changes such as depression and hypomania. Antihypertensive medications such as methyldopa, guanethidine, and clonidine have been associated with the development of depressive syndromes, as have digitalis and antiparkinsonism medications (eg, levodopa). Interferon is strongly associated with depressed mood and fatigue as a side effect; consultation with a psychiatrist prior to prescribing these agents is indicated in cases where there is a history of depression. It is unusual for beta-blockers to produce depression when given for short periods, such as in the treatment of performance anxiety. Sustained use of beta-blockers for medical conditions such as hypertension may be associated with depression in some patients, although most individuals do not suffer this adverse effect. One study associated the use of beta-blockers with a significant reduction in risk of depressive symptoms 1 year after a percutaneous coronary intervention. Infrequently, disulfiram and anticholinesterase medications may be associated with symptoms of depression. All stimulant use results in a depressive syndrome when the drug is withdrawn. Alcohol, sedatives, opioids, and most of the psychedelic drugs are depressants and, paradoxically, are often used in self-treatment of depression. Corticosteroids may be associated with hypomania.
Since depression may be a part of any illness—either reactively or as a secondary symptom—careful attention must be given to personal life adjustment problems and the role of medications (eg, reserpine, corticosteroids, levodopa). Schizophrenia, partial complex seizures, organic brain syndromes, panic disorders, and anxiety disorders must be differentiated. Thyroid dysfunction and other endocrinopathies should be ruled out. Malignancies, including central and gastrointestinal tumors are sometimes associated with depressive symptoms and may antecede the diagnosis of tumor. Strokes, particularly dominant hemisphere lesions, can occasionally present with a syndrome that looks like major depression. Medication-induced depressive symptoms are also quite common.
The most important complication is suicide, which often includes some elements of aggression. Suicide rates in the general population vary from 9 per 100,000 in Spain to 20 per 100,000 in the United States to 58 per 100,000 in Hungary. In individuals hospitalized for depression, the lifetime risk rises to 10–15%. In patients with bipolar I disorder, the risk is higher, with up to 20% of individuals dying of suicide. Men over the age of 50 are more likely to complete a suicide because of their tendency to attempt suicide with more violent means, particularly guns. On the other hand, women make more attempts but are less likely to complete a suicide. An increased suicide rate is being observed in the younger population, aged 15–35. Patients with cancer, respiratory illnesses, AIDS, and those being maintained on hemodialysis have higher suicide rates. Alcohol use is a significant factor in many suicide attempts.
There are several groups of people who make suicide attempts. One group includes those individuals with acute situational problems. These individuals may be acutely distressed by a recent breakup in a relationship or another type of disappointment. This group also includes those who may not be diagnosed as having depression but who are overwhelmed by a stressful situation often with an aspect of public humiliation (eg, victims of cyber-bullying). A suicide attempt in such cases may be an impulsive or aggressive act not associated with significant depression. In such cases, a suicide attempt is clearly a stratagem for controlling or hurting others or an attempted escape.
Another high-risk group includes individuals with severe depression. Severe depression may be due to conditions such as medical illness (eg, AIDS, whose victims have a suicide rate over 20 times that of the general population) or comorbid psychiatric disorders (eg, panic disorders). Anxiety, panic, and fear are major findings in suicidal behavior. A patient may seem to make a dramatic improvement, but the lifting of depression may be due to the patient’s decision to commit suicide. Another high-risk group are individuals with psychotic illness who tend not to verbalize their concerns, are unpredictable, and are often successful in their suicide attempt, although they make up only a small percentage of the total.
Finally, suicide is 10 times more prevalent in patients with schizophrenia than in the general population, and jumping from bridges is a more common means of attempted suicide by patients with schizophrenia than by others. In one study of 100 “jumpers,” 47% had schizophrenia.
The immediate goal of psychiatric evaluation is to assess the current suicidal risk and the need for hospitalization versus outpatient management. Perhaps the one most useful question is to ask the person how many hours per day he or she thinks about suicide. If it is more than 1 hour, the individual is at high risk. Further assessing the risk by inquiring about intent, plans, means, and suicide-inhibiting factors (eg, strong ties to children or the church) is essential. The intent is less likely to be truly suicidal, for example, if small amounts of poison or medication were ingested or scratching of wrists was superficial, if the act was performed in the vicinity of others or with early notification of others, or if the attempt was arranged so that early detection would be anticipated. Alcohol, hopelessness, delusional thoughts, and complete or nearly complete loss of interest in life or ability to experience pleasure are all positively correlated with suicide attempts. Other risk factors are previous attempts, a family history of suicide, medical or psychiatric illness (eg, anxiety, depression, psychosis), male sex, older age, contemplation of violent methods, a humiliating social stressor, and drug use (including long-term sedative or alcohol use), which contributes to impulsiveness or mood swings. Successful treatment of the patient at risk for suicide cannot be achieved if the patient continues to abuse drugs.
The patient’s current mood status is best evaluated by direct evaluation of plans and concerns about the future, personal reactions to the attempt, and thoughts about the reactions of others. Measurement of mood is often facilitated by using a standardized instrument such as the Hamilton or Montgomery-Asberg clinician-administered rating scales or the self-administered Patient Health Questionnaire-9. Blood tests are being developed to diagnose depression and predict antidepressant response. However, more testing is needed to determine the usefulness in routine clinical practice. Common antidepressant scales such as the PHQ-9 allow for initial assessment as well as ongoing treatment tracking. The patient’s immediate resources should also be assessed—people who can be significantly involved (most important), family support, job situation, financial resources, etc. Suicide risk can be specifically assessed using an instrument such as the Columbia-Suicide Severity Risk Scale.
If hospitalization is not indicated (eg, gestures, impulsive attempts; see above), the clinician must formulate and institute a treatment plan or make an adequate referral. (National Suicide Prevention Lifeline, 1-800-273-8255, may be of assistance.) Medication should be dispensed in small amounts to at-risk patients. Although TCAs and SSRIs are associated with an equal incidence of suicide attempts, the risk of a completed suicide is much higher with TCA overdose. Guns and medications should be removed from the patient’s household. Driving should be interdicted until the patient improves. The problem is often worsened by the long-term complications of the suicide attempt, eg, brain damage due to hypoxia, peripheral neuropathies caused by staying for long periods in one position causing nerve compressions, and medical or surgical problems such as esophageal strictures and tendon dysfunctions.
The reasons for self-mutilation, most commonly wrist cutting (but also autocastration, autoamputation, and autoenucleation, which are associated with psychoses), may be very different from the reasons for a suicide attempt. The initial treatment plan, however, should presume suicidal ideation, and conservative treatment should be initiated.
Sleep disturbances in the depressions are discussed below.
Milder forms of depression usually do not require drug therapy and can be managed by psychotherapy and the passage of time. In severe cases—particularly when vegetative signs are significant and symptoms have persisted for more than a few weeks—antidepressant drug therapy is often effective. Drug therapy is also suggested by a family history of major depression in first-degree relatives or a past history of prior episodes.
The antidepressant medications may be classified into four groups: (1) the newer antidepressants, including the SSRIs, SNRIs, and bupropion, vilazodone, vortioxetine, and mirtazapine, (2) the TCAs and clinically similar medications, (3) the MAO inhibitors (Table 25–7), and (4) stimulants. ECT and repetitive transcranial magnetic stimulation are procedural treatments for depression. These modalities are described in greater detail below.
Table 25–7.Commonly used antidepressants. |Favorite Table|Download (.pdf) Table 25–7. Commonly used antidepressants.
|Drug ||Usual Daily Oral Dose (mg) ||Usual Daily Maximum Dose (mg) ||Sedative Effects1 ||Anticholinergic Effects1 ||Cost per Unit ||Cost for 30 Days Treatment Based on Maximum Dosage2 |
|Citalopram (Celexa) ||20 ||40 ||< 1 ||1 ||$2.53/40 mg ||$75.90 |
|Escitalopram (Lexapro) ||10 ||20 ||< 1 ||1 ||$4.51/20 mg ||$135.30 |
|Fluoxetine (Prozac, Sarafem) ||5–40 ||80 ||< 1 ||< 1 ||$2.67/20 mg ||$320.40 |
|Fluvoxamine (Luvox) ||100–300 ||300 ||1 ||< 1 ||$2.64/100 mg ||$237.60 |
|Paroxetine (Paxil) ||20–30 ||50 ||1 ||1 ||$2.64/20 mg ||$161.10 |
|Sertraline (Zoloft) ||50–150 ||200 ||< 1 ||< 1 ||$2.85/100 mg ||$171.00 |
|Desvenlafaxine (Pristiq) ||50 ||100 ||1 ||< 1 ||$11.84/100 mg ||$355.20 |
|Duloxetine (Cymbalta) ||40 ||60 ||2 ||3 ||$5.93/60 mg ||$177.90 |
|Levomilnacipran (Fetzima) ||40 ||120 ||1 ||1 ||$11.97/80 mg ||$359.10 |
|Milnacipran (Savella) ||100 ||200 ||1 ||1 ||$5.36/100 mg ||$321.60 |
|Venlafaxine XR (Effexor) ||150–225 ||225 ||1 ||< 1 ||$4.67/75 mg ||$420.30 |
|Tricyclic and clinically similar compounds |
|Amitriptyline (Elavil) ||150–250 ||300 ||4 ||4 ||$2.14/150 mg ||$128.40 |
|Amoxapine (Asendin) ||150–200 ||400 ||2 ||2 ||$1.67/100 mg ||$200.40 |
|Clomipramine (Anafranil) ||100 ||250 ||3 ||3 ||$11.24/75 mg ||$1348.80 |
|Desipramine (Norpramin) ||100–250 ||300 ||1 ||1 ||$5.74/100 mg ||$498.60 |
|Doxepin (Sinequan) ||150–200 ||300 ||4 ||3 ||$1.79/100 mg ||$161.10 |
|Imipramine (Tofranil) ||150–200 ||300 ||3 ||3 ||$0.64/50 mg ||$115.20 |
|Maprotiline (Ludiomil) ||100–200 ||300 ||4 ||2 ||$2.34/75 mg ||$280.80 |
|Nortriptyline (Aventyl, Pamelor) ||100–150 ||150 ||2 ||2 ||$4.00/75 mg ||$240.00 |
|Protriptyline (Vivactil) ||15–40 ||60 ||1 ||3 ||$3.30/10 mg ||$594.00 |
|Trimipramine (Surmontil) ||75–200 ||200 ||4 ||4 ||$11.43/100 mg ||$685.80 |
|Monoamine oxidase inhibitors |
|Phenelzine (Nardil) ||45–60 ||90 ||… ||… ||$0.84/15 mg ||$151.20 |
|Selegiline transdermal (Emsam) ||6 (skin patch) ||12 ||… ||… ||$60.54/6 mg patch ||$1816.20 |
|Tranylcypromine (Parnate) ||20–30 ||50 ||… ||… ||$7.07/10 mg ||$1060.50 |
|Other compounds |
|Bupropion SR (Wellbutrin SR) ||300 ||4003 ||< 1 ||< 1 ||$3.59/200 mg ||$215.40 |
|Bupropion XL (Wellbutrin XL) ||3004 ||4504 ||< 1 ||< 1 ||$4.77/300 mg ||$286.20 |
|Mirtazapine (Remeron) ||15–45 ||45 ||4 ||2 ||$2.80/30 mg ||$85.53 |
|Nefazodone (Serzone) ||150-600 ||600 ||3 ||1 ||$3.99/200 mg ||$239.40 |
|Trazodone (Desyrel) ||100–300 ||400 ||4 ||< 1 ||$0.73/100 mg ||$87.60 |
|Vilazodone (Viibryd) ||10-40 ||40 ||1 ||1 ||$8.33/40 mg ||$249.90 |
|Vortioxetine (Brintellix) ||10 ||20 ||<1 ||< 1 ||$11.58/20 mg ||$347.40 |
Hospitalization is necessary if suicide is a major consideration or if complex treatment modalities are required.
Medication selection is influenced by the history of previous response or lack thereof if that information is available. A positive family history of response to a particular drug suggests that the patient may respond similarly. If no background information is available, a drug such as sertraline, 25 mg orally daily and increasing gradually up to 200 mg, or venlafaxine at 37.5 mg/day and titrated gradually to a maximum dose of 225 mg/day can be selected and a full trial instituted. The medication trial should be monitored for worsening mood or suicidal ideation with patient assessments every 1–2 weeks until week 6. In patients under 25 years of age, there is an association between antidepressant use and increased suicidality. Younger patients, therefore, should be monitored closely during the first 6–8 weeks of treatment. The STAR*D trial suggests that if the response to the first medication is inadequate, the best alternatives are to switch to a second agent that may be from the same or different class of antidepressant; another option is to try augmenting the first agent with bupropion (150–450 mg/day), lithium (eg, 300–900 mg/day orally), thyroid medication (eg, liothyronine, 25–50 mcg/day orally) or a second-generation antipsychotic (eg, aripiprazole [5–15 mg/day] or olanzapine [5–15 mg/day]). The latter course is often taken when there has been at least a partial response to the initial drug. The Agency for Health Care Policy and Research has produced clinical practice guidelines that outline one algorithm of treatment decisions (Figure 25–2).
Overview of treatment for depression. (Reproduced from Agency for Health Care Policy and Research: Depression in Primary Care. Vol. 2: Treatment of Major Depression. United States Department of Health and Human Services, 1993.)
Psychotic depression should be treated with a combination of an antipsychotic such as olanzapine and an antidepressant such as an SSRI at their usual doses. Mifepristone may have specific and early activity against psychotic depression. ECT is generally regarded as the single most effective treatment for psychotic depression.
Major depression with atypical features or seasonal onset can be treated with bupropion or an SSRI with good results. MAO inhibitors appear more effective than TCAs and an MAO inhibitor may be used if more benign antidepressant strategies prove unsuccessful.
Melancholic depression may respond to ECT, TCAs, and SNRIs, which are preferable to SSRIs. However, SSRIs are often used in the treatment of melancholic depression and are effective in many cases.
Caution: Depressed patients often have suicidal thoughts, and the amount of drug dispensed should be appropriately controlled particularly if prescribing an MAO inhibitor, TCA, and to a lesser extent, venlafaxine. At the same time, adults with untreated depression are at higher risk for suicide than those who are treated sufficiently to reduce symptoms. It has been thought that in children and adolescent populations, antidepressants may be associated with some slightly increased risk of suicidality. One meta-analysis indicates that suicidality persists even after symptoms of depression are treated suggesting other causes, such as increased impulsivity among younger patients. After age 25, antidepressants may have neutral or possibly protective effects until age 65 years or older. The older TCAs have a narrow therapeutic index. One advantage of the newer medications is their wider margin of safety. Nonetheless, even with newer agents, because of the possibility of suicidality early in antidepressant treatment, close follow-up is indicated. In all cases of pharmacologic management of depressed states, caution is indicated until the risk of suicide is considered minimal.
1. SSRIs, SNRIs, and atypical antidepressants
The SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and its enantiomer escitalopram (Table 25–7). The chief advantages of these agents are that they are generally well tolerated, the starting dose is typically a therapeutic dose for most patients, and they have much lower lethality in overdose compared to TCAs or MAO inhibitors. (Notably, citalopram carries a warning regarding QT prolongation in doses above 40 mg, and caution should be used in prescribing in patients at risk for arrhythmia. There is no similar FDA warning for escitalopram as of this writing.) The SNRIs include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. In addition to possessing the strong serotonin reuptake blocking properties of the SSRIs, the SNRIs are also norepinephrine reuptake blockers. The combined serotonergic-noradrenergic properties of these drugs may provide benefits in pain conditions such as neuropathy and fibromyalgia as well as conditions such as stress incontinence. The atypical antidepressants are bupropion, nefazodone, trazodone, vilazodone, vortioxetine, and mirtazapine (Table 25–7). All of these antidepressants are effective in the treatment of depression, both typical and atypical. The SSRI medications have been effective in the treatment of panic disorder, bulimia, GAD, OCD, and PTSD.
Most of the medications in this group tend to be activating and are given in the morning so as not to interfere with sleep. Some patients, however, may have sedation, requiring that the drug be given at bedtime. This reaction occurs most commonly with paroxetine, fluvoxamine, and mirtazapine. The SSRIs can be given in once-daily dosage. Nefazodone and trazodone are usually given twice daily. Bupropion and venlafaxine are available in extended-release formulations and can be given once daily. There is usually some delay in response; fluoxetine, for example, requires 2–6 weeks to act in depression, 4–8 weeks to be effective in panic disorder, and 6–12 weeks in treatment of OCD. The starting dose (10 mg) is given for 1 week before increasing to the average daily oral dose of 20 mg for depression, while OCD may require up to 80 mg daily. Some patients, particularly the elderly, may tolerate and benefit from as little as 10 mg/day or every other day. The other SSRIs have shorter half-lives and a lesser effect on hepatic enzymes, which reduces their impact on the metabolism of other medications (thus not increasing significantly the serum concentrations of other medications as much as fluoxetine). The shorter half-lives also allow for more rapid clearing if adverse side effects appear. Venlafaxine appears to be more effective with doses greater than 200 mg/day orally, although some individuals respond to doses as low as 75 mg/day.
The side effects common to all of these medications are headache, nausea, tinnitus, insomnia, and nervousness. Akathisia has been common with the SSRIs; other extrapyramidal symptoms (eg, dystonias) have occurred infrequently but particularly in withdrawal states. Because SSRIs affect platelet serotonin levels, abnormal bleeding can occur. Sertraline and citalopram appear to be the safest agents in this class when used with warfarin. Sexual side effects of erectile dysfunction, retrograde ejaculation, and dysorgasmia are very common with the SSRIs. Oral phosphodiesterase-5 inhibitors (such as sildenafil, 25–50 mg; tadalafil, 5-20 mg; or vardenafil, 10–20 mg taken 1 hour prior to sexual activity) can improve erectile dysfunction in some patients and have been shown to improve other SSRI-induced sexual dysfunction in both men and women. Adjunctive bupropion (75–150 mg orally daily) may also enhance sexual arousal. Cyproheptadine, 4 mg orally prior to sexual activity, may be helpful in countering drug-induced anorgasmia but also is quite sedating and may counter the therapeutic benefits of SSRIs as well. The SSRIs are strong serotonin uptake blockers and may in high dosage or in combination with MAO inhibitors, including the antiparkinsonian drug selegiline, cause a “serotonin syndrome.” This syndrome is manifested by rigidity, hyperthermia, autonomic instability, myoclonus, confusion, delirium, and coma. This syndrome can be a particularly troublesome problem in the elderly. Research indicates that SSRIs are safer agents to use than TCAs in patients with cardiac disease; the SSRI sertraline is a safe and effective antidepressant treatment in patients with acute myocardial infarction or unstable angina.
Withdrawal symptoms, including dizziness, paresthesias, dysphoric mood, agitation, and a flu-like state, have been reported for the shorter-acting SSRIs and SNRIs but may occur with other classes including the TCAs and MAO inhibitors. These medications should be discontinued gradually over a period of weeks or months to reduce the risk of withdrawal phenomena.
Fluoxetine, fluvoxamine, sertraline, venlafaxine, and citalopram in customary antidepressant doses may increase the risk of major fetal malformation when used during pregnancy; however, the absolute risk of congenital defects is considered low. In one study, fetal exposure to SSRIs has been associated with delayed gross motor development at 6 months. Studies regarding the risk of persistent pulmonary hypertension in the newborns of mothers taking SSRIs remain inconclusive. Postpartum developmental effects of antidepressants have been thought to be minimal, however, this question calls for ongoing investigation. In addition, it is clear that untreated depression in the mother also can contribute substantially to deficits in the verbal, intellectual and motor development of a newborn. Peripartum effects may be a concern and are documented anecdotally in the literature. Maternal major mood disorder in pregnancy by itself carries its own risks to the mother and fetus and has been linked to low birth weight and preterm delivery. Postpartum effects of prenatal depression have not been studied. The decision to use SSRIs and other psychotropic agents during pregnancy and postpartum must be a collaborative decision based on a thorough risk-benefit analysis for each individual.
Venlafaxine lacks significant anticholinergic side effects. Nausea, nervousness, and profuse sweating appear to be the major side effects. Venlafaxine appears to have few drug-drug interactions. It does require monitoring of blood pressure because dose-related hypertension may develop in some individuals. Venlafaxine prescribing in the United Kingdom has been restricted to psychiatrists. Venlafaxine appears to carry a greater risk of lethal arrhythmias in instances of overdose relative to the SSRIs, but less risk than with the TCAs. Desvenlafaxine, a newer form of the drug, is started at its target dose of 50 mg/day orally and does not require upward titration although higher doses have been well studied and some patients benefit from 100 mg/day. Duloxetine may also result in small increases in blood pressure. Common side effects include dry mouth, dizziness, and fatigue. Inhibitors of 1A2 and 2D6 may increase duloxetine levels with a risk of toxicity. Milnacipran, approved for the treatment of fibromyalgia, and levomilnacipran, approved for the treatment of major depression, carry many of the side effects common to other SNRIs including a mild tachycardia, hypertension, sexual side effects, mydriasis, urinary constriction, and occasional abnormal bleeding. Levomilnacipran is started at 20 mg/day orally then increased to 40 mg/day after 2–3 days. The target dose is 40–120 mg given once daily. Milnacipran is typically started at 12.5 mg/day orally, titrated to 12.5 mg twice daily after 2 days, and then to 25 mg twice daily after 7 days. The target dose is typically 100–200 mg/day given in in two divided doses. While not approved for the treatment of major depression, the evidence suggests that milnacipran, like levomilnacipran, is an effective antidepressant agent.
Nefazodone appears to lack the anticholinergic effects of the TCAs and the agitation sometimes induced by SSRIs. Nefazodone should not be given with terfenadine, astemizole, or cisapride, which are not commercially available in the United States. Because nefazodone inhibits the liver’s cytochrome P450 3A4 isoenzymes, concurrent use of these medications can lead to serious QT prolongation, ventricular tachycardia, or death. Through the same mechanism of enzyme inhibition, nefazodone can elevate cyclosporine levels sixfold to tenfold. Nefazodone carries an FDA warning given its association with liver failure in rare cases. Pretreatment and ongoing monitoring of liver enzymes are indicated.
Mirtazapine is thought to enhance central noradrenergic and serotonergic activity with minimal sexual side effects compared with the SSRIs. Its action as a potent antagonist of histaminergic receptors may make it a useful agent for patients with depression and insomnia. It is also an effective antiemetic due to its antagonism of the 5-HT3 receptor. Its most common adverse side effects include somnolence, increased appetite, weight gain, lipid abnormalities, and dizziness. The labeling for mirtazapine indicated that agranulocytosis was seen in 2 of 2796 patients in premarketing studies. Since 2004, a few case reports have linked mirtazapine to neutropenia. However, given the widespread use of mirtazapine over the past 10 years, the association of agranulocytosis or a clinically significant neutropenia with the drug appears to be modest. Although it is metabolized by P450 isoenzymes, it is not an inhibitor of this system. It is given in a single oral dose at bedtime starting at 15 mg and increasing in 15-mg increments every week or every other week up to 45 mg.
Vortioxetine is a newer antidepressant that blocks serotonin reuptake, is a partial agonist of the 5-HT1A receptor, and effects a variety of other serotonin receptor sites. The side effects attributed to its serotonergic effects include gastrointestinal upset and sexual dysfunction. Vortioxetine has demonstrated efficacy in improving cognitive symptoms of depression and received regulatory approval for this indication in Europe. Vortioxetine is typically dosed at 10 mg/day orally and may be increased to 20 mg/day.
2. Tricyclic antidepressants (TCAs) and clinically similar medications
TCAs were the mainstay of drug therapy for depression for many years. They have also been effective in panic disorder, pain syndromes, and anxiety states. Specific ones have been effective in OCD (clomipramine), enuresis (imipramine), psychotic depression (amoxapine), and reduction of craving in cocaine withdrawal (desipramine).
TCAs are characterized more by their similarities than by their differences. They tend to affect both serotonin and norepinephrine reuptake; some medications act mainly on the former and others principally on the latter neurotransmitter system. Individuals receiving the same dosages vary markedly in therapeutic drug levels achieved (elderly patients require smaller doses), and determination of plasma drug levels is helpful when clinical response has been disappointing. Nortriptyline is usually effective when plasma levels are between 50 and 150 ng/mL; imipramine at plasma levels of 200–250 ng/mL; and desipramine at plasma levels of 100–250 ng/mL. High blood levels are not more effective than moderate levels and may be counterproductive (eg, delirium, seizures). Patients with gastrointestinal side effects benefit from plasma level monitoring to assess absorption of the drug. Most TCAs can be given in a single dose at bedtime, starting at fairly low doses (eg, nortriptyline 25 mg orally) and increasing by 25 mg every several days as tolerated until the therapeutic response is achieved (eg, nortriptyline, 100–150 mg) or to maximum dose if necessary (eg, nortriptyline, 150 mg). The most common cause of treatment failure is an inadequate trial. A full trial consists of giving a therapeutic daily dosage for at least 6 weeks. Because of marked anticholinergic and sedating side effects, clomipramine is started at a low dose (25 mg/day orally) and increased slowly in divided doses up to 100 mg/day, held at that level for several days, and then gradually increased as necessary up to 250 mg/day. Any of the TCA-like medications should be started at very low doses (eg, 10–25 mg/day) and increased slowly in the treatment of panic disorder.
The TCAs have anticholinergic side effects to varying degrees (amitriptyline 100 mg is equivalent to atropine 5 mg). One must be particularly wary of the effect in elderly men with prostatic hyperplasia. The anticholinergic effects also predispose to other medical problems such as constipation, confusion, heat stroke, or dental problems from xerostomia. Orthostatic hypotension is fairly common, is not dose-dependent and may not remit with time on medication; this may predispose to falls and hip fractures in the elderly. Cardiac effects of the TCAs are functions of the anticholinergic effect, direct myocardial depression, quinidine-like effect, and interference with adrenergic neurons. These factors may produce altered rate, rhythm, and contractility, particularly in patients with preexisting cardiac disease, such as bundle-branch or bifascicular block. Even relatively small overdoses (eg, 1500 mg of imipramine) have resulted in lethal arrhythmias. Electrocardiographic changes range from benign ST segment and T wave changes and sinus tachycardia to a variety of complex and serious arrhythmias, the latter requiring a change in medication. Because TCAs have class I antiarrhythmic effects, they should be used with caution in patients with ischemic heart disease, arrhythmias, or conduction disturbances. SSRIs or the atypical antidepressants are better initial choices for this population. TCAs lower the seizure threshold so this is of particular concern in patients with a propensity for seizures. Loss of libido and erectile, ejaculatory, and orgasmic dysfunction are fairly common and can compromise compliance. Trazodone rarely causes priapism (1 in 9000), but when it occurs, it requires treatment within 12 hours (epinephrine 1:1000 injected into the corpus cavernosum). Delirium, agitation, and mania are infrequent complications of the TCAs but can occur. Sudden discontinuation of some of these medications can produce “cholinergic rebound,” manifested by headaches and nausea with abdominal cramps. Overdoses of TCAs are often serious because of the narrow therapeutic index and quinidine-like effects (see Chapter 38).
3. Monoamine oxidase inhibitors
The MAO inhibitors are generally used as third-line medications for depression (after a failure of SSRIs, SNRIs, TCAs, or the atypical antidepressants) because of the dietary and other restrictions required (Table 25–8). They should be considered third-line medications for refractory panic disorder as well as depression; however, this hierarchy has become more flexible since MAO inhibitor skin patches (selegiline) have become available. They deliver the MAO inhibitor to the bloodstream bypassing the gastrointestinal tract so that dietary restrictions are not necessary in the lowest dosage strength (6 mg/24 h).
Table 25–8.Principal dietary restrictions in MAOI use. |Favorite Table|Download (.pdf) Table 25–8. Principal dietary restrictions in MAOI use.
Cheese, except cream cheese and cottage cheese and fresh yogurt
Fermented or aged meats such as bologna, salami
Broad bean pods such as Chinese bean pods
Liver of all types
Meat and yeast extracts
Red wine, sherry, vermouth, cognac, beer, ale
Soy sauce, shrimp paste, sauerkraut
Oral MAO inhibitors are administered in gradual stepwise dosage and may be given in the morning or evening, depending upon their effect on sleep. They tend to take effect in a fairly low dosage range (Table 25–7). Blood levels are not congruent with therapeutic response.
The MAO inhibitors commonly cause symptoms of orthostatic hypotension (which may persist) and sympathomimetic effects of tachycardia, sweating, and tremor. Nausea, insomnia (often associated with intense afternoon drowsiness), and sexual dysfunction are common. Zolpidem 5–10 mg orally at bedtime can ameliorate MAO-induced insomnia. Central nervous system effects include agitation and toxic psychoses. Dietary limitations (see Table 25–8) and abstinence from drug products containing phenylpropanolamine, phenylephrine, meperidine, dextromethorphan, and pseudoephedrine are mandatory for MAO-A type inhibitors (those marketed for treatment of depression), since the reduction of available MAO leaves the patient vulnerable to exogenous amines (eg, tyramine in foodstuffs).
Treatment for a resultant hypertensive crisis has been the same as for pheochromocytoma (see Chapter 26), but there have been reports of success with nifedipine, 10 mg chewed and placed under the tongue, normalizing blood pressure in 1–5 minutes. The restrictions on the proscribed foodstuffs and sympathomimetic medications are in effect during treatment and for 2–3 weeks after cessation of therapy. Termination of therapy with MAO inhibitors may be associated with anxiety, agitation, cognitive slowing, and headache. Very gradual withdrawal and short-term benzodiazepine therapy will ameliorate symptoms.
Dextroamphetamine (5–30 mg/day orally) and methylphenidate (10–45 mg/day orally) may be effective for the short-term treatment of some depressive symptoms in medically ill and geriatric patients. The stimulants are notable for rapid onset of action (hours) and a paucity of side effects (tachycardia, agitation) in most patients. They are usually given in two divided doses early in the day (eg, 7 am and noon) so as to avoid interfering with sleep. These agents may also be useful as adjunctive agents in refractory depression. Ketamine infusion has been shown to lead to a rapid improvement in depressive symptoms in some patients; however, effects of a single treatment are short-lived (about 3–7 days). Ketamine and other NMDA antagonists continue to be evaluated in the treatment of resistant depression.
5. Switching and combination therapy
If the therapeutic response has been poor after an adequate trial with the chosen drug, the diagnosis should be reassessed. Assuming that the trial has been adequate and the diagnosis is correct, a trial with a second drug is appropriate. In switching from one group to another, an adequate “washout time” must be allowed. This is critical in certain situations—eg, in switching from an MAO inhibitor to a TCA, allow 2–3 weeks between stopping one drug and starting another; in switching from an SSRI to an MAO inhibitor, allow 4–5 weeks for fluoxetine and at least 2 weeks for other SSRIs. In switching within groups—eg, from one TCA to another (amitriptyline to desipramine, etc)—no washout time is needed, and one can rapidly decrease the dosage of one drug while increasing the other. In clinical practice, adjunctive treatment with lithium, buspirone, or thyroid hormone may be helpful in depression. The adjunctive use of low-dose atypical antipsychotics such as aripiprazole, olanzapine, and quetiapine in the treatment of patients with refractory depression is supported by research. The side effect risk is the same as when treating psychosis. Monotherapy with aripiprazole or quetiapine is FDA approved for this purpose as well as the combination of fluoxetine and olanzapine. Adding an atypical agent requires monitoring body mass index, lipids, and glucose. Combining two antidepressants, or adding an antipsychotic to an antidepressant, requires caution and is usually reserved for clinicians who feel comfortable managing this or after psychiatric consultation.
6. Maintenance and tapering
When clinical relief of symptoms is obtained, medication is continued for 12 months in the effective maintenance dosage, which is the dosage required in the acute stage. The full dosage should be continued indefinitely when the individual has a first episode before age 20 or after age 50, is over age 40 with two episodes, at least one episode after age 50, or has had three episodes at any age. Major depression should often be considered a chronic disease. If the medication is being tapered, it should be done gradually over several months, monitoring closely for relapse.
Interactions with other medications are listed in Table 25–9.
Table 25–9.Antidepressant drug interactions with other medications. |Favorite Table|Download (.pdf) Table 25–9. Antidepressant drug interactions with other medications.
|Drug ||Effects |
|Tricyclic and other non-MAOI antidepressants |
|Antacids ||Decreased absorption of antidepressants |
|Anticoagulants ||Increased hypoprothrombinemic effect |
|Cimetidine ||Increased antidepressant blood levels and psychosis |
|Clonidine ||Decreased antihypertensive effect |
|Digitalis ||Increased incidence of heart block |
|Disulfiram ||Increased antidepressant blood levels |
|Haloperidol ||Increased antidepressant levels |
|Insulin ||Decreased blood sugar |
|Lithium ||Increased lithium levels with fluoxetine |
|Methyldopa ||Decreased antihypertensive effect |
|Other anticholinergic medications ||Marked anticholinergic responses |
|Phenytoin ||Increased blood levels |
|Procainamide ||Decreased ventricular conduction |
|Procarbazine ||Hypertensive crisis |
|Propranolol ||Increased hypotension |
|Quinidine ||Decreased ventricular conduction |
|Rauwolfia derivatives ||Increased stimulation |
|Sedatives ||Increased sedation |
|Sympathomimetic medications ||Increased vasopressor effect |
|Terfenadine,1 astemizole,1 cisapride1 ||Torsades de pointes |
|Antihistamines ||Increased sedation |
|Belladonna-like medications ||Increased blood pressure |
|Dextromethorphan ||Same as meperidine |
|Guanethidine ||Decreased blood pressure |
|Insulin ||Decreased blood sugar |
|Levodopa ||Increased blood pressure |
|Meperidine ||Increased agitation, serotonin syndrome, death |
|Methyldopa ||Decreased blood pressure |
|Pseudoephedrine ||Hypertensive crisis (increased blood pressure) |
|Reserpine ||Increased blood pressure and temperature |
|Succinylcholine ||Increased neuromuscular blockade |
|Sulfonylureas ||Decreased blood sugar |
|Sympathomimetic medications ||Increased blood pressure/hypertensive crisis |
|SSRIs, SNRIs, triptans ||Serotonin syndrome, death |
8. Electroconvulsive therapy
ECT causes a generalized central nervous system seizure (peripheral convulsion is not necessary) by means of electric current. The key objective is to exceed the seizure threshold, which can be accomplished by a variety of means. The mechanism of action is not known, but it is thought to involve major neurotransmitter responses at the cell membrane. Electrical current insufficient to cause a seizure produces no therapeutic benefit.
ECT is the most effective (about 70–85%) treatment of severe depression—particularly the delusions and agitation commonly seen with depression in the elderly. It is indicated when medical conditions preclude the use of antidepressants, nonresponsiveness to these medications, and extreme suicidality. Comparative controlled studies of ECT in severe depression show that it is more effective than pharmacotherapy. It is also effective in the treatment of mania and psychoses during pregnancy (when medications may be contraindicated). It has not been shown to be helpful in chronic schizophrenic disorders, and it is generally not used in acute schizophrenic episodes unless medications are not effective and it is urgent that the psychosis be controlled (eg, a catatonic stupor complicating an acute medical condition).
The most common side effects are memory disturbance and headache. Memory loss or confusion is usually related to the number and frequency of ECT treatments and proper oxygenation during treatment. Unilateral ECT is associated with less memory loss than bilateral ECT. Both anterograde and retrograde memory loss may occur, but short term-retrograde memory loss is more common. While some memory deficits may persist, memory loss tends to improve in a few weeks after the last ECT treatment. There have been reports that lithium administration concurrent with ECT resulted in greater memory loss.
Increased intracranial pressure is a relative contraindication. Other problems such as cardiac disorders, aortic aneurysms, bronchopulmonary disease, and venous thrombosis must be evaluated in light of the severity of the medical problem versus the need for ECT. Serious complications arising from ECT occur in less than 1 in 1000 cases. Most of these problems are cardiovascular or respiratory in nature (eg, aspiration of gastric contents, arrhythmias, myocardial infarction). Poor patient understanding and lack of acceptance of the technique by the public are the biggest obstacles to the use of ECT.
Phototherapy is used in major depression with seasonal onset. It consists of exposure to a light source of greater than 2500 lux for 2 hours daily to increase the photoperiod of the day. Light visors are an adaptation that provides greater mobility and an adjustable light intensity but may not be as effective. The dosage varies, with some patients requiring morning and night exposure. One effect is alteration of biorhythm through melatonin mechanisms.
Transcranial magnetic stimulation appears to be effective in nonpsychotic depression and involves the application of electromagnetic pulses to the dorslolateral prefrontal cortex. Its use in depression is approved by the FDA for individuals who have not tolerated or responded to standard medications. It is usually delivered in a course of 20–30 sessions over 4–6 weeks. While not as effective as ECT, transcranial magnetic stimulation neither requires general anesthesia nor is it associated with cognitive side effects. Vagus nerve stimulation has shown promise in about one-third of extremely refractory cases and is approved by the FDA but has not been approved by many insurers. Deep brain stimulation continues to be explored for the treatment of refractory depression but controlled studies have not shown success to date.
It is seldom possible to engage an individual in penetrating psychotherapeutic endeavors during the acute stage of a severe depression. While medications may be taking effect, a supportive approach to strengthen existing coping mechanisms and appropriate consideration of the patient’s continuing need to function at work, to engage in recreational activities, etc, are necessary as the severity of the depression lessens. If the patient is not seriously depressed, it is often appropriate to initiate intensive psychotherapeutic efforts, since flux periods are a good time to effect change. A catharsis of repressed anger and guilt may be beneficial. Therapy during or just after the acute stage may focus on coping techniques, with some practice of alternative choices. Depression-specific psychotherapies help improve self-esteem, increase assertiveness, and lessen dependency. Interpersonal psychotherapy for depression has shown efficacy in the treatment of acute depression, helping patients master interpersonal stresses and develop new coping strategies. Cognitive behavioral therapy for depression addresses patients’ patterns of negative thoughts, called cognitive distortions, which lead to feelings of depression and anxiety. Treatment usually includes homework assignments such as keeping a journal of cognitive distortions and of positive responses to them. The combination of drug therapy plus interpersonal psychotherapy or cognitive behavioral therapy is generally more effective than either modality alone. It is usually helpful to involve the spouse or other significant family members early in treatment. Mindfulness-based cognitive therapy has reduced relapse rates in several randomized controlled trials. In two studies, it was as effective as maintenance medication in preventing relapse. This therapy incorporates meditation and teaches patients to distance themselves from depressive thinking. It may be a preferable alternative for individuals who wish to have an alternative to long-term medications to stay free of depressive episodes.
Flexible use of appropriate social services can be of major importance in the treatment of depression. Since alcohol abuse is often associated with depression, early involvement in alcohol treatment programs such as Alcoholics Anonymous can be important to future success (see Alcohol Use Disorder [Alcoholism]). The structuring of daily activities during severe depression is often quite difficult for the patient, and loneliness is often a major factor. The help of family, employer, or friends is often necessary to mobilize the patient who experiences no joy in daily activities and tends to remain uninvolved and to deteriorate. Insistence on sharing activities will help involve the patient in simple but important daily functions. In some severe cases, the use of day treatment centers or support groups of a specific type (eg, mastectomy groups) is indicated. It is not unusual for a patient to have multiple legal, financial, and vocational problems requiring legal and vocational assistance.
When depression is a function of self-defeating coping techniques such as passivity, the role-playing approach can be useful. Behavioral techniques, including desensitization, may be used in problems such as phobias where depression is a by-product. When depression is a regularly used interpersonal style, behavioral counseling to family members or others can help in extinguishing the behavior in the patient. Behavioral activation, a technique of motivating depressed patients to begin engaging in pleasurable activities, has been shown to be a useful depression-specific psychotherapy.
Acute manic or hypomanic symptoms will respond to lithium or valproic acid after several days of treatment, but it is increasingly common to use second-generation antipsychotics as first-line agents. The antipsychotics act more rapidly than agents such as lithium or valproate and do not require serum level monitoring. High-potency benzodiazepines (eg, clonazepam) may also be useful adjuncts in managing the agitation and sleep disturbance that are features of manic and hypomanic episodes. Some schizoaffective disorders and some cases of so-called schizophrenia are probably atypical bipolar affective disorder, for which lithium treatment may be effective.
Acute manic symptoms may be treated initially with a second-generation antipsychotic such as olanzapine, (eg, 5–20 mg orally), risperidone (2–3 mg orally), or aripiprazole (15–30 mg) in conjunction with a benzodiazepine if indicated. All of the available oral second-generation antipsychotics and many of the first-generation agents appear to be more rapidly effective in the management of acute mania than are mood stabilizers such as lithium or valproate. Alternatively, when behavioral control is immediately necessary, olanzapine in an injectable form (2.5–10 mg intramuscularly) or haloperidol, 5–10 mg orally or intramuscularly repeated as needed until symptoms subside, may be used. The dosage of the antipsychotic may be gradually reduced after lithium or another mood stabilizer is started. Olanzapine, quetiapine, and aripiprazole are approved as maintenance treatments for bipolar disorder to prevent subsequent cycles of both mania and depression.
Valproic acid (divalproex) is a first-line treatment for mania because it has a broader index of safety than lithium. This issue is particularly important in AIDS or other medically ill patients prone to dehydration or malabsorption with wide swings in serum lithium levels. Valproic acid has also been used effectively in panic disorder and migraine headache. Treatment is often started at a dose of 750 mg/day orally in divided doses, and dosage is then titrated to achieve therapeutic serum levels. Oral loading in acutely manic bipolar patients in an inpatient setting (initiated at a dosage of 20 mg/kg/day) can safely achieve serum therapeutic levels in 2–3 days. Concomitant use of aspirin may increase valproate levels, carbamazepine or phenytoin may decrease valproate levels, while warfarin levels may be elevated by valproate. Gastrointestinal symptoms and weight gain are the main side effects. Liver function tests, complete blood counts, glucose levels, and weight should be monitored at 2 weeks, 4 weeks, and at 3 months initially and annually or more frequently thereafter based on clinical judgment. Significant teratogenic effects are a concern so pregnancy should be ruled out prior to initiation. In utero exposure to valproate has been associated with adversely affecting intellectual development in the fetus and there is an FDA warning to that effect. Thus, alternatives to valproate should be considered in women of childbearing years who might become pregnant.
As a prophylactic drug for bipolar affective disorder, lithium significantly decreases the frequency and severity of both manic and depressive attacks in about 50–70% of patients. Lithium appears to work best in patients with classic bipolar I disorder. Antipsychotics, valproate, lamotrigine, and carbamazepine may be more effective than lithium in the management of rapid cycling and mixed episodes. A positive response to lithium is more predictable if the patient has a low frequency of episodes (no more than two per year with intervals free of psychopathology). A positive response occurs more frequently in individuals who have blood relatives with a diagnosis of manic or hypomanic episodes.
In addition to its use in manic states, lithium is sometimes useful in the prophylaxis of recurrent unipolar depressions (perhaps undiagnosed bipolar disorder). Lithium may ameliorate nonspecific aggressive behaviors and dyscontrol syndromes. The dosages are the same as used in bipolar disorder. Most patients with bipolar disease can be managed long-term with lithium alone, although some will require continued or intermittent use of an antipsychotic, antidepressant, or carbamazepine. An excellent resource for information is the Lithium Information Center, Madison Institute of Medicine, 7617 Mineral Point Road, Suite 300, Madison, WI 53717-1914, http://www.miminc.org/aboutlithinfoctr.html.
Before treatment, the clinical workup should include a medical history and physical examination; complete blood count; T4, thyroid-stimulating hormone, blood urea nitrogen (BUN), serum creatinine, and serum electrolyte determinations; urinalysis; and electrocardiography (in patients over age 45 or with a history of cardiac disease). Compliance with lithium therapy is adversely affected by the loss of some hypomanic experiences valued by the patient. These include social extroversion and a sense of heightened enjoyment in many activities such as sex and business dealings, often with increased productivity in the latter.
The common starting dosage of lithium carbonate is 300 mg orally two or three times daily, with trough blood levels measured after 5 days of treatment. In a small minority of patients, a slow release form or units of different dosage may be required. Lithium citrate is available as a syrup. The dosage is that required to maintain blood levels in the therapeutic range. For acute attacks, this ranges from 1 to 1.5 mEq/L. Although there is controversy about the optimal long-term maintenance dose, many clinicians reduce the acute level to 0.6–1 mEq/L in order to reduce side effects. The dose required to meet this need will vary in different individuals. For acute mania, doses of 1200–1800 mg/day are generally recommended. Augmentation of antidepressants is usually achieved with half of these doses. Once-a-day dosage is acceptable, but most patients have less nausea when they take the drug in divided doses with meals.
Lithium is readily absorbed, with peak serum levels occurring within 1–3 hours and complete absorption in 8 hours. Half of the total body lithium is excreted in 18–24 hours (95% in the urine). Blood for lithium levels should be drawn 12 hours after the last dose. Serum levels should be measured 5–7 days after initiation of treatment and changes in dose. For maintenance treatment, lithium levels should be monitored initially every 1–2 months but may be measured every 6–12 months in stable, long-term patients. Levels should be monitored more closely when there is any condition that causes volume depletion (eg, diarrhea, dehydration, use of diuretics).
Early side effects include mild gastrointestinal symptoms (take lithium with food and in divided doses), fine tremors (treat with propranolol, 20–60 mg/day orally, only if persistent), slight muscle weakness, and some degree of somnolence can occur and are usually transient. Moderate polyuria (reduced renal responsiveness to ADH) and polydipsia (associated with increased plasma renin concentration) are often present. Potassium administration can blunt this effect, as may once-daily dosing of lithium. Weight gain (often a result of calories in fluids taken for polydipsia) and leukocytosis not due to infection are fairly common.
Thyroid side effects include goiter (3%; often euthyroid) and hypothyroidism (10%; concomitant administration of lithium and iodide or lithium and carbamazepine enhances the hypothyroid and goitrogenic effect of either drug). Most clinicians treat lithium-induced hypothyroidism (more common in women) with thyroid hormone while continuing lithium therapy. Changes in the glucose tolerance test toward a diabetes-like curve, nephrogenic diabetes insipidus (usually resolving about 8 weeks after cessation of lithium therapy), nephrotic syndrome, edema, folate deficiency, and pseudotumor cerebri (ophthalmoscopy is indicated if there are complaints of headache or blurred vision) can occur. A metallic taste, hair loss, and Raynaud phenomenon have been reported in a few cases. Thyroid and kidney function should be checked at 4- to 6-month intervals. Hypercalcemia and elevated parathyroid hormone levels occur in some patients. Electrocardiographic abnormalities (principally T wave flattening or inversion) may occur during lithium administration but are not of major clinical significance. Sinoatrial block may occur, particularly in the elderly. Other medications that prolong intraventricular conduction, such as TCAs, must be used cautiously in conjunction with lithium. Lithium impairs ventilatory function in patients with airway obstruction. Lithium alone does not have a significant effect on sexual function, but when combined with benzodiazepines (clonazepam in most symptomatic patients) it causes sexual dysfunction in about 50% of men. Lithium may precipitate or exacerbate psoriasis in some patients. Most of these side effects subside when lithium is discontinued; when residual side effects exist, they are usually not serious.
Side effects from long-term lithium therapy include the development of cogwheel rigidity and, occasionally, other extrapyramidal signs. Lithium potentiates the parkinsonian effects of haloperidol. Long-term lithium therapy has also been associated with a relative lowering of the level of memory and perceptual processing (affecting compliance in some cases). Some impairment of attention and emotional reactivity has also been noted. Lithium-induced delirium with therapeutic lithium levels is an infrequent complication usually occurring in the elderly and may persist for several days after serum levels have become negligible. Encephalopathy has occurred in patients receiving combined lithium and antipsychotic therapy and in those who have cerebrovascular disease, thus requiring careful evaluation of patients who develop neurotoxic signs at subtoxic blood levels.
Some reports have suggested that the long-term use of lithium may have adverse effects on kidney function (with interstitial fibrosis, tubular atrophy, or nephrogenic diabetes insipidus). Persistent polyuria should require an investigation of the kidney’s ability to concentrate urine. A rise in serum creatinine levels is an indication for in-depth evaluation of kidney function and consideration of alternative treatments if the individual can tolerate a change. Incontinence has been reported in women, apparently related to changes in bladder cholinergic-adrenergic balance.
Prospective studies suggest that the overall risk imposed by lithium in pregnancy may be overemphasized. However, lithium exposure in early pregnancy does increase the frequency of congenital anomalies, especially Ebstein and other major cardiovascular anomalies. For women who take psychotropic medications who become pregnant, the decision to make a change in medication is complex and requires informed consent regarding the relative risks to the patient and fetus. Indeed, the risk of untreated bipolar disorder carries its own risks for pregnancy. Formula feeding should be considered in mothers taking lithium, since concentration in breast milk is one-third to half that in serum.
Frank toxicity usually occurs at blood lithium levels greater than 2 mEq/L. Because sodium and lithium are reabsorbed at the same loci in the proximal renal tubules, any sodium loss (diarrhea, use of diuretics, or excessive perspiration) results in increased lithium levels. Symptoms and signs include vomiting and diarrhea, the latter exacerbating the problem since more sodium is lost and more lithium is absorbed. Other symptoms and signs, some of which may not be reversible, include tremors, marked muscle weakness, confusion, dysarthria, vertigo, choreoathetosis, ataxia, hyperreflexia, rigidity, lack of coordination, myoclonus, seizures, opisthotonos, and coma. Toxicity is more severe in the elderly, who should be maintained on slightly lower serum levels. Lithium overdosage may be accidental or intentional or may occur as a result of poor monitoring. Significant overdoses of lithium are typically managed with hemodialysis since the drug is excreted completely by the kidneys.
See Chapter 38 for the treatment of patients with massive ingestions of lithium or blood lithium levels greater than 2.5 mEq/L.
Patients receiving lithium should use diuretics with caution and only under close medical supervision. The thiazide diuretics cause increased lithium reabsorption from the proximal renal tubules, resulting in increased serum lithium levels (Table 25–10), and adjustment of lithium intake must be made to compensate for this. Reduce lithium dosage by 25–40% when the patient is receiving 50 mg of hydrochlorothiazide daily. Potassium-sparing diuretics (spironolactone, amiloride, triamterene) may also increase serum lithium levels and require careful monitoring of lithium levels. Loop diuretics (furosemide, ethacrynic acid, bumetanide) do not appear to alter serum lithium levels. Concurrent use of lithium and angiotensin-converting enzyme inhibitors requires a 50–75% reduction in lithium intake.
Table 25–10.Lithium interactions with other medications.
Carbamazepine is used in the treatment of bipolar patients who cannot be satisfactorily treated with lithium (nonresponsive, excessive side effects, or rapid cycling). It is often effective at 800–1600 mg/day orally. It has also been used in the treatment of trigeminal neuralgias and alcohol withdrawal as well as in patients with behavioral dyscontrol. It suppresses some phases of kindling (see Stimulants) and has been used to treat residual symptoms in previous stimulant abusers (eg, PTSD with impulse control problems). Dose-related side effects include sedation and ataxia. Dosages start at 400–600 mg orally daily and are increased slowly to therapeutic levels. Skin rashes and a mild reduction in white count are common. SIADH occurs rarely. Nonsteroidal anti-inflammatory medications (except aspirin), the antibiotics erythromycin and isoniazid, the calcium channel blockers verapamil and diltiazem (but not nifedipine), fluoxetine, propoxyphene, and cimetidine all increase carbamazepine levels. Carbamazepine can be effective in conjunction with lithium, although there have been reports of reversible neurotoxicity with the combination. Carbamazepine stimulates hepatic microsomal enzymes and so tends to decrease levels of haloperidol and oral contraceptives. It also lowers T4, free T4, and T3 levels. Cases of fetal malformation (particularly spina bifida) have been reported along with growth deficiency and developmental delay. Liver tests and complete blood counts should be monitored in patients taking carbamazepine. Genetic studies suggest that screening for the HLA-B1502 allele in the Han Chinese population and the HLA-A3101 allele in northern Europeans may help target individuals more susceptible to a serious rash. Oxcarbazepine, a derivative of carbamazepine, does not appear to induce its own metabolism and is associated with fewer drug interactions, although it may impose a higher risk of hyponatremia. FDA-approved for partial seizures, oxcarbazepine may have efficacy in acute mania. It appears to be a safer alternative to carbamazepine due to its lower risk of hepatotoxicity.
Lamotrigine is thought to inhibit neuronal sodium channels and the release of the excitatory amino acids, glutamate and aspartate. It is FDA approved for the maintenance treatment of bipolar disorder. Two double-blind studies support its efficacy in the treatment of acute bipolar depression as adjunctive therapy or as monotherapy but several other controlled studies failed to demonstrate benefit. Likewise, lamotrigine has not proven effective in the management of acute mania. Its metabolism is inhibited by coadministration of valproic acid—doubling its half-life—and accelerated by hepatic enzyme-inducing agents such as carbamazepine. More frequent mild side effects include headache, dizziness, nausea, and diplopia. Rash occurring in 10% of patients is an indication for immediate cessation of dosing, since lamotrigine has been associated with Stevens-Johnson syndrome (1:1000) and, rarely, toxic epidermal necrolysis. Dosing starts at 25–50 mg/day orally and is titrated upward slowly to decrease the likelihood of rash. Slower titration and a lower total dose are indicated for patients taking valproic acid.
Most depressive episodes are usually time-limited, and the prognosis with treatment is good if a pathologic pattern of adjustment does not intervene. Major affective disorders frequently respond well to a full trial of drug treatment. However, at least 20% of patients will have a more chronic illness lasting 2 or more years. Many patients do not sustain a complete remission of symptoms and most depressive episodes recur. At least 80% of patients who have a single major depressive episode will have one or more recurrences within 15 years of the index episode. Many patients, therefore, require long-term maintenance therapy with antidepressants.
Mania has a good prognosis with adequate treatment, although patient adherence to treatment is often quite challenging. Few effective treatments exist for bipolar depression, which include quetiapine, lurasidone, and the combination of fluoxetine and olanzapine. Most patients with bipolar disorder require treatment with two or more medications such as lithium, antipsychotics and sleeping agents. Breakthrough manic or depressive episodes are common, even with adherence to maintenance treatments, although maintenance therapy lessens the risk of recurrent episodes.
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Sleep consists of two distinct states as shown by electroencephalographic studies: (1) REM (rapid eye movement) sleep, also called dream sleep, D state sleep, paradoxic sleep, and (2) NREM (non-REM) sleep, also called S stage sleep, which is divided into stages 1, 2, 3, and 4 and is recognizable by different electroencephalographic patterns. Stages 3 and 4 are “delta” sleep. Dreaming occurs mostly in REM and to a lesser extent in NREM sleep.
Sleep is a cyclic phenomenon, with four or five REM periods during the night accounting for about one-fourth of the total night’s sleep (1.5–2 hours). The first REM period occurs about 80–120 minutes after onset of sleep and lasts about 10 minutes. Later REM periods are longer (15–40 minutes) and occur mostly in the last several hours of sleep. Most stage 4 (deepest) sleep occurs in the first several hours.
Age-related changes in normal sleep include an unchanging percentage of REM sleep and a marked decrease in stage 3 and stage 4 sleep, with an increase in wakeful periods during the night. These normal changes, early bedtimes, and daytime naps play a role in the increased complaints of insomnia in older people. Variations in sleep patterns may be due to circumstances (eg, “jet lag”) or to idiosyncratic patterns (“night owls”) in persons who perhaps because of different “biologic rhythms” habitually go to bed late and sleep late in the morning. Creativity and rapidity of response to unfamiliar situations are impaired by loss of sleep. There are also rare individuals who have chronic difficulty in adapting to a 24-hour sleep-wake cycle (desynchronization sleep disorder), which can be resynchronized by altering exposure to light.
The three major sleep disorders are discussed below. Any persistent sleep disorder that is not attributable to another condition should be evaluated by a sleep specialist.
Classification & Clinical Findings
Patients may complain of difficulty getting to sleep or staying asleep, intermittent wakefulness during the night, early morning awakening, or combinations of any of these. Transient episodes are usually of little significance. Stress, caffeine, physical discomfort, daytime napping, and early bedtimes are common factors.
Psychiatric disorders are often associated with persistent insomnia. Depression is usually associated with fragmented sleep, decreased total sleep time, earlier onset of REM sleep, a shift of REM activity to the first half of the night, and a loss of slow wave sleep—all of which are nonspecific findings. In manic disorders, a reduced total sleep time and a decreased need for sleep are cardinal features and important early sign of impending mania. In addition to a decreased amount of sleep, manic episodes are characterized by a shortened REM latency and increased REM activity. Sleep-related panic attacks occur in the transition from stage 2 to stage 3 sleep in some patients with a longer REM latency in the sleep pattern preceding the attacks.
Abuse of alcohol may cause or be secondary to the sleep disturbance. There is a tendency to use alcohol as a means of getting to sleep without realizing that it disrupts the normal sleep cycle. Acute alcohol intake produces a decreased sleep latency with reduced REM sleep during the first half of the night. REM sleep is increased in the second half of the night, with an increase in total amount of slow wave sleep (stages 3 and 4). Vivid dreams and frequent awakenings are common. Chronic alcohol abuse increases stage 1 and decreases REM sleep (most medications delay or block REM sleep), with symptoms persisting for many months after the individual has stopped drinking. Acute alcohol or other sedative withdrawal causes delayed onset of sleep and REM rebound with intermittent awakening during the night.
Heavy smoking (more than a pack a day) causes difficulty falling asleep—apparently independently of the often associated increase in coffee drinking. Excess intake near bedtime of caffeine, cocaine, and other stimulants (eg, over-the-counter cold remedies) causes decreased total sleep time—mostly NREM sleep—with some increased sleep latency.
Sedative-hypnotics—specifically, the benzodiazepines, which are the most commonly prescribed medications to promote sleep—tend to increase total sleep time, decrease sleep latency, and decrease nocturnal awakening, with variable effects on NREM sleep. Nonbenzodiazepine hypnotics, such as zolpidem, have similar effects on sleep as do the benzodiazepines. Withdrawal causes just the opposite effects and results in continued use of the drug for the purpose of preventing withdrawal symptoms. Antidepressants decrease REM sleep (with marked rebound on withdrawal in the form of nightmares) and have varying effects on NREM sleep. The effect on REM sleep correlates with reports that REM sleep deprivation produces improvement in some depressions.
Persistent insomnias are also related to a wide variety of medical conditions, particularly delirium, pain, respiratory distress syndromes, uremia, asthma, thyroid disorders, and nocturia due to benign prostatic hyperplasia. Sleep apnea and restless leg movement are described below. Adequate analgesia and proper treatment of medical disorders will reduce symptoms and decrease the need for sedatives.
In general, there are two broad classes of treatment for insomnia, and the two may be combined: psychological (cognitive-behavioral) and pharmacologic. In situations of acute distress, such as a grief reaction, pharmacologic measures may be most appropriate. With primary insomnia, however, initial efforts should be psychologically based. This is particularly true in the elderly to avoid the potential adverse reactions of medications. The elderly population is at risk for complaints of insomnia because sleep becomes lighter and more easily disrupted with aging. Medical disorders that become more common with age may also predispose to insomnia.
Psychological strategies should include educating the patient regarding good sleep hygiene: (1) Go to bed only when sleepy. (2) Use the bed and bedroom only for sleeping and sex. (3) If still awake after 20 minutes, leave the bedroom, pursue a restful activity (such as a bath or meditation), and only return when sleepy. (4) Get up at the same time every morning regardless of the amount of sleep during the night. (5) Discontinue caffeine and nicotine, at least in the evening if not completely. (6) Establish a daily exercise regimen. (7) Avoid alcohol as it may disrupt continuity of sleep. (8) Limit fluids in the evening. (9) Learn and practice relaxation techniques. (10) Establish a bedtime ritual and a routine time for going to sleep. Research suggests that cognitive behavioral therapy for insomnia is as effective as zolpidem with benefits sustained 1 year after treatment.
When the above measures are insufficient, medications may be useful. Lorazepam (0.5 mg orally nightly), temazepam (7.5–15 mg orally nightly) and the nonbenzodiazepine hypnotics, zolpidem (5–10 mg orally nightly), and zaleplon (5–10 mg orally nightly), are often effective for the elderly population and can be given in larger doses—twice what is prescribed for the elderly—in younger patients. Zolpidem is also available as a sublingual tablet to treat insomnia characterized by middle-of-the-night awakening with difficulty falling back to sleep. The dose is 1.75 mg for women and 3.5 mg for men, taken once per night. A nonbenzodiazepine hypnotic, eszopiclone (2–3 mg orally), is similar in action to zolpidem and zaleplon and like oral zolpidem, is approved for long-term use. A lower dose of 1 mg is indicated in the elderly or those with hepatic impairment. It is important to note that short-acting agents like triazolam or zolpidem may lead to amnestic episodes if used on a daily ongoing basis. Longer-acting agents such as flurazepam (half-life of more than 48 hours) may accumulate in the elderly and lead to cognitive slowing, ataxia, falls, and somnolence. In general, it is appropriate to use medications for short courses of 1–2 weeks. The medications described above have largely replaced barbiturates as hypnotic agents because of their greater safety in overdose and their lesser hepatic enzyme induction effects. Antihistamines such as diphenhydramine (25 mg orally nightly) or hydroxyzine (25 mg orally nightly) may also be useful for sleep, as they produce no pharmacologic dependency; their anticholinergic effects may, however, produce confusion or urinary symptoms in the elderly. Trazodone, an atypical antidepressant, is a non–habit-forming, effective sleep medication in lower than antidepressant doses (25–150 mg orally at bedtime). Priapism is a rare side effect requiring emergent treatment. Ramelteon, 8 mg orally at bedtime, is a melatonin receptor agonist that helps with sleep onset and does not appear to have abuse potential. It appears to be safe for ongoing use without the development of tolerance.
Triazolam was popular as a hypnotic drug because of its very short duration of action. However, because it has been associated with dependency, transient psychotic reactions, anterograde amnesia, and rebound anxiety, it has been removed from the market in several European countries. If used, it should be prescribed only for short periods of time.
The class of hypnotics dual orexin receptor antagonists (DORAs) are approved to help initiate and maintain sleep. DORAs such as suvorexant may be more effective than other hypnotics for some patients. However, the role of suvorexant has not been established relative to other hypnotics and is more expensive since it is not generically available. DORAs have shown a significant increase in depressive symptoms in a subset of patients, so other hypnotics may be a better choice in depressed patients. The dose of suvorexant is 10–20 mg orally given about 30 minutes before bedtime.
2. Hypersomnias (Disorders of Excessive Sleepiness)
Classification & Clinical Findings
A. Breathing-Related Sleep Disorders
Obstructive sleep apnea hypopnea is by far the most common of the breathing-related sleep disorders that include central sleep apnea and sleep-related hypoventilation. Obstructive sleep apnea hypopnea is characterized by snoring, gasping, or breathing pauses during sleep and 5 or more apneas or hypopneas per hour or evidence by polysomnography or 15 or more apneas or hypopneas per hour. (See Chapter 9.)
B. Narcolepsy Hypocretin Deficiency Syndrome
Narcolepsy consists of a tetrad of symptoms: (1) sudden, brief (about 15 minutes) sleep attacks that may occur during any type of activity; (2) cataplexy—sudden loss of muscle tone involving specific small muscle groups or generalized muscle weakness that may cause the person to slump to the floor, unable to move, often associated with emotional reactions and sometimes confused with seizure disorder; (3) sleep paralysis—a generalized flaccidity of muscles with full consciousness in the transition zone between sleep and waking; and (4) hypnagogic hallucinations, visual or auditory, which may precede sleep or occur during the sleep attack. The attacks are characterized by an abrupt transition into REM sleep—a necessary criterion for diagnosis. The disorder begins in early adult life, affects both sexes equally, and usually levels off in severity at about 30 years of age.
REM sleep behavior disorder, characterized by motor dyscontrol and often violent dreams during REM sleep, may be related to narcolepsy.
This syndrome, which occurs mostly in young men, is characterized by hypersomnic attacks three or four times a year lasting up to 2 days, with hyperphagia, hypersexuality, irritability, and confusion on awakening. It has often been associated with antecedent neurologic insults. It usually remits after age 40.
D. Periodic Limb Movement Disorder
Periodic lower leg movements occur only during sleep with subsequent daytime sleepiness, anxiety, depression, and cognitive impairment. Restless leg syndrome includes movements while awake as well.
E. Shift Work Sleep Disorder
Shift work sleep disorder occurs when there is excessive fatigue as a consequence of work occurring during the normal sleep period.
Narcolepsy can be managed by daily administration of a stimulant such as dextroamphetamine sulfate, 10 mg orally in the morning, with increased dosage as necessary. Modafinil and its enantiomer armodafinil are schedule IV medications FDA-approved for treating the excessive daytime fatigue of narcolepsy, sleepiness associated with obstructive sleep apnea as well as for shift work sleep disorder. Usual dosing is 200–400 mg orally each morning for modafinil and 150–250 mg orally in the morning for armodafinil. The mechanism of action of modafinil and armodafil is unknown, yet they are thought to be less of an abuse risk than stimulants that are primarily dopaminergic. Common side effects include headache and anxiety; however, modafinil appears to be generally well tolerated. Modafinil may reduce the efficacy of cyclosporine, oral contraceptives, and other medications by inducing their hepatic metabolism. Imipramine, 75–100 mg orally daily, has been effective in treatment of cataplexy but not narcolepsy.
Periodic limb movement disorder and REM sleep behavior disorder can be treated with clonazepam with variable results. There is no treatment for Kleine-Levin syndrome.
Treatment of sleep apnea is discussed in Chapter 9.
3. Parasomnias (Abnormal Behaviors during Sleep)
These disorders (sleep terror, nightmares, sleepwalking, and enuresis) are fairly common in children and less so in adults.
Classification & Clinical Findings
Sleep terror (pavor nocturnus) is an abrupt, terrifying arousal from sleep, usually in preadolescent boys although it may occur in adults as well. It is distinct from sleep panic attacks. Symptoms are fear, sweating, tachycardia, and confusion for several minutes, with amnesia for the event.
Nightmares occur during REM sleep; sleep terrors in stage 3 or stage 4 sleep.
Sleepwalking (somnambulism) includes ambulation or other intricate behaviors while still asleep, with amnesia for the event. It affects mostly children aged 6–12 years, and episodes occur during stage 3 or stage 4 sleep in the first third of the night and in REM sleep in the later sleep hours. Sleepwalking in elderly people may be a feature of dementia. Idiosyncratic reactions to drugs (eg, marijuana, alcohol) and medical conditions (eg, partial complex seizures) may be causative factors in adults.
Enuresis is involuntary micturition during sleep in a person who usually has voluntary control. Like other parasomnias, it is more common in children, usually in the 3–4 hours after bedtime, but is not limited to a specific stage of sleep. Confusion during the episode and amnesia for the event are common.
Treatment for sleep terrors is with benzodiazepines (eg, diazepam, 5–20 orally mg at bedtime), since it will suppress stage 3 and stage 4 sleep. Somnambulism responds to the same treatment for the same reason, but simple safety measures should not be neglected. Enuresis may respond to imipramine, 50–100 mg orally at bedtime, although desmopressin nasal spray (an ADH preparation) is likely the treatment of choice for nocturnal enuresis. Behavioral approaches (eg, bells that ring when the pad gets wet) have also been successful.
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Aggression and violence are symptoms rather than diseases, and most frequently they are not necessarily associated with an underlying medical condition. Clinicians are unable to predict dangerous behavior with greater than chance accuracy. Depression, schizophrenia, personality disorders, mania, paranoia, temporal lobe dysfunction, and organic mental states may be associated with acts of aggression. Impulse control disorders are characterized by physical abuse (usually of the aggressor’s domestic partner or children), by pathologic intoxication, by impulsive sexual activities, and by reckless driving. Anabolic steroid usage by athletes has been associated with increased tendencies toward violent behavior.
In the United States, a significant proportion of all violent deaths are alcohol related. The ingestion of even small amounts of alcohol can result in pathologic intoxication that resembles an acute organic mental condition. Amphetamines, crack cocaine, and other stimulants are frequently associated with aggressive behavior. Phencyclidine is a drug commonly associated with violent behavior that is occasionally of a bizarre nature, partly due to lowering of the pain threshold. Domestic violence and rape are much more widespread than previously recognized. Awareness of the problem is to some degree due to increasing recognition of the rights of women and the understanding by women that they do not have to accept abuse. Acceptance of this kind of aggressive behavior inevitably leads to more, with the ultimate aggression being murder—20–50% of murders in the United States occur within the family. Police are called more for domestic disputes than all other criminal incidents combined. Children living in such family situations frequently become victims of abuse.
Features of individuals who have been subjected to long-term physical or sexual abuse are as follows: trouble expressing anger, staying angry longer, general passivity in relationships, feeling “marked for life” with an accompanying feeling of deserving to be victimized, lack of trust, and dissociation of affect from experiences. They are prone to express their psychological distress with somatization symptoms, often pain complaints. They may also have symptoms related to posttraumatic stress, as discussed above. The clinician should be suspicious about the origin of any injuries not fully explained, particularly if such incidents recur.
Management of any violent individual includes appropriate psychological maneuvers. Move slowly, talk slowly with clarity and reassurance, and evaluate the situation. Strive to create a setting that is minimally disturbing, and eliminate people or things threatening to the violent individual. Do not threaten and do not touch or crowd the person. Allow no weapons in the area (an increasing problem in hospital emergency departments). Proximity to a door is comforting to both the patient and the examiner. Use a negotiator who the violent person can relate to comfortably. Food and drink are helpful in defusing the situation (as are cigarettes for those who smoke). Honesty is important. Make no false promises, bolster the patient’s self-esteem, and continue to engage the subject verbally until the situation is under control. This type of individual does better with strong external controls to replace the lack of inner controls over the long term. Close probationary supervision and judicially mandated restrictions can be most helpful. There should be a major effort to help the individual avoid drug use (eg, Alcoholics Anonymous). Victims of abuse are essentially treated as any victim of trauma and, not infrequently, have evidence of PTSD.
Pharmacologic means are often necessary whether or not psychological approaches have been successful. This is particularly true in the agitated or psychotic patient. The drugs of choice in seriously violent or psychotic aggressive states are antipsychotics, given intramuscularly if necessary, every 1–2 hours until symptoms are alleviated. A number of second-generation intramuscular antipsychotics are FDA approved in the management of acute agitation, and include aripiprazole (9.75 mg/1.3 mL), ziprasidone (10-mg/0.5 mL), and olanzapine (10 mg/2 mL). The second-generation antipsychotics appear less likely than first-generation drugs like haloperidol (2.5–5 mg) to cause acute extrapyramidal symptoms. However, the second-generation drugs appear no more effective than first-generation drugs and generally are more expensive. Benzodiazepine sedatives (eg, diazepam, 5 mg orally or intravenously every several hours) can be used for mild to moderate agitation but are sometimes associated with a disinhibition of aggressive impulses similar to alcohol. Chronic aggressive states, particularly in intellectual disabilities and brain damage (rule out causative organic conditions and medications such as anticholinergic medications in amounts sufficient to cause confusion), have been ameliorated with risperidone, 0.5–2 mg/day orally, propranolol, 40–240 mg/day orally, or pindolol, 5 mg twice daily orally (pindolol causes less bradycardia and hypotension than propranolol). Carbamazepine and valproic acid are effective in the treatment of aggression and explosive disorders, particularly when associated with known or suspected brain lesions. Lithium and SSRIs are also effective for some intermittent explosive outbursts. Buspirone (10–45 mg/day orally) is helpful for aggression, particularly in patients with intellectual disabilities.
Physical management is necessary if psychological and pharmacologic means are not sufficient. It requires the active and visible presence of an adequate number of personnel (five or six) to reinforce the idea that the situation is under control despite the patient’s lack of inner controls. Such an approach often precludes the need for actual physical restraint. Seclusion rooms and restraints should be used only when necessary (ambulatory restraints are an alternative), and the patient must then be observed at frequent intervals. Narrow corridors, small spaces, and crowded areas exacerbate the potential for violence in an anxious patient.
The treatment of victims (eg, battered women) is challenging and often complicated by their reluctance to leave the situation. Reasons for staying vary, but common themes include the fear of more violence because of leaving, the hope that the situation may ameliorate (in spite of steady worsening), and the financial aspects of the situation, which are seldom to the woman’s advantage. Concerns for the children often finally compel the woman to seek help. An early step is to get the woman into a therapeutic situation that provides the support of others in similar straits. Al-Anon is frequently a valuable asset when alcohol is a factor. The group can support the victim while she gathers strength to consider alternatives without being paralyzed by fear. Many cities offer temporary emergency centers and counseling. Use the available resources, attend to any medical or psychiatric problems, and maintain a compassionate interest. Some states require physicians to report injuries caused by abuse or suspected abuse to police authorities.
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