25-11: Schizophrenia Spectrum Disorders

Schizophrenia is manifested by a massive disruption of thinking, mood, and overall behavior as well as poor filtering of stimuli. The cause of schizophrenia is believed to be multifactorial, with genetic, environmental, and neurotransmitter pathophysiologic components. 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 on this spectrum are conditions that are similar to schizophrenia 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. Schizophrenia

Schizophrenia is the most common of the psychotic disorders that are all characterized by a loss of contact with reality. The term psychosis is broad and most often refers to having paranoia, auditory hallucinations, delusions, or all of these symptoms. One percent of the population suffers from schizophrenia. 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. The average age of onset for men is 18 years and for women is 25 years. Symptoms have been classified into positive and negative categories. Positive symptoms include hallucinations, delusions, and disorganized speech; these symptoms appear to be related to increased dopaminergic (D₂) activity in the mesolimbic region, and all patients have at least one or two of these symptoms to meet criteria for diagnosis. There is often a component of paranoia involved. They may also have disorganized behavior, lack of emotional/cognitive responsiveness, or both. 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. Level of functioning is markedly below that before the onset of symptoms, which must last at least 6 months in some form.

B. Delusional Disorder

Delusional disorders are psychoses in which the predominant symptoms are persistent delusions (ie, beliefs that are false yet fixed despite being shown evidence that they are unfounded) with minimal impairment of daily functioning. 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 schizophrenia 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. The psychotic symptoms begin before the mood episode begins and can continue to linger for some time after resolution of the mood episode but do not remain permanently. Because of this, the long-term prognosis is better than for schizophrenia.

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 month but less than 6 months.

E. Brief Psychotic Disorders

Brief psychotic disorders are defined as psychotic symptoms lasting less than 1 month. 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.

A. Symptoms and Signs

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 mildly to moderately unkempt. 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 patients with schizophrenia 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).

B. Imaging

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, a psychomotor disturbance that may involve decreased motor activity, decreased interaction, or excessive and odd motor activity, is frequently assumed to exist solely as a component of schizophrenic disorders. However, it can actually be 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 schizophrenia and inappropriately treated with more antipsychotic medication. Catatonia is also seen in other major psychiatric disorders, including bipolar disorder and major depression.

A. Pharmacologic (see Side Effects, below)

Hospitalization is sometimes necessary, particularly when the patient’s behavior shows gross disorganization. The presence of competent family members or social support 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 psychosis.

Antipsychotic medications are the treatment of choice. The relapse rate can be reduced by 50% with proper maintenance antipsychotic therapy. Long-acting, injectable antipsychotics are used in patients who are not adherent to medication recommendations or who do not respond to oral medication, or patients who choose the ease of not taking a daily pill.

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 first- and second-generation antipsychotics, but a tendency for the second-generation antipsychotics to be better tolerated leading to enhanced compliance.

The phenothiazines comprise the bulk of the currently used “typical” or first-generation 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 medication 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 medication 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. Multiple case reports have linked olanzapine and clozapine to new-onset type 2 diabetes, and all antipsychotics 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, which occurs in about 0.5–1% of patients.

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. It thus tends to be the antipsychotic of choice when one is required in patients with a movement disorder. 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, and 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. Akathisia, 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.

Beyond antipsychotics, there is early evidence that cannabidiol (CBD), at a dose of 1000 mg/day, added on to existing antipsychotic treatment, effectively improves psychotic symptoms in schizophrenia. This agent may represent a new class of treatment for psychotic disorders.

1. Clinical indications

The antipsychotics are used to treat all forms of the schizophrenias as well as 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 medication 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 and in treating schizophrenia when used in combination with medications.

2. Dosage forms and patterns

The dosage range is quite broad (Table 25–4). For example, risperidone can be effective for some patients with psychotic features at 0.25–1 mg orally at bedtime, whereas up to 6 mg/day may be used in a young patient with acute schizophrenia. 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 genetic-based enzyme differences in metabolizing the antipsychotic medications—eg, many people of Asian descent 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 medication is desired for nighttime sleep, and undesirable sedative effects can be avoided during the day. 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 patients who do not respond 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 12.5 mg monthly to 100 mg weekly. 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 medication. 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.

There have been investigations for novel compounds involving other therapeutics targets such as the glutamate system as well as the inflammatory cascade.

3. Side effects

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).

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, which 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 medication. There is cross-sensitivity among all of the phenothiazines, and a medication 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 biochemical 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, and patients should be closely monitored and treated quickly and preemptively for constipation.

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 medication 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 medication 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 medication. 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. Patients with AIDS seem particularly vulnerable to extrapyramidal side effects. High-potency antipsychotics often require antiparkinsonism medications. 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 clear-cut 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.) However, clozapine is unique in that it has been found to treat antipsychotic-induced tardive dyskinesia. 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 medication necessary to mute the psychotic symptoms. 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.

B. Social

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.

C. Psychological

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. Research suggests that cognitive behavioral therapy—in conjunction with medication management—has 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.

D. Behavioral

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 or smartphones 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 than do positive symptoms. Unavailability of structured work situations and lack of family therapy or access to other social support are two other reasons why the prognosis is so guarded in such a large percentage of patients.