The separation into bipolar and non-bipolar disorder has proved clinically and diagnostically useful. It is supported by family studies, twin studies, and biological studies. It is supported further by differential clinical responses to treatment and differential disease onsets and outcomes. To these factors, we can add the epidemiologic risk factors detailed in Table 18–1.
Table 18–1. Risk Factors for Major Depressive Disorder ||Download (.pdf)
Table 18–1. Risk Factors for Major Depressive Disorder
High risk in families with history of depression (7%) or alcoholism (8%)
May be less common in African Americans
Recent negative life events may precede episode
Insecure, worried, introverted, stress sensitive, obsessive, unassertive, dependent
Early childhood trauma (e.g., significant loss, disruptive, hostile, negative environment)
Depressive episodes common
Relative lack of interpersonal relationships
Symptoms and disorders of the depression spectrum are rather common. Lifetime prevalence rates for significant depressive symptoms are 13–20% and for major depressive disorder 3.7–6.7%. Major depressive disorder is about two to three times as common in adolescent and adult females as in adolescent and adult males. In prepubertal children, boys and girls are affected equally. Rates in women and men are highest in the 25–44-year-old age group.
Boyd JH,Weissman MM: Epidemiology. In: Paykel ES (ed).Handbook of Affective Disorders. New York: Guilford Press, 1982, pp. 109–125.
Weissman MN,Livingston Bruce M,Leaf PJ, Florio LP,Holzer C: Affective Disorders. In: Robins LN, Regier DA (eds). Psychiatric Disorders in America. New York: Free Press, 1991, pp. 53–80.
Despite intensive attempts to establish its etiologic or pathophysiologic basis, the precise cause of major depressive disorder is not known. There is consensus that multiple etiologic factors—genetic, biochemical, psychodynamic, and socioenvironmental—may interact in complex ways and that the modern-day understanding of depressive disorder requires an understanding of the interrelationships among these factors.
Recent evidence confirms that crucial life events, particularly the death or loss of a loved one, can precede the onset of depression. However, such losses precede only a small (though substantial) number of cases of depression. Fewer than 20% of individuals experiencing losses become clinically depressed. Although other major life events may occur prior to the onset of depression, many patients become depressed with little or no apparent provocation. These observations argue strongly for a predisposing factor, probably genetic, developmental, or temperamental in nature.
Associations between mood and monoamines (i.e., norepinephrine, serotonin, and dopamine) were first indicated serendipitously by the mood-altering effects of isoniazid (used initially for the treatment of tuberculosis) and later by reports that isoniazid (a monoamine oxidase inhibitor [MAOI]) affects monoamine concentrations in the brains of laboratory animals. We now know that all clinically-effective antidepressants affect postsynaptic signaling of serotonin, norepinephrine, or both at the postsynaptic membrane. This action has led to the hypothesis that depression is caused by a neurotransmitter deficiency and that antidepressants exert their clinical effect by treating this imbalance.
In the late 1970s, emphasis shifted from acute presynaptic to delayed postsynaptic receptor—mediated events after it was shown that most chronic antidepressant treatments (including pharmacotherapy and electroconvulsive therapy [ECT]) cause subsensitivity of the norepinephrine receptor—coupled adenylate cyclase system in brain. This desensitization of norepinephrine receptor systems was linked to a decrease in the density of β–adrenoceptors. More importantly, it paralleled the delayed onset of action common to all antidepressants. More recent concepts have evolved from the original deficiency hypotheses, emphasizing the integration of multiple intracellular signals that regulate neuronal response (i.e., changes in G protein, cyclic adenosine monophosphate, or protein kinase and the induction of gene transcription). These cellular mechanisms are thought to ultimately affect the expression of specific genes. Therefore, abnormalities of intracellular signal transduction and/or gene expression are now thought to underlie the physiology of depression. Other neurotransmitters (e.g., acetylcholine, gamma amino butyric acid, melatonin, glycine, histamine), hormones (e.g., thyroid and adrenal hormones), and neuropeptides (e.g., corticotropin-releasing hormone, endorphins, enkephalins, vasopressin, cholecystokinin, substance P) may play significant roles in the modulation of mood.
Emotional trauma sometimes immediately precedes the onset of depression. Emotional trauma can also precede the onset of endocrine disorders such as hyperthyroidism and Cushing's disease, both of which are commonly associated with psychological disturbance, most commonly in mood and cognition. When endocrine changes are associated with psychological disturbance it is often unclear whether such changes are precipitants, perpetuating influences, or secondary effects.
The two endocrine systems most extensively studied in psychiatry are the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis. About half of patients with major depression exhibit cortisol hypersecretion that returns to normal once the depression is cured. The evidence of cortisol hypersecretion includes increased adrenocorticotropin (ACTH) secretion, increased plasma concentration and urinary excretion of cortisol and its metabolites, alterations in the normal circadian rhythm of cortisol secretion, relative resistance to glucocorticoid negative feedback inhibition of ACTH secretion, and blunted ACTH responses to corticotropin-releasing hormone. However, not all depressed patients exhibit evidence of significant hypercortisolism. Several studies have attempted to document the psychological effects of manipulating plasma glucocorticoid concentrations in depressed patients. They reported antidepressant effects in some depressed patients after administration of such antiglucorticoid medications as aminoglutethimide, metyrapone, and ketokonazole.
Human studies have also demonstrated a profound effect of thyroid hormones on brain development, maturation, and connectivity. The effects of thyroid hormones on mature brain function, as they pertain to mood, are less marked. The most common effects are as follows: (1) Depression and cognitive decline are the most frequently observed psychiatric symptoms in patients who have adult hypothyroidism, (2) A small dose of thyroid hormone, preferably triiodothyronine (T3), will accelerate the therapeutic effect of various antidepressants, particularly in women, and can convert antidepressant nonresponders into responders in both sexes, (3) Most longitudinal studies have revealed dynamic reductions in serum thyroxine (T4) concentrations in depressed patients during a wide range of somatic treatments, including various antidepressants, lithium, sleep deprivation, and ECT, (4) Administration of thyrotropin-releasing hormone (TRH) may induce an increased sense of well-being and relaxation in normal subjects and in patients with neurologic and psychiatric disease, especially depression, and (5) Although overt thyroid disease is rare in major depression, subtle forms of thyroid dysfunction are common—for example, absence or flattening of the diurnal thyroid-stimulating hormone (TSH) curve, often caused by a reduction in the nocturnal TSH surge; a blunted TSH response after administration of TRH (discussed in greater detail later in this section); and subclinical hypothyroidism or positive antithyroid antibodies.
In recent years, an increasing number of studies have evaluated both the immediate and long-term neurobiological effects of early childhood trauma (e.g., physical or emotional abuse, neglect, or parental loss). Studies of traumatized persons or animal models of early life stress suggest long-lasting effects on neuroendocrine, psychophysiological, and neurochemical systems. Together, these effects may present the biological basis of an enhanced risk for psychopathology, including depression. In addition to having added childhood trauma to the existing list of risk factors for depression, these studies have created a burgeoning awareness and consensus that the high number of children who are exposed in our society to early trauma is unacceptable. Hopefully, further studies may elucidate the many factors that determine individual vulnerability or resilience to the neurobiological effects of early trauma and help to prevent their deleterious neurobiological and psychopathological consequences.
Ahmed N,Loosen PT: Thyroid hormones in major depressive and bipolar disorders. In: Casper R (ed).Women's Health and Emotion. England: Cambridge University Press, 1997, pp. 83–108.
Goodwin FK,Jamison KR:Manic Depressive Illness. New York: Oxford University Press, 1990.
Heim C,Nemeroff CB: Neurobiology of early life stress: Clinical studies. Semin Clin Neuropsych
Loosen PT: Hormones of the hypothalamic-pituitary-thyroid axis: A psychoneuroendocrine perspective. Pharmacopsychiatry
Flores BH,Musselman DL,DeBattista C,Garlow SJ,Schatzberg AF, Nemeroff CB: Biology of mood disorders. In: Schatzberg AF, Nemeroff CB (eds). Textbook of Psychopharmacology, 3rd edn. Washington, DC: American Psychiatric Press, 2004, pp. 717–763.
Nemeroff CB,Loosen PT (eds):Handbook of Clinical Psychoneuroendocrinology. New York: Guilford Press: 1987, pp. 384–396.
Pearson Murphy BE: Steroids and depressiont. J Steroid Biochem Mol Biol 1991;38:537.
Wolkowitz OM,Reus VI: Treatment of depression with antiglucocortoid drugs. Psychosom Med
Wolkowitz OM,Rothschild AJ (eds):Psychoneuroendocrinology
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Psychoanalytic and Psychodynamic Models
In the early 20th century, psychoanalytic interpretations of mental illness were prominent. Karl Abraham (1911) wrote the first important psychoanalytic paper on depression, stating that depression is unconsciously motivated and the result of repressed sexual and aggressive drives. Concurrent writings of Sigmund Freud suggested that depression and, to a lesser extent, mania were understood as precipitated by loss and manifested by regressions to anal and oral phases of libidinal development. These regressions in adult life resulted from an unfortunate combination of predisposition (constitutional overaccentuation of oral eroticism) and critical childhood disappointments. Armed with Freud's concepts on the role of introjection in normal mourning and in melancholia, Abraham wrote of the “severe conflict of ambivalent feelings from which [the patient] can only escape by turning against himself the hostility he originally felt towards his object.”
The precepts that depression is the result of a loss and that it symptomatically represents “anger turned against the self” are part of the enduring legacy of classic psychoanalytic thinking. Freud believed that the real, threatened, or imagined loss of a narcissistic object choice (meaning that the individual's love of the object was equivalent to love of the self) would trigger a withdrawal of libido away from the object and back into the self through introjection of the ambivalently cathected object. The patient then would attack himself (depressive symptoms) as though for misdeeds that were the doing of the lost object. In other words, the depressed patient experiences a loss as a narcissistic wound; suicide becomes an unconscious attempt to destroy the now hated object that dwells in the patient's ego by means of introjection. Like Abraham, Freud also emphasized the importance of somatic factors in predisposing the individual to depression and in the clinical picture itself. Diurnal variation of mood, for example, was beyond psychological explanation. Later psychoanalytic writers (e.g., M. Klein, D. W. Winicott, E. Bibring) sought to expand on Freud's thinking, incorporating further developments in ego-psychology, object relations theory, and self-psychology. Although widely held, traditional psychodynamic theories have not held up to careful study. Moreover, psychoanalysis or most forms of psychodynamic therapy either have not been formally tested or have not been shown to be more effective than simple interpersonal contact.
In the mid-1900s, three models based on behavioral theory emerged (see Chapter 10). Peter Lewinsohn showed that depression can be caused by inadequate or insufficient positive reinforcement. In everyday life, this can occur in two main ways: (1) if an environment lacks positive reinforcement (e.g., through individual or mass unemployment) or (2) if the person is not able to take advantage of reinforcement (e.g., through isolation induced by poor social skills). Inadequate positive reinforcement may lead to a self-perpetuating cycle consisting of dysphoria, a reduction in behaviors that would normally obtain the reinforcement, lowered self-esteem and increased hopelessness, and increased isolation.
Martin Seligman developed the theory of learned helplessness as he was searching for an animal model of depression. Laboratory animals given random shocks from which they cannot escape develop apathy to any stimulus. Generalizing this observation to humans, Seligman's theory suggests that depression can result from situations in which a person has lost (actual or imagined) control over negative life events.
The cognitive-behavioral model of depression developed by Aaron Beck suggests that depression develops when the patient cognitively misinterprets life events. The conceptual core of this model consists of the cognitive triad of depression: (1) a negative self-view (i.e., “things are bad because I am bad”), (2) a negative interpretation of experience (i.e., “everything has always been bad”), and (3) a negative view of the future (i.e., “everything will always be bad”). It is a basic tenet of this theory that a depressed person interprets the world through depressive schemata that distort experiences in a negative direction. Typical cognitive distortions include arbitrary inference (in which the person assumes a negative event was caused by himself or herself), selective abstraction (in which the person focuses on the negative element in an otherwise positive set of information), magnification and minimization (in which the person overemphasizes negatives and underemphasizes positives), and inexact labeling (in which the person gives a distorted label to an event and then reacts to the label rather than to the event).
Beck AT: Cognitive therapy. A 30 year retrospective. Am Psychol
Freud S: Mourning and melancholia (1917). In Strachey J (ed & trans).Standard Edition of the Complete Psychological Works of Sigmund Freud, Vol 14. London: Hogarth, 1957, pp. 237–260.
Roose S: Depression. In Nersessian E,Kopff R (eds).Textbook of Psychoanalysis. Washington, DC: American Psychiatric Press, 1996, pp. 301–318.
Mood disorders are familial, but the exact mode of transmission is not understood (see Chapter 3).
The cardinal feature of a major depressive episode is a depressed mood or the loss of interest or pleasure (see Depressed Mood and Anhedonia below) that predominates for at least 2 weeks and causes significant distress or impairment in the individual's social, occupational, or other important areas of functioning. During this time, the individual must also exhibit at least four additional symptoms (i.e., other than depressed mood or anhedonia), drawn from the following common features of depression:
Depressed mood is the most characteristic symptom, occurring in over 90% of patients. The patient usually describes himself or herself as feeling sad, low, empty, hopeless, gloomy, or down in the dumps. The quality of mood is likely to be portrayed as different from a normal sense of sadness or grief. The physician often observes changes in the patient's posture, speech, facies (e.g., a melancholic expression known as facies melancholica), dress, and grooming consistent with the patient's self-report. Many depressed patients state that they are unable to cry, whereas others report frequent weeping spells that occur without significant precipitants.
A small percentage of patients do not report a depressed mood, sometimes referred to as masked depression. These patients are usually brought to their physician by the family members/coworkers who have noticed the patients’ social withdrawal or decreased activity. Patients may associate depression with feelings of sadness. However, depression as often involves emotional numbness or lack of positive reactivity. Similarly, some children and adolescents do not exhibit a sad demeanor, presenting instead as irritable.
An inability to enjoy usual activities is almost universal among depressed patients. The patient or his or her family may report markedly diminished interest in all, or almost all, activities previously enjoyed such as sex, hobbies, and daily routines.
About 70% of patients observe a reduction in appetite with accompanying weight loss; only a minority of patients experience an increase in appetite, often associated with cravings for particular foods such as sweets.
About 80% of depressed patients complain of some type of sleep disturbance, the most common being insomnia. Insomnia is usually classified as initial (i.e., problems in falling asleep), middle (i.e., problems of staying asleep with frequent awakenings throughout the night), or late (i.e., early morning awakening). The most common and unpleasant form of sleep disturbance in major depressive disorder is late insomnia, with awakenings in the early morning (usually around 4–5 am) and significant worsening of depressive symptoms in the first part of the day. In contrast, initial insomnia is especially common in those with significant comorbid anxiety. Some patients complain of hypersomnia rather than insomnia; hypersomnia is common in atypical depression and seasonal affective disorder (SAD) and is often associated with hyperphagia.
About one-half of depressed patients develop a slowing, or retardation, of their normal level of activity. They may exhibit a slowness in thinking, speaking, or body movement or a decrease in volume or content of speech, with long pauses before answering. In about 75% of depressed women and 50% of depressed men, anxiety is expressed in the form of psychomotor agitation, with pacing, an inability to sit still, and hand-wringing.
Almost all depressed patients report a significant loss of energy (anergia), unusual fatigue or tiredness, and a general lack of efficiency even in small or elementary tasks.
Feelings of Worthlessness and Excessive or Inappropriate Guilt
A depressed individual may experience a marked (and often unrealistic) decrease in self-esteem. In European cultures, well over half of depressed patients exhibit some guilt, ranging from a vague feeling that their current condition is the result of something they have done, to frank delusions and hallucinations of poverty or of having committed an unpardonable sin. In other cultures, shame or humiliation is experienced.
Indecisiveness or Decreased Concentration
About one-half of depressed patients complain of or exhibit a slowing of thought. They may feel that they are not able to think as well as before, that they cannot concentrate, or that they are easily distracted. Frequently they will doubt their ability to make good judgments and find themselves unable to make even small decisions. On formal psychological testing, the patient's accuracy is usually retained, but speed and performance are slow. In severe forms, called pseudodementia, particularly among the elderly, memory deficits may be mistaken for early signs of dementia. In contrast to dementia, pseudodementia usually reverses after treatment of the underlying depression. However, when cognitive symptoms are comorbid with depression, they may represent an emerging dementia that can still be present after the depression has resolved.
Many depressed individuals experience recurrent thoughts of death, ranging from transient feelings that others would be better off without them, to the actual planning and implementing of suicide.
Suicide is the eighth leading cause of death in the United States, accounting for more than 30,000 deaths each year. Major depression accounts for roughly 50% of suicides, and 15% of patients with depression eventually die by suicide. The risk of suicide is present throughout a depressive episode but is probably highest immediately after initiation of treatment and during the 6–9-month period following symptomatic recovery. Table 18–2 lists common predictors of suicide risk.
Table 18–2. Factors Associated with Elevated Risk of Suicide ||Download (.pdf)
Table 18–2. Factors Associated with Elevated Risk of Suicide
Older than 45 yr, male, white (i.e., risk is greater in males, especially white males, where it appears to increase with age)
Prior suicide attempt or history of other self-injury
Family history of suicide or psychiatric illness
Recent severe loss
Present or anticipated poor health
Inability to accept help
Lack of available support from society (e.g., living alone, unemployment)
Comorbid alcoholism or drug abuse
Alcohol and drug dependence account for roughly 25% of suicides, and psychosis is present in 10% of suicides. For each person who completes suicide, 8–10 people attempt suicide, and for every completed suicide, 18–20 attempts are made. Patients with a history of suicide attempts account for 50% of completed suicides. Medical illnesses are associated with as many as 35–40% of suicides, and with as many as 70% of suicides occurring in those over the age of 60 years. As much as 10% of general medical admissions result from failed suicide attempts.
The diagnosis of major depression with melancholic features is made when the patient has either loss of pleasure in all, or almost all, activities, or lack of reactivity to usually pleasurable stimuli, along with three or more of the following: (1) distinct quality of depressed mood (i.e., the mood is different than that experienced after the loss of a loved one); (2) depression regularly worse in the morning, (3) early morning awakening (at least 2 hours prior to the usual time of awakening), (4) marked psychomotor retardation or agitation, (5) significant anorexia or weight loss, and (6) excessive or inappropriate guilt. Other characteristics sometimes associated with melacholia include the absence of personality disturbance before first episode, the occurrence of one or more previous episodes followed by complete remission, and prior good response to specific and adequate somatic antidepressant therapy (e.g., ECT, tricyclic antidepressants [TCAs], MAOIs, lithium).
Although the term depression often calls to mind the pattern of symptoms associated with melancholia (especially insomnia and loss of appetite), some patients experience a reversed pattern – that is, symptoms that are opposite to those seen in melancholia. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria for major depression with atypical features include mood reactivity (that is, mood that brightens in response to a positive event) along with two or more of the following: (1) significant weight gain or increase in appetite, (2) hypersomnia, (3) leaden paralysis (i.e., heavy, leaden feelings in arms or legs), (4) a long-standing pattern of sensitivity to real or perceived interpersonal rejection (that are not limited to episodes of mood disturbance) that results in significant social or occupational impairment. In the case of rejection sensitivity, emotional reactions may occur after imagined, anticipated, or real rejection by others and may be extreme at times. This diagnostic subcategory was derived in the 1960's by British psychiatrists based on differential responses to TCAs and MAOIs. They posited that melancholic depression responded preferentially to the former, while atypical depression to the latter. Subsequent research has confirmed that persons with atypical features respond better to MAOIs than to tricyclics.
Seasonal Affective Disorder
Occasionally patients experience depressive episodes at characteristic times of the year. Most commonly the episodes of SAD begin in fall or winter and remit in spring, but occasionally they can also be observed in summer. SAD with prevalence during the winter months (winter depression) appears to vary with latitude, age, and sex. SAD is more common in higher latitudes (i.e., closer to the north or south poles) and among younger people, particularly in females. SAD is characterized clinically by hypersomnia, anergia, and a craving for sweets. SAD responds particularly well to light therapy and typically to serotonergic agents (i.e., selective serotonin reuptake inhibitors [SSRIs]).
The seasonal pattern specifier is given if all of the following are true: (1) there has been a regular temporal relationship between the onset of major depressive episodes in bipolar I or bipolar II disorder or major depressive disorder, recurrent, and a particular time of the year (e.g., fall or spring), (2) full remissions (or a change from depression to mania or hypomania) also occur at a characteristic time of the year.
Psychological testing has not been found useful in aiding the diagnosis of major depressive disorder.
Laboratory Findings & Imaging
No laboratory findings are diagnostic of a major depressive episode; however, several laboratory findings are abnormal in some patients with major depression, compared to the general population. It appears that most laboratory abnormalities are state dependent (i.e., they occur while patients are depressed), but some findings may precede the onset of an episode or persist after its remission.
Although the dexamethasone suppression test (DST) has little use as a clinical marker for depression, it is worth mentioning some of the more pertinent DST findings: (1) The overall sensitivity (i.e., positive DST outcome) was 44% among all patients with major depression given 1 mg dexamethasone; sensitivity was significantly higher (65%) in elderly depressed patients but dropped to 31% in a smaller group of patients who received 2 mg of dexamethasone, (2) Within the depression spectrum, the rates of DST nonsuppression increased strikingly from grief reactions (10%) and dysthymic disorders (23%), to major depressive disorders (44%), major depressive disorders with melancholia (50%), psychotic affective disorders (69%), and depression with serious suicidality (78%), (3) In some depressed patients, the DST allowed researchers to predict or monitor long-term treatment outcome, (4) DST-positive patients appeared to respond more favorably to biological interventions such as antidepressants or ECT, (5) Among depressed patients, abnormal DST results correlated mostly with initial insomnia, weight loss, loss of sexual interest, ruminative thinking, and psychomotor retardation or agitation, and (6) HPA axis dysregulation contributed to cognitive dysfunction, although it is not known whether hypercortisolemia and cognitive impairment in depression are related indirectly or causally.
A hyperactive HPA axis has been observed in stroke patients with major depression; in pain patients with major depression; and in patients with anorexia nervosa, bulimia nervosa, alcoholism, obsessive–compulsive disorder, or anxiety disorders. It has not been observed in schizophrenic patients.
Corticotropin-Releasing Hormone Test
A blunted adrenocorticotropic hormone response after corticotropin-releasing hormone administration is another HPA axis abnormality commonly observed in major depression.
Most depressed patients appear to be euthyroid; however, longitudinal studies consistently found significant serum T4 reductions during a wide range of somatic treatments, including various antidepressants, lithium, sleep deprivation, or ECT. Evidence indicates that the T4 reduction was greater in treatment responders than in nonresponders. It is not known whether the initial T4 increase in depression is part of the pathophysiology of the illness, or whether it is a compensatory mechanism by which the organism delivers thyroid hormone to the brain.
Subtle thyroid dysfunctions are common in depression. Between 1% and 4% of patients show evidence of overt hypothyroidism, and between 4% and 40% show evidence of subclinical hypothyroidism. Comorbid subclinical hypothyroidism can be associated with cognitive dysfunction or with a diminished response to standard psychiatric treatments. Some depressed patients with subclinical hypothyroidism may respond behaviorally to thyroid hormone substitution.
The TRH test (i.e., measurement of serum TSH following TRH administration) has been used widely in psychiatry. More than 3000 patients have been studied, the majority of whom had major depressive disorder. Approximately 30% of patients had a blunted TSH response during depression, and a smaller number showed TSH blunting during remission; however, definitions of TSH blunting have varied among studies, different assays have been used, and a standard amount of TRH has not always been injected.
There appears to be no association between the TRH-induced TSH response and (1) the patient's body surface or age, (2) serum thyroid hormone or cortisol concentrations, (3) severity of depression, or (4) previous intake of antidepressant drugs (excluding long-term lithium administration). Further, the TRH test does not aid in the distinction between primary and secondary depression or between unipolar and bipolar subgroups. Preliminary evidence suggests that TSH blunting may be associated with a more prolonged course of depression and with a history of violent suicidal behavior.
Within psychiatric disorders, TSH blunting can also occur in some patients who have borderline personality disorder, anorexia nervosa, panic disorder, primary degenerative dementia, chronic pain, premenstrual syndrome, or alcoholism, both during acute withdrawal and after prolonged abstinence. The absence of TSH blunting in both schizophrenic patients and phobic patients during exposure therapy suggests that the abnormality is not a mere correlate of mental distress.
Most depressed patients have insomnia. Sleep problems commonly reported include interruptions throughout the night, early morning awakenings, and less frequently, difficulty falling asleep. Sleep electroencephalogram (EEG) recordings reveal the following: (1) a shortened rapid eye movement (REM) latency (i.e., a shorter than normal interval between sleep onset and first REM period), more common in elderly depressed patients and often associated with unipolar depression; (2) a shift of slow-wave sleep (i.e., sleep stages 3 and 4), normally occurring during the first non-REM period, into the second non-REM period; and (3) an increased REM density (i.e., more frequent REM episodes) during the first few hours of sleep.
Because most of these sleep EEG abnormalities can be found in other illnesses, and some accompany normal aging, there is no agreement as to whether these abnormalities constitute diagnostic markers of depression or whether they reflect abnormal functioning in sleep-related processes but lack diagnostic specificity (see Chapter 27). There is evidence that EEG sleep variables are normal in depressed patients 6 months after an acute episode.
The rapidly increasing sophistication of neuroimaging techniques has improved our understanding of the neural substrates of emotion and its disorders. Neuroimaging studies have been particularly useful in characterizing the circuitry underlying emotional disorders.
Mood disorders may be associated with global and regional changes in cerebral blood flow and metabolism. Global cerebral blood flow and glucose metabolism appear normal, but may be decreased in late life depression. Decreased prefrontal cortex (PFC), especially left PFC, blood flow and metabolism in depressed unipolar patients are the most consistently replicated findings; there is preliminary evidence that they may correlate with severity of illness and cognitive impairment. Basal ganglia abnormalities have also been found in depressed unipolar patients, involving decreased blood flow and metabolism. Increased activity of amygdala is also observed. Other neuroimaging studies in major depression point to abnormalities in the hippocampus, cingulate, and related parts of the striatum and thalamus. These data suggest a neural model in which dysfunction of limbic, striatal, and PFC structures impair the modulation of the amygdala/hippocampus complex, leading to abnormal processing of emotional stimuli.
In unipolar depression, little is known about the state or trait characteristics of these findings, as the exact relationships between functional neuroimaging findings and clinical course has not been systematically investigated. Depression also tends to be associated with lesions in the left frontotemporal or right parieto-occipital regions. This concept is consistent with neuroanatomical and behavioral findings in stroke patients. Patients with dominant anterior or nondominant posterior strokes are especially vulnerable to secondary depressions, whereas patients with nondominant anterior or dominant posterior strokes are especially vulnerable to mania or hypomania.
Major depressive disorder may be preceded by dysthymic disorder (10% in community samples, and 15–25% in clinical samples). Table 18–14 summarizes the course and prognosis of both non-bipolar disorders and bipolar disorders.
Table 18–14. Course and Prognosis of Mood Disorders ||Download (.pdf)
Table 18–14. Course and Prognosis of Mood Disorders
Age at onset
Duration of episode
Before 1960: 7–13 months; after 1960: 2–4 months
Before 1960: 24% develop episodes > 1 yr; after 1960: 18% develop episodes > 1 yr
5–10% do not recover from index episode
More chronic course, more episodes, length of cycle shortens with more frequent episodes
More benign in one-third of patients, length of cycle shortens with more frequent episodes
Mortality and suicide
Completed suicide occurs in 10–15% of patients with bipolar I disorder
Up to 15% commit suicide
Major depressive disorder may begin at any age, with an average age at onset in the mid-teens to late 20s. Symptoms typically develop over days to weeks, and prodromal symptoms and preexisting comorbid conditions (e.g., generalized anxiety, panic attacks, phobias) are common. Although some patients have only a single episode, with full return to premorbid functioning, approximately 50% of patients with such episodes will eventually have another episode, at which time they will meet criteria for recurrent depression.
The course of recurrent depression is variable. Some patients have a few isolated episodes separated by stable intervals (years) of normal functioning. Others have clusters of episodes, and still others have increasingly frequent episodes with shortening of the interepisode interval and generally increased disease severity. Some patients experience a major depression without full remission before the next; this is referred to as major depression without interepisode recovery. About 50% of patients with one depressive episode will have a recurrence, and about 90% of patients who have had three episodes can be expected to have a fourth. Thus the number of past episodes can serve as a predictor of the future (i.e., as the number of recurrences increases, the episodes lengthen in duration and increase in both frequency and intensity). The average number of lifetime episodes is around five. About 5–10% of patients with an initial diagnosis of major depressive disorder subsequently develop a manic episode.
Depressive episodes may remit completely, partially, or not at all. The patient's functioning usually returns to the premorbid level between episodes, but 20–35% of patients show persistent residual symptoms and social or occupational impairment. Data from the prepsychopharmacology era (i.e., before 1960) suggest that, if untreated, a depressive episode may last about 12 months. Relapse is common. Almost 25% of patients relapse within the first 6 months of remission, especially if they have discontinued their antidepressant medications; 30–50% relapse in the first 2 years; and 50–75% relapse within the first 5 years. The risk of relapse during early remission can be reduced significantly by maintaining patients on antidepressants for at least 6 months—a regimen now generally viewed as important in managing the recurring nature of the illness.
A major depressive episode often follows acute psychosocial stressors, such as death, loss of a loved one, divorce, or acute medical illness. There is evidence that psychosocial stressors are more important in triggering or facilitating the first two depressive episodes and that their influence becomes less important in subsequent episodes.
Ahmed N, Loosen PT: Thyroid hormones in major depressive and bipolar disorders. In: Casper R (ed).Women's Health and Emotion. England: Cambridge University Press, 1997, pp. 83–108.
Beyer JL,Krishnan KR: Volumetric brain imaging findings in mood disorders. Bipolar Disord
Drevets WC: Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res
Goodwin FK,Jamison KR:Manic Depressive Illness. New York: Oxford University Press, 1990.
Loosen PT: Hormones of the hypothalamic-pituitary-thyroid axis: A psychoneuroendocrine perspective. Pharmacopsychiatry
Nemeroff CB,Loosen PT (eds):Handbook of Clinical Psychoneuroendocrinology. New York: Guilford Press, 1987.
Soares JC,Mann JJ: The functional neuroanatomy of mood disorders. J Psychiat Res
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An important aspect of the treatment of depression is for the physician to discuss with patients and their families the illness, its symptoms and course, and particularly its recurrent nature. Patients should recognize that the illness may recur; they—and their close family members—should be cognizant of the premonitory signs and symptoms of an impending episode (i.e., insomnia, especially early morning awakening, loss of energy, loss of appetite and libido, and diurnal changes in well-being); and they should be told to return to their physician as soon as they have noticed any combination of the premonitory signs for, say, longer than 1 week. This, of course, is best achieved if patients are followed up closely in and out of episodes, if the communication between the physician and the patient or patient's family is open and continuous, and if all parties are thoroughly aware that the nature of the illness necessitates both close, continuous observation of its course and early, decisive intervention to prevent relapse. It is also important to recognize that clinical features often have significant treatment implications. A summary of these features and their suggested solutions is provided in Table 18–4.
Table 18–4. Clinical Features Influencing Treatment and Their Solutions ||Download (.pdf)
Table 18–4. Clinical Features Influencing Treatment and Their Solutions
Even mild depression, if unresponsive to nonsomatic treatment, should be considered for antidepressants.
Consider for maintenance therapy.
Prior mania or hypomania
Somatic treatments may provoke (hypo)manic episodes in approximately 5–20% of patients (most have a history of bipolar disorder). Such treatments may also precipitate rapid-cycling bipolar disorder. The treatments of choice are lithium alone or in combination with a MAOI or buproprion.
Depression with psychotic features
Carries a higher risk of suicide and recurrent depression. Combine a neuroleptic with an antidepressant or use amoxapine.
Depression with catatonic features
If intravenous injections of lorazepam or amobarbital are not immediately helpful, consider ECT.
Depression with atypical features
Features include anxiety, reverse polarity (e.g., hypersomnia, hyperphagia, marked mood reactivity), and a sense of severe fatigue. TCAs are useful in only 35–50% of patients; in contrast, MAOIs yield response rates of 55–75%.
Depression with alcohol and/or substance abuse
A patient who has major depression with comorbid addiction is more likely to require hospitalization, more likely to attempt suicide, and less likely to comply with treatment than is a patient without such comorbidity. Advisable to detoxify the patient before initiating antidepressant treatment.
Depression with panic and/or anxiety disorder
Panic disorder complicates major depression in 15–30% of cases. Good response to non-MAOI antidepressants, especially imipramine.
Lacks the signs of cortical dysfunction seen in true dementia (e.g., aphasia, apraxia, agnosia); treat early and aggressively.
Depressive symptoms complicate the course of schizophrenia in 25% of cases. Add antidepressant to neuroleptic regimen.
Depression during or after pregnancy
Carefully assess the benefit-risk ratio, especially if treatment is prescribed during the first trimester. If possible, avoid pharmacologic treatment in nursing mothers. Be aware of the possible teratogenic effects of benzodiazepines (i.e., cleft lip and palate) and lithium (i.e., cardiac malformations). Consider ECT as alternative treatment.
Depression superimposed on dysthymia
Antidepressant treatment may resolve both major depression and underlying dysthymia. SSRIs and MAOIs may be the most helpful.
Depression superimposed on personality disorder
Frequently associated with atypical features; more likely to respond to MAOIs or SSRIs. Patients usually show less satisfactory treatment response in regard to both social functioning and residual depressive symptoms.
The following general principles provide a useful framework for the clinical use of antidepressants in major depressive disorder: (1) diagnose properly; (2) avoid treatment of symptoms (e.g., agitation, insomnia, memory disturbances) if possible, because most symptoms fit into specific diagnostic entities; and (3) be aware of the cycling course of the disease, because it necessitates different treatment approaches: Acute treatment for florid symptoms; continuation therapy to prevent early relapse; and maintenance therapy to make relapse (i.e., recurrence) less likely or, if it occurs, less severe.
Antidepressant drugs are used successfully to treat a variety of psychiatric and other conditions (19.1–4). In mood disorders, they are used most widely in the treatment of major depressive disorder, but they also have some (albeit reduced) therapeutic activity in treating dysthymic disorder and bipolar disorder (see sections on Dysthymic Disorders and Bipolar Disorders later in this chapter).
The effectiveness of antidepressants in young patients remains controversial, because some controlled clinical trials failed to show consistent beneficial effects in children and adolescents. Even though mitigating factors such as different study designs, medication compliance, and the impact of exogenous factors (e.g., family discord) on symptom manifestation limit the interpretation of these studies, antidepressant drugs are used widely in depressed children and adolescents. Moreover, antidepressants may increase risk of self-injury transiently. However, the best data suggest that the overall risk of suicide in children and adolescents is reduced by antidepressant treatment.
In contrast, antidepressants are very useful in elderly depressed patients, in whom daily dosage requirements are normally reduced because of pharmacokinetic changes associated with aging (i.e., reductions in both hepatic clearance and protein binding).
Antidepressants are usually initiated at a low dosage and increased over a 7–10-day period to achieve the initial target dosage. The dosage may have to be increased further in some patients in order to achieve the best results. With suicidal patients, the physician must take extra care early in the treatment because behavioral activation can precede observable mood effects, providing patients with sufficient energy to act on suicidal impulses.
Response to treatment should be evaluated every 3–4 weeks. If the patient is not fully recovered, and if there are no dose-limiting side effects, the dosage should be increased to the next incremental level. This plan should be followed until remission is achieved, dose-limiting side effects occur, or the upper end of the therapeutic range is reached. Absent full remission, the treatment should then be switched to a drug of a different therapeutic class. Augmentation or combination therapy should be considered if there is only partial response.
Once a therapeutic effect is achieved, the antidepressant medication should be continued through the period of high vulnerability for relapse (i.e., at least 6 months for continuation therapy). Because more than 60% of depressed patients will eventually relapse, especially if unprotected by medication, and because future episodes are more severe, it has been proposed that some depressed patients be placed on long-term treatment. Such maintenance therapy for extended periods of time (even years) should be considered if (1) the patient is older than 40 years and had two or more prior episodes of illness, (2) the first episode occurred at age 50 years or older, (3) the patient has a history of three or more depressive episodes, or (4) the patient has been depressed or dysthymic for 2 or more years before treatment.
Slow tapering of the antidepressant medication can be considered after at least 5 years of treatment if the patient is completely asymptomatic and is not experiencing or anticipating significant stressors. Some patients prefer lifetime treatment rather than risking a return of depression.
Table 18–5 lists common adverse effects associated with antidepressant drugs, their possible mechanisms, and their management. Table 18–6 indicates the relative potency of antidepressants at producing these effects (Table 18–7).
Table 18–5. Common Clinical Uses of Antidepressants ||Download (.pdf)
Table 18–5. Common Clinical Uses of Antidepressants
Major depressive disorder
Generalized anxiety disorder
Bipolar disorder, depressed type
Panic disorder (with or without agoraphobia)
Chronic pain syndromes*
Table 18–6. Mechanisms and Management of Common Antidepressant Side Effects of Antidepressants ||Download (.pdf)
Table 18–6. Mechanisms and Management of Common Antidepressant Side Effects of Antidepressants
Dry mouth, blurred vision, constipation, urinary retention, mild sinus tachycardia, memory problems.
Dry mouth: Candy, sugarless gum.
Constipation: Hydration, bulk laxatives.
Urinary retention: Bethanechol, 30–200mg/day. Use bupropion, sertraline, or trazodone.
Orthostatic hypotension, dizziness, reflex tachycardia, flushing, diaphoresis, potentiation of the antihypertensive effect of prazosin.
Orthostatic hypotension: Increase dosage slowly, use safer agents such as nortriptyline, desipramine, bupropion, or SSRIs. Exert especial caution in elderly patients who are susceptible to falls and fractures.
TCAs, MAOIs, trazodone, nefazodone
Histaminic (H) antagonism
Somnolence, weight gain, hypotension, and potentiation of CNS depressants.
Weight gain: Bupropion, fluoxetine, sertraline, and trazodone are alternatives; bupropion and fluoxetine may reduce weight.
NE reuptake blockade
Tremor, tachycardia, insomnia, anxiety, erectile and orgasmic dysfunction, blockade of the antihypertensive effect of guanethidine and guanadrel.
TCAs, most heterocyclics
5-HT reuptake blockade
Nausea, diarrhea, anorexia, anxiety, headache, insomnia, sexual dysfunction (loss of erectile or ejaculatory function in men, loss of libido and anorgasmia in women).
Sexual dysfunction: Neostigmine, 7.5–15.0 mg taken 30 min before intercourse will enhance libido and reverse delayed ejaculation. Cyproheptadine, 4 mg/day orally may reverse anorgasmia.
SSRIs, clomipramine, venlafaxine, MAOIs
DA reuptake blockade
Psychomotor activation, insomnia, anxiety, aggravation of psychosis, potentiation of antiparkinsonian agents.
TCAs (weak), bupropion
DA receptor blockade
Parkinsonian (i.e., extrapyramidal) effects, elevation of prolactin with gynecomastia and galactorrhea.
Amoxapine, TCAs (weak)
5-HT receptor antagonism
Trazodone, nefazodone, amitriptyline
Neurologic side effects: Seizures, mild myoclonus, toxic confusional state.
Seizures: Fluoxetine, sertraline, trazodone, and MAOIs carry a lower risk to induce seizures.
Myoclonus: Clonazepam, 0.25 mg three times daily.
Toxic confusional state: Seen at higher dose and blood levels, responds to lowering the dose.
Effects like those of class I antiarrhythmic agents
Cardiovascular effects: TCAs may induce symptomatic conduction defects and orthostatic hypotension
Monitor those patients carefully who take already another class I antiarrhythmic agent.
among patients with preexisting but asymptomatic conduction defects. TCAs may also provoke arrhythmia in patients with subclinical sinus node dysfunction.
Evaluate patients for preexisting but asymptomatic conduction defects such as interventricular conduction delay and bundle branch block.
Be aware that patients with prolonged QT intervals, whether preexisting or drug-induced, are predisposed to the development of ventricular tachycardia.
Obtain ECG in all patients older than 40 yr before initiating treatment.
Insomnia and anxiety.
Minimize anxiety by starting at a low dose.
Manage insomnia by adding trazodone, 100 mg at bedtime (be aware that trazodone can induce priapism in some patients).
Fluoxetine (anxiety and insomnia); desipramine and bupropion (anxiety)
Table 18–7. Clinical Characteristics of Antidepressants ||Download (.pdf)
Monoamine Oxidase Inhibitors
Common side effects of MAOIs include those associated with α1-adrenergic or muscarinic/cholinergic antagonism (see Table 18–5). They are generally manageable by slowing the dose titration or by adjusting the maximum dosage. Less common reactions include ataxia, color blindness, hepatotoxicity, or induction of mania in bipolar patients. Withdrawal reactions—including anxiety, restlessness, insomnia, nausea, agitation, myoclonus, and in extreme cases, the induction of mania—may occur after abrupt discontinuation.
The most serious side effect associated with MAOI use is the development of an acute hypertensive crisis. The metabolism of certain dietary amino acids, especially tyramine, is blocked by MAOIs. The resulting increase in neurotransmitter availability can lead to an acute hypertensive crisis, with patients complaining about pounding headaches and presenting with flushing and blood vessel distention. The reaction must be considered a medical emergency to be treated with slow intravenous administration of the α-adrenergic antagonist phentolamine, 5 mg (which may be repeated hourly as needed).
MAOIs may also produce acute toxicity by interfering with the metabolic clearance of other drugs, including general anesthetics, barbiturates and other sedatives, antihistamines, alcohol, narcotics (particularly meperidine), anticholinergic agents, TCAs, and sympathomimetic amines (e.g., pseudoephedrine used commonly in decongestants).
Coadministration of MAOIs with either SSRIs or l-tryptophan can provoke a central serotonin syndrome, characterized by acute mental status changes (e.g., confusion, hypomania), restlessness, myoclonus, diaphoresis, tremor, diarrhea, hyperreflexia, and occasionally, seizures, coma, and death. The syndrome is usually mild in nature and resolves within 24 hours after drug discontinuation. MAOIs should therefore not be started within 2 weeks of discontinuation of most SSRIs (5 weeks in the case of fluoxetine, because of its long half-life time [HLT] [see next section]).
Coadministration of TCAs and MAOIs (used occasionally for the management of treatment-refractory depression) can produce serious side effects, including delirium and hypertension. It is therefore advisable to wait at least 2 weeks after discontinuing TCAs before initiating treatment with MAOIs. Table 18–8 lists foods and drugs that can produce serious adverse effects. Patients should be given a copy of this list before beginning treatment with MAOIs.
Table 18–8. Dietary and Drug Restrictions Associated with MAOI Antidepressants ||Download (.pdf)
Table 18–8. Dietary and Drug Restrictions Associated with MAOI Antidepressants
Very dangerous (must be avoided under all circumstances)
All cheese (cottage cheese, cream cheese, and yogurt are safe)
Asthma inhalants (pure steroid inhalants are safe)
Decongestants, cold, and sinus medications
Serotonin-active antidepressants (e.g., clomipramine, fluoxetine, sertraline, paroxetine, fluvoxamine)
Moderately dangerous (should be avoided)
All fermented or aged foods (e.g., aged corned beef, salami, fermented sausage, pepperoni, summer sausage, pickled herring)
Fermented alcohol beverages (e.g., red wine, sherry, vermouth, cognac, beer, and ale) (clear alcoholic drinks are permitted in true moderation)
Broad bean pods (e.g., English broad beans, Chinese pea pods)
Liver (chicken, beef or pork) or liverwurst
Meat or yeast extracts
Spoiled fruit (e.g., spoiled bananas, pineapples, avocados, figs, raisins)
Local anesthetics with epinephrine (safe without epinephrine—e.g., carbocaine)
Narcotics (codeine is safe)
TCAs (e.g., imipramine, amitriptyline, nortriptyline, desipramine, doxepin)
Minimal danger (rarely associated with hypertensive episodes and can be eaten in small amounts)
TCAs & Related Antidepressants
Tricyclic-induced side effects are the result of their binding to both specific (e.g., norepinephrine or serotonin) and nonspecific (e.g., histamine, muscarinic) sites. Table 18–6 summarizes these actions and their consequences.
The tertiary amine TCAs—amitriptyline, imipramine, and doxepin—tend to be more potent at binding sites unrelated to the mechanism of action and, therefore, tend to produce more severe side effects than the secondary amine TCAs nortriptyline and desipramine (see Tables 18–6 and 18–7).
TCAs and trazodone can affect the heart in the same way as the class 1 antiarrhythmics quinidine or procainamide, inducing atrioventricular (A-V) conduction delays. Special care should be taken with patients who have a first-degree A-V block (a relative contraindication) or a second-degree A-V block (an absolute contraindication) (see Table 18–6). As type 1 antiarrhythmics, these antidepressants may pose greater long-term risk than previously thought. The primary antiarrhythmics can increase the risk of sudden death from a presumed arrhythmic source. This may explain the long-standing observation of increased risk of sudden death in patients treated chronically with TCAs.
Maprotiline is associated with an increased risk for seizures at higher dosages and plasma levels and has never gained wide use in the United States. Venlafaxine, a mixed norepinephrine and serotonin reuptake inhibitor, can produce mild hypertensive reactions, especially at dosages greater than 300 mg/day. Risk factors for hypertension, such as age, race, or preexisting renal or hypertensive disorder, are usually not associated with this effect.
Selective Serotonin Reuptake Inhibitors
SSRIs potently and selectively block the uptake of serotonin, thereby producing characteristic side effects such as nausea, diarrhea, anorexia, anxiety, headache, insomnia, and orgasmic dysfunction (see Table 18–6). Sexual dysfunction is troublesome and can be persistent. It can be managed by reducing the dosage or by switching to bupropion or nefazodone. Cyproheptadine, yohimbine, or methylphenidate are also occasionally useful in reversing these effects. Finally, sildenafil has been shown in controlled trials to be beneficial in both men and women.
All antidepressant drugs are highly lipophilic and are absorbed readily from the gastrointestinal tract. Plasma peaks typically occur within 30–60 minutes and remain unbound for 30 minutes.
Most (80–90%) antidepressants are highly protein bound, although individual differences in binding can produce a fourfold variation in the amount of free drug. Tissue distribution and demethylation, the first step in metabolism of tertiary heterocyclics, occur rapidly. All antidepressants can be displaced by other drugs with similar protein-binding characteristics. Similarly, antidepressants will displace other compounds that are highly protein bound (e.g., the anticoagulant warfarin); this can increase the free fraction of these drugs and, therefore, both its therapeutic and its adverse effects.
Antidepressants are metabolized mainly in the liver. Metabolism includes demethylation, hydroxylation, and glucuronide conjugation. Individual differences in a patient's microsomal enzyme activity produce steady-state plasma concentrations (bound and unbound) that may vary as much as 40-fold. During the first pass through the liver, about 80% of the drug is degraded (the so-called first-pass effect). The first demethylation of imipramine and amitriptyline produces (the clinically highly active) desipramine and nortriptyline, respectively; these and other drugs have active metabolites that significantly prolong their biological half-lives. Glucuronide conjugation occurs after hydroxylation and makes the derivative water soluble; approximately 65% of the drug is eventually eliminated in the urine. Plasma clearance is slow.
Impairment of hepatic or renal function will reduce plasma clearance of antidepressants and thus potentiate their effects. Antipsychotics, by competing for metabolism, can have a similar effect. Conversely carbamazepine and barbiturates, by inducing metabolism, can reduce their therapeutic efficacy.
After a single oral dose, distribution is most important in regard to clinical efficacy; after chronic dosing, HLT becomes more important. The HLTs of the most commonly used antidepressants are given in Table 18–9.
Table 18–9. HLTs of Common Antidepressants
Predicting Treatment Response & Managing Treatment Failure
Several factors are useful in predicting a patient's clinical response (positive and negative) to an antidepressant (Table 18–10).
Table 18–10. Predictors of Antidepressant Response ||Download (.pdf)
Table 18–10. Predictors of Antidepressant Response
Vegetative symptoms (anorexia, weight loss, middle and late insomnia)
Diurnal mood variation
Psychomotor agitation or retardation
Autonomous and pervasive symptoms
Family history of depression
Dose of imipramine (or equivalent dose of another heterocyclic) above 125–150 mg/day
Blood levels of desipramine (or imipramine and desipramine) above 200 ng/ml, and nortryptiline between 50 and 150 ng/ml
Coexistence of other significant psychiatric disturbances (particularly with hysterical or externalizing features)
Hypochondriacal concerns or predominant somatic features
Previous drug trial failure(s)
History of sensitivity to adverse reactions
Between 60% and 70% of persons with major depressive disorder respond to an adequate antidepressant drug trial. However, only about one-third of patients fully recover. The reasons for treatment failure include inadequate dose and/or serum level, inadequate duration of treatment (minimum 6 weeks), prominent side effects, noncompliance, and incorrect diagnosis.
Because single doses of antidepressants can produce widely varying drug serum levels, the patient's plasma levels should be measured in order to ensure optimal dosing when available. Unfortunately, only plasma levels of tricyclics are widely available. Associations between plasma levels and clinical response are known for several antidepressants (Table 18–11). The monitoring of the plasma level of nortriptyline is particularly important because there appears to be a therapeutic window in which the drug is most effective. Plasma levels can also be assessed for other antidepressants, including fluoxetine, but the relationship between plasma levels and clinical response is less well understood for these agents. Indications for monitoring drug levels of antidepressants are (1) failure to respond to a presumably adequate trial in terms of dose and duration; (2) concurrent physical illness, especially cardiovascular disease; (3) use of higher than usual doses (i.e., greater than 300 mg/day of imipramine); (4) treatment in the very young or old (or in any patient with decreased protein binding); (5) the presence of side effects uncertainly related to drug treatment; and (6) drug overdose.
Table 18–11. Therapeutic Plasma Levels of Antidepressants
When a true treatment failure has occurred, the physician needs to consider an alternative approach. This may involve trying another treatment approach (e.g., ECT or combining TCAs with an MAOI) or using one of several augmentation strategies (Table 18–12). A large body of evidence supports these strategies, and particularly in tertiary care centers (to which most nonresponders normally are referred) they are widely and safely used.
Table 18–12. Alternative Therapies for Treatment-Resistant Depression ||Download (.pdf)
Table 18–12. Alternative Therapies for Treatment-Resistant Depression
Augmentation of TCAs or MAOIs with
Psychostimulants (amphetamine, methylphenidate—in combination with TCAs only)‡
TCA/MAOI combination (use with extreme care)†
ECT (reserved primarily for severe intractable depression or when the patient is acutely suicidal)*
Phototherapy or light therapy†
Psychostimulants alone (reserved largely for treatment in elderly depressed patients)‡
Psychotherapy (cognitive-behavioral and interpersonal psychotherapy) alone or in combination with TCAs†
Lithium carbonate, thyroid hormone (preferably T3), or sleep deprivation are effective in augmenting the therapeutic effects of TCAs. Among these strategies, sleep deprivation is the least invasive and most easily conducted technique. Its antidepressant effects, observed in about 65% of patients after only one night of wakefulness, are immediate; it is entirely free of side effects; and patients can repeat it easily and safely even after they have been discharged from the hospital. Care must be taken, however, since patients may relapse quickly after recovery sleep. Lithium can be titrated to standard serum levels and T3 started at 25 μg/day; both augmentation strategies should be maintained for a minimum of 3 weeks in the absence of therapeutic response. About half of patients who have not responded to the standard antidepressants will experience sudden clinical improvement. It is not known whether lithium or T3 should be continued after a clinical response has occurred. T3 appears to be effective in the augmentation of SSRI's and related newer medications. However, the effectiveness of lithium has been called into question.
Alternative methods for treating refractory depression include the use of a combination of a noradrenergic antidepressant such as desipramine or bupropion with a serotonergic one such as fluoxetine. If TCA's are used, care must be taken to measure the plasma level since SSRIs are competitive inhibitors of metabolism by liver cytochrome enzymes, especially CYP2D6. This can lead to a dangerous increase in plasma levels. Hence TCA plasma levels should be measured with concomitant use. Psychostimulants such as amphetamine or methylphenidate may be useful in some patients but in a more limited way.
The addition of cognitive–behavioral psychotherapy (CBT) to antidepressant treatment also appears to be beneficial in many patients. In particular, a version of CBT specifically designed to aid in chronic depression, referred to as cognitive behavioral analysis system of psychotherapy (CBASP) has been shown to be effective in one large scale clinical trial. The effects of other psychotherapies have not been established.
If these techniques are ineffective, two other options remain. The first is to use a TCA and an MAOI together, but this strategy bears some risk of acute and potentially serious side effects. As well, the data supporting the effectiveness of this combination is very limited. Imipramine and phenelzine are commonly employed. Typically, the MAOI is started first. Once a stable dose is achieved, a tricyclic may be started at low dose. Patients must be cautioned regarding potential negative consequences, including hypertensive reactions. ECT is another available treatment that can be used in the face of nonresponse. A more extensive discussion of ECT is found below.
American Psychiatric Association: Practice guidelines for the treatment of patients with major depressive disorder in adults. Am J Psychiatry 2000;157(Suppl 4):1–45.
Baldessarini RJ: Drugs and the treatment of psychiatric disorders, depression and mania. In: Hardman JG,Limbird LE (eds).The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 1996, pp. 431–459.
Charney DS,Berman RM,Miller HL: Treatment of depression. In: Schatzberg AF,Nemeroff CB (eds).Textbook of Psychopharmacology, 2nd edn. Washington, DC: American Psychiatric Press, 1998.
Glassman AH,Roose SP,Bigger JT, Jr.: The safety of tricyclic antidepressants in cardiac patients: Risk-benefit reconsidered. J Am Med Assoc
Goodwin FK,Jamison KR:Manic Depressive Illness. New York: Oxford University Press, 1990.
Schatzberg AF,Nemeroff CB (eds):Textbook of Psychopharmacology, 2nd edn. Washington, DC: American Psychiatric Press, 1998.
Keller MB,McCullough JP,Klein DN, et al.: A comparison of nefazodone
, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med
Between 80% and 90% of all ECT treatments in the United States are performed for the treatment of major depressive disorder. Although ECT appears to be most effective in the most severely depressed patients, attempts to use clinical symptoms, patient history, demographics, or other factors as predictors of clinical response have been largely unsuccessful.
ECT has shown efficacy in all types of major depressive disorder. Recent evidence suggests that it is less useful in patients whose depressive episodes occur in the context of a concurrent mental or medical disease (i.e., secondary depression) or in the treatment of depression that has been refractory to medications during the present episode.
The decision to refer a patient for treatment with ECT is made only after careful considerations of its risks and benefits. ECT is used as primary treatment when (1) an urgent need (either psychiatrically or medically) for a rapid response exists, (2) there is less risk with ECT than with other treatment alternatives, (3) there is a patient history of better response to ECT, or (4) there is a strong patient preference for its use. A majority of patients referred for ECT do not meet these criteria. ECT is used as a secondary treatment when (1) the patient has responded poorly to or is intolerant of alternative treatments or (2) the patient has deteriorated to the point at which a rapid response is needed urgently.
There are no absolute contraindications to the use of ECT, but some conditions are relative contraindications (Table 18–13). If treatment with ECT becomes necessary on a life- saving basis, these risks can generally be minimized to some extent using appropriate pharmacologic interventions. With appropriate preparation, ECT can be used effectively and safely in both pregnant and elderly patients.
Table 18–13. Relative Contraindications to ECT ||Download (.pdf)
Table 18–13. Relative Contraindications to ECT
Space-occupying intracerebral lesions (except for small, slow growing tumors without edema or other mass effect)
Conditions with increased intracranial pressure
Unstable vascular aneurysms or malformations
Recent myocardial infarction
Adverse Outcomes of Treatment
The overall mortality rate of ECT is extremely low; it approximates that of brief general anesthesia. Estimates range between 1 in 10,000 (0.01%) and 1 in 1000 (0.1%) patients.
There is no relationship between ECT and brain damage; however, temporary cognitive changes do occur and are often the most notable and most distressing side effects. Three types of cognitive change may be observed:
Postictal confusion. Because ECT induces seizure activity, all patients experience some transient confusion, lasting from a few minutes to a few hours, after they awaken from the ECT treatment. Most patients usually will not remember the immediate postictal period and will not experience the cognitive changes following a seizure as a significant disturbance. Reassurance, support, and avoidance of cognitive demands during the acute postictal period are typically all that is necessary for treatment. Postictal sedation with a short-acting benzodiazepine such as midazolam may be necessary if the patient becomes agitated.
Interictal confusion. Occasionally postictal confusion may not disappear fully, and when severe, it may develop into an interictal confusional state or delirium. This phenomenon, which is uncommon, may be cumulative over the ECT course but disappears rapidly over a period of days after the conclusion of treatments.
Memory impairment. Amnesia often occurs with ECT and varies considerably in both severity and persistence. Memory disturbances consist of both retrograde amnesia (i.e., difficulty in recalling information learned prior to the ECT course) and anterograde amnesia (i.e., difficulty in retaining newly learned information). When present, anterograde and retrograde amnesia disappear rapidly over a period of days to weeks after completion of the ECT course.
A small group of patients report that their memory never returned to normal after ECT. The etiology for this phenomenon is unclear, and objective memory testing generally does not substantiate the subjective complaint. Possible explanations for this phenomenon may include (1) patients incorrectly attribute memory problems associated with depression to prior ECT, (2) anesthetic misadventure (e.g., hypoxia), or (3) other, occult memory impairment (e.g., evolving dementia).
During the seizure and acute postictal period, the sympathetic and parasympathetic autonomic systems are stimulated sequentially. Activation of the sympathetic system increases heart rate, blood pressure, and myocardial oxygen consumption, placing an increased demand on the cardiovascular system. Activation of the parasympathetic system causes a transient reduction in cardiac rate. These changes in heart rate and cardiac output challenge the cardiovascular system, occasionally giving rise to transient arrhythmias and, in susceptible individuals, transient ischemic changes. Most cardiovascular changes are minor, and the risk of complications can be diminished greatly by the use of oxygen and appropriate medications in susceptible patients.
General somatic complaints (i.e., headaches, nausea, muscle soreness) are common after ECT. Analgesics may be given prophylactically prior to ECT to patients who routinely have post-ECT headaches. The dosage of muscle relaxant should be increased if muscle soreness and headaches are due to inadequate relaxation.
About 7% of depressed bipolar patients switch into a manic or mixed state after ECT. This state can be managed by either continuing ECT or stopping ECT and administering an antimanic agent.
A typical ECT course involves 6–12 treatments, but the number required may be as low as 3 or as high as 20. Alterations in the ECT course should be considered for nonresponders or for patients whose clinical progress is minimal after approximately six treatments. Alterations may include changing from unilateral to bilateral electrode placement, increasing stimulus intensity, or potentiating the seizure pharmacologically. If there is still no response after three or four additional treatments, or if the patient's response has reached a plateau below a full level of remission, the ECT course should be terminated.
Multiple monitored electroconvulsive therapy (MMECT) was developed in an attempt to decrease the average length of the treatment course by inducing multiple seizures (usually 2–10) during a single treatment. MMECT appears to be associated with a more rapid clinical response, but the total number of seizures required is greater. There is also evidence that MMECT is associated with a higher frequency of prolonged seizure activity, exaggerated cardiovascular responses, and increased cognitive side effects.
In the United States, most ECT treatments are given three times a week (e.g., Monday, Wednesday, and Friday). An increase in the frequency is associated with a more rapid response but also increased cognitive side effects.
Most psychiatrists agree that after the remission of a depressive or manic episode, ECT treatment should be continued for at least 6–12 months. After the conclusion of a course of ECT, there are three options for continued treatment: (1) administration of appropriate psychotropic medications (e.g., antidepressants); (2) continuation of ECT; or (3) psychotherapy, combined with pharmacotherapy or ECT.
Because of the severity and chronicity of some patients’ illnesses, many practitioners now prophylactically continue pharmacotherapy or ECT for longer time periods, particularly when attempts to discontinue treatment have resulted in a recurrence of the illness. Maintenance ECT treatments may be given monthly, although some individuals require more frequent administration (e.g., weekly). There is no lifetime maximum number of treatments that a patient may have. Cumulative amnestic effects are not usually seen.
American Psychiatric Association: The Practice of ECT: Recommendations for Treatment, Training, and Privileging. Washington, DC, American Psychiatric Press, 1990.
Weiner RD,Coffey CE: Electroconvulsive therapy in the medical and neurologic patient. In: Stoudemire A,Fogel BS (eds).Psychiatric Care of the Medical Patient. New York: Oxford University Press, 1993, pp. 207–224.
A number of clinical studies have shown that vagus nerve stimulation (VNS) has antidepressant effects in patients with depression resistant to four or more treatments. Improvement with VNS result in enhanced neurocognitive function in many patients. VNS appears to be most effective in patients with low to moderate antidepressant resistance. Response rates usually range from 30–40%, and long-term VNS treatment appears to be associated with sustained symptomatic improvement. VNS is also known to improve mood in depressed patients with epilepsy.
Transcranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive and easily tolerated method of altering cortical physiology. Clinical studies support an antidepressant effect of high-frequency rTMS administered to the left PFC; however, antidepressive efficacy is not consistent, and where efficacy is demonstrated, degree of clinical improvement appears to be small. The absence of psychosis, and younger age may be predictors of treatment success. Low frequency TMS to the right PFC also has shown promise. Repetitive TMS may be useful in augmenting or hastening the response of antidepressant drugs in patients with major depressive disorder.
The establishment and maintenance of a supportive therapeutic relationship, wherein the therapist gains the patient's confidence and is available in times of crisis, is crucial in the treatment of depression. Beyond pure psychotherapeutic management the therapeutic relationship contains other important factors. These include observing emerging destructive impulses toward self or others; providing ongoing education, knowledge, and feedback about the patient's illness, its prognosis, and treatment; discouraging the patient from making major life changes while he or she is depressed; setting realistic, attainable, and tangible goals; and enlisting the support of others in the patient's social network.
Depression is often treated with psychotherapy, either alone or in combination with antidepressants. This is particularly true for unipolar depression. The psychosocial interventions that have fared well in controlled trials relative to antidepressants include interpersonal psychotherapy, cognitive–behavioral therapy, and some of the marital and family interventions. Traditional dynamic psychotherapy has not proved effective but may not have been evaluated adequately.
Interpersonal psychotherapy seeks to recognize and explore depressive precipitants that involve interpersonal losses, role disputes and transitions, social isolation, or deficits in social skills. It focuses on current interpersonal problems and deemphasizes childhood antecedents or extensive attention to transference in the therapeutic relationship. Interpersonal psychotherapy can be effective in reducing depressive symptoms in the acute phase of nonmelancholic major depression of lesser severity. It seems to produce a greater change in social functioning than antidepressants; this change may not appear until after several months of treatment (or until several months after treatment is over).
Cognitive–behavioral therapy is based on the premise that helping patients recognize and correct erroneous beliefs and maladaptive behaviors can relieve their affective distress. It also can be effective in reducing depressive symptoms in the acute phase of major depression. Cognitive–behavioral therapy may have an enduring effect that protects the patient against subsequent relapse following treatment termination. A recent large-scale clinical trial has shown that CBT is about as effective as the antidepressant paroxetine in moderate to severe major depression. Moreover, CBT reduced the likelihood of relapse over continuation placebo or medication over the subsequent year. Comorbid generalized anxiety disorder favored treatment with paroxetine. In the treatment of very severe depression in outpatients neither interpersonal therapy nor cognitive–behavioral therapy are quite as effective as antidepressant drugs.
A recent multi-center trial of patients with chronic depression compared the antidepressant effects of an antidepressant (Nefazodone), Cognitive Behavioral Analysis System of Psychopathology (CBASP), a psychotherapy method designed for chronic depression, or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma or abuse, psychotherapy alone was superior to antidepressant monotherapy, suggesting an important role of psychotherapy in the management of patients with chronic forms of major depression and a history of childhood trauma.
Marital Therapy & Family Therapy
Marital and family problems are common in the course of mood disorders. They may be a consequence of depression but may also increase the patient's vulnerability to depression and in some instances retard recovery. Research suggests that marital therapy and family therapy may reduce depressive symptoms and the risk of relapse in patients with marital or family problems.
Selection of Specific Therapies
Patient preference plays a large role in the selection of a particular form of psychotherapy. In choosing the most appropriate form, the psychiatrist should consider that an interpersonal approach may be more useful for patients who are in the midst of conflicts with significant others and for those having difficulty adjusting to an altered career or social role or other life transition. A cognitive approach can be helpful for patients who seek and are able to tolerate explicit, structured guidance from another party.
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