DEPRESSION - KAPPLAN

Among the several implicated alleles is the gene that codes for the promoter region of the serotonin transporter (5-HTT), which has been found by a number of researchers to moderate the association between stressful life events and the risk of depression

Modern affective neuroscience focuses on the importance of four brain regions in the regulation of normal emotions: The PFC, the anterior cingulate, the hippocampus, and the amygdala (Fig. 13.4-2). The PFC is viewed as the structure that holds representations of goals and appropriate responses to obtain these goals. Such activities are particularly important when multiple, conflicting behavioral responses are possible or when it is necessary to override affective arousal. There is evidence of some hemispherical specialization in PFC function. For example, left-sided activation of regions of the PFC is more involved in goal-directed or appetitive behaviors, whereas regions of the right PFC are implicated in avoidance behaviors and inhibition of appetitive pursuits. Subregions in the PFC appear to localize representations of behaviors related to reward and punishment.

The anterior cingulate cortex (ACC) is thought to serve as the point of integration of attentional and emotional inputs. Two subdivisions have been identified: An affective subdivision in the rostral and ventral regions of the ACC and a cognitive subdivision involving the dorsal ACC. The former subdivision shares extensive connections with other limbic regions, and the latter interacts more with the PFC and other cortical regions. It is proposed that activation of the ACC facilitates effortful control of emotional arousal, particularly when goal attainment has been thwarted or when novel problems have been encountered.

The hippocampus is most clearly involved in various forms of learning and memory, including fear conditioning, as well as inhibitory regulation of the hypothalamic–pituitary–adrenal (HPA) axis activity. Importantly, the hippocampus is also one of the few sites of the brain capable of neurogenesis (i.e., the process of differentiation of stem cells into potentially functional neurons). Emotional or contextual learning appears to involve a direct connection between the hippocampus and the amygdala.

The amygdala appears to be a crucial way station for processing novel stimuli of emotional significance and coordinating or organizing cortical responses. Located just above the hippocampi bilaterally, the amygdala has long been viewed as the functional center of the limbic system. Although most research has focused on the role of the amygdala in responding to fearful or painful stimuli, novelty and ambiguity can also bring the amygdala “on line.”

Acute stress activates cell bodies of norepinephrine (NE) neurons in the locus ceruleus, whose ascending axons signal noradrenergically mediated increases in cortical arousal and whose descending axons signal increased adrenergic (predominantly epinephrine) output by the sympathetic nervous system and adrenal medulla. Behaviorally, the perception of acute stress elicits perceptual vigilance, preparedness for response, and inhibition of consummatory activities, such as foraging and pursuit of sexual activity

Serotoninergic neurons project from the brainstem dorsal raphe nuclei to the cerebral cortex, hypothalamus, thalamus, basal ganglia, septum, and hippocampus. The 5-HT pathways have inhibitory and facilitatory functions in the brain. For example, much evidence suggests that 5-HT is an important regulator of sleep, appetite, body temperature, metabolism, and libido. Moreover, 5-HT inhibits aggressive behavior across mammalian and reptilian species. Serotoninergic neurons projecting to the suprachiasmatic nucleus (SCN) of the hypothalamus help regulate circadian rhythms (e.g., sleep–wake cycles, body temperature, and HPA axis function). The 5-HT also permits or facilitates goal-directed motor and consummatory behaviors in conjunction with NE and DA.

Dopaminergic Systems

There are four relatively discrete DA pathways in the brain. The tuberoinfundibular system projects from cell bodies in the hypothalamus to the pituitary stalk, exerting inhibitory control over prolactin secretion. The nigrostriatal system originates from cell bodies in the substantia nigra and projects to the basal ganglia, regulating involuntary motor activity. The cell bodies of the mesolimbic pathway are located in the ventral tegmentum and project diffusely to the nucleus accumbens, amygdala, hippocampus, medial dorsal nucleus of the thalamus, and cingulate gyrus. This pathway modulates emotional expression, learning and reinforcement, and hedonic capacity. The fourth DA pathway, also originating in the ventral tegmentum, is the mesocortical pathway, which projects to the orbitofrontal and the prefrontal cortical regions. The mesocortical pathway helps regulate motivation, concentration, and initiation of goal-directed and complex executive cognitive tasks. Decreased mesocortical and mesolimbic DA activity has obvious implications in the cognitive, motor, and hedonic disturbances associated with depression and is a target for action for some investigational compounds. Across pathways, increased DA activity is potentiated by nicotinic inputs and glucocorticoids, and DA levels are inversely correlated with indices of brain 5-HT activity.

The amino acids glutamate and glycine are the major excitatory and inhibitory neurotransmitters in the CNS. Glutamate and glycine bind to sites associated with the N-methyl-D-aspartate (NMDA) receptor, and an excess of glutamatergic stimulation can cause neurotoxic effects. Importantly, there is a high concentration of NMDA receptors in the hippocampus. Glutamate may thus work in conjunction with hypercortisolemia to mediate the deleterious neurocognitive effects of severe recurrent depression and may be proximally implicated in atrophic changes documented in some regions of the cerebral cortex. There is emerging evidence that ketamine (Ketalar) and other drugs that antagonize NMDA receptors have antidepressant effects

An even larger subgroup of depressed patients (20 to 30 percent) shows a blunted TSH response to TRH challenge. This type of response would usually suggest hyperthyroidism, yet few depressed patients have clinically significant elevations of thyroid hormones. A blunted TSH response in a euthyroid person thus may result from pituitary downregulation consequent to increased TRH “drive.” As neurons containing TRH have been identified in a variety of cortical regions, this abnormality may have a suprahypothalamic origin. Increased central TRH secretion, in turn, could result from a homeostatic response to decreased noradrenergic neurotransmission. Joffe and colleagues further speculate that the therapeutic benefit of 1-triiodothyronine (T₃) augmentation therapy is mediated by a dampening of this failed homeostatic response. To date, the major therapeutic implication of a blunted TSH response is evidence of an increased risk of relapse despite preventive antidepressant therapy. Of note, unlike the dexamethasone suppression test (DST), blunted TSH response to TRH often does not normalize with effective treatment.

Depression is associated with a premature loss of deep (slow wave) sleep and an increase in nocturnal arousal. The latter is reflected by four types of disturbance: (1) an increase in nocturnal awakenings, (2) a reduction in total sleep time, (3) increased phasic REM sleep, and (4) increased core body temperature. The combination of increased REM “drive” and decreased slow wave sleep results in a significant reduction in the first period of NREM sleep, a phenomenon referred to as reduced REM latency.

Modern magnetic resonance imaging (MRI) scans permit visualization of the living brain, with high resolution of cortical structures such as the hippocampus and anterior cingulate, as well as white matter lesions. One abnormality commonly observed in the depressive disorders is increased frequency of hyperintensities in subcortical regions such as periventricular regions, the basal ganglia, and the thalamus. More common in bipolar I disorder and among the elderly, these hyperintensities appear to reflect atherosclerotic change and, as such, illustrate the deleterious effects of the interaction of aging and recurrent affective episodes. Ventricular enlargement, cortical atrophy, and sulcal widening have been observed in some studies of patients with more severe recurrent affective illness. More recent studies utilizing higher resolution MRI scans have documented reduced volume in a number of relevant regions, including the hippocampus, medial orbital cortex, and anterior cingulate. Diffuse and focal areas of atrophy have been associated with increased illness severity, bipolarity, and increased cortisol levels. In several studies the hippocampal volume reduction has been associated with measures of illness chronicity, such as lifetime days of untreated depression. Volume reduction is thought to at least partly result from reduction of the glial matter that supports neurons rather than actual neuronal death, although prolonged suppression of BDNF-mediated neurogenesis also may be implicated. However, it is also true that reduced hippocampal volume has been documented in a study of individuals suffering a first depressive episode and, at least in primates, is partly under heritable control. The most widely replicated PET finding in depression is decreased anterior brain metabolism, which is generally more pronounced on the left side. Thus, depression may be characterized by a relative increase in nondominant hemispheric activity

Clinical findings

Evidence from long-term prospective studies indicates that the course of mood disorders consists of various gradations of affective oscillations from the subsyndromal level to the syndromic level. Major episodes represent an operational convention to define a clinical threshold. Subchronic course, dominated by subthreshold symptoms, occurs in 50 to 60 percent. This is equally true for major depressive disorder and bipolar disorders. Detecting the illness in its subthreshold stage and treating interepisodic subthreshold phases are important clinical considerations

Sadness and Joy

The normal emotions of sadness and joy are part of everyday life and should be differentiated from major depressive disorder and mania. Sadness, or normal depression, is a universal human response to defeat, disappointment, or other adversities. The response may be adaptive, in an evolutionary sense, by permitting withdrawal to conserve inner resources, or it might signal the need for support from significant others. Transient depressive periods also occur as reactions to certain holidays or anniversaries, as well as during the premenstrual phase and the first week postpartum. Termed, respectively, holiday blues, anniversary reactions, premenstrual tension, and maternity blues, they are not psychopathological per se, but individuals predisposed to mood disorder may develop clinical depression during such times. As premenstrual tension is described later in the chapter under its clinically relevant extreme expression termed premenstrual dysphoric disorder as an example of depression not otherwise specified (where DSM-IV-TR has placed it), this section focuses on other normative mood continua.

Grief

Normal bereavement or grief, considered the prototype of reactive depression, occurs in response to significant separations and losses, such as death, divorce, romantic disappointment, leaving familiar environments, forced emigration, or civilian catastrophes. DSM-IV-TR tends to limit the concept of normal grief to loss due to the death of a loved one—a condition that it considers as an exclusionary criterion for major depression. However, the work of Elie Karam and colleagues showed that bereavement and other losses associated with the civil war in Lebanon served as potent forces in depression formation. The same was true for the losses due to the earthquake in Armenia. The boundary behavior and clinical depression are blurred in reactions to such complex losses. In addition to depressed affect that is appropriate to the loss, bereavement reactions are characterized by the prominence of sympathetic arousal and restlessness believed to represent, from an evolutionary perspective, physiological and behavioral mechanisms to facilitate the search for the lost object. Like other adversities, bereavement and loss do not generally seem to cause depressive disorder, except in individuals predisposed to mood disorder. Reactions to major catastrophes might represent a partial exception

Elation

The positive emotion of elation is popularly linked to success and achievement. However, paradoxical depressions may also follow such positive events, possibly because of the increased responsibilities that often have to be faced alone. Elation is conceptualized psychodynamically as a defense against depression or as a denial of the pain of loss, as exemplified by maniacal grief, a rare form of bereavement reaction in which elated hyperactivity may replace the expected grief. The character of the “merry widow” in opera seems to be of similar derivation.

Other pseudomanic states include the brief energetic and unusually lucid periods encountered in dying patients or in those who need to take superhuman action in the face of unusual duress, both of which have been conceptualized as a flight into health. In predisposed persons, such reactions might be the prelude to a genuine manic episode. Sleep deprivation, which commonly accompanies major stressors, might represent one of the intermediary mechanisms between stressor and adverse clinical outcome

Affective Temperaments

Another mediating factor between normal and pathological moods is temperament. Most persons have a characteristic pattern of basal affective oscillations that defines their temperament. For instance, some are easily moved to tears by sad or happy circumstances, whereas others tend to remain placid. Normally, oscillations in affective tone are relatively minor, tend to resonate with day-to-day events, and do not interfere with functioning. Some persons exhibit greater variability of emotional responses whereby, with no obvious provocation, the person alternates between normal mood and sadness or elation. Temperament traits tend to cluster into basic types. A worrying temperament associated with generalized anxiety disorder is often complicated by depressive episode: It overlaps considerably with the depressive temperament; such inclination to melancholy makes the person more easily sink into weary and sad moods and occurs in 3 to 6 percent of the general population. The hyperthymic temperament, in which the person is naturally inclined toward cheerful moods, has been reported in 2 to 5 percent; the cyclothymic temperament, swinging between cheerful and sad moods, characterizes 4 to 6 percent of young adults. All four types have an early insidious onset and tend to persist throughout adult life. Of interest, these temperaments may be the prelude to episodes of depressive or hypomanic and manic polarity, which underscores the inherent instability of temperamental inclinations. Marked irritable-explosive traits occur in 2 to 3 percent of young persons and tend to attenuate by middle age. Current data suggest that such traits often coexist with the mood-labile cyclothymic type, representing the dark “borderline” side of this temperament.

with a depressive temperament is hard working, dependable, sensitive to the suffering and needs of others, and suitable for jobs that require long periods of devotion to meticulous detail; such persons are said to shoulder the burdens of existence without experiencing its pleasures. A person with the hyperthymic temperament, endowed with high levels of energy, extroversion, and humor, assumes leadership positions in society or excels as a performer in media or entertainment; such persons are also successful from a Darwinian perspective in that they are adept in amorous advances and engender a large number of offspring. In talented persons, the cyclothymic temperament, which alternates between sadness and elation, could provide the inspiration for love and for the emotional intensity needed for composing music, writing poetry, and painting. A person with the irritable temperament might be best suited for a military career or even revolutionary action. The danger with persons with extreme temperaments is that they could swing too far in one or the other direction or in both directions (i.e., major depressive, manic, or mixed episodes). Use of such substances as alcohol, caffeine, and other stimulants might further destabilize affective regulation in persons with those attributes. Some adolescent girls with irritable cyclothymia might develop the extreme emotional disequilibrium that, in contemporary psychiatry, is considered borderline personality disorder. Temperament concepts can enrich understanding of the boundary between normal moods and emotional disorders and can supplement the somewhat arid DSM-IV-TR descriptors of personality disorders with valuable information about individual vulnerability and assets. A new instrument—the Temperament Evaluation of Memphis, Pisa, Paris and San Diego—has been developed in an autoquestionnaire version (TEMPS-A) and validated in at least 12 languages

morbid states: Pathological Mood Change

Pathological moods are distinguished from their normal counterparts by being out of proportion to any concurrent stressor or situation; being unresponsive to reassurance; being sustained for weeks, months, and, sometimes, years; and having a pervasive effect on the person, such that judgment is seriously compromised by the mood

Endoreactive Moods

Depression and mania are diagnosed, respectively, when sadness or elation is overly intense and continues beyond the expected impact of a stressful life event. Indeed, the morbid mood might arise without apparent or significant life stress. The pathological process in mood disorders is thus partly defined by the ease with which an intense emotional state is released and, especially, by its tendency to persist autonomously even when the offending stressor is no longer operative. Rather than being endogenous (i.e., occurring in the absence of precipitants), mood disorders are best conceptualized as endoreactive (i.e., once released, they tend to persist autonomously). The homeostatic dyscontrol of mood, which is part of a more pervasive mood dysregulation, resists reversal to the habitual baseline affective tone.

To recapitulate, dysregulation in mood disorders can take different forms. It could be expressed as a single severe episode that persists autonomously for many months and sometimes years, or it might recur with episodes of varying severity, years apart or in rapid succession, with or without interepisodic remission. Recent observations have also revealed another pattern of impairment. In dysthymic and cyclothymic disorders, which represent an intensification of temperamental instability, impairment is not due to the severity of the mood disturbance per se but to the cumulative impact of the dysregulation beginning in the juvenile or early adult years and continuing unabated or intermittently over long periods; hence, the frequent confusion with character pathology. Here, the impairment is more subtle but nonetheless is pervasive. Persons with cyclothymic disorder tend to be dilettantes, whereas those with dysthymic disorder often lead morose and colorless lives. The fundamental causes of mood disorders must be sought in the preclinical expressions in the offspring of adults with these disorders

Mood Disturbances

Mood change, usually considered the sine qua non of morbid depression, manifests in a variety of disturbances, including (1) painful arousal, (2) hypersensitivity to unpleasant events, (3) insensitivity to pleasant events, (4) insensitivity to unpleasant events, (5) reduced anticipatory pleasure, (6) anhedonia or reduced consummatory pleasure, (7) affective blunting, and (8) apathy. The phenomenology and psychometric properties of this broad range of mood disturbances are under investigation at the Salpêtrière Hospital in Paris. The focus in the description that follows is primarily on painfully aroused mood (depression) and diminished capacity for pleasure (anhedonia), two mood disturbances given selective weight in DSM-IV-TR and ICD-10

The term depressed mood refers to negative affective arousal, variously described as depressed, anguished, mournful, irritable, or anxious. These descriptions tend to trivialize a morbidly painful emotion, typically experienced as worse than the severest physical pain. Thus, depressed mood has a somatic quality that, in the extreme, is indescribably painful. Even when not so severe, depressive suffering is qualitatively distinct from its “neurotic” counterparts, taking the form of groundless apprehensions with severe inner turmoil and torment. This description is particularly apt for middle-aged and elderly persons, who were once considered to be experiencing involutional melancholia. The sustained nature of the mood permits no respite, although it tends to lift somewhat in the evening. Suicide may represent an attempt to find deliverance from such unrelenting psychic torment; death can be conceived as comforting Patients with a milder form of the malady typically seen in primary care settings might deny experiencing mournful moods and instead complain of physical agony from headache (Fig. 13.7-3), epigastric pain, precordial distress, and so on, in the absence of any evidence of diagnosable physical illness. Such conditions have been described as depressio sine depressione or masked depression. In such cases, which are commonly observed in older patients, the physician should corroborate the presence of mood disturbance by the depressed affect in the patient's facial expression, vocal inflection, and overall appearance

Patients with severe depression may complain of being emotionally cut off from others and experience depersonalization and a world that seems strange to them (derealization). The impact of the loss of emotional resonance can be so pervasive that patients may denounce values and beliefs that had previously given meaning to their lives. For instance, members of the clergy might present with the complaint that they no longer believe in the Church and that they have lost God. The inability of the person with depressive disorder to experience normal emotions (commonly observed among young depressed patients) differs from the schizophrenic patient's flat affect, in that the loss of emotions is itself experienced as painful; that is, the patient suffers immensely from the inability to experience emotions

Psychomotor Retardation, agitation, pseudodementia, stupor

Underlying many of the deficits seen in clinical depression, some authorities believe psychomotor retardation to be the core, or primary, pathology in mood disorders. Morbid depression—what patients describe as being “down”—can be understood in terms of moderate to extreme psychomotor slowing. The patient experiences inertia, being unable to act physically and mentally. Recent brain imaging research that has revealed subcortical (extrapyramidal system) disturbances in mood disorders tends to support the centrality of psychomotor dysfunction in these disorders

Long neglected in psychopathological research, psychomotor retardation can be measured with precision. The Salpêtrière Retardation Scale developed by Daniel Widlocher and colleagues places special emphasis on the following disturbances: (1) paucity of spontaneous movements; (2) slumped posture with downcast gaze (Fig. 13.7-5); (3) overwhelming fatigue (patients complain that everything is an effort); (4) reduced flow and amplitude of speech and increased latency of responses, often giving rise to monosyllabic speech; (5) a subjective feeling that time is passing slowly or has stopped; (6) poor concentration and forgetfulness; (7) painful rumination or thinking that dwells

Stupor

Psychomotor slowing in young persons is sometimes so extreme that patients might slide into a stupor, unable to participate even in basic biological functions, such as feeding themselves. Such an episode is often the precursor of bipolar disorder, which later declares itself in a manic episode. Today, depressive disorder is diagnosed in its earlier stages, and subtle stupor is much more likely to be encountered clinically.

A 20-year-old male college student seen in the emergency room spoke of “being stuck—as if I have fallen into a black hole and can't get out.” Further evaluation revealed that the patient was metaphorically describing his total loss of initiative and drive and was engulfed by the disease process. A clinician without the requisite phenomenological training might consider such a patient bizarre and perhaps even psychotic. Yet, the patient responded dramatically to fluoxetine (Prozac) and, in 2 weeks, was back in school

Cognitive Disturbances

The cognitive view of depression considers negative evaluations of the self, the world, and the future (the negative triad) central to understanding depressed mood and behavior, but it is equally likely that the depressed mood colors perceptions of the self and others or that disturbed psychomotor activity leads to negative self-evaluations. Therefore, instead of being considered causal, the cognitive triad in depression is best approached empirically as a psychopathological manifestation of depression. Faulty thinking patterns are clinically expressed as (1) ideas of deprivation and loss; (2) low self-esteem and self-confidence; (3) self-reproach and pathological guilt; (4) helplessness, hopelessness, and pessimism; and (5) recurrent thoughts of death and suicide

Mood-Congruent Psychotic Features

In depressive disorder with psychotic features (Table 13.7-3), negative thinking acquires grossly delusional proportions and is maintained with such conviction that the thoughts are not amenable to change by evidence to the contrary. According to Kurt Schneider, delusional thinking in depression derives from humankind's four basic insecurities—those regarding health, financial status, moral worth, and relationship to others. Thus, severely depressed patients may have delusions of worthlessness and sinfulness, reference, and persecution: They believe that they are being singled out for their past mistakes and that everyone is aware of their incompetence. Persecutory ideation in depression is often prosecutory, in that it derives from the belief that one deserves punishment for such transgressions. A severely depressed man may feel so incompetent in all areas of functioning, including the sexual sphere, that he may suspect his wife of having an affair (delusion of infidelity). Other depressed persons believe that they have mismanaged their finances in such a way that their children will starve (delusions of poverty); that they are harboring an occult illness, such as cancer or the acquired immune deficiency syndrome (AIDS) (delusions of ill health); or that parts of their bodies are missing (nihilistic delusions). In more severe illness, the patient might feel that the world has changed and that calamity and destruction await everyone. In rare tragic instances, a parent with such delusions might kill his or her young children to save them from moral or physical decay and then commit suicide. In women with psychotic depression, infanticide is most likely to occur in the postpartum period, often leading to all types of inappropriate interpretations in the media. Finally, a minority of depressed persons have fleeting auditory or visual hallucinations with extremely unpleasant content along the lines of their delusions (e.g., hearing accusatory voices or seeing themselves in coffins or graveyards). All of these psychotic experiences are genuine affective delusions or hallucinations. They are mood congruent in the sense that they are phenomenologically understandable in light of the prevailing pathological mood

Mood-Incongruent Psychotic Features

Sometimes so-called first-rank or schneiderian-type symptoms can arise in the setting of a major depressive episode.

A 42-year-old civil servant said that she was so paralyzed by depression that she felt that she had no personal initiative and volition left; she believed that some malignant force had taken over her actions and that it was commenting on every action that she was undertaking. The patient recovered fully with thymoleptic medication. There is no reason to believe that, in this patient, the feelings of somatic passivity and running commentary indicated a schizophrenic process.

Thus, with proper phenomenological probing, certain classes of apparently mood-incongruent psychotic experiences listed in DSM-IV-TR can be understood as arising from the pathological mood and the profound changes in psychomotor activity that accompany them. (In other instances, the clinician must seek a history of alcohol or substance use disorder or withdrawal as a putative explanation for mood incongruence in psychotic depression.) In brief, incidental schneiderian first-rank symptoms should not distract from the diagnosis of an affective psychosis if otherwise typical signs and symptoms of mood disorder are present.

Hopelessness and suicide: The suicide attempt is not, however, undertaken in the depth of melancholia. When asked if she had any suicide plans, a severely depressed patient replied, “Doctor, I don't exist—I am already dead.”

The biological concomitants of melancholia include profound reductions in appetite, sleep, and sexual functioning, as well as alterations in other circadian rhythms, especially matinal worsening of mood and psychomotor performance. These disturbances are central to the DSM-IV-TR concept of melancholia (Table 13.7-4), a form of depression in which such biological concomitants predominate

Anorexia, weight gain, insomnia: Sleep disturbance, a cardinal sign of depression, often is characterized by multiple awakenings, especially in the early hours of the morning, rather than by difficulty falling asleep

Hypersomnia

Young depressed patients, especially those with bipolar tendencies, often exhibit excessive sleep and have difficulty getting up in the morning. Hypersomnia associated with lethargy should actually raise strong suspicion of bipolar disorder in young depressive patients. In the elderly, organic or brain pathology should be suspected.

Few data exist on the consistency of sleep electroencephalographic (EEG) abnormalities in patients from episode to episode. However, clinical experience suggests that a patient observed over time (even during the same episode) may exhibit insomnia and morning worsening of mood and activity during one period of the disorder and hypersomnia extending to late morning hours during another period. In either case, persons with depressive disorder are characteristically tired in the morning, which means that even prolonged sleep is not refreshing for them. The propensity to exhibit such divergent patterns of sleep disturbance is more likely in bipolar disorders. Patients with major depressive disorder tend to exhibit insomnia more stereotypically episode after episode; despite extreme fatigue, they rarely oversleep. Such fatigue coexisting with negative affective arousal is even more exhaust

Seasonality

Another classic biorhythmic disturbance in mood disorders is seasonal (especially autumn–winter) accentuation or precipitation of depression. Most of those patients experience increased energy and activation, if not frank hypomania, in the spring. In the fall and winter, they complain of fatigue, tend to crave sugars, and overeat and oversleep. The hypersomnia in some of these patients is associated with delayed (rather than short) REM latencies. These data suggest dysregulation of circadian rhythms in depressive disorders rather than mere phase advance

This is less likely to occur in the sildenafil (Viagra) era, but even treatment with such agents would not necessarily resolve the impotence in clinically depressed patients without competent treatment of the mood disorder. Selective serotonin reuptake inhibitors (SSRIs) typically aggravate the sexual dysfunction, whereas bupropion (Wellbutrin) tends to improve it

The increased sexual drive can be considered the fifth reverse vegetative sign (after evening worsening of mood, initial insomnia, hypersomnia, and weight gain). Several patients have derived temporary reversal of their depression after intense sexual encounters. In these depressed persons, increased sexual drive, intensity, or both may indicate a mixed episode of bipolar disorder (type II). Further scrutiny in such cases often reveals a premorbid cyclothymic or hyperthymic temperament. Current data suggest that, depending on the breadth of the criteria used, 30 to 70 percent of depressions with atypical features belong to the bipolar spectrum

The broad category of depressive disorders includes major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified

A: Course of major depressive disorder, recurrent, with no antecedent dysthymic disorder and a period of full remission between the episodes. This pattern predicts the best future prognosis. B: Course of major depressive disorder, recurrent, with no antecedent dysthymic disorder but with prominent symptoms persisting between the two most recent episodes (i.e., partial remission is attained). C: Rare pattern (present in fewer than 3 percent of persons with major depressive disorder) of major depressive disorder, recurrent with antecedent dysthymic disorder but with full interepisode recovery between the two most recent episodes. D: Course of major depressive disorder, recurrent, with antecedent dysthymic disorder and no period of full remission between the two most recent episodes. This pattern, commonly referred to as double depression, is seen in approximately 20 to 25 percent of persons with major depressive disorder

Dpression: Single-Episode and Recurrent Subtypes

A significant minority—perhaps one third—of all major depressive episodes do not recur (Table 13.7-15). Such patients tend to be older and less likely to have a positive family history for mood disorders and have a more protracted (1 to 2 years) course of the disorder. Patients with single-episode major depressive disorder should be distinguished from thoseexperiencing their first episodes of recurrent major depressive disorder (Table 13.7-16). The latter group tends to be younger, and the disorder is more likely to have been preceded by a depressive temperament or dysthymic disorder. Those who switch to bipolar disorder are more likely to have experienced recurrent depressions (5 or more episodes).

Research has established that recurrent major depressive disorders are more familial than their single-episode counterparts. The average length of episodes is 6 months, whereas the mean interval between episodes tends to vary (typically years). The mean number of major episodes over a lifetime, according to retrospective and prospective studies, is five to six, in contrast to an average of eight to nine major episodes in bipolar disorder. These figures are probably underestimates, in that they are typically ascertained on the basis of clinical referral or hospitalization, or both

Melancholic feautures: endogenous depression became melancholic features, a qualifying phrase for major depressive disorders in which anhedonia, guilt, and psychomotor–vegetative disturbances dominate the clinical picture (Table 13.7-4). DSM-IV-TR retains these conventions

This is embodied in Donald Klein's concept of endogenomorphic depression, which could be precipitated and mild (endoreactive) while exhibiting disturbances of hedonic mechanisms refractory to current interpersonal contexts. Many authorities believe that such features dictate the need to use somatic approaches to reverse the maladaptive autonomy and to restore response to interpersonal feedback; that is, psychotherapeutic approaches are deemed largely ineffective until the autonomy is somatically lysed

Atypical Features

Reverse vegetative signs with rejection sensitivity, often contrasted to melancholia on phenomenological and pharmacological grounds, represent a major depressive disorder qualifier occurring in as many as one third of all major depressive disorders. Atypical features are so common in bipolar disorder, especially bipolar II disorder, that some consider them to be clinical markers for soft bipolar disorders. Although there is no consensus on this question, before diagnosing major depressive disorder in such cases, it is clinically wise to exclude bipolar II disorder, especially where hostile-labile features predominate

Psychotic Features

From 10 to 15 percent of major depressive disorders, usually from the rank of those with melancholic features, develop into delusional depressions. In young persons, they tend to be retarded, even stuporous, and are best considered initial episodes of a bipolar disorder until proven otherwise. More typically, psychotic depression that develops for the first time after 50 years of age often presents with severe agitation, delusional guilt, hypochondriacal preoccupations, early-morning awakening, and weight loss. The premorbid adjustment of such patients is classically characterized as obsessoid. Their mournful-anxious mood and agitation are autonomous, being refractory to psychological interventions, and they endure great psychic suffering. Except for the fact that generally one to two episodes occur in late-onset (so-called involutional) depressions, they represent a severe variant of DSM-IV-TR melancholia. Kraepelin's postulation of a cerebrovascular basis for such cases makes the ventricular enlargement and white matter opacities reported in psychotic depressions of some interest. Their etiological specificity for persons with late-onset psychotic depression has been controversial, however, because younger (more bipolar) persons with psychotic depression may exhibit similar findings. Brain imaging findings tend to be correlated with the neurocognitive deficits observed in psychotic depressions. Those features do not seem to define a distinct depressive subtype but one of greater severity that some authorities now classify as vascular depressions Finally, despite attempts to suggest a neurochemical uniqueness based largely on the need for antipsychotic treatment in the acute phase of many of those patients, familial and other external validations have failed to support psychotic depression as a separate entity; hence, the decision in DSM-IV-TR to use psychotic features as a specifier for major depressive episode.

Chronic depression:The DSM-IV-TR criteria for chronic specifier appear in Table 13.7-19. The clinical situation, however, is much more complex than these conventions. For instance, the symptom profile in chronic depressions usually displays low-grade intensity rather than severe syndromic chronicity. Severe depressive disorder, in its psychotic forms, is so agonizing that the patient is at risk of committing suicide before the disorder has a chance to become chronic. More commonly, the psychotic symptoms respond to medication or to electroconvulsive therapy (ECT), but residual depressive symptoms may linger for a long time

Dysthymic Disorder

Dysthymia (Table 13.7-20) is distinguished from chronic depressive disorder by the fact that it is not a sequel to well-defined major depressive episodes. Instead, in the most typical cases, patients complain that they have always been depressed. Thus, most cases are of early onset, beginning in childhood or adolescence and certainly by the time patients reach their 20s. A late-onset subtype, much less prevalent and not well characterized clinically, has been identified among middle-aged and geriatric populations, largely through epidemiological studies in the community.

Although the dysthymic disorder category in DSM-IV-TR can occur as a secondary complication of other psychiatric disorders, the core concept of dysthymic disorder refers to a subaffective disorder with (1) low-grade chronicity for at least 2 years, (2) insidious onset with origin often in childhood or adolescence, and (3) persistent or intermittent course. Although not part of the formal definition of dysthymic disorder, the family history is typically replete with depressive

Social adjustment: The dedication of persons with dysthymic disorder to work has been suggested to be an overcompensation and a defense against their battle with depressive disorganization and inertia. Nevertheless, Ernst Kretschmer suggested that such persons are the “backbone of society,” dedicating their lives to jobs that require dependability and great attention to detail

This pattern, commonly seen in clinical practice, consists in the baseline dysthymic disorder fluctuating in and out of depressive episodes. The more prototypical patients with dysthymic disorder often complain of having been depressed since birth or of feeling depressed all the time. They seem, in the apt words of Kurt Schneider, to view themselves as belonging to an “aristocracy of suffering

Clinical Picture

The profile of dysthymic disorder overlaps with that of major depressive disorder but differs from it in that symptoms tend to outnumber signs (more subjective than objective depression). This means that marked disturbances in appetite and libido are uncharacteristic, and psychomotor agitation or retardation is not observed. This all translates into a depression with attenuated symptomatology. However, subtle endogenous features are not uncommonly observed: Inertia and anhedonia that are characteristically worse in the morning. Because patients presenting clinically often fluctuate in and out of a major depression, the core DSM-IV-TR criteria for dysthymic disorder tend to emphasize vegetative dysfunction, whereas the alternative Criterion B for dysthymic disorder (Table 13.7-21) in a DSM-IV-TR appendix lists cognitive symptoms

Prospective studies on children have revealed an episodic course of dysthymia with remissions, exacerbations, and eventual complications by major depressive episodes, 15 to 20 percent of which might even progress to hypomanic, manic, or mixed episodes postpuberty. Persons with dysthymic disorder presenting clinically as adults tend to pursue a chronic unipolar course that may be complicated by major depression. They rarely develop spontaneous hypomania or mania. However, when treated with antidepressants, some of them may develop brief hypomanic switches that typically disappear when the antidepressant dose is decreased

Minor Depressive Disorder

In so-called minor depression (Table 13.7-23), observed in primary care settings, the depression is subthreshold, milder than major depressive disorder, and yet not protracted enough to be considered dysthymic. These varied manifestations of depression argue for a continuum model (Fig. 13.7-7) as originally envisaged by Kraepelin. Lewis Judd and collaborators at the University of California at San Diego have suggested that subthreshold depressive symptoms—without necessarily meeting the criterion for mood change—might actually represent the most common expressions of a depressive diathesis. From such a subsyndromal symptomatic depressive base, individuals predisposed to depressive illness are said to fluctuate in and out of the various DSM-IV-TR and subthreshold subtypes of depressive disorders. This viewpoint is presently most cogent for subsyndromal symptomatic depression that follows major depressive disorder, a strong predictor of subsequent frequent relapse or chronic course. There is an important message for the clinician here: Treat subsyndromal symptomatic depression residual to major depressive disorder

Reactive depression: love loss

Chronic Demoralization

Conceptually, however, one can envision chronically unsatisfactory life situations that might lead to chronic helplessness. However, such a condition, which could warrant the designation of chronic reactive depression, is a contradiction in terms. The question often raised is why a person would continue to stay in the situation. Sometimes psychodynamic authors invoke the concept of masochism to explain why certain persons cannot rid themselves of painful life situations, implying that they somehow contribute to their maintenance. Current thinking is that some of those presumed self-defeating traits are more situation specific than previously believed and might resolve with the elimination of the situation. So-called self-defeating features then are best considered psychodynamic mechanisms rather than indicators of a specific personality. At the present stage of knowledge, they do not deserve to be raised to the level of a nosological entity (hence, their disappearance from DSM-IV-TR). Chronic adjustment disorder might describe the chronic demoralization observed among some individuals stuck in chronically unsatisfactory life situations.

Neurasthenia

A century-old term developed by the American neuropsychiatrist George Beard, neurasthenia refers to a more chronic stage of anxious-depressive symptomatology. The anxiety generated by overstimulation is so excessive that it is replaced by a chronic disposition to irritability, fatigue (especially mental fatigue), lethargy, and exhaustion. It is as if the patient's mind refuses to take on new stresses. The clinical picture described by Beard suggests that anxious manifestations were preeminent in his time. They included headache, scalp tenderness, backache, heavy limbs, vague neuralgias, yawning, dyspepsia, palpitations, sweating hands and feet, chills, flushing, sensitivity to weather changes, insomnia, nightmares, pantaphobia, asthenopia, and tinnitus.

Although the diagnosis of neurasthenia is now used more in China than in the rest of the world, the recent worldwide popularity of the concept of chronic fatigue syndrome attests to the clinical acumen of classic physicians

Postpsychotic Depressive Disorder of Schizophrenia

The essential feature is a Major Depressive Episode that is superimposed on, and occurs only during, the residual phase of Schizophrenia. The residual phase of Schizophrenia follows the active phase (i.e., symptoms meeting Criterion A) of Schizophrenia. It is characterized by the persistence of negative symptoms or of active-phase symptoms that are in an attenuated form (e.g., odd beliefs, unusual perceptual experiences). The superimposed Major Depressive Episode must include depressed mood (i.e., loss of interest or pleasure cannot serve as an alternate for sad or depressed mood). Most typically, the Major Depressive Episode follows immediately after remission of the active-phase symptoms of the psychotic episode. Sometimes it may follow after a short or extended interval during which there are no psychotic symptoms. Mood symptoms due to the direct physiological effects of a drug of abuse, a medication, or a general medical condition are not counted toward postpsychotic depressive disorder of Schizophrenia

An attenuated bipolar disorder that typically begins insidiously before 21 years of age, cyclothymic disorder is characterized in DSM-IV-TR by frequent short cycles of subsyndromal depression and hypomania

Prospective and other systematic studies have shown that each of the following features—especially in combination—is predictive of bipolar disorder:

• Early age at onset
• Psychotic depression before 25 years of age
• Postpartum depression, especially one with psychotic features
• Rapid onset and offset of depressive episodes of short duration (less than 3 months)
• Recurrent depression (more than five episodes)
• Depression with marked psychomotor retardation
• Atypical features (reverse vegetative signs)
• Seasonality
• Bipolar family history
• High-density three-generation pedigrees
• Trait mood lability (cyclothymia)
• Hyperthymic temperament
• Hypomania associated with antidepressants
• Repeated (at least three times) loss of efficacy of antidepressants after initial response
• Depressive mixed state (with psychomotor excitement, irritable hostility, racing thoughts, and sexual arousal during major depression)

As with alcohol and substance use disorders, it is generally preferable to diagnose mood disorders at the expense of personality disorders, which should not be difficult to justify in most cases that satisfy the validating strategies outlined previouslyAlthough not all personality disturbances recede with the competent treatment of mood disorders, so many experienced clinicians have seen such disturbances melt away with the successful resolution of the mood disorder that erring in favor of mood disorders is justified

This case illustrates the intimate relationship among atypical depression, borderline personality, and bipolar II disorder. These three conditions, listed as distinct nosological entities in the DSM-IV-TR, may nonetheless share an underlying psychobiological or genetic diathesis. The complaint is often heard that, even when a mood disorder is diagnosed in a “borderline” patient, response to antidepressants is disappointing. The problem is that affective disorders in these patients usually conform to bipolar II disorder—often complicated by ultrarapid cycling—and many clinicians trained in an earlier era, including some with biological orientation, may lack sufficient experience in the art of pharmacologically managing patients who markedly deviate from classic bipolar I disorder. Recently, lamotrigine has shown promise for such patients

Before diagnosing depression, psychiatrists must ensure that they are not dealing with pseudodepression: (1) functional loss due to physical illness; (2) vegetative signs, such as anorexia and weight loss, as manifestations of such an illness; (3) stress and demoralization secondary to the hospitalization; (4) pain and discomfort associated with the physical illness; and (5) medication adverse effects. On the other hand, nonpsychiatric physicians who manage such patients must consider the diagnosis of depression in the presence of persistent anhedonia; observed depressed mood with frequent crying; observed psychomotor retardation or agitation; indecisiveness; convictions of failure, worthlessness, or guilt; and suicidal ideation