There is a pitch of unhappiness so great that the goods ofnature may be entirely forgotten, and all sentiment of theirexistence vanish from the mental field. For this extremity ofpessimism to be reached, something more is needed thanobservation of life and reflection upon death. The individualmust in his own person become the prey of pathologicalmelancholy. . . . Such sensitiveness and susceptibility tomental pain is a rare occurrence where the nervous constitu-tion is entirely normal; one seldom finds it in a healthy subjecteven where he is the victim of the most atrocious cruelties ofoutward fortune . . . it is positive and active anguish, a sort ofpsychical neuralgia wholly unknown to healthy life.
The varieties of religious experience.
Depression and euphoria are the primary symptoms of mood disor-ders, but not the only ones. Associated with low moods are suchsymptoms as insomnia, anorexia, suicidal thoughts, and feelings ofworthlessness or of being a burden to others; associated with euphoriaare such symptoms as hyperactivity, decreased need for sleep, andflight of ideas. The extent of depression or euphoria is often inap-propriate to the patient’s life situation, a fact sometimes as obvious topatients as to their relatives and friends. Formerly known as ‘ affectivedisorders,’’ these conditions were renamed ‘‘mood disorders’’ in the1987 edition of the American Psychiatric Association’s diagnosticmanual, DSM-III-R.
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS Whatever the name, the definition remains unchanged. It refers to a group of disorders characterized by prolonged disturbances of mood accompanied byseveral symptoms as described above. Mood disorders have been divided andsubdivided endlessly as investigators endeavor to distinguish ‘‘normal’’ from‘‘abnormal’’ mood and to create clinical clusters with distinct natural histories,familial prevalence, course and prognoses, and response to treatment. Aftermore than a century there is still disagreement about the most satisfactoryclassification.
Amid all this diversity, there is a common theme: Mood disorders are primarily characterized by depressed mood, elevated mood (mania), or alterna-tions of depressed and elevated moods. Severe depression is termed ‘‘majordepression.’’ The building blocks for defining mood disorders are mood epi-sodes, which represent a distinct and persistent change from a person’s typicalmood with accompanying symptoms, lasting 2 weeks for a major depressiveepisode and 1 week for a manic episode.
The most recent classification of mood disorders is provided by DSM-IV-TR, published by the American Psychiatric Association in 2000. Criteria for majordepressive and manic episodes are presented in Tables 2.1 and 2.2, respectively.
Manic and major depressive episodes by themselves do not constitute diagnoses, because a patient with a mood disorder may experience differenttypes of mood episodes over the course of a single illness, and the differentepisodes would not be diagnosed as separate disorders. This is illustrated by theclassical term for manic mood disorder, ‘‘manic depressive illness,’’ reflectingthe presence of both manic and major depressive episodes as part of thedisorder. A newer term, ‘‘bipolar disorder,’’ also expresses this same centralfeature of the disorder. The two terms are interchangeable.
Mood disorders are defined as bipolar when mania occurs, regardless of whether depressions occur. When the disorder involves solely depression, theterm ‘‘unipolar’’ or major depression is often used. (A natural initial impressionof the terms ‘‘bipolar’’ and ‘‘unipolar’ is that bipolar disorder implies a historyof both mania and depression, whereas unipolar implies a history of one or theother alone. ‘‘Bipolar’’ actually refers to a history of mania regardless of whetherdepression has also been present. ‘‘Unipolar’’ refers to episodes of depressionwithout mania.) As many as 40% of patients meeting criteria for bipolar disorder have episodes with both depressive and manic features, called mixed episodes.
Bipolar illness with four or more episodes of mania within 12 months isspecified as rapid cycling.
Milder depressive syndromes are called ‘‘dysthymia’’; milder forms of mania are called ‘‘hypomania.’’ Milder expressions of bipolar disorder with TABLE 2.1 Diagnostic Criteria for Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1)depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations.
(1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).
Note: In children and adolescents, can be irritable mood (2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) (3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every dayNote: In children, consider failure to make expected weight gains (4) Insomnia or hypersomnia nearly every day(5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) (6) Fatigue or loss of energy nearly every day(7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) (8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) (9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).
D. The symptoms are not better accounted for by bereavement (i.e., after the loss of a loved one).
Adapted from diagnostic criteria in the DSM-IV-TR (234).
both hypomanic and depressive episodes in the absence of manic or psychoticepisodes are referred to as ‘‘cyclothymia’’ or bipolar II disorder.
For all these terms, more than disturbed mood is required. There must be a syndrome, a group of characteristic clinical features that distinguish one dis-order from another.
Descriptions of mood disorders began with Hippocrates. The term ‘‘melanch-olia’’ is usually attributed to him, as is the notion that it results from theinfluence of black bile and phlegm on the brain ‘‘darkening the spirit andmaking it melancholy’ (133).
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS TABLE 2.2 Diagnostic Criteria for Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary) B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: (1) Inflated self-esteem or grandiosity(2) Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)(3) More talkative than usual or pressure to keep talking(4) Flight of ideas or subjective experience that thoughts are racing(5) Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)(6) Increase in goal-directed activity (either socially, at work or school, or sexually) or (7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolishbusiness investments) C. The mood disturbance is sufficiently severe so as to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitatehospitalization to prevent harm to self or others, or there are psychotic features.
D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
Adapted from diagnostic criteria in the DSM-IV-TR (234).
About 500 years later, early in the second century A.D., Aretaeus of Cappadocia recognized and recorded an association between melancholia andmania: Those affected with melancholia are not everyone of them affectedaccording to one particular form; they are either suspicious ofpoisoning or flee to the desert from misanthropy, or turnsuperstitious, or contract a hatred of life. If at any time a relaxationtakes place, in most cases hilarity supervenes . . . the patients aredull or stern, dejected or unreasonably torpid, without any manifestcause . . . they also become peevish, dispirited, sleepless, and start upfrom a disturbed sleep. Unreasonable fear also seizes them, if thedisease tends to increase . . . they complain of life, and desire to die(114). Aretaeus observed that affective disorder was often episodic butalso occurred in a chronic, unremitting form. Like Hippocrates, heattributed the cause to a humoral imbalance: If it [black bile] bedetermined upwards to the stomach and diaphragm, it formsmelancholy, for it produces flatulence and eructations of the fetid andfishy nature, and it sends rumbling wind downwards and disturbs theunderstanding (133).
The nineteenth-century French physician Falret described an episodic variety of depression with remissions and attacks of increasing duration, anillness occurring more frequently among women than men, sometimes asso-ciated with precipitating events, sometimes alternating with mania (la foliecirculaire). Falret and his contemporary Baillarger (who also described recur-ring attacks of mania and melancholia) probably influenced Kraepelin’s laterconcept of manic depressive psychosis.
In 1896 Kraepelin made his major contribution to psychiatry by separating the functional psychoses into two groups, dementia praecox and manic depres-sive psychosis. Dementia praecox was chronic and unremitting with a generallybad prognosis. Manic depressive psychosis, on the other hand, did not usuallyend in chronic invalidism. After publishing the sixth edition of his textbook in1896, Kraepelin continued to define the limits of dementia praecox narrowly,but he expanded those of manic depressive psychosis to include almost allabnormalities of mood. Chronic depression was included as well as episodicillness; mania was included as well as depression (126, 221).
Kraepelin had insisted that manic depressive psychosis was generally independent of social and psychological forces, that the cause of theillness was ‘‘innate.’ Freud and the psychoanalysts assumed the opposite.
Freud in Mourning and Melancholia, published in 1917, outlined his the-ories of the psychodynamic genesis of depression (70). He hypothesizedthat depression had in common with the process of mourning a responseto the loss of a ‘‘love-object,’’ that is, the loss of something greatly valued.
Grief, a healthy response, differed from melancholia in that the latterinvolved direction of unresolved, negative feelings inward, resulting indespair, a sense of worthlessness, thoughts of self-harm, and other depres-sive symptoms.
Since early in the twentieth century there has been considerable contro- versy over the distinction between ‘‘endogenous’’ depression and ‘‘reactive’depression. This controversy had its origin partially in the differing viewpointsof the Kraepelinians and Freudians toward mental phenomena in general.
Kraepelin and his followers searched for the limits of pathological behaviorby describing the symptoms of syndromes in keeping with the traditions ofnineteenth-century German medicine. Freud and his pupils searched formental mechanisms that might be most obvious in pathological states butwere not limited to those states. Such differences in attitude were augmentedby the fact that Kraepelinian psychiatrists dealt chiefly with severely ill, hospi-talized patients, whereas Freudian psychiatrists tended to treat mildly ill, non-hospitalized patients. The differences have never been fully resolved. Over theyears, the field has seen classification after classification of the mood disorders, GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS most frequently in terms of dichotomies: endogenous opposed to reactive,psychotic opposed to neurotic, agitated opposed to retarded.
For centuries, it was assumed tacitly that two major forms of depression exist, ‘‘reactive’ and ‘‘endogenous’’ depression (53). Reactive depression wasconsidered a direct result of precipitating events or unique individual responsesof social and psychological stress, and equated with neurotic features.
Endogenous depression, in contrast, was equated with psychotic features.
Reactive depression was considered to be less responsive to somatic therapiesyet milder than endogenous forms of depression, although empirical researchhas not confirmed these assumptions (168). The current diagnostic classifica-tion of depressive disorders in DSM-IV-TR does not mention reactive/endo-genous subtypes. However, controversy persists about the validity of thisdistinction. Recent discovery of a genetic variant of serotonin regulation inindividuals prone to major depression in the context of stressful situations hasstimulated further interest in the role of stressful environment in the etiology ofdepression in biologically vulnerable individuals (41).
An alternative subclassification of major depressive disorder that avoids inference about cause is the concept of primary or secondary disorders. ‘‘Primaryaffective disorder’ applies to major depression in individuals who have had noprevious psychiatric disorder aside from episodes of depression or mania.
‘‘Secondary affective disorder’’ refers to major depressive disorder in patientswith a preexisting psychiatric illness other than depression or mania. In otherwords, if the first onset of a mood disorder precedes other psychiatric disorderswithin an individual it is considered primary, and if it follows onset of any otherdisorder it is considered secondary. Patients with mild or severe depression,with or without psychotic symptoms such as hallucinations or delusions, withmany episodes or with few, and regardless of age of onset, may be diagnosed ashaving either primary or secondary affective disorder.
Although DSM-IV-TR does not distinguish between ‘‘primary’’ and ‘ secondary’’ affective disorder, we make the distinction for the followingreason: The symptoms of primary and secondary affective disorder aresimilar, but the two conditions have different prognostic and therapeuticimplications (60, 180, 182, 224). Primary affective disorder, which occursin the absence of a preexisting psychiatric disorder or a chronic debilitatingmedical illness, consists of discrete episodes interspersed with periods of nor-mality. In the case of secondary affective disorders, when the preexisting illness ischronic, which is usually the case, the patient is not well between episodes.
Depressive syndromes that are indistinguishable symptomatically from primary affective disorder occur commonly in association with obsessive-com-pulsive disorder, phobic disorders, panic disorder, somatization disorder, alcohol and drug dependence, and antisocial personality. In fact, almost allpsychiatric disorders, including schizophrenia and brain syndromes, are asso-ciated with an increased risk of secondary depression. (Secondary mania ismuch less common.) A further advantage of the primary-secondary distinction is that some studies indicate that primary affective disorder involves a higher risk of suicidethan does secondary affective disorder (except for cases with comorbid alco-holism, which adds considerable suicide risk) (203, 211). Finally, decisionsabout treatment will be influenced by distinguishing primary from secondaryaffective disorder; the preexisting illness as well as the depressive syndromemust be treated in the latter (87).
The separation of mood disorders into unipolar and bipolar subtypes was first proposed by Leonhard et al. (131). Support for the separation has emergedfrom several decades of supporting research evidence from studies in Europe andthe United States (18, 19, 23, 155, 176, 222, 223). Patients with bipolar illness havea somewhat earlier age of onset than unipolar patients. Their histories arecharacterized by more frequent and shorter episodes, which is true for depressiveas well as manic episodes. There is a greater prevalence of mood disorder amongrelatives of bipolar patients than among relatives of unipolar patients.
Many of the questions about the classification of mood disorders that have plagued investigators are still unresolved. At present there is no way to evaluatethe importance of precipitating events in either bipolar or unipolar illness. Anabiding problem is an old question of how to separate the experience ofbereavement from that of depression.
Estimates of the prevalence of primary affective disorder depend on the sampleor population studied and on the definition of the illness. Older studies haveestimated the lifetime prevalence of major depression at 5%–9% in the generalpopulation (69, 91, 162). The Epidemiologic Catchment Area study, a nationalhousehold study of psychiatric disorders conducted a quarter of a century agousing structured diagnostic interviews, provided a 5% lifetime prevalence ofmajor depression in the U.S. general population (220). A much higher rate of17% was reported by a more recent national household study of psychiatricdisorders, the National Comorbidity Survey, which used a different diagnosticinstrument, provided memory cues, and studied a younger sample (119, 219).
Such methodological differences in these studies make it difficult to knowwhich data are most accurate (218, 219). A recent systematic review of 18 GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS population prevalence studies determined pooled lifetime prevalence rates tobe 6.7% for major depression and 0.8% for bipolar disorder (218). The authorswere unable to account for all of the variability across studies on the basis ofcommon methodological differences.
Another potential explanation for the variability is that cultural and genetic differences may be important in determining the actual prevalence of affectivedisorders. For example, a 1983 study of 12,500 Amish individuals inPennsylvania yielded a prevalence rate of 1% for primary affective disorder(59). The Amish are a culturally and genetically homogeneous populationconsisting of large extended families living in a socially cohesive environmentin which alcoholism, drug abuse, and sociopathy are virtually absent. It isconceivable that reports of higher rates of affective disorder were based onsamples ‘‘contaminated’’ by individuals with other psychiatric disorders orpossibly that the Amish have a smaller genetic propensity for affective disordersthan other populations. Finally, as the Amish study was one of the first to useDSM-III criteria, a third potential explanation is that previous studies usedlooser criteria that produced inflated rates because of false-positives.
In any case, private psychiatric hospitals report that major depression is the problem for which patients are most frequently admitted, and the same is trueof many psychiatric clinics. Furthermore, whatever the chief diagnosis, depres-sion is a common reason for psychiatric consultation. Among patients withpanic disorder in one study, for example, one-third presented with a secondarydepression (11). Secondary depression is also frequently the reason for psychia-tric consultation in alcoholism, somatization disorder, and other disorders seenin psychiatric practice (130, 151, 232). Depression—primary and secondary—isclearly the most common diagnosis in psychiatry (120, 124, 218, 233).
Most studies show that mood disorders are more common in women than men. However, this may only apply to unipolar disorder where women, in somestudies, outnumber men by two to one (68, 127, 218). Apparently, men andwomen share about equally the risk of suffering bipolar disorder (68, 92, 218).
Among patients with bipolar disorder, however, women have more depressiveepisodes and men have more manic episodes (127).
There is growing evidence of increasing prevalence of major depression in successively younger birth cohorts in the last century (68, 119, 218). The age of onsethas been dropping, and the likelihood of recurrent episodes has increased (68).
A number of studies in both humans and animals have concluded that early adverse life events result in lifelong brain changes mediated by the HPAaxis that may relate to vulnerability to depression later in life (84, 164). Earlyadverse environmental factors have been implicated in adult development ofmood disorders (75, 90). Much of the evidence supporting theories of the role of adverse early childhood experiences in the development of mood disorderseither comes from animal studies without adequate human equivalents, or itis confounded by associations of risk factors for early adverse experience withother risk factors for development of adult psychopathology.
Although a link between bipolar affective disorder and above-average occupational or educational achievement has been suggested (225), studieshave demonstrated lower socioeconomic levels in bipolar patients comparedto the rest of the population (81, 190). Their relatives may also have a socio-economic advantage (217).
Depressive disorders are more prevalent in industrialized countries and in urban settings (68). Reviews of population studies internationally havereported that lifetime rates of both unipolar and bipolar disorder are highestin European studies and lowest in Asian studies (218).
The chief complaints of patients with a depressive episode are usually psycho-logical: feelings of worthlessness, despair, or ideas of self-harm. But it is alsocommon for depressed patients to complain chiefly of pains, tachycardia,breathing difficulty, gastrointestinal dysfunction, headache, or other somaticdisturbances (17, 110, 112, 202).
The dysphoric mood experienced by patients with depressive illness is usually characterized as sadness or despondency, but some patients describethemselves as feeling hopeless, irritable, fearful, worried, or simply discour-aged. Occasionally, patients will present with what seems to be major depres-sion, though they report minimal feelings of dysphoria. Such patients maycomplain of insomnia and anorexia. They may even cry profusely while tellingthe examining physician that they do not feel sad. These patients are unusual,but not unknown to psychiatrists. Regardless, a patient with depressive illnesscan have no symptoms of sadness or low mood if anhedonia is predominantduring the episode (3). It may seem counterintuitive that major depression canpresent without depressed mood, but recognition of this possibility can help theclinician identify cases like these, which may occur more often in medicalsettings.
Other characteristic symptoms of depression are anorexia with weight loss; insomnia; early morning awakening; loss of energy, described as general tired-ness or fatigability; agitation or (its opposite) psychomotor retardation; loss ofinterest in usual activities, including loss of interest in sex; feelings of self-reproach or guilt, which may be delusional in intensity; inability to focus one’s GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS thoughts, often with a simultaneous awareness of slowed thinking; and recur-rent thoughts of death or suicide.
It is common for patients with major depression to say, ‘‘Something is wrong with my mind.’’ Patients will often tell their physician that they fear theyare losing their mind or have a sense of emotions out of control. It is alsocommon for depressed patients to have a low expectancy of recovery. Such apessimistic outlook should serve as a warning that the patient may bedepressed. Medically ill patients seldom give up all hope of improvement,even if seriously ill.
In some depressed patients agitation is so overwhelming that other symp- toms go almost unnoticed. These patients are brought to physicians when theyare found by relatives or friends pacing, wringing their hands, bemoaning theirfate, clinging to anyone who will listen. They ask for reassurance, they beg forhelp, yet nothing satisfies them.
In other patients retardation is prominent. Marked slowing of both thought and motor behavior occurs. Tasks that once took minutes may requirehours. These patients may be so slowed that it is painful to listen to theirconversation. Psychomotor retardation can be so severe that a patient becomesmute or even stuporous (63, 207).
Paranoid symptoms can occur among patients with major depression.
There are usually exaggerated ideas of reference associated with notions ofworthlessness. Characteristic delusions of patients with depression are those ofa hypochondriacal or nihilistic type. Some severely ill depressed patients seemto feel they are so guilty and evil that they have become the focus of universalabhorrence or even that the world is disintegrating because of their terribleinadequacies and failures.
Hallucinations may also occur in major depression. These commonly involve accusatory voices or visions of deceased relatives associated with feel-ings of guilt. Delusions and hallucinations occurring in major depression areusually ‘‘mood congruent,’’ their content consistent with the person’s dominantmood. If delusions and hallucinations occur during major depression, thethemes are commonly guilt, disease, poverty, death, or deserved punishment.
Delusions and hallucinations occurring as part of mania are often of inflatedworth, power, or special relationship to a deity or famous person.
DSM-IV-TR includes mood-congruence as a diagnostic feature of mood disorders. Mood-incongruent psychotic features are more often seen in schizo-phrenia, where, for example, the patient may seem cheerful and relaxed whiledescribing terrifying, delusional experiences. The importance of mood-congru-ence is based mainly on a widespread clinical impression rather than sys-tematic studies.
Depressed patients may or may not mention events that they consider important in producing their illness. When a precipitating event is described,it is sometimes surprisingly trivial and difficult for the examining physician totake seriously. Furthermore, some symptoms actually began before the so-called precipitating event. This suggests that some patients who begin to feeldepressed search for reasons to explain their depression, unable or unwilling tobelieve they could feel as they do for no apparent reason.
Stressful events frequently mentioned by women as precipitants of depres- sion are pregnancy and childbirth. In a series of women with mood disorders,the first episode of depression occurred during pregnancy or postpartum in37% of bipolar and 17% of unipolar cases (101).
A change in drinking habits often accompanies depressive illness (93, 194). Middle-aged individuals with no previous history of alcoholism whobegin to drink heavily may be suffering from depression. On the other hand,some individuals drink less than usual when depressed.
A physician (178) has written movingly about how it feels to have the Firstly, it is very unpleasant: depressive illness is probably moreunpleasant than any disease except rabies. There is constant mentalpain and often psychogenic physical pain too. If one tries to get such apatient to titrate other pains against the pain of his depression onetends to end up with a description that would raise eyebrows even in amedieval torture chamber.
Naturally, many of these patients commit suicide. They may not hope to get to heaven but they know they are leaving hell. Secondly, thepatient is isolated from family and friends, because the depressionitself reduces his affection for others and he may well have ideas thathe is unworthy of their love or even that his friendship may harmthem. Thirdly, he is rejected by others because they cannot stand thesight of his suffering.
There is a limit to sympathy. Even psychiatrists have protective mechanisms for dealing with such cases: the consultant may refer thepatient to an outpatient clinic; he may allow too brief a consultation toelicit the extent of the patient’s suffering; he may, on the grounds thatthe depression has not responded to treatment, alter his diagnosis to oneof personality disorder—comforting, because of the strange butwidespread belief that patients with personality disorders do not suffer.
Fourthly, and finally, the patient tends to do a great cover-up.
Because of his outward depression he is socially unacceptable, and GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS because of his inward depression he feels even more sociallyunacceptable than he really is. He does not, therefore, tell others howbad he feels.
Most depressives, even severe ones, can cope with routine work— initiative and leadership are what they lack. Nevertheless, many ofthem can continue working, functioning at a fairly low level, and theirdeficiencies are often covered up by colleagues. Provided someminimal degree of social and vocational functioning is present, theworld leaves the depressive alone and he battles on for the sake of hisgod or his children, or for some reason which makes his personaltorment preferable to death.
Psychologist Kay Jamison (100) described the emotional suffering of her Profound melancholia is a day-in, day-out, night-in, night-out, almostarterial level of agony. It is a pitiless unrelenting pain that affords nowindow of hope, no alternative to a grim and brackish existence, andno respite from the cold undercurrents of thought and feeling thatdominate the horribly restless nights of despair. (p. 114) Jamison also described her experience of mania: . . . the seductiveness of these unbridled and intense moods ispowerful; and the ancient dialogue between reason and the senses isalmost always more interestingly and passionately resolved in favor ofthe senses. The milder manias have a way of promising—and, for avery brief while, delivering—springs in the winter and epochalvitalities. In the cold light of day, however, the reality anddestructiveness of rekindled illness tend to dampen the evocativenessof such selective remembered, wistful, intense, and gentle moments.
Any temptation that I now may have to recapture such moods byaltering my medication is quickly hosed down by the cold knowledgethat a gentle intensity soon becomes first a frenetic one and then,finally, an uncontrolled insanity. (p. 212) The cardinal features of mania are euphoria, hyperactivity, and flight of ideas. Not all manic moods are euphoric; some are irritable instead. Flight ofideas is a rapid digression from one idea to another. One’s response to a patientwith mania is often that of sympathetic amusement. In fact, experiencedclinicians who find themselves amused by a patient immediately consider the possibility that the patient’s condition is either mania or hypomania (mildmania). Flight of ideas, unlike the incoherence and tangentiality of schizo-phrenia, is usually understandable, even though some connections betweenideas may be tenuous. (Comedians often use a well-controlled flight of ideas toamuse audiences.) Attention is often called to this symptom by a push ofspeech, that is, speech in which a great deal is said in a short period of time.
Such speech may exhibit rhyming, punning, and jocular associations.
Psychotic symptoms also occur: persecutory and grandiose delusions, hallucinations, and ideas of reference. They are usually mood-congruent.
Some patients exhibit depression and mania simultaneously. They may crywhile speaking euphorically or show other unusual combinations ofsymptoms.
The currently accepted dichotomy of mood disorders into bipolar and unipolar forms is based on fundamental differences in the characteristics ofthese two forms. Compared to unipolar disorders, bipolar disorders tend tohave an earlier age of onset, cyclical depressions, a higher frequency of post-partum onsets, and a greater tendency for suicide attempts. Unipolar caseshave a somewhat older age of onset and are more likely to have single episodesand confounding with anxiety (64, 181, 188, 217, 224). Bipolar disorder casesare more likely to be psychotic and to manifest psychomotor retardation andanhedonia. Unipolar cases more often have agitated depressions and accom-panying anxiety and somatization (50, 155, 157).
Some children have episodes of depression that resemble major depres- sion in adulthood: crying, social withdrawal, hypersensitivity, and behavioralproblems (200). It is not clear whether such episodes are an early manifestationof primary affective disorder. Two observations suggest that they may not be:(1) unlike adult depression, childhood depression is not more common infemales (200); (2) the sleep of depressed children does not differ from that ofage-matched normal children, whereas depressed adults differ from normalsubjects in taking longer to fall asleep, awakening more often throughout thenight, and experiencing greater early morning wakefulness (27, 216).
Depression in adults is also associated with a reduction in slow-wave sleep (stages 3 and 4), shortened rapid eye movement (REM) latency, and increasedREM density (12, 216). Sleep studies of depressed children demonstrate none ofthese differences (27).
This suggests either that a sleep disorder makes a rather abrupt appearance within the depressive syndrome or that the depressive disorders of children andadults differ in important ways. Because human growth hormone (HGH) isexcreted mostly during sleep, sleep has an additional function in children notpresent in adults. As a physiological state, sleep may be more protected in GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS children than in adults. In any event, it appears that sleep measures are lessuseful as markers for childhood depression than for depressive illness in lateryears.
Over the last two decades, a monoamine model of depression has evolved,primarily implicating serotonin and noradrenaline. Various other brain neuro-transmitter systems have also been implicated in both mania and depression:dopamine, glutamate, and GABA (107). It has been pointed out, however, thatabnormalities in these systems are not proven fundamental to the etiology ofmood disorders, and they may instead reflect sequelae of the disorder or riskfactors for it (54).
Neuroimaging studies have demonstrated abnormalities in blood flow and glucose metabolism in limbic, prefrontal, and anterior cingulate cortex as wellas in the hippocampus and amygdala (107). Cryoarchitectural changes havebeen identified in prefrontal cortex, especially involving glial loss and reducedneuronal size and density, and in hippocampal and subcortical structuresinvolving synaptic terminals and dendrites, in neuropathological studies ofmood disorder (89). Reduced hippocampal volume has been found to beproportional to depressive illness duration (137). Increased neurogenesis hasbeen demonstrated in rodent hippocampus in response to antidepressanttreatment (189). These findings have stimulated theories of impaired neuro-plasticity and hippocampal neurogenesis in mood disorders, but furtherresearch is needed to determine how such processes might be involved.
For decades, researchers have sought to identify biological correlates of bipolar and unipolar mood disorders. Scores of studies have investi-gated neurochemical measures such as platelet imipramine binding,monoamine oxidase activity, catechol-O-methyltransferase activity, braindopamine activity, cerebrospinal serotonin and metabolites, plasmaGABA and cortisol levels, urinary norepinephrine and metabolites, insulintolerance, mitochondrial energy transduction, and platelet intracellularcalcium levels. Despite scattered reports of significant findings, no con-sistent replicable evidence of biological differences between unipolar andbipolar depression has emerged (50, 158, 228). Brain imaging studies havealso demonstrated strong parallels rather than consistent distinctionsbetween bipolar and unipolar depression (50). Few studies, however,have compared unipolar and bipolar depression directly, most compari-sons being drawn between separate studies.
The dexamethasone suppression test (DST), introduced by Carroll (39), was heralded as psychiatry’s first laboratory test. For more than two decades, DSTgenerated both enthusiasm and criticism while establishing itself as the mostused biomarker for mood disorders (64, 97). The DST is only fairly sensitive formood disorders: About 50% of patients with depression test positive, that is,resist suppression of blood cortisol levels following a dose of dexamethasone. Thespecificity of the test is higher. Only about 10% of normal control subjects arenonsuppressors. However, the specificity drops to less than 70% in some psy-chiatric conditions—including dementia and alcohol abuse—and in medicalconditions involving weight loss. Initial DST status in depression does notpredict antidepressant response sufficiently to guide treatment decisions (6).
More recently, a combined dexamethasone/corticotrophin-releasing hor- mone (dex/CRH) test was developed as a tool for assessing hypothalamic-pituitary-adrenal (HPA) axis changes associated with depressive disorders(97). With effective antidepressant treatment, the dex/CRH normalizes, sug-gesting potential utility of this test for predicting drug efficacy and treatmentresponse. Another laboratory diagnostic test proposed for depression involvesadministering thyroid-releasing hormone (TRH) to patients suspected to havedepression. Results vary, but in some studies half or more of unipolar patientshave a ‘‘blunted’’ response of thyroid-stimulating hormone (TSH) secretionfollowing a challenge with TRH. To date, neither the dex/CRH nor the TRHtests have provided consistent biological markers for depression (98).
The natural history of mood disorders is variable. The age of risk extendsthroughout life. Together with the usual episodic nature of the illness, thisdistinguishes mood disorders from most other psychiatric illnesses.
The average age of onset of major depression is in the fourth decade (57). For bipolar disorder, the average age of onset is in the third decade (181). Studies havefound a significant correlation between family members in age of onset (135).
A longstanding view that mania in children is extremely rare or nonexis- tent has been increasingly replaced with a view that the disorder is much morecommon than previously recognized. Part of the reason for its lack of recogni-tion is thought to relate to difficulty in diagnosis of the disorder. Pediatricmania is atypical by adult standards in its characteristic presentation and long-itudinal course, comorbidity patterns, and response to treatment (29).
How often do patients experience a single episode of mood disorder without recurrence? Most patients who have a manic episode have multiple GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS recurrences of depression and mania (77). About 50%–75% of patients whohave a major depressive episode will have one or more subsequent episodesof depression in their lifetime (9, 95). Thus, mood disorders are increas-ingly being recognized as lifetime disorders, as opposed to the historicalcross-sectional focus on isolated episodes of illness (82, 111, 119, 177). Inabout 10% of patients presenting with a depressive episode, the illness willeventually declare itself as bipolar, with the appearance of subsequentepisodes of full mania in about 5% and hypomania in about 5% (2, 46).
About 20% of patients with mood disorders develop a chronic illnessdifficult for physicians to manage (47, 68, 78, 129).
Between episodes of major depression, residual symptoms are not uncommon (116, 117). Analysis of data from the NIMH National CollaborativeDepression Study demonstrated that patients may experience some symptomsmore than half of the time when not experiencing full depressive episodes (104).
Bipolar disorder exhibited a similar pattern: Patients continued to have residualsymptoms about half the time between episodes, with depressive symptomspredominating over manic symptoms (105). With treatment, episodes aremuch diminished in frequency and intensity, and bipolar patients often returnto completely healthy functioning between episodes of illness (78, 213).
The length of individual episodes of major depression is extremely vari- able, ranging from a few days to many years. About half of patients recoverwithin 6 months and 80% recover by 2 years (9). By 6 years, 90% haverecovered, but recovery is unlikely thereafter (111).
The period for highest risk of relapse is shortly after recovery. The longer the patient remains well, the lower is his or her current risk of relapse. A long-term follow-up study reviewed by Angst (9) showed that within 6 months, 13%of patients with major depression relapsed. The risk of relapse doubled by 1 yearand tripled by 2 years following which the rate declined; by 5 years, three-quarters of patients had relapsed. With each subsequent episode of depression,the next episode is likely to occur sooner and be more severe than previousepisodes (82, 118). Increased risk of relapse is associated with (1) length of theindex episode of depression, (2) residual symptoms, (3) number of episodes,and (4) psychiatric comorbidity (9, 118). Treatment differences may account fordifferent rates of relapse.
Primary depression and suicide are clearly connected: 50%–70% of those whocommit suicide can be found retrospectively to have had symptoms characteristic of depression. A review of 17 studies of suicide in major depres-sion found that 15% will eventually die by suicide (85). However, the patientsstudied were severe cases in inpatient settings, and not necessarily representa-tive of all depressed patients, who may have substantially lower rates (184).
Suicide rates have not been studied in more representative populations.
Regardless, the specific suicide rate in relation to mood disorders is elevated10 to 30 times the rate in the general population (10, 169).
Although a large proportion of people who commit suicide have made previous suicide attempts, only a fraction of attempters eventually kill them-selves. About 1 out of 10 or 20 attempters will be found dead by suicide within 5to 10 years after an attempt (73, 171, 208). The period of highest risk appears tobe during the first 2 follow-up years (73, 208). The medical seriousness of theattempt is a weak predictor at best; medically trivial attempts are also some-times followed by completed suicide. In the end, prior suicide attempts are nota robust predictor of suicide completion.
The risk of suicide is not necessarily correlated with symptom severity.
Suicide risk is associated with psychiatric illness, age greater than 65 years,being male, living alone, recent stressors (especially major losses), access tofirearms, hopelessness, prior attempts, and communication of suicidalintent (76). The two disorders most frequently associated with suicide areprimary affective disorder and substance use disorders, but schizophreniaand personality disorders are also prominently represented among completedsuicides (28, 99, 214).
Folklore that patients who talk of suicide do not commit suicide is untrue.
Suicidal communication may impart increased risk. However, those who areserious about completing the act often do not convey intent to others in theirfinal days (99).
Most of the increased mortality that is found among patients from primary affective disorder is from unnatural causes, especially suicide, accounting for55% of excess deaths and conveying a mortality risk 8 times more thanexpected. Patients with primary affective disorder may also have an increasedmortality from causes other than suicide compared with matched members ofthe general population (99). Deaths from natural causes account for 45% ofexcess deaths with a risk 1.3 times more than expected, with infections, mental,nervous, circulatory, and respiratory system disorders accounting for most ofthe excess risk (88).
Alcoholism may be a complication of primary affective disorder. This is particularly true when a person begins to drink heavily in mid or late life,because ‘‘primary’’ alcoholism usually begins earlier. Drug abuse may also be acomplication of primary affective disorder.
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS Poor judgment is another complication of primary affective disorder. Poor judgment, spending sprees, and impulsive, unrealistic decisions are character-istic of manic episodes. Bad decisions also commonly accompany depressiveepisodes. Decisions to leave a job, to move to a different city, or to separate froma spouse may result from the restless dissatisfaction associated with depres-sion. Clinicians often advise depressed patients not to make major life deci-sions until they are clearly in remission.
Studies of psychiatric illness in the postpartum period indicate that bipolar women are more likely to have episodes of depression or mania during thepuerperium than at other times in their lives. Having had a postpartum episodeof depression, the likelihood that a woman with bipolar illness will haveanother episode after subsequent pregnancy is high. Studies have demon-strated episodes of puerperal mania or psychosis in 20%–30% of bipolarwomen after delivery; a family history of puerperal psychosis increases therate to more than 50% of bipolar women after delivery (42, 103).
Three recent studies have demonstrated that major depression is signifi- cantly related to poor academic performance, including college dropout (8, 96,150). In one study at a large university, diagnosed depression was associatedwith a drop of half a letter grade point average, but those who received treat-ment for depression evidenced a nearly equivalent gain in grade point average(96). In another study at a major university, students who withdrew fromschool because of depression did not fare as well on return to classes as otherreturning students who did not have depression (150).
On cognitive testing, patients with major depression may show impaired attention, deficits in explicit verbal and visual memory (but implicit memoryappears to be preserved), impairment in executive functioning, and slowing inmotor and cognitive domains. Severity of depression is associated with degreeof cognitive impairment (146). These abnormalities are more pronounced inthe elderly (13, 80, 154).
Sometimes the memory impairment with depression is so profound that a mistaken diagnosis of dementia is made. The true identity of the problem isrevealed when memory returns to normal after recovery from the depression.
Memory impairment owing to depression is called ‘‘pseudodementia,’’ a cen-tury-old term that has garnered recent controversy because it implies that thesyndrome is reversible or at least distinct from other forms of dementia.
Particularly in the elderly, findings from brain imaging studies have impliedsome blurring of these distinctions (167, 230).
Cognitive difficulties have been observed in manic as well as depressive phases of bipolar illness (146, 179). Several studies have suggested that reversalof cognitive impairments in mood disorders may not always accompany recovery from the mood episode (13, 45, 143–145). The cognitive impairments inbipolar disorder are thought to represent trait markers that may also be some-what state modulated. During bipolar episodes, cognitive impairment may beas severe as that observed in schizophrenia; however, between episodes, cog-nitive functioning in patients with bipolar disorder is far superior than inpatients with schizophrenia (45, 179).
Several studies in the 1960s reached similar conclusions about familial pat-terns of affective disorders: Affective disorders tend to be familial and can besubdivided into bipolar and unipolar types. Before 1960, family studies did notdifferentiate between unipolar depression and bipolar disorder, but demon-strated that mood disorders in general tend to be inherited in families (196).
In general, bipolar patients have bipolar relatives and unipolar patients haveunipolar relatives (102, 193, 206).
These relationships may be more complex than previously realized. Family studies consistently find bipolar illness more often in relatives of patients withbipolar illness than in relatives of unipolar depression, but unipolar depressionis observed with equal frequency in relatives of patients with unipolar depres-sion and relatives of patients with bipolar illness (7, 148, 153, 193). Overall, thesefindings support conceptual distinctions between unipolar and bipolar mooddisorders (7).
Meanwhile, data from adoption and twin studies have provided strong evi- dence for the role of genetic factors in mood disorders (153, 193, 196). There havebeen numerous twin studies of mood disorders (4), the first conducted in 1928(196). Twin studies of both bipolar disorder and unipolar depression have consis-tently shown far higher rates of concordance among monozygotic than amongdizygotic twin pairs (148, 153, 193, 196). The heritability of unipolar depression hasbeen estimated at 30%–45%, while the heritability estimates for bipolar disorderare considerably higher, 60%–80% (115, 148, 153, 193). Thus, bipolar illnessappears to be more strongly influenced by genetic factors than unipolar illness.
Adoption studies are the most powerful design for testing the relative contributions of genetic and environmental factors to heredity by comparingrates of disorders in biologic and adoptive family members (153, 196). The fewadoption studies that have been conducted on mood disorders have demon-strated significant associations between unipolar depression in adoptees andtheir biological but not their adoptive relatives; the same pattern was found forbipolar disorder (153, 193).
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS An association between unipolar depression and alcoholism was proposed by Winokur and his coworkers more than a quarter of a century ago (109). In aseries of publications they contrasted ‘‘pure depressive illness’’ with ‘‘depressivespectrum disease.’’ The latter refers to families with a high prevalence ofalcoholism and sociopathy among the men and a high prevalence of early-onset unipolar depression among the women. Four adoption studies reviewedby Cadoret (36) demonstrated that daughters of alcoholics who were notadopted away showed significantly greater depression than control subjectsand their female siblings who had been adopted away, and, conversely, morealcoholism among biological relatives of depressed than among nondepressedadoptees. These findings suggest that the association of depression with alco-holism in family members may be influenced by environmental factors.
A family history of severe psychiatric illness in a first-degree relative of a patient with major depression may predict poor long-term outcome (56).
Research indicates that when a patient with primary affective disorder oralcoholism has a family history of suicide attempt, the risk of suicide isincreased (187). A family history of attempted suicide does not seem to predictsuccessful suicide, however, in patients with sociopathy, hysteria, or opiateaddiction. The mode of genetic transmission in mood disorders is non-Mendelian and almost certainly polygenic.
The first genome-wide linkage analysis for bipolar disorder was conducted in 1993, and since that time another 20 such studies have been performed to searchfor cosegregation of the disorder with genetic markers or mutations. Neithersusceptibility gene linkage nor association studies have yielded consistently replic-able results (170, 175). Two meta-analyses suggested two regions of potentialsignificance, 13q32 and 22q12-13, and three other regions of possible interest,9p21-22, 10q11-22, and 14q24-32 (15, 192). Leading authors have concluded thatthere is not a single locus for bipolar disorder (i.e., accounting for at least half of thevulnerability in at least half of people with bipolar disorder) (139). Bipolar disordermust result from the effects of several genes interacting with one another and withenvironmental factors. Heterogeneity, phenotypes, and incomplete penetrancelikely provide further pieces in the genetic puzzle of bipolar disorder (138, 175).
Genetic studies in major depression have not fared any better over two decades of study (38, 226). Fourteen different gene region candidates haveemerged from replication in at least two studies (1p, 1q, 2q, 3centr, 4q, 5q, 6q,7p, 8p, 11q [2], 12q, 15q and 18q), but no region has been universally identified(38, 226). Chromosome q33-34 is of particular interest because it has beenidentified in women in both linkage and association studies (226). Studies ofsex specificity and genetically distinct subtypes may help to unravel the geneticbasis of major depression (38).
Making the distinction between grief and major depression can be difficult.
Bereaved people may present with symptoms of both grief and depression tosome degree (134, 212). During the first 2 months after the loss of a loved one,depressive symptoms are common, and even if the individual would otherwisemeet full criteria for a diagnosis of major depression, diagnosis of depression isdeferred and the syndrome is considered bereavement. After 2 months, majordepression is diagnosed. A diagnosis of major depression is appropriate at anytime, however, if the symptom picture involves markedly impaired func-tioning, preoccupations of worthlessness, suicidality, psychosis, or psycho-motor retardation, or if the symptoms persist longer than 2 months (3, 134).
Symptoms of grief are not generally responsive to antidepressant treatment,but depressive symptoms in the context of bereavement are (134).
Differential diagnosis between panic disorder and primary affective dis- order can be difficult because anxiety symptoms occur frequently in primaryaffective disorder and depressive symptoms occur frequently in panic disorder.
The distinction depends chiefly on chronology. If anxiety symptoms antedatethe depressive symptoms, the diagnosis is panic disorder. If depressive symp-toms appeared first, the diagnosis is primary affective disorder. Panic disorderalmost always begins relatively early in life. Current evidence suggests that inprimary affective disorder, secondary panic appears to represent a severitymarker more than a separate comorbid condition (121). Conversely, whendepression is secondary to panic disorder, the depression appears not to repre-sent a separate condition but an epiphenomenon of the panic disorder (52).
Patients with primary affective disorder often report somatic symptoms.
Conversely, affective symptoms are often reported as part of somatizationdisorder. If depressive and anxiety symptoms predominate, the diagnosis ofsomatization disorder should be made with caution, particularly if the illnessdid not occur until the patient was 30 years or older. Though patients withprimary affective disorder may report many somatic symptoms, these symp-toms are seldom spread throughout the system review. Furthermore, the hall-mark combination of conversion symptoms (unexplained neurologicalsymptoms) and menstrual symptoms of somatization disorder occurs onlyinfrequently in primary affective disorder.
Obsessions are common in primary affective disorder. The distinction between obsessional illness and primary affective disorder is also made onthe basis of chronology. If obsessions and compulsions antedate depressivesymptoms, a diagnosis of primary affective disorder should not be made.
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS Distinguishing between schizophrenia and primary affective disorder is usually not a problem. Schizophrenia, a chronic illness of insidious onset, isnot characterized by the remitting course found in primary affective dis-order. Patients with primary affective disorder do not develop the formalthought disorder characteristically seen in schizophrenia. Occasionally, thedistinction between mania and schizophrenia may be difficult. Bizarre anddramatic hallucinations, delusions, and other abnormalities of mental con-tent like those seen in schizophrenia may occur in mania. A previoushistory of episodic illness with remission or the presence of euphoria,hyperactivity, or flight of ideas indicates that the diagnosis may be maniarather than schizophrenia. Although schizophrenia and bipolar disorder arewell documented to segregate separately in families, overlap of these twodisorders in some families is also known to occur, especially in psychoticforms of bipolar illness (26, 48, 49, 139). Thus, a family history of bipolardisorder in a patient presenting with psychosis should encourage the clin-ician to consider the possibility of an affective disorder in the differentialdiagnosis of schizophrenia, although it does not necessarily rule againstschizophrenia.
For many years, clinicians assumed that both schizoaffective psychosis and schizophreniform illness were more closely related to schizophrenia than toprimary affective disorder (22, 113). Longitudinal studies have demonstratedthat schizophreniform disorder, which is defined as a brief and milder versionof the psychotic symptoms of schizophrenia (3), sometimes evolves into aschizophrenic disorder and sometimes into a mood disorder (22). Patientswith good prognosis features (sudden onset, good premorbid functioning,and lack of flat affect) appear to have family histories and course more consis-tent with mood disorders; those without good prognosis features appear to havefamily Schizoaffective disorders, defined by the presence of both prominent psychoticand mood features, were previously divided into predominantly schizophrenicand predominantly affective illnesses (113). A recent review affirmed that theillness of patients with schizoaffective disorders more closely resembles schizo-phrenia (e.g., positive symptoms of psychosis) in some ways, and bipolardisorder (e.g., mood symptoms and distress) in other ways (14). Increasingevidence now suggests that the characteristics of this psychiatric illness occu-pying a diagnostic space somewhere between schizophrenia and bipolar illnessare unstable over time and tend to evolve to either predominantly schizo-phrenic or bipolar illness (14, 22, 43). Today, both schizophreniform illnessand schizoaffective psychosis are classified as part of the schizophrenia-relatedpsychotic disorders rather than with the mood disorders (3, 113).
Depressive symptoms may accompany chronic and acute brain syn- dromes. Patients with vascular disease have elevated rates of associated depres-sion. Vascular depression is especially pernicious, being more disabling andresulting in poorer outcomes compared to other kinds of depression (106).
Patients with depression of clearly vascular origins do not have the associatedfamily history of major depression observed in patients with major depressivedisorder (106). Gross memory impairment in severely depressed and elderlypatients may create diagnostic dilemmas in determining the primary source ofthe problem—the depression or the dementia (230). Although guidelines havebeen proposed to help make this distinction (230), it may ultimately prove moreuseful to pursue understanding of the neuroanatomical substrates thatunderlie both depression and cognitive impairment than to try to differentiatethem clinically (167).
Psychiatric symptoms are side effects of certain drugs. It has long been known that steroids can precipitate psychotic, manic, and depressive states(174). Other medications implicated in the emergence of depressive syndromesare antihypertensive agents, lipid-lowering drugs (statins), and estrogen-receptor modulators (125, 174). Available evidence implicates interferon-alpha, interleukin-2, gonadotropin-releasing hormone agonists, mefloquine,progestin-releasing contraceptives, and propranolol in the occurrence ofdepressive-like symptoms. Studies utilizing diagnostic instruments, however,do not support a role for these agents in generating major depression (125, 174).
Bipolar disorder should always be considered in the differential diagnosis of patients with unipolar depression, because approximately 1 out of 10 depres-sions will eventually declare themselves as part of a bipolar illness (2, 79, 218).
Switching from apparent unipolar to bipolar illness is most common early inthe course of the illness in individuals with onset before the age of 25 years (68).
Bipolar disorder must be differentiated from substance use disorders andpersonality disorders, and, in children, from conduct disorder and attention-deficit/hyperactivity disorder.
The management of major depressive disorder always involves supportivepsychotherapy (4). Many clinicians believe that insight-directed psychotherapy,involving examination of motives and deep feelings, is probably not wisebecause it tends to increase the patient’s feelings of guilt. Available evidence,however, indicates that certain types of psychotherapy may be useful for mild ormoderate depression. The studies are of three types: (1) psychotherapy alone GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS compared with control group, (2) psychotherapy compared with antidepressantdrugs, and (3) combined psychotherapy and drugs compared with psy-chotherapy alone and drugs alone. Five main types of psychotherapy havebeen employed in the studies: (1) cognitive therapy, (2) behavioral therapy,(3) interpersonal therapy, (4) group therapy, and (5) marital therapy.
The goal of cognitive therapy is to identify existing negative cognitions and replace them with more positive functionally adaptive ones (21, 128, 231). Inbehavior therapy, the patient learns new behavioral and interpersonal skills toachieve desired responses from others (195). ‘‘Social skills training’’ is a type ofbehavior therapy that emphasizes assertiveness training and verbal and non-verbal competencies, utilizing role play for developing proficiency (21, 105, 195).
Interpersonal psychotherapy facilitates return to healthy functioning by focusingon the present rather than the past and interpersonal rather than intrapsychicprocesses; goals are development of coping, problem solving, and social andinterpersonal skills (58, 142). In group therapy, a psychotherapist and a group ofpatients attempt to effect changes in the emotional states and behavior of thepatients. Marital therapy may be conducted with an individual, a couple orfamily, or a group of couples.
Several comprehensive reviews of studies comparing psychotherapy, phar- macotherapy, and/or combinations of these therapies for the treatment of lesssevere forms of major depression have concluded that psychotherapy alone andpharmacotherapy alone are both efficacious and superior to nontreatment (40,71, 94, 172). Studies concluding that psychotherapy and antidepressant medi-cation have similar efficacy have been criticized for selective inclusion ofpatients who are especially good psychotherapy candidates and not representa-tive of most patients with major depression (54). Thus, both psychotherapy andpharmacotherapy may be considered first-line treatments in mild to moderatedepression in general medical practice and outpatient mental health practice(40). Medication provides benefits of rapid and robust response (94).
Psychotherapy appears to help keep patients engaged in therapy and reducerelapse, especially after medication discontinuation (71, 94). Further, psy-chotherapy appears to be associated with gains in interpersonal skills, socialadjustment, well-being, and treatment satisfaction not provided by pharma-cotherapy alone (94, 172). Reviews of studies comparing combinations oftreatment with pharmacotherapy and psychotherapy have concluded that com-bined treatment appears to have small but consistent advantages over eithertreatment alone (71, 94, 172).
Some patients may not be good candidates for one therapy or another.
Pregnancy and intolerable side effects may deter the use of medications(40). Some patients may resist psychotherapy; others may not accept medications (40). Fortunately, the research findings indicate that patients withless severe depression can generally be offered the treatment alternative theyfind most suitable, because outcomes of pharmacotherapy and psychotherapyare generally similar. Among patients with severe depression, however, com-bined pharmacotherapy and psychotherapy are recommended (71). The twomajor somatic approaches to the management of depressive episodes arepharmacotherapy and electrotherapy.
The first antidepressant medications were of the monoamine oxidase inhibitor-A (MAO-A) inhibitor class (229). Initially developed for the treatmentof tuberculosis, these medications were found to have energizing effects.
Monoamine oxidase inhibitors (MAOIs) have potentially serious side effects.
Foods and beverages containing tyramine (a pressor substance)—particularlycheese, some wines, and beer—should be avoided because of the danger of ahypertensive crisis. To avoid hypertensive crises, patients taking MAOIs shouldalso not take drugs containing amphetamines or sympathomimetic sub-stances. Over the years, safety concerns have limited the broad use of MAOIantidepressants (185).
Selegiline is a recently FDA-approved treatment for depression, packaged in a transdermal system. Selegiline is a selective MAO-B inhibitor at low doses,but at higher doses it also inhibits MAO-A (66, 185). The tyramine dietarymodifications are not needed at lower doses (up to 6 mg per 24 hours), butmore experience is needed before recommending higher doses without tyramineavoidance. The main side effects of the transdermal preparation are dermalreactions and insomnia; classic MAOI side effects such as sexual dysfunctionand excessive weight gain are fortunately uncommon with selegiline (185).
For many years, tricyclic antidepressants (e.g., imipramine and amitripty- line) supplanted MAOIs as the mainstay of pharmacotherapy for depression.
Tricyclic antidepressants have several unpleasant side effects: dry mouth,orthostatic hypotension, tremor, oversedation, and weight gain. These effectsoften diminish as the drug is continued. Less common, but potentially seriousside effects, are cardiac arrhythmias.
Individuals vary widely in their ability to metabolize tricyclic antidepres- sants; as much as a 40-fold difference has been reported between fast and slowmetabolizers. What a physician assumes to be a therapeutic dose may actuallyproduce toxic plasma levels or, alternatively, subtherapeutic levels of the drug.
For this reason, monitoring plasma levels of tricyclics is advised when aseemingly therapeutic dose produces either no improvement or significantside effects.
In the late 1980s a new class of antidepressants became available. The selective serotonin-uptake inhibitors (SSRIs) were developed because of GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS evidence that serotonin is involved in depression (191). This class includesfluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram(Celexa), among many others. These medications are as effective as tricyclicantidepressants but have fewer serious side effects (e.g., cardiotoxicity is nearlynonexistent) (20). Subsequently, classes of antidepressants were developedwith dual actions to block not only norepinephrine but also serotonin (venla-faxine [Effexor]) or dopamine (bupropion [Wellbutrin]) (191). All these antide-pressant medications, regardless of class, must be administered for at least 3 or4 weeks before significant antidepressant effects can be anticipated.
Following symptom remission in depression, there is believed to be a period of increased risk of symptom recurrence. Because there is no way todetermine the length of this period, it is common practice to continue anti-depressant medication for at least 6 months after the remission of acutesymptoms.
Unlike their well-appreciated utility for treatment of major depression, antidepressants do not seem to be particularly beneficial for bipolar depression(165, 166). Antidepressants can precipitate mania in approximately one-third ofdepressed bipolar patients and may induce mixed episodes (with simultaneousfeatures of mania and depression) and ‘‘rapid cycling’’ between states of maniaand depression (65, 79, 132, 160). Hence, antidepressants, the treatment ofchoice for unipolar depression, may be deleterious in bipolar depression,especially for continuing treatment of bipolar depressive episodes. Caution isrecommended for use of antidepressants for either acute or prophylactic treat-ment of bipolar depression (65). Tricyclic antidepressants and venlafaxine maybe more likely to precipitate switches to mania and bupropion, and SSRIs maybe less likely to do so (67, 74, 79, 132). When possible, therefore, it is recom-mended that antidepressants should be discontinued during the maintenancephase of bipolar disorder (67), or at least be used in conjunction with a moodstabilizer, which may help prevent switching to mania (79).
Although lithium is a strong choice for the treatment of mania, its utility as a primary treatment for unipolar depression is limited, with response rates of only30%–40% (61, 141, 165, 166, 197, 197). Addition of lithium has been welldocumented, however, as effective in augmenting the therapeutic effects ofantidepressant medication in unipolar illness (61, 197). If the unipolar patienthas a positive family history of bipolar disorder or hypomanic symptoms, lithiummay exert a more antidepressant effect than if neither of these features exists (55).
Some patients experience depression during certain times of the year, especially in the fall and early winter. DSM-IV-TR includes seasonal affectivedisorder (SAD) as a subcategory of major depressive disorder (30). Criteria forSAD include a temporal relationship between the onset of bipolar disorder, or recurrent major depression, and a specific period of the year (e.g., regularappearance of depression in the fall). A growing body of literature indicates thatan effective treatment may exist for the condition. This involves prolongedexposure in the fall and winter months to fluorescent lighting with wavelengthssimilar to sunlight (209). Devices currently on the market provide such lighting.
There is disagreement about the length of exposure or the time of day whenexposure is most efficacious (209). The effectiveness of the treatment—if defi-nitely shown to exist—may depend on suppressing nighttime melatonin produc-tion or some other manipulation of biological rhythms (186). Investigatorsrecommend that patients sit for as long as 4 hours within a few feet of the light.
The possibility of resultant cataracts or retinal damage has not been fully assessed.
The drug literature is replete with warnings against combining alcohol with psychotropic drugs used in treatment of depression. In the case of alcoholand barbiturates, the combination may be lethal. There is less additive effectbetween alcohol and benzodiazepine tranquilizers. Combining alcohol withtricyclic antidepressants increases sedative effects of both. Acute alcohol inges-tion increases plasma concentrations of tricyclic antidepressants, increasingthe likelihood of fatal poisoning (205). Alcoholics, however, metabolize anti-depressant medications at an accelerated rate, resulting in generally reducedblood levels (205).
Choosing the most suitable antidepressant agent for a particular patient is informed by science (210), but it is also an art. Effectiveness of various antide-pressant agents is essentially comparable; therefore, the decision is essentiallybased on the drug’s side effect profile (4). Antidepressant medications vary inside effect profiles, allowing the clinician to tailor the side effects to the patient’sspecific situation. For example, bupropion (Wellbutrin) has an energizing effectand may interfere with sleep. Mirtazepine (Remeron) causes sedation, a propertythat may be useful in the treatment of depression associated with sleeplessnessor agitation. Mirtazepine may significantly increase body weight; if anything,bupropion may be associated with weight loss. When weight gain is undesirableand alertness is desirable, bupropion may be a reasonable choice. For treatmentof depression in emaciated or apprehensive cancer patients, the weight gain andsedation associated with mirtazepine favor this drug as a treatment option.
Antidepressant drugs—demonstrated in controlled studies to shorten depressive episodes, reduce the intensity of symptoms, and possibly preventrecurrence—have not demonstrably reduced suicide among patients withmood disorders (16, 159, 215). Suicide-prevention centers, established inmany cities during the 1960s, had no apparent effect on the suicide rate. Incontrast, lithium maintenance treatment has been demonstrated to yield adistinct suicide reduction advantage (16, 86, 159).
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS A placebo-controlled study found significant improvement in depressive symptoms with the N-methyl-D-aspartate (NMDA) receptor antagonist drugketamine within 72 hours of intravenous administration, suggesting a poten-tial role for drugs of this type in the treatment of depression (25). Replication isneeded with larger controlled studies to verify this finding, which was aserendipitous result and not the primary aim of this study (147). The clinicalapplicability of NMDA antagonist medications may be limited by their psycho-tomimetic effects and the potential for abuse with many of these agents.
Electroconvulsive therapy (ECT) is still considered the most effective form of treatment available for depression and one of the most efficacious of allmedical treatments, with documented efficacy rates as high as 80%–90% (58,83). However, the use of ECT declined after effective medications for thetreatment of depression became accessible. Despite the fact that ECT hasbeen making a comeback in recent years (44), it still tends to be reserved forpatients who do not respond to antidepressants or who are so ill that theycannot be treated outside a hospital (140). In part, this is because of unfavorablepublic perception and continuing negative media depiction of the practice (44).
When ECT was first introduced into clinical practice in the early 1940s, itfrequently caused vertebral and other fractures. As advances in the medicalmodification of electrotherapy have been made, the treatment has evolved intoa technologically sophisticated procedure with a proven track record of safety(83). Now the procedure is less frightening to patients and is less commonlyassociated with complications. Patients are anesthetized briefly with a veryrapid-acting barbiturate and then are given a muscle relaxant, usually succinyl-choline. Electrodes are placed in the frontotemporal regions and a small,measured amount of electricity is passed between them (1, 5).
The most troublesome side effect of ECT is memory loss (83). This unde- sirable aspect of the treatment typically applies to the treatment interval, a briefperiod before initiating treatment, and several weeks after the course. Mostpatients do not find this to be a problem (5, 83). Delivering unilateral ECT to thenondominant side of the brain minimizes this side effect (58, 83).
Electroconvulsive therapy is generally considered the safest procedure performed under general anesthesia (83). Risk of death following ECT isincreased with recent myocardial infarction or states of elevated intracranialpressure. These concerns should be weighed against the risk of not treatingsevere depression. Electroconvulsive therapy may be the safest and most effec-tive treatment of mood disorders for women in their first trimester of preg-nancy or postoperatively (92) and for severely depressed patients with variousmedical illnesses (44). It is safely used in children under age 18 and the elderly(83, 108, 183, 204). First-line treatment with ECT should be considered when risks of the psychiatric illness are greater than the risks of the procedure,especially in the context of life-threatening psychiatric situations such asthose involving suicidality or severe nutritional compromise (140).
Additionally, because response to ECT is generally more rapid and robustthan to antidepressant medication, it should be considered when fast responseis important (83, 122, 140). It should also be considered first for patients with ahistory of poor medication response and good ECT response, and for patientsexpressing a preference for ECT.
Repetitive transcranial magnetic stimulation (rTMS), a procedure that applies alternating electromagnetic fields to stimulate brain cortex without pro-ducing seizures, has been investigated for the treatment of major depression.
Recent research has demonstrated statistically significant, though not clinicallylarge, therapeutic effects of rTMS in the treatment of depression (35, 136, 173).
Studies to date have generally been small and inconsistent in key methodologicalfeatures, limiting comparisons of findings. rTMS has recently received U.S. Foodand drug Administration (FDA) approval for use with major depression. Vagalnerve stimulation has also been shown effective in the treatment of refractorydepression and also in preventing relapse (163). This method has been approvedby the FDA for treatment-resistant depression.
Lithium carbonate has historically been the drug of choice in the treatment of mania (152, 197). Some clinicians began to treat mania with both a neuro-leptic and lithium, stopping the neuroleptic after 4 or 5 days when lithium hasbegun to take effect. Economic pressures to achieve improvement quickly sothat the patient can be discharged from hospital reduced enthusiasm forlithium, which is not effective until at least 1 week and often 2 or 3 weeks oftreatment (31). Mixed, rapid-cycling, secondary, and comorbid mania are not asresponsive as pure mania is to lithium.
Optimal serum levels of lithium for effective maintenance therapy of bipolar disorder are in the range of 0.8–1.0 mEq/l (149). Lower doses mayallow subthreshold symptoms to persist (149) but may be effective in pre-venting depressive episodes; higher doses appear to be more effective againstmania (123). Generally, total doses of 1,200–2,400 mg of lithium per day individed form (300 to 600 mg per dose) are required to achieve such serumlevels. Many patients find the once-daily dosing of Lithobid and Eskalith CRpreferable and have better compliance with taking it. Because lithium is apotentially toxic drug, its use must be monitored by repeatedly checkingserum levels, particularly early in treatment. Most patients experience a finetremor of the hands at therapeutic levels of lithium (0.8 to 1.5 mEq/l). At higherlevels, ataxia, disorientation, somnolence, seizures, and finally circulatory col-lapse may occur.
GOODWIN AND GUZE’S PSYCHIATRIC DIAGNOSIS The usefulness of lithium is not limited to the treatment of acute mania. It also has a robust response rate of about 70%–80% in bipolar depression (197).
Lithium is effective at preventing bipolar depressive as well as manic episodes(67). There is considerable evidence that lithium reduces morbidity and mayhave specific anti-suicide properties in bipolar illness (32, 159, 213, 215).
Anticonvulsant drugs are used in mania for their mood-stabilizing properties. The divalproex form of valproate is approved by the FDA fortreatment of acute mania. Valproate appears to be effective in mixed,secondary, comorbid, rapid-cycling, and psychotic forms of acute mania aswell as in pure mania (25). Most patients respond to doses of 15 mg/kg individed doses two to three times a day. Serum levels must be followed andmaintained in the 45–60 mg/mL range, up to 125 mg/mL for patients notachieving full symptom resolution at lower serum levels. Above 125 mg/mL,adverse effects of nausea, vomiting, and asthenia become more likely (33).
Risk for thrombocytopenia increases with these higher valproate levels. Thesustained release preparation of valproate, divalproex (Depakote) is prefer-able for most patients due to better tolerance and a once-daily dosingschedule. The sprinkle form of divalproex may be associated with fewergastrointestinal side effects (72).
Use of the anticonvulsant drug carbamazepine in treatment of mania requires slow dosage escalation and has a slow onset of action of 5 to 28 days.
Treatment is begun at 200 mg once or twice daily and increased every 5 daysuntil levels of 12–14 mg/mL are reached. Neuromuscular and cognitive sideeffects are common, especially with rapid dosage escalation. Other adverseeffects occur relatively early in treatment, including rashes often with avascular component, hypothyroidism, thrombocytopenia, low white bloodcount, and elevated hepatic enzymes, necessitating close clinical and labora-tory monitoring (25).
Both depressive and manic symptoms improved in a trial of lamotrigine and an antipsychotic for patients with refractory bipolar disorder (201). FDA-approved for the adjunct treatment of partial seizures, lamotrigine decreasesglutamate release. Other promising anticonvulsant medications used in thetreatment of bipolar disorder as adjunctive agents and for treatment-resistantcases include gabapentin, topiramate, and zonisamide, but not tiagabine asadjunctive treatment, but further study is needed to confirm their efficacy (34,37, 51, 227).
Neuroleptics provide rapid benefit for psychosis and agitation in mania, especially for the one-third of patients with mania who have psychotic symp-toms. However, in randomized comparisons, neuroleptics have been consis-tently less effective than lithium. Although lower dosages of neuroleptics may be required in the treatment of mania than for schizophrenia, tardive dyski-nesia more commonly occurs in patients with bipolar disorder (25). Olanzapinehas more evidence of efficacy in mania than other atypical antipsychotic agents,although evidence is emerging for the use of risperidone and ziprasidone aswell in the treatment of mania (24).
When treatment with a single agent fails, two or more medications may be used in combination. Although such polypharmacy is common practice, sup-porting data from controlled trials are lacking (199).
High-potency benzodiazepines, especially clonazepam and lorazepam, are commonly used to augment pharmacotherapy of acute mania by providingsedation and reducing anxiety (156, 199). Because sleep disturbance maypredispose to manic episodes, judicious short-term use of benzodiazepinesmay help prevent episodes.
As with unipolar depression, ECT is considered a very effective treatment for bipolar depression (92, 122, 197). It is also useful in the treatment formania, and it may be more effective than medications (62, 161, 197, 198).
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