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Chapter 16 - MOOD DISORDERS

16.1 MOOD DISORDERS: INTRODUCTION AND OVERVIEW

HAGOP S. AKISKAL M.D.

PRESENT SCOPE OF MOOD DISORDERS

PUBLIC HEALTH SIGNIFICANCE

Known for nearly 2,500 years, mood disorders continue to command major public health interest. Especially in their depressive forms, they are among the most common maladies, affecting at least 12 percent of women and 8 percent of men at some time during life. Those figures are extrapolated from the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area studies performed in five sites in the United States. Despite the availability of effective treatment, many persons with mood disorders are disabled, and rates of suicide, a complication occurring in about 15 percent of depressive disorders, are high in young and, especially, elderly men. Thus, although depressive disorders are more common in women, more men than women die of suicide.

The epidemiological trends cannot be ascribed to underdiagnosis and undertreatment alone. The arguments are several. First, Gerald Klerman and colleagues suggest that the incidence of mood disorders may be increasing in younger age groups, especially in cohorts born in the 1960s, and may be associated with rising rates of alcohol and substance abuse. Second, mood disorders, once believed to be essentially adult disorders, are increasingly diagnosed in children and adolescents. Third, clinical studies suggest higher rates of chronicity, recurrence, and refractoriness than previously believed. For instance, chronicity, reported by Emil Kraepelin to be no more than 5 percent at the turn of the century in Germany, is now seen in about 15 percent of cases of mood disorders in Western countries.

BROADENING THE BOUNDARIES OF MOOD DISORDERS

Current conceptualization of mood disorders in the United States embraces a wide spectrum of disorders, including many conditions previously diagnosed as schizophrenia, personality disorder, or neurosis. The diagnostic shift occurred in part as a result of the United States-United Kingdom Diagnos-tic Project, which demonstrated that schizophrenia was being diagnosed at the expense of mood disorders (Figure 16.1-1) (Figure Not Available) . The broadening of the conceptual boundaries was further stimulated by the availability of new and effective treatments, both somatic and psychotherapeutic, and by the high risk for tardive dyskinesia and suicide in persons with mood disorders incorrectly given other diagnoses. Present research interest in mood disorders emanated from a landmark NIMH conference on the psychobiology of affective illnesses, published in 1972. The NIMH Collaborative Depression Study--a long-term prospective project deriving directly from recommendations made at the conference--has legitimatized the broader perspective. Nevertheless, current data (summarized by Martin Keller and collaborators) suggest widespread undertreatment of mood disorders.

In Europe, where the concept of mood disorders has historically embraced a broad spectrum of disorders, the work of two British schools of thought has been influential. The Maudsley school--Aubrey Lewis and his followers--has promoted a continuum model from anxiety disorders to mild neurotic depressions to severe endogenous and psychotic depressions, whereas the Newcastle school, led by Martin Roth, has sharply demarcated those conditions from one another. Although vestiges of both approaches are still influential in clinical and basic research, their significance seems overshadowed by continental European studies that subdivide mood disorders on the basis of polarity: unipolar (depressive episodes only) and bipolar (depressive episodes plus manic or hypomanic episodes). That subdivision, supported by studies in the United States, has served as the basis for much recent research into and classification of mood disorders, as reflected in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the 10th revision of the International Classification of Diseases and Related Health Problems (ICD-10).

CONCEPTS AND DEFINITIONS

Mood disorders encompass a large group of psychiatric disorders in which pathological moods and related vegetative and psychomotor disturbances dominate the clinical picture. Known in previous editions of DSM as affective disorders, the term "mood disorders" is preferred today because it refers to sustained emotional states and not merely to the external (affective) expression of the present emotional state. Mood disorders are best considered as syndromes (rather than discrete diseases) that consist of a cluster of signs and symptoms that are sustained over a period of weeks to months, represent a marked departure from a person's habitual functioning, and tend to recur, often in periodic or cyclical fashion.

MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDERS

Major depressive disorder, sometimes called unipolar depression (not a DSM-IV term), is the most common mood disorder. It may manifest as a single episode or as recurrent episodes. The course may be somewhat protracted--up to two years or longer--in those with the single episode form. Whereas the prognosis for recovery from an acute episode is good for most patients with major depressive disorder, two out of three patients experience recurrences throughout life, with varying degrees of residual symptoms between episodes.

Bipolar disorder, previously called manic-depressive disorder (not a DSM-IV diagnosis), consists of at least one excited (manic or hypomanic) episode; although some patients experience only manic episodes, most end up having one or more depressive episodes. During the numerous recurrences of the


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Figure 16.1-1 (Figure Not Available) Comparison of British (London) and United States (New York) concepts of schizophrenia.(Figure from J E Cooper, R E Kendell, B J Garland, L Sharpe, J R M Copeland, R Simon: Psychiatric Diagnosis in New York and London. Oxford University Press, London, 1972. Used with permission).

alternating or cyclical phases, about one third of patients also develop mixed states, comprising simultaneous depressive and manic symptoms. The bipolar disorders were classically described as psychotic mood disorders with both manic and major depressive episodes (now termed bipolar I disorder), but recent clinical studies have shown the existence of a spectrum of ambulatory depressive states that alternate with milder and short-lived periods of hypomania rather than full-blown mania (bipolar II disorder). Those subdivisions within the larger group of bipolar disorders have focused attention on the entire range of bipolar disorders. Bipolar II disorder, which is not always easily discriminable from recurrent major depressive disorder, illustrates the need for more research to elucidate the relationship between bipolar disorders and major depressive disorder.

CYCLOTHYMIC DISORDER AND DYSTHYMIC DISORDER

Clinically, it is observed that major depressive episodes often arise from low-grade intermittent or chronic depression known as dysthymic disorder. Likewise, many instances of bipolar disorders, especially ambulatory forms, represent episodes of mood disorder superimposed on a cyclothymic background, that is, numerous brief periods of hypomania alternating with numerous brief periods of depression. Dysthymia and cyclothymia were two of the basic temperaments described by Kraepelin and Ernst Kretschmer as predisposing persons to affective illness. Cyclothymic disorder and dysthmic disorder frequently coexist with borderline personality disorder.

It is not always easy to demarcate full-blown syndromal episodes of depression and mania from their subsyndromal temperamental counterparts commonly observed during the interepisodic periods. The subsyndromal episodes appear to be fertile ground for interpersonal conflicts and postaffective pathological character developments that may ravage the lives of patients and their families. In North America many such patients end up being labeled with borderline personality disorder.

Cyclothymic disorder and dysthymic disorder also exist in the community as subaffective disorders without progression to full-blown mood disorder episodes. However, at least one out of three persons with those disorders does make the transition to a major mood disorder. Understanding the factors that mediate the transition is important for preventing manic and depressive episodes.

COMORBID DISORDERS

Mood disorders, especially depressive disorders, overlap considerably with anxiety disorders. As summarized in an NIMH monograph edited by Jack Maser and Robert Cloninger, anxiety disorders can occur during an episode of depression, may be a precursor to the depressive episode, and, less commonly, may occur during the future course of a mood disorder. Those findings suggest that at least some depressive disorders share a common diathesis with certain anxiety disorders. Other NIMH epidemiological research indicates that comorbidity of mood (especially bipolar) disorder and substance and alcohol abuse is common. In some cases the alcohol or substance abuse may represent an attempt at self-treatment of the mood disorder. Finally, physical illness--both systemic and cerebral--occurs in association with mood disorders with a frequency greater than would be expected by chance alone.

NEED FOR CLINCAL INTEGRATION

Research on comorbid conditions is in early stages and is not further elaborated in this section. Instead, the discussion focuses on the major conceptual developments that have shaped current views of mood disorders and have contributed to an integrative pathogenetic framework that takes into account the interactions of social, psychological, and biological factors as originally formulated by the author and William McKinney in 1973. An integrated framework of pathogenesis is necessary for understand-ing psychopharmacological, somatic, and psychotherapeutic approaches in the clinical management of patients with mood disorders.

CLASSICAL DESCRIPTIONS OF MELANCHOLIA AND MANIA

Much of what is known today about mood disorders was described by the ancient Greeks and Romans. The terms "melancholia" and "mania" were coined and their relation was noted. The ancients also hypothesized a temperamental origin for those disorders. Much of modern thinking about mood disorders, as exemplified by the work of the French and German schools in the middle and latter part of the 19th century--which influenced current British and American concepts--can be traced back to these ancient concepts.

MELANCHOLIA

Hippocrates (460-357 BC) described melancholia ("black bile") as a state of "aversion to food, despondency, sleeplessness, irritability, [and] restlessness." Thus, in choosing the name of the condition, Greek physicians, who may have borrowed the concept from ancient Egyptians, postulated the earliest biochemical formulation of any mental disorder. They further believed the illness often arose from the substrate of the somber melancholic temperament, which, under the influence of the planet Saturn, made the spleen secrete black bile, which ultimately darkened the mood through its influence on the brain. Greek descriptions of the clinical manifestations of depression and of the temperament prone to melancholia are reflected in the DSM-IV and in the subdepressive lethargy, self-denigration, and habitual gloom of the person with dysthymic disorder.


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One of the Hippocratic aphorisms recognized the close link between anxiety and depressive states: "Patients with fear ... of long-standing are subject to melancholia." According to Galen ( AD 131-201), melancholia manifested in "fear and depression, discontent with life, [and] hatred of all people." A few hundred years later another Roman, Aurelianus, citing the now lost works of Soranus of Ephesus, amplified the role of aggression in melancholia (and its link to suicide) and described how the illness assumed delusional coloring: "Animosity toward members of the household, sometimes a desire to live and at other times a longing for death, suspicion on the part of the patient that a plot is being hatched against him."

In addition to natural melancholia, which arose from an innate predisposition to overproduce the dark humor and led to a more severe form of the malady, Greco-Roman medicine recognized such nonnatural (environmental) contributions to melancholia as immoderate consumption of wine, perturbations of the soul due to the passions (for example, love), and disturbed sleep cycles. Autumn was considered to be the season most disposing to melancholy.

MANIA

A state of raving madness with exalted mood was noted by the ancient Greeks, although it referred to a somewhat broader group of excited psychoses than in modern nosology. Its relation to melancholia was probably noted as early as the first century BC, but according to Aurelianus, Soranus discounted it. Nonetheless, Soranus had observed the coexistence of manic and melancholic features during the same episode, consisting of continual wakefulness and fluctuating states of anger and merriment, sometimes of sadness and futility. Soranus thus seemed to have described what today are called mixed episodes in DSM-IV. Although natural melancholy was generally considered a chronic disorder, Soranus noted the tendency for attacks to alternate with periods of remission.

Although others prior to him hinted at it, Aretaeus of Cappadocia (circa AD 150) is generally credited with making the connection between the two major mood states: "It appears to me that melancholy is the commencement and a part of mania." He described the cardinal manifestations of mania as it is known today:

There are infinite forms of mania but the disease is one.... If mania is associated with joy, the patient may laugh, play, dance night and day, and go the market crowned as if victor in some contest of skill.... The ideas the patients have are infinite.... [They] believe they are experts in astronomy, philosophy, or poetry....

Aretaeus described the extreme psychotic excitement that could complicate the foregoing clinical picture of mania:

The patient may become excitable, suspicious, and irritable.... [H]is hearing may become sharp.... [S]ome get noises and buzzing in the ears ... or may have visual hallucinations ... bad dreams and his sexual desires may get uncontrollable.... [I]f aroused to anger, he may become wholly mad and run unrestrainedly, roar aloud ... kill his keepers, and lay violent hands upon himself.

Noting the fluctuating nature of symptoms in the affectively ill, Aretaeus commented:

They are prone to change their mind readily; to become base, mean-spirited, illiberal, and in a little time ... extravagant, munificent, not from any virtue of the soul, but from the changeableness of the disease.

Aretaeus was thus keenly aware of the characterological distortions so commonly manifested during the different phases of cyclical mood disorders.

Finally, consolidating the knowledge of several centuries, Aretaeus described mania as a disease of adolescent and young men given intermittently to "active habits ... drunkenness, lechery" and an immoderate life-style (what today might be called cyclothymic disorder). Exacerbations were most likely to occur in the spring.

AFFECTIVE TEMPERAMENTS

The concept of health and disease in Greco-Roman medicine was based on harmony and balance of the four humors, of which the sanguine humor was deemed the healthiest. But even a desirable humor like blood, which made people habitually active, amiable, and prone to jest, could in excess lead to the pathological state of mania. The melancholic temperament, dominated by black bile and predisposed to pathological melancholia, was described as lethargic, sullen, and given to brooding or contemplation; its modern counterparts are depressive personality disorder and dysthymic disorder. A long tradition dating back to Aristotle (384-322 BC) attributed creative qualities to the otherwise tortured melancholic temperament in such fields as philosophy, the arts, poetry, and politics. The remaining two temperaments, choleric and phlegmatic, were less desirable, as yellow bile made people choleric (irritable, hostile, and given to rage) and phlegm made them phlegmatic (indolent, irresolute, and timid). The choleric and phlegmatic temperaments would probably be recognized today as borderline and avoidant personality disorders, respectively.

Many of the original Greek texts on melancholia were transmitted to posterity through medieval Arabic texts such as those of Ishaq Ibn Imran and Avicenna (and their Latin rendition by Constantinus Africanus). In describing different affective states, Avicenna developed the theory of the temperaments to its fullest. He speculated that a special form of melancholia supervened "if black bile ... be mixed with phlegm" when the illness was "coupled with inertia, lack of movement, and quiet." Further, mania was not necessarily linked to the sanguine (hypomanic) temperament, as many forms of excited madness were believed to represent a mixture of black and yellow bile. Avicenna further observed that the appearance of anger, restlessness, and violence heralded the transition of melancholia to mania. Those elaborations on Galen's tempermental types might be considered the forerunners of current personality dimensions, deriving mood states from various mixtures of neuroticism and introversion-extroversion. Finally, the speculation on how diverse depressive phenomena could be understood as a mix of humors anticipated modern multiple-transmitter hypotheses of depression.

Ishaq Ibn Imran summarized the existing knowledge of melancholia by considering the interaction of genetic factors ("injured prenatally as the result of the father's sperm having been damaged") with a special temperament given to "mental overexertion"--though not necessarily physical overactivity--and that in turn was associated with "disruption of the correct rhythms ... of sleeping and waking." Those views, too, have a very modern ring to them.

BEGINNINGS OF MULTIFACTORIAL CONCEPTUALIZATION

The first English text (Figure 16.1-2) entirely devoted to affective illness was Robert Burton's Anatomy of Melancholy, published in 1621. A scholarly review of two millennia of medical and philosophical wisdom, the text also gives a sufferer's perspective. The concept of affective disorder endorsed by Burton was rather broad--as it always has been in the United Kingdom--embracing mood disorders and many of the disorders today considered somatoform disorders, including hypochondriasis. Although he described "causeless" melancholias, Burton also categorized the various forms of love melancholy and grief. Particularly impressive was his catalog of causes, culminating in a grand conceptualization:


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Figure 16.1-2 Frontispiece of Robert Burton's Anatomy of Melancholy (1621).

Such as have ... Saturn ... misaffected in their genitures ... such as are born of melancholy parents ... as offend in those six non-natural things, are of a high sanguine complexion ... are solitary by nature, great students, given to much contemplation, lead a life out of action, are most subject to melancholy. Of sexes both, but men more often.... Of seasons of the year, autumn is most melancholy. Jobertus excepts neither young nor old....

Burton's six nonnatural things referred to such environmental factors as diet, alcohol, biological rhythms, and perturbations of the passions such as intense love. Burton himself did not definitively indicate age prevalences. Like nearly all of his predecessors, he favored male (rather than the currently reported female) preponderance. Finally, Burton considered both the melancholic (contemplative) and the sanguine (hot-blooded) temperaments to be substrates of melancholia. Burton's work clearly links certain forms of depression with the softer expressions of the manic disposition, or bipolar II disorder.

EARLY MODERN ERA

CONCEPT OF AFFECTIVE DISORDER

Although Celsus (circa AD 30) had described forms of madness that go no further than sadness, the French alienist Jean-Philippe Esquirol (1772-1840) may have been the first psychiatrist in modern times to suggest that a primary disturbance of mood might underlie many forms of depression and related paranoid psychoses. Until Esquinol's work melancholia had been categorized as a form of insanity--that is, ascribed to deranged reasoning or thought disturbance. Esquirol's observations on melancholic patients led him to postulate that their insanity was partial--dominated by one delusion, a monomania--and that "the symptoms were the expression of the disorder of the affections.... [T]he source of the evil is in the passions." He coined the term "lypemania" (from the Greek, "sorrowful insanity") to give nosological status to a subgroup of melancholic disorders that were affectively based. Esquirol cited Benjamin Rush (1745-1813), the father of American psychiatry, who had earlier described tristimania, a form of melancholia in which sadness predominated.

Esquirol's influence led other European psychiatrists to propose milder states of melancholia without delusions, which were eventually categorized as simple melancholias and, ultimately, as primary depressions. Such descriptions culminated in the Anglo-Saxon psychiatric term "affective disorder." The term was coined by Henry Maudsley (1835-1918), the renowned British psychiatrist after whom the London hospital is named:

The affective disorder is the fundamental fact.... [I]n the great majority of cases it precedes intellectual [delusional] disorder.... [I]t frequently persists for a time after this has disappeared.

MANIC-DEPRESSIVE ILLNESS AND THE QUESTION OF PSYCHOGENIC DEPRESSIONS

Although the connection between mania and depression had been sporadically rediscovered since it was first described 2,000 years ago, the clinical work that finally established "circular insanity" (Jean-Pierre Falret's term) as folie a double forme (Jules Baillarger's term) was undertaken by those two Esquirol disciples in the 1850s. That accomplishment built on Philippe Pinel's reforms, which championed the humane treatment of the mentally ill in Paris around the turn of the 18th century and emphasized systematic clinical observations of patients, detailed in case records. French alienists made longitudinal observations on the same patient from one psychotic attack into another. Further, Esquirol had introduced the chronicling of events in statistical tables. Thus, the Hippocratic approach to defining a particular case by its onset, circumstances, course, and outcome was applied by French alienists in studying the affectively ill. The humanitarian reforms introduced in the 19th century ensured that standards of general health and nutrition would improve the outlook for the mentally ill--especially those with potentially reversible disorders like affective disorders--who could now be discharged from the asylums. The French school, then, by segregating the nondeteriorating mood disorders from the dementing types of insanity, paved the way for the Kraepelinian system.

Kraepelin's (1856-1926) unique contribution was not so much his grouping together of all the forms of melancholia and mania, but his methodology and painstaking longitudinal observations, which established manic-depressive illness as a nosological and, he hoped, a disease entity. His rationale was as follows: (1) The various forms had a common heredity measured as a function of familial aggregation of homotypic and heterotypic cases. (2) Frequent transitions from one form to the other occurred during longitudinal follow-up. (3) A recurrent course with illness-free intervals characterized most cases. (4) The superimposed episodes were commonly opposite to the patient's habitual temperament; that is, mania was superimposed on a depressive temperament and depression was superimposed on a hypomanic temperament. (5) Both depressive and manic features could occur during the same episode (mixed states). Kraepelin's synthesis was developed as early as the


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sixth (1899) edition of his Lehrbuch der Psychiatrie and most explicitly stated in the opening passages of the section on manic-depressive psychosis in the eighth edition (published in four volumes, 1909-1915):

Manic-depressive insanity ... includes on the one hand the whole domain of so-called periodic and circular insanity, on the other hand simple mania, the greater part of the morbid states termed melancholia and also a not inconsiderable number of cases of [confusional insanity]. Lastly, we include here certain slight and slightest colorings of mood, some of them periodic, some of them continuously morbid, which on the one hand are to be regarded as the rudiment of more severe disorders, on the other hand, pass over without ... boundary into the domain of personal predisposition.

For Kraepelin, the core pathology of clinical depression consisted of lowering of mood and slowed (retarded) physical and mental processes. In mania, by contrast, the mood was elated and both physical and mental activity accelerated. Although his earlier observations on what he termed "involutional melancholia" (referring to 40- to 65-year-old patients with extreme anxiety, irritability, agitation, and delusions) had led him to separate that entity from the broader manic-depressive rubric, in the eighth edition of Lehrbuch der Psychiatrie he united it with the manic-depressive group with the justification that it was a special form of mixed state.

The classification of depressive disorders is still evolving. Karl Leonhard in 1957, Jules Angst in 1966, Carlo Perris in 1966, and George Winokur, Paula Clayton, and Theodore Reich in 1969, working independently in four different countries, proposed that depressive disorders without manic or hypomanic episodes (major depressive disorder) that appear in middle age and later are distinct from depressive episodes that begin at earlier ages and alternate with manic or hypomanic episodes (bipolar disorder). The main difference between the two disorders is the greater familial loading for mood disorder, especially for bipolar disorder.

Kraepelin had conceded the occurrence of psychogenic states of depression occasioned by situational misfortune. Manic-depressive illness, on the other hand, he believed to be hereditary. Yet he could not document postmortem anatomopathological findings in the brains of manic-depressive patients. Therefore, manic-depression had to be conceptualized as a functional mental disorder in which brain disturbances were presumed to lie in altered physiological functions. Such biological factors were deemed absent in the psychogenic depressions. Thus, Kraepelin's classification of mood disorders is both dualistic and unitary. It is dualistic to the extent that he divided them as either psychologically occasioned or somatically caused. It is unitary with respect to disorders in the latter group, which have been termed endogenous affective disorders (that is, due to internal biological causes). In other words, Kraepelin restricted the concept of clinical depression to what DSM-IV terms "major depressive disorder with melancholic features." Moreover, he postulated a continum between that condition and what DSM-IV terms "bipolar disorder."

As summarized in Table 16.1-1 , in the past century endogenous depressions have been contrasted with those of exogenous cause (that is, external and, presumably, psychogenic causes). Transitions between the two groups are so frequent, however, that the two-type thesis of depression has been largely abandoned in official classifications in North American psychiatry. The endogenous-exogenous dichotomous grouping still has many adherents in the United States, Europe, and elsewhere in the world who continue to research actively its potential for clinical predictions. Those research endeavors generally attempt to validate the various subtypes based on their clinical characteristics rather than presumed etiology. Indeed, most clinical
TABLE 16.1-1 -- Overlapping Dichotomies of Affective Disorders That Are Not Necessarily Synonymous
Manic-depressive Psychogenic
S (somatic) type J (justified) type
Autonomous Reactive
Endogenous Exogenous
Psychotic Neurotic
Acute Chronic
Major Minor
Melancholic Neurasthemic
Typical Atypical
Primary Secondary
Biological Characterological

researchers today would probably agree that most forms of depression have endogenous and exogenous etiological components. Consensus would be less likely on how to delimit clinical depressive disorder from potentially comorbid disorders such as the various anxiety disorders, substance use disorders, and personality disorders. Clarifying the boundaries between those disorders has emerged as a principal challenge in the classification of mood disorders.

Cartesian thinking in 17th-century France conceptually separated mind from body, thereby providing physicians autonomy over the somatic sphere, freed from interference by the Church. The dichotomous paradigm ensured that study of the two aspects of the human organism would be unconfounded by the complexities of mind-body interactions. That is one reason why Kraepelin's descriptive observations have proved valuable to subsequent generations of clinicians. Further, his approach exemplifies the best tradition of scientific humanism in medicine: Description and diagnostic categorization of an individual patient are necessary if the physician is to offer the patient the fruits of knowledge gained from past observations made on similarly described and diagnosed patients. One limitation to the Kraepelinian approach is its biological reductionism, as a result of which it is not sufficiently articulate to account for mind-body interactions in the genesis of mental disorders.

DEPRESSIONS AS PSYCHOBIOLOGICAL AFFECTIVE REACTION TYPES

Bridging the divide between psyche and soma was the ambition of the Swiss-born Adolf Meyer (1866-1950), who dominated psychiatry from his chair at Johns Hopkins University during the first half of the 20th century. Meyer coined the term "psychobiology" to emphasize that both psychological and biological factors could enter into the causation of depressive disorders and other mental disorders. Because of the nascent state of brain science during Meyer's time, he was more adept at biography than biology and therefore paid greater attention to psychosocial causation. He preferred the term "depression" ("pressed down") to "melancholia" because of its lack of biological connotation. He conceived of depressive states in terms of unspecified constitutional or biological factors interacting with a series of life situations beginning at birth or even at conception. From that viewpoint arose the unique importance accorded to personal history in depressive reactions to life events.

Meyer's terminological revision left a somewhat confusing legacy in that the term "depression" is now applied to a broad range of affective phenomena ranging from sadness and adjustment disorders to clinical depressive disorders and bipolar disorders. Repercussions can be seen in the low threshold for diagnosing major depressive disorder in DSM-IV, which renders difficult the differentiation of major depressive disorder from transient life stresses that produce adjustment disorder with


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depressed mood. Nosological nuances to which Meyerians paid little attention, such as the difference between melancholic depression and more mundane depressions, are not just a matter of semantics. To the extent that those two forms of depression are seen in different clinical settings, hypotheses based on one population may not apply to the other. For instance, study subjects may have learned, as a consequence of uncontrollable traumatic events in their biography, to feel helpless or to view the world in a negative light, but that does not equate with clinical illness. Failure to make such nosological distinctions further clouds interpretations of the results of trials of psychotherapy versus pharmacotherapy for depressive disorders.

The Meyerian emphasis on biographical factors and their meaning for the patient represented a more practical approach to depth psychology. Recent sociological interpretations of depression can also be traced to Meyer's work. But in the final analysis the Meyerian concern for the uniqueness of the individual has proved heuristically sterile. It de-emphasizes what is diagnostically common to different individuals, thereby obscuring the relevance of accrued clinical wisdom for the index patient. For that reason the Meyerian approach, after enjoying clinical popularity for several decades in North America, has given way to neo-Kraepelinian rigor. However, the psychobiological vision of bridging biology and psychology, one of the major preoccupations of psychiatric thought and research today, represents a Meyerian legacy.

CONTEMPORARY ETIOLOGICAL MODELS OF DEPRESSION

From classical times through the early part of the 20th century, advances in understanding mood disorders broadly involved conceptual shifts from supernatural to naturalistic explanations, from reductionistic, unitarian theories of causation to pluralistic theories, and from dualism to psychobiology. Knowledge of those conceptual developments provides a useful base from which to scrutinize more recent models and concepts of mood disorder, developed later in the 20th century. The new approaches, derived from competing theoretical positions, have generated models for understanding various aspects of mood disorders, particularly depressive disorders (Table 16.1-2) (Table Not Available) .

The formative influence of early experience as it is dynamically shaped by emerging mental structures during development is the common denominator for the psychoanalytic concepts of psychopathological phenomena. By contrast, behavioral approaches in their more traditional formulations focus on the pathogenetic impact of proximate contexts. The cognitive approaches, which are akin to the behavioral-pathogenetic tradition, nonetheless concede that negative styles of thinking might mediate between proximate stressors and more remote experiences. All three schools--psychoanalytic, behavioral, and cognitive--emphasize psychological constructs in explaining the origin of mood disorders. The biological models, on the other hand, are concerned with defining the somatic mechanisms that underlie or predispose to morbid affective experiences. The schism between psychological and biological conceptualizations is an instance of the mind-body dichotomy that has characterized the Western intellectual tradition since Descartes. It must not be forgotten that psychological and somatic approaches represent merely convenient investigational strategies that attempt to bypass the methodological gulf between neural and mental structures. The ultimate aim is to understand how mood disorders develop within the psychoneural framework of a given person.

AGGRESSION - TURNED - INWARD MODEL

Sigmund Freud was initially interested in a psychoneural project for all mental phenomena. Limitations of the brain sciences of the day led him to adopt instead a model that relied on a concept of mental function borrowed from physics. The notion that depressed affect is derived from retroflexion of aggressive impulses directed against an ambivalently loved internalized object was actually formulated by his Berlin disciple, Karl Abraham, and later elaborated by Freud. Abraham and Freud hypothesized that turned-in anger was intended as punishment for the love object that had thwarted the depressed patient's need for dependency and love. Because, in an attempt to prevent the traumatic loss, the object had already been internalized, the patient now became the target of his or her own thanatotic impulses. A central element in those psychic operations was the depressed patient's ambivalence toward the object, which was perceived as a frustrating parent. Aggression directed at a loved object (parent) was therefore attended by considerable guilt. In the extreme such ambivalence, guilt, and retroflexed anger could lead to suicidal behavior.

According to that model, depression was an epiphenomenon of the transduction of thanatotic energy, a reaction that took place in the closed hydraulic space of the mind. In Freud's earlier writings anxiety had similarly been viewed as derived from the transformation of dammed-up sexual libido. Although Freud envisioned that neuroanatomical localization of psychoanalytic constructs would one day be realized, the hydraulic mind is a metaphor that does not refer to actual physiochemical space in the brain.

The conceptualization of emotional behavior as an arena of incompatible forces confined to a psyche that is relatively impervious to current influences outside the organism is the major liability of the aggression-turned-inward model and perhaps of orthodox psychoanalysis itself. Although the sexual energy transduction hypothesis of anxiety has been discarded in modern psychoanalytic thought, in modified version the aggression-turned-inward model continues to be used in clinical conceptualization today. The lingering popularity of the model may be due in part to its compatibility with the clinical observation that many depressed patients suffer from lack of assertion and outwardly directed aggressiveness. Yet a substantial number of hostile depressed patients are also encountered in clinical practice, and clinical improvement typically leads to a decrease rather than increase in hostility. Those observations shed doubt on the aggression-turned-inward mechanism as a universal explanation for depressive behavior. Finally, there is little evidence to support the contention that the outward expression of anger is of therapeutic value in clinical depression.

Outwardly directed hostility in depression is not a new clinical observation--the Greco-Roman physicians cited earlier noted as much--and can be considered a common manifestation rather than cause of depressive disorder, especially when the disorder is attended by mixed bipolar features. The hostility of the depressed patient can also be understood as an exaggerated reaction to frustrating love objects, as secondary to self-referential attributions, or simply as nonspecific irritability of an ego in affective turmoil. Such commonsense explanations that do not invoke unobservable hydraulic transmutations have greater appeal from heuristic and clinical perspectives.

OBJECT LOSS AND DEPRESSION

Object loss refers to traumatic separation from significant objects of attachment. Ego-psychological reformulations of the Abraham-Freud conceptualization of depression have paid greater attention to the impact of such losses on the ego, de-emphasizing the id-libidinal


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TABLE 16.1-2 -- Contemporary Major Models of Depression
Table adapted from H Akiskai, W McKinney: Overview of recent research in depression: Integration of 10 conceptual models into a comprehensive clinical frame. Arch Gen Psychiatry 32: 285, 1975.
(Not Available)

and related hydraulic aspects. It is often noted that the depressant impact of separation events resides in their symbolic meaning for a person rather than in any arbitrary objective weight that the event may have for clinical raters. However, love loss, bereavement, and other exits from the social scene, as defined by the London psychiatrist Eugene Paykel, are presently the concepts most commonly used in practice and research.

Although love melancholy had been described since antiquity, it was in Freud's 1917 paper on mourning and melancholia that grief and melancholia were systematically compared for the first time. According to current data, the transition from grief to pathological depression occurs in no more than 2 to 5 percent of adults and 10 to 15 percent of children. Those figures suggest that such transition occurs largely in persons predisposed to mood disorders.

The work of John Bowlby of the Tavistock Clinic, London, is a comprehensive clinical investigation of the attachment that the child establishes with the mother or mother substitutes during development; that bond is considered the prototype for all subsequent bonds with other objects. Like many psychoanalytic explanations of adult symptom-formation, the object loss model is formulated as a two-step hypothesis, consisting of early breaks in affectional bonds, which provide the behavioral predisposition to depression, and adult losses, which are said to revive the traumatic childhood loss, thereby precipitating depressive episodes. However, the role of proximate separations in provoking depressive reactions rests on more solid clinical evidence than the hypothesized sensitization resulting from developmental object loss. That realization has led Bowlby to regard childhood sensitization resulting from early deprivation as a generic characterological vulnerability to a host of adult psychopathological conditions.

Compared with aggression turned inward, object loss is more directly relevant to clinical depression; yet it is still pertinent to question whether it is an etiological factor. Studies at the Wisconsin


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Primate Center have indicated that optimal homeostasis with the environment is most readily achieved when the individual is securely attached to significant others, and the dissolution of such ties appears relevant to the emergence of a broad range of psychopathological disturbances rather than depression per se. A related methodological question is whether object loss operates independently of other etiological factors. For instance, a history of early breaks in attachment may reflect the fact that one or both of the patient's parents had mood disorder, with resultant separation, divorce, suicide, and so forth.

On balance, the ego-psychological object loss model is conceptually superior to its id-psychological counterpart. In postulating an open system of exchange between a person and the environment, the model permits consideration of etiological factors other than separation--such as heredity, character structure, and adequacy of social support--all of which might modulate the depressant impact of adult separation events. Conceptualizing the origin of depression along those lines is in the mainstream of current ideas of adaptation, homeostasis, and disease. An important treatment implication is the value of social support in preventing relapse and mitigating chronicity of depression. That is indeed an ingredient in the interpersonal psychotherapy of depression, which can be conceptualized as a form of brief, focused, and practical psychodynamic therapy.

DEPRESSION AS LOSS OF SELF-ESTEEM

Reformulation of the dynamics of depression in terms of the ego suffering a collapse of self-esteem represents a further conceptual break with the original id-psychological formulation: Depression is said to originate from the ego's inability to give up unattainable goals and ideals. The model further posits that the narcissistic injury that crushes the depressed patient's self-esteem is imposed by the internalized values of the ego rather than the hydraulic pressure of retroflected thanatotic energy deriving from the id. Because the construct of the ego is rooted in social and cultural reality, loss of self-esteem may result from symbolic losses involving power, status, roles, identity, values, and purpose for existence. Thus, the existential and sociocultural implications of depression conceived as a derivative ego state provide the clinician with a far more flexible and pragmatic tool for understanding depressed persons than the archaic hydraulic metaphors related to libidinal vicissitudes. That model represents one of the first attempts to formulate depression in terms that subsequent psychological theory and research could operationalize in more testable form.

Self-esteem is part of the habitual core of the individual and as such is integral to the personality structure. Indeed, low self-esteem conceived as a trait is a major defining attribute of the depressive (melancholic) personality. While it is understandable how such individuals can easily sink into melancholia in the face of environmental adversity, it is not obvious why persons with apparently high self-esteem, such as those with hypomanic and narcissistic personalities, also succumb to melancholy with relative ease. To explain such cases, one must invoke an underlying instability in the system of self-esteem that renders it vulnerable to depression. The opposite is also known to occur; that is, manic episodes may develop from a baseline of low self-esteem, as sometimes occurs in patients with dysthymic disorder.

The foregoing considerations suggest that the vicissitudes of self-esteem deemed central to the model of depression as loss of self-esteem are manifestations of a more fundamental mood dysregulation. In classical psychoanalysis it is conceded that such dysregulation is of constitutional origin. In general, attempts by psychoanalytic writers to account for bipolar oscillations have not progressed beyond metapsychological jargon, with the possible exception of denial of painful affects as a mechanism in the phenomenology of mania.

COGNITIVE MODEL

The cognitive model, developed by Aaron Beck at the University of Pennsylvania, hypothesizes that thinking along negative lines (for example, thinking that one is helpless, unworthy, or useless) is the hallmark of clinical depression. In effect, depression is redefined in terms of a cognitive triad, according to which the patient thinks of him- or herself as helpless, interprets most events in an unfavorable light vis-a-vis the self, and believes the future to be hopeless. In more recent formulations in academic psychology, those cognitions are said to be characterized by a negative attributional style that is global, internal, and stable and to exist in the form of latent mental schemata that generate biased interpretations of life events.

Because the cognitive model is based on retrospective observations of already depressed persons, it is virtually impossible to prove that causal attributions such as negative mental schemata precede and hence predispose to clinical depression; they can just as readily be regarded as clinical manifestations of depression. The importance of the cognitive model lies in the conceptual bridge it provides between ego-psychological and behavioral models of depression. It has also led to a new system of psychotherapy that attempts to alter the negative attributional style, to alleviate the depressive state, and, ultimately, to fortify the patient against future lapses into negative thinking, despair, and depression.

The cognitive model therefore has the cardinal virtue of focusing on key reversible clinical dimensions of depressive illness, such as helplessness, hopelessness, and suicidal ideation, while providing a testable and practical psychotherapeutic approach. That approach, however, is less likely to succeed in patients with the full-blown melancholic manifestations of a depressive disorder. It is doubtful that negative cognitions alone could account for the profound disturbances in sleep, appetite, and autonomic and psychomotor functions encountered in melancholic depressions. Further, to conceptualize a multifaceted malady such as depression largely or solely as a function of distorted cognitive processes is reminiscent of pre-Esquirolian notions that emphasized impaired reasoning in the development of depression.

LEARNED HELPLESSNESS

The learned helplessness model is in some ways an experimental analog of the cognitive model. The model proposes that the depressive posture is learned from past situations in which the person was unsuccessful in initiating action to terminate undesirable contingencies. The model is based on experiments in dogs that were prevented from taking adaptive action to avoid unpleasant electrical shock and subsequently showed no motivation to escape such aversive stimuli, even when escape avenues were readily available. Armed with evidence from many such experiments, the University of Pennsylvania psychologist Martin Seligman postulated a trait of learned helplessness--a belief that it is futile to initiate personal action to reverse aversive circumstances--that is formed from the cumulation of past episodes of uncontrollable helplessness.

The learned helplessness paradigm is a general one and refers to a broader mental disposition than depression. Thus, it is potentially useful in understanding such diverse conditions as social powerlessness, defeat in sporting events, and posttraumatic


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stress disorder. In addition, past events might shape a characterological cluster, consisting of passivity, lack of hostility, and self-blame, relevant to certain depressive phenomena. The low hostility observed in some patients during clinical depression could, for instance, be ascribed to the operation of such factors. Learned helplessness could thereby provide plausible links between aspects of personal biography and clinical phenomenology in depressive disorders. Therapeutic predictions for alleviating depression and related psychopathological states capitalize on new cognitive strategies geared to modifying expectations of uncontrollability and the negative attributional style. That is an illustration on how insights gained from experimental paradigms can be fruitfully combined to address clinical disorders.

Nonetheless, the clinician should be wary of unwarranted clinical extrapolations. For instance, some clinicians have argued that the depressed patient's passivity is manipulative, serving to obtain interpersonal rewards. It has also been claimed that such factors have a formative influence on the development of the depressive character. That interpretation appears more relevant to selected aspects of depression than to the totality of the disorder. Depressive behavior and verbalizations clearly have a powerful interpersonal impact, but to speculate that depression represents merely a masochistic life-style developed for the purpose of securing interpersonal advantages represents a circular argument that is mechanistic and could be viewed as disrespectful of the clinical agony of patients with mood disorders. Finally, although most formulations focusing on helplessness have emphasized acquisition through learning, recent experimental research in animals tends to implicate genetic factors in the vulnerability to learning to behave helplessly.

REINFORCEMENT AND DEPRESSION

Other behavioral investigators, notably Peter Lewinsohn, have developed clinical formulations of depression that hinge on certain deficits in reinforcement mechanisms. According to the reinforcement model, depressive behavior is associated with lack of appropriate rewards and, more specifically, with the receipt of noncontingent rewards. The model identifies several contributory mechanisms. Some environments may consistently deprive persons of rewarding opportunities, thereby placing them in a chronic state of boredom, pleasurelessness, and, ultimately, despair. That reasoning, however, may offer more insight into social misery than clinical depression. A more plausible postulated mechanism is the provision of rewards that are not in response to the recipient's actions; in other words, the gratis provision of what a person considers undeserved rewards may lead to lowering of self-esteem. Predisposition to depression is formulated in terms of deficient social skills, which are hypothesized to decrease a person's chances of responding to potentially rewarding contingencies in any environment. Indeed, recent research on the relation between personality and mood disorder suggests that such deficits might contribute to certain nonbipolar depressions. Therefore, psychotherapeutic approaches designed to enlarge a patient's repertoire of social skills may prove valuable in preventing depressive episodes.

The concepts of depression that have been derived from behavioral methodology and developed in the past three decades are scientifically articulate and therefore testable approaches to the clinical phenomena of depression. Yet in the behavioral literature the distinction between depression on self-report inventories and clinical depression is sometimes overlooked. Further, the behavioral model does not address the distinct possibility that reinforcement deficits may simply represent the psychomotor inertia of depressive illness. Nevertheless, by focusing on reward mechanisms, the behavioral model provides a conceptual bridge between purely psychological and emerging biological conceptualizations of depression.

BIOGENIC AMINE IMBALANCE
Chemistry of the emotional brain

The formulation of sophisticated biological explanations of mood disorders had to await the development of neurobiological techniques that could probe parts of the brain involved in emotions. Although the complex physiology of the limbic-diencephalic centers of emotional behavior is generally inaccessible to direct observation in humans, much has been learned from animal work. The limbic cortex is linked with both the neocortex, which subserves higher symbolic functions, and the midbrain and lower brain centers, which are involved in autonomic control, hormonal production, and sleep and wakefulness. Norepinephrine-containing neurons are involved in many of the functions that are profoundly disturbed in melancholia, including mood, arousal, appetite, reward, and drives. Other biogenic amine neurotransmitters that mediate such functions are the catecholamine dopamine, especially important for psychomotor activity, and the indoleamine serotonin, involved in mood and sleep and inhibitory control. Cholinergic neurons, secreting acetylcholine at their dendritic terminals, are generally antagonistic in function to catecholaminergic neurons. Although the opioid system might, on experimental and theoretical grounds, also serve as one of the neurochemical substrates for mood regulation, in the author's opinion no cogent model of mood disorders involving that system has appeared to date.

Biogenic amine hypotheses

Joseph Schildkraut at Harvard University and William Bunney and John Davis at NIMH published the first reports formally hypothesizing a connection between depletion or imbalance of biogenic amines, specifically norepinephrine, and clinical depression. The serotonin counterpart of the model was emphasized in the models proposed by Alec Coppen in England and I.P. Lapin and G.F. Oxenkrug in Russia. Both catecholamine and indoleamine hypotheses were essentially based on two sets of pharmacological observations. First, reserpine, a medication that decreases blood pressure by depleting biogenic amine stores, was known to precipitate clinical depression in some patients. Second, antidepressant medications, which alleviate clinical depression, were found to raise the functional capacity of the biogenic amines in the brain. That style of thinking is known as the pharmacological bridge, extrapolating from evidence on mechanism of drug action to the neurotransmitter pathologies presumed to underlie a given psychiatric disorder. Such pharmacological strategies have been of heuristic value in developing research methods for the investigation of mood disorders and schizophrenia. Indeed, the research methodology developed by the relatively few investigators working in the area in the past three decades is among the most elegant in the history of psychiatry.

Different variations of the biogenic amine model give somewhat different importance to the relative weight of the biogenic amines norepinephrine and serotonin in the development of pathological mood states. Arthur Prange and colleagues at the University of North Carolina formulated a permissive biogenic amine hypothesis according to which serotonin deficits permit the expression of catecholamine-mediated depressive or manic states. That hypothesis was supported by subsequent animal research showing that an intact serotonin system is necessary


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for the optimal functioning of noradrenergic neurons. In a recent study, the omission of tryptophan from the diet of antidepressant-responsive depressed patients annulled the efficacy of the antidepressant. Although that finding is intriguing, the precursor-loading strategy to increase the brain stores of serotonin (for example, with l-tryptophan) has not been unequivocally successful in addressing clinical depression. Dietary loading with catecholamine precursors has fared even worse than serotonin precursor loading in the treatment of depression.

The cholinergic-noradrenergic imbalance hypothesis as proposed by David Janowsky and colleagues represents yet another attempt to elucidate the roles of biogenic amines. More recent formulations by Larry Siever and Kenneth Davis at the Mount Sinai Hospital in New York have hypothesized noradrenergic dysregulation as an alternative neurochemical mechanism for depressive disorders. The model envisions oscillation from one output mode to the other at different phases of depressive illness. In a provocative extrapolation from that model, bipolar depression would emerge as being of low noradrenergic output, but many instances of major depressive disorder, like some anxiety disorders, could be biochemically conceptualized as high-output conditions.

Despite three decades of extensive research and indirect evidence, however, it has not been proved that a deficiency or excess of biogenic amines in specific brain structures is necessary or sufficient for the occurrence of mood disorders. The role of dopamine, though less extensively studied than that of norepinephrine, deserves greater recognition: It might have relevance to atypical and bipolar depression as well as mania. The putative permissive role of serotonin appears more relevant to aggressive suicide attempts than to depression per se. It is also of theoretical and clinical interest that serotonergic dysfunction might subserve other conditions characterized by lack of inhibitory control, among them obsessive-compulsive and panic phenomena, bulimia nervosa, certain forms of insomnia, alcoholism, and a host of impulse-ridden personality disorders. Such considerations have led the Dutch psychiatrist Herman van Praag and his colleagues to postulate a dimensional neurochemical disturbance generic to a large group of disorders within the traditional nosology. That hypothesis might be variously regarded as a challenge to psychiatric nosology or as a statement of the need to supplement clinical classification with biochemical parameters.

The biogenic amine models provide meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders. Although the predisposition to mood disorder is not specified in those models, it is implied that the biochemical faults are genetically determined.

Neuroendocrine links

Inadequate or excessive mobilization of neurotransmitters such as noradrenaline in the face of continued or repeated stress, as reflected in pathological modification of noradrenergic receptor function, could represent a neurochemical final common pathway of homeostatic failure. Such mechanisms could also provide links with psychoendocrine dysfunction; the hypothesized neurotransmitter deficits may underlie the disinhibition of the hypothalamic-pituitary-adrenal axis, characterized by steroidal overproduction, the most widely studied endocrine disturbance in depressive illness. When challenged with dexamethasone, the altered axis has been found resistant to suppression, thereby offering Bernard Carroll and colleagues at the University of Michigan the possibility of developing the dexamethasone suppression test (DST) for melancholia (the test is currently of uncertain specificity for melancholia). That line of research has culminated in the demonstration by Charles Nemeroff and other investigators of increased concentrations of corticotropin-releasing factor (CRF) in the cerebrospinal fluid of patients with major depressive disorder. CRF also appears relevant to the pathophysiology of anxiety disorders, such as panic disorder.

Another neuroendocrine index of noradrenergic dysregulation--blunted growth hormone response to the alpha2 -adrenergic receptor agonist clonidine--likewise points to limbic-diencephalic disturbance. However, studies performed in the United States suggest that it is positive in both endogenous depression and severe anxiety disorder (panic disorder). Thyroid-stimulating hormone (TSH) blunting upon thyrotropin (TRH) stimulation, another common neuroendocrine disturbance in depression, is also of limited specificity (it is often positive in alcoholism).

What is remarkable, however, is that the DST, clonidine, and TRH challenge data in aggregate identify the majority of persons with clinical depression. The more relevant point is that such evidence of midbrain disturbance argues for considering clinical depression a legitimate illness. Finally, the data tend to argue for shared mechanisms between certain mood and anxiety disorders.

Stress, biogenic amines, and depression

The concept of a pharmacological bridge implies two-way traffic. The hypothesized chemical aberrations may be primary or biologically induced. Provision should also be made, however, for the likelihood that psychological events, which serve as precipitants of clinical depression, might induce or initiate neurochemical imbalance in vulnerable subjects. That suggestion is supported by studies in animals, where separation and inescapable frustration are known to effect profound alterations in the turnover of biogenic amines and in postsynaptic receptor sensitivity. It is conceivable that, in genetically predisposed persons, environmental stressors might more easily lead to perturbations of limbic-diencephalic neurotransmitter balance. Finally, it is plausible that in vulnerable individuals, especially during the formative years of childhood, the psychological mechanisms discussed earlier might more easily perturb midbrain neurochemistry.

NEUROPHYSIOLOGICAL APPROACHES
Electrolyte metabolism and neuronal hyperexcitability

Abnormalities in neuronal electrolyte balance (an excess of residual sodium, defined by radioisotope techniques) and hypothesized secondary neurophysiological disturbances were the focus of investigations by Coppen and colleagues in the early 1960s. The existing data appear compatible with the hypothesized movement of excess sodium into the neuron during an episode of mood disorder and redistribution toward the preillness electrolyte balance across the neuronal membrane during recovery; intraneuronal leakage of sodium is postulated in both depressive and manic disorders but deemed more extreme in the latter. Because the harmonious activity of the neuronal cell--and, by implication, that of a group of neurons--depends on the electrical gradient maintained across its membrane by the differential distribution of sodium, abnormalities in sodium concentrations and transport are hypothetically relevant to the production of an unstable state of neurophysiological hyperexcitability.

The view that mania represents a more extreme electrophysiological dysfunction in the same direction as depression violates the commonsense notion of symptomatological opposition between the two kinds of disorder, yet it may in part account for the existence of mixed states in which symptoms of depression and mania coexist. That many depressed patients with a


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bipolar substrate respond to lithium salts--a provocative finding first documented by the NIMH team led by Frederick Goodwin--further supports the concept of a neurophysiological common denominator to mania and depression.

Rhythmopathy and depression

Recent neurophysiological formulations by Thomas Wehr and Norman Rosenthal, working at NIMH, have focused on abnormalities in the circadian regulation of temperature, activity, and sleep cycles, thereby paving the way for new theoretical constructs and therapeutic possibilities. It has been found that depressed patients are phase-advanced in many of their biological rhythms, including the latency to first rapid eye movement (REM) in sleep. Shortening of REM latency, which has been extensively studied by David Kupfer and colleagues at the University of Pittsburgh, has been proposed as another biological test for depressive disorder. Finally, it has been hypothesized that sleep deprivation (originally developed by European investigators) and exposure to bright white light (demonstrated by NIMH research) might correct phase disturbances and thereby terminate depressive episodes, especially in patients with periodic and seasonal illness. Although the specificity and efficacy of those neurophysiological indices and manipulations for mood disorders require more extensive research, cumulatively they point to midbrain dysregulation as the likely common neurophysiological substrate of depressive disorders.

The foregoing considerations further suggest that the ancient Greeks, who ascribed melancholia to malignant geophysical influences, did not indulge in mere poetic metaphor. It is also striking that the ancients had observed the disturbed circadian patterns and advocated their readjustment to restore euthymia.

Affective dysregulation as the fundamental pathology

The ultimate challenge for research in mood disorders is to characterize the basic molecular mechanisms that underlie the neurophysiological rhythmopathies, which in turn might account for the recurrent nature of the affective pathology as envisioned by Kraepelin. This means that in the most typical recurrent forms of the disorders, the constitutional foundations--manifested as cyclothymic and dysthymic temperaments--are so unstable that the illness may run its entire course more or less autonomously, with the environment largely serving the role of turning on and off the more florid phases (episodes). The Parisian psychiatrist Jean Delay also emphasized affective dysregulation as the fundamental pathology in the spectrum of mood disorders. Robert Post, at NIMH, has hypothesized that the electrophysiological substrates could be kindled, such that an oligoepisodic disorder, initially triggered by environmental stressors, could assume an autonomous and polyepisodic course. The monograph on manic-depressive illness by Goodwin and Kay Jamison presents eloquent arguments for a fundamental cyclical thymopathy, based on current psychobiological understanding.

CONCEPTUAL INTEGRATION

TOWARD PATHOPHYSIOLOGICAL UNDERSTANDING

Modern psychobiology attempts to link experience and behavior to the central nervous system. To build sturdy conceptual bridges between the psychological and biological approaches to mood disorders, sophisticated strategies are needed that go beyond the Cartesian notion of limited mind-body interactions through the pineal gland and the more pedestrian generalizations of the Meyerian school.

In collaboration with Peter Whybrow at the University of Pennsylvania, William McKinney and the author have further developed the conceptual framework that considers the syndromes of melancholia and mania as the final common pathway of various psychological and biological processes. The overarching hypothesis is that psychological and biological etiological factors converge in reversible deficits in the diencephalic substrates of pleasure and reward. Those areas of the brain subserve the functions that are disturbed in melancholia and mania. The integrative model links the central chemistry and physiology of reward mechanisms with the object loss and behavioral models of depression, both of which give singular importance to the depressant role of loss of rewarding interpersonal bonds; an essential element of the model is the circadian disturbances observed since ancient times in both depressive and manic syndromes. Both syndromes then are conceptualized as the clinical manifestations of a disordered limbic system with its subcortical and prefrontal extensions. Multiple factors converge in producing dysregulation in the system and are described below.

Predisposing heredity

Current evidence indicates that genetic factors play a significant role in the causation of bipolar and recurrent major depressive disorders. Genetic heterogeneity is likely, and may involve single-gene-dominant inheritance with variable penetrance or polygenic inheritance. Although it is not known exactly what is inherited, recent research by Kenneth Kendler and associates suggests that heritability involves a broad spectrum of disorders, including milder depressive episodes.

Developmental predisposition

As parents with mood disorders are often in conflict, which may lead to separation, divorce, and suicide, it can be said that heredity often determines the type of environment into which the child predisposed to mood disorder is born. Developmental object loss, although not causing mood disorder, might modify the expression of the illness, possibly by leading to earlier onset, more severe episodes, and an increased likelihood of personality disorder and suicide attempts.

Temperament

Since ancient times, persons prone to mania and melancholia have been described as possessing certain temperamental attributes, representing variations on the theme of what today is subsumed under cyclothymia and dysthymia. The fact that many monozygotic twins discordant for mood disorders studied by Aksel Bertelsen's Danish research team exhibited affective instability along such temperamental lines strongly suggests that such attributes represent genetically determined traits. That research and research conducted by Kendler and associates suggest that many of the temperamental attributes might be transmitted as part of the overall genetic liability to mood disorders. The author's research has identified those temperaments in the prepubertal offspring of parents with bipolar (manic-depressive) disorders, suggesting that they precede by years to decades the onset of major mood disorder episodes. Those temperaments in turn generate much interpersonal friction, emotional arousal, and sleep loss, and thereby might give rise to many of the life stressors that precipitate episodes of mood disorders. The use of stimulant drugs--either to self-treat lethargy or enhance hypomanic episodes--can also precipitate such episodes.

Life events

Most individuals do not develop clinical depression when exposed to environmental adversity. Such adversity seems to play a pathogenic role in those with an affective diathesis. Thus, current data suggest that social stressors in the onset of depression are more relevant to the early course of the illness. The evidence linking such events to mania is less robust. At any rate, socially stressful events often appear to be triggered by the temperamental instability that precedes clinical episodes. Interpersonal losses are common events in the lives of individuals with intense temperaments. Indeed, a recent study by Peter McGuffin and associates at the Institute of Psychiatry, London, raised the possibility that one mechanism by which heredity produces depression is by creating environmental adversities in the lives of individuals predisposed to this illness. Whatever the origin of environmental adversity, it is common clinical experience that loss represents an important--perhaps even central--theme in clinical depression. Variables that seem to modulate the impact of adult losses include concurrent life events, resultant changes in life-style, lack of interpersonal


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support, deficient social skills, and the symbolic meaning of the loss.

Biological stressors

Many physical diseases and pharmacological agents are known to precede the onset of both depressive and manic episodes. Like psychosocial stressors, however, they do not generally seem to cause de novo episodes but mobilize them in those persons with a personal and family history of mood disorders.

Sex

Clinical and epidemiological studies concur in suggesting that women are at higher risk for mood disorders, with the risk highest for the milder depressive states. Although it is customary to ascribe the increased risk to social and interpersonal variables, biological factors appear equally relevant. Women have higher levels of brain monamine oxidase (the enzyme that breaks down monamine transmitters), have more precarious thyroid status (often associated with chronic and rapid-cycling mood episodes), experience postpartum precipitation, experience premenstrual accentuation of dysphoric mood, and are vulnerable to the depressant effect of steroidal contraceptives. Recent data reported by Giulio Perugi and associates at the University of Pisa, Italy, have raised the hypothesis that female sex might also favor the greater expression of dysthymic attributes, whereas hypomanic traits appear favored by male sex. Those considerations tend to parallel, respectively, the ruminative and active cognitive response styles reported by Stanford's Susan Nolen-Hoeksema to distinguish the sexes. What specific sex-related biographical factors might interact with sex-related biological factors to produce such trait differences is presently unknown.

The model presented here (Figure 16.1-3) goes beyond the general provisions of the unified approach developed two decades earlier. It is submitted that, at least in the highly recurrent forms of the malady, affective temperaments represent the intermediary stage between remote (for example, hereditary) and proximate (for example, stressful) factors, and that limbic-diencephalic dysfunction is best characterized as the biological concomitant of the clinical manifestations of the affective syndromes. Like the temperamental dysregulations, those biological disturbances represent a stage in the pathogenetic chain: They emerge as temperamental instabilities that react to, provoke, or invite life events, substance use, and rhythmopathies, which in turn usher in the behavioral and subjective manifestations of the illness.

IMPLICATIONS FOR TREATMENT AND PREVENTION

The foregoing integrative model envisions the joint use of somatic-pharmacological and psychosocial interventions. Although the milder forms of mood disorders can be managed with psychotherapy, somatic treatments are usually required for reversing the biological disturbances in melancholia before the patient can respond to interpersonal feedback. Depressive disorders with psychotic features often necessitate more definitive somatic interventions such as electroconvulsive therapy. Continued psychopharmacological treatment is also effective in decreasing rates of relapse and future recurrence.

Psychosocial therapy by skilled therapists can provide support, combat demoralization, change maladaptive self-attributions, and improve conjugal and vocational functioning. Whether such therapy can also modify personality traits to fortify the patient against new episodes is a future research challenge. In the author's view, it may prove more profitable to attempt to help patients explore professional and object choices that match their temperamental proclivities and assets and that in turn might provide them greater harmony and adaptation in life. Although much needs to be learned about the indications for medication and psychotherapy in different subtypes of mood disorders, research to date not only does not indicate a negative


Figure 16.1-3 An integrative pathogenetic model of mood disorders.

interaction between the two forms of treatment but in some instances suggests additive and even synergistic interaction.

The challenge for psychiatric research in the decade ahead is to elucidate the basic mechanisms whereby the predisposing, precipitating, and mediating variables reviewed here, and others yet to be identified, interact to produce the final common path of decompensation in melancholia. Because of the heterogeneity of depressive conditions presenting as a psychobiological final common syndrome, and because antidepressant agents, irrespective of specificity to one or another biogenic amine, are about equally effective in two thirds of those with depressive disorder with melancholic features, the antidepressant agents, effective as they are, may be acting not on the primary lesions of the depressive disorders but on a neurochemical substrate distal to the underlying biological faults. The choice of antidepressants is still very much guided by the side effect profile least objectionable to a given patient's constitution, physical condition, and life-style.

Current evidence suggests that in depressed patients with bipolar disorder antidepressants might provoke mixed episodes, hypomanic episodes, or both and, possibly, increased cycling in the subsequent course of the disorder. The value of lithium in such cases does suggest some biochemical specificity. The kindling-sensitization model further suggests the utility of anticonvulsant medication on escalation of the disorder and represents another example of pathophysiology-based intervention. Interventions geared to disturbed rhythms of the disorder represent yet another example. Thus, mood clinics should educate patients and their significant others on how to dampen stimulation so that it is kept at an optimal level for depressed patients with cyclothymic disorder. All offending drugs (for example, cocaine, caffeine) should be eliminated and circadian disruptions and sleep loss minimized. The greater challenge is how to curb the tempestuous romantic liaisons or ill-fated financial ventures that periodically jolt the lives of patients with cyclothymic disorder. Psychoeducation and psychotherapy have the task of ameliorating the resulting social problems. Assuring compliance to a lithium regimen--which in many would have attenuated episodes and prevented such sequelae--is not easily achieved. Research on both compliance-enhancing techniques and the physiochemical mechanisms of lithium is needed before


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the drug can be used efficiently in the large number of patients who might benefit from it.

It is tempting to suggest that biogenic amines, the humors of modern psychobiology, play the same heuristic role as the ancient humors did for many centuries. The black humor, appropriately evoked in the construct of melancholia in DSM-IV, may not have the same claim for etiological relevance to depressive disorders as biogenic amines but at least has a classical heritage. In any discipline, scientific truth is a function of its technology, but understanding the phenomena under consideration is a matter of philosophical temperament that seeks integration and the hope for a unified vision. Research into the causes and treatment of mood disorders has generated an abundance of recent data suitable for integration into theory and practice, and conceptualizing the origin and treatment of mood disorders can no longer be justified on the ground of ideological preference alone.

SUGGESTED CROSS-REFERENCES

The other sections of Chapter 16 cover the various aspects of mood disorders in detail. Epidemiology is the subject of Section 16.2; biochemical aspects are the focus of 16.3; Section 16.4 is a discussion of genetic aspects; psychodynamic etiology is the subject of Section 16.5. Clinical features are covered in Section 16.6, somatic treatment in Section 16.7, and a discussion of psychosocial treatments concludes the chapter in Section 16.8.



REFERENCES

Abraham K: Notes on the psychoanalytical investigation and treatment of manic-depressive insanity and allied conditions. In Selected Papers of Karl Abraham, p 137. Hogarth Press, London, 1948.

Akiskal H S: Temperament, personality, and depression. In Research in Mood Disorders: An Update, H Hippius, C Stefanis, editors, p 45. Hogrefe & Hubes, Gottingen, 1994.

*Akiskal H S, McKinney W T: Depressive disorders: Toward a unified hypothesis. Science 182: 20, 1973.

Angst J: The etiology and nosology of endogenous depressive psychoses. Foreign Psychiatry 2: 1, 1973.

Aretaeus of Cappadocia: The Extant Works of Aretaeus, the Cappadocian, F Adams, editor-translator. Sydenham Society, London, 1856.

*Beck A T: Depression: Causes and Treatment. University of Pennsylvania Press, Philadelphia, 1967.

Bertelsen A, Harvald B, Hauge M: A Danish twin study of manic-depressive disorders. Br J Psychiatry 130: 330, 1977.

Bowlby J: Process of mourning. Int J Psychoanal 45: 317, 1961.

Bunney W E Jr, Davis J M: Norepinephrine in depressive reactions: A review. Arch Gen Psychiatry 13: 483, 1965.

Carroll B J, Feinberg M, Greden J F, Tarika J, Albala A A, Haskett R F, James N M, Kronfol Z, Lohr N, Steiner M, de Vigne J P, Young E: A specific laboratory test for the diagnosis of melancholia: Standardization, validation, and clinical utility. Arch Gen Psychiatry 38: 15, 1981.

Coppen A: The biochemistry of affective disorders. Br J Psychiatry 113: 1237, 1967.

Delay J: Les Dereglements de L'humeur. Presses Universitaires de France, Paris, 1946.

Freud S: Mourning and melancholia. In Standard Edition of the Complete Psychological Works of Sigmund Freud, vol 4, J Strachey, editor, p 152. Hogarth Press, London, 1975.

*Goodwin F K, Jamison K R: Manic-Depressive Illness. Oxford University Press, New York,