29 | THE DIAGNOSIS OF MOOD DISORDERS

JAN FAWCETT AND BRANT HAGER

Every established order tends to produce (to very different degrees and with very different means) the naturalization of its own arbitrariness. . . . Schemes of thought and perception can produce the objectivity that they do produce by misrecognition of the limits of the cognition that they make possible, thereby founding immediate adherence . . . to the world of tradition experienced as a “natural world” and “taken for granted.”    PIERRE BOURDIEU, in Wilson (1993)

INTRODUCTION

Sadness and distress are part of everyday life, as are elation, irritability, and associated fluctuations in energy, activity, enjoyment, and cognition. More severe, disabling mood traits and states, which today we conceptualize as mood disorders, have been described throughout recorded history. Ancient mood disorder diagnostic concepts served the early physician by identifying putative underlying mechanisms, guiding correspondingly appropriate treatment, and estimating patient prognosis. Modern mood disorder diagnostic concepts continue to aid the contemporary physician in similar ways. However, modern mood disorder diagnostic concepts serve many other masters, including research, public health, financial, and medico-legal endeavors.

In mental health clinical care, an optimally conceptualized categorical mood disorder diagnosis validly, accurately, reliably, and rapidly identifies an individual patient as belonging to one or more specific mood disorder diagnostic groups, and not belonging to others. For the clinician, such an optimal mood disorder diagnosis allows for rapid identification of disorder type, determination of caseness, diagnostic elimination of other conditions, concise formulation about putative underlying mechanisms, selection of optimally effective therapy, and prediction of course and prognosis.

In mental health research, an optimally conceptualized categorical mood disorder diagnosis validly, accurately, reliably, and efficiently defines a controlled, descriptively homogeneous mood disorder group for study. Making such an optimal diagnosis allows for statistically robust conclusions regarding mood disorder diagnosis-related natural history, correlations, and outcomes in response to treatment. Given the need for diagnostic homogeneity, an optimal research diagnosis values the elimination of false positives over the elimination of false negatives (Spitzer et al., 1978). Diagnostic false positives dilute the sameness of a research sample, and the exclusion of diagnostic false negatives may be mitigated by increased sample sizes. Ultimately, an optimal research diagnosis, subjected to rigorous study, may point to candidate disease mechanisms, and fruitful areas for possible intervention, control, and cure.

In addition, categorical mood disorder diagnoses also help to establish the fact that a given diagnosis is of public health significance, worthy of reimbursement for treatment, and appropriate for research funding. These latter three diagnostic purposes serve as a crucial bridge between clinical and research efforts, as the clinician’s diagnostic task ultimately relies on payment for services, research into neurobiologic etiogenesis and treatments, and empirical data on diagnostic validity, accuracy, reliability, and outcomes.

As we shall see, however, current categorical diagnostic approaches to mood disorders, even ones as optimally conceptualized previously, pose problems for both clinical care and research. To explore this crucial issue, the following chapter will outline an early history of mood disorder diagnostic concepts, discuss the evolution of contemporary mood disorder diagnostic concepts up to the most current diagnostic systems, and finally address the myriad questions of how clinical description of mood disorders might be improved to further the usefulness of diagnosis for treatment and research.

What criteria are most valid and reliable for determining when sadness, distress, elation, irritability, and associated fluctuations in energy, activity, enjoyment, and cognition constitute a disorder, indicating altered pathophysiology, and requiring treatment? How might we improve mood disorder diagnosis to better advance our efforts to predict course and specific treatment response, understand underlying causes, and develop more effective treatments? This chapter will address these questions.

HISTORY

EARLY HISTORY OF MOOD DISORDER DIAGNOSIS

The earliest lineaments of psychiatry contain remarkable descriptors of pathological mood states and traits, and trace prescient contours of our current dilemmas in mood disorder diagnosis. Ancient physicians throughout Europe, the Middle East, South Asia, and East Asia, described sundry accounts of what we might today call syndromes of depression, mania, psychosis, agitated excitement, anxiety, and adjustment reactions, among others (Horowitz and Wakefield, 2007; Maciocia, 2009; Sharma, 1994; Solomon, 2001). Hippocrates, writing in the 5th and 4th centuries B.C.E., illuminated several cases of melancholia, and distinguished between melancholia with and without external cause (Horowitz and Wakefield, 2007). Aristotle himself added the notion of melancholia as a temperament as well as an illness. Hippocrates also mentioned the maniacal affliction, and stated that both maniacal and melancholic diseases occur especially during spring (Hippocrates and Adams (Tr.), 2010: p. 135). Speculations about the relationship between melancholia and mania began to appear in the occidental literature circa 1st century B.C.E., and came to full fruition between the efforts of Aretaeus of Cappadocia, 2nd century C.E., and Alexander of Tralles, 6th century C.E. (Goodwin and Jamison, 2007).

Equally elaborative, yet seldom referenced in allopathic literature, are mood descriptors from Ayurvedic and Chinese medicine. The Caraka Samhita, a core Ayurvedic document with origins conservatively dated to the 7th century B.C.E., features a chapter on insanity, including syndromes of euphoric excitement, irritable agitation, and withdrawn despondency. The Caraka Samhita includes allowances for simultaneous occurrence of any combination of these three syndromes, and is replete with lists of prodromal symptoms, vivid syndromic descriptors, and references to humoral as well as exogenous mechanisms (Sharma, 1994). The Rites of Zhou, a 12th ­century B.C.E. Chinese non-medical text, mentions Kuang, the disease of irritable raving, and by the 2nd century B.C.E., Chinese medical texts, such as the Spiritual Axis and the Classic of Difficulties, linked irritable raving, both cyclically and mechanistically, to Dian, the disease of withdrawn, worried, unresponsive dullness (Maciocia, 2009). Other ancient Chinese medicine contributions, especially the Essential Prescriptions of the Golden Chest, circa 3rd century C.E., included additional syndromes of restless fatigue and agitated sadness (Maciocia, 2009).

Taken together, these first forays into mood diagnosis demonstrate an ostensible distillation of case-based observations, rooted firmly in humoral heuristics, without the apparent benefit of formal statistical empiricism.

The Middle Ages in Europe saw a period of supernatural etiologic speculation in medicine. Mood disorders, along with other forms of mental illness, took on the assumption and stigma of demonic possession and religious uncleanliness, whose care, cure, and punishment was the ken of the priesthood (Solomon, 2001). Later, the Renaissance, the Enlightenment, and the associated Scientific Revolution in Europe heralded a resurgence of classical, case-based psychiatric observations, with humoral explanations, dovetailed with sundry attempts at anatomical correlation (Goodwin and Jamison, 2007).

These ancient forays into mood disorder diagnosis established melancholia and mania as facts of human existence, posed questions about the relationships between them, and hypothesized about the mechanisms underlying such conditions. Furthermore, they delimited a spectrum of philosophic conceptualizations of, and reactions to, mood disorders, from the Greek protomedical model of mood disorders as diseases to be treated, to the Aristotelian notion of melancholia in particular as character to be valued, to the medieval notion of mood disorders as evil to be despised and eradicated. Such ontologic, epistemologic, nosologic, and ethical treatment issues pertaining to mood disorders persist to this day.

RECENT HISTORY OF MOOD DISORDER DIAGNOSIS

The contemporary era of empirical, medical model mood disorder diagnosis, based on systematic amassment of case-based observations without humoral assumptions, began in earnest in the 19th century C.E. In 1838 Jean Etienne Dominique Esquirol proposed the idea that the psychological faculty of mood could be disordered independently from the behavioral problems of melancholic underactivity and manic hyperactivity, laying groundwork for our current conceptions of mood rather than activity as central to mood disorder diagnosis (Healy, 2002: p. 15). In 1854, echoing Aretaeus of Cappadocia and Alexander of Tralles, Jean Pierre Falret and Jules Bailarger independently proposed that mania and depression represented manifestations of an underlying, unitary illness, which Falret termed folie circulaire, and Bailarger named folie de double forme (Healy, 2002: p. 16). In 1881 Emanuel Mendel defined hypomania as “that form of mania which typically shows itself only in the mild stages abortively, so to speak,” and in 1882 Karl Kahlbaum published his observations of a milder, cyclic, manic-depressive illness, cyclothymia (Goodwin and Jamison, 2007: p. 7). Kahlbaum is also credited as first describing dysthymia, a state of chronic unhappiness lacking the full neurovegetative manifestations of melancholia, as well as first advocating the full, historical description of all of a psychiatric patient’s signs and symptoms, in order to form diagnostic syndromes (Healy, 2002, pp. 19–20).

From the late 19th century into the first part of the 20th century, Emil Kraeplin arose as a major figure in descriptive psychiatry, melding disparate psychiatric diagnostic concepts into an overarching, comprehensive, and parsimonious classification scheme. Whereas Kraeplin did not invent nosological empiricism, he built creatively on the syndrome concept of Kahlbaum, and brought to bear a dedicated, systematic, and at the time unparalleled method of tracking and analyzing psychiatric signs and symptoms. Kraeplin leveraged detailed, longitudinal clinical observations to synthesize a unitary concept of manic-depressive illness, including the concept of mixed states, which resonates to this day in our current DSM and ICD classifications. Kraeplin’s synthetic concepts allowed for better prediction of the course and prognosis of major mental illness, and sharper delimitation of mood from psychotic disorders (Goodwin and Jamison, 2007).

In contrast with Kraeplin, Bleuler, in 1924, proposed that mood (termed affective by Bleuler) and psychotic illnesses fell along a spectrum without a firm boundary, presaging the current concepts of schizoaffective disorder and recent findings into the extensive genetic overlap between bipolar disorder and schizophrenia (Goodwin and Jamison, 2007).

Since the late 19th and early 20th centuries—with the exception of the psychoanalytic and psychobiologic influences in American psychiatry during the majority of the 20th century, as well as the constructivist-humanist critiques of the antipsychiatry movement—mood disorder diagnosis worldwide has largely taken on a stance valuing the medical model of descriptive empiricism over models with more rationalistic explanatory power (McHugh and Slavney, 1983). However, to this day mental health clinicians treating mood disorders continue to employ a plethora of useful rationalistic diagnostics, through the lenses of psychoanalytic, psychodynamic, cognitive-behavioral, and biopsychosocial formulations, as well as through the persistent clinical assumptions of the monoamine hypothesis and associated theories of biological etiogenesis (Beck, 2011; Driessen et al., 2009; Engel, 1977, 1980; Gabbard, 2005).

EVOLUTION OF THE DSM AND ICD

The American Diagnostic and Statistical Manual (DSM) traces its origins to two key predecessors, The Statistical Manual for the Use of Institutions for the Insane, and the Nomenclature of Psychiatric Disorders and Reactions, War Department Technical Bulletin, Medical 203.

The Statistical Manual for the Use of Institutions for the Insane was created in 1918 through collaboration between the Committee on Statistics of the American Medico-Psychological Association and the US Census Bureau (American Psychiatric Association, 1952; Grob, 1991). Prior to this time, the US Census Bureau had made successive attempts to keep count of patients with various disorders housed in state hospitals. The Bureau’s accounting of mental illness, however, was of little clinical use to practicing psychiatrists. For example, in the 1840 US Census, the Bureau recorded only one category of mental illness: “idiocy/insanity” (American Psychiatric Association, 2000). By the 1880 US Census, the Bureau distinguished seven categories of mental illness: mania, melancholia, monomania, paresis, dementia, dipsomania, and epilepsy (American Psychiatric Association, 2000). The massive expansion of asylum psychiatry in the early 19th century appears to have driven this nosological enrichment, as alienists of the day observed progressively larger numbers of institutionalized patients, and discerned increasingly differentiated shades of madness and insanity (Healy, 2002). Such efforts at continual nosological improvement, in conjunction with increasing scientific and political interest in the social, demographic, and economic correlates of mental illness, culminated in the aforementioned Statistical Manual for the Use of Institutions for the Insane, including 22 principle categories (Grob, 1991). However, it was not until the events of World War II that psychiatric nosology in the United States became clinically useful, and its further evolution clinically driven.

In World War II, American psychiatry—influenced by psychobiologic and psychoanalytic thinking, in combination with barbiturate-aided abreactions—asserted its usefulness by mitigating the effects of psychiatric reactions among soldiers, thus ameliorating chronic disability and consequent attrition of fighting troops. During the war, the Army Medical Corps’ psychiatric division, led by Brigadier General William C. Menninger, used the Nomenclature of Psychiatric Disorders and Reactions, War Department Technical Bulletin, Medical 203, as its primary diagnostic manual (Office of the Surgeon General, Army Service Forces, 1946). Medical 203 applied to inpatients as well as outpatients, and thus had broader clinical utility for both military and civilian psychiatric clinicians. With the exception of organic psychoses and character, intellectual, and paranoid disorders, Medical 203 conceptualized the majority of psychiatric disorders as reactions to the stresses of war, a conceptualization with clear situational pertinence and convincing rationale, traceable to both Pierre Janet and Adolf Meyer.

After World War II, the World Health Organization (WHO) began work on ICD-6, published in 1948. The release of ICD-6 represented a significant event in international psychiatric nosology. ICD-6 marked the first attempt by the WHO to attempt classification of causes of morbidity as well as mortality, including Section V, on mental, psychoanalytic, and personality disorders (Moriyama et al., 2011). Psychiatric classification in ICD-6 largely followed that used by the US military and related Veterans Administration system, and eventually by DSM-I (American Psychiatric Association, 1952).

As with the ICD-6, the concept of psychiatric disorders as reactions was incorporated into the DSM-I by the American Psychiatric Association in 1952 (American Psychiatric Association, 1952). In this way, DSM-I was influenced heavily by the psychobiologic work of Adolf Meyer, who taught that psychiatric disorders were reactions to various stresses at various phases of the life cycle. Similarly, DSM-I was also influenced strongly by psychoanalytic theories, which were pervasive at the time and originally incorporated into the language of Medical 203, leading some diagnoses to be defined in psychodynamic terms (Grob, 1991). In the Medical 203, affective (mood) disorder diagnoses included neurotic depressive reaction, manic-depressive reaction, psychotic depressive reaction, and melancholia, with related diagnostic categories of note including acute situational maladjustment, and cyclothymic personality. In DSM-I, a similar rubric obtained for mood disorder diagnoses, called affective reactions, which were also enriched by additional symptomatic descriptors to aid the diagnostician. DSM-I also further subdivided adjustment reactions into various time periods across the life span, and added a category for schizophrenic reaction, schizoaffective type.

DSM-II, appearing in 1968, retained Meyerian psychobiologic influences in the categories of psychotic depressive reaction and adjustment reactions subdivided across the lifespan. DSM-II also demonstrated increased psychoanalytic influences through the various categories of neuroses, including depressive neurosis. Cyclothymia remained as a personality disorder. However, DSM-II dropped the reaction designation for most mood disorders, and indeed divorced the occurrence of major mood disorders from their psychobiologic context. DSM-II stipulated that, regarding the major affective disorders, “The onset of the mood does not seem to be related directly to a precipitating life experience” (American Psychiatric Association, 1968, pp. 35–36). The major affective disorders in DSM-II included involutional melancholia, manic depressive illness (manic, depressed, and circular types), and other and unspecified major affective disorders. These reorganizations of DSM-II occurred in the overarching context of nosologic synchronization with ICD-8 (American Psychiatric Association, 1965).

The WHO adopted ICD-9 in 1975. ICD-9 expanded the list of ICD mental disorder categories, and included narrative descriptions of disorders similar to that of DSM-II (American Psychiatric Association, 1980; Moryama et al., 2011). The related ICD-9-CM, or clinical modification, released in 1978, included more detailed coding procedures, for categorizing and tracking clinical morbidity. The DSM has continued to use the ICD-9-CM coding system since release of the DSM-III, discussed next.

DSM-III, published in 1980, embodied a major departure from prior DSM and ICD editions, by focusing on operationalized symptom criteria validated by family history and follow-up studies, tested for interrater reliability, and almost totally divorced from a priori etiologic designations. DSM-III arose almost entirely from Spitzer et al.’s (1978) Research Diagnostic Criteria, which in turn evolved directly from Feighner et al.’s (1972) diagnostic criteria (Feighner et al., 1972; Spitzer et al., 1978). DSM-III dropped the etiologically presumptive diagnoses of depressive neurosis, involutional melancholia, and psychotic depressive reaction from DSM II, although it retained synonymic mention of depressive neurosis under the new category of dysthymic disorder. DSM-III also reclassified adjustment disorders according to the type of emotional disturbance (depressed mood, anxious mood, or both), and/or disturbance of conduct.

The psychopharmacologic revolution, which burgeoned in the early 1950s and came to full fruition in the 1960s, informed the shift of DSM-III toward the medical model of diagnosis, and away from the psychobiologic and psychoanalytic stances of prior editions. The discovery and demonstration of empirical effectiveness of the neuroleptic chlorpromazine, the tricyclic antidepressant imipramine, the monoamine oxidase inhibitor isocarboxazid, and the mood stabilizer lithium carbonate served as potent stimuli for a disease-oriented approach to psychoses and mood disorders, and led to a paradigm shift that supported a proliferation of neurobiologic research into mood disorders.

Furthermore, the social, political, and economic climate of the 1960s and 1970s placed American psychiatry in a position necessitating justification of its services. The influence of the antipsychiatry movement, the failure of psychoanalysis to impact severe and persistent mental illness, and governmental budgetary tightening all exerted pressure on American psychiatry to identify itself as a useful and necessary specialty. Part of this justification included the effort to demarcate more sharply between normal and abnormal states, that is, defining those disorders requiring treatment and deserving reimbursement for care (Wilson, 1993). One unforeseen consequence of American psychiatry’s need to justify its existence and funding through nosologic definition has been a tendency to pathologize as disordered what might otherwise be interpreted as normative human emotional experience (Healy, 1997; Horowitz and Wakefield, 2007).

Another important change in DSM-III comprised the shift from the diagnostic category of manic-depressive illness, which captured recurrent depression as well as mania, mixed states, and cyclic alterations between the three, to the diagnostic category of bipolar disorder, which required only the historical presence of mania for diagnosis, and the category of major depression, which required only the historical presence of one major depressive episode for diagnosis. As Goodwin and Jamison (2007) have pointed out, this shift prioritized the polarity of a mood disorder (bipolar versus unipolar) over the recurrence or longitudinal course of a mood disorder. In DSM-III, bipolar disorders were further subdivided according to the polarity of their current episode, and included an additional category of atypical bipolar disorder, which captured the disorder of hypomania in a person with a prior major depressive episode, later designated Bipolar II Disorder in DSM-IV. DSM-III furthermore reclassified cyclothymia as an affective disorder, rather than a personality disorder (American Psychiatric Association, 1980).

Lastly, DSM-III added prognostically informative specifiers to describe the current manic or major depressive disorder, and a category of Atypical Depression. Manic Episode specifiers included In Remission, With Psychotic Features (Mood-congruent vs. Mood-incongruent), and Without Psychotic Features. Major Depressive Episode specifiers included the preceding, plus With Melancholia and Without Melancholia. The category of Atypical Depression introduced a place where clinicians could diagnose clinically significant depressive symptoms that did not meet full criteria for a previously defined specific affective disorder (American Psychiatric Association, 1980).

DSM-III-R added some changes in 1987. Notably, in an attempt to define better caseness, the diagnosis of major mood episodes now required a change from prior level of functioning (for major depressive episode), or impairment in functioning (for manic episode) (American Psychiatric Association, 1987).

DSM-IV updated these changes in 1994, and made further revisions leading to DSM-IV-TR in 2000. DSM-IV was fashioned based on 150 literature reviews, including data-reanalyses, field trials comparing DSM-III, DSM-III-R, ICD-10, and proposed DSM-IV criteria (American Psychiatric Association, 1994). Proposed changes had to be supported by published empirical data. For example, in one DSM-IV mood disorders field trial, 91% of subjects, who presented with depressed mood plus two other depressive disorder symptoms, met the criteria for current or lifetime major depression or dysthymia, suggesting to the authors that additional categories for milder forms of depression were not needed to account for the vast majority of depressive morbidity (Keller et al., 1995). As a result, the categories of minor depressive disorder and recurrent brief depressive disorder did not rise to the level of independent diagnoses, but instead remained under the rubric of depressive disorder, not otherwise specified. In 2000, DSM-IV-TR was completed to correct factual errors in DSM-IV, and include relevant research data developed since 1994.

The release of ICD-10 in 1995 brought the ICD system up to date regarding operationalized psychiatric diagnostic criteria (World Health Organization, 1993). Although their coding differs, the diagnostic criteria for mood disorders in ICD-10 largely correspond to those of DSM-IV-TR, as outlined in the following.

CURRENT MOOD DISORDER DIAGNOSTIC SYSTEMS

Following the example of DSM-III and its progeny, current mood disorder diagnostic systems, including the DSM IV-TR and ICD-10 Diagnostic Criteria for Research, emphasize the recognition of discrete, non-overlapping syndromes, comprising various combinations of core, prototypal mood episodes. An abbreviated list of mood disorder diagnostic criteria from ICD-10 Diagnostic Criteria for Research may be found in Table 29.1. For comparison with current DSM mood disorder diagnostic criteria, the reader is directed to DSM-IV-TR (American Psychiatric Association, 2000), described in brief in the following text, and the imminent DSM-5, scheduled for release in May 2013.

TABLE 29.1. ICD-10 mood disorders (World Health Organization, 1993)

F30–F39 MOOD [AFFECTIVE] DISORDERS

F30 MANIC EPISODE

F30.0 Hypomania

A. The mood is elevated or irritable to a degree that is definitely abnormal for the individual concerned and sustained for at least four
consecutive days.

B. At least three of the following must be present, leading to some interference with personal functioning in daily living:

(1) increased activity or physical restlessness;

(2) increased talkativeness;

(3) difficulty in concentration or distractibility;

(4) decreased need for sleep;

(5) increased sexual energy;

(6) mild spending sprees, or other types of reckless or irresponsible behavior;

(7) increased sociability or overfamiliarity.

C. The episode does not meet the criteria for mania (F30.1 and F30.2), bipolar affective disorder (F31.-), depressive episode (F32.-), cyclothymia (F34.0), or anorexia nervosa (F50.0).

D. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0.

F30.1 Mania without psychotic symptoms

A. A mood that is predominantly elevated, expansive, or irritable, and definitely abnormal for the individual concerned. This mood change must be prominent and sustained for at least a week (unless it is severe enough to require hospital admission).

B. At least three of the following must be present (four if the mood is merely irritable), leading to severe interference with personal functioning in daily living:

(1) Increased activity or physical restlessness;

(2) Increased talkativeness (“pressure of speech”);

(3) Flight of ideas or the subjective experience of thoughts racing;

(4) Loss of normal social inhibitions resulting in behavior that is inappropriate to the circumstances;

(5) Decreased need for sleep;

(6) Inflated self-esteem or grandiosity;

(7) Distractibility or constant changes in activity or plans;

(8) Behavior that is foolhardy or reckless and whose risks the subject does not recognize, e.g., spending sprees, foolish enterprises, reckless driving;

(9) Marked sexual energy or sexual indiscretions.

C. The absence of hallucinations or delusions, although perceptual disorders may occur (e.g., subjective hyperacusis, appreciation of colors as specially vivid, etc.).

D. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0.

F30.2 Mania with psychotic symptoms

A. The episode meets the criteria for mania without psychotic symptoms (F30.1) with exception of criterion C.

B. The episode does not simultaneously meet the criteria for schizophrenia (F20) or schizoaffective disorder, manic type (F25.0).

C. Delusions or hallucinations are present, other than those listed as typical schizophrenic in F20 G1.1b, c, and d (i.e., delusions other than those that are completely impossible or culturally inappropriate, and hallucinations that are not in the third person or giving a running commentary). The commonest examples are those with grandiose, self-referential, erotic, or persecutory content.

D. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0.

A fifth character may be used to specify whether the hallucinations or delusions are congruent or incongruent with the mood:

F30.20 mania with mood congruent psychotic symptoms (such as grandiose delusions or voices telling the subject that he has superhuman powers)

F30.21 mania with mood incongruent psychotic symptoms (such as voices speaking to the subject about affectively neutral topics, or delusions of reference or persecution)

F30.8 Other manic episodes

F30.9 Manic episode, unspecified

F31 BIPOLAR AFFECTIVE DISORDER

Note: Episodes are demarcated by a switch to an episode of opposite or mixed polarity or by a remission.

F31.0 Bipolar affective disorder, current episode hypomanic

A. The current episode meets the criteria for hypomania (F30.0).

B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), depressive episode (F32.-), or mixed affective episode (F38.00).

F31.1 Bipolar affective disorder, current episode manic without psychotic symptoms

A. The current episode meets the criteria for mania without psychotic symptoms (F30.1).

B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), depressive episode (F32.-), or mixed affective episode (F38.00).

F31.2 Bipolar affective disorder, current episode manic with psychotic symptoms

A. The current episode meets the criteria for mania with psychotic symptoms (F30.2).

B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-), depressive episode (F32.-), or mixed affective episode (F38.00).

A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with the mood:

F31.20 with mood-congruent psychotic symptoms

F31.21 with mood-incongruent psychotic symptoms

F31.3 Bipolar affective disorder, current episode moderate or mild depression

A. The current episode meets the criteria for a depressive episode of either mild (F32.0) or moderate severity (F32.1).

B. There has been at least one other affective episode in the past, meeting the criteria for hypomanic or manic episode (F30.-) or mixed affective episode (F38.00).

A fifth character may be used to specify the presence of the somatic syndrome as defined in F32, in the current episode of depression:

F31.30 without somatic syndrome

F31.31 with somatic syndrome

F31.4 Bipolar affective disorder, current episode severe depression without psychotic symptoms

A. The current episode meets the criteria for a severe depressive episode without psychotic symptoms (F32.2).

B. There has been at least one well-authenticated hypomanic or manic episode (F30.-) or mixed affective episode (F38.00) in the past.

F31.5 Bipolar affective disorder, current episode severe depression with psychotic symptoms

A. The current episode meets the criteria for a severe depressive episode with psychotic symptoms (F32.3).

B. There has been at least one well-authenticated hypomanic or manic episode (F30.-) or mixed affective episode (F38.00) in the past.

A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with the mood.

F31.50 with mood-congruent psychotic symptoms

F31.51 with mood-incongruent psychotic symptoms

F31.6 Bipolar affective disorder, current episode mixed

A. The current episode is characterized by either a mixture or a rapid alternation (i.e., within a few hours) of hypomanic, manic, and depressive symptoms.

B. Both manic and depressive symptoms must be prominent most of the time during a period of at least 2 weeks.

C. There has been at least one well-authenticated hypomanic or manic episode (F30.-), depressive (F32.-) or mixed affective episode (F38.00) in the past.

F31.7 Bipolar affective disorder, currently in remission

A. The current state does not meet the criteria for depressive or manic episode in any severity, or for any other mood disorder in F3 (possibly because of treatment to reduce the risk of future episodes).

B. There has been at least one well-authenticated hypomanic or manic episode (F30.-) in the past and, in addition, at least one other affective episode (hypomanic or manic (F30.-), depressive (F32.-), or mixed (F38.00).

F31.8 Other bipolar affective disorders

F31.9 Bipolar affective disorders, unspecified

F32 DEPRESSIVE EPISODE

G1. The depressive episode should last for at least 2 weeks.

G2. There have been no hypomanic or manic symptoms sufficient to meet the criteria for hypomanic or manic episode (F30.-) at any time in the individual’s life.

G3. Most commonly used exclusion clause: The episode is not attributable to psychoactive substance use (F10–F19) or to any organic mental disorder (in the sense of F00-F09).

SOMATIC SYNDROME

Some depressive symptoms are widely regarded as having special clinical significance and are here called “somatic.” (Terms such as “biological,” “vital,” “melancholic,” or “endogenomorphic” are used for this syndrome in other classifications.) A fifth character (as indicated in F31.3; F32.0 and F32.1; F33.0 and F33.1) may be used to specify the presence or absence of the somatic syndrome. To qualify for the somatic syndrome, four of the following symptoms should be present:

(1) marked loss of interest or pleasure in activities that are normally pleasurable;

(2) lack of emotional reactions to events or activities that normally produce an emotional response;

(3) waking in the morning 2 hours or more before the usual time;

(4) depression worse in the morning;

(5) objective evidence of marked psychomotor retardation or agitation (remarked on or reported by other people);

(6) marked loss of appetite;

(7) weight loss (5% or more of body weight in the past month);

(8) marked loss of libido.

In The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines, the presence or absence of the somatic syndrome is not specified for severe depressive episode, since it is presumed to be present in most cases. For research purposes, however, it may be advisable to allow for the coding of the absence of the somatic syndrome in severe depressive episode.

F32.0 Mild depressive episode

A. The general criteria for depressive episode (F32) must be met.

B. At least two of the following three symptoms must be present:

(1) depressed mood to a degree that is definitely abnormal for the individual, present for most of the day and almost every day, largely uninfluenced by circumstances, and sustained for at least 2 weeks.

(2) loss of interest or pleasure in activities that are normally pleasurable;

(3) decreased energy or increased fatigability.

C. An additional symptom or symptoms from the following list should be present, to give a total of at least four:

(1) loss of confidence and self-esteem;

(2) unreasonable feelings of self-reproach or excessive and inappropriate guilt;

(3) recurrent thoughts of death or suicide, or any suicidal behavior;

(4) complaints or evidence of diminished ability to think or concentrate, such as indecisiveness or vacillation;

(5) change in psychomotor activity, with agitation or retardation (either subjective or objective);

(6) sleep disturbance of any type;

(7) change in appetite (decrease or increase) with corresponding weight change

A fifth character may be used to specify the presence or absence of the “somatic syndrome” (as defined in F32):

F32.00 Without somatic syndrome

F32.01 With somatic syndrome

F32.1 Moderate depressive episode

A. The general criteria for depressive episode (F32) must be met.

B. At least two of the three symptoms listed for F32.0, criterion B, must be present.

C. Additional symptoms from F32.0, criterion C, must be present, to give a total of at least six.

A fifth character may be used to specify the presence or absence of the “somatic syndrome” as defined in F32:

F32.10 Without somatic syndrome

F32.11 With somatic syndrome

F32.2 Severe depressive episode without psychotic symptoms

Note: If important symptoms such as agitation or retardation are marked, the patient may be unwilling or unable to describe many symptoms in detail. An overall grading of severe episode may still be justified in such a case.

A. The general criteria for depressive episode (F32) must be met.

B. All three of the symptoms in criterion B, F32.0, must be present.

C. Additional symptoms from F32.0, criterion C, must be present, to give a total of at least eight.

D. There must be no hallucinations, delusions, or depressive stupor.

F32.3 Severe depressive episode with psychotic symptoms

A. The general criteria for depressive episode (F32) must be met.

B. The criteria for severe depressive episode without psychotic symptoms (F32.2) must be met with the exception of criterion D.

C. The criteria for schizophrenia (F20.-) or schizoaffective disorder, depressive type (F25.1) are not met.

D. Either of the following must be present:

(1) delusions or hallucinations, other than those listed as typically schizophrenic in F20, criterion G1(1)b, c, and d (i.e., delusions other than those that are completely impossible or culturally inappropriate and hallucinations that are not in the third person or giving a running commentary); the most common examples are those with depressive, guilty, hypochondriacal, nihilistic, self-referential, or persecutory content;

(2) depressive stupor.

A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with mood:

F32.30 With mood-congruent psychotic symptoms (i.e., delusions of guilt, worthlessness, bodily disease, or impending disaster, derisive or condemnatory auditory hallucinations)

F32.31 With mood-incongruent psychotic symptoms (i.e., persecutory or self-referential delusions and hallucinations without an affective content)

F32.8 Other depressive episodes

Episodes should be included here that do not fit the descriptions given for depressive episodes in F32.0–F32.3, but for which the overall diagnostic impression indicates that they are depressive in nature. Examples include fluctuating mixtures of depressive symptoms (particularly those of the somatic syndrome) with non-diagnostic symptoms such as tension, worry, and distress, and mixtures of somatic depressive symptoms with persistent pain or fatigue not due to organic causes (as sometimes seen in general hospital services).

F32.9 Depressive episode, unspecified

F33 RECURRENT DEPRESSIVE DISORDER

G1. There has been at least one previous episode, mild (F32.0), moderate (F32.1), or severe (F32.2 or F32.3), lasting a minimum of 2 weeks and separated from the current episode by at least 2 months free from any significant mood symptoms.

G2. At no time in the past has there been an episode meeting the criteria for hypomanic or manic episode (F30.-).

G3. Most commonly used exclusion criteria: the episode is not attributable to psychoactive substance use (F1) or any organic mental disorder, in the sense of F0.

It is recommended to specify the predominant type of previous episodes (mild, moderate, severe, uncertain).

F33.0 Recurrent depressive disorder, current episode mild

A. The general criteria for recurrent depressive disorder (F33) are met.

B. The current episode meets the criteria for depressive episode, mild severity (F32.0).

A fifth character may be used to specify the presence of the somatic syndrome, as defined in F32, in the current episode:

F33.00 without somatic syndrome

F33.01 with somatic syndrome

F33.1 Recurrent depressive disorder, current episode moderate

A. The general criteria for recurrent depressive disorders (F33) are met.

B. The current episode meets the criteria for depressive episode, moderate severity (F32.1).

A fifth character may be used to specify the presence of the somatic syndrome, as defined in F32, in the current episode:

F33.10 without somatic syndrome

F33.11 with somatic syndrome

F33.2 Recurrent depressive disorder, current episode severe without psychotic symptoms

A. The general criteria for recurrent depressive disorders (F33) are met.

B. The current episode meets the criteria for severe depressive episode without psychotic symptoms (F32.2).

F33.3 Recurrent depressive disorder, current episode severe with psychotic symptoms

A. The general criteria for recurrent depressive disorders (F33) are met.

B. The current episode meets the criteria for severe depressive episode with psychotic symptoms (F32.3).

A fifth character may be used to specify whether the psychotic symptoms are congruent or incongruent with the mood:

F33.30 with mood congruent psychotic symptoms

F33.31 with mood incongruent psychotic symptoms

F33.4 Recurrent depressive disorder, currently in remission

A. The general criteria for recurrent depressive disorder (F33) have been met in the past.

B. The current state does not meet the criteria for a depressive episode (F32.-) of any severity, or for any other disorder in F3 (the patient may receive treatment to reduce the risk of further episodes).

F33.8 Other recurrent depressive disorders

F33.9 Recurrent depressive disorder, unspecified

F34 PERSISTENT MOOD [AFFECTIVE] DISORDERS

F34.0 Cyclothymia

A. A period of at least 2 years of instability of mood involving several periods of both depression and hypomania, with or without intervening periods of normal mood.

B. None of the manifestations of depression or hypomania during such a 2-year period should be sufficiently severe or long-lasting to meet criteria for manic episode or depressive episode (moderate or severe); however, manic or depressive episode(s) may have occurred before, or may develop after, such a period of persistent mood instability.

C. During at least some of the periods of depression at least three of the following should be present:

(1) A reduction in energy or activity;

(2) Insomnia;

(3) Loss of self-confidence or feelings of inadequacy;

(4) Difficulty concentrating;

(5) Social withdrawal;

(6) Loss of interest or enjoyment in sex and other pleasurable activities;

(7) Less talkative than normal;

(8) Pessimistic about the future or brooding over the past.

D. During at least some of the periods of mood elevation at least three of the following should be present:

(1) Increased energy or activity;

(2) Decreased need for sleep;

(3) Inflated self-esteem;

(4) Sharpened or unusually creative thinking;

(5) More gregarious than normal;

(6) More talkative or witty than normal;

(7) Increased interest and involvement in sexual and other pleasurable activities;

(8) Overoptimism or exaggeration of past achievements.

Note: If desired, specify whether onset is early (in late teenage or the twenties) or late (usually between age 30 to 50 subsequent to an affective episode).

F34.1 Dysthymia

A. A period of at least 2 years of constant or constantly recurring depressed mood. Intervening periods of normal mood rarely last for longer than a few weeks and there are no episodes of hypomania.

B. None, or very few, of the individual episodes of depression within such a 2-year period are severe enough, or last long enough, to meet the criteria for recurrent mild depressive disorder (F33.0).

C. During at least some of the periods of depression at least three of the following should be present:

(1) A reduction in energy or activity;

(2) Insomnia;

(3) Loss of self-confidence or feelings of inadequacy;

(4) Difficulty concentrating;

(5) Often in tears;

(6) Loss of interest or enjoyment in sex and other pleasurable activities;

(7) Feeling of hopelessness or despair;

(8) A perceived inability to cope with the routine responsibilities of everyday life;

(9) Pessimistic about the future or brooding over the past;

(10) Social withdrawal;

(11) Less talkative than normal.

Note: If desired, specify whether onset is early (in late teenage or the twenties) or late (usually between age 30 to 50 subsequent to an affective episode).

F34.8 Other persistent mood [affective] disorders

A residual category for persistent affective disorders that are not sufficiently severe or long-lasting to fulfill the criteria for cyclothymia (F34.0) or dysthymia (F34.1) but that are nevertheless clinically significant. Some types of depression previously called “neurotic” are included here, provided that they do not meet the criteria for either cyclothymia (F34.0) or dysthymia (F34.1) or for depressive episode of mild (F32.0) or moderate (F32.1) severity.

F34.9 Persistent mood [affective] disorder, unspecified

F38 OTHER MOOD [AFFECTIVE] DISORDERS

There are so many possible disorders that could be listed under F38 that no attempt has been made to specify criteria, except for mixed affective episode (F38.00). Investigators requiring criteria more exact than the Diagnostic Guidelines should construct them according to the requirements of their study.

F38.0 Other single mood [affective] disorders

F38.00 Mixed affective episode

A. The episode is characterized by either a mixture or a rapid alternation (i.e., within a few hours) of hypomanic, manic, and depressive symptoms.

B. Both manic and depressive symptoms must be prominent most of the time during a period of at least 2 weeks.

C. No previous hypomanic, depressive, or mixed episodes.

F38.1 Other recurrent mood [affective] disorders

F38.10 Recurrent brief depressive disorder

A. The disorder meets the symptomatic criteria of either mild (F32.0), moderate (F32.1), or severe depressive episode (F32.2)

B. The depressive episodes occur about once a month over the past year.

C. The individual episodes last less than 2 weeks (typically 2 to 3 days).

D. The episodes do not occur solely in relation to the menstrual cycle.

F38.8 Other specified mood [affective] disorders

This is a residual category for affective disorders that do not meet the criteria for any other categories F30-F38.

F39 Unspecified mood [affective] disorder

The DSM-IV-TR chapter on mood disorders stresses the exclusion of medically induced conditions, substance-induced conditions, stress-induced conditions such as bereavement, other mood disorders, and symptomatically similar psychotic disorders. ICD-10 stipulates the exclusion of other mood disorders, and medically induced or substance-induced conditions. DSM-IV-TR requires the presence of clinically significant distress or impairment for mood disorder diagnosis, whereas ICD-10 does not. In both texts, bipolar syndromes assume hierarchical precedence over unipolar syndromes, and syndromes with higher symptom counts assume hierarchical precedence over syndromes with lower symptom counts. In DSM-IV-TR, a variety of prognostically informative specifiers add further characterization to the current mood episode, and to the overarching mood disorder. Both the DSM-IV-TR and the ICD-10 attempt to capture dimensionality in mood disorder diagnosis by identifying, for the current episode, polarity (manic, mixed, or depressed), severity (mild, moderate, or severe), and presence or absence of psychotic features (assumed to occur only during severe mood episodes, an assumption disentangled by the upcoming DSM-5). Dimensionality in diagnosis is also implied by a spectrum covering syndromes with fewer to greater symptom counts (dysthymic disorder, cyclothymic disorder, major depressive disorder, bipolar II disorder, bipolar I disorder).

The structure of both current nosologic systems relies on syndromic prototypology, with diagnoses based on the presence of one or more core stem criteria, and the addition of any combination of a defined number of associated criteria. This prototypal approach inherently results in diagnostic heterogeneity, with hundreds of possible combinations underlying a single clinical diagnosis. Another consequence of this prototypal approach is the assumption of symptomatic equivalence amongst the criteria. In DSM-IV-TR major depressive episode, for example, depressed mood and anhedonia assume equivalent and interchangeable importance as stem criteria, and the remaining seven symptoms/signs also carry equal diagnostic weight as associated criteria.

EPISODES

MAJOR DEPRESSIVE EPISODE

Depressed mood and/or anhedonia comprise the core stem criteria for DSM-IV-TR major depressive episode. Additional criteria for major depressive disorder in DSM-IV-TR include: weight loss/gain or appetite increase/decrease; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or inappropriate guilt; diminished ability to think or concentrate, or indecisiveness; and recurrent thoughts of death or recurrent suicidal ideation or suicide attempt or suicide plan. The DSM-IV-TR diagnosis of a major depressive episode requires the presence of at least one core stem criterion, plus four of the other listed depressive signs or symptoms, for at least two weeks. The DSM-IV-TR diagnosis of a major depressive episode furthermore stipulates that criteria are not currently met for a mixed episode, that depressive symptoms cause clinically significant distress or impairment, and that symptoms are not better accounted for by substance use, a general medical condition, or bereavement. ICD-10 criteria for a depressive episode echo most of the DSM-IV-TR criteria, with the exceptions that ICD-10 also recognizes diminished energy or increased fatigability as a core stem criterion, ICD-10 does not stipulate a bereavement exclusion, ICD-10 excludes patients who have ever met criteria for a lifetime hypomanic or manic episode, ICD-10 recognizes loss of confidence and self-esteem as an additional criterion, ICD-10 does not require clinically significant distress or impairment, and ICD-10 has a diagnostic threshold of four total symptoms instead of five. ICD-10 may thus pick up less severe depressive states than DSM-IV-TR.

MANIC EPISODE

In both DSM-IV-TR and ICD-10, core stem criteria for a manic episode include elevated, expansive, or irritable mood. Elevated or expansive mood carry more weight as core criteria, as their presence requires only three additional associated criteria to make the diagnosis, whereas irritable mood requires four. Additional criteria for manic episode in DSM-IV-TR include: inflated self-esteem or grandiosity; decreased need for sleep; flight or ideas or racing thoughts; distractibility, increase in goal directed activity or psychomotor agitation; and excessive involvement in pleasurable activities with high potential for painful consequences. The diagnosis requires syndromic duration of one week, or lesser duration if hospitalization is required. Again, DSM-IV-TR also requires clinically significant distress or impairment for diagnosis, whereas ICD-10 does not. DSM-IV-TR and ICD-10 also differ in some of their additional criteria for a manic episode. For example, ICD-10 recognizes as an additional criterion the loss of normal social inhibitions with resultant inappropriate behavior. ICD-10 also separates marked sexual energy or indiscretions from foolhardy or reckless behavior with a high degree of risk, whereas in DSM-IV-TR these phenomena are subsumed under one criterion.

MIXED EPISODE

The diagnosis of mixed episode in DSM-IV-TR requires the simultaneous presence of criteria for a major depressive episode and a manic episode. In ICD-10, a mixed episode is captured under the diagnosis of F38.0, mixed affective episode, and bipolar disorder current episode mixed. ICD-10 does not require the full depressive and manic syndromes to be present concurrently for a mixed episode diagnosis, but rather the mixture or rapid alternation of manic and depressive symptoms for two weeks, with the number and intensity of symptoms not defined. As such, ICD-10 may pick up a wider variety of mixed states, including agitated depressive episodes or subsyndromal hypomanic states concurrent with depressive episodes.

HYPOMANIC EPISODE

In DSM-IV-TR, the diagnosis of hypomanic episode differs from that of manic episode only in required duration (minimum four days versus minimum one week), and degree of dysfunction (hypomanic episode defined as not severe enough to cause hospitalization or marked impairment). ICD-10 criteria for a hypomanic episode share the same duration requirements as DSM-IV-TR, but require only three additional symptoms, regardless of whether the core mood is elevated or irritable. ICD-10 furthermore does not recognize expansive mood as a core criterion for a hypomanic episodes, yet recognizes some different additional criteria, such as increased sociability or overfamiliarity.

DISORDERS

MAJOR DEPRESSIVE DISORDER AND RECURRENT DEPRESSIVE DISORDER

The DSM-IV-TR diagnosis of major depressive disorder requires the presence of one or more major depressive episodes, and the exclusion of other mood disorders, concurrent psychotic disorders, or medically induced or substance-induced mood disorders. The diagnosis of ICD-10 recurrent depressive disorder requires at least two depressive episodes, and exclusion of medically induced or substance-induced mood disorders, whereas exclusion of bipolar mood disorders is already implied in the ICD-10 criteria for depressive episode.

BIPOLAR I AND II DISORDERS, AND BIPOLAR AFFECTIVE DISORDER

Bipolar I disorder in DSM-IV-TR requires the presence of at least one manic or mixed episode, although the current episode may be specified as hypomanic, manic, mixed, or depressed. Bipolar II disorder is defined as the presence of one or more major depressive episodes, and at least one episode of hypomania, without history of full mania or mixed episodes. For both bipolar I and II disorders, schizoaffective disorders and psychotic disorders must not better account for the disorder at hand. ICD-10 bipolar affective disorder stipulates the presence of a hypomanic, manic, mixed, or depressive episode, plus at least one other mood episode, which must be hypomanic or manic if the current episode is depressed. In this way, ICD-10 groups together the DSM-IV-TR diagnoses of bipolar I and II disorders.

DYSTHYMIC DISORDER AND CYCLOTHYMIA

Dysthymic disorder in DSM-IV-TR requires the presence of a predominantly depressed mood, plus two or more additional depressive symptoms, whose total does not meet or exceed the threshold for major depressive disorder, plus no more than two months of euthymia, during a period of at least two years. Additional criteria for dysthymic disorder in DSM-IV-TR include: poor appetite or overeating; insomnia or hypersomnia; low energy or fatigue; poor concentration or difficulty making decisions; and feelings of hopelessness. Major depressive episodes or other mood episodes may supervene after two years of the diagnosis of DSM-IV-TR dysthymic disorder. Of course, all the usual DSM-IV-TR mood disorder exclusionary criteria apply. ICD-10 defines dysthymia in largely the same way as DSM-IV-TR, although in addition to the stem core criterion of depressed mood, ICD-10 requires at least three additional depressive symptoms. ICD-10 also allows for the possibility of a full depressive episode during the initial diagnostic period of dysthymia, and recognizes a greater diversity of additional diagnostic criteria, such as tearfulness, loss of interest or enjoyment in pleasurable activities, perceived inability to cope, pessimism or brooding, social withdrawal, and diminished talkativeness.

DSM-IV-TR cyclothymia requires the presence of two years of alternating periods of hypomania and depressive symptoms not meeting criteria for major depressive episode, without more than two months of euthymia at any time during the disturbance. The patient must not have evidence of full mania, mixed states, or major depressive episodes for the first two years of the disorder, but may go on to develop full blown bipolar disorder after this time. The usual exclusion of other mood disorders, psychotic disorders, and medically induced as well as substance-induced disorders apply. ICD-10 defines cyclothymia in much the same fashion as DSM-IV-TR, although without the two-month limit on euthymic periods, and with specifically spelled-out symptom criteria for the periods of hypomania and depressive symptoms, including some unique hypomanic symptoms such as sharpened or unusually creative thinking, increased gregariousness, increased wittiness, and overoptimism or exaggeration of past achievements.

MEDICALLY INDUCED AND SUBSTANCE-INDUCED Mood Disorders

Mood disturbances comprise common manifestations of many general medical conditions, substance use syndromes, and treatment with prescribed medical therapies. Medically ill patients require screening for and evidenced-based treatment of mood disorders (Evans et al., 2005), as do patients with substance use disorders, and patients undergoing known mood-altering medical therapies.

Clinically significant depressive symptoms have been reported in 14–43% of patients with HIV (Cysique et al., 2007; Gibbie et al., 2007), up to 85% of patients with Hepatitis C (Nelligan et al., 2008), 8–18% of patients with diabetes (Gendelman et al., 2009; Li et al., 2008), 20% of patients with COPD (Cleland et al., 2007), 50% of patients with asthma (Van Lieshout et al., 2009), 9–31% of patients after CVA (Brodaty et al., 2007), 14% of patients with CAD (Shanmugasegaram et al., 2012), 20% of patients after acute myocardial infarction (Thombs et al., 2006), 20–55% of patients with epilepsy (Kanner, 2003), 19–61% of patients after TBI (Kim et al., 2007), 40–60% of patients with multiple sclerosis (Wallin et al., 2006), 30–50% of patients with Alzheimer’s disease (Lee and Lyketsos, 2003), 22–29% of patients with cancer (Raison and Miller, 2003), 20–30% of patients with obesity (Stunkard et al., 2003), 30–54% of patients with chronic pain conditions (Campbell et al., 2003), and 4–75% of patients with idiopathic Parkinson’s disease (McDonald et al., 2003). Depressive symptoms also feature prominently in patients with endocrine disturbances, including 57–80% of patients with Cushing’s syndrome (Haskett, 1985; Kelly, 1996), 30% of patients with hyperthyroidism (Kathol and Delahunt, 1986), and frequently in hypothyroidism (Whybrow et al., 1969). Hyperparathyroidism, hypoparathyroidism, Addison’s
disease, B vitamin deficiencies, folic acid deficiency, malnutrition, electrolyte imbalances, acid-base disturbances, and uremia have also been associated with clinically significant depressive symptoms, among other neuropsychiatric disturbances (Harrison and Kopelman, 2009, pp. 617–688).

Depressive symptoms in HIV correlate with treatment non-adherence and decreased viral response (Sumari de-Boer et al., 2012; Tsai et al., 2013), and in hepatitis C correlate with treatment non-adherence (Liu et al., 2010). Depressive symptoms in type I diabetes associate with lower therapeutic adherence (Van Tilburg et al., 2001), increased risk of medical complications (de Groot et al., 2001), and increased mortality (Milano and Singer, 2007). Depressive symptoms after CVA correlate with poor functional recovery and higher mortality (Gothe et al., 2012). Depressive symptoms following myocardial infarction predict repeat MI and death (Barth et al., 2004; Glassman et al., 2002). A diagnosis of major depressive disorder in hospitalized elderly patients correlates with increased in-hospital mortality and length of inpatient care (Koenig et al., 1989). Depressive symptoms in cancer patients correlate with greater physical disability (Bukberg, 1984) and increased mortality (Brown et al., 2003). Furthermore, depressive symptoms in the context of many general medical disorders, such as hepatitis C undergoing interferon treatment (Kraus et al., 2008), HIV (Tsai et al., 2013), CVA (Hackett et al., 2008), and multiple sclerosis (Mohr et al., 2001) are responsive to treatment.

Clinically significant manic symptoms have been reported in 1% of post-CVA patients and 9% of post-TBI patients (Jorge et al., 1993), 2–12% of Huntington’s disease patients (Mendez, 1994), 39% of patients with thyrotoxicosis (Brownlie et al., 2000), 27% of patients with Cushing’s syndrome (Haskett, 1985), and 3–22% of patients with epilepsy (Robertson, 1992). Clinically significant manic symptoms have also been associated with CNS tumors; multiple sclerosis; complex partial seizures; viral, fungal, and Treponemal meningoencephalitides; Parkinson’s disease; Wilson’s disease; Cushing’s disease; hyperthyroidism; B vitamin deficiencies,; and other general medical conditions (Krauthammer and Klerman, 1978; Levenson 2011: p. 227; Mendez, 2000).

In an effort to account for mood disturbances in the context of general medical conditions and substance use disorders: DSM-IV-TR and ICD-10 list diagnostic criteria for mood disorders due to general medical condition, and DSM-IV-TR in particular lists diagnostic criteria for substance-induced mood disorder.

DSM-IV-TR criteria for Mood Disorder due to a General Medical Condition stipulate the presence of prominent and persistent mood symptoms corresponding to the core stem criteria for Major Depressive Episode and/or Manic Episode, in addition to evidence that the disorder is a physiologic consequence of a general medical condition, not better accounted for by another mental disorder, not occurring exclusively during the course of delirium, and causing clinically significant distress or impairment. In contrast to the diagnoses of primary idiopathic mood disorders, the DSM-IV-TR diagnosis of Mood Disorder due to a General Medical Condition does not dictate a threshold number of symptoms; the presence of one stem criterion suffices for the diagnosis. DSM-IV-TR further specifies subtypes, including With Depressive Features, With Manic Features, With Mixed Features, and With Major Depressive-Like Episode. ICD-10 criteria for Mental Disorders due to Brain Damage and Dysfunction and to Physical Disease require objective evidence or history of a medical disorder known to cause cerebral dysfunction, a presumed temporal relationship between development of the medical condition and the mental disorder, recovery or improvement of mental disorder following recovery or improvement from the medical condition, absence of convincing evidence for alternative causation of the mental disorder, and full criteria for one of the primary mood disorders outlined later in ICD-10. The latter criterion makes ICD-10 criteria more stringent than DSM-IV-TR in diagnosing mood disorders due to general medical conditions. ICD-10 further defines subtypes of Organic Manic/Bipolar/Depressive/Mixed Affective Disorder. ICD-10 delineates between provisional and certain diagnoses of organic mood disorders, with certainty dictated by the presence of evidence of recovery or improvement of mental disorder following recovery or improvement from the medical condition.

Similarly, many substance intoxication and withdrawal syndromes include core mood disorder disturbances. For example, euphoria, increased sociability, excitement, inexhaustibility, rambling speech, insomnia, mood lability, agitation, irritability, dysphoria, aggression, heightened sexuality, restlessness, anxiety, depression, interpersonal sensitivity, appetite changes, fatigue, psychomotor retardation, hypersomnia, fatigue, and hallucinations may occur during intoxication or withdrawal from ethanol, amphetamines, cocaine, caffeine, cannabis, or hallucinogens (American Psychiatric Association, 2000). Furthermore, many drug therapies for general medical conditions have been associated with clinically significant depressive symptoms, including corticosteroids, interferon alpha, interleukin 2, GRH agonists, mefloquine, and propranolol (Patten and Barbui, 2004). Drug therapies for general medical conditions have also been associated with clinically significant manic symptoms, including dopaminergic agents, noradrenergic agents, serotonergic agents, corticosteroids, and anabolic steroids (Krauthammer and Klerman, 1978; Levenson, 2011: p. 227).

DSM IV-TR criteria for Substance-Induced Mood Disorder require the presence of prominent and persistent mood symptoms, corresponding to core stem criteria for Major Depressive Episode and/or Manic Episode, in addition to evidence that the mood symptoms are temporally (within one month) or etiologically linked to substance use, intoxication, or withdrawal, not better accounted for by another mood disorder, not occurring exclusively during the course of delirium, and causing clinically significant distress or impairment. DSM-IV-TR does not dictate a threshold number of additional mood symptoms for diagnosis. Subtypes include With Depressive Features, With Manic Features, and With Mixed Features. Specifiers include With Onset During Intoxication, and With Onset During Withdrawal. ICD-10 does not define specific criteria for substance-induced mood disorders.

OTHER MOOD DISORDERS

Other mood disorders in DSM-IV-TR are captured by diagnoses of depressive disorder NOS, bipolar disorder NOS, and mood disorder NOS. ICD-10 similarly accounts for several other mood disorders. DSM-IV-TR in particular allows that these diagnoses may be made when the clinician cannot determine whether the mood disorder is primary or due to a general medical condition.

SPECIFIERS

DSM IV-TR includes prognostically informative specifiers for major depressive, manic, mixed, and recurrent episodes. Episode specifiers include severity, psychotic features, partial or full remission, single or recurrent episodes, melancholic features (for MDE only), atypical features (for MDE and dysthymia only), catatonic features, postpartum onset, and chronicity (for MDE only). Specifiers for recurrent mood episodes include with or without full interepisode recovery, with seasonal pattern, or with rapid cycling. In ICD-10, specifiers for severity, psychotic features, and recurrence apply to depressive episodes singly or as part of bipolar or recurrent depressive disorders, and are implied for manic, mixed, or hypomanic episodes in the diagnosis of bipolar affective disorder. In the following are presented selected specifiers, with brief descriptions and clinical implications.

SEVERITY

Severity in DSM-IV-TR mood disorders is defined in two ways: total symptom counts above that required for diagnosis, and degree of impairment attributable to the disorder. ICD-10 defines the severity of depressive episodes in terms of total symptom counts, and defines hypomanic versus manic episodes in terms of symptom counts and degree of impairment.

A study by Lux et al. (2010) examined the coherence and validity of the DSM-IV definition of the severity of major depression in a sample of 1,015 Caucasian twins who met criteria for major depressive disorder in the year prior to the study interview. The authors operationalized three measures of severity, including criteria counts (the DSM-IV definition of severity), scaled severity of individual symptoms (which is not present in DSM-IV), and impairment of function in occupational, social, and relational domains (which is not present in the DSM-IV diagnostic criteria, but is reflected to some extent in the separate GAF rating on axis V). Validators of severity in the study included co-morbid psychiatric conditions, personality traits, charactersistics of the index episode, prior history of depression, demographic characteristics at index episode, future episodes, and depressive episodes of the co-twin. The authors found that criteria count and severity of individual symptoms were each significantly associated with 14 validators, and that functional impairment was associated with 12 validators. No one measure of severity accounted for all validators, and each measure of severity appeared to tap into different sets of validators. The authors concluded that clinicians should probably use a combination of severity measures, including the severity of individual symptoms.

Severity can be attributed to other aspects of a mood disorder as well, including duration (chronic MDE is shown to respond more poorly to treatment), comorbid symptom severity [several studies have shown severe anxiety correlates with increased time spent in depression over decades, as well as higher risk for suicide], and comorbid substance abuse (predictive of poor long-term outcomes, and suicidal behavior) (Kim et al., 2011; Rush et al., 2012).

Severity in research studies of major mood disorders often takes the form of arbitrarily defined cutoffs on the more common mood disorder rating scales, such as the Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale, Young Mania Rating Scale, and so on.

Severity of depressive and manic episodes among patients with bipolar I and II disorders correlates longitudinally with degree of psychosocial dysfunction (Judd et al., 2005). In addition, severe depressive episodes in both major depressive disorder and bipolar disorder have been associated with treatment resistance (Mendlewicz et al., 2010; Souery et al., 2007). However, antidepressant trials in major depressive disorder tend to show larger effect sizes in more severely depressed populations (Fournier et al., 2010).

PSYCHOTIC FEATURES

DSM-IV-TR defines “with psychotic features” as the presence of delusions or hallucinations concurrent with the mood episode. DSM-IV-TR allows for both mood-congruent and mood-incongruent psychotic features. ICD-10 defines with psychotic features similarly, but excludes those delusions most typical of schizophrenia, such as bizarre delusions or voices with running commentary. In ICD-10, psychotic features in depressive, manic, or mixed episodes may also be mood-congruent or mood-incongruent. Neither DSM-IV-TR nor ICD-10 allows for psychotic features in mild or moderate depressive episodes or hypomania.

Baseline psychotic features in major depressive disorder tend to recur highly in subsequent major depressive episodes (Coryell et al., 1994). Psychotic features in major depressive disorder also appear to portend later onset of mania or hypomania (Fiedorowicz et al., 2011) Furthermore, psychotic features in mood disorders in general associate with worse prognosis. For example, over 10 years of follow-up, psychotic features in major depressive disorder portend longer duration of depressive episodes, shorter intervals between depressive episodes, and greater persistence of subthreshold mood symptoms (Coryell et al., 1996).

PARTIAL OR FULL REMISSION

DSM-IV-TR defines partial remission of a mood episode as having some symptoms of a mood episode, but not meeting full criteria, for at least two months. Full remission is defined as not demonstrating any symptoms of a mood episode for at least two months. ICD-10 defines remission in mood disorders as no longer meeting full criteria for an episode within the disorder, thus grouping together partial and full remission groups. ICD-10 does not define how long mood episode criteria need to be absent for remission.

In general, partial remission carries continued illness-
related morbidity and risk of relapse. In major depressive disorder, for example, partial remission and other subthreshold depressive states are associated longitudinally with greater psychosocial impairment than full remission, with the gradient of impairment increasing with increasing numbers of depressive symptoms (Judd et al., 2000). This finding holds true with regard to subthreshold depressive states in bipolar I and II disorders as well (Judd et al., 2005).

SINGLE OR RECURRENT MAJOR DEPRESSIVE DISORDER

DSM-IV-TR defines recurrence in major depressive disorder as two or more major depressive episodes, as does ICD-10. As described in the text of the DSM-IV-TR, within major depressive disorder, a single major depressive episode has about a 60% change of recurrence, a second major depressive episode increases the risk of recurrence to about 70%, and a third major depressive episode increases recurrence risk to 90%. Although DSM-IV-TR and ICD-10 define recurrence in major depressive disorder as two or more major depressive episodes, highly recurrent major depressive disorders begin to behave more akin to bipolar disorder than major depressive disorder (Goodwin and Jamison, 2007). For example, highly recurrent major depressive disorder probands show family histories enriched with bipolar disorders, convert to frank bipolarity more often than single episode or lowly recurrent major depressive disorder probands, and may respond preferentially to treatments shown to be effective in bipolar disorders. For these reasons, the DSM-IV-TR and ICD-10 definitions of recurrence have been criticized for not delineating definitions for highly recurrent major depressive disorder.

MELANCHOLIC FEATURES

Melancholic features, including dense anhedonia, non-reactive mood, diurnal variation, and neurovegetative signs, are among the oldest described symptoms in psychiatry. DSM-IV-TR defines melancholic features as requiring either loss of pleasure or lack of reactivity to usually pleasurable stimuli, plus three or more additional criteria such as: distinct quality of depressed mood; depression worse in the morning; early morning awakening; marked psychomotor retardation or agitation; and excessive or inappropriate guilt. ICD-10 refers to melancholic features as the somatic syndrome, defined similarly to DSM-IV-TR but without drawing a distinction between core and stem criteria. ICD-10 also notes that many other monikers have accompanied this syndrome in other classification schemes.

Melancholic features in major depressive disorder associate with increased comorbidity of anxiety disorders, greater number of lifetime depressive episodes, more severe impairment, lower levels of neuroticism, and increased risk of major depressive disorder in both mono- and dizygotic co-twins (Kendler, 1997). Melancholic features in major depressive disorder, bipolar I disorder, and bipolar II disorder also correlate with treatment resistance (Mendlewicz et al., 2010; Souery et al., 2007).

ATYPICAL FEATURES

In contrast to the implications of the term, atypical features of depression are not unusual in mood disorders. Historically, the term “atypical depression” stemmed from the striking difference between the clinical appearance of such presentations and that of the more classical endogenous or melancholic depressive syndromes, as well as the differential response of a particular form of atypical depression to MAOI pharmacotherapy as demonstrated by a research group from Columbia University (Davidson, 2007). The DSM-IV-TR criteria for atypical features in depression, derived from the criteria described by the aforementioned Columbia University group, include the stem criterion of mood reactivity, plus at least two of the following additional criteria: increased appetite or weight gain; hypersomnia; leaden paralysis; and a long-standing pattern of extreme sensitivity to perceived interpersonal rejection, occurring most of the time over a two-week period. ICD-10 does not include an atypical features specifier for depressive disorders.

Earlier studies in atypical depression that showed a higher rate of response to MAOI medications than tricyclic antidepressants have been eclipsed by more recent studies showing that SSRI antidepressants such as fluoxetine are equally effective as MAOIs in atypical depression.

CATATONIC FEATURES

The DSM-IV-TR catatonic features specifier is applied when the clinical picture of a mood episode is characterized by marked psychomotor disturbance including two or more of the following: marked motoric immobility such as catalepsy or stupor; excessive motor activity; extreme negativism or mutism; peculiarities of motor movement such as posturing or stereotypies or mannerisms or grimacing; and echolalia or echopraxia. ICD-10 does not have a catatonic features specifier in its section on mood disorders.

A patient with catatonia requires careful supervision to avoid self-harm, or harm to others. Malnutrition, exhaustion, hyperpyrexia, or self-inflicted injury may occur. Catatonic states have been reported in up to 5–9% of psychiatric inpatients. Between 25 and 50% of cases of catatonia occur in mood disorders and 10–15% occur in schizophrenia (American Psychiatric Association, 2000). Catatonia also occurs in postpartum psychosis in 0.1–0.5% of women within weeks of delivery, although it can occur within hours (Strain et al., 2012). However, catatonia is not unique to psychiatric conditions, as it has also been associated with a plethora of general medical conditions. Lastly, as with all catatonic syndromes, catatonic features in mood disorders may respond preferentially to high dose benzodiazepine pharmacotherapy, and may require electroconvulsive therapy (ECT) for definitive treatment.

POSTPARTUM ONSET

The DSM-IV-TR postpartum specifier can be applied to a mood disorder if the onset is within 4 weeks after childbirth. Symptoms may include fluctuations in mood, mood lability, and preoccupation with infant well-being, which may range from overconcern to frank delusions. The presence of severe ruminations or delusional thoughts about the infant is associated with a significantly increased risk of harm to the infant. ICD-10 does not specify postpartum onset. Postpartum depression affects 10–15% of women within six months after delivery. It is important to distinguish postpartum mood episodes from the “baby blues” that affect up to 70% of women within 10 days of delivery (American Psychiatric Association, 2000; Strain, 2012).

CHRONIC MAJOR DEPRESSIVE EPISODE

DSM-IV-TR defines a chronic specifier for major depressive episode, whereas ICD-10 does not. Chronicity in DSM-IV-TR requires that full major depressive episode criteria have been met for at least the past two years. Chronicity in a major depressive episode confers a poorer prognosis. Chronic major depressive disorder in particular has been associated with greater baseline socioeconomic disadvantage, lower baseline quality of life, lower baseline social and occupational functioning, and higher baseline medical disease and anxiety disorder burden. Furthermore, after treatment with antidepressant pharmacotherapy, chronic depression demonstrates continued poorer functioning and greater anxiety, despite an adjusted treatment response rate statistically indistinguishable from non-chronic depression (Sung et al., 2012). Another report, from the STAR*D study, demonstrates that patients with chronic index episodes of major depressive disorder have lower and slower remission rates, as well as higher relapse rates, than patients with non-chronic index episodes (Rush et al., 2012). In addition, unlike in many studies of non-chronic major depressive disorder, in chronic major depressive disorder the addition of psychotherapy to pharmacotherapy does not appear consistently to provide short-term or long-term treatment benefits above pharmacotherapy alone, with the exception of small add-on effects on quality of life (von Wolff et al., 2012). CBASP (Cognitive Behavioral Analysis System of Psychotherapy) may represent one exception to these latter findings, as this form of psychotherapy has demonstrated add-on effects to pharmacotherapy in chronic major depressive disorder (Keller et al., 2000).

FULL INTEREPISODE RECOVERY

DSM-IV-TR defines full interepisode recovery as full remission attained between the two most recent mood episodes. Similar to partial versus full remission, full interepisode recovery portends better functionality.

SEASONAL PATTERN

In DSM-IV-TR, the seasonal pattern specifier describes a regular temporal occurrence of major depressive episodes in major depressive, bipolar I, or bipolar II disorders. Criteria require that both onset and remission of major depressive episodes occur at characteristic times of the year, that at least two major depressive episodes have occurred with this temporal seasonal pattern over the past two years, and that the number of major depressive episodes occurring during this temporal seasonal pattern outnumber the non-seasonal episodes. ICD-10 does not stipulate a seasonal pattern specifier in its mood disorders chapter. Seasonal major depressive episodes in major depressive disorder may respond to light therapy, although this therapy may also increase the rate of switching to hypomanic or manic episodes when used to treat seasonal depressive episodes in bipolar I or II disorder (American Psychiatric Association, 2000).

WITH RAPID CYCLING

The DSM-IV-TR rapid cycling specifier is applied to either bipolar I or bipolar II disorder diagnoses. The essential feature of the DSM-IV-TR definition of rapid-cycling bipolar disorder is the occurrence of four or more mood episodes during the previous year. ICD-10 does not account for a rapid cycling specifier. Rapid cycling occurs in 10–20% of individuals with bipolar disorder, and is much more commonly found in females, who comprise 70–90% of individuals with a rapid cycling pattern. These episodes are not linked to any particular phase of the menstrual cycle and are seen in both pre- and postmenopausal women (American Psychiatric Association, 2000). Induction of rapid cycling has been reported in association with maintenance tricyclic antidepressant use in five bipolar patients, despite concurrent treatment with lithium (Wehr and Goodwin, 1979). Successful treatment of rapid cycling bipolar disorder has been demonstrated using high dose levothyroxine, carbamazepine, and lamotrigine (Joyce, 1988; Stancer and Persad, 1982; Stromgren and Boller, 1985; Wang et al., 2010) .

MOOD DISORDERS IN LATE LIFE

Neither DSM-IV-TR nor ICD-10 outlines criteria for depressive or bipolar disorders in late life (typically defined as older than 60–65 years). However, some important biopsychosocial considerations and phenomenological differences bear mentioning. Normative aging may be associated with altered sleep patterns, diminished sleep quality, diminished energy, decreased cognitive performance, motoric slowing, and interpersonal losses associated with sadness and bereavement. Furthermore, older patients typically manifest more general medical conditions, including conditions themselves linked to clinically significant depressive and/or manic symptoms. Lastly, given the physiologic effects of aging on pharmacokinetics, in combination with frequent pharmacologic treatment of general medical and psychiatric conditions, late life patients may be at particular risk for exposure to mood-altering pharmacotherapy.

Onset of major depressive disorder after age 60 is common, accounting for up to 50% of major depressive disorder diagnoses in late life. Adults with onset of major depressive disorder after age 60 typically evidence a history of less personality dysfunction, and lower burden of psychiatric family history. Patients with major depressive disorder in late life may exhibit more prominent melancholic symptoms, and psychotic symptoms, including prominent delusions of persecution, incurable illness, guilt, and nihilism or non-existence (Blazer and Steffens, 2009: p. 286). Furthermore, patients with depressive disorders in late life may also exhibit cognitive disturbances suggestive of dementia, termed pseudodementia (Snowdon, 2011), which typically demonstrates slowed processing speed, dysexecutive problems, and memory retrieval deficits. With successful treatment of depressive illness, pseudodementia appears reversible in the short term, yet predictive of later onset primary dementia (Saez-Fonseca et al., 2007). Similar to findings that late life patients with major depressive disorder demonstrate less comorbid personality pathology than younger patients with major depressive disorder (Devanand et al., 2002), late life patients with dysthymia also differ from younger patients with dysthymia in that they exhibit less comorbid personality pathology (Devanand et al., 2000). Specifically, late life patients with dysthymia or major depressive disorder appear preferentially to demonstrate cluster C personality pathology, in contradistinction to the cluster B personality pathology preferentially common in younger patients with dysthymia or major depressive disorder.

Bipolar disorder in late life may exhibit less classic euphoric mania, and more mixed depressive and manic symptomatology, with agitated depression and dysphoric mania commonly seen (Shulman and Post, 1980; Spar et al., 1979). Delirious mania may also present in late life bipolar disorder, exhibiting symptoms of mania along with catatonic symptoms and disturbed cognition (Blazer and Steffens, 2009: p. 285).

SEPARATION FROM OTHER CONDITIONS, DIFFERENTIAL DIAGNOSIS, AND COMORBIDITY

As outlined previously, in both DSM-IV-TR and ICD-10, diagnosing a primary idiopathic mood disorder requires exclusion of other mood disorders, psychotic disorders, and medically induced or substance-induced disorders. Both systems leave it to the clinician’s discernment to determine whether the apparent episode or disorder at hand is better accounted for by another condition. This diagnostic task is non-trivial, as many psychiatric disorders, general medical conditions, and substance use syndromes feature signs and symptoms that overlap significantly with mood disorders. For example, hypothyroidism and major depressive disorder both share possible symptoms of anergia, lassitude, impaired concentration and memory, weight gain, depressed mood, and dullness of expression. For the purposes of appropriate treatment planning, however, it remains clinically important to differentiate between primary idiopathic mood disorders, symptomatically overlapping psychiatric conditions, mood disorders due to general medical conditions, substance-induced mood disorders, and co-occurrence of primary and secondary disorders. A differential diagnosis list of possible medically induced and substance-induced mood disorders, as well as symptomatically overlapping psychiatric conditions, is listed in Table 29.2.

TABLE 29.2. General differential diagnosis for mood episodes and mood disorders

Substance-Induced Mood Disorder

Alcohol intoxication, withdrawal, abuse, or dependence

Sedative or hypnotic intoxication, withdrawal, abuse, or dependence

Stimulant intoxication, withdrawal, abuse, or dependence

Opioid intoxication, withdrawal, abuse, or dependence

Cannabis intoxication, withdrawal, abuse, or dependence

Anabolic steroid abuse or therapy

Corticosteroid therapy or withdrawal

Other immunomodulatory therapies

Chemotherapy for oncologic disease

HAART

Interferon therapy, e.g., in hepatitis C

Beta blockers

Malarial prophylaxis, especially with mefloquine

SSRIs, SNRIs, NRIs, TCAs, MAOIs

Stimulant therapy

Mood Disorder due to a General Medical Condition

Obstructive Sleep Apnea

Hyperthyroidism or Hypothyroidism

Hyperparathyroidism or Hypoparathyroidism

Hyperpituitarism or Hypopituitarism

Hypercortisolemia or Hypocortisolemia

Hypotestosteronemia

Diabetes

Electrolyte Disturbances

Acid-Base Disturbances

Malnutrition

Vitamin Deficiency

Renal Failure

Hepatic Failure

Wilson’s Disease

Malignancy

Brain Tumor or Metastasis

Systemic Effects of Peripheral Malignancy

Paraneoplastic Syndromes

Paraneoplastic Limbic Encephalitis

Coronary Artery Disease

Other Cardiovascular Disease

Anemia

Arrhythmias

Congestive Heart Failure

Valvular Heart Disease

Respiratory Illness

COPD

Asthma

Obstructive Sleep Apnea

Infectious Disease

HIV / AIDS

Viral Hepatitis

Osteomyelitis

Endocarditis

Mononucleosis

Lyme Disease

Opportunistic Infections

Autoinflammatory Disease

Multiple Sclerosis

Systemic Lupus Erythematosis

Autoimmune Encephalitis

Cerebrovascular Disease

Cerebrovascular Accident

Vascular Dementia

Cerebrovascular Malformation

Parkinsonism

Idiopathic Parkinson’s Disease

Antipsychotic-Induced Parkinsonism

Parkinson’s Dementia

Dementia with Lewy Bodies

Progressive Supranuclear Palsy

Multisystem Atrophy

Huntington’s Disease

Other Dementias

Dementia of Alzheimer’s Type

Frontotemporal Dementia

Amyotrophic Lateral Sclerosis

Seizure Disorders

Ictal

Postictal

Interictal

Traumatic Brain Injury

Chronic Pain

Delirium

Catatonia due to General Medical Condition

Brief Psychotic Disorder, Schizophrenia, Schizophreniform Disorder, Schizophrenia, Delusional Disorder, or Psychotic Disorder NOS

Schizoaffective Disorder

Bipolar I or II Disorder

Major Depressive Disorder

Dysthymic or Cyclothymic Disorder

Adjustment Disorder

Bereavement

Demoralization

Attention Deficit Hyperactivity Disorder

Posttraumatic Stress Disorder

Generalized Anxiety Disorder

Eating Disorders

Neurasthenia

Primary Sleep Disorder

Personality Disorders

In keeping with the broad differential diagnosis of mood disorder symptoms, psychiatric standards of care stipulate screening evaluations for general medical conditions and substance use syndromes that may mimic primary idiopathic mood disorders. History of present illness, past medical history, past psychiatric history, substance use history, current medications, family history, social history, developmental history, legal history, review of systems, and focused physical examination are indicated when evaluating patients with mood disorder symptoms. Cognitive screening examinations, such as the MMSE (Folstein et al., 1975) or MOCA (Nasreddine et al., 2005), are also indicated in the routine evaluation of mood disorders, especially so in older patients and patients with a known or suspected cognitive disorder. Routine and inexpensive screening tests in mood disorder diagnosis may include CBC, chemistry panel, liver function tests, TSH, free T4, B12, folic acid, thiamine, T. pallidum antibody, HCG, urine drug metabolite screen, and ECG. Further tests indicated by history and physical examination may include an HIV screen, infectious hepatitis panel, ESR, ANA, timed serum or salivary cortisol, free testosterone, prolactin, EEG, polysomnography, and MRI. Medical or neurological consultation is also warranted, whenever a general medical or neurologic condition is suspected.

Discerning the source of mood symptoms in the face of multiple likely etiologies requires recognition of several logical diagnostic possibilities. Given the presence of two mood-
related conditions, A and B, diagnostic possibilities include:

1. An overarching unitary condition AB that has been erroneously, conceptually split

2. A and B represent related conditions arising from a shared root cause

3. Condition A causes condition B

4. Condition B causes condition A

5. Condition A is causally independent from but influences condition B

6. Condition B is causally independent from but influences condition A

7. Condition A and B are causally independent from each other, but mutually influence each other

8. Condition A and B are fully causally independent and do not influence each other.

These logical possibilities underscore the difficulty of diagnostic separation of mood disorders from other conditions, differential diagnosis, and comorbidity assessment. Stemming from these logical possibilities, several approaches obtain to diagnosing mood disorders in the context of known mood-altering medical conditions, substance use, and overlapping psychiatric conditions. These approaches may exist in pure, or combined, forms.

1. Inclusive approach: applies signs and symptoms that satisfy mood disorder diagnostic criteria, or normative cutoffs on depressive symptom screening instruments, without subtracting signs and symptoms that may be related to another condition. Threshold severity and number of total signs and symptoms required for diagnosis remain unchanged from those applied to primary mood disorder diagnosis. This approach maximizes sensitivity and reliability, but minimizes specificity. Examples include the assessment of depressive symptoms in general medical conditions using low cutoff scores on the PHQ-9 (Kroenke et al., 2001; Lamers et al., 2008; Stafford et al., 2007) or CES-D (Jones et al., 2005; Koenig et al., 1998; Weissman et al., 1977).

2. Exclusive approach: applies signs and symptoms that satisfy mood disorder diagnostic criteria, while subtracting signs and symptoms that may be related to other conditions. Threshold severity and number of total signs and symptoms required for diagnosis remain unchanged. An example of this approach may be found in Bukberg et al.’s (1984) assessment of depressive symptoms in hospitalized cancer patients. This approach encourages specificity at the expense of sensitivity.

3. Increased threshold approach: applies signs and symptoms that satisfy mood disorder diagnostic criteria, or signs and symptoms from depressive screening instruments, with or without subtracting signs and symptoms that may be related to other conditions. However, the threshold symptom severity, number of total signs and symptoms, or cutoff score required for diagnosis increase. Examples include the assessment of depressive symptoms in general medical conditions using high cutoff scores on the PHQ-9 (Justice et al., 2004 ; Williams et al., 2005) or CES-D (Hermanns et al., 2006). This approach also encourages specificity at the expense of sensitivity.

4. Symptom substitution approach: applies signs and symptoms that satisfy mood disorder diagnostic criteria, while subtracting signs and symptoms that may be related to a general medical condition or substance use. These subtracted signs and symptoms are replaced by other signs and symptoms intended to more closely capture mood symptoms, as opposed to general medical condition or other psychiatric disorder manifestations. Threshold severity and number of total signs and symptoms required for diagnosis may increase or remain the same. This approach, as exemplified in Endicott’s (1984) examination of depression in patients with cancer, is also evident in the structure of numerous depressive screening instruments for use in patients with possibly confounding comorbid conditions, including the Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983), the Geriatric Depression Scale (Yesavage et al., 1982–1983), and the Calgary Scale for Depression in Schizophrenia (Addington et al., 1992). The various versions of the Beck Depression Inventory (Beck et al., 1961, 1996) also exemplify a symptom substitution approach, as they rely more heavily on mood and cognitive symptoms than neurovegetative symptoms. This approach also encourages specificity at the expense of sensitivity.

5. Etiologic approach: attempts to ascribe specific symptoms to their most likely underlying etiology, whether primary idiopathic, medical, or substance-induced, then arrives at a mood disorder diagnosis by applying only those symptoms attributable to the mood disorder. Both DSM-IV-TR and ICD-10 exemplify this approach to mood disorder diagnosis, which also encourages specificity at the expense of sensitivity.

In their classic paper on depression in 460 medically ill older adults, Koenig et al. (1997) outlined the prevalence of major and minor depressive disorders in this population according to inclusive, etiologic, exclusive-inclusive, exclusive-etiologic, substitutive-inclusive, or substitutive-etiologic approaches. The authors demonstrated that an inclusive approach resulted in the highest prevalence rates for major and minor depression, an exclusive-etiologic approach resulted in the lowest prevalence of major depression, and an etiologic approach resulted in the lowest prevalence of minor depression. The exclusive-etiologic approach identified the most severe and persistent major depressions. However, the authors also showed that known depression-associated characteristics (predictive validity) and associations with depression scale scores (convergent validity) did not vary remarkably. The authors concluded by suggesting that clinicians or researchers choose from the various diagnostic approaches based on the goals and purpose of the examination. For example, an epidemiologist studying depressive morbidity in a general medical condition may wish to utilize an inclusive approach in order to highlight the problem for public health attention, whereas a clinician working in a resource-limited setting may wish to use an exclusive-etiologic approach to identify those patients with the most severe depressive symptoms for treatment.

DIAGNOSTIC VALIDITY

In their landmark paper on diagnostic criteria for psychiatric research, Feighner et al. (1972) outlined five phases for establishing diagnostic validity in psychiatric illness: clinical description, laboratory studies, delimitation from other disorders, follow-up study, and family study.

Certainly, current mood disorder nosologies contain a wealth of clinical descriptors, and take pains to delimit specific mood disorders. Furthermore, family and twin studies have repeatedly demonstrated the heritable nature of all the major mood disorder syndromes, although specific genes appear to explain only small effects in the etiology of mood disorders. Patients with mood disorders also demonstrate a plethora of laboratory abnormalities, although none so sensitive or specific to point to a unified biological etiogenesis. This last fact points to the need further to define mood disorder subtypes, symptom components, and cross-syndromic dimensional constructs, which may serve better to elucidate candidate mechanisms for neurobiologic investigation.

In addition to the preceding problems with genetic and laboratory investigation, follow-up study also points to some weaknesses in the validity of current mood disorder diagnoses. DSM-IV-TR and ICD-10 emphasize cross-sectional diagnosis, causing problems with recall bias and diagnostic instability over time. For example, patients with prior hypomania show demonstrably poor recall of having had hypomania, and a non-trivial portion of patients diagnosed with major depressive disorder turn out rather to have bipolar disorder (Fiedorowicz et al., 2011; Goodwin and Jamison, 2007).

Furthermore, individual symptoms or signs within a given mood disorder diagnosis may vary in their individual validity. For example, a study by Lux et al. (2010) investigated a sample of 1,015 Caucasian twins using logistic regression analyses to compare the associations of individual symptom criteria, and two groups of criteria reflecting cognitive and neurovegetative symptoms, with a wide range of diagnostic validators including demographic factors, risk for future episodes in the co-twin, pattern of comorbidity, and personality traits. Cognitive symptoms included “depressed mood,” “loss of interest,” “worthlessness-guilt,” and “suicidal ideation.” Neurovegetative symptoms included “sleep,” “appetite/weight,” “psychomotor changes,” and “fatigue.” “Trouble concentrating” was excluded as a criterion. Interestingly, the investigators found that individual symptom criteria differed substantially in their associations with specific diagnostic validators, and that the cognitive criteria group generally produced stronger associations with diagnostic validators than did the neurovegetative criteria group. These results challenge the equivalence assumption inherent to the criteria for major depressive disorder, and suggest a degree of covert heterogeneity among these criteria, part of which is captured by the cognitive symptoms being more strongly associated with the most clinically relevant characteristics. They suggest that a detailed evaluation of DSM-IV major depressive episode criteria is overdue.

Recently the construct validity of major depression has been tested with item response theory analysis. Carragher et al. (2011) have shown that the current criteria for major depressive disorder performed well in defining a latent continuum for major depression. In general, the criteria fell along a range of depression severity, with death/suicidal thoughts, ­worthlessness/guilt, and psychomotor difficulties appearing along the severe end of the range, and concentration ­difficulties/indecision and sleep disturbance appearing along the middle to mild end of the range.

DIAGNOSTIC ACCURACY

The soft, syndromic, heterogeneous, and cross-sectional nature of current mood disorder diagnoses makes difficult the establishment of a gold standard reference. Structured diagnostic interviews, combined with medical record review and expert reassessment, appear to come closest to a gold standard approach to diagnosis in routine clinical research. Spitzer’s (1983) “LEAD Standard”—L = Longitudinal evaluation of symptomatology, E = Evaluation by expert consensus, AD = All Data from multiple sources—captures the essence of such combined methods. Numerous studies have demonstrated that structured diagnostic interviews outperform routine clinical diagnosis, and that the addition of medical record review brings diagnostic accuracy close to that attained from use of all four LEAD sources (Basco et al., 2000; Miller et al., 2001). However, whereas such methods allow for the calculation of accuracy and reliability data, they do not take advantage of statistical methods such as latent class analysis, which may contribute to improved accuracy in the assessment of such markedly complex phenomena as mood disorder diagnosis (Faraone and Tsuang, 1994).

DIAGNOSTIC RELIABILITY

Field trials of mood disorder diagnoses from DSM-IV and ICD-10 reveal marked variability in interrater reliability. One DSM-IV mood disorders field trial, reported by Keller et al. (1995), included 524 adult patients, comprising approximately 100 patients from each of five US university medical center sites. The study selected patients based on complaint of depressed mood, plus the presence of at least two other DSM-III-R symptoms of major depression or dysthymia, with no minimum duration of symptoms required. The interrater reliability investigation protocol utilized videotaped interviews. In reported results, diagnoses of both major depression and dysthymia demonstrated good to excellent intrasite interrater reliability, and fair to good intersite interrater reliability. Six month test-retest interrater reliability was poor to fair for the diagnosis of major depression, and fair for the diagnosis of dysthymia.

In contrast, the ICD-10 field trial included 11,491 adult patients, unselected by any preconceived symptomatic threshold for inclusion. The ICD-10 field trial reported only intrasite reliability, between pairs of raters from 32 countries. The study reported good to excellent intrasite interrater reliability for overarching categories of manic episode, bipolar affective disorder, depressive episode, recurrent depressive disorder, and schizoaffective disorder. Subtypes of these overarching categories had fair to good intrasite interrater reliability, as had dysthymia and adjustment disorders. Mixed anxiety depressive disorder demonstrated very poor intrasite interrater reliability (Sartorius et al., 1995).

It is important to note that the former field trial included enriched clinical samples, thereby potentially inflating real-world clinical reliability, whereas the latter used unenriched convenience samples, more closely approximating usual clinical practice.

DIAGNOSTIC TESTS

The search for laboratory anomalies associated with the major mood disorders has a long and convoluted history. For example, John Cade’s discovery of the mood stabilizing properties of lithium occurred in the context of testing his hypothesis that excess urea in the urine of mentally ill patients signified a general marker of mental illness. In an animal model of this hypothesis, Cade used lithium urate to increase the amount of urea he could administer to his guinea pigs, and observed that lithium protected against the toxic effects of urea. Other lithium salts appeared to tranquilize the animals, and successful trials of lithium for manic agitation soon followed (Cade, 1949).

The era of modern, neohumoral mechanisms as etiologies and diagnostic tests, however, began in earnest with the monoamine and catecholamine hypotheses. Various authors investigated catecholamine metabolites as diagnostic tests for major depression, and later as tests for predicting response to tricyclic antidepressants. However, neither endeavor resulted in evidence supporting a diagnostic or predictive role for these markers.

Other investigators have examined the HPA axis, the hypothalamic-pituitary-thyroid axis, EEG abnormalities, neurotrophic factors, neuroimaging patterns, inflammatory markers, risk conferring genes, and second messenger system components in relation to mood disorders. While such investigations have contributed unquestionably to our understanding of aspects of mood disorder pathophysiology, none have resulted in diagnostic tests able to discern between disordered and non-disordered patients with enough accuracy to warrant clinical use. One recent attempt at compiling various inflammatory, neurotrophic, and neuroendocrine markers in the diagnosis of major depressive disorder, resulted in a reported sensitivity of 91.1%, specificity of 81.3%, positive predictive value of 79%, and negative predictive value of 92% (Papakostas, 2011). This effort represents a significant advance over prior attempts, but if used alone would still result in possibly harmful exposure to unnecessary antidepressant pharmacotherapy or psychotherapy for 21 out of 100 “positive” patients. Note also that the study used DSM-IV criteria, diagnosed via a structured clinical interview, as the comparative gold standard, suggesting that clinicians simply use these clinical procedures for diagnosis in the first place.

LIMITATIONS OF CURRENT CATEGORICAL DIAGNOSES

“With the publication of DSM-III, psychiatrists had an agreed-upon language for naming what they saw, yet this language did not explicitly engage the issue of the nature of the disorders it named.”

MITCHELL WILSON (Wilson, 1993)

IMPORTANT PROGNOSTIC SPECIFIERS NOT INCLUDED IN DSM

TREATMENT RESISTANCE

Several authors have proposed that treatment resistance in major depressive disorder represents an independent and important prognostic feature. Systematic methods for assessing treatment resistance include the Maudsley Staging Method (MSM), the Antidepressant Treatment History Form (ATHF), the Massachusetts General Hospital Staging Model (MGH-s), the Thase Rush Staging Model (TRSM), and the European Staging Model (ESM) (Ruhe et al., 2012). In general, these models attempt to assess treatment resistance by scoring the number and adequacy of prior medication trials, the presence of augmentation trials, dose optimizations, and combination strategies, and the use of ECT. The MSM additionally includes measures of index episode duration and severity, which, as demonstrated in the specifiers section, have their own prognostic implications.

A recent review by Ruhe et al. (2012) illustrates the value of the treatment resistant depression concept. In a series of ECT studies, the highest scoring antidepressant trial on baseline ATHF correlated with higher relapse one year status post ECT (Sackeim et al., 1990), lower response to ECT (Prudic et al., 1996), and higher relapse on Li after effective ECT (Shapira et al., 1995). In addition, in outpatient MDD treatment, higher scores on the MGH-s, but not the TRSM, correlated retrospectively with absence of remission (Petersen et al., 2005). Lastly, Fedaku et al. (2009a, 2009b) demonstrated that total MSM score correlated with short-term failure to achieve remission, as well as long-term persistence of a depressive episode, and presence of a depressive episode over 50% of follow-up time. In contrast, total TRSM score correlated more weakly with short-term failure to achieve remission, and did not correlate with long-term outcomes (Fedaku et al., 2009b). Of the preceding treatment resistant depression models, only the ATHF has published interrater reliability data, with a reported intraclass correlation coefficient of 0.94. (Sackeim et al., 1990). Overall, treatment resistance in unipolar depressive disorders appears to have prognostic importance in predicting lack of treatment response, and delineation of treatment resistance may be a helpful diagnostic concept in developing future treatment studies in this therapeutically challenging subgroup.

ANXIETY

A recent review by Goldberg and Fawcett (2012) found that both anxiety diagnoses and anxiety symptoms occur frequently in both unipolar and bipolar depression, and that both anxiety diagnoses and severity of anxiety symptoms in unipolar and bipolar depression also correlate with poor treatment outcomes and higher risk for suicidal behavior and completed suicide.

Fava et al. (2008) reported from the STAR*D study, one of the largest major depressive disorder treatment outcome studies ever conducted, that severity of anxiety symptoms, as extracted from a subscale of the Hamilton Depression Scale, also predicted poor treatment outcomes in this sample.

As Coryell et al. (2012) note, “Many longitudinal studies of depressive disorders have associated comorbid anxiety with poorer outcomes as reflected in a lower likelihood of treatment response, longer times to recovery from index episodes and greater amounts of depressive morbidity over time.” (Coryell et al., 2012: p. 210) Drawing from the NIMH Collaborative Depression Study sample, Coryell and colleagues further delineated this relationship by showing that severity of anxiety symptoms during an index depressive episode correlated with duration of future depressive episodes for both unipolar and bipolar depression (Coryell et al., 2012). Furthermore, baseline anxiety symptom severity predicted duration of future depressive episodes more strongly than did baseline depressive symptom severity, and the predictive power of baseline anxiety symptom severity outlasted that of baseline depressive symptom severity. In addition, the same group also demonstrated that severity of anxiety symptoms during an index bipolar depressive episode correlated with greater percentage of time spent in subsequent depressive episodes versus manic or hypomanic episodes (Coryell et al., 2009). Both of these findings showed dose-response relationships between baseline global anxiety symptom severity and outcomes—­relationships that persisted over two decades of follow-up. In neither study did comorbid anxiety disorders at baseline correlate with outcomes at follow-up, indicating that anxiety symptom severity during depressive episodes represents an important prognostic feature inherent to mood disorder diagnosis.

SUBSYNDROMAL MIXED STATES

Cassano et al. (1999) have noted that a failure to recognize subthreshold expressions of mania has contributed to the underdiagnosis of bipolar disorder. More recent studies have shown a frequent occurrence of subthreshold manic symptoms in unipolar mood disorders that correlates with rates of switching to bipolar diagnoses over time. (Fiedorowicz et al., 2011)

TRAUMA HISTORY

Childhood sexual trauma is a risk factor for many mental disorders, including bulimia, alcohol dependence, other drug dependence, and mood disorders. Kendler et al. (2000) found that, of 1,411 adult female twins, 30.4% reported any childhood sexual abuse (CSA), and 8.4% reported childhood sexual intercourse. In turn, any CSA was associated with an increased risk (OR 1.93) for major depressive disorder in adulthood in this sample, and childhood sexual intercourse was associated with an even higher risk (OR 3.24) for major depressive disorder in adulthood. A case control study by Cong et al. (2011) similarly reported that any form of CSA was associated with an increased risk for recurrent major depressive disorder in adulthood, and that incrementally greater severity of CSA heightened this risk. Heim et al. (2010) also reported that a particularly strong link has been found between childhood trauma in general and the mood and anxiety disorders, and Sareen et al. (2012) found in an epidemiological study of Canadian Forces that adverse childhood experiences (ACE) increased the risk of mood and anxiety disorders among active military personnel. Furthermore, it has been reported that childhood abuse dramatically increases the risk for later suicide attempts. Studies of the stress of maternal separation in rats have yielded lasting changes in the HPA axis function, leading to theories that comparable early traumatic events in humans may increase the risk of various disorders, including mood and anxiety disorders, through similar biological mechanisms.

ARBITRARY SELECTION OF CORE CRITERIA

It is worthwhile to note that selection of the core criteria for many of our current psychiatric categorical diagnoses arose from arbitrary processes. For example, between the Feighner criteria and Research Diagnostic Criteria, researchers dropped the terms “fearful” and “worried” from the list of acceptable dysphoric moods, and elevated the “presence of a pervasive loss of interest or pleasure” as one of the core stem criteria (Spitzer et al., 1978). Spitzer et al. (1978) report that the former change occurred to avoid the inclusion of patients with only anxiety, a reasonable justification. However, given the preceding evidence on the importance of anxiety in depression, evidence whose roots were apparent at the time, why not list “fearful and worried” as an additional criterion? Furthermore, the elevation of anhedonia to a core stem criterion occurred based on “the clinical recognition that many patients with an obvious depressive syndrome do not acknowledge feeling depressed” (Spitzer et al., 1978). Fair enough, yet the authors cited no empirical evidence to support either change.

THRESHOLDS, CASENESS, AND DISCRIMINATIVE ABILITY

ARBITRARINESS OF THRESHOLDS AND FLUIDITY OF CASENESS

In an interesting historical account of the development of the Feighner criteria, Kendler et al. (2010) report that W. L. Cassidy, one of Feighner’s main influences in constructing the diagnostic criteria for major depression, decided on his diagnostic threshold of 6 out of 10 criteria, because: “it sounded about right” (Kendler et al., 2010).

Furthermore, why is the duration of two weeks of symptoms a criterion for a major depressive episode? The early Feighner criteria, precursors of the Research Diagnostic Criteria that were in turn a model for DSM-III in 1980, used a one-month duration criterion. It is difficult to generate the data to justify any particular duration, but the problem of an overlap with “normal reactions of distress to an event” or “demoralization” still exists, as evidenced by current arguments for dropping or keeping the DSM-IV bereavement exclusion for the diagnosis of a major depressive episode. It is worth considering whether to define clinical depression as a binary state, or whether it should be considered on a severity continuum with a certain number of symptoms, severity of individual symptoms, chronicity, and impairment levels defining a spectrum for the syndrome.

RELATED CONDITIONS BLURRING WITH MOOD DISORDERS

Is there a difference between demoralization (learned hopelessness) and depression (Clarke and Kissane, 2002)? When does demoralization become clinical depression? Are these conditions more similar or different when it comes to treatment response? Could descriptive diagnoses be determined that would separate these conditions with respect to specific treatment response, are they on a severity dimension, or are they indistinguishable in terms of mechanism or treatment? Is there a point in the development of learned hopelessness or demoralization when a basic change takes place to establish major depression? Is that point defined by the inability to respond to positive input? Does demoralization become a clinical depression when an individual is no longer capable of responding to positive stimuli, that is, when the dopaminergic pleasure system is turned off (Treadway and Zald, 2011)? On one hand, maybe there is some other mechanism that leads to a qualitative change. On the other hand, maybe there is no discontinuous mechanism but simply a severity or coping mechanism spectrum that is quantitative, not qualitative. In order to determine this, we need the best possible system for behavioral classification. Even then this may not be a possible discrimination.

Maybe there are risk factors (e.g., negative affect) that can be discriminated behaviorally. Recently, in studying subjects of early abuse (before age 18) that were over 45 (allowing a characterization of their life trajectory), LaNoue et al. (2012) found that patients who scored high on the construct of negative affect (which has been shown to be a lifelong trait) were more likely to see their entire life as “ruined,” in contrast to those who scored low on negative affect on the NEO Personality Inventory (McCrae, 1991). In contrast, patients with low negative affect were less likely to experience lasting impairment and recurrence of symptoms after experiencing early abuse. The patients with low negative affect were more likely to agree that childhood abuse ruined their childhood, but that it did not affect them in adulthood. Responses like “that was then, but this is now” and even “it made me stronger” were volunteered by these subjects, as opposed to “it ruined my childhood and my life” being a characteristic view expressed by high negative affect subjects. High negative affect or “neuroticism” has also been shown to predict recurrence in patients with major depression (Lanoue et al., 2012). Interestingly, despite the concept that neuroticism is a stable trait, SSRI treatment in depression may reduce levels of neuroticism, underscoring a potential mechanism for serotonergic antidepressant action (Tang et al., 2009).

A study by Kendler et al. (2001) showed moderate effects for genetic vulnerability (65% and 50% in females and males, respectively), as well as moderate effects for stress in the origin of depression. Caspi et al.’s (2003) findings demonstrating genetic moderation of life stress on the occurrence of depression point to tantalizing epigenetic methods of understanding vulnerability and resiliency, which may eventually aid in combined genetic-behavioral description of patients who are demoralized versus depressed.

Perhaps our understanding of mood disorder causes and treatments must be tempered not by either-or thinking, but by empirically based pluralism, as discussed by Kendler (2012).

FAILURE OF CURRENT DIAGNOSTIC SYSTEMS TO ELUCIDATE NEUROBIOLOGICAL MECHANISMS OR DEVELOP MORE EFFECTIVE TREATMENTS

The pharmacologic revolution of the 1960s led to a massive increase in neurobiological research starting with the measurement of metabolic and hormonal peripheral changes, to EEG sleep studies, to animal studies of functional brain changes associated with the recently successful antipsychotic and antidepressant medications. Family and twin studies attested to the familial transmission of various major disorders such as schizophrenia, bipolar disorder, and depressive disorders. Technology accelerated and in the late 1980s and early 1990s molecular biology, genetics, and human brain imaging became possible, offering the promise of more basic understanding of brain function and the pathophysiology of mental disorders.

These technical advances have led to a great increase in knowledge about the complexities of all mental disorders, including mood disorders. As more progress has been attained, the basic understanding of the etiology of mood disorders and other mental disorders has remained elusive, with much work yet to be done.

One reason is the unfolding complexity leading to boxes inside of boxes in the psychobiology of the brain, and the recognition of complex interactions between genetics and environmental inputs, termed epigenetics, which has added a massive layer of complexity to our understanding of the interaction of our brains’ gene expression with environmental circumstances. Another problem that has surfaced is the limitation of our current categorical system of diagnoses in mapping with both genetic and imaging findings.

PROPOSED SOLUTIONS: DIMENSIONAL CONSTRUCTS

SPECTRUM CONCEPTS LINKING SYNDROMES

As Cassano et al. (1999) point out, failure to recognize subthreshold symptoms of mania contributes to frequent underdiagnosis of bipolar disorder Reasons for the non-recognition of subthreshold bipolar symptoms include the relative lack of suffering compared with depressive symptoms, enhanced productivity, ego-syntonicity, and the assumption by clinicians that such symptoms represent the instability of affect associated with comorbid personality disorders. From the National Comorbidity Survey Replication, Angst et al. (2010) reported that 40% of patients with a diagnosis of major depressive disorder had subthreshold hypomanic symptoms. From the Collaborative Depression Study (CDS) Akiskal et al. (1995) found that, of 559 patients diagnosed with unipolar major depression and followed over 11 years, 8.6% converted to a diagnosis of Bipolar II Disorder, and 3.9% converted to a diagnosis of Bipolar I Disorder. A more recent publication from the CDS found that, of 142 patients diagnosed with Bipolar Disorder I or II, 76% had subsyndromal manic symptoms accompanying their depressive episodes (Judd et al., 2012). Overt irritability and psychomotor agitation were the most prominent symptoms (57% and 39% respectively), and the subsyndromal symptoms were associated with increased severity of depression. These findings show that depression is often on a spectrum with bipolar features. The recent literature showing evidence that response to antidepressants may be diminished in bipolar patients and may lead to more mood instability also stands as a reminder of the importance of distinguishing patients presenting with major depressive episodes that are on a bipolar spectrum (Fountoulakis et al., 2012; Phelps et al., 2008; Sidor and MacQueen, 2011). Given such findings, bipolar spectrum concepts have attempted to unify our understanding of the fluidity between unipolar disorders, bipolar disorders, and monomanic disorders, and, within each of these disorders, the fluidity between normal symptom expression, temperamental expression, and full disorder expression (Angst, 2007; Phelps et al., 2008).

BEHAVIORAL CONSTRUCTS DESCRIBING SYNDROME COMPONENTS

In the area of psychopharmacologic treatment, which stimulated our current era of psychobiologic, genetic, and imaging research, it has become clear that, while medications are approved by the Federal Drug Administration as efficacious for various diagnostic categories such as Major Depressive Disorder or Bipolar Disorder, these medications actually seem to address various “behavioral dimensions” that cross diagnostic categories.

Neither the DSM-IV-TR nor the ICD-10 encourages dimensional characterization of manic, mixed, or depressed episodes according to the relative severity of specific symptom components such as depressed mood, motor retardation, anxiety/agitation, insomnia, hostility/interpersonal sensitivity, anhedonia, or suicidality (Bagby et al., 2004; Katz et al., 2004). Katz et al. (2011) have argued for the regular measurement of specific symptom components in treatment studies. Symptom components of depressed mood, motor retardation, and hostility appear to respond differentially to distinct classes of pharmacotherapy. Such differential responses appear to arise early in the course of pharmacotherapy, and these early responses appear to predict later overall and sustained responses. Symptom components that cluster together in factor analytic studies, and show differential responses to treatment, may serve as candidate endophenotypes for further study.

For example, a study by Katz et al. (2004) showed that symptom components of major depression, identified by cluster analysis, not only include symptoms absent from the accepted DSM criteria, but also show different response times when treated with noradrenergic versus serotonergic medications. Another study, by Martinotti et al. (2012), demonstrated differential improvement of anhedonia in major depressive disorder using agomelatine versus venlafaxine XR, in the context of equivalent improvement of the overall syndrome.

Study of other behavioral components of depression such as anticipatory anhedonia, consummatory anhedonia, psychomotor slowing, anxiety-agitation, or angry impulsiveness, may yield specific targets for treatment, or reveal correlations with research domains such as genetic endophenotypes, brain circuit changes, epigenetic events like childhood abuse or adversity, or biomarkers such as HPA axis activation or changes in glucocorticoid receptor function.

The use of theoretically related clinical components, such as decisional anhedonia, anxiety severity, and impulsiveness with affective lability, may also come to prove more useful for understanding the clinical effect of various available or experimental medications (e.g., ketamine, pramipexole) with fairly well understood mechanisms of action. A categorical diagnosis supplemented by severity measures of various behavioral components of mood disorders may prove a valuable advance in clinical utility compared to categorical diagnoses alone. Studies by Katz et al. may prove a starting point for such efforts.

TOWARD FUTURE MODELS: DSM-5 AND RESEARCH DOMAIN CRITERIA

Current categorical diagnoses based on clinical consensus have failed to align with findings emerging from clinical science and genetics, which has slowed the development of new treatments targeted to underlying pathological mechanisms. As mentioned previously, it has been proposed that studying various measurable behavioral traits and dimensions, and looking for correlates with various domains such as genetics, electrical brain functions, or imaging studies, may produce more useful findings than looking for correlates of these domains using categorical diagnoses. Such proposals have led to the development of the Research Domain Criteria (RDoC) by the NIMH (Insel and Cuthbert, 2010).

Behavioral dimensions such as depression, anxiety, psychosis, impulsivity, irritability, agitation, emotional liability, anhedonia, blunting, and negative affect are all “targets” for psychotropic medication, various electronic treatments, and psychotherapies. Many of these symptom complexes occur across categorical diagnoses. For instance, various forms of psychosis occur across schizophrenia, mood disorders, dementias, drug addictions, and even borderline personality disorder. Impulsivity is seen as a behavioral trait across a similar range of disorders. The RDoC hope to leverage such cross-cutting behavioral dimensions in order to better understand the pathogenesis of mental illness, and develop the next generation of treatments.

Currently, DSM-5 is under development for release in 2013. Like DSM-IV-TR, DSM-5 has used literature reviews, results of field trials, review of proposed changes ­by a ­scientific review committee, and, where necessary, review of changes by a community public health review ­committee, as the basis for decisions about changes in diagnostic criteria, or the addition/deletion of diagnoses. In ­addition, DSM-5 has also used feedback from Internet postings of changes under consideration. DSM-5 has retained most of the diagnostic criteria of DSM-IV-TR, but has added a ­dimensional perspective to diagnoses in some areas such as mood disorders, psychotic disorders, and personality ­disorders, in order to address diagnostic overlap and increase the clinical information relevant for treatment planning. Evidence showing the existence of frequent mixed symptoms across mania, hypomania, and depression (depressive ­symptoms in the manias and manic or hypomanic symptoms in depression) has led to a mixed specifier in DSM-5, allowing the clinician to acknowledge the presence of a mood disorder spectrum in treatment planning. Building evidence for the importance of comorbid anxiety symptoms in the prognosis and treatment mood disorders has also led to the availability of an anxiety severity dimension across all mood disorder diagnoses in DSM-5. Finally, across all DSM-5 diagnoses, clinicians will be asked to record their assessment of the level of concern for suicide in individual patients. The suicide risk assessment will be based off of a list of risk factors for suicide, in combination with the clinician’s own clinical judgment, and will be reflected in the clinician’s treatment plan.

These changes in DSM-5 reflect recognition of the spectrum-like nature of psychiatric diagnoses, and the importance of individual symptom severity in psychiatric disorders, including mood disorders. Such changes may further lead to additional identification of symptom components in major depression, mania, and mixed states relevant to specific medication response prediction, as well as biological correlates and endophenotypes in research paradigms of etiologic mechanisms.

CONCLUSION

What we know today is mood disorders make up an indelible part of the human experience. Since antiquity, the diagnosis of mood disorders has evinced increasing levels of sophistication, in keeping with historical paradigms and scientific influences. Current mood disorder diagnostic classification schemes comprise a collection of atheoretical, prototypal, categorical, operationalized diagnostic criteria, which have modest clinical utility, and have led to intriguing neurobiologic hypotheses. Even so, we have come to expect more clinical and research utility from mood disorder diagnoses, in order to make further progress in understanding mood disorder mechanisms and developing the next generation of mood disorder treatments. After reviewing the development and current state of mood disorder diagnosis, it appears that empirical efforts to elucidate further behavioral components and dimensional constructs salient to mood disorders may help in advancing both treatment and neurobiologic research.

DISCLOSURES

Dr. Hager has no conflicts of interest to disclose.

Dr. Fawcett has not disclosed any conflicts of interest.

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