APA Format

DEPRESSION AND ANXIETY 31:459–471 (2014)

Review MAJOR DEPRESSIVE DISORDER IN DSM-5:

IMPLICATIONS FOR CLINICAL PRACTICE AND RESEARCH OF CHANGES FROM DSM-IV

Rudolf Uher, M.D., Ph.D.,1,2∗ Jennifer L. Payne, M.D.,3 Barbara Pavlova, Ph.D., D.Clin.Psy,1 and Roy H. Perlis, M.D., M.Sc.4

The changes in diagnostic criteria for major depressive disorder (MDD) from the fourth to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) may appear small but have important consequences for how the diagnosis is used. In DSM-5, MDD is part of the new “Depressive disorders” section, which is separate from “Bipolar disorders”, marking a division in what had been known as “Mood disorders”. A small wording change has expanded the core mood criterion to include hopelessness, potentially broadening the diag- nosis. The replacement of an operationalized bereavement exclusion with a call for clinical judgment in distinguishing normal reactions to significant loss from a disorder in need of clinical attention makes the diagnosis less objective and complicates investigations of the relationship between adversity and depression. A new persistent depressive disorder category is intended to encompass both dys- thymia and chronic depression, but its relationship to MDD is ambiguous with conflicting statements on whether the two diagnoses should be concurrent if both sets of criteria are fulfilled. Clarification is also needed on whether MDD can be concurrent with the new broad “other specified bipolar and related disorders”. New specifiers of MDD “with anxious distress” and “with mixed features” allow characterization of additional symptoms. The specifier “with perinatal onset” ex- pands on the DSM-IV “postnatal onset” to include onset during pregnancy. We review the changes in MDD definition, provide guidance on their implementa- tion and discuss their implications for clinical practice and research. Depression and Anxiety 31:459–471, 2014. C© 2013 Wiley Periodicals, Inc.

Key words: major depressive disorder; persistent depressive disorder; classifica- tion; psychopathology; assessment; diagnosis

FROM DSM-IV TO DSM-5 At first blush, the definition of major depressive disor- der (MDD) in the fifth edition of the Diagnostic and Sta- tistical Manual of Mental Disorders (DSM-5)[1] is close to a carbon copy of the 19-year-old DSM-IV. Conse- quently, many clinicians and researchers may be won-

1Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada 2Institute of Psychiatry, King’s College London, London, UK 3Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland 4Center for Experimental Drugs and Diagnostics, Department of Psychiatry and Center for Human Genetic Research, Mas- sachusetts General Hospital, Boston, Massachusetts

dering if there is any need for updating their practice or assessment tools to accommodate the new classification.

Contract grant sponsor: Corcept. Dr. Uher is supported by the Canada Research Chairs program (http://www.chairs- chaires.gc.ca/)

∗Correspondence to: Rudolf Uher, Mood Disorders Program, Abbie J. Lane Building, 3rd floor, 5909 Veterans’ Memorial Lane, Halifax, Nova Scotia, B3H 2E2, Canada. E-mail: [email protected] Received for publication 22 September 2013; Accepted 28 October 2013

DOI 10.1002/da.22217 Published online 22 November 2013 in Wiley Online Library (wileyonlinelibrary.com).

C© 2013 Wiley Periodicals, Inc.

460 Uher et al.

Yet, there are several changes that may significantly in- fluence how the diagnosis is used in both clinical and research settings. Changes in related categories have potentially even greater impact through their influence on the delineation of MDD and rates of comorbidity. We will review the changes in MDD definition, provide guidance on their practical implementation and discuss their likely impact on clinical practice and research.

THE PLACE OF MDD IN DSM-5 Perhaps the most visible change in MDD is one of

location: the “Mood disorders” chapter of previous edi- tions has been split into two separate chapters in DSM-5: “Bipolar and related disorders” and “Depressive disor- ders”. Across the two chapters, the number of categories has increased. MDD is now located in the “Depres- sive disorders” section, among the new “disruptive mood dysregulation disorder”, persistent depressive disorder, and premenstrual dysphoric disorder. In each chapter, “other specified” and “unspecified” disorder categories allow for diagnosis of individuals who fall short of diag- nostic criteria for the core specific disorders.

There are pros and cons for separating the bipolar from the unipolar depressive disorders. The separation aims to reflect the finding that bipolar disorders have a similar degree of phenomenological and genetic overlap with schizophrenia and with depression.[2–5] Conversely, most cases of bipolar disorder first present with depres- sion and the switch from MDD to bipolar disorder is one of the most common and important diagnostic tran- sitions in psychiatry.[6, 7]

The separation has two practical consequences. First, there is no “mood disorder not otherwise specified” and so the clinician is forced to make a call between bipolar and depressive when diagnosing unclear or undifferen- tiated cases. This challenge will most often be an issue early in the course of illness.[8] Second, the residual and subthreshold categories are listed separately for bipolar and depressive disorders and their relationship to the core disorders is left unclear. For example, “other speci- fied bipolar and related disorder” is not an exclusion cri- terion for the diagnosis of MDD and the two diagnoses can therefore coexist. However, this is not made explicit in diagnostic guidelines leaving room for inconsistencies in coding.

CRITERIA FOR MAJOR DEPRESSIVE DISORDER

Most of the criteria for MDD are identical in DSM- IV and DSM-5 (Table 1). The disorder is defined by one or more major depressive episodes (MDE) and the lifetime absence of mania and hypomania. To meet cri- teria for an MDE, it is required that five of nine symp- toms are present during the same 2-week period. One of these symptoms must be depressed mood or anhedonia (loss of interest or pleasure). The required frequency and

pervasiveness during the 2-week period varies somewhat by symptom, but most have to be present “nearly every day” (Table 1). The requirement that for a symptom to count toward the diagnosis, it must be either newly present or must have clearly worsened compared to pre- vious status, has also been retained in DSM-5. MDD is only diagnosed if an MDE is not better explained by a psychotic disorder (schizophrenia, schizoaffective disor- der, schizophreniform disorder, delusional disorder, or other psychotic disorder) and if there is no history of hypomania or mania.

Three changes have been made in the MDD criteria (Table 1). First, the statement that mood-incongruent delusions or hallucinations should not count toward the diagnosis of MDE/MDD has been removed. This change is probably inconsequential. It is hard to imag- ine how a delusion or hallucination could constitute one of the depressive symptoms if it were not congruent with depressed mood.

Second, the word “hopeless” has been added to the subjective descriptors of depressed mood. Interpreted literally, a subject who reports feeling hopeless but not sad fulfils the mood criterion in DSM-5 but not in DSM- IV. This is a subtle but potentially important change. Hopelessness figures prominently in important texts on depression[9] and is included (as ‘bleak and pessimistic view of the future’) in the definition of depressive episode in the International Classification of Diseases (ICD-10), but not in DSM-IV. Most psychopathological schools see hopelessness as phenomenologically distinct from depressed mood.[10, 11] Hopelessness occurs in the ab- sence of depressed mood and vice versa.[12, 13] For ex- ample, in a treatment study of over 800 individuals with MDD, 11% reported feeling sad but not discouraged about the future or hopeless and 8% reported being discouraged about the future or hopeless but not feel- ing sad.[14] Since depressed mood is one of the required criteria and a proportion of individuals report feeling hopeless in the absence of depressed mood, this small change will broaden the diagnosis. Perhaps more con- cerning, it may reduce reliability of diagnosis since some diagnosticians may accept subjective report of hopeless- ness as fulfilling the “depressed mood” criterion (based on the DSM-5 text), while others may not (based on their knowledge of psychopathology). This small unan- nounced change may have unpredicted consequences.

Third, the “bereavement exclusion” for the diagno- sis of MDE has been removed in DSM-5 and replaced by a note calling for clinical judgment when diagnosing MDD in the context of a significant loss. Since this is by far the most significant and controversial change, the removal of bereavement exclusion is discussed in more detail, below.

THE BEREAVEMENT EXCLUSION Reflecting the fact that depressive symptoms can be

part of normal grief reaction, DSM-III, DSM-III-R, and DSM-IV raised the threshold for diagnosing depression

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TABLE 1. DSM-5 criteria for major depressive disorder

DSM-5 Changes from DSM-IV-TR

A Five or more out of nine symptoms (including at least one of depressed mood and loss of interest or pleasure) in the same 2-week period. Each of these symptoms represents a change from previous functioning.

DSM-IV statement on not counting “mood-incongruent delusions and hallucinations” was removed from DSM-5.

Frequency requirements: 1. Depressed mood (subjective or observed); can be

irritable mood in children and adolescents Most of the day, nearly

every day Subjective descriptors of depressed mood in

DSM-IV included “sad or empty”, in DSM-5 these include “sad, empty or hopeless”.

2. Loss of interest or pleasure Most of the day, nearly every day

3. Change in weight or appetite Appetite: Nearly every day Weight: 5% change over

1 month 4. Insomnia or hypersomnia Nearly every day 5. Psychomotor retardation or agitation (observed) Nearly every day 6. Loss of energy or fatigue Nearly every day 7. Worthlessness or guilt Nearly every day 8. Impaired concentration or indecisiveness Nearly every day 9. Thoughts of death or suicidal ideation or attempt Thoughts: recurrent

Attempt: any B Symptoms cause significant distress or impairment. C Episode not attributable to a substance or medical

condition. Note 1: Criteria A–C represent a major depressive

episode (MDE). Criteria for an MDE and MDD were in separate

tables of DSM-IV (with MDD referring to MDE), but are merged into a single list in DSM-5.

Note 2: Clinical judgement is inevitably required to distinguish if MDE is present in addition to a normal response to a significant loss.

MDE criterion E of DSM-IV stating that “The symptoms are not better accounted for by bereavement” was removed from DSM-5 and replaced by Note 2.

D Episode not better explained by a psychotic disorder. E There has never been a manic or hypomanic episode.

Note 3: Exclusion E does not apply if (hypo)manic episode was substance induced or attributable to medical condition.

Wording of criteria in this table is simplified and abbreviated. For exact wording, please consult the DSM-5 manual.[1]

in recently bereaved individuals. In DSM-IV, depression could be diagnosed after a recent death of a loved per- son, only if, in addition to fulfilling the MDE criteria, it lasted longer (more than two months), caused marked functional impairment or included one or more symp- toms thought to be uncharacteristic of normal grief and pathognomonic of depressive illness. These symptoms included morbid preoccupation with worthlessness, sui- cidal ideation, psychotic symptoms, and psychomotor retardation. Since any one of these criteria (duration, impairment, or symptoms) was sufficient to meet the diagnosis of MDD in a recently bereaved person, the diagnostic threshold was not raised by much.

Several lines of evidence have challenged the bereavement exclusion. Bereavement-related episodes of depression had, on average, onset at a later age, were associated with less neuroticism and less comor- bid anxiety, but did not differ from nonbereavement- related MDE in many other respects including symp- tom profile and family history of depression.[15–20]

Response to treatment and short-term prognosis

seems to be the same for bereavement-related and bereavement-unrelated depressive episodes, putting into question the utility of discriminating between them.[17, 21] Depression recurrence was less common after brief bereavement-related episodes than after nonbereavement-related episodes, indicating that the distinction had prognostic validity.[18, 22] But the pres- ence of the presumably pathognomonic symptoms or duration did not alter prognosis, putting into question the limits of the exclusion criterion.[23] Finally, there is consensus that episodes starting after the death of a loved person do not meaningfully differ from episodes starting after other severe stressful life events (e.g. loss of job or property, relationship breakdown, . . . ).[16, 19] Given this evidence, the retention of the exclusion in its DSM-IV form was untenable and the DSM-5 task force faced the difficult decision between extending the exclusion to all significant loss events and removing the exclusion al- together. The task force decided to scrap the exclusion. This decision provoked criticism[24] and the result of the ensuing debate is a compromise in the form of an added

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“note” calling for “clinical judgment” when making the distinction between “understandable and appropriate re- action to a significant loss” and MDE, which may still occur in the context of significant loss. In addition, there is a “footnote” attempting to provide guidance on distin- guishing normal grief from MDE. Neither the “signif- icant loss” note nor the “grief” footnote provide opera- tionalized criteria for what is and what is not diagnosed as MDE.

The replacement of the operationalized “bereavement exclusion” with the note and footnote has significant and different implications for research and clinical care. In the research setting, the removal of the bereavement exclusion makes an operationalized diagnosis of MDD purely symptomatic and independent of any environ- mental factors. This will be advantageous for the study of environmental factors in the etiology of MDD since the diagnostic procedure will not confound the outcome (MDD) with the exposure (bereavement or other loss). The “loss” note and “grief” footnote, however, appear most unfortunate from a research perspective since they have the potential to blur the distinction between MDD and normality in an unsystematic and unpredictable way, reducing the reliability of the diagnosis. Given the con- troversy surrounding the bereavement exclusion, it is likely that most epidemiological research will continue to record and report bereavement-related cases separately from nonbereavement cases to provide additional data on this distinction and avoid the accusation of trivializ- ing depression. In clinical settings, it is likely that each psychiatrist will interpret the criteria according to the context and their own beliefs. Consequently, the distinc- tion between MDD and a normal reaction to “significant loss” or “grief” will become a matter of opinion. The room for clinical judgment may be welcomed by some and deplored by others. It will almost certainly increase the differential between the use of the diagnostic criteria in research (where the vague “note” and “footnote” are likely to be ignored) and in the clinic (where the call for clinical judgment is likely to be adopted).

SPECIFIERS OF MAJOR DEPRESSIVE DISORDER

DIAGNOSIS In DSM-5, the MDD diagnosis can be divided into

14 subcategories using a combination of coded course and severity specifiers. In addition, the depressive disor- ders section of DSM-5 concludes with a list of uncoded specifiers that can be added to diagnoses in this section, including “with anxious distress”, “with mixed features”, “with melancholic features”, “with atypical features”, “with mood-congruent psychotic features”, “with mood- incongruent psychotic features”, “with catatonia”, with “peripartum onset”, and “with seasonal pattern”.

Coded course and severity specifiers allow combining either “single episode” (296.2) or “recurrent episodes” (296.3) with one of seven severity descriptors: mild, mod-

erate, severe, with psychotic features, in partial remis- sion, in full remission, or unspecified. This subcategoriz- ing is consistent with DSM-IV, except for two changes. First, the specifier “With psychotic features” is rated ir- respective of episode severity in DSM-5, whereas it was only combined with the highest grade of severity as “Se- vere with psychotic features” in DSM-IV. This change allows recording the presence of psychotic symptoms in the small number of subjects who do not meet the gen- eral severity criteria at the expense of losing the infor- mation on severity for all subjects with psychotic symp- toms. Second, the specifier “Chronic” is removed with the assumption that most chronic cases will fulfill criteria for the new “persistent depressive disorder”. This means that information on chronicity will be lost in the minor- ity of chronic MDD cases where criteria for persistent depressive disorder are not met (see below).

There have been more significant changes in the un- coded specifiers. Two new specifiers “with anxious dis- tress” and “with mixed features” have been added and the “postpartum onset” specifier has been expanded to “peripartum onset”.

“With anxious distress” is defined by the presence of two or more of five symptoms on most days during an MDE (Table 2). The specifier is further graded as mild, moderate, moderate-severe if two, three, or four symptoms are present. The fourth grade “severe” also re- quires psychomotor agitation. Four of the five defining symptoms overlap with symptoms diagnostic of gener- alized anxiety disorder (GAD; Table 2). The fifth symp- tom, fear of losing control, is more typical of panic. The large overlap means that most individuals with GAD and MDD will also receive this specifier. The reverse is not true because of the higher threshold for GAD in terms of symptom count and duration and the requirement that at least some symptoms also occur outside MDE. The advantage of the anxious distress specifier is that in- formation on anxiety will be more routinely recorded in individuals with MDD, even when the criteria for anxiety disorders are not met. Anxiety symptoms have been found to predict suicide risk[25, 26] and worse out- come with antidepressant treatment in some but not all studies.[27, 28] The specifier is likely to be tested as a pre- dictor of treatment outcome and prognostic indicator in future treatment trials and cohort studies. Since no spe- cific treatment is known that is more effective for anx- ious depression, this specifier may not affect treatment choice.

A second new uncoded specifier designates depression “with mixed features”. This should be understood in the context of parallel changes that occurred in crite- ria for bipolar disorders. In DSM-IV, a mixed episode would have been diagnosed if criteria for a manic episode and depressive episode (except duration) were met at the same time. In DSM-5, “mixed episodes” have been re- moved and replaced with “mixed features” specifiers for manic, hypomanic, and depressive episodes. Without the mixed episode option, diagnosticians will have to make a call between an episode being predominantly manic or

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TABLE 2. DSM-5 depressive disorder specifier with anxious distress and a comparison with criteria for generalized anxiety disorder

With anxious distress specifier criteria Generalized anxiety disorder criteria

A. Excessive anxiety and worry most days for 6 months. B. Finds it difficult to control the worry.

Two or more out of five symptoms on most days of episode. C. Three or more out of six symptoms on most days for 6 months. 1. Feeling keyed up or tense 1. Feeling restless, keyed up, or on edge 2. Feeling unusually restless (part of 1) 3. Difficulty concentrating because of worry 3. Difficulty concentrating or mind going blank 4. Fear that something awful may happen (overlaps with criterion A, worry) 5. Feeling that the individual might lose control of herself (panic)

2. Being easily fatigued 4. Irritability 5. Muscle tension 6. Sleep disturbance

Corresponding criteria are on the same line. Arabic numbers correspond to the order in which criteria are listed in DSM-5.[1]

predominantly depressive. If criteria for a hypomanic or manic episode are met, the diagnosis should be bipolar disorder. Therefore, the “with mixed features” specifier for depressive disorders is limited to cases that do not fulfill the criteria for a manic or hypomanic episode but have subthreshold bipolar features during a predomi- nantly depressive episode. The specifier is defined as presence of three out of seven symptoms nearly every day during an MDE.1 The seven symptoms defining the “mixed features” specifier replicate the criteria for a (hypo)manic episode with the exception of irritability, agitation, and distractibility (Table 3), the three symp- toms felt to be characteristic of both depression and ma- nia and thus difficult to assign to either with precision. The inclusion of the “mixed features” specifier reflects the ongoing interest in subthreshold bipolarity. It has been proposed that bipolar features short of the cri- teria for bipolar disorders are common and may affect outcomes of antidepressant treatment in MDD,[29] but the latter prediction has not been confirmed in a large antidepressant treatment study.[30] Through recording the presence of manic features in individuals with an MDE who are just short of the diagnosis of mania or hypomania, the specifier will facilitate further research into the value of subthreshold bipolar features for treat- ment selection and prognosis. However, the decision of the DSM taskforce to base the specifier exclusively on pure manic symptoms that do not overlap with the phe- nomenology of depression is likely to restrict its use to a relatively small number of patients. Ironically, the DSM- 5 definition omits many patients who would have been understood to have typical mixed symptom picture in prior literature.[31, 32] Irritability and distractibility are the hallmarks of classical descriptions of mixed affective states, but they do not contribute to the specifier, leaving a large proportion of mixed states unspecified.[33] This restriction excludes prototypical cases of mixed states

1The wording in the DSM-5 manual is “nearly every day during the majority of days”, which is obviously a mistake.

like excited depression.[32] Another problematic feature is the requirement that the manic symptoms be present nearly every day during the entire MDE. This require- ment excludes episodes where mixed features develop in stages and are only present for part of the episode. Again, development of mixed symptomatology at transitional phases or at the height of the episode severity is described in classic texts and is considered typical.[31, 32, 34] These restrictions limit the sensitivity and usefulness of the mixed feature specifier. In addition, DMS-5 allows cod- ing of these mental states, traditionally considered mixed but not fulfilling the mixed feature specifier criteria, as “other specified bipolar disorder.” In a rather inconsis- tent way, the DSM-5 leaves the option open for other specified bipolar disorder to be concurrent with MDD (since only presence of manic or hypomanic episodes is an exclusion criterion for MDD diagnosis). DSM-5 also leaves it unclear whether the mixed feature specifier is used in reference to the present or most recent depressive episode or if it reflects lifetime presence of mixed symp- toms within any of the depressive episodes. Since the specifier is attached to the diagnoses of MDD, it should probably reflect lifetime presence of mixed features.

There was also a small change in the definition of the specifier “with melancholic features”. This involves the “distinct quality of depressed mood”, which was de- fined as “qualitatively distinct from the feelings experi- enced after the death of a loved one” in DSM-IV, but is defined as “characterized by profound despondency, de- spair, and/or moroseness or by so-called empty mood” in DSM-5. Like some of the other small changes, this comes unannounced and the reasons for this change are unclear. One can see the problems with the DSM- IV requirement to compare with grief, but there may also be challenges with the new definition, since specific evidence for its validity is lacking. One of the few stud- ies that attempted to explore the distinct quality of mood criterion has suggested that it is not separable from over- all depression severity.[35] The impact of this criterion change on the rates of melancholic depression within MDD is uncertain.

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TABLE 3. DSM-5 depressive disorder specifier with mixed features and a comparison with criteria for manic episodes

With mixed features specifier criteria Manic episode criteria

A. A distinct period of elevated, expansive, or irritable mood and increased goal-directed activity or energy most of the day nearly every day for 1 week or longer.

Three or more of seven symptoms nearly every day of depressive episode.

B. Three (four if mood irritable) or more of seven symptoms during the same period.

1. Elevated or expansive mood Criterion A 2. Inflated self-esteem or grandiosity 1. Inflated self-esteem or grandiosity 3. More talkative than usual or pressure of speech 3. More talkative than usual or pressure of speech 4. Flight of ideas or racing thoughts 4. Flight of ideas or racing thoughts 5. Increased energy or goal-directed activity Criterion A/6. Increased goal-directed activity or

agitation 6. Excessive involvement in risky activities 7. Excessive involvement in risky activities 7. Decreased need for sleep 2. Decreased need for sleep

5. Distractibility (reported or observed)

Corresponding criteria are on the same line. Arabic numbers correspond to the order in which criteria are listed in DSM-5.[1]

As noted above, the specifier “with psychotic features” has been made independent of overall severity and sepa- rated into “with mood-congruent psychotic features” and “with mood-incongruent psychotic features”, depending on whether the content of hallucinations and delusions is in line with the depressed mood. This in- troduces into the DSM a traditional psychopathological concept of mood congruence. The total number of cases classified as psychotic depression may slightly increase as the severity requirement is omitted. Cases where psy- chotic symptoms also occur outside depressive episodes should be diagnosed as schizoaffective disorder.

The specifier “with catatonia” has also changed in DSM-5. Instead of a specifier in the depressive disorders section, there is a semi-independent category of “Cata- tonia associated with another mental disorder” (293.89) described in the psychotic disorder section. If the cata- tonia criteria (Table 4) are fulfilled, the specifier “with catatonia” is used alongside the additional 293.89 code. The content of the criteria is essentially the same, but it has been disassociated into more symptoms (Table 4). The requirement of three out of 12 features is likely to slightly increase the rate of diagnosing catatonia com- pared to the two out of five requirement in DSM-IV. This new and broadened definition of catatonia awaits validation as to response to specific treatments, like ben- zodiazepines and electroconvulsive therapy.

The DSM-IV specifier “with postnatal onset” has been expanded to “with peripartum onset” in DSM- 5. In addition to onsets within 4 weeks after delivery, this now includes onsets during the entire pregnancy. This specifier can be applied to the current or most recent episode. This change reflects the finding that a proportion of “postpartum” depressive episodes actually begin during pregnancy and continue and often worsen postpartum.[36] The change in wording acknowledges that the previously held belief that pregnancy is protec- tive against the development of an MDE is false and recognizes the importance of managing mood disorders both during and after pregnancy. However, the com-

bination of pregnancy and postpartum onset may ob- scure important differences in epidemiology, presenta- tion, and prognosis. The relapse rate of MDD and bipo- lar disorder is high during pregnancy in women who dis- continue their medications when planning to conceive or upon conceiving.[37–40] The incidence of new mood episodes is higher in the first postpartum month.[39, 41, 42]

Depressive episodes with postpartum onset are more of- ten associated with obsessive-compulsive and psychotic symptoms[43] whereas depression in pregnancy is more often a recurrence of previously present MDD.[43] First onsets of depression in the postnatal period are as- sociated with prospectively increased risk of bipolar disorder;[44] while there is no clear evidence of increased risk of bipolar disorder with onset during pregnancy. Risk factors for postpartum episodes include a family history of postpartum mood episodes and a history of significant premenstrual mood symptoms.[45–47] It is not known whether depression with onset in pregnancy and postpartum responds differentially to treatment. The combination of prenatal and postnatal onset in a single specifier may thus hide important differences, including prognostic features.[44] The fact that this specifier applies only to the most recent episode means that prognosti- cally relevant information may be erased after a nonperi- natal recurrence. Therefore, clinicians and researchers alike may do well to record whether the onset occurred during pregnancy or postnatally. Postnatal onset should be kept as part of psychiatric history given its potential long-term prognostic implications.

DIMENSIONAL RATINGS The single most talked-about issue in the develop-

ment of DSM-5 was the introduction of dimensional measures.[48] The strong arguments for the introduction of dimensions include the lack of discrete boundaries be- tween psychopathology and normality and the superior predictive explanatory power of dimensions compared to categorical diagnoses.[49] The counterarguments

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TABLE 4. DSM-5 depressive disorder specifier with catatonia (equal with Catatonia associated with another mental disorder) and a comparison with DSM-IV catatonic feature specifier

DSM-5 catatonia associated with another mental disorder DSM-IV with catatonic features

A. Presentation dominated by three or more of: Presentation dominated by two or more of: 1. Stupor 1. Immobility (catalepsy or stupor) 2. Catalepsy (1.) 3. Waxy flexibility 4. peculiarities of movement (posturing, grimacing, . . . ) 4. Mutism 3. Extreme negativism or mutism 5. Negativism (3.) 6. Posturing (4.) 7. Mannerism (4.) 8. Stereotypy (4.) 9. Agitation 2. Excessive purposeless motor activity 10. Grimacing (4.) 11. Echolalia 5. Echolalia or echopraxia 12. Echopraxia (5.)

Corresponding criteria are on the same line. Arabic numbers correspond to the order in which criteria are listed in DSM-5.[1]

include the difficulties with using dimensions in practice, where most clinical decisions have a-yes-or-no charac- ter, the lack of convergence on how many and which dimensions are needed, and the relevance of the entire range of distribution to clinical practice.[49] Yet, the an- nounced dimensional revolution in psychiatric classifi- cation did not happen. DSM-5 remains centered around an increasing number of diagnostic categories.

Several ordinal ratings are incorporated into the cate- gorical diagnoses. Like DSM-IV, DSM-5 allows grading of the severity of MDE as mild, moderate, or severe. The only change in this grading is that it has been separated from the presence of psychotic symptoms (see above). In addition, DSM-5 includes a direction for a four-level rating of the uncoded specifier “with anxious distress” as mild, moderate, moderate-severe, or severe.

Several self-report and clinician-rated scales are in- cluded in section III “Emerging Measures and Mod- els”. The introduction of additional dimensional mea- sures is unlikely to have a major impact on clinical prac- tice and research. Placement of these measures in the appendix-like section III, lack of psychometric infor- mation, and absence of guidelines on how these mea- sures should be used either alone or in conjunction with the categorical diagnoses in clinical decision-making re- duce the potential for uptake. Clinicians and researchers will likely continue using the validated continuous mea- sures of psychopathology that allow comparison of out- comes between individuals and with published reports. The NIMH Research Diagnostic Criteria (RDoC) ini- tiative will stimulate use of dimensional measures of psy- chopathology in combination with neuroscience and ge- netic methods that may shape future classifications of psychopathology.[50] This new direction will encour- age the researchers to carry out studies on samples that are not restricted by categorical diagnoses, mak- ing the results more informative for future classifica- tion efforts.[49, 50] However, this new direction is un- likely to remove the need for categorical research diag-

noses in most areas of research, especially in treatment trials.

RELATIONSHIP TO OTHER DIAGNOSTIC CATEGORIES

In addition to changes in the criteria for MDD itself, the use of this diagnosis and comorbidity will be affected by changes in criteria for other more or less related dis- orders.

The prevalence rates of MDD will be most directly affected by its new immediate neighbor, the “persis- tent depressive disorder” (PDD). In DSM-IV, MDD trumped the diagnosis of dysthymia, which was defined by symptoms that are long standing (lasting two years or longer), but fall short of MDD criteria. In DSM-5, the new category of PDD aims to combine dysthymia and chronic depression, but its relationship to MDD is ambiguous with conflicting statements on whether the two diagnoses should be concurrent if both sets of cri- teria are fulfilled. PDD is not listed as an exclusion cri- terion for MDD and MDD is not listed as exclusions criterion for PDD. Under “Diagnostic features” (page 169),[1] it is stated that “Individuals whose symptoms meet major depressive disorder criteria for 2 years should be given a diagnosis of persistent depressive disorder as well as major depressive disorder”. Under “Differ- ential Diagnosis” (page 170–171),[1] it is stated that “If the symptom criteria are sufficient for a diagnosis of a major depressive episode at any time during this period, then the diagnosis of major depression should be noted, but it is coded not as a separate diagnosis but rather as a specifier with the diagnosis of persistent depres- sive disorder.” The latter statement suggests that PDD trumps MDD diagnosis, at least at the level of coding. In addition, the symptomatic criteria for PDD and MDD differ (Table 5). Criteria for PDD are the same as the DSM-IV dysthymia criteria. Depressed mood is

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TABLE 5. Comparison of criteria for major depressive disorder (MDD) and persistent depressive disorder (PDD) in DSM-5

DSM-5 major depressive disorder DSM-5 persistent depressive disorder

A. Five or more out of nine symptoms (including at least one of depressed mood and loss of interest or pleasure) in the same 2-week period. Each of these symptoms represents a change from previous functioning.

A. Depressed mood for most of the day, for more days than not, for 2 years or longer.

B. Presence of two or more of the following during the same period: 1. Depressed mood (subjective or observed). (required in A) 2. Loss of interest or pleasure 3. Change in weight or appetite 1. Poor appetite or overeating 4. Insomnia or hypersomnia 2. Insomnia or hypersomnia 5. Psychomotor retardation or agitation (observed) 6. Loss of energy or fatigue 3. Low energy or fatigue 7. Worthlessness of guilt 4. Low self-esteem 8. Impaired concentration or indecisiveness 5. Impaired concentration or indecisiveness 9. Thoughts of death or suicidal ideation or attempt 6. Hopelessness

C. Never without symptoms for more than 2 months. In children and adolescents, mood can be irritable. In children and adolescents, mood can be irritable and duration must be 1 year or longer.

Corresponding criteria are on the same line. Arabic numbers correspond to the order in which criteria are listed in DSM-5.[1]

required. Loss of interest and pleasure, psychomotor retardation or agitation, weight loss, guilt or suicidal ideation do not figure among the PDD criteria. Low-self esteem replaces guilt and worthlessness. Hopelessness is a criterion symptom for PDD, separate from mood (while it is included under the description of mood for MDD, see above). These changes have potentially major implications. The prevalence of MDD will decrease (due to the subtraction of most chronic cases, which will be di- agnosed as PDD). The PDD will be more common than DSM-IV dysthymia (since it is no longer trumped by MDD), but cases that would have been dysthymia can be specified as “with pure dysthymic syndrome”. Due to dif- ferences in symptomatic criteria, there will be a (presum- ably small) group of chronic cases that will fulfill the cri- teria for MDD but not for PDD. This group may include patients who have significant anhedonia and fatigue, but not persistently depressed mood. The long duration of these cases will not be recorded since the “chronic” spec- ifier has been removed. The combination of dysthymia and chronic depression is clinically meaningful, since the two respond to the same treatments.[51, 52] However, the different symptom requirements for MDD and PDD will cause confusion and anomalies, including cases that fulfill criteria for MDD but not PDD even though they last longer than 2 years. The contradictory statements on whether MDD and PDD diagnoses should be used concurrently will likely lead to inconsistent use of hi- erarchy between these diagnoses, reducing comparabil- ity between diagnosticians. The unclear correspondence between chronic MDD and PDD may also affect biolog- ical research since chronic depression may have a distinct etiology.[53, 54]

The new category “disruptive mood dysregulation disorder” (DMDD) defined by the combination of tem-

per outbursts and long-standing irritability can coexist with MDD. DMDD can be diagnosed between ages 6 and 18. Since irritability counts toward the mood crite- rion of MDD in children, the criteria for the two disor- ders overlap. This will increase the rates of comorbidity of MDD in children and adolescents and in adults who may retain the DMDD diagnosis. Clinical implications for this new comorbidity are unclear since there are no treatment indications associated with DMDD at present. From prospective data, it is clear that DMDD is not re- lated to bipolar disorders.[55]

Another new category among depressive disorders is the “premenstrual dysphoric disorder” (PmDD)”, which is marked by affective lability, irritability, and depressive symptoms in the last week of the men- strual cycle in women. PmDD can be co-morbid with MDD with the stipulation that it is not merely an ex- acerbation of an MDE. PmDD is relatively common, with a prevalence between 1.3 and 3.1% of menstru- ating women in the general population,[56, 57] and may become even more common with the relatively broad definition adopted in DSM-5. Consequently, the comor- bidity rates of depression in women will increase fur- ther. The one possible clinical implication of comorbid PmDD lies in its rapid and specific response to seroton- ergic antidepressants.[58, 59]

Changes in the newly separate “bipolar disorders” section may also affect how the MDD is used. In addition to bipolar I disorder (BPI), bipolar II disorder (BPII), and cyclothymic disorder (CTD), this section contains a new broad group of “other specified bipolar and related disorders” (OSBRD), which include various presenta- tions that fall short of a BPI or BPII diagnosis in terms of either duration or symptom count. The diagnosis of hypomania and mania (and hence of BPI and BPII) in

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DSM-5 has been tightened by the requirement for in- creased energy and/or activity in addition to elated or irritable mood. The diagnosis of any bipolar disorder has been broadened by the inclusion of OSBRD. When making the diagnosis of MDD, lifetime history of hypo- manic or manic episode is an exclusion criterion. This means that the diagnosis of MDD is not compatible with the diagnosis of BPI or BPII (which requires a manic or hypomanic episodes, respectively), but it can be com- bined with the diagnoses of cyclothymia or OSBRD. The tightening of diagnostic criteria for hypomanic and manic episode will therefore result in a slight increase in the rate of MDD, which will now include cases that fail the increased energy/activity criterion for (hypo)manic episodes. However, there will be a substantial group of cases where a diagnosis of MDD is “comorbid” with a diagnosis from the bipolar disorders section (CTD, OSBRD). Since the diagnoses of bipolar disorder and “unipolar” MDD have been traditionally considered as exclusive of one another, it is likely that the exclusion criterion for MDD will be applied inconsistently.

Criteria for “generalized anxiety disorder” (GAD) have not changed in DSM-5. This will remain a common comorbidity of MDD. This comorbidity has currently little implication for specific treatment. Most clinicians will consider a combined treatment with antidepressants and cognitive behavioral therapy if the latter is available.

Criteria for “posttraumatic stress disorder” (PTSD) have changed markedly. The trauma criterion has been broadened to include direct and indirect expo- sures to a number of potentially traumatic experiences. The immediate reaction criterion (A2 in DSM-IV) has been removed. Symptoms from four (instead of three) clusters are now required for diagnoses, but the criteria are less stringent in that the selection of symptoms is broader and now includes relatively nonspecific symp- toms (e.g. irritability and anger are now included).[60]

A lower diagnostic threshold is introduced for children. Given the multiple changes, it is difficult to predict the impact on PTSD prevalence in the general population and among patients with MDD, but it is likely that the overall prevalence of PTSD will increase.[61] This may further increase the rates of comorbid disorders among patients with MDD. Since the pharmacological treat- ment for MDD and PTSD is similar, the clinical impli- cations of this comorbidity include primarily considera- tion of PTSD-focused psychological therapy.

DSM-5 introduced a new and potentially common “somatic symptom disorder” (SSD) defined as a pres- ence of any somatic symptom combined with signifi- cant preoccupation, anxiety, or excessive time devoted to health concerns. SSD replaces the much narrower DSM- IV diagnoses of somatization disorder and pain disorder. In DSM-5, SSD effectively trumps “illness anxiety dis- order”, which can only be diagnosed in the absence of significant somatic symptoms. The introduction of SSD will likely increase the rates and numbers of comorbidity among MDD patients. It is presently unclear if this has any implications for clinical care.

The poorly defined but frequently used “adjust- ment disorders”, including the specifier “with de- pressed mood” were retained in DSM-5. Like in DSM- IV, these are subthreshold disorders, trumped by MDD or other specific diagnosis. Therefore, adjustment dis- orders increase the number of diagnosable individuals in population, but do not affect the boundaries or comor- bidity of MDD. Somewhat surprisingly, the bereave- ment exclusion is retained in the definition of “adjust- ment disorders” and is only slightly modified by the in- sertion of the word “normal” in “The symptoms do not represent normal bereavement”.

CONDITIONS FOR FURTHER STUDY

Several potential categories related to MDD are in- cluded among “Conditions for further study” in Section III of DSM-5. “Depressive episodes with short-duration hypomania” is a combination of MDD with hypomania that lasts at least 2 but less than 4 days. It overlaps with OSBRD. This section also includes “Persistent com- plex bereavement disorder”, “Suicidal behavior disor- der”, and “Nonsuicidal self-injury”, all of which overlap with MDD. DSM-5 clearly states that these disorders are not intended for clinical use.

WHAT HAS NOT CHANGED AND WHAT IS MISSING

Having reviewed the changes from DSM-IV to DSM- 5, it is worthwhile considering the implications of the aspects of the diagnostic criteria for MDD that have not changed. First, the diagnosis of MDD remains based on symptom count: five out of nine symptoms are re- quired for the diagnosis. Although this is an easy and practical way to decide on diagnosis, it is important to note that symptom count has only a weak relationship to measures of depression severity and impairment.[62]

Symptoms like loss of interest, worthlessness, and suici- dality contribute more strongly to indicators of severity and prognosis than changes in appetite or sleep.[14, 62, 63]

Second, some symptoms that are commonly present dur- ing depressive episodes and are relevant to prognosis are not part of the DSM diagnostic criteria. One prominent example is irritability, which is seen in up to 40% of out- patients with MDD, contributes to episode severity, and predicts recurrence.[64–66] Irritability is part of the cri- teria for GAD and DMDD, but is not included among criteria for MDD in adults, not even in the mixed feature specifier. Third, to contribute to the diagnosis of MDE, each symptom has to represent a distinct change from previous functioning. This is perhaps the most com- monly ignored part of the DSM definition of depression. Although this is not required for the PDD, it remains a requirement for MDE and therefore MDD. If applied consistently, this means that trait factors like low self- esteem and sense of worthlessness cannot contribute to

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the diagnosis of MDD unless they are definitely worse during an MDE. Fourth, although the episodic course of the disorder was considered essential for the diag- nosis in classic psychiatric texts,[32] DSM does not take into account the course of illness. Episodicity of MDE is assumed (by its description in terms of depressive episodes), but not defined. Although long-standing, per- sistent, and highly recurrent forms of depression may have distinct etiology and prognosis,[53, 54, 67–69] these as- pects of clinical course are not recorded other than in the MDD versus PDD distinction. Since the differentiation between MDD and PDD may be based on symptom profile in addition to duration, even this little informa- tion on clinical course may be lost. The implications for clinicians and researchers are clear: DSM-5 diagnosis is not a sufficient summary of patient characteristics rele- vant to treatment and prognosis. As a minimum, the age of onset, degree of episodicity, recurrence, presence of irritability, and magnitude of change from previous func- tioning should be noted in addition to diagnosis, family, and treatment history.

WHAT NEEDS TO BE CLARIFIED The DSM-5 text is inconsistent or ambiguous on sev-

eral issues. These will no doubt be clarified in future revi- sions. However, in the meantime we attempt to provide interim guidance that is in agreement with the general intentions and logic of DSM-5. The first issue concerns the question whether MDD and PDD should be diag- nosed concurrently if both sets of diagnostic criteria are met. There are contradictory statements on this ques- tion in the DSM-5 text (pp. 169 vs. 170–171).[1] Since the specifiers of PDD capture the distinction between conditions where full MDD criteria are met or not, sep- arate coding of MDD appears superfluous. The two con- ditions clearly cannot be conceived as “comorbid”. We therefore suggest that MDD and PDD diagnoses should not be coded concurrently.

The second issue that requires clarification is whether the diagnosis of MDD can be concurrent with bipolar and related disorders. Since only an episode of hypo- mania or mania constitutes an exclusion criterion for MDD, the types of bipolar disorders that do not re- quire an episode of hypomania or mania, cyclothymia, or other specified bipolar disorders, can be diagnosed concurrently with MDD. However, this is not stated ex- plicitly in DSM-5.

RELIABILITY OF DIAGNOSIS The value of any diagnosis is limited by its reliabil-

ity, i.e. the agreement between diagnosticians on mak- ing the same diagnosis in the same patient. Reliability is most typically indexed with the kappa coefficient, which ranges from zero (chance agreement) to one (perfect agreement). Benchmarks have been proposed with val- ues above .6 considered to be good or very good, val- ues between .4 and .6 moderate, .2 to .4 fair, and be-

Figure 1. Interrater reliability of the diagnosis of major depres- sive disorder in DSM-III, DSM-III-R, DSM-IV, and DSM-5. Axis y shows the degree of interrater agreement indexed by the kappa coefficient. Axis x shows individual published studies (see text and bibliography for references). Hollow markers show relia- bility based on the same interview (joint or recorded), full mark- ers show reliability based on separate interviews. Circles show reliability for lifetime diagnoses and squares show reliability for current diagnosis. DSM-5 filed-trials (diamond) do not report whether the diagnosis is current or lifetime.

low .2 poor.[70, 71] Since the introduction of operational- ized criteria in DSM-III, there has been a strong em- phasis on diagnostic reliability[72] and early field trials and studies of structured diagnostic instruments consis- tently showed reliability in the good or very good range, irrespective of whether it was measured between two in- dependent interviews or was based on the same interview (Fig. 1).[73–75] With DSM-IV, the reliability of MDD di- agnosis appears to have slipped toward the .4 mark, es- pecially when it was based on separate interviews.[76, 77]

The DSM-5 field trials have yielded the lowest ever re- ported interrater reliability for the MDD diagnosis, with a kappa of .28 (95% confidence interval .20 to .35) based on separate interviews by physicians who received train- ing in the use of DSM-5.[78] Since the design of these field trials ensured that diagnoses were carried out in a way that is representative of psychiatric practice and with an appropriate level of training, the low agreement between clinicians is bad news for the validity of the MDD diagnosis and the credibility of psychiatry. It is important to ask what factors might have contributed and how the reliability of MDD diagnosis could be im- proved. Figure 1 shows a gradual decline from DSM-III to DSM-5, suggesting that the loss of reliability is prob- ably not entirely due to the relatively minor changes in- troduced in DSM-5. It is possible that a change of at- titude among clinicians and evolution in the design of reliability studies toward being more representative and inclusive play roles. Yet, the reliability figure from the DSM-5 field trials has been the lowest ever reported, calling attention to potential problems. In this review, we have pointed out several changes that might have in- creased the variance between diagnosticians: inclusion of hopelessness in the definition of mood, replacement of

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bereavement exclusion with a call for clinical judgment and uncertain boundaries between MDD and PDD and bipolar disorders may be among these factors. We hope that the analysis of diagnostic criteria and recommenda- tions for practice offered in this review will be among the first steps toward improving the reliability of the MDD diagnosis.

CONCLUSIONS The diagnosis of major depressive disorder has

changed in subtle but potentially important ways from DSM-IV to DSM-5. The most significant changes in- clude the removal of the bereavement exclusion and the carving out of the persistent depressive disorder cate- gory. The replacement of the bereavement exclusion with an ambiguous note, small unannounced changes in criteria and unclear diagnostic boundaries may combine to produce unexpected consequences, including reduced diagnostic reliability. Changes in other categories will likely further increase the numbers of comorbid condi- tions among individuals with MDD. This review pro- vides interim guidance on diagnostic practice, research, and clinical implications and calls for clarification of am- biguous issues.

Acknowledgements. The authors thank Dr. Mar- tin Alda for his comments on an earlier version of this manuscript. Dr. Uher is supported by the Canada Research Chairs program (http://www.chairs- chaires.gc.ca/).

Conflicts of interest Dr. Uher and Dr. Pavlova declare no conflicts of inter-

est. Dr. Payne has served on advisory board for Pfizer, provided expert testimony for Astra Zeneca and John- son and Johnson and received research funding from Corcept. Dr. Perlis has served on scientific advisory boards for, or consulted to Genomind, Pamlab, Proteus Biomedical, Perfect Health, Pfizer, Psybrain, and RID- Ventures. Dr. Perlis also provided analysis to the APA’s DSM-5 workgroup for bipolar disorder as a consultant, but had no role in writing or approving the DSM-5 criteria.

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Depression and Anxiety

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