CHAPTER 11

Depressive Disorders

Melvin G. Mclnnis, M.D., F.R.C.Psych.

Michelle Riba, M.D., M.S.

John F. Greden, M.D.

DSM-5 (American Psychiatric Association 2013) represents an important stage in the clinical classification of depressive disorders, and will evolve with emerging advances in neurobiology. The DSM-5 categories will continue as the "clinical currency" in medical practice; however, the deepening of understanding of the pathological processes and etiology in neuroscience is likely to reveal biological blurring of boundaries between the current categories. It is therefore critical that DSM-5 be adaptive and open to receive new information that has been vetted and independently replicated with confidence. As biological markers emerge from genetics, biochemistry, and cell biology, they will be studied on a large scale; markers that reflect biological mechanisms should be incorporated into classification systems and further studied, and the understanding of the biology of depression then refined. The process is iterative and informative. An emphasis on the refinement of knowledge, advancement, and development of research ideas and hypotheses to be sequentially tested in large patient populations will provide DSM-5 with fertile soil to evolve with emerging knowledge.

Much of the recent "understanding" of mood disorders is based on observations that are 50 years old and anchored in single receptor or neurotransmitter systems. New paradigms that incorporate many biological systems will be based on the anatomy and function of the human genome, the biological pathways within and between living cells, and the functional circuitry of the nervous systems (Mclnnis 2009). Fundamental to the progress of research into human biological systems is the individual with the disorder and the phenomena to be studied. Time has not dulled the need for the highest quality of clinical assessment and care; rather, as genetic susceptibility factors emerge, the need for deep clinical knowledge of the individual increases. DSM-5 categorizations of mood disorders will become a "living document" with deepening of knowledge at the biological level with clarity of the human sequence and technology for derivation of the sequence. Complex cellular mechanisms in relation to biology and clinical manifestations will identify therapeutic targets. The complexity of the clinical patterns of disease over the lifetime will build on the prescient work The Perspectives of Psychiatry (McHugh and Slavney 1998), which parses details of individual experience toward a detailed understanding of neuropsychiatric phenomena.

The common language for communication between science, clinicians, administrators, patients, and families is DSM-5, which provides an organized approach to clinical nosology in the current environment of low understanding of the etiology of the disease phenomena and the methods by which the medical interventions work.

The DSM-5 depressive disorders include the categories listed in Table 11-1. New to the depressive disorders diagnostic class are disruptive mood dysregulation disorder (DMDD) and premenstrual dysphoric disorder (PMDD). "Specifiers" are additional descriptors of severity, course, or comorbid clinical features and are available for improved objective clinical documentation. Risk of self-harm may be assessed and characterized within the DSM-5 Level 1 Cross-Cutting Symptom Measure for the purpose of communicating risk and prevention planning integral to the clinical evaluation based on DSM-5 criteria. Minor differences in the wording of the criteria for major depressive episode are seen from DSM-III (American Psychiatric Association 1980) to the current DSM-5; in more than 30 years of research, a core uniform definition of major depressive episode has essentially been used. Bereavement is no longer considered an exclusion to a depressive disorder diagnosis within the first 2 months of the loss.

DSM-5 emphasizes specifiers aimed toward helping to further subcategorize and manage disease patterns (Box 11-1 lists the DSM-5 specifiers for depressive disorders). The coexistence of at least three manic/hypomanic symptoms (insufficient for a manic episode) within a major depressive episode is indicated in DSM-5 by the specifier "with mixed features." There is no evidence that individuals with this symptom profile will develop bipolar disorder; however, the clinical manifestation of mixed features may have treatment and etiological relevance. Episode severity may now be coded independently from presence of psychotic features. Psychosis is specified according to mood congruency; mood-congruent psychotic features are consistent with underlying mood (e.g., psychotic guilt), whereas mood-incongruent psychotic features are generally bizarre and unexplained by mood symptoms. The presence of psychosis is often, but not always, associated with greater severity.

New diagnostic categories were placed in the Depressive Disorders class after careful scientific review of the evidence. PMDD has been moved from DSM-IV-TR Appendix B, "Criteria Sets and Axes Provided for Further Study" (American Psychiatric Association 2000), to become a stand-alone diagnosis. DMDD refers to the presentation of children with severe, recurrent temper outbursts. Although initial clinical impressions suggested that these phenomena may be related to childhood bipolar disorder, long-term outcome studies found that children with this presentation developed major depressive disorder.

The Depressive Disorders chapter coupled with the Assessment Measures chapter in DSM-5 Section III reflects refinements aimed at improving the recognition and treatment of these disorders by encouraging the clinician to record and consider important dimensional measures that are not conveyed by the categorical diagnoses themselves in arriving at a treatment plan for a specific patient. The Level 1 Cross-Cutting Symptom Measure is highlighted within DSM-5 to improve characterization and rate the severity of comorbid symptoms (e.g., anxiety, substance abuse) that have been shown to have a significant effect on clinical outcome of treatment as well as risk of self-harm in individuals with mood disorders.

Disruptive Mood Dysregulation Disorder

DMDD is a new disorder in DSM-5 whose core phenomenology is characterized by frequent and severe verbal and/or behavioral outbursts to common stressors That are pervasive, are outside the developmental stage, and occur in the background of a chronic negative mood. The age at onset is between ages 6 and 10.

The diagnosis emerges from research on severe mood dysregulation and irritability and observations on the overlapping phenomenology of bipolar disorder and specific mood symptoms of irritability (Leibenluft 2011; Leibenluft et al. 2003). It is placed in the depressive disorders diagnostic class because longitudinal follow-up evidence predicts emergence of depressive disorders (and not bipolar disorder) both in a short-term follow-up of 2 years (Stringaris et al. 2010) and in a long-term follow-up 20 years later (Stringaris et al. 2009). Children previously considered to be within the bipolar spectrum are anticipated to be included in this new diagnostic category.

Phenomenology and Diagnostic Features

The key phenomenological feature of DMDD is irritability that is both acutely reactive and persistently chronic. (DSM-5 diagnostic criteria for DMDD are presented in Box 11-2.) Reactive agitated temper outbursts, profound and beyond the expected developmental stage, occur at least three times weekly in response to daily frustrations. The verbal component of irritability includes shouting and screaming with wanton disregard for the feelings of others; the physical and behavioral aspect may include reckless aggression to people, animals, or property. The nature and extent of the outbursts must be documented in three settings (e.g., home, school, or social with peers) and must be considered to be severe in one setting (requiring the supervising adult to suspend the current activity to focus on the management of the individual). The agitated outbursts must be frequent, occurring on average three times weekly over the course of 1 year and on the background of a chronic irritable, upset, or angry mood present nearly every day. The chronic irritable mood will often be described by the parent or caretaker as being the child's temperament.

Epidemiology

Prevalence

DMDD is a new clinical category and entity within DSM-5, and therefore minimal epidemiological data are available. Based on estimates of irritability in youth and using criteria very similar to those for DSM-5 DMDD (Brotman et al. 2006), the overall prevalence of the disorder is estimated to be around 3%.

Course and Development

The chronic irritability and random temper outbursts of youths with DMDD in response to mundane provocation showed several distinctive features in comparison to those of youths with classic episodic bipolar disorder (Leibenluft 2011). Individuals with DMDD are less likely to have a parent with bipolar disorder and more likely to develop major depressive disorders (Stringaris et al. 2009, 2010), and the specific symptoms (irritable outbursts) of DMDD become less common with the transition to adulthood (Leibenluft et al. 2006). The lack of association of childhood dysregulation of mood with later bipolar disorder was also found in a longitudinal study of Dutch children followed to adulthood (Althoff et al. 2010). The current research and understanding of the clinical course of childhood irritability and dysregulated moods clearly place DMDD in the DSM-5 class of depressive disorders rather than among bipolar and related disorders.

Etiological Factors

Risk and protective etiological factors of DMDD are not known. Children with DMDD frequently present with a complex psychiatric and temperamental history with an extensive pattern of irritability and other comorbidities that manifest before the full criteria of the syndrome are in fact met. The family history is generally noncontributory. It has been found that children with a dysregulated mood profile on the Child Behavior Checklist (CBCL) have a substantial background of psychosocial adversity, which may be either a cause or an effect of the syndrome (Jucksch et al. 2011).

Differential Diagnosis

Individuals with pediatric bipolar disorder exhibit discrete episodic periods of mood disturbance with sustained volitional and cognitive changes. The phenomenology, including duration, is similar to that of bipolar disorder in the young adult population. In contrast, DMDD is a disorder with acute temperamental outbursts on a background of chronic irritability. Distinct periods of euphoria, grandiosity, racing thoughts, and lack of need for sleep in a sustained energized state characterize bipolar disorder rather than DMDD. An explosive, chronically cranky, sensitive, and unhappy child would more likely have DMDD.

Oppositional defiant disorder will be frequently, if not invariably, found in children with DMDD. Oppositional defiant disorder may be diagnosed before age 6, after which there may be debate as to which diagnostic category is most applicable to the clinical course. The primary phenomenology of explosive irritability on a background of a chronic state of anger and irritability warrants application of DMDD as a primary diagnosis. The absence of the chronic unhappy irritability criteria (including time duration) would support oppositional defiant disorder as the sole diagnosis.

Attention-deficit [hyper activity disorder (ADHD) may frequently coexist with DMDD, and the diagnosis is made according to the criteria of ADHD. The chronic irritability of DMDD may contribute to the appearance of boredom and difficulty maintaining focus that is a part of ADHD. The impulsivity of ADHD is unlikely to be confused with the profound outbursts of temper in DMDD.

Major depressive disorder and persistent depressive disorder (dysthymia) often have irritability as a prominent clinical symptom. The lack of irritable outbursts and temper tantrums would call for a diagnosis of persistent depressive disorder in the chronically irritable and upset child. Should the average weekly number of outbursts over the course of a year be estimated to be three or more by the parent or caregiver, the DMDD diagnosis should be considered. There may be variable numbers of symptoms of depression in the context of DMDD, and there is evidence that DMDD frequently evolves into major depression. Once the criteria for major depression are met, that becomes the preferred diagnostic category.

Intermittent explosive disorder is an exclusion diagnostic category for the child with frequent outbursts of temper (similar to the child with DMDD) but with no evidence of persistent mood disruption between outbursts. A child with chronic and persistent annoyed, sensitive, and irritable mood with temper outbursts would receive a diagnosis of DMDD; a child with "normal" mood between temper outbursts would receive a diagnosis of intermittent explosive disorder.

Substance use disorders should not be overlooked despite a person's young age, because young individuals may be exposed to a variety of substances in their environment. A chronically underprivileged sociological base as well as other stigmata will alert the clinician to review the history and perform specific tests to assess for a substance use disorder.

Comorbid Diagnoses

It is anticipated that DMDD will have many comorbid diagnoses. Three diagnostic categories—bipolar disorder, intermittent explosive disorder, and oppositional defiant disorder—are exclusionary. The presence of symptoms from mood, anxiety, and developmental disorders is expected, and the formulation of the patient's clinical problems provides for prioritization of such problems and emphasis of the preferred diagnostic category.

Management

The formulation of DMDD within the class of depressive disorders rather than bipolar and related disorders has implications for therapeutic management. The current approach to management is symptomatic and problem focused. Optimal treatment for individuals with DMDD is not clear, and several individual and combined treatments are under consideration; however, there is no currently validated treatment for this disorder. Clinical trials involving antidepressants and other medication classes are under way, predicated on the inclusion of DMDD within the class of depressive disorders. Aggressive outbursts are prominent features of the disorder. The treatment of aggression (covert and overt) in the context of ADHD found effect sizes between 0.69 and 0.84 for stimulant medication (Connor et al. 2002). Irritability has been shown to be responsive to selective serotonin reuptake inhibitors (SSRIs) in the context of a nonbipolar illness. If a manic episode occurs in the context of antidepressant therapy, the clinician should reconsider the overall diagnosis, with bipolar disorder a strong possibility. A small placebo-controlled study of DMDD with lithium was negative; trials of divalproex and risperidone have shown some support of management of the irritability (Leibenluft 2011). Although no formal psychotherapy trials have been reported, anecdotal reports indicate that irritability and aggression have improved with behavioral management strategies.

Prognosis

In a longitudinal study (Brotman et al. 2006), subjects were monitored for more than 15 years in four distinct assessment "waves" for the evidence for DMDD (called "severe mood dysregulation" in the study). The fact that DMDD was found in only one wave for 80% of the participants implies that the diagnosis may be time limited (i.e., DMDD was not diagnosed at each assessment time point). The risk of developing major depression in early adulthood was predicted by the mood dysregulation diagnosis at only one of the assessment waves. Other functional outcomes have not been published and await further research (Leibenluft 2011).

Major Depressive Disorder

Major depressive disorder (MDD) is a unique diagnostic category in the current descriptive understanding of the illness. This diagnosis represents the clinical manifestation of heterogeneous illnesses likely to have complex biopsychosocial etiologies with symptom patterns that may change in quality and severity over the lifetime of the individual. Medical and psychological texts, as well as literature and art in most cultures, provide articulate descriptions and interpretations of the perceived underlying pathology of depression. Central to the definition is a disordered affect. Affect is defined as the objective and behavioral expression of internal mood states with concomitant observable motor components, in the form of expressive features of facial and other bodily movements. Diminished volitional and cognitive expressions are generally, but not always, aligned with the degree of disordered and depressed mood.

The term depression is complicated because, in addition to referring to the heterogeneous manifestation of the medical disorders that are captured by the concept of major depression, single or recurrent episodes, it is used in daily language with its own culturally determined meanings. DSM-5 represents the current approach to the clinical understanding of major depression, putting framework around the observations and providing a clinical base for the etiological and translational research that is ongoing and will ultimately lead to further clarification of understandings of specific etiologies, pathways, and treatments.

Phenomenology and Diagnostic Features

The core feature of MDD is the major depressive episode, represented by criteria A-C of the DSM-5 diagnostic criteria for major depressive disorder (Box 11-3).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Criterion A in DSM-5 requires the individual to have experienced at least five of nine listed symptoms simultaneously during a 2-week period and to have undergone a change from previous functioning. Either depressed mood or anhedonia (loss of interest or pleasure) must be one of the symptoms. The depressed mood of major depression goes beyond transient mood changes experienced in response to the vicissitudes of everyday life, which may lead to temporary demoralization but can usually be relieved by situational remediation. The depressed mood of a major depressive episode is objective, is sustained, and preoccupies most (>50%) of the time nearly every day; the patient often describes it as a profound sense of hopelessness or internal emptiness. In less mature individuals (e.g., children, people with intellectual disabilities), the expression of depressed mood may be irritability with a cranky, easily annoyed disposition that is sustained.

Anhedonia is the second anchor criterion of depression. Its insidious onset in the absence of depressed mood may be associated with diminished capacity to recognize the presence of a depressive episode. Key to the assessment is the qualitative change and reference points that include timelines and activities. Those knowledgeable of the patient (family members) may be immeasurably helpful in providing necessary clinical data to establish these criteria.

Several vegetative signs and symptoms are included in the criteria for a depressive episode. Appetite change and unintended weight loss reflect the physical symptoms related to depression; the desire to eat, the pleasure of a favorite food, and the volitional drive of self-care are diminished. Patterns of sleep disturbances within a depressive episode vary across individuals, and an individual may experience episode variability and evolution of the depressive sleep pattern over time. Characteristically, the individual feels that he or she is not getting enough sleep and experiences fatigue or exhaustion during waking hours. The patterns of insomnia include initial insomnia (difficulty falling asleep), middle insomnia (awaking during the night), and terminal insomnia (early awakening and difficulty falling back asleep). A subgroup of individuals show "reverse vegetative" symptoms, wherein the eating and sleeping patterns are reversed from the typical pattern; these individuals experience increased appetite and carbohydrate craving, and their sleep patterns, compared with baseline, are characterized by oversleeping, often over 10 hours per day.

Altered psychomotor activity is expressed in agitation or retardation. Psychomotor agitation is an inner irritability with an objective motor component, such as the hand-wringing of a depressed elderly person or the gesticulated pacing of a fretting despondent individual. Psychomotor retardation refers to the notable slowing of all objective body activity, including walking, eating, talking, and gestures. Fatigue and loss of energy maybe subjective, objective, or both.

Thoughts and cognitive processes are disrupted. The content of thought is often disrupted, and sufferers may have unfavorable thoughts toward themselves and their own actions that are not consistent with the rational assessment of an observer. An individual with MDD may have feelings of unworthiness or excessive or inappropriate guilt that are delusional (e.g., unfounded blaming of self for a major catastrophe). The individual's thinking may be disrupted by the diminished ability to think or concentrate or by indecisiveness. The capacity to perform at previously documented levels is impaired (e.g., a professor will have difficulty reading and critiquing research papers, a carpenter will have difficulty organizing and executing tasks of the day that were normally done with ease, pleasure, and a sense of self-fulfillment).

Recurrent thoughts of death and suicide are a common feature of the depressive episode. Immediate risk is indicated if an individual has a plan to kill him- or herself, or has prepared and planned for his or her own demise (e.g., has recently prepared a will and planned for disposition of property). Direct questions such as "Do you have thoughts of killing yourself?" are helpful. The depressed patient is more likely than not to have contemplations of death that may be magnified by the current depressive episode, and delineation of the extent and frequency of these thoughts should guide treatment.

The Level 1 Cross-Cutting Symptom Measure provided in the Assessment Measures chapter of DSM-5 Section III is a very pragmatic self-rated instrument to assess symptoms and severity; it is highly recommended that clinicians use this or a similar clinical measure in their evaluations. The DSM-5 Assessment Measures chapter also refers to the Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (www.nihpromis.org), which have been used extensively in clinical outcomes research (www.nihpromis.org/science/Publications Years). In addition, the Patient Health Questionnaire (PHQ-9; (Kroenke et al. 2001), a validated tool for assessment of DSM-5 symptom severity, is useful because it combines categorical and dimensional assessments of the symptoms. The Level 1 Cross-Cutting Symptom Measure, the PROMIS instruments, and the PHQ-9 are relatively easy to use, time efficient, and internally consistent measures of mood symptoms (based on self-report). It is anticipated that use of such measures will be expected by insurers and administrative oversight entities.

Epidemiology

Prevalence

Estimates of the lifetime prevalence of MDD are variable and range from 4.4% in the Epidemiological Catchment Area study (Robins and Regier 1991) to 30% in the Virginia Twin Study (Kendler et al. 1993). The National Comorbidity Study found the lifetime prevalence to be in the range of 16%, with confidence intervals of 15%-17%, which is widely considered to be an accurate estimate of major depression in Western culture (Kessler et al. 2003). The 1-month prevalence in the National Comorbidity Study was estimated to be 6%. Interpretation of population estimates of disease frequency should be done with caution and in consideration of the sample size, methodology, diagnostic criteria, and culture.

Course of Illness: Recurrent Versus Single Episode

DSM-5 differentiates a single episode from recurrent episodes of MDD. For an episode to be considered recurrent, it must have been preceded by a period of at least 2 months during which criteria for major depressive disorder were not met (see Box 11-3, DSM-5 diagnostic criteria for MDD). The signs and symptoms of recurrent and single episodes of major depression are identical; it is the course of the illness that categorizes the disorder. Clearly, the illness begins with a single episode; however, in the majority of cases, the episodes are destined to become recurrent (estimates of recurrence range from ~50% within the first year to up to 85% during a lifetime; Mueller et al. 1999).

The length of a depressive episode is in the range of 5-6 months, with approximately 20% of episodes becoming chronic (i.e., lasting beyond 2 years). The distribution of duration of episodes is log-normal, which dilutes the meaning of means and averages for the clinician and patient alike. The course of symptoms through an episode varies according to the success of targeted treatment of symptoms. Because volition and energy may pick up early in treatment relative to mood and emotional symptoms, a patient may feel distressed that others comment that he or she appears somewhat better even though he or she still feels emotionally lousy, sad, and overwhelmed. The improvement in volition and energy is generally a good sign of initial response to treatment; however, the lag in improvement in mood relative to volition may result in despondency and suicidal behavior.

Risk and Prognostic Factors

Environmental factors. Adverse childhood experiences, particularly when there are multiple experiences of diverse types, comprise a set of potent risk factors for MDD. Stressful life events are well recognized as precipitants of major depressive episodes, but the presence or absence of adverse life events near the onset of episodes does not appear to provide a useful guide to prognosis or treatment selection.

Genetic and physiological factors. First-degree family members of individuals with MDD have a risk for MDD that is 2 to 4 times higher than that of the general population. Relative risks appear to be higher for early-onset and recurrent forms. Heritability is approximately 40%, with the personality trait neuroticism accounting for a substantial portion of this genetic liability (Sullivan et al. 2000).

Temperament factors. Neuroticism is a well-established risk factor for the onset of MDD, and high levels appear to render individuals more likely to develop depressive episodes in response to stressful life events.

Course modifiers. Features associated with lower recovery rates, other than current episode duration, include psychotic features, prominent anxiety, personality disorders, and symptom severity. The risk for recurrence falls slowly as time in remission increases and is higher when the preceding episode was severe, especially in younger individuals and in those who have already experienced multiple episodes (Kanai et al. 2003). The persistence of even mild depressive symptoms during remission is a powerful predictor of recurrence. Essentially, all major nonmood-related disorders increase the risk of an individual's developing depression (Kessler et al. 1997). Major depressive episodes that develop against the background of another disorder often follow a more refractory course. Substance use, anxiety, and borderline personality disorders are among the most common of these, and the presenting depressive symptoms may obscure and delay their recognition (Kessler et al. 2005). However, sustained clinical improvement in depressive symptoms may depend on the appropriate treatment of underlying illnesses. Chronic or disabling medical conditions also increase risks for major depressive episodes. Such prevalent illnesses as diabetes, morbid obesity, and cardiovascular disease are often complicated by depressive episodes, which are more likely to become chronic than are depressive episodes in medically healthy individuals (McIntyre et al. 2012).

Suicidal Ideation

The possibility of suicidal behavior exists at all times during major depressive episodes. Although the most consistently described risk factor is a past history of suicide attempts or threats, most completed suicides are not preceded by unsuccessful attempts. Other features associated with an increased risk for completed suicide include male sex, being single or living alone, and prominent feelings of hopelessness. The presence of borderline personality disorder markedly increases risks for future suicide attempts.

Clinical Expression Related to Gender and Age

Despite consistent differences between genders in prevalence rates for depressive disorders, there appear to be no clear differences by gender in phenomenology, course, or treatment response. The higher prevalence in females is the most reproducible finding in the epidemiology of MDD. Risks for suicide attempts are higher in women; however, risks for completion of suicides in women are lower. There are no consistent differences between genders in symptoms, course, treatment response, or functional consequences.

Similarly, there are no clear effects of current age on the course or treatment response of MDD. Some symptom differences exist, however, such that reverse vegetative symptoms are more likely in younger individuals, and melancholic symptoms, particularly psychomotor disturbances, are more common in older individuals. The likelihood of suicide attempts lessens in middle and late life, although the risk of completed suicide does not. Depressions with earlier ages at onset are more familial and are more likely to involve personality disturbances. The course of MDD within individuals does not generally change with aging. Mean times to recovery appear to be stable over long periods, and the likelihood of being in an episode does not generally increase or decrease with time.

Etiological Factors

Although over 90,000 references are identified when etiology and depression are searched in Medline, the etiology of major depression remains an enigma. Much is known and is being researched, yet consistently reproducible results remain on the horizon. One of the most helpful discussions for beginning an understanding of the complex etiologies behind a heterogeneous disorder such as major depression is in The Perspectives of Psychiatry by McHugh and Slavney (1998). Therein, the student of mood disorders and other psychiatric illnesses learns that there are (at least) four perspectives to approaching and understanding these illnesses and phenomena. The biological perspective considers the increased genetic risk in affected family members, as well as biochemical and immunological factors such as inflammatory molecules and stress-related markers of the endocrine system. The behavioral perspective takes into account the role of motivated behaviors contributing to the clinical picture, including unhealthy lifestyle choices and related behaviors; smoking, drinking, unhealthy eating habits leading to obesity, and gambling are examples of behaviors that compromise moods and contribute to the etiology of major depression. Personality features and temperament contributing to mood disorders are captured in the dimensional perspective. Finally, the life-story perspective describes the influences that life events and environmental influences may have on the development of the disorder.

Differential Diagnosis

The list of medical diseases that may have depressive symptoms as a concomitant feature is extensive and includes diseases of most organ systems of the body. A newly diagnosed patient with depression clearly warrants a comprehensive medical examination that includes standard hematological and biochemistry screens as well as other screens indicated from the physical examination. The diagnostic formulation of the symptoms of a major depressive episode is especially difficult when they occur in an individual who also has a general medical condition (e.g., cancer, stroke, myocardial infarction, diabetes, pregnancy). Some of the criterion signs and symptoms of a major depressive episode are identical to those of general medical conditions (e.g., weight loss with untreated diabetes, fatigue with cancer, hypersomnia early in pregnancy, insomnia later in pregnancy or during the postpartum period). Such symptoms count toward a major depressive diagnosis except when they are clearly and fully attributable to a general medical condition. Nonvegetative symptoms of dysphoria, anhedonia, guilt or worthlessness, impaired concentration or indecision, and suicidal thoughts should be assessed with particular care in such cases. Definitions of major depressive episodes that have been modified to include only these nonvegetative symptoms appear to perform in a nearly identical fashion to the complete DSM-5 definition.

A thorough psychiatric examination will consider and weigh the evidence for psychotic illness, such as schizophrenia, although there may be mood-congruent or mood-incongruent psychotic features within major depression that manifest with expressions of guilt. The more systematized and bizarre the psychotic features are, the greater the likelihood that a schizophrenia-related illness is present. Bipolar disorder commonly presents with an episode of major depression, and a thorough review of the patient's history and family members may reveal concerns about bipolar disorder. At the moment, however, the diagnosis is based on the current phenomenology, not the concerns of the future or the symptoms of the family member. Anxiety and substance use disorders may be considered comorbid to depression or may in fact be the primary disorder should they be the primary presenting problem.

DSM-5 allows for the specification of the current clinical status and severity (mild, moderate, or severe; see Box 11-1, "DSM-5 Specifiers for Depressive Disorders"). Assessment tools that measure symptom severity in depression without psychotic features include the PHQ-9 (Kroenke et al. 2001) and the Quick Inventory of Depressive Symptoms (QIDS; Trivedi et al. 2004). A PHQ-9 score of >20 indicates a severe classification, 15-19 is rated moderate, and 10-14 is considered mild. A measure of severity is recommended to provide a dimensional measure for ongoing monitoring of disease. Disorder-specific severity measures and additional dimensional assessments can be found online at www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures.

Management

The management of the individual with MDD follows a thorough assessment that encompasses the four perspectives of psychiatric practice as outlined by McHugh and Slavney (1998; see "Etiological Factors" earlier in this section). DSM-5 is a classification system and is not meant to be a set of treatment guidelines. We discuss several broad treatment categories, however, to provide a starting point for the care provider. Both treatment of the acute episode and long-term management will involve medical and psychological treatments, either alone or in combination. Gilbert et al. (1998) developed algorithms that guide the selection of therapy options. Kendrick and Peveler (2010) review the updated National Institute for Health and Clinical Excellence (NICE) guidelines (National Collaborating Centre for Mental Health 2009), developed in the United Kingdom. The Texas Medication Algorithm Project Procedural Manual provides quick-reference flowcharts with sequential recommendations on treatment options (Sueha et al. 2008).

Medical management of MDD generally begins with an antidepressant, typically from the SSRI class of medications. The advantage of the SSRI class is ease of use. No consistently reliable biological or clinical markers support the use of one antidepressant over another. The practitioner and patient are encouraged to continue medication for at least 3-5 weeks at a therapeutic dose to evaluate a drug's efficacy. If no minimal improvement occurs during this time, a decision is made to either augment the treatment or switch to another antidepressant. The time to remission is often as long as 8-12 weeks, and if there are indicators of response at the 3- to 5-week window, the patient is strongly advised to continue at the maximally tolerated therapeutic dose. Augmentation is generally from another class of medications or with an antidepressant with a different mechanism of action (Rush et al. 2004). Clinicians should consider using a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI).

An SSRI is generally the initial medication tried for management of depression and related disorders. Most SSRIs have biological half-lives in the 24-hour range, which makes them ideal for once-daily dosing. (Exceptions are fluoxetine and fluvoxamine, with half-lives of 7-9 days and ~ 15 hours, respectively.) Therapeutic dosage ranges are noted in Table 27-11 (see Chapter 27 in this volume, "Psychopharmacology," by Ferrando et al.), and the recommendation for the otherwise healthy adult is to begin at the entry-level dose and gradually (weekly) increase the dose as tolerated. Medically compromised patients often require a lower starting dose. Predictable side effects include initial gastrointestinal discomfort, an akathisia-like restlessness, insomnia, and headache; these are usually limited to the early phase of treatment. Sexual dysfunction is relatively common and frequently endures.

Following a failed trial of one or two SSRIs, a serotonin-norepinephrine reuptake inhibitor (SNRI) is frequently tried. SNRIs are generally relatively easy to use. Dose increases should be weekly, and discontinuation of the medication should be monitored carefully for withdrawal syndrome (flu-like malaise with gastrointestinal symptoms, headache, and irritability).

Bupropion, a norepinephrine and dopamine reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, are considered atypical antidepressants. Bupropion is considered more activating and mirtazapine more sedating; they may be used alone or in combination with other antidepressants. Both are noteworthy because of their low frequency of sexual side effects.

TCAs were introduced in the late 1950s and were the mainstay of pharmacological treatment until the introduction of the SSRIs in the late 1980s. Unfortunately, many physicians and psychiatrists-in-training have had little exposure to this class of medicine. Many classical phenomenologically oriented psychiatrists consider this class of antidepressants to be more effective than the SSRIs, and this class may be effective in the patient who has significant vegetative symptoms (e.g., sleep and appetite disturbances) and appears to be treatment resistant. The prudent prescriber will become clinically and academically familiar with one or two TCAs and use them aggressively when appropriate. Key considerations include the need for gradual dose increase, the risk of anticholinergic side effects, and the cardiotoxic effect of this class of medications.

MAOIs were the first class of medications associated with an antidepressant effect when improved moods were observed in patients with tuberculosis treated with isoniazid, which was later discovered to have monoamine oxidase-inhibiting properties and found to be effective in the pharmacological management of depression. This class of medication is generally shunned by the prescribing care provider because of concerns about needs for dietary restriction and for monitoring patients for potential drug interactions. The dietary restriction requirement is based on the patient's need to restrict tyramine intake while taking an oral MAOI, which irreversibly inhibits the monoamine oxidase enzyme in the gut as well as in the central nervous system. The lack of this enzyme in the gastrointestinal tract allows the absorption of tyramine, the end result of which is the central displacement of norepinephrine into the extracellular space, with the pharmacological consequence being a sudden rapid increase in blood pressure (hypertensive crisis). To prevent such an occurrence, the patient avoids foods high in tyramine such as aged cheeses (e.g., 1 oz of Stilton cheese may contain up to 60 g of tyramine, an amount sufficient to precipitate a hypertensive crisis). Fermented foods with an aroma associated with a specialty delicatessen are often high in tyramine. Most individuals do not find the tyramine restriction in their diets problematic and with simple counseling are able to manage easily.

Physical treatments include electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). ECT is a specialty-based treatment that may be done on either an inpatient or outpatient basis. Typically, a patient with severe treatment-resistant depression who is suicidal or unable to care for him- or herself is admitted to the hospital and begins receiving ECT, which is completed in the outpatient setting (Agarkar et al. 2012). When a patient tolerates medication very poorly, rTMS is offered on an outpatient basis in a specialty setting (Husain and Lisanby 2011).

Extensive publications on the psychotherapies have been designed with the trainee and nonpsychotherapist clinician in mind (Bateman et al. 2010; Slavney 2005). Two specific psychotherapies have been shown to be very effective in depressive disorders. Interpersonal psychotherapy is a manual-based approach that is time limited and focused on relationships (Weissman et al. 2000). Cognitive-behavioral therapies are also well manualized, time limited, and focused on the individuals' thoughts and perspectives toward themselves and their environment (Beck 2011). All interactions between caregiver and patient are forms of psychotherapy, and there are many options for applications for psychotherapy techniques, many of which are disproportionately magnified in the popular media. A comprehensive text evaluating landmark studies of psychotherapy and discussing evidence-based data provides guidance about matching patients and diagnostic categories with the methods (Roth and Fonagy 2005).

Prognosis

There are no consistent predictors of therapy response or the course of illness that can be expected. The prognosis for major depression is influenced by vulnerability factors (untoward life events and stressful environmental influences) and protective factors (supportive relationships and nurturing environment). The chronicity of the disorder is exemplified in the 85% lifetime recurrence rate and the 1-year remission rate of around 40%. The prognosis is positively influenced by a long-term strategy for medical and psychological management that focuses on the patient, as well as his or her family and environment, and that maximizes the protective factors and minimizes the vulnerabilities.

Persistent Depressive Disorder (Dysthymia)

Dysthymia (literally "bad mood") has long been recognized as a phenomenon in the context of a temperamental predisposition to depression, with overlapping symptoms and a chronicity that weighs heavily on the individual and family. Dysthymia is a chronic low-grade depression characterized and defined by the presence of a depressed mood for at least 2 years (or 1 year in children and adolescents) and at least two of six designated symptoms of depression that are present most (>50%) of the time and that result in clinically significant distress or impairment. Persistent depressive disorder (Box 11-4) may be diagnosed before or after a major depressive episode, reflecting the dimensional nature of depressive symptoms. It is not diagnosed in the context of a chronic psychotic disorder or when it is caused by a substance or another medical condition. Dysthymia has not been a dedicated focus of research over the years; much of the research that has been done is that of Akiskal (2001).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

Unlike the DSM-IV-TR criteria for dysthymic disorder, the DSM-5 criteria for persistent depressive disorder do not require the absence of a major depressive episode during the first 2 years of the mood disturbance or stipulate that criteria for cyclothymic disorder have never been met. These requirements were dropped because such information is unlikely to be reliably remembered in sufficient detail to provide clarity.

Phenomenology and Diagnostic Features

The core phenomenological feature of persistent depressive disorder is a longstanding subthreshold depression with vicissitudes of mood and temperament. The individual usually has a sullen disposition with low energy and drive, preoccupation with guilt and failure, and a tendency to ruminate. The symptoms tend to outweigh the signs. Common subjective symptoms include sadness, diminished concentration or indecisiveness, a pervasive sense of hopelessness, and low self-worth or self-esteem; objective clinical signs include appetite and sleep disturbances (increased or decreased) and notable changes in energy levels. The illness is a chronic disorder, and the individual reports having "always been this way." The individual may alternate between mood states that sometimes reach criteria for major mood disorders.

Epidemiology

Major epidemiological studies in the United States estimate the frequency of dysthymia to range from 1.5% to 3% of the population. It is more common in women and is among commonly diagnosed depressive illnesses of the primary care population. Up to 50% of those with the disorder, however, are undiagnosed and seek medical care for perceived physical reasons.

Differential Diagnosis

The presence of dysthymic or low-grade depressive symptoms should always prompt the clinician to inquire about changes in physical health, especially in individuals who are older and have no previous psychiatric history. Many medical disorders may have dysthymic symptoms among the presenting clinical picture. A comprehensive medical examination at initial presentation is indicated.

From a psychiatric perspective, the differential diagnosis of persistent depressive disorder includes most major psychiatric illnesses. The primary differential is MDD; the relationship between these two disorders is complex, with the two disorders overlapping and episodes fading in and out of each other, resulting in the so-called "double depression," which is a major depressive episode on top of a dysthymic disorder. A rational diagnostic formulation is based on a medical history and mental status examination that encompasses the four perspectives of psychiatric practice as outlined by McHugh and Slavney (1998) and the diagnostic criteria of DSM-5.

The specifiers for persistent depressive disorder are helpful in the formulation of the clinician's global view of the patient, allowing the rationale to be advanced that the individual is primarily someone with persistent depressive disorder but with specific clinical (e.g., melancholic, anxious, atypical, psychotic) features (see Box 11-1, DSM-5 Specifiers for Depressive Disorders") or if there are episodes of major depression interspersed within the persistent depressive disorder ("with intermittent major depressive episodes"; see diagnostic criteria in Box 11—4). Persistent depressive disorder that begins before age 21 is referred to as early onset, and after age 21 as late onset. Severity may be specified as mild, moderate, or severe based on clinical impressions, but preferably using objective assessment measures (see Assessment Measures chapter in DSM-5 Section III).

Management

The care and psychiatric management of a patient with persistent depressive disorder may be challenging. Typically, these patients are treated with an antidepressant (following the recommendations discussed earlier in this chapter in the section "Major Depressive Disorder"), frequently in combination with an anxiolytic. Psychotherapy alone or in combination with medication is often successful in managing symptoms and alleviating suffering. The use of combined medications and treatments makes it difficult to appreciate which interventions are providing the most relief. Combination therapy is indicated in many patients; however, target symptoms and goals need to be established and evaluated systematically. Symptom severity scales and functional outcome measures should be used to monitor progress.

Prognosis

Persistent depressive disorder is frequently a chronic illness that persists despite seemingly aggressive treatment. Symptom severity may wax and wane, particularly if there is a reactive component in the temperament of the person with the disorder. The individual may experience long-term variability in symptoms, which can change in a gradual manner over time and as influenced by environmental conditions (e.g., bad relationships or enduring stressful emotional conditions). There is a risk for suicide that is increased with all. known suicidal risk factors; hopelessness often emerges due to the chronic nature of the disorder. Although at first glance the symptoms are less severe than those of major depression, the effect on vocational, personal, and social functioning may be devastating at the individual level, resulting in substantive loss of status or relationships.

Premenstrual Dysphoric Disorder

Phenomena associated with PMDD were initially described as late luteal phase dysphoric disorder in DSM-III-R (American Psychiatric Association 1987) and were renamed PMDD in DSM-IV (American Psychiatric Association 1994). In several general community and clinical samples of women, PMDD has been shown to be a clinically significant psychiatric disorder with discriminate biological markers, and to be amenable to a variety of pharmacological, hormonal, and psychotherapeutic treatments (Epperson et al. 2012). PMDD involves changes specific to the menstrual cycle, which include emotional lability, as well as adverse changes in volition, energy, concentration ability, and self-perception. Physiological disruptions in sleep and appetite are common (but are not necessary for diagnosis), as are somatoform discomforts and sensations. The disorder manifests in the week prior to the onset of menses, with increasing intensity that usually peaks immediately prior to the onset of menstruation, and then wanes quickly thereafter. There is notable clinical distress or interference with social, vocational, or personal relationships. Typically, 1 week after the onset of menstruation, there are minimal symptoms. The symptoms must have occurred in most (>50%) menstrual cycles during the past year, and must have an adverse effect on work or social functioning.

Phenomenology and Diagnostic Features

PMDD may occur any time after menarche and often changes as an individual ages. It is important to obtain a good assessment, initially by history, of symptoms related to cognitive, emotional, and physical distress associated with functional impairment or avoidance. A clinician may be able to provide a provisional diagnosis of PMDD based on history, but using rating scales of PMDD symptoms, in a provisional manner for at least two symptomatic cycles, is advised to confirm the diagnosis. The Premenstrual Tension Syndrome Rating Scales (Steiner et al. 2011) capture the clinical features in an objective self-rated manner.

At least one of the essential PMDD phenomenological features—which include mood lability, irritability, depressed mood, and anxiety (tension or feeling "keyed up")—must be present (Box 11-5). Additional symptoms often present are listed in criterion C; five symptoms from criteria B and C must be met for most (>50%) menstrual cycles in the past year. Typically, an anxious tension builds in a crescendo with irritability and apparent interpersonal conflict. Physical symptoms, which include bloating and general joint or soft tissue (including breast) discomfort, magnify daily and create a sense of being overwhelmed. Examples of disturbed functioning in home, work, and social life include conflict or challenges in performing roles. The critical diagnostic feature is the timing of the onset and dissipation of symptoms surrounding the menstrual cycle. Symptoms and signs wax with the impending menses and wane following the onset of menstruation. The symptoms are minimal or absent in the week postmenses.

Epidemiology

Prevalence

The 12-month prevalence of PMDD is between 1.8% and 5.8% (Gehlert et al. 2009; Wittchen et al. 2002). PMDD is not a culture-bound syndrome and has been observed in women in the United States, India, Europe, and Asia.

Course and Development

Although symptoms of PMDD often emerge in early adulthood, women often do not seek treatment until they are over age 30. Women often try oral birth control pills to modify hormonal variability; modify their diets; change their work, school, or social routines and commitments to align with their menses; and let their friends, family, and partners know when to expect mood lability and emotional dyscontrol. PMDD symptoms are often mitigated as a result of ovulatory changes, such as during pregnancy and after menopause.

Etiological Factors

The specific etiology for PMDD is not known. Reproductive hormones, genetics, serotonin, and endogenous opiates have been hypothesized as being involved. Proposed causes of PMDD include declining levels of ovarian steroid hormones in the late luteal phase of the menstrual cycle and a hormonal ratio imbalance related to high estrogen levels compared to progesterone levels. Lines of active inquiry include the roles of serotonergic and related transmitters, γ-aminobutyric acid (GABA), and growth factors such as brain-derived neurotrophic factor. Other endocrine equilibria, inflammatory factors, and genetic vulnerabilities may influence the expression of PMDD. Finally, psychological and social factors that destabilize the individual may contribute to the condition. A recent review of etiological factors provides additional discussion (Matsumoto et al. 2013). Psychological factors may also play an important role for some women regarding feelings of dyscontrol, poor coping, and feelings of anger and depression.

Differential Diagnosis

Colloquially, premenstrual syndrome (PMS) and premenstrual dysphoric disorder are often used as interchangeable terms. Although PMS and PMDD have similarities, they are different clinical problems and are not synonymous. PMS refers to subthreshold PMDD. The majority of menstruating women have symptoms of PMS but are not (by definition) impaired by this condition. Subthreshold criteria should be examined carefully to determine whether the individual is suffering from a specific mood, anxiety, or behavioral disorder. Symptoms of major depression and anxiety may become exacerbated during the menstrual period; any psychopathology may become more problematic during menses. The key determining features of PMDD are the progressive increase in severity of symptoms up to the onset of menses and the rapid waning of symptoms in the week following onset of menses. PMS will exacerbate existing illness, such as major depression; the menstrual period amplifies the experience of mood symptoms, and there is no rapid relief of symptoms within a week of menstruation onset. In PMDD, significant mood swings or change within this time period is primary and required for diagnosis.

Management

The management of PMDD includes a discussion of environmental and medical interventions. Lifestyle modifications that are encouraged and recommended include reductions in use of caffeine, salt, alcohol, and tobacco. In addition, regular physical activity, relaxation, and psychotherapy are integrated (Zukov et al. 2010).

An impressive pharmacological observation is the rapid response of PMDD to SSRIs. An SSRI antidepressant may be used in the week prior to the onset of menses or be taken on a regular basis. The relief of symptoms is usually immediate (within 24 hours). Additional considerations include contraception medication, diuretics, nutritional supplements, and pain-relieving medications (Yonkers et al. 2008).

Cognitive-behavioral treatments have been found to benefit PMDD symptoms, especially when cognitive, emotional, or physical changes occur on a predictable basis related to the menses (Steiner et al. 2006).

Treating co-occurring psychiatric or other medical conditions may improve the severity of the PMDD symptoms.

Prognosis

Due to the long-term nature of PMDD, it is important to stress a multidisciplinary approach to care (psychiatry, obstetrics-gynecology, endocrinology), lifestyle changes (diet, exercise) that may be necessary, and the need to monitor daily and monthly symptoms over a period of time. Systematic evaluation of therapeutic interventions with self-ratings of symptoms and response will guide the clinician and patient to an effective treatment strategy.

Substance/Medication-Induced Depressive Disorder

Substance/medication-induced depressive disorder (SMIDD) remains relatively unchanged from DSM-IV to DSM-5 (Box 11-6). Although the criteria are straightforward, the underlying relationship between the effects of psychotropic substances and depression are complex, intertwined, and reflective of the fact that depressed individuals often use substances and individuals with addiction problems become depressed. SMIDD is essentially MDD that is likely to be caused by the physiological effects of a chemical substance with psychotropic properties. Virtually all of the substances of abuse can cause depressive disorder symptoms (criterion A). In SMIDD, the symptoms begin soon (within 1 month) after use of a substance capable of inducing depression, as established by clinical (historical) or laboratory evidence of the substance use or dependence. Alternatively, SMIDD may begin in the context of substance withdrawal.

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

A primary condition may exist. For example, a depressed patient who drinks to alleviate symptoms would be clearly excluded based on the criteria. However, an alcohol-dependent person who becomes demoralized and overwhelmed by the effects of drinking may meet criteria for MDD for a significant portion of a 2-week period and might therefore be considered to have SMIDD. If the alcohol-dependent person is successfully withdrawn from alcohol and maintains sobriety for over 1 month but continues to have signs and symptoms of depression, the diagnosis would be major depressive disorder and not SMIDD.

Phenomenology

The phenomenology and diagnostic features of the depression are those of a depressive episode (see DSM-5 diagnostic criteria for MDD, presented in Box 11-3), and there are psychological and physical stigmata of substance abuse or dependence.

Epidemiology

Results from the National Epidemiologic Survey on Alcohol and Related Conditions suggested that the lifetime prevalence of SMIDD is 0.26%; co-occurring substance abuse and depression were most often comorbid in nature, rather than causal (Blanco et al. 2012). Rates of psychiatric disorder, including depression, are generally high in the population of substance abusers, a highly vulnerable group, who are seeking treatment.

Etiological Factors

The etiology of SMIDD is intrinsic in the nomenclature; it is the chemical substance or the withdrawal from the same that causes the major depressive episode. Depression has been clearly associated with the use of various substances (e.g., interferon or reserpine, which is widely quoted as a cause but is rarely seen clinically) and withdrawal from others (e.g., chemicals in the stimulant class). The general working rule for the clinician evaluating a depressed patient motivated to use non-medically prescribed substances is to carefully consider the possibility that the depression may be caused by the substance. DSM-5 stipulates that there must be evidence that the substance is capable of producing a depressive disorder. The capability of producing depression for the emerging synthetic substances that are abused is hypothetical, but most psychoactive substances that are abused are likely to have undesired long-term sequelae, including depressed mood. The presence of depressive episodes prior to the use of substances may indicate an independent depressive disorder, but the disorder is likely exacerbated by the substance use. Also, if the depressed mood remains after 1 month of abstinence, it should be considered independent of the substance.

Clinically indicated medications that may destabilize mood include steroids, interferon, β-blockers, and cytotoxic agents. Interferon is an ideal model for the study of SMIDD because of the relatively high frequency and predictable onset and course of SMIDD in individuals taking the agent. The temporal association of depression with the initiation of medical therapy is the most informative historical evidence in the etiological link between the agent and the depressive episode.

Differential Diagnosis

SMIDD is a broad category, and the causal substance driving the depressive episode is less critical than the observation of an association between the substance and the depression. DSM-5 stipulates that the substance must be capable of producing a depressive disorder. Although novel substances of abuse cannot yet be known to be capable of inducing SMIDD, their membership in the class of substances of abuse provides a compelling rationale for the possibility. The empirical test would be a month of abstinence from the suspected noxious chemical, and if the depression resolves, it is likely to have been caused by or associated with SMIDD. The depression is considered to be independent of the substance abuse if depression occurred prior to the onset of abuse or continues once abstinence is reliably achieved for at least 1 month. Also, the withdrawal of substances may precipitate a depression; in particular, the stimulant substances are notorious for contributing to a depressive crash after a period of heavy use and bingeing. The temporal relationship between use (starting and stopping) and the emergence of depression is the key. For some of the longer-acting benzodiazepines, however, the withdrawal syndrome may last beyond this time frame. Finally, major depression and substance abuse may be comorbid conditions, occurring together, with one exacerbating the other in what often appears to be a self-perpetuating cycle of deteriorating mood and substance abuse.

The substance or substances associated with the SMIDD are indicated by coding accordingly. The DSM-5 criteria for substance/medication-induced depressive disorder (see Box 11-6) provide codes for the following: alcohol; phencyclidine; other hallucinogen; inhalant; opioid; sedative, hypnotic, or anxiolytic; cocaine; and other (or unknown) substance.

Management

The care of a patient with SMIDD addresses the primary clinical problem of the substance abuse as indicated by the severity and nature of the condition and comorbid features. Debate over the years has centered on whether the depression should be treated concomitantly if a substance is clearly inducing the depression. By DSM-5 definition, depressive episodes will remit with the removal of the noxious substance; however, depending on the nature of symptoms associated with the depression, treatment may be clinically warranted. Treatment is clearly indicated when life-threatening conditions, suicidality, or inability to care for self is present.

Individuals taking clinically indicated medications (e.g., interferon, steroids) that are focused on a specific medical treatment and are known to cause depression should be monitored closely for emerging depression. As symptoms and signs of depression emerge and the clinician anticipates the need for ongoing treatment, aggressive treatment should be implemented and continued for at least 1 month following discontinuation of the causal substance.

Prognosis

The prognosis for SMIDD that is due to clinically indicated medications is generally good. Most patients taking interferon or steroids recover from an associated depression once the causal agent is no longer present. The prognosis (and diagnosis) is less clear when the purported causal substance has not been widely associated with SMIDD; for some substances, there may have been case reports in the world literature but no supportive systematic study showing significant effect that is replicated. An example of a medication widely associated with depression is propranolol. Concerns raised following a 'Tetter to the editor" (Kalayam and Shamoian 1982) triggered several case reports and established the "link" between propranolol and depression, yet subsequent meta-analyses have not supported this link (Ko et al. 2002). The average psychiatrist, however, is still likely to associate propranolol with depression.

The outcome and prognosis for SMIDD that is related to recreational substance abuse are dependent on the successful management of the substance abuse. In the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, SMIDD was associated with elevated severity measures and low rates of treatment (Blanco et al. 2012). Successful management of the abuse or addiction is a life-changing experience, and there is every expectation that the SMIDD will remit as well. However, depending on the substance, abuse over a lifetime may result in neurological damage and associated clinical phenomena (e.g., alcoholic dementia) that will adversely affect the prognosis according to the nature and severity of these phenomena.

Depressive Disorder Due to Another Medical Condition

A depressive disorder attributable to another medical condition is generally considered in the context of the medical disorder and its manifestations. The mere presence of chronic or debilitating physical illness is associated with an increased but variable risk of depression. The approach to this category of depression will be influenced by whether the clinician is approaching a patient with known medical disease (cancer, cardiovascular disease, or neurological disease) and evaluating whether MDD is present, or whether the patient is presenting with depressive symptoms and is in need of a comprehensive medical workup. All patients presenting with a new lifetime onset of depressive symptoms should be evaluated medically for physical illness, and a physical and laboratory assessment should be guided by the patient's primary care physician.

In individuals with certain medical conditions, clinical symptoms of depression and emotional instability develop in a relatively predictable manner. These conditions include neurological disorders such as Huntington's disease, Parkinson's disease, and stroke. Cancer and rheumatological, endocrine, and inflammatory disorders commonly cause considerable demoralization and depression. Cardiological disorders such as myocardial infarction frequently result in significant depressive symptoms postinfarction. DSM-5 stipulates that the episode of depression is the direct physiological effect of another medical condition (Box 11-7).

NOTICE. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.

In the patient who has been diagnosed with major depression in the past, it is unlikely that the current medical condition is the sole direct physiological cause of the depression, and the diagnosis of depressive disorder due to another medical condition is unwarranted. A new lifetime onset of an episode, however, in the context of a recent cancer or rheumatological, inflammatory, or endocrine disorder can be arguably attributed to the underlying medical condition.

The phenomenology of the depressive episodes is essentially that of classic episodes. Depressions caused by general medical conditions have no distinct mood features. It is critical to identify and treat these and all depressions, because the management of the underlying medical conditions is negatively affected by the presence of depression. The treatment of the depression involves management of the underlying medical disorder as well as the depression. The underlying medical condition, particularly a neurological disorder, may impede and slow the rate of improvement of the depression. Many endocrine disorders (e.g., thyroid, parathyroid, or adrenal disease) must be primarily managed before the psychiatric and mood instability can be adequately addressed.

The prognosis of depression due to another medical condition is related to that of the other medical condition. Chronic medical conditions will continue to stress the physiology and impede the depression treatment; terminal cancers likewise will compromise medical and psychological systems. Successful management of medical conditions will affect the outcome of depression favorably, especially when the medical disorder and depression are treated concurrently.

Other Specified or Unspecified Depressive Disorder

The diagnoses of other specified depressive disorder (Box 11-8) and unspecified depressive disorder (Box 11-9) are intended to be used for individuals who have symptoms of mood pathology but do not meet diagnostic criteria for a specific depressive disorder. In addition, the other specified or unspecified depressive disorder symptoms may not be attributable to the direct physiological effects of a substance or another medical condition. To avoid overuse of these diagnoses, the clinician should be critical and use these categories only for individuals whose symptoms cause significant distress or impairment that requires clinical care.

In DSM-IV-TR, the other specified and unspecified depressive disorders were in the category named "depressive disorder not otherwise specified (NOS)." Premenstrual dysphoric disorder (PMDD) was included in this category but PMDD has been moved into its own disorder category in DSM-5. Likewise, minor depressive disorder (which has a lower threshold than MDD) was a NOS entity in DSM-IV-TR but now falls within the "other specified depressive disorder" DSM-5 category and is termed short-duration depressive episode (4-13 days).

Frequently, individuals with such presentations are evaluated in a busy emergency room or primary care office, where clinicians are pressed for time. These individuals clearly need monitoring for emerging psychopathology, and the symptom measures and assessment schedules in DSM-5 Section III are an excellent approach to beginning the ongoing evaluation process.

Conclusion

Most of science and advances in knowledge are incremental and such is the case for DSM-5 and the category and subcategories of depressive disorders. The scientific observations of Leibenluft (2011) led to a significant shift in our understanding of dysregulated moods in youth and their outcomes, greater frequency of MDD in early adulthood, suggest the clinical diagnostic category disruptive mood dys-regulation disorder is currently best placed within the Depressive Disorders. The inclusion of premenstrual dysphoric disorder within depressive disorders recognizes the clinical research that emphasizes the dysphoric and depressive nature of the phenomenology that responds to antidepressant medication, albeit in different time frame and manner. It reflects the prevailing current understanding of the disorder and associated in this nosology. The criteria for major depressive disorder itself has changed little from the criteria set forth in DSM-III; this is because the current understanding of the disorder remains relatively constant and that there has been no compelling evidence scientific evidence to emend the criteria or the category. The philosophy of DSM-5 is to be adaptive, integrative, and informative—adapting the science to the understanding of psychiatric disease, integrating the understandings into a rational approach to categorizing disorders, and informing the community such that the DSM-5 and its derivatives represent the current clinical currency for exchanging and mediating ideas. Depressive disorders represent a category that will surely experience dynamic shifts in understandings and organization with emerging research and evolving editions of the DSM-5.

Key Clinical Points

• Depressive disorders are a complex class of affect disturbances involving volitional, emotional, cognitive, and psychological functioning. Assessment includes the dimensions of social, environmental, and biological elements.
• Disruptive mood dysregulation disorder is an illness of childhood with irritability and aggressive outbursts outside of the expected range of behavior for the developmental stage. It is associated with development of depressive (not bipolar) disorders in later years.
• Premenstrual dysphoric disorder shows many of the features of depression in the week prior to menses and dissipates within a week following menstruation onset. This disorder responds quickly to selective serotonin reuptake inhibitors (SSRIs).
• Major depressive disorder is a clinical diagnosis. It is a common, treatable, and frequently recurrent and chronic disorder that is often associated with other medical and psychiatric illnesses.
• Management of major depressive disorder may require the integration of psychological, social, and medical treatments. Medical management usually begins with an SSRI. If the patient has no minimal response within 3-5 weeks, the prudent course is to change or augment the current treatment plan as well as reevaluate the diagnosis.
• Concurrent medical and psychiatric disorders should be managed accordingly.

¹ In distinguishing grief from a major depressive episode (MDE), it is useful to consider that in grief the predominant affect is feelings of emptiness and loss, while in MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These waves tend to be associated with thoughts or reminders of the deceased. The depressed mood of MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of grief may be accompanied by positive emotions and humor that are uncharacteristic of the pervasive unhappiness and misery characteristic of MDE. The thought content associated with grief generally features a preoccupation with thoughts and memories of the deceased, rather than the self-critical or pessimistic ruminations seen in MDE. In grief, self-esteem is generally preserved, whereas in MDE feelings of worthlessness and self-loathing are common. If self-derogatory ideation is present in grief, it typically involves perceived failings vis-a-vis the deceased (e.g., not visiting frequently enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks about death and dying, such thoughts are generally focused on the deceased and possibly about "joining" the deceased, whereas in MDE such thoughts are focused on ending one's own life because of feeling worthless, undeserving of life, or unable to cope with the pain of depression.

References

Agarkar S, Hurt S, Lisanby S, et al: ECT use in unipolar and bipolar depression. J ECT 28:e39-e40, 2012

Akiskal HS: Dysthymia and cyclothymia in psychiatric practice a century after Kraepelin. J Affect Disord 62:17-31, 2001

Althoff RR, Verhulst FC, Rettew DC, et al: Adult outcomes of childhood dysregulation: a 14-year follow-up study. J Am Acad Child Adolesc Psychiatry 49:11 OS-1116, 2010

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric Association, 1987

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA, American Psychiatric Association, 2013

Bateman A, Brown D, Pedder J: Introduction to Psychotherapy: An Outline of Psychodynamic Principles and Practice. New York, Routledge, 2010

Beck JS: Cognitive Behavior Therapy: Basics and Beyond. New York, Guilford, 2011

Blanco C, Alegria AA, Liu SM, et al: Differences among major depressive disorder with and without co-occurring substance use disorders and substance-induced depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 73:865-873, 2012

Brotman MA, Schmajuk M, Rich BA, et al: Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children. Biol Psychiatry 60:991-997, 2006

Connor DF, Glatt SJ, Lopez ID, et al: Psychopharmacology and aggression, I: a metaanalysis of stimulant effects on overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry 41:253-261, 2002

Epperson CN, Steiner M, Hartlage SA, et al: Premenstrual dysphoric disorder: evidence for a new category for DSM-5. Am J Psychiatry 169:465-475, 2012

Gehlert S, Song IH, Chang CH, et al: The prevalence of premenstrual dysphoric disorder in a randomly selected group of urban and rural women. Psychol Med 39:129-136, 2009 18366818

Gilbert DA, Altshuler KZ, Rago WV, et al: Texas Medication Algorithm Project: definitions, rationale, and methods to develop medication algorithms. J Clin Psychiatry 59:345-351, 1998

Husain MM, Lisanby SH: Repetitive trans-cranial magnetic stimulation (rTMS): a noninvasive neuromodulation probe and intervention. J ECT 27:2, 2011

Jucksch V, Salbach-Andrae H, Lenz K, et al: Severe affective and behavioural dys-regulation is associated with significant psychosocial adversity and impairment. J Child Psychol Psychiatry 52:686-695, 2011

Kalayam B, Shamoian CA: Propranolol, psychoneuroendocrine changes, and depression. Am J Psychiatry 139:1374-1375, 1982

Kanai T, Takeuchi H, Furukawa TA, et al: Time to recurrence after recovery from major depressive episodes and its predictors. Psychol Med 33:839-845, 2003

Kendler KS, Neale MC, Kessler RC, et al: A longitudinal twin study of 1-year prevalence of major depression in women. Arch Gen Psychiatry 50:843-852, 1993

Kendrick T, Peveler R: Guidelines for the management of depression: NICE work? Br J Psychiatry 197:345-347, 2010

Kessler RC, Zhao S, Blazer DG, et al: Prevalence, correlates, and course of minor depression and major depression in the National Comorbidity Survey. J Affect Disord 45:19-30, 1997

Kessler RC, Berglund P, Dernier O, et al: The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095-3105, 2003

Kessler RC, Chiu WT, Dernier O, et al: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:617-627, 2005

Ko DT, Hebert PR, Coffey CS, et al: Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 288:351-357, 2002

Kroenke K, Spitzer RL, Williams JB: The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 16:606-613, 2001

Leibenluft E: Severe mood dysregulation, irritability, and the diagnostic boundaries of bipolar disorder in youths. Am J Psychiatry 168:129-142, 2011

Leibenluft E, Charney DS, Towbin KE, et al: Defining clinical phenotypes of juvenile mania. Am J Psychiatry 160:430-437, 2003

Leibenluft E, Cohen P, Gorrindo T, et al: Chronic versus episodic irritability in youth: a community-based, longitudinal study of clinical and diagnostic associations. J Child Adolescent Psychopharmacol 16:456-466, 2006

Matsumoto T, Asakura H, Hayashi T: Bio-psychosocial aspects of premenstrual syndrome and premenstrual dysphoric disorder. Gynecol Endocrinol 29:67-73, 2013

McHugh PR, Slavney PR: The Perspectives of Psychiatry. Baltimore, MD, Johns Hopkins University Press, 1998

Mclnnis MG: Paradigms lost: rethinking psychiatry in the postgenome era. Depress Anxiety 26:303-306, 2009

McIntyre RS, Rosenbluth M, Ramasubbu R, et al: Managing medical and psychiatric comorbidity in individuals with major depressive disorder and bipolar disorder. Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. Ann Clin Psychiatry 24:163-169, 2012

Mueller TI, Leon AC, Keller MB, et al: Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry 156:1000-1006, 1999

National Collaborating Centre for Mental Health: Depression: The Treatment and Management of Depression in Adults. London, National Institute for Health and Clinical Excellence, 2009. Available at: http://guideline.gov/content.aspx?id=15521. Accessed February 26, 2013.

Robins LN, Regier DA (eds): Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, Free Press, 1991

Roth A, Fonagy P: What Works for Whom? A Critical Review of Psychotherapy Research, 2nd Edition. New York, Guilford, 2005

Rush AJ, Fava M, Wisniewski SR, et al: Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials 25:119-142, 2004

Slavney PR: Psychotherapy: An Introduction for Psychiatry Residents and Other Mental Health Trainees. Baltimore, MD, Johns Hopkins University Press, 2005

Steiner M, Pearlstein T, Cohen LS, et al: Expert guidelines for the treatment of severe PMS, PMDD, and comorbidities: the role of SSRIs. J Womens Health 15:57-69, 2006

Steiner M, Peer M, Macdougall M, et al: The premenstrual tension syndrome rating scales: an updated version. J Affect Disord 135:82-88, 2011

Stringaris A, Cohen P, Pine DS, et al: Adult outcomes of youth irritability: a 20-year prospective community-based study. Am J Psychiatry 166:1048-1054, 2009

Stringaris A, Baroni A, Haimm C, et al: Pediatric bipolar disorder versus severe mood dysregulation: risk for manic episodes on follow-up. J Am Acad Child Adolesc Psychiatry 49:397-405, 2010

Sueha B, Argo TR, Bendele SD, et al: Texas Medication Algorithm Project Procedural Manual: Major Depressive Disorder Algorithms. Austin, Texas Department of State Health Services, 2008. Available at: http://www.pbhcare.org/pubdocs/upload/documents/TMAP%20Depression%202010.pdf. Accessed February 27, 2013.

Sullivan PF, Neale MC, Kendler KS: Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552-1562, 2000

Trivedi MH, Rush AJ, Ibrahim HM, et al: The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med 34:73-82, 2004

Weissman MM, Markowitz JC, Klerman G: Comprehensive Guide to Interpersonal Psychotherapy. New York, Basic Books, 2000

Wittchen HU, Becker E, Lieb R, et al: Prevalence, incidence and stability of premenstrual dysphoric disorder in the community. Psychol Med 32:119-132, 2002

Yonkers KA, O'Brien PM, Eriksson E: Premenstrual syndrome. Lancet 371:1200-1210, 2008

Zukov I, Ptacek R, Raboch J, et al: Premenstrual dysphoric disorder: review of actual findings about mental disorders related to menstrual cycle and possibilities of their therapy. Prague Med Rep 111:12-24, 2010

Suggested Readings

Greden JF, Riba MB, Mclnnis MG (eds): Treatment-Resistant Depression: A Roadmap for Effective Care. Washington, DC, American Psychiatric Publishing, 2011

Styron W: Darkness Visible: A Memoir of Madness. New York, Random House, 1990

Online Resources

American Psychiatric Association: DSM-5 Online Assessment Instruments: http://www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures

Depression and Bipolar Support Alliance: www.dbsalliance.org

National Institute of Mental Health: Depression: www.nimh.nih.gov/health/topics/depression/index.shtml

National Network of Depression Centers (provides links to 21 academic centers): http://nndc.org