Depressive Disorders PDF

7 1215-1283 Depressive Disorders THE CLINICAL PRESENTATION A depressed mood and a loss of interest or pleasure are the key symptoms of depression. Patients may say that they feel blue, hopeless, in the dumps, or worthless. For a patient, the depress...

7 1215-1283 Depressive Disorders THE CLINICAL PRESENTATION A depressed mood and a loss of interest or pleasure are the key symptoms of depression. Patients may say that they feel blue, hopeless, in the dumps, or worthless. For a patient, the depressed mood often has a distinct quality that differentiates it from the normal emotion of sadness or grief. Patients often describe the symptom of depression as one of agonizing emotional pain. Alternately they perceive it as a physical illness in which they feel exhausted and unmotivated. Others report feeling little, being unable to cry, and finding it difficult to experience any pleasure. The classic presentation of a depressed patient is a person with a stooped posture, decreased movement, and a downward averted gaze. In practice, there is a considerable range of behaviors ranging from persons with no observable symptoms to the catatonically depressed patient. Among observable signs of depression, generalized psychomotor retardation is the most often described, in which patients show little spontaneous movement. At times it may be so severe as to be challenging to differentiate from catatonia. Ms. A, a 34-year-old literature professor, presented to a mood clinic with the following complaint: “I am in a daze, confused, disoriented, staring. My thoughts do not flow, my mind is arrested.… I seem to lack any sense of direction, purpose.… I have such an inertia, I cannot assert myself. I cannot fight; I have no will.”  Psychomotor agitation may occur, including such behaviors as hand wringing and hair pulling. Many depressed patients have a decreased rate and volume of speech; they respond to questions with single words and exhibit delayed responses to questions. When present, observable symptoms are helpful in the diagnosis; however, the lack of such symptoms does not imply that a patient has no disorder. It is not abnormal, for example, to encounter patients who can maintain a measure of social appropriateness, even smiling and laughing when with others, despite feeling internally miserable. The most typical somatic symptoms of depression are called the neurovegetative symptoms of depression and typically include a variety of physical symptoms. Table 7-1 lists typical neurovegetative symptoms. Almost all depressed patients (97 percent) complain about reduced energy; they have difficulty finishing tasks, are impaired at school and work, and have less motivation to undertake new projects. About 80 percent of patients complain of trouble sleeping, especially early morning awakening (i.e., terminal insomnia) and multiple awakenings at night, during which they ruminate about their problems. Many patients have decreased appetite and weight loss, but others experience increased appetite and weight gain and sleep longer than usual. These are sometimes called reversed neurovegetative symptoms or atypical features. Depression is, by definition, a mood disorder, and disturbances of mood are at the core. Patients feel “bad” and may use words such as “sad,” “depressed,” “blue,” “down,” or similar words to describe this feeling. Here we use the term dysphoria to encompass these various depressive feelings as a way to avoid the confusion inherent in using the word “depressed” to mean both the diagnosis and the core symptom. Also, many patients are reluctant to use the word “depressed” as they may have difficulty coming to terms with their diagnosis. In such cases, other synonyms, including those above, may seem less threatening to the patient. Some patients deny dysphoria altogether, but instead, describe feeling unable to enjoy things that are usually enjoyable to them. We call this anhedonia or a lack of pleasure. In addition to dysphoria and anhedonia, many depressed patients also report feeling anxious. The critical point is that although sadness and even depression may be, in themselves, normal reactions, when encountered in the context of a depressive disorder, patients do not experience them as normal. Patients will often feel genuinely ill and be able to distinguish their emotional state from “normal” feelings of sadness. Many will first interpret this as indicative of medical illness and present to their primary care doctor complaining of feeling “sick” rather than depressed. Depressed patients customarily have negative views of the world and themselves. Their thought content often includes nondelusional ruminations about loss, guilt, suicide, and death. About 10 percent of all depressed patients have marked symptoms of a thought disorder, usually thought blocking and profound poverty of content. A 42-year-old civil servant said that she was so paralyzed by depression that she felt that she had no personal initiative and volition left; she believed that some malignant force had taken over her actions and that it was commenting on every action that she was undertaking. The patient recovered fully with thymoleptic medication. There is no reason to believe that, in this patient, the feelings of somatic passability and running commentary indicated a schizophrenic process. Depressed patients may complain of either delusions or hallucinations associated with their depressive episode: such patients may have a major depressive episode with psychotic features, often called psychotic depression. Delusions and hallucinations that are consistent with a depressed mood are said to be mood-congruent. Mood-congruent delusions in a depressed person include those of guilt, sinfulness, worthlessness, poverty, failure, persecution, and terminal somatic illnesses (such as cancer and a “rotting” brain). The content of mood-incongruent delusions or hallucinations is not consistent with a depressed mood. For example, a mood-incongruent delusion in a depressed person might involve grandiose themes of exaggerated power, knowledge, and worth. Table 7-1 Neurovegetative Symptoms of Depression Common:  Fatigue, low energy Inattention Insomnia, early morning awakening Poor appetite, associated weight loss Sometimes included: Decreased libido and sexual performance Menstrual irregularities Worse depression in the AM About two-thirds of all depressed patients contemplate suicide, and 10 to 15 percent commit suicide. Those recently hospitalized with a suicide attempt or suicidal ideation have a higher lifetime risk of successful suicide than those never hospitalized for suicidal ideation. Depressed patients with psychotic features occasionally consider killing a person as a result of their delusional systems, but the most severely depressed patients often lack the motivation or the energy to act impulsively or violently. Patients with depressive disorders are at increased risk of suicide as they begin to improve and regain the energy needed to plan and carry out suicide (paradoxical suicide). About 50 to 75 percent of all depressed patients have some measure of cognitive impairment. Cognitive symptoms include subjective reports of an inability to concentrate (84 percent of patients in one study) and impairments in thinking (67 percent of patients in another study). Most depressed patients are oriented, although some may not have sufficient energy or interest to answer questions about these subjects during an interview. Memory can be challenging to disentangle from concentration difficulties. However, some patients appear to have genuine memory difficulties in addition to other cognitive deficits. Some depressed patients sometimes seem unaware of their depression and do not complain of a mood disturbance even though they exhibit withdrawal from family, friends, and activities that previously interested them. Other depressed patients, particularly those with disordered thoughts, may be overly negative, hyperbolic in their symptomatic description, and hopeless about their future. It may be difficult to convince such patients that improvement is possible. We can assess judgment by reviewing patients’ actions in the recent past and their behavior during the interview. Patients with particularly negative outlooks should be cautioned not to make important life decisions (e.g., around a relationship or job) until they are “thinking normally” again. In interviews and conversations, depressed patients may emphasize the bad and minimize the good. They may be pessimistic about past treatment trials. A common clinical mistake is to unquestioningly believe a depressed patient who states that a previous trial of antidepressant medications did not work. Such statements may be false, and they require a confirmation from another source. Psychiatrists should not view patients’ misinformation as an intentional fabrication; the admission of any hopeful information may be impossible for a person in a depressed state of mind. Other patients, particularly those with poor insight, may have difficulty reporting symptoms or past episodes. Asking about changes in functioning rather than emotional states may be helpful (“have there been times that you felt unable to work, or care for your children?”). Presentation in Special Populations Depression in Children and Adolescents. School phobia and excessive clinging to parents may be symptoms of depression in children. Poor academic performance, substance abuse, antisocial behavior, sexual promiscuity, truancy, and running away may be symptoms of depression in adolescents. Depression in Older People. Depression is more common in older persons than it is in the general population. Various studies have reported prevalence rates ranging from 25 to almost 50 percent, although the percentage of these cases that are caused by major depressive disorder is uncertain. Several studies indicate that depression in older persons correlates with low socioeconomic status, the loss of a spouse, a concurrent physical illness, and social isolation. Other studies have indicated that depression in older persons is underdiagnosed and undertreated, perhaps particularly by general practitioners. The underrecognition of depression in older persons may occur because the disorder appears more often with somatic complaints in older than in younger, age groups. Further, ageism may influence and cause clinicians to accept depressive symptoms as usual in older patients. DIAGNOSIS Depressive disorders can take many forms, depending on their severity and chronicity. The disorder that we most associate with “classic” depression is major depressive disorder, and this is the disorder most often referred to when someone reports that they suffer from depression. However, it is essential to understand the different varieties of depressive disorders, including those not included in some formal classifications, as all are significant sources of morbidity. Major Depressive Disorder The primary feature of major depressive disorder is the occurrence of at least one episode of major depression, which is significant depressive symptoms that last for a significant time. Table 7-2 compares the different approaches to diagnosing major depressive disorder. With Psychotic Features. The presence of psychotic features in major depressive disorder reflects severe disease and is a poor prognostic indicator. We often categorize psychotic symptoms as either mood-congruent, that is, in harmony with the mood disorder (“I deserve punishment because I am so bad”), or mood-incongruent, not in harmony with the mood disorder. Patients with mood-incongruent psychotic symptoms may be more likely to have a comorbid primary psychotic disorder, such as schizoaffective disorder or schizophrenia. With Melancholic Features. Melancholia is one of the oldest terms used in psychiatry, dating back to Hippocrates in the 4th century to describe the dark mood of depression. We still use it to refer to a depression characterized by severe anhedonia, early morning awakening, weight loss, and profound feelings of guilt (often over trivial events). It is not uncommon for patients who are melancholic to have suicidal ideation. Melancholia is associated with changes in the autonomic nervous system and endocrine functions. For that reason, we sometimes refer to melancholia as “endogenous depression” or depression that arises in the absence of external life stressors or precipitants. Table 7-2 Major Depressive Disorder DSM-5 ICD-10 Diagnostic name Major Depressive Major Depressive Disorder Episode Duration 2 wk Symptoms Dysphoria or feeling ↓ mood depressed ↓ energy Anhedonia ↓ activity ↑ or ↓ weight or ↓ capacity for appetite enjoyment ↑ or ↓ sleep ↓ interest ↑ or ↓ activity ↓ concentration ↓ energy Fatigue after even Depressing thoughts: minimal effort worthlessness, guilt Disturbed sleep/early ↓ concentration morning awakening Suicidal ideation/plan Disturbed appetite/ ↓ weight ↓ self esteem ↓ self-confidence Guilt or worthlessness Mood unreactive to circumstances Anhedonia Worse symptoms in the AM Psychomotor disturbance: agitation or retardation  ↓ libido Required number 5 (1 has to be one of of symptoms the first two listed) Psychosocial Distress or impaired Depends on severity consequences functioning (social, of symptoms occupational, or other significant areas) Exclusions (Not Medical illness Adjustment disorder better Substance Conduct disorder explained by): Other psychiatric Recurrent depressive disorder disorder (which is History of mania or considered a hypomania separate diagnosis) Symptom With anxious distress Depressive reaction specifiers 2+ symptoms of Psychogenic depression anxiety Reactive depression With mixed features 3+ manic/hypomanic symptoms during the depressive episode (if occur independently, diagnose bipolar disorder) With melancholic features Loss of pleasure or reactivity to pleasure 3+ of the following Severe depression/despair Mood worse in AM  Early morning awakening Psychomotor disturbance Anorexia/weight loss Guilt With atypical features Mood reactivity 2+ of following Increased appetite/weight Hyposomnia Leaden paralysis Rejection sensitivity With mood-congruent psychotic features With mood- incongruent psychotic features With catatonia Must be present during most of depressive episode With peripartum onset With seasonal pattern Usually occurs during a specific season Course specifiers With psychotic Recurrent Depressive features Disorder (Coded as Psychotic symptoms separate disorder): occurring only during Repeated episodes of the depressive the above symptoms.  episode No mania. Mood-congruent Mood-incongruent In partial remission Full criteria no longer met In full remission 0 symptoms for 2 mo Severity Mild: minimal Mild specifiers symptoms 2–3 symptoms Moderate: between Functions normal mild and severe despite distress Severe: # of symptoms Moderate and 4+ symptoms severity/dysfunction Difficulty with well beyond that functioning required for Severe diagnosis Several symptoms marked and distressing Loss of self- esteem/feels worthless and guilty Suicidal ideation/acts Somatic symptoms of depression Severe with psychotic symptoms As above but with psychosis Other Atypical depression  Single episodes of “masked depression” Unspecified With Atypical Features. Patients with major depressive disorder with atypical features have specific, predictable characteristics. As described above, these tend to be the reverse of the neurovegetative symptoms. They may, for example, overeat or oversleep. Patients with atypical features have a younger age of onset and more severe psychomotor slowing. They also are more likely to have comorbid disorders, including anxiety disorders, substance use disorder, or somatic symptom disorder. They are easy to misdiagnose as having an anxiety disorder rather than a mood disorder. Patients with atypical features may also have a long-term course, a diagnosis of bipolar I disorder, or a seasonal pattern to their disorder. Kevin, a 15-year-old adolescent, was referred to a sleep center to rule out narcolepsy. His main complaints were fatigue, boredom, and a need to sleep all the time. Although he had always started the day somewhat slowly, he now could not get out of bed to go to school. That alarmed his mother, prompting sleep consultation. Formerly a B student, he had been failing most of his courses in the 6 months before referral. Psychological counseling, predicated on the premise that his family’s recent move from another city had led to Kevin’s isolation, had not been beneficial. Extensive neurologic and general medical workup findings had also proven negative. He slept 12 to 15 hours per day but denied cataplexy, sleep paralysis, and hypnagogic hallucinations. During psychiatric interview, he denied being depressed but admitted that he had lost interest in everything except his dog. He had no drive, participated in no activities, and had gained 30 lb in 6 months. He believed that he was “brain damaged” and wondered whether it was worth living like that. The question of suicide disturbed him because it was contrary to his religious beliefs. These findings led to the prescription of an antidepressant. Not only did the antidepressant reverse the presenting complaints, but it also pushed him to the brink of a manic episode. (Courtesy of HS Akiskal, M.D.) With Catatonic Features. As a symptom, catatonia can be present in several mental disorders, most commonly, schizophrenia and mood disorders. The hallmark symptoms of catatonia are stupor, blunted affect, extreme withdrawal, negativism, and marked psychomotor retardation. The presence of catatonic features in patients with mood disorders may have prognostic and treatment significance. Postpartum Onset. We diagnose the postpartum subtype if the onset of symptoms is within 4 weeks postpartum. Postpartum mental disorders commonly include psychotic symptoms. Seasonal Pattern. Patients with a seasonal pattern to their mood disorders tend to experience depressive episodes during a particular season, most commonly winter. The pattern has become known as seasonal affective disorder (SAD), although DSM-5 does not use this term. There is some controversy regarding whether this represents a subtype of major depressive disorder or a distinct entity. Either way, the presence of the disorder has implications for treatment, as patients with a seasonal pattern to their depression may preferentially respond to light therapy. Dysthymic Disorder Dysthymic disorder (also called dysthymia) is the presence of depressive symptoms that are less severe than those of major depressive disorder. Although less severe than a major depressive disorder, it is often more chronic. Table 7-3 compares the different approaches to diagnosing. The most typical feature of dysthymia, also known as persistent depressive disorder, is the presence of a depressed mood that lasts most of the day and is present almost continuously. There are associated feelings of inadequacy, guilt, irritability, and anger; withdrawal from society; loss of interest; and inactivity and lack of productivity. The term dysthymia, which means “ill- humored,” was introduced in 1980. Before that time, we tended to classify patients having dysthymia as having “neurotic depression.” Dysthymia is distinguished from major depressive disorder by the fact that patients complain that they have always been depressed. Thus, most cases are of early-onset, beginning in childhood or adolescence, and, almost always, by a patient’s 20s. Table 7-3 Dysthymic Disorder DSM-5 ICD-10 Diagnostic name Persistent Depressive Dysthymia [F43.1] Disorder Duration 2+ yr (1+ yr for children) ≤2-mo symptom free during illness Symptoms Depressed mood most of Chronically depressed the time mood that does not ↓ appetite meet criteria for a ↓ or ↑ sleep depressive ↓ energy episode, though ↓ self-esteem criteria may have ↓ concentration/decision- been met in the making ability past Hopelessness Required number First symptom and 2+ of of symptoms rest Psychosocial Distress and functional consequences impairment of symptoms Exclusions History of bipolar disorder Anxiety Another mental illness Depression Substance Bereavement Another medical illness Schizophrenia Symptom With pure dysthymic specifiers syndrome: criteria for depressive episode not met in the last 2 yr With persistent major depressive episode: has met diagnostic criteria for a depressive episode for entire 2-yr period With intermittent major depressive episode, with current episode: in current episode, 8 wk+ in last 2 yr with subdiagnostic symptoms episode With intermittent major depressive episode, without current episode: Not currently in episode, 1+ depressive episode in past 2 yr With anxious distress ≥2 of following: Feeling tense Restlessness ↓ concentration due to worrying ↑ fear without apparent cause Fear of loss of control With mixed features —depressive or manic/hypomanic  episode, + with additional symptoms of other episode but subdiagnostic With melancholic features: see Table 7- 2 With atypical features: see Table 7-2 With psychotic features Mood-congruent Mood-incongruent Course specifiers With peripartum onset— episode is during pregnancy or ≤4 wk after delivery Severity Mild: minimal symptoms specifiers Moderate: between mild and severe Severe: # of symptoms and severity/dysfunction well beyond that required for diagnosis A 27-year-old male grade-school teacher presented with the chief complaint that life was a painful duty that had always lacked luster for him. He said that he felt “enveloped by a sense of gloom” that was nearly always with him. Although he was respected by his peers, he felt “like a grotesque failure, a self-concept I have had since childhood.” He stated that he merely performed his responsibilities as a teacher and that he had never derived any pleasure from anything he had done in life. He said that he had never had any romantic feelings; sexual activity, in which he  had engaged with two different women, had involved pleasureless orgasm. He said that he felt empty, going through life without any sense of direction, ambition, or passion, a realization that itself was tormenting. He had bought a pistol to put an end to what he called his “useless existence” but did not carry out suicide, believing that it would hurt his students and the small community in which he lived. (Courtesy of HS Akiskal, M.D.) A late-onset subtype, much less prevalent and not well characterized clinically, has been identified among middle-aged and geriatric populations, mainly through epidemiologic studies in the community. The family history of patients with dysthymia is typically replete with both depressive and bipolar disorders, which is one of the more robust findings supporting its link to primary mood disorder. Other Diagnoses Minor Depressive Disorder. Minor depressive disorder consists of episodes of depressive symptoms that are less severe than those seen in major depressive disorder. The difference between dysthymia and minor depressive disorder is primarily the episodic nature of the symptoms in the latter. Between episodes, patients with minor depressive disorder have a euthymic mood, but patients with dysthymia have virtually no euthymic periods. DSM- 5 does not include this diagnosis. However, ICD-10 includes it as a mild type of depressive episode. DSM-5 would diagnose it as an “Other Specified Depressive Disorder.” Recurrent Brief Depressive Disorder. Recurrent brief depressive disorder consists of brief periods (less than 2 weeks) during which depressive episodes are present. Patients with the disorder would meet the diagnostic criteria for a major depressive disorder if their episodes lasted longer. Patients with recurrent brief depressive disorder differ from patients with dysthymia on two counts: they have an episodic disorder, and their symptoms are more severe. ICD-10 lists this as an “Other Recurrent Mood Disorder,” whereas DSM-5 would diagnose it as an “Other Specified Depressive Disorder.” Double Depression. An estimated 40 percent of patients with major depressive disorder also meet the criteria for dysthymia, a combination often referred to as a double depression. Available data support the conclusion that patients with double depression have poorer prognoses than patients with major depressive disorder alone. The treatment of patients with double depression should be directed toward both disorders because the resolution of the symptoms of major depressive episode still leaves these patients with significant psychiatric impairment. Objective Rating Scales for Depression There is a growing literature suggesting that the use of objective scales can significantly improve the reliability of depressive diagnoses. They can also be useful for tracking the course of an episode. Several validated scales exist. Clinician Administered Scales. The Hamilton Rating Scale for Depression (HAM-D) is a widely used depression scale. It contains up to 24 items, each rated on a 0 to 4 or 0 to 2 scale. The clinician evaluates the patient’s answers to questions about feelings of guilt, thoughts of suicide, sleep habits, and other symptoms of depression, and derives the ratings from that interview. The usual scoring cutoffs are 10 to 13 for mild depression, 14 to 17 for mild-to-moderate depression, and >17 for moderate-to-severe depression. Self-Administered Scales. The Zung Self-Rating Depression Scale is a 20-item report scale. A normal range is 34 or less; a depressed score is 50 or more. The scale provides a global index of the intensity of a patient’s depressive symptoms, including the affective expression of depression. The Raskin Depression Scale is a clinician-rated scale that measures the severity of a patient’s depression, as reported by the patient and as observed by the physician, on a 5-point scale of three dimensions: verbal report, displayed behavior, and secondary symptoms. The scale has a range of 3 to 13; a normal score is 3, and a depressed score is 7 or more. DIFFERENTIAL DIAGNOSIS The symptoms of depressive disorders commonly overlap with other syndromes and disorders. As a result, the differential is wide. Often a careful history and examination will make the differential clear. In other cases, one may have to observe the disorder over time before the diagnosis becomes clear. General Medical Disorders It is essential to consider whether a patient’s depression is due to a general medical condition. Failure to obtain a good clinical history or to consider the context of a patient’s current life situation can lead to diagnostic errors. Clinicians should have depressed adolescents tested for mononucleosis, and we should test patients who are markedly overweight or underweight for adrenal and thyroid dysfunctions. We should test patients with appropriate risk factors for HIV, and older patients for viral pneumonia and other medical conditions. Table 7-4 lists some pharmacologic and medical conditions that can cause depression. Table 7-4 Pharmacologic Factors and Physical Diseases Associated with Onset of Depression Pharmacologic Steroidal contraceptives Reserpine, methyldopa Anticholinesterase insecticides Amphetamine or cocaine withdrawal Alcohol or sedative–hypnotic withdrawal Cimetidine, indomethacin Phenothiazine antipsychotic drugs Thallium, mercury Cycloserine Vincristine, vinblastine Interferon Endocrine–metabolica Hypothyroidism and hyperthyroidism Hyperparathyroidism Hypopituitarism Addison disease Cushing syndrome Diabetes mellitus Infectious General paresis (tertiary syphilis) Toxoplasmosis Influenza, viral pneumonia Viral hepatitis Infectious mononucleosis Acquired immune deficiency syndrome Collagen Rheumatoid arthritis Lupus erythematosus Nutritional Pellagra Pernicious anemia Neurologic Multiple sclerosis Parkinson disease Head trauma Complex partial seizures Sleep apnea Cerebral tumors Cerebrovascular infarction (and disease) Neoplastic  Abdominal malignancies Disseminated carcinomatosis aCholesterol is not mentioned because low levels as a factor in depression have been inconsistently reported. Many neurologic and medical disorders and pharmacologic agents can produce symptoms of depression. Patients with depressive disorders often first visit their general practitioners with somatic complaints. We can detect most medical causes of depressive disorders with a comprehensive medical history, a complete physical and neurologic examination, and routine blood and urine tests. The workup should include tests for thyroid and adrenal functions because disorders of both of these endocrine systems can appear as depressive disorders. In substance-induced mood disorder, a reasonable rule of thumb is that any drug a depressed patient is taking should be considered a potential factor in the mood disorder. Cardiac drugs, antihypertensives, sedatives, hypnotics, antipsychotics, antiepileptics, antiparkinsonian drugs, analgesics, antibacterials, and antineoplastics are all commonly associated with depressive symptoms. Neurologic Conditions The most common neurologic problems that manifest depressive symptoms are Parkinson disease, dementing illnesses, epilepsy, cerebrovascular diseases, and tumors. About 50 to 75 percent of all patients with Parkinson disease have marked symptoms of depressive disorder that do not correlate with the patient’s physical disability, age, or duration of illness but do correlate with the presence of abnormalities found on neuropsychological tests. The motor symptoms of Parkinson disease can mask a depressive disorder as the motor symptoms are similar. Depressive symptoms often respond to antidepressant drugs or ECT. The interictal changes associated with temporal lobe epilepsy can mimic a depressive disorder, especially if the epileptic focus is on the right side. Depression is a frequent complicating feature of cerebrovascular diseases, particularly in the 2 years after the episode. Depression is more common in anterior brain lesions than in posterior brain lesions and, in both cases, often responds to antidepressant medications. Tumors of the diencephalic and temporal regions are particularly likely to be associated with depressive disorder symptoms. Dementia. Major depressive disorder can have a profound effect on concentration and even memory, and can occasionally be confused with a neurodegenerative illness such as Alzheimer disorder. At times the term “pseudodementia” has been used to describe this. However, that may be ill- advised as it implies that the cognitive symptoms are not genuine, which is not the case. Clinicians can usually differentiate cognitive symptoms of a major depressive disorder from the dementia of a disease, such as dementia of the Alzheimer type, on clinical grounds. The cognitive symptoms in major depressive disorder have a sudden onset, and other symptoms of the disorder, such as self-reproach, are also present. A diurnal variation in the cognitive problems, not seen in primary dementias, may occur. Whereas depressed patients with cognitive difficulties often do not try to answer questions, patients with dementia may confabulate. During an interview, depressed patients can sometimes be coached and encouraged into remembering, an ability that demented patients lack. Other Mental Disorders Depression can be a feature of virtually any mental disorder. Other Mood Disorders. Clinicians must consider a range of diagnostic categories before arriving at a final diagnosis. We should determine whether a patient has had episodes of mania-like symptoms, which might indicate any one of the bipolar disorders. The depressive episode of a bipolar disorder may be identical to that of a major depressive disorder. However, there may be certain features that are more predictive of a bipolar disorder, and we list these in Table 7-5. Table 7-5 Features of a Depressive Episode that Are More Predictive of Bipolar Disorder Early age at onset Psychotic depression before 25 yr of age Postpartum depression, especially one with psychotic features Rapid onset and offset of depressive episodes of short duration (less than 3 mo) Recurrent depression (more than five episodes) Depression with marked psychomotor retardation Atypical features (reverse vegetative signs) Seasonality Bipolar family history High-density three-generation pedigrees Trait mood lability (cyclothymia) Hyperthymic temperament Hypomania associated with antidepressants Repeated (at least three times) loss of efficacy of antidepressants after initial response Depressive mixed state (with psychomotor excitement, irritable hostility, racing thoughts, and sexual arousal during major depression) From Akiskal. Mood disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 10th ed. Philadelphia, PA: Wolters Kluwer; 2017. If a patient’s symptoms are solely depressive, the patient most likely has a depressive disorder. Even then, we must differentiate between the various depressive disorders discussed in this chapter. To do this, we must understand the severity and the course of the disorder in detail. Other Mental Disorders. Substance-related disorders, psychotic disorders (Table 7-6), eating disorders, adjustment disorders, and somatoform disorders are all commonly associated with depressive symptoms and should be considered in the differential diagnosis of a patient with depressive symptoms.  Perhaps the most challenging differential is that between anxiety disorders with depression and depressive disorders with marked anxiety. Table 7-7 compares the unique features of depression with those of anxiety. Table 7-6 Common Causes of Misdiagnosis of Mood Disorder as Schizophrenia Reliance on cross-sectional rather than longitudinal picture Incomplete interepisodic recovery equated with schizophrenic defect Equation of bizarreness with schizophrenic thought disorder Ascribing irritable and cantankerous mood to paranoid delusions Mistaking depressive anhedonia and depersonalization for schizophrenic emotional blunting Flight of ideas perceived as loose associations Lack of familiarity with the phenomenologic approach in assessing affective delusions and hallucinations Heavy weight given to incidental Schneiderian symptoms Adapted from Akiskal HS, Puzantian VR. Psychotic forms of depression and mania. Psychiatr Clin North Am. 1979;2:419. Table 7-7 Unique Cross-Sectional Profiles of Clinical Anxiety and Depression Anxiety Depression Hypervigilance Psychomotor retardation Severe tension and panic Severe sadness Perceived danger Perceived loss Phobic avoidance Loss of interest—anhedonia Doubt and uncertainty Hopelessness—suicidal Insecurity Self-deprecation Performance anxiety Loss of libido Early-morning awakening Weight loss Reprinted with permission from Akiskal HS. Toward a clinical understanding of the relationship of anxiety and depressive disorders. In: Maser JP, Cloninger CR, eds. Comorbidity of Mood and Anxiety Disorders. Washington, DC: American Psychiatric Press; 1990. Uncomplicated Bereavement. Uncomplicated bereavement is not a mental disorder even though about one-third of all bereaved spouses for a time meet the diagnostic criteria for major depressive disorder. Some patients with uncomplicated bereavement do develop a major depressive disorder, but we do not make this diagnosis unless the grief does not resolve. The severity and course of symptoms are significant differences. Table 7-8 lists features that would indicate that normal bereavement has progressed to a depressive disorder. A 75-year-old widow was brought to treatment by her daughter because of severe insomnia and total loss of interest in daily routines after her husband’s death 1 year before. She had been agitated for the first 2 to 3 months and thereafter “sank into total inactivity—not wanting to get out of bed, not wanting to do anything, not wanting to go out.” According to her daughter, she was married at 21 years of age, had four children, and had been a housewife until her husband’s death from a heart attack. Her past psychiatric history was negative; premorbid adjustment had been characterized by compulsive traits. During the interview, she was dressed in black; appeared moderately slowed; and sobbed intermittently, saying “I search everywhere for him …. I don’t find him.” When asked about life, she said, “Everything I see is black.” Although she expressed no interest in food, she did not seem to have lost an appreciable amount of weight. The patient declined psychiatric care, stating that she “preferred to join her husband rather than get well.” She was too religious to commit  suicide, but by refusing treatment, she felt that she would “pine away … find relief in death and reunion.” (Courtesy of HS Akiskal, M.D.) In cases of severe bereavement, regardless of diagnosis, some suggest that it would be clinically unwise to withhold antidepressants from many persons experiencing such intense mourning. COMORBIDITY Individuals with major depressive disorders are at an increased risk of having one or more additional comorbid disorders. The most frequent disorders are alcohol abuse or dependence, panic disorder, obsessive-compulsive disorder (OCD), and social anxiety disorder. Conversely, individuals with substance use disorders and anxiety disorders also have an elevated risk of lifetime or current comorbid depressive disorders. Table 7-8 Signs that a Bereaved Person Has Progressed to a Depressive Disorder Beliefs. Grieving persons and their relatives perceive bereavement as a normal reaction, whereas those with depressive disorder often view themselves as sick and may actually believe they are losing their minds. Emotional reactivity. Unlike the melancholic person, the grieving person reacts to the environment and tends to show a range of positive effects. Psychomotor activity. Marked psychomotor retardation is not observed in normal grief. Guilt. Although bereaved persons often feel guilty about not having done certain things that they believe might have saved the life of the deceased loved one (guilt of omission), they typically do not experience guilt of commission. Delusions. Delusions of worthlessness or sin and psychotic  experiences in general point toward mood disorder. Suicidal ideation. Active suicidal ideation is rare in grief but common in major depressive disorder. Behaviors. “Mummification” (i.e., keeping the belongings of the deceased person exactly as they were before his or her death) indicates serious psychopathology. Anniversaries. Severe anniversary reactions should alert the clinician to the possibility of psychopathology. From Akiskal. Mood disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 10th ed. Philadelphia, PA: Wolters Kluwer; 2017. Anxiety In anxiety disorders, DSM-5 notes the existence of mixed anxiety–depressive disorder. Significant symptoms of anxiety can and often do coexist with significant symptoms of depression. Whether patients who exhibit significant symptoms of both anxiety and depression are affected by two distinct disease processes or by a single disease process that produces both sets of symptoms are not yet resolved. Patients of both types may constitute a group of patients with mixed anxiety–depressive disorder. Substance Use Disorder Alcohol dependence frequently coexists with mood disorders. Both patients with major depressive disorder and those with bipolar I disorder are likely to meet the diagnostic criteria for an alcohol use disorder. The available data indicate that alcohol dependence is more strongly associated with a coexisting diagnosis of depression in women than in men. In contrast, the genetic and family data about men who have both a mood disorder and alcohol dependence indicate that they are likely to have two genetically distinct disease processes. Substance-related disorders other than alcohol dependence are also commonly associated with mood disorders. The abuse of substances may be involved in precipitating an episode of illness or, conversely, may represent patients’ attempts to treat their illnesses. Although manic patients seldom use sedatives to dampen their euphoria, depressed patients often use stimulants, such as cocaine and amphetamines, to relieve their depression. Patients with dysthymia commonly meet the diagnostic criteria for a substance-related disorder. This comorbidity can be logical; patients with dysthymia tend to develop coping methods for their chronically depressed state that involve substance abuse. Therefore, they are likely to use alcohol, stimulants such as cocaine, or marijuana, the choice perhaps depending primarily on a patient’s social context. The presence of a comorbid diagnosis of substance abuse presents a diagnostic dilemma for clinicians; the long- term use of many substances can result in a symptom picture indistinguishable from that of dysthymia. Medical Conditions Depression commonly coexists with medical conditions, especially in older persons. When depression and medical conditions coexist, clinicians must try to determine whether the underlying medical condition is pathophysiologically related to the depression or whether any drugs that the patient is taking for the medical condition are causing the depression. Many studies indicate that the treatment of a coexisting major depressive disorder can improve the course of the underlying medical disorder, including cancer. COURSE Studies of the course and prognosis of mood disorders have generally concluded that mood disorders tend to have long courses and that patients tend to have relapses. Major Depressive Disorder Onset. About 50 percent of patients having their first episode of major depressive disorder exhibited significant depressive symptoms before the first identified episode. Therefore, early identification and treatment of early symptoms may prevent the development of a full depressive episode. Although symptoms may have been present, patients with major depressive disorder usually have not had a premorbid personality disorder. The first depressive episode occurs before age 40 years in about 50 percent of patients. Later onset is associated with the absence of a family history of mood disorders, antisocial personality disorder, and alcohol abuse. Duration. An untreated depressive episode lasts 6 to 13 months; most treated episodes last about 3 months. The withdrawal of antidepressants before 3 months has elapsed almost always results in the return of the symptoms. As the course of the disorder progresses, patients tend to have more frequent episodes that last longer. Over 20 years, the mean number of episodes is five or six. Other Depressive Disorders About 50 percent of patients with dysthymia experience an insidious onset of symptoms before age 25 years. Despite the early onset, patients often suffer from the symptoms for a decade before seeking psychiatric help and may consider early-onset dysthymia part of life. Patients with an early onset of symptoms are at risk for either major depressive disorder or bipolar I disorder in the course of their disorder. Studies of patients with the diagnosis of dysthymia indicate that about 20 percent progressed to major depressive disorder, 15 percent to bipolar II disorder, and fewer than 5 percent to bipolar I disorder. The prognosis for patients with dysthymia varies. Antidepressive agents and specific types of psychotherapies (e.g., cognitive and behavior therapies) have positive effects on the course and prognosis of dysthymia. The available data about previously available treatments indicate that only 10 to 15 percent of patients are in remission 1 year after the initial diagnosis. About 25 percent of all patients with dysthymia never attain complete recovery. Overall, however, the prognosis is good with treatment. PROGNOSIS Major depressive disorder is not a benign disorder. It tends to be chronic, and patients tend to relapse. Patients hospitalized for the first episode of major depressive disorder have about a 50 percent chance of recovering in the first year. The percentage of patients recovering after repeated hospitalization decreases with time. Many unrecovered patients remain affected by a dysthymic disorder. About 25 percent of patients have a recurrence in the first 6 months after leaving the hospital. Another 30 to 50 percent recur in the following 2 years. About 50 to 75 percent of all patients will have a recurrence within 5 years. The incidence of relapse is lower than these figures in patients who continue prophylactic psychopharmacological treatment and in patients who have had only one or two depressive episodes. In general, as a patient experiences more and more depressive episodes, the time between the episodes decreases, and the severity of each episode increases. Prognostic Indicators Many studies have focused on identifying both good and bad prognostic indicators in the course of major depressive disorder. Table 7-9 lists some of the positive and negative predictors. TREATMENT APPROACH The treatment of mood disorders is rewarding for psychiatrists. Specific treatments are available for depressive episodes, and data indicate that prophylactic treatment is also useful. We should be optimistic, as the prognosis for each episode is excellent. This fact tends to be welcome news for patients and families. Mood disorders are chronic, however, and the psychiatrist must educate the patient and the family about future treatment strategies. Historically, patients with dysthymia either received no treatment or received long-term, insight-oriented psychotherapy. Contemporary data suggest that the treatments for dysthymia are similar to those for major depressive disorder. There are several treatment goals. First, the patient’s safety must be guaranteed. Second, a complete diagnostic evaluation of the patient is necessary. Third, we should initiate a treatment plan that addresses not only the immediate symptoms but also the patient’s prospective well-being. Although current treatment emphasizes pharmacotherapy and psychotherapy addressed to the individual patient, stressful life events increase the chance of relapse. Thus, treatment should address the number and severity of stressors in patients’ lives. Table 7-10 lists the phases of treatment and the typical goals and activities for each phase.  Table 7-9 Prognostic Indicators for Depression Positive Indicators Clinical Mild severity No psychotic symptoms Short hospital stay No comorbid disease (medical/psychiatric) No more than 1 hospitalization Advanced age of onset Psychosocial Solid friendships during adolescence Stable family functioning Good social/occupational functioning in previous 5 yr Negative Indicators Comorbid dysthymic disorder and major depressive disorder Substance use disorder Anxiety symptoms >1 previous episodes Male Hospitalization The first and most critical decision a physician must make is whether to hospitalize a patient or attempt outpatient treatment. Definite indications for hospitalization are the risk of suicide or homicide, a patient’s grossly reduced ability to get food and shelter, and the need for diagnostic procedures. A history of rapidly progressing symptoms and the rupture of a patient’s natural support systems are also indications for hospitalization. A physician may safely treat dysthymia and other forms of milder depression in the office, seeing the patient frequently. Clinical signs of impaired judgment, weight loss, or insomnia should be minimal. The patient’s support system should be reliable, neither overinvolved nor withdrawing from the patient. Any adverse changes in the patient’s symptoms or behavior or the attitude of the patient’s support system may suffice to warrant hospitalization. Patients with mood disorders are often unwilling to enter a hospital voluntarily, and we may have to commit them involuntarily. These patients often cannot make decisions because of their slowed thinking, negative Weltanschauung (world view), and hopelessness. Choosing a Treatment Combined Treatments May Offer the Best Option. We often combine medication and psychotherapy. If physicians view mood disorders as fundamentally evolving from psychodynamic issues, their ambivalence about the use of drugs may result in a poor response, noncompliance, and probably inadequate dosages for too short a treatment period. Alternatively, if physicians ignore the psychosocial needs of a patient, the outcome of pharmacotherapy may be compromised. Several trials of a combination of pharmacotherapy and psychotherapy for chronically depressed outpatients have shown a higher response and higher remission rates for the combination than for either treatment used alone. Although combination remains the general—and our—recommendation— we should point out that there are other views. Some have argued that most data suggest that single treatment, either psychopharmacological or psychotherapeutic, alone is sufficient for most people, and that combining treatments exposes patients to unnecessary costs and adverse effects. Somatic Treatments Pharmacotherapy. The efficacy of pharmacotherapy for major depressive disorder has been well established in more than 500 randomized controlled studies. In general, all available antidepressants show an at least modest effect compared with placebo. Efficacy is broadly similar across agents, at least when compared against placebo. However, tolerability and acceptability vary. After establishing a diagnosis, we can formulate a pharmacologic treatment strategy. Accurate diagnosis is crucial because unipolar and bipolar spectrum disorders require different treatment regimens. The objective of pharmacologic treatment is symptom remission, not just symptom reduction. Patients with residual symptoms, as opposed to full remission, are more likely to experience a relapse or recurrence of mood episodes and to experience ongoing impairment of daily functioning. The use of specific pharmacotherapy approximately doubles the chances that a depressed patient will recover in 1 month. All currently available antidepressants may take up to 3 to 4 weeks to exert significant therapeutic effects, although they may begin to show their effects earlier. The choice of antidepressants partly depends on the side effect profile that is least objectionable to a given patient’s physical status, temperament, and lifestyle. Chapter 21 discusses the many classes of antidepressants. Although most antidepressants seem to have similar mechanisms of action and hence similar efficacy, there are some variations across classes. This variation gives us some diversity of choice. Although the first antidepressant drugs, the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), are still in use, newer compounds have made the treatment of depression more “clinician and patient-friendly.” Table 7-10 Phases of Treatment Treatment Duration Goals Activities Phase Acute and 8–12 wk Achieve Establish therapeutic continuation symptomatic alliance remission Provide Monitor side psychoeducation effects Select optimal Restore function antidepressant treatment(s) Supportive and measurement- based care Monitor progress Maintenance 6–24 mo Return to full Continue or function and psychoeducation longer quality of life Rehabilitate Prevention of Manage recurrence comorbidities Monitor for recurrence Modified from Lam RW, McIntosh D, Wang J, Enns MW, Kolivakis T, Michalak EE, Sareen J, Song WY, Kennedy SH, MacQueen GM, Milev RV, Parikh SV, Ravindran AV; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 1. Disease burden and principles of care. Can J Psychiatry. 2016;61(9):510–523. Table 7-11 SSRI and SNRI Antidepressant Medications and Their Side Effect Profiles Side Effect Frequency Drug Class Recommended 10–30% >30% Dose Range (mg) SSRI Citalopram 20–40 Nausea, dry mouth, None sweating Escitalopram 10–20 Male sexual None dysfunction and nausea Fluoxetine 20–60 Nausea, dry mouth, None somnolence, nervousness, anxiety, insomnia, tremor, anorexia Fluvoxamine 100–300 Dry mouth, Nausea  headaches, somnolence, agitation, insomnia, sweating, tremor, anorexia, dizziness, constipation Paroxetine 20–60 Nausea, diarrhea, None dry mouth, headaches, somnolence, insomnia, sweating, asthenia, male sexual dysfunction, dizziness Sertraline 50–200 Nausea, diarrhea, None dry mouth, headaches, somnolence, insomnia, fatigue, tremor, male sexual dysfunction, dizziness SNRI Venlafaxine 75–375 Headaches, Nausea somnolence, dry mouth, dizziness, nervousness, insomnia,  sweating, male sexual dysfunction Desvenlafaxine 50–100 Dry mouth, None dizziness, nausea, sweating Duloxetine 30–120 Nausea, dry mouth, None constipation, insomnia, male sexual dysfunction Levomilnacipran 20–80 Nausea, dry mouth, None headaches, male sexual dysfunction Other Second-Generation and Novel Antidepressants Agomelatinea 25–50 None None Bupropion 150–450 Insomnia, dry Headaches mouth, nausea Mirtazapine 15–60 Dry mouth, Somnolence constipation, increased appetite, weight gain Moclobemidea 300–600 None None Vilazodone 10–40 Diarrhea, nausea, None headaches Vortioxetine 10–20 Nausea None aNot routinely available in the United States. Data from Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, Hasnain M, Jollant F, Levitt AJ, MacQueen GM, McInerney SJ, McIntosh D, Milev RV, Müller DJ, Parikh SV, Pearson NL, Ravindran AV, Uher R; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry. 2016;61(9):540–560; Kennedy SH, Rizvi SJ. Chapter 246: SSRIs and related compounds. In: Stolerman I, ed. Encyclopedia of Pharmacology. New York: Springer; 2010. Table 7-11 lists selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) by class as well as their side-effect profiles. GENERAL CLINICAL GUIDELINES. The most common clinical mistake leading to an unsuccessful trial of an antidepressant drug is the use of too low a dosage for too short a time. Unless adverse events prevent it, the dosage of an antidepressant should be raised to the maximum recommended level and maintained at that level for at least 4 or 5 weeks before a drug trial is considered unsuccessful. Alternatively, if a patient is improving clinically on a low dosage of the drug, this dosage should not be raised unless clinical improvement stops before obtaining a maximal benefit. When a patient does not begin to respond to appropriate dosages of a drug after 2 or 3 weeks, clinicians may decide to obtain a plasma concentration of the drug if such a test is available. The test may indicate either noncompliance or a particularly unusual pharmacokinetic disposition of the drug and may thereby suggest an alternative dosage. INITIAL MEDICATION SELECTION. The available antidepressants do not differ in overall efficacy, speed of response, or long-term effectiveness. Antidepressants, however, do differ in their pharmacology, drug–drug interactions, short- and long-term side effects, the likelihood of discontinuation symptoms, and ease of dose adjustment. Most often, we start with second- and third-generation antidepressants. Among them, the selective serotonin reuptake inhibitors (SSRIs) remain the most commonly used medications for depression. Selection of the initial treatment depends on the chronicity of the condition, course of illness (a recurrent or chronic course increases the likelihood of subsequent depressive symptoms without treatment), family history of illness and treatment response, symptom severity, concurrent general medical or other psychiatric conditions, prior treatment responses to other acute-phase treatments, potential drug–drug interactions, and patient preference. In general, approximately 45 to 60 percent of all outpatients with uncomplicated (i.e., minimal psychiatric and general medical comorbidity), nonchronic, nonpsychotic major depressive disorder who begin treatment with medication respond (i.e., achieve at least a 50 percent reduction in baseline symptoms); however, only 35 to 50 percent achieve remission (i.e., the virtual absence of depressive symptoms). DURATION AND PROPHYLAXIS. We should maintain antidepressant treatment for at least 6 months or the length of a previous episode, whichever is greater. When discontinuing antidepressant treatment, the drug dose should be tapered gradually over 1 to 2 weeks, depending on the half-life of the particular compound. Prophylactic treatment with antidepressants is effective in reducing the number and severity of recurrences. One study concluded that when episodes are less than 21/2 years apart, we should recommend prophylactic treatment. Another factor suggesting prophylactic treatment is the seriousness of previous depressive episodes. Episodes that have involved significant suicidal ideation or impairment of psychosocial functioning may indicate that the risk of stopping treatment is too considerable. Prevention of new mood episodes (i.e., recurrences) is the aim of the maintenance phase of treatment. Only patients with recurrent or chronic depressions are candidates for maintenance treatment. Several studies indicate that maintenance antidepressant medication appears to be safe and effective for the treatment of chronic depression. TREATMENT OF SPECIFIC DEPRESSIVE DISORDERS. Clinical types of major depressive episodes may have varying responses to particular antidepressants or drugs other than antidepressants. Antidepressants with dual action on both serotonergic and noradrenergic receptors may have greater efficacy in melancholic depressions. We can treat patients with seasonal winter depression with light therapy. Treatment of major depressive episodes with psychotic features may require a combination of an antidepressant and an atypical antipsychotic. Several studies have also shown that ECT is useful for this indication— perhaps more effective than pharmacotherapy. For those with atypical symptom features, strong evidence exists for the effectiveness of MAOIs. SSRIs and bupropion are also of use in atypical depression. COMORBID DISORDERS. The simultaneous presence of another disorder can affect initial treatment selection. For example, the successful treatment of an OCD associated with depressive symptoms usually results in remission of the depression. Similarly, when panic disorder occurs with major depression, medications with demonstrated efficacy in both conditions are preferred (e.g., tricyclics and SSRIs). In general, the nonmood disorder dictates the choice of treatment in comorbid states. Concurrent substance abuse raises the possibility of a substance-induced mood disorder, which must be evaluated by history or by requiring abstinence for several weeks. Abstinence often results in remission of depressive symptoms in substance-induced mood disorders. For those with continuing significant depressive symptoms, even with abstinence, an independent mood disorder is diagnosed and treated. General medical conditions are established risk factors in the development of depression. The presence of a major depressive episode is associated with increased morbidity or mortality of many general medical conditions (e.g., cardiovascular disease, diabetes, cerebrovascular disease, and cancer). THERAPEUTIC USE OF SIDE EFFECTS. Choosing more sedating antidepressants (such as mirtazapine or paroxetine) for more anxious, depressed patients or more activating agents (bupropion) for more psychomotor-retarded patients is not as helpful as one might think. For example, any short-term benefits with paroxetine or mirtazapine on symptoms of anxiety or insomnia may become liabilities over time. These drugs often continue to be sedating in the longer run, which can lead to patients prematurely discontinuing medication and increase the risk of relapse or recurrence. Some practitioners use adjunctive medications, such as hypnotics or anxiolytics, combined with antidepressants to provide more immediate symptom relief or to cover those side effects to which most patients ultimately adapt.  Understanding a patient’s prior treatment history is essential because an earlier response typically predicts future responses. A documented failure on a properly conducted trial of a particular antidepressant class is grounds to choose an agent from an alternative class. The history of a first-degree relative responding to a particular drug is associated with a positive response to the same class of agents in the patient. ACUTE TREATMENT FAILURES. Patients may not respond to medication, because (1) they cannot tolerate the side effects, even in the face of an excellent clinical response; (2) an idiosyncratic adverse event may occur; (3) the clinical response is not adequate; or (4) the wrong diagnosis has been made. Acute phase medication trials should last 4 to 6 weeks to allow for adequate time for meaningful symptom reduction. Most (but not all) patients who ultimately respond fully show at least a partial response by the fourth week, assuming an adequate dose. A “partial response” is defined as at least a 20 to 25 percent reduction in pretreatment depressive symptom severity. Patients who have not even a partial response in that time likely need a change of treatment. More extended periods—8 to 12 weeks or longer—are needed to define the ultimate degree of symptom reduction achievable with a medication. Approximately half of patients require a second medication treatment trial because the initial treatment is poorly tolerated or ineffective. Selecting Second Treatment Options. When the initial treatment is unsuccessful, switching to an alternative treatment or augmenting the current treatment is a standard option. The choice between switching from the single initial treatment to a new single treatment (as opposed to adding a second treatment to the first one) rests on the patient’s prior treatment history, the degree of benefit achieved with the initial treatment, and patient preference. As a rule, switching rather than augmenting is preferred after an initial medication failure. On the other hand, augmentation strategies are helpful with patients who have gained some benefit from the initial treatment but who have not achieved remission. A review of the different strategies suggested there is some evidence suggesting that both strategies do confer some benefit. However, the evidence is inadequate to suggest one strategy over another. When switching from one monotherapy to another, the usual suggestion is to pick a medication in a different class. For example, we might switch from an SSRI to an SNRI. However, when putting these assumptions to the test, it is difficult to find any advantage for any particular strategy. For example, in the landmark STAR*D study, which remains one of the most extensive studies of treatment strategies following initial failure, although medication switches were modestly helpful, both switches within and outside a class were equally effective. Among augmentation options, several approaches have reasonable evidence. Several antipsychotics, most notably quetiapine and aripiprazole, are effective for augmentation. Lithium augmentation is also effective for augmenting both SSRIs and TCAs. There are also positive studies of thyroid hormone. However, this strategy is rarely used in clinical practice owing to the need for ongoing monitoring and potential adverse effects. Several other agents have been studied, including bupropion, buspirone, lamotrigine, methylphenidate, and pindolol; however, these have limited placebo- controlled data. One meta-analysis of the available data on switching strategies concluded that quetiapine and aripiprazole have the best evidence as augmentation agents. However, we should use these cautiously given their side effect profile. NOVEL PHARMACOLOGIC AGENTS Ketamine. The anesthetic agent ketamine is effective in treatment-resistant depression. It has a mechanism of action that inhibits the postsynaptic glutamate-binding protein N-methyl-D-aspartate (NMDA) receptor. Because abnormalities in glutamatergic signaling seem to have a role in major depressive disorder, this may account for its efficacy. Until recently, ketamine was only available intravenously, limiting its use as we had to monitor patients while they received an infusion of the drug over 30 minutes in a clinical setting. The most common side effects are dizziness, headache, and poor coordination, which are transitory. Dissociative symptoms, including hallucinations, may also occur. A positive response is usually seen within 24 hours, making this a genuinely novel substance in that it appears to act much more rapidly than standard antidepressants. However, the effect seems to be short-lived, and wears off after between 2 and 7 days, again limiting its use. There are little data on longer-term treatment as well as concern over associated adverse effects, particularly the psychogenic effect. Also, the agent has an abuse potential, making it less attractive as a long-term option. More recently, esketamine in a nasal spray formulation was approved by the FDA for treatment-resistant depression. Given the abuse risk, it is only available through a restricted distribution system. Most of the supportive evidence for the agent is from short-term use. However, one longer-term study suggested that continuation treatment could be effective for some patients. Brexanolone. Brexanolone is an intravenous formulation of allopregnanolone, which was approved by the FDA in 2019 for the treatment of postpartum depression. It is a neuroactive steroid that also has a neuroactive effect, functioning as an allosteric modulator of GABAA, which may be central to the mechanism of postpartum depression. It is also only available in the United States through a restricted program that requires administrating the drug in a clinical setting over 60 hours. The most common adverse effects are sleepiness, dry mouth, loss of consciousness, and flushing. As with ketamine, brexanolone differs from standard antidepressants in its apparent rapid effect, reducing depressive symptoms as early as 24 hours after administration. In trials, the effect continued for at least 30 days. As of this writing, phase 3 trials for an oral version of the medication have promising results. Other Somatic Treatments NEUROSTIMULATION mechanism unkown Vagal Nerve Stimulation. Experimental stimulation of the vagus nerve in several studies designed for the treatment of epilepsy found that patients showed improved mood. This observation led to the use of left vagal nerve stimulation (VNS) using an electronic device implanted in the skin, similar to a cardiac pacemaker. Preliminary studies have shown that many patients with chronic, recurrent major depressive disorder went into remission when treated with VNS. The mechanism of action of VNS to account for improvement is unknown. The vagus nerve connects to the enteric nervous system and, when stimulated, may cause the release of peptides that act as neurotransmitters. Transcranial Magnetic Stimulation. Transcranial magnetic stimulation (TMS) shows promise as a treatment for depression. It involves the use of very short pulses of magnetic energy to stimulate nerve cells in the brain. The FDA has indicated this treatment for depression in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode. Repetitive transcranial magnetic stimulation (rTMS) produces focal secondary electrical stimulation of targeted cortical regions. It is nonconvulsive, requires no anesthesia, has a safe side effect profile, and is not associated with cognitive side effects. The patients do not require anesthesia or sedation and remain awake and alert. It is a 40-minute outpatient procedure that is prescribed by a psychiatrist and performed in a psychiatrist’s office. The treatment is typically administered daily for 4 to 6 weeks. The most common adverse event related to treatment was scalp pain or discomfort. TMS therapy is contraindicated in patients with implanted metallic devices or nonremovable metallic objects in or around the head. PHOTOTHERAPY. Phototherapy (light therapy) was introduced in 1984 as a treatment for SAD (mood disorder with seasonal pattern). In this disorder, patients typically experience depression as the photoperiod of the day decreases with advancing winter. Women represent at least 75 percent of all patients with seasonal depression, and the mean age of presentation is 40 years. Patients rarely present older than the age of 55 years with SAD. Phototherapy typically involves exposing the affected patient to bright light in the range of 1,500 to 10,000 lux or more, typically with a lightbox that sits on a table or desk. Patients sit in front of the box for approximately 1 to 2 hours before dawn each day. Some patients may also benefit from exposure after dusk. Alternatively, some manufacturers have developed light visors, with a light source built into the brim of the hat. These light visors allow mobility, but recent controlled studies have questioned the use of this type of light exposure. Trials have typically lasted 1 week, but longer treatment durations may be associated with a more significant response. Phototherapy is usually well tolerated. Newer light sources tend to use lower light intensities and come equipped with filters; patients are instructed not to look directly at the light source. As with any effective antidepressant, phototherapy, on rare occasions, has been implicated in switching some depressed patients into mania or hypomania. In addition to seasonal depression, the other significant indication for phototherapy may be in sleep disorders. Phototherapy can decrease the irritability and diminished functioning associated with shift work. Sleep disorders in geriatric patients have reportedly improved with exposure to bright light during the day. Likewise, some evidence suggests that jet lag might respond to light therapy. Preliminary data indicate that phototherapy may benefit some patients with OCD that has a seasonal variation. SLEEP DEPRIVATION. Sleep disturbances are common in depression. Depression can be associated with either hypersomnia or insomnia. Sleep deprivation may temporarily relieve depression in those who have unipolar depression. Approximately 60 percent of patients with depressive disorders exhibit significant but transient benefits from total sleep deprivation. The positive results usually reverse by the next night of sleep. Several strategies have been used in an attempt to achieve a more sustained response to sleep deprivation. One method used serial total sleep deprivation with a day or two of normal sleep in between. This method does not achieve a sustained antidepressant response because the depression tends to return during the “normal sleep” days. Another approach used phase delay in the time patients go to sleep each night, or partial sleep deprivation. In this method, patients may stay awake from 2 AM to 10 PM daily. Up to 50 percent of patients get same-day antidepressant effects from partial sleep deprivation, but this benefit also tends to wear off in time. In some reports, however, serial partial sleep deprivation has been used successfully to treat insomnia associated with depression. The third, and probably most useful strategy combines sleep deprivation with pharmacologic treatment of depression. Several studies have suggested that total and partial sleep deprivation followed by immediate treatment with an antidepressant or lithium sustains the antidepressant effects of sleep deprivation. Likewise, several reports have suggested that sleep deprivation accelerates the response to antidepressants. Sleep deprivation may also improve premenstrual dysphoria.  Table 7-12 Evidence-Based Psychotherapies for Major Depressive Disorder Treatment Conceptualization of Sample Interventions Disorder Etiology Behavioral Deficit of reinforcers, Increase activity level therapy including pleasant activities and positive Structured goal setting interpersonal contacts Interpersonal skills training Cognitive- Interaction of beliefs with Identify and challenge behavioral matching stressor automatic thoughts therapy Engage in activities that provide evidence disproving dysfunctional beliefs Modify core beliefs by reviewing evidence Interpersonal Interpersonal Develop awareness of psychotherapy vulnerabilities arising patterns in primary from early attachment relationships and the and learned therapeutic relationship patterns relationship Interpersonal skills training Communication analysis Behavioral Marital distress Assertive marital increases stress communication  therapy while impairing training support resources Active listening exercises Problem-solving skills Increasing reinforcing behaviors toward spouse Psychosocial Therapy Three types of short-term psychotherapies—cognitive therapy, interpersonal therapy, and behavior therapy—have extensive studies for the treatment of major depressive disorder. In addition to these individual therapies, there are positive studies for behavioral marital therapy as well. Table 7-12 lists the evidence-based psychotherapies for major depressive disorder. There are no generally accepted guidelines for choosing one therapy over another. The National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program did find some possible predictors of good response to specific treatments. Table 7-13 summarizes those findings. Cognitive Therapy. Cognitive therapy, originally developed by Aaron Beck, focuses on the cognitive distortions postulated to be present in major depressive disorder. Such distortions include selective attention to the negative aspects of circumstances and unrealistically morbid inferences about consequences. For example, apathy and low energy result from a patient’s expectation of failure in all areas. The goal of cognitive therapy is to alleviate depressive episodes and prevent their recurrence by helping patients identify and test negative cognitions; develop alternative, flexible, and positive ways of thinking; and rehearse new cognitive and behavioral responses. In this example, the therapist takes a cognitive approach when a patient shows up late to an appointment.  Therapist: You mentioned that you were upset because you were late. Can you tell me what you were thinking when you realized you were late? Patient: I figured you’d be angry. Therapist: Okay, and when you thought I’d be angry, how did you feel? Patient: Pretty nervous. Therapist: So that is what we will focus on in here, how your thinking in different situations influences how you feel. In this case, you were late, thought “he’ll be angry,” and felt nervous. Our goal is to test out the beliefs, like “he’ll be angry,” and change them when they aren’t healthy or accurate. The great thing is that you sort of implicitly tested out the belief that I’ll be angry by showing up. Was I angry? Patient: You didn’t seem angry. Table 7-13 Predictors of Response to Several Therapies for Depression Treatment Predictors Interpersonal psychotherapy Low social dysfunction High depression severity Cognitive-behavioral therapy Low cognitive dysfunction Pharmacotherapy Low cognitive dysfunction High depression severity High work dysfunction Data from Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF, Elkin I, Watkins JT, Imber SD, Leber WR, Moyer J, Oliveri ME. Patient predictors of response to psychotherapy and pharmacotherapy: findings in the NIMH Treatment of Depression Collaborative Research Program. Am J Psychiatry. 1991;148:997–1108. Therapist: How anxious did you feel once we started talking? Patient: Well, I’m feeling more comfortable. Therapist: What thoughts do you have now about me being angry?  Patient: I don’t think you’re angry. Therapist: So, this is an example of what we’re going to be doing in therapy—I’ll be helping you to identify thoughts that make you feel bad. We’re then going to work together to come up with ways to check them out and change them if they’re not true or accurate. You checked out whether I was angry by observing me, and you changed your thought, and, now, I get the impression that you feel better. Studies have shown that cognitive therapy is useful in the treatment of major depressive disorder. Most studies found that cognitive therapy is equal in efficacy to pharmacotherapy and is associated with fewer adverse effects and better follow-up than pharmacotherapy. Some of the best-controlled studies have indicated that the combination of cognitive therapy and pharmacotherapy is more efficacious than either therapy alone, although other studies have not found that additive effect. Interpersonal Therapy. Interpersonal therapy, developed by Gerald Klerman, focuses on one or two of a patient’s current interpersonal problems. This therapy has two assumptions. First, current interpersonal problems are likely to have their roots in early dysfunctional relationships. Second, current interpersonal problems are likely to be involved in precipitating or perpetuating the current depressive symptoms. Controlled trials have indicated that interpersonal therapy is effective for treatment of major depressive disorder and, not surprisingly, may be specifically helpful in addressing interpersonal problems. Some studies indicate that interpersonal therapy may be the most effective method for severe major depressive episodes when the treatment choice is psychotherapy alone. The interpersonal therapy program usually consists of 12 to 16 weekly sessions and is characterized by an active therapeutic approach. Intrapsychic phenomena, such as defense mechanisms and internal conflicts, are not addressed. Discrete behaviors—such as lack of assertiveness, impaired social skills, and distorted thinking—may be addressed but only in the context of their meaning in, or their effect on, interpersonal relationships. Behavior Therapy. Behavior therapy rests on the hypothesis that maladaptive behavioral patterns result in a person’s receiving little positive feedback and perhaps outright rejection from society. By addressing maladaptive behaviors in therapy, patients learn to function in the world in such a way that they receive positive reinforcement. Behavior therapy for major depressive disorder has not yet been the subject of many controlled studies. The limited data indicate that it is an effective treatment for major depressive disorder. Psychoanalytically Oriented Therapy. Although not as well researched as those three therapies, many clinicians use psychoanalytically oriented psychotherapy as their primary method. What differentiates the short-term psychotherapy methods from the psychoanalytically oriented approach are the active and directive roles of the therapist, the directly recognizable goals, and the endpoints for short-term therapy. The psychoanalytic approach to mood disorders uses psychoanalytic theories about depression. The goal of psychoanalytic psychotherapy is to effect a change in a patient’s personality structure or character, not merely to alleviate symptoms. Improvements in interpersonal trust, capacity for intimacy, coping mechanisms, the capacity to grieve, and the ability to experience a wide range of emotions are some of the aims of psychoanalytic therapy. Treatment often requires the patient to experience periods of heightened anxiety and distress during therapy, which may continue for several years. Accumulating evidence is encouraging about the efficacy of dynamic therapy. In a randomized, controlled trial comparing psychodynamic therapy with cognitive-behavioral therapy, the outcome of the depressed patients was the same in the two treatments. Family Therapy. Family therapy is usually the first-line treatment for major depressive disorder, but increasing evidence indicates that helping a patient with a mood disorder to reduce and cope with stress can lessen the chance of a relapse. We should consider family therapy if the disorder jeopardizes a patient’s marriage or family functioning or if the mood disorder is promoted or maintained by the family situation. Family therapy examines the role of the mood-disordered member in the overall psychological well-being of the whole family; it also examines the role of the entire family in the maintenance of the patient’s symptoms. Patients with mood disorders have a high rate of divorce, and about 50 percent of all spouses report that they would not have married or had children if they had known that the patient was going to develop a mood disorder. THE EPIDEMIOLOGY OF DEPRESSION Research on the epidemiology of depression, both in the United States and worldwide, has considerably broadened our understanding of the disorder. We have discovered that depression is much more common than once thought. It is also one of the more debilitating disorders known to humanity, as it often affects individuals during what should be their most productive years. Hence the depressive disorders are one of the most costly disorders in society. Measuring the Incidence and Prevalence of Major Depressive Disorder Is Challenging Measuring the true incidence of major depressive disorder is complicated and highly dependent on the methods used to collect the sample, definitions of the disorder, and the particular instruments used to measure depression. For example, studies that use self-assessment tend to report higher incidences than studies using clinician-rated instruments. The timing of a study likely affects the results as well. As depressive illness become less stigmatized, persons may be more willing to endorse symptoms of the disorder to the well-meaning strangers who knock at their door, call their phone, or email them and identify themselves as researchers. Incidence and Prevalence In a reasonably recent meta-analysis, which included 90 studies from 30 countries done from 1994 to 2014, with combined data on more than 1 million participants, the point prevalence for depression was 12.9 percent, the 1-year prevalence was 7.2 percent, and the lifetime prevalence was 10.8 percent. There was significant heterogeneity among the different studies.  FIGURE 7-1 Lifetime prevalence of major depression across the world. In the United States, the most recent epidemiologic data is from the National Survey on Drug Use and Health (NSDUH), sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA). Using a definition of a major depressive episode based on DSM-5, they found the overall 1-year prevalence of a major depressive episode to be 7.1 percent, hence very similar to the international data. Figure 7-1 summarizes some of the international prevalence data as it related to per capita income. Sex An almost universal observation, independent of country or culture, is that depression is more common in women than men. In the international meta- analysis, the aggregate prevalence for women was 14.4 percent versus 11.5 percent in men. In the United States, women were more likely to report a major depressive episode in the past year (8.7 percent) than men (5.3 percent). There are various possible explanations, both biologic, psychological, and social, for this difference. A women’s unequal status in many societies may make women more vulnerable to depression. Although this remains a valid hypothesis, it is notable that in societies where women have gained a better level of status, such as many Western societies, the ratio has not significantly changed. Although the explanation is undoubtedly complex and multifactorial, the weight of existing evidence suggests that biologic differences between men and women, such as variations in hormonal levels, do account for at least part of this difference. Age The mean age of onset for major depressive disorder is about 40 years, with 50 percent of all patients having an onset between the ages of 20 and 50 years. Major depressive disorder can also begin in childhood or old age. Some epidemiologic data suggest that the incidence of major depressive disorder may be increasing among younger persons. For example, in the SAMHSA study, major depressive disorder was almost twice as prevalent in adolescents as it was in adults, the most substantial difference being seen in adolescent females who reported a 1-year prevalence of major depression of 20 percent. The highest 1-year prevalence for major depressive disorder was in younger adults (adults ages 18 to 25). Marital Status Major depressive disorder occurs most often in persons without close interpersonal relationships and in those who are divorced or separated. Socioeconomic and Cultural Factors There is no proven correlation between socioeconomic status and major depressive disorder. Depression may be more common in rural areas than in urban areas. However, the most recent international meta-analysis described above did not find such a difference. It may be that technology and globalization have been able to narrow the differences between rural and urban settings. Racial and ethnic differences may be particularly challenging to measure and may be highly dependent on method, approach, and locale. In the SAMSHA study, the highest prevalence was seen in White and Native American respondents. THE NEUROBIOLOGY OF DEPRESSION Since the time of Kraepelin, researchers have examined the brains, bodies, and behaviors of depressed patients in the search for clues of the underlying pathology of depression. This search is complicated by the fact that most experts on depression agree what we call major depressive disorder is not a single disease, but rather a collection of disorders with overlapping phenomenology but different etiologies and pathologies. Although this assumption seems likely, we have yet to find definitive subtypes or distinct patterns that we can confidently group into separate disorders. This area of research is a rapidly changing field, and improvements in technology, including higher-resolution imaging, more efficient genotyping, and more powerful computing power are getting us closer to the search for valid “biotypes” of depression. What follows here are examples of pathologic findings, most of which have been reasonably replicated by different investigators. Some are long known, others are recent. However, the growing collection of pathologic findings is helping us to understand what is happening when a patient says that they are “depressed.” Depression as a Disorder of Homeostasis Depression and the Hypothalamic–Pituitary–Adrenal Axis. We have known for more than 50 years that, on average, depressed patients have an overactive hypothalamic–pituitary–adrenal (HPA) axis. Compared with controls, depressed patients have increased cortisol levels over 24 hours. We have documented elevated HPA activity in depression via excretion of urinary-free cortisol (UFC), 24-hour (or shorter time segments) intravenous (IV) collections of plasma cortisol levels, salivary cortisol levels, and tests of the integrity of feedback inhibition. Evidence of increased HPA activity is apparent in