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Depressive Disorders

by William Coryell, MD

Depressive disorders are characterized by sadness severe enough or persistent enough to interfere with function and often by decreased interest or pleasure in activities. Exact cause is unknown but probably involves heredity, changes in neurotransmitter levels, altered neuroendocrine function, and psychosocial factors. Diagnosis is based on history. Treatment usually consists of drugs, psychotherapy, or both and sometimes electroconvulsive therapy.

The term depression is often used to refer to any of several depressive disorders. Some are classified in the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) by specific symptoms:

  • Major depressive disorder (often called major depression)

  • Persistent depressive disorder (dysthymia)

  • Other specified or unspecified depressive disorder

Others are classified by etiology:

  • Premenstrual dysphoric disorder

  • Depressive disorder due to another medical condition

  • Substance/medication-induced depressive disorder

Depressive disorders occur at any age but typically develop during the mid teens, 20s, or 30s. In primary care settings, as many as 30% of patients report depressive symptoms, but < 10% have major depression.

Demoralization and grief

The term depression is often used to describe the low or discouraged mood that results from disappointments (eg, financial calamity, natural disaster, serious illness) or losses (eg, death of a loved one). However, better terms for such moods are demoralization and grief. The negative feelings of demoralization and grief, unlike those of depression, occur in waves that tend to be tied to thoughts or reminders of the inciting event, resolve when circumstances or events improve, may be interspersed with periods of positive emotion and humor, and are not accompanied by pervasive feelings of worthlessness and self-loathing. The low mood usually lasts days rather than weeks or months, and suicidal thoughts and prolonged loss of function are much less likely. However, events and stressors that cause demoralization and grief can also precipitate a major depressive episode, particularly in vulnerable people (eg, those with a past history or family history of major depression).

Etiology

Exact cause is unknown, but genetic and environmental factors contribute.

Heredity accounts for about half of the etiology (less so in late-onset depression). Thus, depression is more common among 1st-degree relatives of depressed patients, and concordance between identical twins is high. Also, genetic factors probably influence the development of depressive responses to adverse events.

Other theories focus on changes in neurotransmitter levels, including abnormal regulation of cholinergic, catecholaminergic (noradrenergic or dopaminergic), and serotonergic (5-hydroxytryptamine) neurotransmission. Neuroendocrine dysregulation may be a factor, with particular emphasis on 3 axes: hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, and growth hormone.

Psychosocial factors also seem to be involved. Major life stresses, especially separations and losses, commonly precede episodes of major depression; however, such events do not usually cause lasting, severe depression except in people predisposed to a mood disorder.

People who have had an episode of major depression are at higher risk of subsequent episodes. People who are less resilient and/or who have anxious tendencies may be more likely to develop a depressive disorder. Such people often do not develop the social skills to adjust to life pressures. Depression may also develop in people with other mental disorders.

Women are at higher risk, but no theory explains why. Possible factors include greater exposure to or heightened response to daily stresses, higher levels of monoamine oxidase (the enzyme that degrades neurotransmitters considered important for mood), higher rates of thyroid dysfunction, and endocrine changes that occur with menstruation and at menopause. In postpartum depression (see Postpartum Depression), symptoms develop within 4 wk after delivery; endocrine changes have been implicated, but the specific cause is unknown.

In seasonal affective disorder, symptoms develop in a seasonal pattern, typically during autumn or winter; the disorder tends to occur in climates with long or severe winters.

Depressive symptoms or disorders may accompany various physical disorders, including thyroid and adrenal gland disorders, benign and malignant brain tumors, stroke, AIDS, Parkinson disease, and multiple sclerosis (see Table: Some Causes of Symptoms in Depression and Mania). Certain drugs, such as corticosteroids, some β-blockers, interferon, and reserpine, can also result in depressive disorders. Abuse of some recreational drugs (eg, alcohol, amphetamines) can lead to or accompany depression. Toxic effects or withdrawal of drugs may cause transient depressive symptoms.

Some Causes of Symptoms in Depression and Mania

Type of Disorder

Depression

Mania

Connective tissue

SLE

Rheumatic fever

SLE

Endocrine

Addison disease

Cushing disease

Diabetes mellitus

Hyperparathyroidism

Hyperthyroidism

Hypothyroidism

Hypopituitarism

Hypogonadism

Hyperthyroidism

Infectious

AIDS

General paresis (parenchymatous neurosyphilis)

Influenza

Infectious mononucleosis

TB

Viral hepatitis

Viral pneumonia

AIDS

General paresis

Influenza

St. Louis encephalitis

Neoplastic

Cancer of the head of the pancreas

Disseminated carcinomatosis

Neurologic

Cerebral tumors

Complex partial seizures (temporal lobe)

Head trauma

Multiple sclerosis

Parkinson disease

Sleep apnea

Stroke (left frontal)

Complex partial seizures (temporal lobe)

Diencephalic tumors

Head trauma

Huntington disease

Multiple sclerosis

Stroke

Nutritional

Pellagra

Pernicious anemia

Other*

Coronary artery disease

Fibromyalgia

Renal or hepatic failure

Pharmacologic

Amphetamine withdrawal

Amphotericin B

Anticholinesterase insecticides

Barbiturates

β-Blockers (some, eg, propranolol)

Cimetidine

Corticosteroids

Cycloserine

Estrogen therapy

Indomethacin

Interferon

Mercury

Methyldopa

Metoclopramide

Oral contraceptives

Phenothiazines

Reserpine

Thallium

Vinblastine

Vincristine

Amphetamines

Certain antidepressants

Bromocriptine

Cocaine

Corticosteroids

Levodopa

Methylphenidate

Sympathomimetic drugs

Mental

Alcoholism and other substance use disorders

Antisocial personality

Anxiety disorders

Borderline personality disorder

Dementing disorders in the early phase

Schizophrenic disorders

*Depression commonly occurs in these disorders, but no causal relationship has been established.

Symptoms and Signs

Depression causes cognitive, psychomotor, and other types of dysfunction (eg, poor concentration, fatigue, loss of sexual desire, loss of interest or pleasure in nearly all activities that were previously enjoyed, sleep disturbances), as well as a depressed mood. People with a depressive disorder frequently have thoughts of suicide and may attempt suicide (see Suicidal Behavior). Other mental symptoms or disorders (eg, anxiety and panic attacks) commonly coexist, sometimes complicating diagnosis and treatment.

Patients with all forms of depression are more likely to abuse alcohol or other recreational drugs in an attempt to self-treat sleep disturbances or anxiety symptoms; however, depression is a less common cause of alcoholism and drug abuse than was once thought. Patients are also more likely to become heavy smokers and to neglect their health, increasing the risk of development or progression of other disorders (eg, COPD).

Depression may reduce protective immune responses. Depression increases risk of cardiovascular disorders, MIs, and stroke, perhaps because in depression, cytokines and factors that increase blood clotting are elevated and heart rate variability is decreased—all potential risk factors for cardiovascular disorders.

Major depression (unipolar disorder)

Patients may appear miserable, with tearful eyes, furrowed brows, down-turned corners of the mouth, slumped posture, poor eye contact, lack of facial expression, little body movement, and speech changes (eg, soft voice, lack of prosody, use of monosyllabic words). Appearance may be confused with Parkinson disease. In some patients, depressed mood is so deep that tears dry up; they report that they are unable to experience usual emotions and feel that the world has become colorless and lifeless. Nutrition may be severely impaired, requiring immediate intervention. Some depressed patients neglect personal hygiene or even their children, other loved ones, or pets.

For diagnosis, ≥ 5 of the following must have been present nearly every day during the same 2-wk period, and one of them must be depressed mood or loss of interest or pleasure:

  • Depressed mood most of the day

  • Markedly diminished interest or pleasure in all or almost all activities for most of the day

  • Significant (> 5%) weight gain or loss or decreased or increased appetite

  • Insomnia (often sleep-maintenance insomnia) or hypersomnia

  • Psychomotor agitation or retardation observed by others (not self-reported)

  • Fatigue or loss of energy

  • Feelings of worthlessness or excessive or inappropriate guilt

  • Diminished ability to think or concentrate or indecisiveness

  • Recurrent thoughts of death or suicide, a suicide attempt, or a specific plan for committing suicide

Persistent depressive disorder

Depressive symptoms that persist for 2 yr without remission are classified as persistent depressive disorder (PDD), a category that consolidates disorders formerly termed chronic major depressive disorder and dysthymic disorder.

Symptoms typically begin insidiously during adolescence and may persist for many years or decades. The number of symptoms often fluctuates above and below the threshold for major depressive episode. Affected patients may be habitually gloomy, pessimistic, humorless, passive, lethargic, introverted, hypercritical of self and others, and complaining. Patients with PDD are also more likely to have underlying anxiety, substance use, or personality (ie, borderline personality) disorders.

For diagnosis, patients must have had a depressed mood for most of the day for more days than not for ≥ 2 yr plus ≥ 2 of the following:

  • Poor appetite or overeating

  • Insomnia or hypersomnia

  • Low energy or fatigue

  • Low self-esteem

  • Poor concentration or difficulty making decisions

  • Feelings of hopelessness

Premenstrual dysphoric disorder

Premenstrual dysphoric disorder involves mood and anxiety symptoms that are clearly related to the menstrual cycle, with onset during the premenstrual phase and a symptom-free interval after menstruation. Symptoms must be present during most menstrual cycles during the past year. Manifestations are similar to those of premenstrual syndrome (see Premenstrual Syndrome (PMS)) but are more severe, causing clinically significant distress and/or marked impairment of social or occupational functioning. The disorder may begin any time after menarche; it may worsen as menopause approaches but ceases after menopause. Prevalence is estimated at 2 to 6% of menstruating women in a given 12-mo interval.

For diagnosis, patients must have ≥ 5 symptoms during the week before menstruation. Symptoms must begin to remit within a few days after onset of menses and become minimal or absent in the week after menstruation. Symptoms must include ≥ 1 of the following:

  • Marked mood swings (eg, suddenly feeling sad or tearful)

  • Marked irritability or anger or increased interpersonal conflicts

  • Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts

  • Marked anxiety, tension, or an on-edge feeling

In addition, ≥ 1 of the following must be present:

  • Decreased interest in usual activities

  • Difficulty concentrating

  • Low energy or fatigue

  • Marked change in appetite, overeating, or specific food cravings

  • Hypersomnia or insomnia

  • Feeling overwhelmed or out of control

  • Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a feeling of being bloated, and weight gain

Other depressive disorder

Clusters of symptoms with characteristics of a depressive disorder that do not meet the full criteria for other depressive disorders but that cause clinically significant distress or impairment of functioning are classified as other depressive (specified or unspecified) disorder. Included are recurrent periods of dysphoria with ≥ 4 other depressive symptoms that last < 2 wk in people who have never met criteria for another mood disorder (eg, recurrent brief depression) and depressive periods that last longer but that include insufficient symptoms for diagnosis of another depressive disorder.

Specifiers

Major depression and persistent depressive disorder may include one or more specifiers that describe additional manifestations during a depressive episode:

  • Anxious distress: Patients feel tense and unusually restless; they have difficulty concentrating because they worry or fear that something awful may happen, or they feel that they may lose control of themselves.

  • Mixed features : Patients also have ≥ 3 manic or hypomanic symptoms (eg, elevated mood, grandiosity, greater talkativeness than usual, flight of ideas, decreased sleep).

  • Melancholic: Patients have lost pleasure in nearly all activities or do not respond to usually pleasurable stimuli. They may be despondent and despairing, feel excessive or inappropriate guilt, or have early morning awakenings, marked psychomotor retardation or agitation, and significant anorexia or weight loss.

  • Atypical: Patients' mood temporarily brightens in response to positive events (eg, a visit from children). They also have ≥ 2 of the following: overreaction to perceived criticism or rejection, feelings of leaden paralysis (a heavy or weighted-down feeling, usually in the extremities), weight gain or increased appetite, and hypersomnia.

  • Psychotic: Patients have delusions and/or hallucinations. Delusions often involve having committed unpardonable sins or crimes, harboring incurable or shameful disorders, or being persecuted. Hallucinations may be auditory (eg, hearing accusatory or condemning voices) or visual. If only voices are described, careful consideration should be given to whether the voices represent true hallucinations.

  • Catatonic: Patients have severe psychomotor retardation, engage in excessive purposeless activity, and/or withdraw; some patients grimace and mimic speech (echolalia) or movement (echopraxia).

  • Peripartum onset : Onset is during pregnancy or in the 4 wk after delivery. Psychotic features may be present; infanticide is often associated with psychotic episodes involving command hallucinations to kill the infant or delusions that the infant is possessed.

  • Seasonal pattern : Episodes occur at a particular time of year, most often fall or winter.

Diagnosis

  • Clinical criteria (DSM-5)

  • CBC, electrolytes, and TSH, vitamin B 12 , and folate levels to rule out physical disorders that can cause depression

Diagnosis is based on identification of the symptoms and signs and the clinical criteria described above. To help differentiate depressive disorders from ordinary mood variations, there must be significant distress or impairment in social, occupational, or other important areas of functioning.

Several brief questionnaires are available for screening. They help elicit some depressive symptoms but cannot be used alone for diagnosis. Specific close-ended questions help determine whether patients have the symptoms required by DSM-5 criteria for diagnosis of major depression.

Severity is determined by the degree of pain and disability (physical, social, occupational) and by duration of symptoms. A physician should gently but directly ask patients about any thoughts and plans to harm themselves or others, any previous threats of and/or attempts at suicide, and other risk factors (see Suicidal Behavior). Psychosis and catatonia indicate severe depression. Melancholic features indicate severe or moderate depression. Coexisting physical conditions, substance abuse disorders, and anxiety disorders may add to severity.

Differential diagnosis

Depressive disorders must be distinguished from demoralization and grief. Other mental disorders (eg, anxiety disorders) can mimic or obscure the diagnosis of depression. Sometimes more than one disorder is present. Major depression (unipolar disorder) must be distinguished from bipolar disorder (see Bipolar Disorders).

In elderly patients, depression can manifest as dementia of depression (formerly called pseudodementia), which causes many of the symptoms and signs of dementia such as psychomotor retardation and decreased concentration (see Dementia). However, early dementia may cause depression. In general, when the diagnosis is uncertain, treatment of a depressive disorder should be tried.

Differentiating chronic depressive disorders, such as dysthymia, from substance abuse disorders may be difficult, particularly because they can coexist and may contribute to each other.

Physical disorders must also be excluded as a cause of depressive symptoms. Hypothyroidism often causes symptoms of depression and is common, particularly among the elderly. Parkinson disease, in particular, may manifest with symptoms that mimic depression (eg, loss of energy, lack of expression, paucity of movement). A thorough neurologic examination is needed to exclude this disorder.

Testing

No laboratory findings are pathognomonic for depressive disorders. Tests for limbic-diencephalic dysfunction are rarely indicated or helpful. However, laboratory testing is necessary to exclude physical conditions that can cause depression. Tests include CBC, TSH levels, and routine electrolyte, vitamin B 12 , and folate levels. Testing for illicit drug use is sometimes appropriate.

Treatment

  • Support

  • Psychotherapy

  • Drugs

Symptoms may remit spontaneously, particularly when they are mild or of short duration. Mild depression may be treated with general support and psychotherapy. Moderate to severe depression is treated with drugs, psychotherapy, or both and sometimes electroconvulsive therapy. Some patients require a combination of drugs. Improvement may not be apparent until after 1 to 4 wk of drug treatment.

Depression, especially in patients who have had > 1 episode, is likely to recur; therefore, severe cases often warrant long-term maintenance drug therapy.

Most people with depression are treated as outpatients. Patients with significant suicidal ideation, particularly when family support is lacking, require hospitalization, as do those with psychotic symptoms or physical debilitation.

Depressive symptoms in patients with substance abuse disorders often resolve within a few months of stopping substance use. Antidepressant treatment is much less likely to be effective while substance abuse continues.

If a physical disorder or drug toxicity could be the cause, treatment is directed first at the underlying disorder. However, if the diagnosis is in doubt or if symptoms are disabling or include suicidal ideation or hopelessness, a therapeutic trial with an antidepressant or a mood-stabilizing drug may help.

Initial support

Until definite improvement begins, a physician may need to see patients weekly or biweekly to provide support and education and to monitor progress. Telephone calls may supplement office visits.

Patients and loved ones may be worried or embarrassed about the idea of having a mental disorder. The physician can help by explaining that depression is a serious medical disorder caused by biologic disturbances and requires specific treatment and that the prognosis with treatment is good. Patients and loved ones should be reassured that depression does not reflect a character flaw (eg, laziness, weakness). Telling patients that the path to recovery often fluctuates helps them put feelings of hopelessness in perspective and improves adherence.

Encouraging patients to gradually increase simple activities (eg, taking walks, exercising regularly) and social interactions must be balanced with acknowledging their desire to avoid activities. The physician can suggest that patients avoid self-blame and explain that dark thoughts are part of the disorder and will go away.

Psychotherapy

Numerous controlled trials have shown that psychotherapy, particularly cognitive-behavioral therapy and interpersonal therapy, is effective in patients with major depressive disorder, both to treat acute symptoms and to decrease the likelihood of relapse. Patients with mild depression tend to have better outcomes than those with more severe depression, but the magnitude of improvement is greater in those with more severe depression.

Selective serotonin reuptake inhibitors (SSRIs)

These drugs prevent reuptake of serotonin (5-hydroxytryptamine [5-HT]). SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. Although these drugs have the same mechanism of action, differences in their clinical properties make selection important. SSRIs have a wide therapeutic margin; they are relatively easy to administer, with little need for dose adjustment (except for fluvoxamine).

By preventing reuptake of 5-HT presynaptically, SSRIs result in more 5-HT to stimulate postsynaptic 5-HT receptors. SSRIs are selective to the 5-HT system but not specific for the different 5-HT receptors. They stimulate 5-HT 1 receptors, with antidepressant and anxiolytic effects, but they also stimulate 5-HT 2 receptors, commonly causing anxiety, insomnia, and sexual dysfunction, and 5-HT 3 receptors, commonly causing nausea and headache. Thus, SSRIs can paradoxically relieve and cause anxiety.

A few patients may seem more agitated, depressed, and anxious within a week of starting SSRIs or increasing the dose. Patients and their loved ones should be warned of this possibility and instructed to call the physician if symptoms worsen with treatment. This situation should be closely monitored because some patients, especially younger children and adolescents, become increasingly suicidal if agitation, increased depression, and anxiety are not detected and rapidly treated. Several analyses of the FDA database of industry-sponsored trials led to a black box warning that antidepressants in general are associated with an increased risk of emergence of suicidal ideas and suicide attempts in patients aged ≤ 24 yr. Subsequent analyses of FDA and other data have cast doubt on this conclusion.

Sexual dysfunction (especially difficulty achieving orgasm but also decreased libido and erectile dysfunction) occurs in one third or more of patients. Some SSRIs cause weight gain. Others, especially fluoxetine, may cause anorexia in the first few months. SSRIs have few anticholinergic, adrenolytic, and cardiac conduction effects. Sedation is minimal or nonexistent, but in the early weeks of treatment, some patients tend to be sleepy during the day. Loose stools or diarrhea occurs in some patients.

Drug interactions are relatively uncommon; however, fluoxetine, paroxetine, and fluvoxamine can inhibit cytochrome P-450 (CYP450) isoenzymes, which can lead to serious drug interactions. For example, these drugs can inhibit the metabolism of certain β-blockers, including propranolol and metoprolol, potentially resulting in hypotension and bradycardia. Discontinuation symptoms (eg, irritability, anxiety, nausea) can occur if the drug is stopped abruptly; such effects are less likely with fluoxetine.

Serotonin modulators (5-HT 2 blockers)

These drugs block primarily the 5-HT 2 receptor and inhibit reuptake of 5-HT and norepinephrine. Serotonin modulators include trazodone and mirtazapine. Serotonin modulators have antidepressant and anxiolytic effects but do not cause sexual dysfunction.

Trazodone does not inhibit 5-HT reuptake presynaptically. It has caused priapism (in 1/1000) and, as an α 1 -noradrenergic blocker, may cause orthostatic (postural) hypotension. It is very sedating, so its use in antidepressant doses (> 200 mg/day) is limited. It is most often given in 50- to 100-mg doses at bedtime to depressed patients with insomnia.

Mirtazapine inhibits 5-HT reuptake and blocks α 2 -adrenergic autoreceptors, as well as 5-HT 2 and 5-HT 3 receptors. The result is increased serotonergic function and increased noradrenergic function without sexual dysfunction or nausea. It has no cardiac adverse effects, has minimal interaction with drug-metabolizing liver enzymes, and is generally well-tolerated, although it does cause sedation and weight gain, mediated by H 1 (histamine) blockade.

Serotonin-norepinephrine reuptake inhibitors

These drugs (eg, desvenlafaxine, duloxetine, levomilnacipran, venlafaxine, vortioxetine) have a dual 5-HT and norepinephrine mechanism of action, as do tricyclic antidepressants. However, their toxicity approximates that of SSRIs. Nausea is the most common problem during the first 2 wk; modest dose-dependent increases in BP occur with high doses. Discontinuation symptoms (eg, irritability, anxiety, nausea) often occur if the drug is stopped suddenly. Duloxetine resembles venlafaxine in effectiveness and adverse effects.

Norepinephrine-dopamine reuptake inhibitor

By mechanisms not clearly understood, these drugs favorably influence catecholaminergic, dopaminergic, and noradrenergic function. They do not affect the 5-HT system.

Bupropion is currently the only drug in this class. It can help depressed patients with concurrent attention-deficit/hyperactivity disorder or cocaine dependence and those trying to stop smoking. Bupropion causes hypertension in a very few patients but has no other effects on the cardiovascular system. Bupropion can cause seizures in 0.4% of patients taking doses> 150 mg tid (or > 200 mg sustained-release [SR] bid or > 450 mg extended-release [XR] once/day); risk is increased in patients with bulimia. Bupropion does not have sexual adverse effects and interacts little with coadministered drugs, although it does inhibit the CYP2D6 hepatic enzyme. Agitation, which is common, is considerably attenuated by using the SR or XR form.

Heterocyclic antidepressants

This group of drugs, once the mainstay of treatment, includes tricyclic (tertiary amines amitriptyline and imipramine and their secondary amine metabolites nortriptyline and desipramine), modified tricyclic, and tetracyclic antidepressants. Acutely, these drugs increase the availability of primarily norepinephrine and, to some extent, 5-HT by blocking reuptake in the synaptic cleft. Long-term use downregulates α 1 -adrenergic receptors on the postsynaptic membrane—a possible final common pathway of their antidepressant activity.

Although effective, these drugs are now rarely used because overdose causes toxicity and they have more adverse effects than other antidepressants. The more common adverse effects of heterocyclics are due to their muscarinic-blocking, histamine-blocking, and α 1 -adrenolytic actions. Many heterocyclics have strong anticholinergic properties and are thus unsuitable for the elderly and for patients with benign prostatic hypertrophy, glaucoma, or chronic constipation. All heterocyclics, particularly maprotiline and clomipramine, lower the threshold for seizures.

Monoamine oxidase inhibitors (MAOIs)

These drugs inhibit the oxidative deamination of the 3 classes of biogenic amines (norepinephrine, dopamine, 5-HT) and other phenylethylamines. Their primary value is for treating refractory or atypical depression when SSRIs, tricyclic antidepressants, and sometimes even electroconvulsive therapy are ineffective.

MAOIs marketed as antidepressants in the US (eg, phenelzine, tranylcypromine, isocarboxazid) are irreversible and nonselective (inhibiting MAO-A and MAO-B). Another MAOI (selegiline), which inhibits only MAO-B at lower doses, is available as a patch.

MAOIs that inhibit MAO-A and MAO-B can cause hypertensive crises if a sympathomimetic drug or food containing tyramine or dopamine is ingested concurrently. This effect is called the cheese reaction because mature cheese has a high tyramine content. MAOIs are used infrequently because of concern about this reaction. The lower dosage of the selegiline patch is considered safe to use without specific dietary restrictions, unless the dosage must be higher than starting levels (a 6-mg patch). More selective and reversible MAOIs (eg, moclobemide, befloxatone), which inhibit MAO-A, are relatively free of these interactions but are not available in the US. To prevent hypertension and febrile crises, patients taking MAOIs should avoid sympathomimetic drugs (eg, pseudoephedrine), dextromethorphan, reserpine, and meperidine as well as malted beers, Chianti wines, sherry, liqueurs, and overripe or aged foods that contain tyramine or dopamine (eg, fava or broad beans, yeast extracts, canned figs, raisins, yogurt, cheese, sour cream, soy sauce, pickled herring, caviar, liver, banana peel, extensively tenderized meats). Patients can carry 25-mg tablets of chlorpromazine and, as soon as signs of such a hypertensive reaction occur, take 1 or 2 tablets as they head to the nearest emergency department.

Common adverse effects include erectile dysfunction (least common with tranylcypromine), anxiety, nausea, dizziness, insomnia, pedal edema, and weight gain. MAOIs should not be used with other classes of antidepressants, and at least 2 wk (5 wk with fluoxetine, which has a long half-life) should elapse between use of the 2 classes of drugs. MAOIs used with antidepressants that affect the 5-HT system (eg, SSRIs) may cause neuroleptic malignant syndrome (malignant hyperthermia, muscle breakdown, renal failure, seizures, and eventual death—see Neuroleptic Malignant Syndrome). Patients who are taking MAOIs and who also need antiasthmatic or antiallergic drugs, a local anesthetic, or a general anesthetic should be treated by a psychiatrist plus an internist, a dentist, or an anesthesiologist with expertise in neuropsychopharmacology.

Melatonergic antidepressant

Agomelatine is a melatonergic (MT1/MT2) agonist and a 5-HT 2C receptor antagonist. It is used for major depressive episodes. This drug has fewer adverse effects than most antidepressants and does not cause daytime sedation, insomnia, weight gain, or sexual dysfunction. It is not addictive and does not cause withdrawal symptoms. It may cause headache, nausea and diarrhea. It may also increase liver enzyme levels, and these levels should be measured before therapy is started and every 6 wk thereafter. It is contraindicated in patients with hepatic dysfunction. It is taken at bedtime at a dose of 25 mg.

Drug choice and administration

Choice of drug may be guided by past response to a specific antidepressant. Otherwise, SSRIs are often the initial drugs of choice. Although the different SSRIs are equally effective for typical cases, certain properties of the drugs make them more or less appropriate for certain patients (see Table: Antidepressants).

Antidepressants

Drug

Starting Dose*

Therapeutic Dosage Range

Precautions

Heterocyclics

Contraindicated in patients with coronary artery disease, certain arrhythmias, angle-closure glaucoma, benign prostatic hypertrophy, or esophageal hiatus hernia

Can cause orthostatic hypotension leading to falls and fractures, potentiate the effect of alcohol, and raise the blood level of antipsychotics

With significant overdose, potentially lethal

Amitriptyline

50 mg once/day

150–300 mg

Causes weight gain

Amoxapine

50 mg bid

150–400 mg

Can have extrapyramidal adverse effects

Clomipramine

25 mg once/day

100–250 mg

Lowers seizure threshold at doses of > 250 mg/day

Desipramine

25 mg once/day

150–300 mg

Doxepin

25 mg once/day

150–300 mg

Causes weight gain

Imipramine

25 mg once/day

150–300 mg

May cause excessive sweating and nightmares

Maprotiline

75 mg once/day

150–225 mg

Increased risk of seizures with rapid dose escalation at high doses

Nortriptyline

25 mg once/day

50–150 mg

Effective within the therapeutic window

Protriptyline

5 mg tid

15–60 mg

Has long half-life (74 h)

Trimipramine

50 mg once/day

150–300 mg

Causes weight gain

MAOIs

Serotonergic syndrome possible when taken with an SSRI

Hypertensive crisis possible when taken with other antidepressants, sympathomimetic or other selective drugs, or certain foods and beverages

With significant overdose, potentially lethal

Isocarboxazid

10 mg bid

30–60 mg

Causes orthostatic hypotension

Phenelzine

15 mg tid

45–90 mg

Causes orthostatic hypotension

Selegiline, transdermal

6 mg once/day

12 mg

Can cause application site reactions and insomnia

Tranylcypromine

10 mg bid

30–60 mg

Causes orthostatic hypotension

Has amphetamine-type stimulant effects and modest abuse potential

SSRIs

Cause discontinuation symptoms if stopped abruptly (less likely with fluoxetine)

Citalopram

20 mg once/day

20–40 mg

Lower potential for drug interactions because it has less effect on CYP450 isoenzymes

Risk of QT-interval prolongation that limits doses to ≤ 40 mg/day

Escitalopram

10 mg once/day

10–20 mg

Same as for citalopram

Fluoxetine

10 mg once/day

20–60 mg

Has very long half-life

Less likely to cause discontinuation symptoms

The only antidepressant proven effective in children

Fluvoxamine

50 mg once/day

100–200 mg

Can cause clinically significant elevation of theophylline, warfarin, and clozapine blood levels

Has potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type IC antiarrhythmics

Has CYP450 profile similar to fluoxetine

Paroxetine

20 mg once/day

25 mg CR once/day

20–50 mg

25–62.5 mg CR

Has potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type IC antiarrhythmics

Has CYP450 profile similar to fluoxetine

Of SSRIs, may cause the most weight gain

Sertraline

50 mg once/day

50–200 mg

Of SSRIs, has highest incidence of loose stools

Vilazodone

10 mg po once/day for 7 days, then increase to 20 mg daily for 7 days

10–40 mg (titrate by 5–10 mg q 7 days)

May increase risk of bleeding if the drug is taken with aspirin, other NSAIDs, or other drugs that affect coagulation

Should not be stopped abruptly; reduce dose gradually

Serotonin-norepinephrine reuptake inhibitors

Cause discontinuation symptoms if stopped abruptly

Desvenlafaxine

50 mg once/day

50–100 mg

May increase BP or HR (control BP before initiating the drug and monitor BP and HR while patients are taking the drug)

Duloxetine

20 mg bid

60–120 mg

Modest dose-dependent increase in systolic and diastolic BP

May cause mild urinary hesitancy in males

Less potential for drug-drug interactions because it has less effect on CYP450 isoenzymes

Levomilnacipran

20 mg once/day for 2 days, then 40 mg once/day

40–120 mg (increase dose in increments of 40 mg/day at intervals of ≥ 2 days; not to exceed 120 mg/day)

May increase BP or HR (control BP before initiating the drug and monitor BP and HR while patients are taking the drug)

May increase risk of bleeding (caution required if the drug is taken with aspirin, other NSAIDs, or anticoagulants)

Can affect urinary hesitation or retention (caution required in patients with obstructive urinary disorders; stop the drug if symptoms develop)

Venlafaxine

25 mg tid

37.5 mg XR once/day

75–375 mg

72–225 mg XR

Modest dose-dependent increase in diastolic BP

Dual norepinephrine and 5-HT reuptake effect at about 150 mg

Rarely, increase in systolic BP (not dose-dependent)

If stopped, should be tapered slowly

Less potential for drug-drug interactions because it has less effect on CYP450 isoenzymes

Vortioxetine

5–10 mg once/day

10–20 mg

Should caution patients about increased risk of bleeding when the drug is taken with aspirin, other NSAIDs, or other drugs that affect coagulation or bleeding

Serotonin modulators (5-HT 2 blockers)

Mirtazapine

15 mg once/day

15–45 mg

Causes weight gain and sedation

Has fewer sexual adverse effects than SSRIs and serotonin-norepinephrine reuptake inhibitors

Trazodone

50 mg tid

150–300 mg

May cause priapism

May cause orthostatic hypotension

Norepinephrine-dopamine reuptake inhibitor

Bupropion

100 mg bid

150 mg SR once/day

150 mg XL once/day

200–450 mg

Contraindicated in patients who have bulimia or who are seizure-prone

May interact with HCAs, increasing the risk of seizures

May cause dose-dependent recent memory loss

Melatonergic antidepressant

Agomelatine (5-HT 2C receptor antagonist)

25 mg once/day at bedtime

25–50 mg

Should be stopped immediately if symptoms or signs of potential liver injury develop or if serum transaminases increase to > 3 times the upper limit of normal

*All drugs are given orally except for transdermal selegiline.

CR = continuous release; CYP450 = cytochrome P-450 system; HCAs = heterocyclic antidepressants; HR = heart rate; 5-HT = 5-hydroxytryptamine (serotonin); MAOIs = monoamine oxidase inhibitors; SR = sustained release; XL = extended release; XR = extended release.

If one SSRI is ineffective, another SSRI can be substituted, or an antidepressant from a different class may be used instead. Tranylcypromine 20 to 30 mg po bid is often effective for depression refractory to sequential trials of other antidepressants; it should be given by a physician experienced in use of MAOIs. Psychologic support of patients and loved ones is particularly important in refractory cases.

Insomnia, a common adverse effect of SSRIs, is treated by reducing the dose or adding a low dose of trazodone or another sedating antidepressant. Initial nausea and loose stools usually resolve, but throbbing headaches do not always go away, necessitating a change in drug class. An SSRI should be stopped if it causes agitation. When decreased libido, impotence, or anorgasmia occur during SSRI therapy, dose reduction or a change to a serotonin modulator or a norepinephrine-dopamine reuptake inhibitor may help.

SSRIs, which tend to stimulate many depressed patients, should be given in the morning. Giving the entire heterocyclic antidepressant dose at bedtime usually makes sedatives unnecessary, minimizes adverse effects during the day, and improves adherence. MAOIs are usually given in the morning and early afternoon to avoid excessive stimulation.

Therapeutic response with most classes of antidepressants usually occurs in about 2 to 3 wk (sometimes as early as 4 days or as late as 8 wk). For a first episode of mild or moderate depression, the antidepressant should be given for 6 mo, then tapered gradually over 2 mo. If the episode is severe or is a recurrence or if there is suicidal risk, the dose that produces full remission should be continued during maintenance.

For psychotic depression, the combination of an antidepressant and an antipsychotic is more effective than either used alone. Patients who have recovered from psychotic depression are at higher risk of relapse than those who had nonpsychotic depression, so prophylactic treatment is particularly important.

Continued therapy with an antidepressant for 6 to 12 mo (up to 2 yr in patients > 50) is usually needed to prevent relapse. Most antidepressants, especially SSRIs, should be tapered off (by decreasing the dose by about 25%/wk) rather than stopped abruptly; stopping SSRIs abruptly may result in discontinuation syndrome (nausea, chills, muscles aches, dizziness, anxiety, irritability, insomnia, fatigue). The likelihood and severity of withdrawal varies inversely with the half-life of the SSRI.

Medicinal herbs are used by some patients. St. John’s wort (see St. John’s Wort) may be effective for mild depression, although data are contradictory. St. John’s wort may interact with other antidepressants and other drugs. Some placebo-controlled studies of ω-3 supplementation, used as augmentation or as monotherapy, have suggested that eicosapentaenoic acid 1 to 2 g once/day has useful antidepressant effects.

Electroconvulsive therapy (ECT)

Severe suicidal depression, depression with agitation or psychomotor retardation, delusional depression, or depression during pregnancy is often treated with ECT if drugs are ineffective. Patients who have stopped eating may need ECT to prevent death. ECT is particularly effective for psychotic depression. Response to 6 to 10 ECT treatments is usually dramatic and may be lifesaving. Relapse after ECT is common, and drug therapy is often maintained after ECT is stopped.

Phototherapy

Phototherapy is best known for its effects on seasonal depression but appears to be equally effective for nonseasonal depression. Treatment can be provided at home with 2,500 to 10,000 lux at a distance of 30 to 60 cm for 30 to 60 min/day (longer with a less intense light source). In patients who go to sleep late at night and rise late in the morning, phototherapy is most effective in the morning, sometimes supplemented with 5 to 10 min of exposure between 3 pm and 7 pm . For patients who go to sleep and rise early, phototherapy is most effective between 3 pm and 7 pm .

Other therapies

Psychostimulants (eg, dextroamphetamine, methylphenidate) are sometimes used, often with antidepressants; however, they have not been studied in controlled clinical trials.

Vagus nerve stimulation involves intermittently stimulating the vagus nerve via an implanted pulse generator. It may be useful for depression refractory to other treatments but usually takes 3 to 6 mo to be effective.

Substantial evidence from controlled trials supports the use of repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depressive disorder. Low-frequency rTMS may be applied to the right dorsolateral prefrontal cortex (DLPC), and high-frequency rTMS can be applied to the left DLPC. The most common adverse effects are headaches and scalp discomfort; both occur more often when high-frequency rather than low-frequency rTMS is used.

Deep brain stimulation targeting the subgenual cingulate or the anterior ventral internal capsule/ventral striatum has had promising results in uncontrolled case series. Controlled trials are underway.

Key Points

  • Depression is a common disorder that involves depressed mood and/or near-complete loss of interest or pleasure in activities that were previously enjoyed; somatic (eg, weight change, sleep disturbance) and cognitive manifestations (eg, difficulty concentrating) are common.

  • Depression may markedly impair the ability to function at work and to interact socially; risk of suicide is significant.

  • Sometimes depressive symptoms are caused by physical disorders (eg, thyroid or adrenal gland disorders, benign or malignant brain tumors, stroke, AIDS, Parkinson disease, multiple sclerosis) or use of certain drugs (eg, corticosteroids, some β-blockers, interferon, some recreational drugs).

  • Diagnosis is based on clinical criteria; physical disorders must be ruled out by clinical evaluation and selected testing (eg, CBC; electrolyte, TSH, B 12 and folate levels).

  • Treatment involves psychotherapy and usually drugs; SSRIs are usually tried first, and if they are ineffective, other drugs that affect serotonin and/or norepinephrine may be tried.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • REGLAN
  • No US brand name
  • MARQIBO KIT
  • No brand name
  • INDERAL
  • SEROMYCIN
  • INDOCIN
  • PARLODEL
  • TAGAMET
  • CONCERTA, RITALIN
  • ZOLOFT
  • PROZAC, SARAFEM
  • LEXAPRO
  • LOPRESSOR, TOPROL-XL
  • PAXIL
  • LUVOX
  • CELEXA
  • LEVOPHED
  • OLEPTRO
  • REMERON
  • CYMBALTA
  • PRISTIQ
  • EFFEXOR XR
  • FETZIMA
  • WELLBUTRIN, ZYBAN
  • ANAFRANIL
  • AVENTYL
  • TOFRANIL
  • NORPRAMIN
  • NARDIL
  • DEMEROL
  • DELSYM
  • AFRINOL, SUDAFED
  • PARNATE
  • ELDEPRYL
  • MARPLAN
  • VIVACTIL
  • ZONALON
  • COUMADIN
  • CLOZARIL
  • ELIXOPHYLLIN
  • TEGRETOL
  • DEXEDRINE

* This is a professional Version *