Clinical Manifestations
Major depression is defined as depressed mood on a daily basis for a minimum duration of 2 weeks (Table 371-9). An episode may be characterized by sadness, indifference, apathy, or irritability and is usually associated with: changes in sleep patterns, appetite, and weight; motor agitation or retardation; fatigue; impaired concentration and decision-making; feelings of shame or guilt; and thoughts of death or dying. Patients with depression have a profound loss of pleasure in all enjoyable activities, exhibit early morning awakening, feel that the dysphoric mood state is qualitatively different from sadness, and often notice a diurnal variation in mood (worse in morning hours).

Approximately 15% of the population experiences a major depressive episode at some point in life, and 6 to 8% of all outpatients in primary care settings satisfy diagnostic criteria for the disorder. Depression is often undiagnosed, and, even more frequently, it is treated inadequately.

If a physician suspects the presence of a major depressive episode, the initial task is to determine whether it represents unipolar or bipolar depression or is one of the 10 to 15% of cases that are secondary to general medical illness or substance abuse. Physicians should also assess the risk of suicide by direct questioning, as patients are often reluctant to verbalize such thoughts without prompting. If specific plans are uncovered or if significant risk factors exist (e.g., a past history of suicide attempts, profound hopelessness, concurrent medical illness, substance abuse, or social isolation), the patient must be referred to a mental health specialist for immediate care. The physician should specifically probe each of these areas in an empathic and hopeful manner, being sensitive to denial and possible minimization of distress. The presence of anxiety, panic, or agitation significantly increases near-term suicidal risk. Approximately 4 to 5% of all depressed patients will commit suicide; most will have sought help from a physician within 1 month of their death.

In some depressed patients, the mood disorder does not appear to be episodic and is not clearly associated with either psychosocial dysfunction or change from the individual’s usual experience in life. Dysthymic disorder consists of a pattern of chronic (at least 2 years), ongoing, mild depressive symptoms that are less severe and less disabling than those found in major depression; the two conditions are sometimes difficult to separate, however, and can occur together (“double depression”). Many patients who exhibit a profile of pessimism, disinterest, and low self-esteem respond to antidepressant treatment. Dysthymic disorder exists in 5% of primary care patients. The term minor depression is used for individuals who experience at least two depressive symptoms for 2 weeks, but who do not meet the full criteria for major depression. Despite its name, minor depression is associated with significant morbidity and disability and also responds to pharmacologic treatment.

Depression is approximately twice as common in women as in men, and the incidence increases with age in both sexes. Twin studies indicate that the liability to major depression in adult women is largely genetic in origin. Negative life events can precipitate and contribute to depression, but genetic factors influence the sensitivity of individuals to these stressful events. In most cases, both biologic and psychosocial factors are involved in the precipitation and unfolding of depressive episodes. The most potent stressors appear to involve death of a relative, assault, or severe marital or relationship problems.

Unipolar depressive disorders usually begin in early adulthood and recur episodically over the course of a lifetime. The best predictor of future risk is the number of past episodes; 50 to 60% of patients who have a first episode have at least one or two recurrences. Some patients experience multiple episodes that become more severe and frequent over time. The duration of an untreated episode varies greatly, ranging from a few months to 1 year. The pattern of recurrence and clinical progression in a developing episode are also variable. Within an individual, the nature of attacks (e.g., specific presenting symptoms, frequency and duration of episodes) may be similar over time. In a minority of patients, a severe depressive episode may progress to a psychotic state; in elderly patients, depressive symptoms may be associated with cognitive deficits mimicking dementia (“pseudodementia”). A seasonal pattern of depression, called seasonal affective disorder, may manifest with onset and remission of episodes at predictable times of the year. This disorder is more common in women, whose symptoms are anergy, fatigue, weight gain, hypersomnia, and episodic carbohydrate craving. The prevalence increases with distance from the equator, and improvement may occur by altering light exposure.

Etiology and Pathophysiology
Although evidence for genetic transmission of unipolar depression is not as strong as in bipolar disorder, monozygotic twins have a higher concordance rate (46%) than dizygotic siblings (20%), with little evidence for any effect of a shared family environment. A recent study indicated that a functional polymorphism in the serotonin transporter (5-HTT) gene may interact with stressful life events to markedly increase risk of depression and suicide. Positron emission tomography (PET) studies show decreased metabolic activity in the caudate nuclei and frontal lobes in depressed patients that returns to normal with recovery. Single-photon emission computed tomography (SPECT) studies show comparable changes in blood flow.

Postmortem examination of brains of suicide victims indicate altered noradrenergic activity, including increased binding to _α1-, _α2-, and ß-adrenergic receptors in the cerebral cortex and decreased numbers of noradrenergic neurons in the locus coeruleus. Involvement of the serotonin system is suggested by findings of reduced plasma tryptophan levels, a decreased cerebrospinal fluid level of 5-hydroxyindolacetic acid (the principal metabolite of serotonin in brain), and decreased platelet serotonergic transporter binding. An increase in brain serotonin receptors in suicide victims and decreased expression of the cyclic AMP response element-binding (CREB) protein are also reported. Depletion of blood tryptophan, the amino acid precursor of serotonin, rapidly reverses the antidepressant benefit in depressed patients who have been successfully treated. However, a decrement in mood after tryptophan reduction is considerably less robust in untreated patients, indicating that, if presynaptic serotonergic dysfunction occurs in depression, it likely plays a contributing rather than a causal role.

Neuroendocrine abnormalities that reflect the neurovegetative signs and symptoms of depression include (1) increased cortisol and corticotropin-releasing hormone (CRH) secretion, (2) an increase in adrenal size, (3) a decreased inhibitory response of glucocorticoids to dexamethasone, and (4) a blunted response of thyroid-stimulating hormone (TSH) level to infusion of thyroid-releasing hormone (TRH). Antidepressant treatment leads to normalization of these pituitary-adrenal abnormalities. Major depression is also associated with an upregulation of proinflammatory cytokines, which normalizes with antidepressant treatment.

Diurnal variations in symptom severity and alterations in circadian rhythmicity of a number of neurochemical and neurohumoral factors suggest that biologic differences may be secondary to a primary defect in regulation of biologic rhythms. Patients with major depression show consistent findings of a decrease in rapid eye movement (REM) sleep onset (REM latency), an increase in REM density, and, in some subjects, a decrease in stage IV delta slow-wave sleep.

Although antidepressant drugs inhibit neurotransmitter uptake within hours, their therapeutic effects typically emerge over several weeks, implicating adaptive changes in second messenger systems and transcription factors as possible mechanisms of action. Antidepressant drugs have been shown to regulate neural plasticity and cell survival by increasing the expression of brain-derived neurotrophic factor (BDNF) through upregulation of the CREB protein and to alter stress responsivity through an increase in glucocorticoid receptor transcription. Secondary effects on activation of the mitogen-activated protein (MAP) kinase and phosphoinositol-3 kinase/AKT pathways and increased expression of the antiapoptotic protein, Bcl-2, are also thought to be critical to antidepressant actions.

Treatment
Treatment planning requires coordination of short-term symptom remission with longer term maintenance strategies designed to prevent recurrence. The most effective intervention for achieving remission and preventing relapse is medication, but combined treatment, incorporating psychotherapy to help the patient cope with decreased self-esteem and demoralization, improves outcome (Fig. 371-1). About 40% of primary care patients with depression drop out of treatment and discontinue medication if symptomatic improvement is not noted within a month, unless additional support is provided. Outcome improves with (1) increased intensity and frequency of visits during the first 4 to 6 weeks of treatment, (2) supplemental educational materials, and (3) psychiatric consultation as indicated. Despite the widespread use of SSRIs, there is no convincing evidence that this class of antidepressant is more efficacious than TCAs. Between 60 and 70% of all depressed patients respond to any drug chosen, if it is given in a sufficient dose for 6 to 8 weeks. There is no ideal antidepressant; no current compound combines rapid onset of action, moderate half-life, a meaningful relationship between dose and blood level, a low side-effect profile, minimal interaction with other drugs, and safety in overdose. A rational approach to selecting which antidepressant to use involves matching the patient’s preference and medical history with the metabolic and side effect profile of the drug (Tables 371-4 and 371-5). A previous response, or a family history of a positive response, to a specific antidepressant would suggest that that drug be tried first. Before initiating antidepressant therapy, the physician should evaluate the possible contribution of comorbid illnesses and consider their specific treatment. In individuals with suicidal ideation, particular attention should be paid to choosing a drug with low toxicity if taken in overdose. The SSRIs and other newer antidepressant drugs are distinctly safer in this regard; nevertheless, the advantages of TCAs have not been completely superseded. The existence of generic equivalents make TCAs relatively cheap, and for several tricyclics, particularly nortriptyline, imipramine, and desipramine, well-defined relationships among dose, plasma level, and therapeutic response exist. The steady-state plasma level achieved for a given drug dose can vary more than tenfold between individuals. Plasma levels may help in interpreting apparent resistance to treatment and/or unexpected drug toxicity. The principal side effects of TCAs are antihistamine (sedation) and anticholinergic (constipation, dry mouth, urinary hesitancy, blurred vision). Cardiac toxicity due to conduction block or arrhythmias can also occur but is uncommon at therapeutic levels. TCAs are probably contraindicated in patients with serious cardiovascular risk factors. Overdoses of tricyclic agents can be lethal, with desipramine carrying the greatest risk. It is judicious to prescribe only a 10-day supply when suicide is a risk. Most patients require a daily dose of 150 to 200 mg of imipramine or amitriptyline or its equivalent to achieve a therapeutic blood level of 150 to 300 ng/mL and a satisfactory remission; some patients show a partial effect at lower doses. Geriatric patients may require a low starting dose and slow escalation. Ethnic differences in drug metabolism are significant; Hispanic, Asian, and African-American patients generally require lower doses than Caucasians to achieve a comparable blood level.
Figure 371-1
A guideline for the medical management of major depressive disorder. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Second-generation antidepressants include amoxapine, maprotiline, trazodone, and bupropion. Amoxapine is a dibenzoxazepine derivative that blocks norepinephrine and serotonin reuptake and has a metabolite that shows a degree of dopamine blockade. Long-term use of this drug carries a risk of tardive dyskinesia. Maprotiline is a potent noradrenergic reuptake blocker that has little anticholinergic effect but may produce seizures. Bupropion is a novel antidepressant whose mechanism of action is thought to involve enhancement of noradrenergic function. It has no anticholinergic, sedating, or orthostatic side effects and has a low incidence of sexual side effects. It may, however, be associated with stimulant-like side effects, may lower seizure threshold, and has an exceptionally short half-life, requiring frequent dosing. An extended-release preparation is available.

SSRIs such as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and duloxetine cause a lower frequency of anticholinergic, sedating, and cardiovascular side effects but a possibly greater incidence of gastrointestinal complaints, sleep impairment, and sexual dysfunction than do TCAs. Akathisia, involving an inner sense of restlessness and anxiety in addition to increased motor activity, may also be more common, particularly during the first week of treatment. A concern is the risk of “serotonin syndrome,” thought to result from hyperstimulation of brainstem 5HT1A receptors and characterized by myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, and potentially death. Serotonergic agonists taken in combination should be monitored closely for this reason. Considerations such as half-life, compliance, toxicity, and drug-drug interactions may guide the choice of a particular SSRI. Fluoxetine and its principal active metabolite, norfluoxetine, for example, have a combined half-life of almost 7 days, resulting in a delay of 5 weeks before steady-state levels are achieved and a similar delay for complete drug excretion once its use is discontinued. All the SSRIs may impair sexual function, resulting in diminished libido, impotence, or difficulty in achieving orgasm. Sexual dysfunction frequently results in noncompliance and should be asked about specifically. Sexual dysfunction can sometimes be ameliorated by lowering the dose, by instituting weekend drug holidays (two or three times a month), or by treatment with amantadine (100 mg tid), bethanechol (25 mg tid) buspirone (10 mg tid), or bupropion (100–150 mg/d). Paroxetine appears to be more anticholinergic than either fluoxetine or sertraline, and sertraline carries a lower risk of producing an adverse drug interaction than the other two. Rare side effects of SSRIs include angina due to vasospasm and prolongation of the prothrombin time. Escitalopram is the most specific of currently available SSRIs and appears to have no specific inhibitory effects on the P450 system.

Recently, case-control studies have shown an association between initiation of SSRI medications for depression and an increased risk of suicidal ideation. This risk has been demonstrated mainly in children and adolescents and is highest just after beginning therapy. Based on this data, the United States Food and Drug Administration in 2004 issued a warning urging physicians to carefully monitor suicidal symptoms in their pediatric as well as adult patients after initiation of these medicines.

Venlafaxine, like imipramine, blocks the reuptake of both norepinephrine and serotonin, but it produces relatively little in the way of traditional tricyclic side effects. Unlike the SSRIs, it has a relatively linear dose-response curve. Patients should be monitored for a possible increase in diastolic blood pressure, and multiple daily dosing is required because of the drug’s short half-life. An extended-release form is available and has a somewhat lower incidence of gastrointestinal side effects. Nefazadone is a selective 5HT₂ receptor antagonist that also inhibits the presynaptic reuptake of serotonin and norepinephrine. Its side effects are similar to those of the SSRIs, and twice-daily dosing produces a steady state within 4 to 5 days. The drug is related structurally to trazodone, which is currently used more for its sedative than its antidepressant properties. Nefazadone appears to produce a lower incidence of sexual side effects than do the SSRIs. Mirtazapine is a tetracyclic antidepressant that has a unique spectrum of activity. It increases noradrenergic and serotonergic neurotransmission through a blockade of central _α2- adrenergic receptors and postsynaptic 5HT₂ and 5HT₃ receptors. It is also strongly antihistaminic and, as such, may produce sedation.

With the exception of citalopram and escitalopram, each of the SSRIs, as well as nefazadone, may inhibit one or more cytochrome P450 enzymes. Depending on the specific isoenzyme involved, the metabolism of a number of concomitantly administered medications can be dramatically affected. Fluoxetine and paroxetine, for example, by inhibiting 2D6, can cause dramatic increases in the blood level of type 1C antiarrhythmics, while sertraline and nefazadone, by acting on 3A4, may alter blood levels of terfenadine, carbamazepine, and astemizole. Many of these compounds have a narrow therapeutic window and can cause iatrogenic ventricular arrhythmias at toxic levels; thus, the possibility of an adverse drug interaction should always be considered.

The MAOIs are highly effective, particularly in atypical depression, but the risk of hypertensive crisis following intake of tyramine-containing food or sympathomimetic drugs makes them inappropriate as first-line agents. Common side effects include orthostatic hypotension, weight gain, insomnia, and sexual dysfunction. MAOIs should not be used concomitantly with SSRIs, because of the risk of serotonin syndrome, or with TCAs, because of possible hyperadrenergic effects.

Electroconvulsive therapy is at least as effective as medication, but its use is reserved for treatment-resistant cases and delusional depressions. Transcranial magnetic stimulation (TMS) is an investigational treatment of depression that has been shown to have efficacy in several controlled trials; it is uncertain whether the observed benefits were clinically meaningful, however. Vagus nerve stimulation (VNS) appeared to be effective in treatment-resistant depression in an initial open study, only to fail in a controlled trial.

Regardless of the treatment undertaken, the response should be evaluated after 2 months. Three-quarters of patients show improvement by this time, but if remission is inadequate the patient should be questioned about compliance and an increase in medication dose should be considered if side effects are not troublesome. If this approach is unsuccessful, referral to a mental health specialist is advised. Strategies for treatment then include selection of an alternative drug, combinations of antidepressants, and/or adjunctive treatment with other classes of drugs, including lithium, thyroid hormone, and dopamine agonists. Patients whose response to an SSRI wanes over time may benefit from the addition of buspirone (10 mg tid) or pindolol (2.5 mg tid) or small amounts of a TCA such as desipramine (25 mg bid or tid). Once significant remission is achieved, drug treatment should be continued for at least 6 to 9 months to prevent relapse. In patients who have had two or more episodes of depression, indefinite maintenance treatment should be considered.

It is essential to educate patients both about depression and the benefits and side effects of medications they are receiving. Advice about stress reduction and cautions that alcohol may exacerbate depressive symptoms and impair drug response are helpful. Patients should be given time to describe their experience, their outlook, and the impact of the depression on them and their families. Occasional empathic silence may be as helpful for the treatment alliance as verbal reassurance. Controlled trials have shown that cognitive-behavioral and interpersonal therapies are effective in improving psychological and social adjustment and that a combined treatment approach is more successful than medication alone for many patients.