Medications for Treatment of Depression

Patients and their loved ones should be warned that a few patients may seem more agitated, depressed, and anxious within a week of starting an antidepressant or increasing the dose; symptoms that worsen with treatment should be reported to the physician. This situation should be closely monitored because some patients, especially children and adolescents, become increasingly suicidal if agitation, increased depression, and anxiety are not detected and rapidly treated.

Several analyses of the Food and Drug Administration (FDA) database of industry-sponsored trials led to a boxed warning that antidepressants in general are associated with an increased risk of emergence of suicidal ideas and suicide attempts in patients aged ≤ 24 years. Subsequent analyses of FDA and other data have cast doubt on this conclusion (1).

Evidence suggests that risk of suicidality does not differ among classes of antidepressants, including SSRIs, SNRIs, tricyclic antidepressants, and MAOIs. Evidence is not adequate to determine quantitatively the risk associated with specific antidepressants.

These medications prevent reuptake of serotonin (5-hydroxytryptamine [5-HT]). SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. Although these medications have the same mechanism of action, differences in their clinical properties make selection important. Selective serotonin reuptake inhibitors (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-HT₁ receptors, with antidepressant and anxiolytic effects, but they also stimulate 5-HT₂ receptors, commonly causing anxiety, insomnia, and sexual dysfunction, and 5-HT₃ 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, and there have been concerns about SSRIs and potential suicidality.

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 medications can inhibit the metabolism of certain beta-blockers, including propranolol and metoprolol, potentially resulting in hypotension and bradycardia.

Discontinuation symptoms (eg, irritability, anxiety, nausea) can occur if the medication is stopped abruptly; such effects are less likely with fluoxetine.

These medications block primarily the 5-HT₂ receptor and inhibit reuptake of 5-HT and norepinephrine. Serotonin modulators include

• Trazodone

• Mirtazapine

Serotonin modulators have antidepressant and anxiolytic effects but do not cause sexual dysfunction.

Trazodone has caused priapism (in 1/1000) and, as an alpha-1 noradrenergic blocker, may cause orthostatic (postural) hypotension. It is very sedating, so its use in antidepressant doses (eg, > 200 mg/day) is limited. It is most often given at bedtime to depressed patients with insomnia.

Mirtazapine is a 5-HT antagonist and blocks alpha-2 adrenergic autoreceptors, as well as 5-HT₂ and 5-HT₃ 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 H₁ (histamine) blockade.

These medications (eg, desvenlafaxine, duloxetine, levomilnacipran, venlafaxine, vortioxetine) have a dual 5-HT and norepinephrine mechanism of action, as do tricyclic antidepressants (TCAs).

However, their toxicity approximates that of selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common problem during the first 2 weeks; modest dose-dependent increases in blood pressure (BP) occur with high doses. Discontinuation symptoms (eg, irritability, anxiety, nausea) often occur if the medication is stopped suddenly.

Duloxetine resembles venlafaxine in effectiveness and adverse effects.

By mechanisms not clearly understood, this medication class favorably influences dopaminergic and noradrenergic function and does not affect the 5-HT system.

Bupropion is currently the only medication in this class. It can help depressed patients with concurrent attention-deficit/hyperactivity disorder or cocaine use disorder 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 three times a day (or > 200 mg sustained-release [SR] twice a day or > 450 mg extended-release [XR] once a day) (1); 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.

This group of medications, 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, heterocyclic antidepressants increase the availability of primarily norepinephrine and, to some extent, 5-HT by blocking reuptake in the synaptic cleft. Long-term use downregulates alpha-1 adrenergic receptors on the postsynaptic membrane—a possible final common pathway of their antidepressant activity.

Although effective, these medications 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 alpha-1 adrenolytic actions. Many heterocyclics have strong anticholinergic properties and are thus unsuitable for older patients and those with benign prostatic hypertrophy, glaucoma, or chronic constipation. All heterocyclics, particularly maprotiline and clomipramine, lower the threshold for seizures.

These medications 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 selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and sometimes even electroconvulsive therapy (ECT) are ineffective.

Monoamine oxidase inhibitors (MAOIs) marketed as antidepressants in the United States (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.

Hypertensive crises can occur if MAOIs that inhibit MAO-A and MAO-B are ingested concurrently with a sympathomimetic medication or food containing tyramine or dopamine. 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 United States.

To prevent hypertension and febrile crises, patients taking MAOIs should avoid sympathomimetic medications (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).

Common adverse effects of MAOIs 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 weeks (5 weeks 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 serotonin syndrome (a potentially life-threatening condition whereby patients may exhibit mental status changes, hyperthermia, and autonomic and neuromuscular hyperactivity).

Patients who are taking MAOIs and who also need anti-asthmatic or anti-allergy medications, 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.

Agomelatine is a melatonergic (MT1/MT2) agonist and a 5-HT_2C receptor antagonist that is taken at bedtime. It is used for major depressive episodes.

Agomelatine 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 weeks thereafter. It is contraindicated in patients with hepatic dysfunction.

Numerous studies have shown that subanesthetic, rather than anesthetic, doses of ketamine often produce a uniquely rapid, though typically short-lived, resolution of depressive symptoms in patients with treatment-resistant major depressive disorder (1). The s-enantiomer of ketamine, esketamine, is also available for use in this population (2).

The presumed mechanism of action of subanesthetic ketamine is of particular interest because it does not primarily involve action at monoamine receptors, as is the case with nearly all other currently approved antidepressants. Instead, effects are thought to begin with the blockade of the N-methyl-D-aspartic acid (NMDA) receptor that disinhibits glutamate release. This, in turn, increases brain-derived neurotrophic factor (BDNF) synthesis, and through the activation of both mammalian target of rapamycine (mTOR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors, leads to rapid increases in dendritic spine density in the cortical pyramidal cells specifically affected by chronic stress and hypercortisolemia.

The majority of patients given an antidepressant dose of ketamine experience a global improvement in depressive symptoms that peaks in 3 to 4 hours and then, in most cases, wanes over the next 1 to 2 weeks. Multiple administrations over several weeks lengthen the duration of improvement, but relapse rates are high over the ensuing months. Many ketamine clinics titrate the interval between treatments, and some patients can maintain improvement with only monthly treatments

Adverse effects are generally limited to a period of one to 2 hours following administration and include derealization, increases in blood pressure, nausea, and vomiting. Because ketamine has a well-known abuse potential, administration should be confined to the office or hospital setting.

Ketamine is typically given intravenously in this setting but is also available orally or intranasally. Esketamine is given intranasally.

The patient should be monitored in the clinic for 2 hours after administration and be advised not to drive until the following day. Acutely increased blood pressure may require intervention.

Choice of medication may be guided by past response to a specific antidepressant. Otherwise, selective serotonin reuptake inhibitors (SSRIs) are often the initial medications of choice. Although the different SSRIs are equally effective for typical cases, certain properties make them more or less appropriate for certain patients (see table Antidepressants).

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

Insomnia, a common adverse effect of SSRIs, is managed by reducing the dose, giving the dose in the morning, or adding a low dose of trazodone or another sedating antidepressant at bedtime. Initial nausea and loose stools usually resolve, but throbbing headaches do not always remit, necessitating a change in medication 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 weeks (sometimes as early as 4 days or as late as 8 weeks). For a first episode of mild or moderate depression, the antidepressant should be given for 6 months, then tapered gradually over 2 months. If the episode is severe or is a recurrence or if there is suicidal risk, the dose that produces full remission should be continued as maintenance.

For psychotic depression, the combination of an antidepressant and an antipsychotic is more effective than either used alone (1). 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 months (up to 2 years in patients > 50) is usually needed to prevent relapse.

Most antidepressants, especially SSRIs, should be tapered off (by decreasing the dose by about 25%/week) rather than stopped abruptly; stopping SSRIs abruptly may result in discontinuation syndrome (nausea, chills, muscle aches, dizziness, anxiety, irritability, insomnia, fatigue). The likelihood and severity of withdrawal varies inversely with the half-life of the SSRI.