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Drug Treatment of Depression

By William Coryell, MD, George Winokur Professor of Psychiatry, Carver College of Medicine at University of Iowa

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Several drug classes and drugs can be used to treat depression:

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 (Antidepressants).

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-HT1 receptors, with antidepressant and anxiolytic effects, but they also stimulate 5-HT2 receptors, commonly causing anxiety, insomnia, and sexual dysfunction, and 5-HT3receptors, 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 (1).

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 beta-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.

Selective serotonin reuptake inhibitors (SSRIs) reference

Serotonin Modulators (5-HT 2 Blockers)

These drugs 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 does not inhibit 5-HT reuptake presynaptically. It 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 (> 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 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.

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, 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 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 alpha-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.

Hypertensive crises can occur if MAOIs that inhibit MAO-A and MAO-B are ingested concurrently with a sympathomimetic drug 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 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).

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-HT2C receptor antagonist. 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 wk thereafter. It is contraindicated in patients with hepatic dysfunction.

Agomelatine 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).



Starting Dose*

Therapeutic Dosage Range



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


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


10 mg once/day

10–20 mg

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


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


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


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


50 mg once/day

50–200 mg

Of SSRIs, has highest incidence of loose stools


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 modulators (5-HT2 blockers)


15 mg once/day

15–45 mg

Causes weight gain and sedation

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


50 mg tid

150–300 mg

May cause priapism

May cause orthostatic hypotension

Serotonin-norepinephrine reuptake inhibitors

Cause discontinuation symptoms if stopped abruptly


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)


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


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)


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


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

Norepinephrine-dopamine reuptake inhibitor


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


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


50 mg once/day

150–300 mg

Causes weight gain


50 mg bid

150–400 mg

Can have extrapyramidal adverse effects


25 mg once/day

100–250 mg

Lowers seizure threshold at doses of > 250 mg/day


25 mg once/day

150–300 mg


25 mg once/day

150–300 mg

Causes weight gain


25 mg once/day

150–300 mg

May cause excessive sweating and nightmares


75 mg once/day

150–225 mg

Increased risk of seizures with rapid dose escalation at high doses


25 mg once/day

50–150 mg

Effective within the therapeutic window


5 mg tid

15–60 mg

Has long half-life (74 h)


50 mg once/day

150–300 mg

Causes weight gain


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


10 mg bid

30–60 mg

Causes orthostatic hypotension


15 mg tid

45–90 mg

Causes orthostatic hypotension

Selegiline, transdermal

6 mg once/day

12 mg

Can cause application site reactions and insomnia


10 mg bid

30–60 mg

Causes orthostatic hypotension

Has amphetamine-type stimulant effects and modest abuse potential

Melatonergic antidepressant

Agomelatine (5-HT2C 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.

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