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Drug Treatment of Depression

By

William Coryell

, MD, Carver College of Medicine at University of Iowa

Last full review/revision Mar 2020| Content last modified Mar 2020
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Topic Resources

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 (see table Antidepressants and Depressive Disorders: Treatment).

Antidepressants and suicide risk

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 younger 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 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 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, serotonin- norepinephrine reuptake inhibitors, tricyclic antidepressants, and MAOIs. Evidence is not adequate to determine the risk associated with specific antidepressants.

General reference

  • 1. Dragioti E, Solmi M, Favaro A, et al: Association of antidepressant use with adverse health outcomes: A systematic umbrella review. JAMA Psychiatry 76 (12):1241–1255, 2019. .

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-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 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.

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 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 drug is stopped suddenly.

Duloxetine resembles venlafaxine in effectiveness and adverse effects.

Norepinephrine-Dopamine Reuptake Inhibitor

By mechanisms not clearly understood, this class of drug favorably influences catecholaminergic, dopaminergic, and noradrenergic function and does 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 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); 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 older patients and those 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 selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and sometimes even electroconvulsive therapy (ECT) are ineffective.

Monoamine oxidase inhibitors (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 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 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 weeks thereafter. It is contraindicated in patients with hepatic dysfunction.

Agomelatine is taken at bedtime at a dose of 25 mg.

Ketamine-Like Drug

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. The Food and Drug Administration (FDA) recently awarded an indication for the use of esketamine, the s-enantiomer of ketamine, in this population.

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 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 one 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.

The starting dose is 0.5 mg/kg for IV ketamine and 56 mg for intranasal esketamine. There is no evidence of increased effectiveness for doses above 0.5 mg/kg for IV ketamine. The therapeutic range for intranasal esketamine is 56 to 84 mg.

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.

Drug Choice and Administration of Antidepressants

Choice of drug may be guided by past response to a specific antidepressant. Otherwise, selective serotonin reuptake inhibitors (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).

Table
icon

Antidepressants

Drug

Starting Dose*

Therapeutic Dosage Range

Precautions

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

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

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 1C 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 1C 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 orally once/day for 7 days, then increase to 20 mg daily for 7 days

10–40 mg (titrate by 5–10 mg every 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)

Cause discontinuation symptoms† if stopped abruptly

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 three times/day

150–300 mg

May cause priapism and sedation

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 twice a day

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 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 three times/day

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

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

Norepinephrine- dopamine reuptake inhibitor

Bupropion

100 mg twice/day

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

Heterocyclics

Contraindicated in patients with coronary artery disease, certain arrhythmias, angle-closure glaucoma, benign prostatic hyperplasia, 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

Cause discontinuation symptoms† if stopped abruptly

With significant overdose, potentially lethal

Amitriptyline

50 mg once/day

150–300 mg

Causes weight gain

Amoxapine

50 mg twice/day

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

Metabolized only via CYP2D6 isoenzyme: Drugs that inhibit this enzyme markedly increase plasma levels

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 three times/day

15–60 mg

Has long half-life (74 hours)

Trimipramine

50 mg once/day

150–300 mg

Causes weight gain

MAOIs

Serotonin 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 twice/day

30–60 mg

Phenelzine

15 mg three times/day

45–90 mg

Selegiline, transdermal

6 mg once/day

12 mg

Can cause application site reactions and insomnia

Tranylcypromine

10 mg twice/day

30–60 mg

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 aminotransferases increase to > 3 times the upper limit of normal

* All drugs are given orally except for transdermal selegiline.

† Discontinuation symptoms include nausea, chills, muscle aches, dizziness, anxiety, irritability, insomnia, and fatigue.

BP = blood pressure; CR = continuous release; CYP450 = cytochrome P-450 system; HCAs = heterocyclic antidepressants; HR = heart rate; 5-HT = 5-hydroxytryptamine ( serotonin); MAOIs = monoamine oxidase inhibitors; NSAID = nonsteroidal anti-inflammatory; SR = sustained release; SSRIs = selective serotonin reuptake inhibitors; 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 orally twice a day 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. Monoamine oxidase inhibitors (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 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 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%/wk) 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.

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