Several drug classes and drugs are used to treat depression:
Serotonin modulators (5-HT2 blockers)
Heterocyclic antidepressants (HCAs), including tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
Choice and Initiation of Antidepressants
Choice of medication may be guided by the patient's 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. Antidepressant medications are often used in conjunction with psychotherapy (see table and Depressive Disorders: Treatment).
Antidepressants
Drug Class | Specific Medication | Selected Precautions* |
|---|---|---|
Selective Serotonin Reuptake Inhibitors (SSRIs) | Cause discontinuation symptoms† if stopped abruptly (less likely with fluoxetine)Cause discontinuation symptoms† if stopped abruptly (less likely with fluoxetine) | |
CitalopramCitalopram | 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 | |
FluoxetineFluoxetine | Has very long half-life Less likely to cause discontinuation symptoms† The only antidepressant proven effective in children | |
FluvoxamineFluvoxamine | Can cause clinically significant elevation of theophylline, warfarin, and clozapine blood levelsCan 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 antiarrhythmicsHas potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type 1C antiarrhythmics Has CYP450 profile similar to fluoxetineHas CYP450 profile similar to fluoxetine | |
ParoxetineParoxetine | Has potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type 1C antiarrhythmicsHas potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type 1C antiarrhythmics Has CYP450 profile similar to fluoxetineHas CYP450 profile similar to fluoxetine Of SSRIs, may cause the most weight gain | |
SertralineSertraline | Of SSRIs, has highest incidence of loose stools | |
VilazodoneVilazodone | May increase risk of bleeding if taken with aspirin, other NSAIDs, or other drugs that affect coagulationMay increase risk of bleeding if 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 | |
MirtazapineMirtazapine | Causes weight gain and sedation Has fewer sexual adverse effects than SSRIs and SNRIs | |
TrazodoneTrazodone | May cause priapism and sedation May cause orthostatic hypotension | |
Serotonin-norepinephrine reuptake inhibitors (SNRIs) | — | |
— | DesvenlafaxineDesvenlafaxine | May increase BP or HR (control BP before initiating the medication and monitor BP and HR while patients are on it) |
DuloxetineDuloxetine | Modest dose-dependent increase in systolic and diastolic BP May cause mild urinary hesitancy in males Less potential for drug interactions because it has less effect on CYP450 isoenzymes | |
LevomilnacipranLevomilnacipran | May increase BP or HR (control BP before initiating the medication and monitor BP and HR while patients are on it) May increase risk of bleeding if it is taken with aspirin, other NSAIDs, or anticoagulantsMay increase risk of bleeding if it is taken with aspirin, other NSAIDs, or anticoagulants Can affect urinary hesitation or retention (caution required in patients with obstructive urinary disorders; stop it if symptoms develop) | |
Milnaciprin | Similar to levomilnacipranSimilar to levomilnacipran Nausea is most common side effect | |
VenlafaxineVenlafaxine | Modest dose-dependent increase in diastolic BP Dual norepinephrine and 5-HT reuptake effect at approximately 150 mg Rarely, increase in systolic BP (not dose-dependent) If stopped, should be tapered slowly Less potential for drug interactions because it has less effect on CYP450 isoenzymes | |
VortioxetineVortioxetine | May increase risk of bleeding if taken with aspirin, other NSAIDs, or other medications that affect coagulation or bleedingMay increase risk of bleeding if taken with aspirin, other NSAIDs, or other medications that affect coagulation or bleeding | |
Norepinephrine-dopamine reuptake inhibitor-dopamine reuptake inhibitor | — | |
BupropionBupropion | 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 | |
N-methyl D-aspartate (NMDA) antagonist/sigma-1 agonist | — | |
Bupropion/dextromethorphanBupropion/dextromethorphan | Common side effects include dizziness, headache, diarrhea, sleepiness, dry mouth, sexual dysfunction, hyperhydrosis Serious side effects include seizures, mania, acute angle-closure glaucoma, elevated blood pressure, and serotonin syndrome | |
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 | |
AmitriptylineAmitriptyline | Causes weight gain | |
AmoxapineAmoxapine | Can have extrapyramidal adverse effects | |
ClomipramineClomipramine | Lowers seizure threshold at doses of > 250 mg/day | |
DesipramineDesipramine | Metabolized only via CYP2D6 isoenzyme: Medications that inhibit this enzyme markedly increase plasma levels | |
DoxepinDoxepin | Causes weight gain | |
ImipramineImipramine | May cause excessive sweating and nightmares | |
MaprotilineMaprotiline | Increased risk of seizures with rapid dose escalation at high doses | |
NortriptylineNortriptyline | Has long half-life (74 hours) | |
ProtriptylineProtriptyline | Has long half-life (74 hours) | |
TrimipramineTrimipramine | Causes weight gain | |
Monoamine oxidase (MAO) inhibitors | Serotonin syndrome possible when taken with an SSRI Hypertensive crisis possible when taken with other antidepressants, sympathomimetic or other selected medications, or certain foods and beverages With significant overdose, potentially lethal | |
IsocarboxazidIsocarboxazid | Causes orthostatic hypotension | |
PhenelzinePhenelzine | Causes orthostatic hypotension | |
Selegiline, transdermalSelegiline, transdermal | Can cause application site reactions and insomnia | |
TranylcypromineTranylcypromine | Causes orthostatic hypotension Has amphetamine-type stimulant effects and modest abuse potentialHas amphetamine-type stimulant effects and modest abuse potential | |
Psychostimulants | ||
DextroamphetamineDextroamphetamine MethylphenidateMethylphenidate | Sometimes used as adjunctive therapy in treatment-resistant depression | |
Melatonergic antidepressant | ||
Agomelatine (5-HT2C receptor antagonist) | 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 Not available in the United States | |
Ketamine and esketamineKetamine and esketamine | ||
KetamineKetamine | Nausea, dizziness, headache, increased blood pressure, increased heart rate, anxiety, feeling of detachment, addiction Ketamine (used in lower doses than used for anesthesia) is used in combination with oral antidepressants for treatment-resistant depression.Ketamine (used in lower doses than used for anesthesia) is used in combination with oral antidepressants for treatment-resistant depression. Ketamine can be given intravenously, orally, or as a nasal spray.Ketamine can be given intravenously, orally, or as a nasal spray. Ketamine is sometimes used as a drug of abuse.Ketamine is sometimes used as a drug of abuse. | |
EsketamineEsketamine | Nausea, dizziness, headache, feeling of detachment Esketamine is used in combination with other oral antidepressants for treatment-resistant depression.Esketamine is used in combination with other oral antidepressants for treatment-resistant depression. Esketamine is available as a nasal spray.Esketamine is available as a nasal spray. | |
* Antidepressant use may increase the risk of suicidal thinking and behavior in pediatric and young adult patients with major depressive disorder and other psychiatric disorders. Refer to a drug information resource for more detailed information regarding dosing, adverse reactions, and other safety considerations. † Discontinuation symptoms include nausea, chills, muscle aches, dizziness, anxiety, irritability, insomnia, and fatigue. BP = blood pressure; CYP = cytochrome P450 system; HCAs = heterocyclic antidepressants; HR = heart rate; 5-HT = 5-hydroxytryptamine (serotonin); NSAID = nonsteroidal anti-inflammatory. | ||
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 clinician experienced in use of monoamine oxidase inhibitors (MAOIs). Psychological support of patients and loved ones is particularly important in refractory cases.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 clinician experienced in use of monoamine oxidase inhibitors (MAOIs). Psychological support of patients and loved ones is particularly important in refractory cases.
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.
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.
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 approximately 25% each 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.
Choice and administration of antidepressants reference
1. Kruizinga J, Liemburg E, Burger H, et al. Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev.12(12):CD004044, 2021. doi: 10.1002/14651858.CD004044.pub5
Classes of Antidepressant Medications
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs 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).(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.
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.
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.
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, erectile dysfunction, or anorgasmia occur during SSRI therapy, dose reduction or a change to a , 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, erectile dysfunction, or anorgasmia occur during SSRI therapy, dose reduction or a change to aserotonin modulator or a norepinephrine–dopamine reuptake inhibitor may help.
Sexual dysfunction (especially difficulty achieving orgasm but also decreased libido and erectile dysfunction) occurs in more than half of patients (1, 2). 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.). 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 in the liver and other tissues, 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; the metabolism of other medications, including clonidine and lidocaine, can also be affected. Genetic testing for these metabolic enzymes is available. However, the clinical usefulness remains limited (especially in youths). Clinicians who order these tests need to help families interpret the results.Drug interactions are relatively uncommon; however, fluoxetine, paroxetine, and fluvoxamine can inhibit cytochrome P-450 (CYP450) isoenzymes in the liver and other tissues, 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; the metabolism of other medications, including clonidine and lidocaine, can also be affected. Genetic testing for these metabolic enzymes is available. However, the clinical usefulness remains limited (especially in youths). Clinicians who order these tests need to help families interpret the results.
Discontinuation symptoms (eg, irritability, anxiety, nausea) can occur if the medication is stopped abruptly; such effects are less likely with fluoxetine.Discontinuation symptoms (eg, irritability, anxiety, nausea) can occur if the medication is stopped abruptly; such effects are less likely with fluoxetine.
Serotonin modulators (5-HT blockers)
These medications block primarily the 5-HT2 receptor and inhibit reuptake of 5-HT and norepinephrine. Serotonin modulators include:
TrazodoneTrazodone
MirtazapineMirtazapine
Serotonin modulators have antidepressant and anxiolytic effects but do not cause sexual dysfunction.
TrazodoneTrazodone has caused priapism 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.
MirtazapineMirtazapine 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.
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
These medications (eg, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, venlafaxine, vortioxetine) have a dual 5-HT and These medications (eg, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, venlafaxine, vortioxetine) have a dual 5-HT andnorepinephrine 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 (3); 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.Duloxetine resembles venlafaxine in effectiveness and adverse effects.
Norepinephrine-dopamine reuptake inhibitor
By mechanisms not clearly understood, this medication class favorably influences dopaminergic and noradrenergic function and does not affect the 5-HT system.
BupropionBupropion 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 dosesand 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) (4); 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. . 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.
N-methyl -aspartate (NMDA) antagonist/sigma-1 agonist
A combination bupropion/dextromethorphanbupropion/dextromethorphan preparation offers yet another mechanism of action. As a strong inhibitor of CYP-2D6 bupropion in the combination serves to limit the metabolism of dextromethorphan, which exerts antidepressant effects through NMDA antagonism and sigma-1 receptor agonism.preparation offers yet another mechanism of action. As a strong inhibitor of CYP-2D6 bupropion in the combination serves to limit the metabolism of dextromethorphan, which exerts antidepressant effects through NMDA antagonism and sigma-1 receptor agonism.
Heterocyclic antidepressants (HCAs)
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.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.. All heterocyclics, particularly maprotiline and clomipramine, lower the threshold for seizures.
Monoamine oxidase inhibitors (MAOIs)
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.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.. 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 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 ordopamine (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.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 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 causeserotonin 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.
Melatonergic antidepressant
Agomelatine is a melatonergic (MT1/MT2) agonist and a 5-HT2C receptor antagonist that is taken at bedtime. It is used for major depressive episodes.
Agomelatine has fewer adverse effects than most antidepressants (5) 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.
Ketamine and esketamine
Ketamine and esketamine (the s-enantiomer of Ketamine and esketamine (the s-enantiomer ofketamine) are N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptors are a subtype of glutamate receptors (6). These 2 agents have been found to be effective therapy in patients with treatment-resistant unipolar depression.
The presumed mechanism of action of subanesthetic ketamine is 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 rapamycin (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.
As a treatment for depression, ketamine is usually administered intravenously, but it can also be administered orally or intranasally. Use of ketamine for treatment of depression is not approved by the U.S. Food and Drug Administration (FDA). Ketamine is also used clinically as an anesthetic. It is also sometimes used as a drug of abuse (6).
A single infusion of ketamine (dosages studied range from 0.1 to 1.0 mg/kg) results in remission of depressive symptoms and has been found to decrease depressive symptoms within 4 hours, with a peak effect at about 24 hours (7, 8). The therapeutic effect of a single dose typically dissipates within 1 to 2 weeks. Multiple administrations over several weeks lengthen the duration of improvement, but relapse rates are high over the ensuing months (9). Clinicians who administer ketamine often titrate the interval between treatments, and some patients can maintain improvement with monthly treatments.
Most adverse effects of intravenous ketamine are limited to a period of 1 to 2 hours following administration and may include nausea, dizziness, headache, dissociation, anxiety, increases in blood pressure, and increases in heart rate (10). Because ketamine has a well-known abuse potential, administration should be performed in a clinical setting. 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.
Esketamine is FDA-approved as therapy for treatment-resistant depression and major depressive disorder with suicidality. It is administered intranasally twice weekly for 4 weeks; continued administration depends upon clinical evaluation. Esketamine is FDA-approved as therapy for treatment-resistant depression and major depressive disorder with suicidality. It is administered intranasally twice weekly for 4 weeks; continued administration depends upon clinical evaluation.
Esketamine has been found to be effective for treatment-resistant depression and has been studied as co-therapy with an oral antidepressant or monotherapy (11, 12). Adverse effects usually manifest within 2 hours of administration include nausea, dizziness, headache, and dissociation (13).
Classes of antidepressant medications references
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9. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. . Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.Am J Psychiatry. 2021;178(5):383-399. doi:10.1176/appi.ajp.2020.20081251
10. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. . Side-effects associated with ketamine use in depression: a systematic review.Lancet Psychiatry. 2018;5(1):65-78. doi:10.1016/S2215-0366(17)30272-9
11. Ouyang Y, Li J. Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies. . Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies.Medicine (Baltimore). 2025;104(9):e41495. doi:10.1097/MD.0000000000041495
12. Janik A, Qiu X, Lane R, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial.JAMA Psychiatry. 2025;82(9):877-887. doi:10.1001/jamapsychiatry.2025.1317
13. SPARVATO. Package insert. Janssen Pharmaceuticals; 2019.
Antidepressants and Suicide Risk
Patients with depression and other psychiatric conditions have a significant risk of suicide and should be carefully monitored for suicidal behaviors and ideation. Risk of suicide may be increased early in the treatment of depression, when psychomotor retardation and indecisiveness have been ameliorated but the depressed mood has only partially improved. When antidepressants are started or when doses are increased, some patients experience agitation, anxiety, and increased severity of depressed mood, which may increase the likelihood of suicidal thoughts and even, in rare instances, suicidal behavior.
Multiple studies suggest a weak association between initiation of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants and increased risk of suicidal thoughts (and, rarely, attempts) in children, adolescents, and adults under 25 years old, although not all studies have reported this effect (1–4) (see also Suicidal Behavior and Treatment of Depressive Disorders in Children and Adolescents).
Public health warnings issued by the U.S. Food and Drug Administration about the possible association between use of antidepressants and suicidal thoughts and attempts in children, adolescents, and young adults initially led to a significant reduction (> 30%) in antidepressant prescriptions to these populations in the United States. Thereafter, youth suicide rates increased (5–7). Thus, by discouraging pharmacologic treatment of depression, these warnings may have temporarily resulted in more, not fewer, deaths by suicide.
Effective treatment of depression with medications and/or some form of psychotherapy is considered an effective way to reduce suicide risk overall.
Taking into consideration both the importance of effective treatment of depression and potential risks, the best approach is to encourage appropriate treatment administered with appropriate precautions, such as (8):
Providing more frequent monitoring and visits early in treatment
Giving a clear warning to patients and to family members and significant others to be alert for symptoms such as agitation, insomnia, or suicidal ideation
Instructing patients, family members, and significant others to immediately call the prescribing clinician or seek care elsewhere if symptoms worsen or suicidal ideation occurs
Prescribing antidepressants that are not lethal if taken in overdose
Dispensing antidepressants in sublethal amounts
When patients have been identified by their clinician as having risk of suicide, best practice is to dispense smaller allotments of medications to avoid the potential use of medications in a suicide attempt. Although most medications have a high enough therapeutic index that overdoses tend not to be lethal, a few select medications do have a narrow therapeutic index; therefore, dispensing smaller allotments of medications is considered best practice across any medication being prescribed to a patient at higher risk. Additionally, clinicians consider not only the risks of medications, but also the risk of not maximizing the management of the primary psychiatric illness with medications or therapy, and the potential negative impact on suicide risk when treatment is not fully optimized.
Antidepressants and suicide risk references
1. Eugene AR. Country-specific psychopharmacological risk of reporting suicidality comparing 38 antidepressants and lithium from the FDA Adverse Event Reporting System, 2017-2023. . Country-specific psychopharmacological risk of reporting suicidality comparing 38 antidepressants and lithium from the FDA Adverse Event Reporting System, 2017-2023.Front Psychiatry. 2024;15:1442490. Published 2024 Nov 1. doi:10.3389/fpsyt.2024.1442490
2. Björkenstam C, Möller J, Ringbäck G, Salmi P, Hallqvist J, Ljung R. An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study. PLoS One. 2013;8(9):e73973. Published 2013 Sep 9. doi:10.1371/journal.pone.0073973
3. Cheung K, Aarts N, Noordam R, et al. Antidepressant use and the risk of suicide: a population-based cohort study. J Affect Disord. 2015;174:479-484. doi:10.1016/j.jad.2014.12.032
4. Dragioti E, Solmi M, Favaro A, et al. Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review [published correction appears in JAMA Psychiatry. 2021 May 1;78(5):569. doi: 10.1001/jamapsychiatry.2021.0314.]. JAMA Psychiatry. 2019;76(12):1241-1255. doi:10.1001/jamapsychiatry.2019.2859
5. Lu CY, Zhang F, Lakoma MD, et al. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ. 2014;348:g3596. Published 2014 Jun 18. doi:10.1136/bmj.g3596
6. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363. doi:10.1176/appi.ajp.2007.07030454
7. National Library of Medicine. DailyMed. Label: PROZAC- fluoxetine hydrochloride capsule. Accessed October 2, 2025.. DailyMed. Label: PROZAC- fluoxetine hydrochloride capsule. Accessed October 2, 2025.
8. Zisook S, Domingues I, Compton J. Pharmacologic Approaches to Suicide Prevention. Focus (Am Psychiatr Publ). 2023;21(2):137-144. doi:10.1176/appi.focus.20220076
