Medications for Treatment of Depression

ByWilliam Coryell, MD, University of Iowa Carver College of Medicine
Reviewed/Revised Oct 2023
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Several drug classes and drugs can be used to treat depression:

Choice of medication may be guided by past response to a specific antidepressant. Otherwise, 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 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 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.

General reference

  1. 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. doi: 10.1001/jamapsychiatry.2019.2859

Selective Serotonin Reuptake Inhibitors (SSRIs)

These medications prevent reuptake of serotonin

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

Serotonin Modulators (5-HT Blockers)

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

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

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.

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)

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.

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.

is currently the only medication in this class. It can help depressed patients with concurrent attention-deficit/hyperactivity disorder or > 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

Norepinephrine-dopamine reuptake inhibitor reference

  1. 1. Dhillon S, Yang LP, Curran MPDrugs 68(5):653-689, 2008. doi: 10.2165/00003495-200868050-00011. Erratum in: Drugs 68(7):980, 2008.

Heterocyclic Antidepressants (HCAs)

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

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.

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

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).

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.

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 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

12).

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.

Adverse effects are generally limited to a period of one to 2 hours following administration and include derealization

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.

Ketamine and esketamine references

  1. 1. Caddy C, Amit BH, McCloud TL, et alCochrane Database Syst Rev 9:CD011612, 2015. doi: 10.1002/14651858.CD011612.pub2. Update in: Cochrane Database Syst Rev. 9:CD011612, 2021. PMID: 26395901

  2. 2. Singh JB, Fedgchin M, Daly E, et alBiol Psychiatry. 80(6):424-431, 2016. doi: 10.1016/j.biopsych.2015.10.018

Choice and Administration of Antidepressants

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).

Table
Table

Insomniaserotonin 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.

Choice and administration of antidepressants reference

  1. 1. Kruizinga J, Liemburg E, Burger H, et al: Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev12(12):CD004044, 2021. doi: 10.1002/14651858.CD004044.pub5

Drugs Mentioned In This Article
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