Understanding Antidepressant Mechanism of Action and Its Effect on Efficacy and Safety

Anita H. Clayton, MD

Department of Psychiatry and Neurobehavioral Sciences and the Outpatient Psychiatry Clinic and Center for Psychiatric Clinical Research, University of Virginia School of Medicine, Charlottesville

Clinicians may prescribe medication without considering mechanism of action. However, mechanisms of action set antidepressants apart from each other, and specific mechanisms of action are likely to be associated with individual differences in response to antidepressant therapy and are particularly relevant to safety and tolerability issues that influence adherence. As our understanding of the mechanisms of action of antidepressants grows, clinicians may be able to use this knowledge to match an antidepressant to an individual patient to optimize efficacy and tolerability.

Mechanism of Action of Antidepressants

AV 1. Mechanism of Action and Adverse Events of Antidepressants (03:36)

Antidepressants are categorized on the basis of their mechanism(s) of action, including neurotransmitter uptake blockers (NDRIs, NRIs, SNRIs, SSRIs, and TCAs), enzyme inhibitors (MAOIs), and neurotransmitter receptor blockers (antidepressants with a unique mechanism of action). Some agents have multiple modes of action, which gives them a greater potential for efficacy but also a greater risk of side effects than agents with fewer modes of action. In clinical practice, variations in mechanism of action among antidepressants are more likely to be recognized through the occurrence of adverse effects than through differences in efficacy (AV 1).1,2 Additionally, patients and/or their families may have a genetic predisposition to respond to particular antidepressants based on the mechanism of action.3

Onset of Efficacy and Adverse Events

The onset of both therapeutic benefits and adverse events is linked to a medication’s mechanism of action. For example, neurotransmitter reuptake inhibitors have a delayed therapeutic effect—they increase neurotransmitter availability, which triggers negative feedback mechanisms that require subsequent desensitization of postsynaptic neurotransmitter receptors, a process that takes time. Antidepressants with a unique mechanism of action may uncouple these feedback control mechanisms and enhance neurotransmission more rapidly, leading to a more rapid onset of effect.

AV 2. Antidepressant Efficacy: Acute Adverse Events and Therapeutic Benefit (00:31)

Based on Stahl1 and Bull et al4

Although the antidepressant’s therapeutic benefit may not be apparent for several weeks after treatment initiation, side effects can begin with the first dose of an antidepressant (AV 2).2,4 For some patients, these effects may be particularly trying because an early improvement in depression is not evident. In some instances, safety and tolerability risks may outweigh benefits and a different medication may need to be selected.


Acute adverse effects may gradually resolve or may persist, and chronic side effects may emerge over time.4 Some acute and chronic/persisting adverse effects from antidepressants are as follows:

Acute Effects

  • GI effects (nausea, vomiting, diarrhea, constipation)
  • Sleep disturbances (sedation, insomnia)
  • Behavioral effects (activation, retardation)
  • Headache


Chronic/Persisting Effects

  • Sexual dysfunction
  • Sleep disturbance/fatigue
  • Weight gain
  • Cognitive and emotional blunting


Persistent side effects from antidepressants can contribute to a reduced quality of life and to health problems. Additionally, they may be so bothersome that patients do not take their medication as prescribed or they stop taking the medication altogether.4

Common Chronic Side Effects and Mechanism of Action

AV 3. Top Patient-Reported Reasons for Antidepressant Nonadherence and Discontinuation and Adverse Effects Experienced (00:31)

Based on Ashton et al5

When surveyed about their reasons for antidepressant nonadherence, patients cited weight gain and sexual dysfunction most often (after forgetfulness) and also described fatigue as being very bothersome (AV 3).5

Weight gain. The cause of weight gain can be difficult to discern as it may be a symptom of depression,6 a sign of recovery from a depressive episode,7 or a persisting adverse event from some antidepressants.8 Comparing data about weight gain can also be difficult because most drug trials have an inadequate duration to accurately capture gradual weight gain. Measurements of weight gain may also be an issue in comparing trial data because some studies use mean change in body weight while others use ≥ 7% change from baseline, and patients who are obese at baseline may not be comparable with those who are not.

      Because of the difficulties associated with tracking and measuring weight over time, how the mechanisms of action of antidepressants specifically affect weight change is unclear.8,9 Possible mechanisms include effects on the hormones leptin and prolactin and the histamine-H1, 5-HT2C, dopamine, and neuropeptide Y receptors.7,9 With most of the SSRIs/SNRIs, patients have an initial modest weight loss, but weight gain can happen over the long-term (≥ 4 months).8 With TCAs and mirtazapine, weight gain typically occurs in both the acute and long-term phases of treatment. Bupropion has been associated with short-term weight loss that is maintained past the acute treatment period,8 and nefazodone appears to be weight-neutral over the long-term.9

Sexual dysfunction. While untreated MDD is associated with decreased sexual interest and arousal, sexual problems can also be related to the mechanism of action of antidepressants.10 Antidepressants that stimulate serotonin commonly inhibit at least 1 phase of sexual function (ie, desire, arousal, and orgasm).11 For example, in a sample without other risk factors for sexual dysfunction, the SSRI citalopram and the SNRI venlafaxine were associated with rates of sexual dysfunction more than 4 times greater than that of the NDRI bupropion.12 In women, SRIs diminish the functioning of the excitatory neurotransmitters dopamine and norepinephrine, which modulate desire and arousal, and may also diminish bioavailable testosterone and/or increase prolactin, leading to broad effects on sexual function.13 Men taking SSRIs have been shown to have decreased activation in areas of the brain associated with erotic stimulation.14 In addition, genetic polymorphisms may influence vulnerability to sexual dysfunction induced by SSRIs.10

Antidepressants with other mechanisms of action are not associated with significant sexual side effects. For example, agents that enhance dopamine and/or norepinephrine have a low propensity to induce sexual problems; these include bupropion,12 transdermal selegiline (an MAOI),10 and reboxetine (a selective NRI).15 Additionally, antagonists of the 5-HT2C receptor, such as mirtazapine (a tetracyclic antidepressant and also 5-HT3 antagonist)16 and agomelatine,17 are less likely to cause sexual dysfunction. Vilazodone has serotonin reuptake inhibitory effects but has potentially protective effects against sexual dysfunction via its additional 5-HT1A agonist action.18

Fatigue and sleepiness. Sleep problems are common in MDD,6 but they can also be related to antidepressant mechanism of action. Although fatigue and lack of energy occur in the general population, these problems are present in the majority of patients with MDD.19 Sleepiness is particularly common among young patients with depression. Hypersomnia occurs in 10% to 20% of those with MDD and in about 36% of patients with atypical depression.19 Additionally, primary sleep disorders such as obstructive sleep apnea are frequently comorbid with MDD.20

      Antidepressants associated with sleepiness and fatigue include the TCAs, mirtazapine, duloxetine, and trazodone.19 Mirtazapine is a histamine-H1 receptor antagonist, which may account for its sedative effects.16 Taking these medications at bedtime can help reduce daytime sleepiness. Medications less likely to be associated with sleepiness and fatigue are SSRIs, bupropion, venlafaxine, reboxetine, agomelatine, and MAOIs19; within this group, however, differences in effect due to mechanism of action do occur. For example, in patients whose MDD remitted, bupropion led to greater resolution of hypersomnia and fatigue than SSRI treatment.19 Additionally, agomelatine (also a melatonergic receptor agonist) showed superior improvement in sleep dysfunction compared with the SSRI sertraline.21


Examining antidepressant mechanism of action may help clinicians individualize antidepressant selection and avoid undesirable side effects. Because tolerability issues with antidepressants may lead patients to be nonadherent, matching the mechanism of action of antidepressants with patients’ needs and preferences may improve long-term outcomes.

For Clinical Use

  • Switch to an antidepressant with a different mechanism of action if weight gain, sexual dysfunction, fatigue and sleepiness, or other intolerable adverse events occur
  • Inform your patient if mechanism of action may delay the therapeutic onset of an antidepressant
  • Alert patients to possible side effects of particular antidepressants before initiating treatment

Drug Names

bupropion (Wellbutrin, Aplenzin, and others), citalopram (Celexa and others), duloxetine (Cymbalta), mirtazapine (Remeron and others), selegiline transdermal system (EMSAM), sertraline (Zoloft and others), trazodone (Oleptro and others), venlafaxine (Effexor and others), vilazodone (Viibryd)


5-HT = serotonin, GI = gastrointestinal, MAOI = monoamine oxidase inhibitor, MDD = major depressive disorder, NDRI = norepinephrine-dopamine reuptake inhibitor, NRI = norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin-norepinephrine reuptake inhibitor, SRI = serotonin reuptake inhibitor, TCA = tricyclic antidepressant

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