What are the common and serious side effects of antidepressant medications, including selective serotonin reuptake inhibitors, serotonin‑norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and atypical agents, in adult patients?

Antidepressant Side Effects in Adults

Overview of Adverse Effect Burden

Approximately 63% of patients receiving second-generation antidepressants will experience at least one adverse effect during treatment, with nausea and vomiting being the most common reasons for medication discontinuation. 1

Common Side Effects (Occur Frequently)

Second-Generation Antidepressants (SSRIs, SNRIs, Atypical Agents)

The following adverse effects are commonly reported across this class: 1

• Gastrointestinal: Diarrhea, nausea, vomiting (most frequent cause of discontinuation)
• Neurological: Dizziness, headache, tremor
• Autonomic: Dry mouth, sweating
• Systemic: Fatigue, weight gain
• Sexual: Sexual dysfunction (common across TCAs, SSRIs, and venlafaxine) 2

Class-Specific Differences in Tolerability

SNRIs (duloxetine and venlafaxine) cause higher rates of adverse effects than SSRIs, particularly nausea and vomiting, with 67% and 40% increased risk of discontinuation respectively compared to SSRIs as a class. 1

The number needed to harm causing discontinuation differs substantially by drug class: 1

• TCAs: 4 to 30 patients
• SSRIs: 20 to 90 patients

This means TCAs are significantly more likely to cause intolerable side effects requiring discontinuation compared to SSRIs.

Serious Adverse Effects (Rare but Potentially Life-Threatening)

Serotonin Syndrome

Serotonin syndrome occurs in 14% to 16% of SSRI overdoses and can be insidious and lethal, especially when SSRIs are combined with other serotonergic medications including certain analgesics. 1, 2

Clinical manifestations include: 1

• Tremor
• Diarrhea
• Delirium
• Neuromuscular rigidity
• Hyperthermia

Critical pitfall: The risk of serotonin syndrome increases significantly with combination therapies and augmentation strategies—always review all medications for serotonergic properties before adding agents. 2

Cardiovascular Effects

TCAs cause conduction defects and carry significant risk of lethal overdose, making them more dangerous than newer agents in overdose situations. 2

Gastrointestinal Bleeding

Antidepressants increase gastrointestinal bleeding risk with odds ratios of 1.2 to 1.5, with higher risk when combined with antiplatelet agents. 1

Falls and Fractures (Particularly in Older Adults)

Duloxetine specifically increases fall risk compared to placebo during 24 weeks of treatment in patients 65 years and older. 3

Seizures

While uncommon, seizure risk exists with all antidepressant classes and must be discussed with patients, though the absolute risk remains low. 2

Cognitive Impairment

Cognitive impairment occurs especially with TCAs, and apathy can develop with SSRI therapy. 2

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

SIADH has been reported with most antidepressants but appears more common with serotonergic agents and in elderly patients. 2

Special Population Considerations

Pregnancy

Antidepressant use during pregnancy has not been shown to improve outcomes of untreated maternal depression and may increase the risk of preterm delivery. 1

Specific pregnancy-related concerns include: 1

• Paroxetine: FDA pregnancy category D due to concerns about cardiac malformations (though recent large cohort studies of nearly 1 million pregnant women found no link between first-trimester antidepressant use and cardiac malformations)
• Late pregnancy SSRI exposure: Conflicting evidence regarding persistent pulmonary hypertension of the newborn (PPHN), with number needed to harm of 286 to 351 if the association is real
• Other potential associations: Lower Apgar scores, ADHD, speech delay (high-quality evidence lacking)

Breastfeeding

Sertraline and paroxetine transfer to breast milk in lower concentrations than other antidepressants, making them preferred choices during breastfeeding. 1

Older Adults (≥65 Years)

In older adults, paroxetine and fluoxetine should generally be avoided due to higher rates of adverse effects; preferred agents include citalopram, escitalopram, sertraline, mirtazapine, venlafaxine, and bupropion. 1

SNRIs cause more overall adverse events than placebo in older adults (high strength of evidence), while SSRIs show statistically similar frequency of overall adverse events compared to placebo (moderate strength of evidence). 3

Both SSRIs and SNRIs lead to more study withdrawals due to adverse events versus placebo in older adults. 3

Overdose and Toxicity

In 2012, antidepressants ranked third (after analgesics and sedatives/hypnotics) in toxic exposures among adults, with SSRIs involved in 89 fatalities. 1

The relative safety of SSRIs in overdose compared to TCAs and MAOIs makes them more desirable despite the risk of serotonin syndrome. 4

Sleep Disturbances

Antidepressant drugs vary in their sleep effects, which is clinically important since sleep disturbances are common in depression and sleep regulation is crucial to mood. 2

Key Clinical Pitfalls to Avoid

• Do not combine serotonergic agents without careful consideration—this dramatically increases serotonin syndrome risk 1, 2
• Do not ignore sexual dysfunction complaints—this commonly leads to noncompliance and self-discontinuation 2
• Do not use paroxetine or fluoxetine as first-line in older adults—choose citalopram, escitalopram, or sertraline instead 1
• Do not overlook fall risk in older adults on duloxetine—implement fall prevention strategies 3
• Do not dismiss early adverse effects—nausea/vomiting causes 15.4% dropout rate and is the primary reason for treatment failure 5