What are the potential side effects of Selective Serotonin Reuptake Inhibitor (SSRI) treatment, particularly in patients with a history of medical conditions such as diabetes, high blood pressure, or glaucoma?

SSRI Side Effects

SSRIs cause common adverse effects including gastrointestinal symptoms (nausea, diarrhea), sexual dysfunction, sleep disturbances, and headaches in the majority of patients, with serious but rare risks including serotonin syndrome, increased suicide attempts in younger patients, hyponatremia, seizures, and bleeding complications that require careful monitoring. 1

Common Side Effects (Occur in >10% of Patients)

Gastrointestinal Effects

• Nausea and vomiting are the most frequent adverse effects and the leading cause of treatment discontinuation in clinical trials 1
• Diarrhea occurs more commonly with sertraline compared to other SSRIs 1
• Constipation, dry mouth, and heartburn are frequently reported during extended use 2

Sexual Dysfunction

• Sexual side effects occur in a substantial proportion of patients but are likely underreported in clinical trials 1
• Manifestations include ejaculatory delay, erectile dysfunction, and anorgasmia 2
• Paroxetine causes higher rates of sexual dysfunction than fluoxetine, fluvoxamine, or sertraline 1
• Bupropion has significantly lower rates of sexual adverse events compared to SSRIs and should be considered when sexual dysfunction is problematic 1

Neurological Effects

• Headache, dizziness, and tremor are commonly reported 1
• Somnolence and fatigue occur frequently 1
• Insomnia affects 12-33% of patients depending on the specific SSRI and indication 3

Other Common Effects

• Sweating and diaphoresis are frequent autonomic effects 2
• Weight changes can occur, with some SSRIs causing weight gain (particularly mirtazapine and paroxetine) while others may cause weight loss 1, 3

Serious Adverse Effects Requiring Monitoring

Suicidality (Highest Priority in Young Patients)

• All SSRIs carry an FDA boxed warning for increased suicidal thinking and behavior in patients aged 24 years or younger 2
• Meta-analyses demonstrate SSRIs increase the risk of nonfatal suicide attempts (odds ratio 1.57-2.25) compared to placebo 1
• The absolute risk increase is 0.7% with a number needed to harm of 143, meaning suicidal ideation occurs in 1% on antidepressants versus 0.2% on placebo 2
• Close monitoring is essential during the first weeks of treatment and after dose changes, particularly in adolescents and young adults 2

Serotonin Syndrome (Life-Threatening Emergency)

• Serotonin syndrome is a potentially fatal condition that occurs with SSRI overdose (14-16% of cases) or when SSRIs are combined with other serotonergic medications 1, 3
• Clinical features include mental status changes (agitation, confusion, coma), autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (hyperreflexia, tremor, rigidity), and gastrointestinal symptoms (nausea, vomiting, diarrhea) 3
• SSRIs are absolutely contraindicated with MAOIs, and extreme caution is required when combining with triptans, tramadol, or other serotonergic agents 3
• Serotonin syndrome requires immediate discontinuation of all serotonergic medications 3

Hyponatremia and SIADH

• Hyponatremia may result from syndrome of inappropriate antidiuretic hormone secretion (SIADH), with cases of serum sodium below 110 mmol/L reported 3
• Elderly patients and those taking diuretics or who are volume depleted face the highest risk 3
• Symptoms include headache, confusion, memory impairment, weakness, and unsteadiness leading to falls; severe cases can cause seizures, coma, and death 3
• Discontinue the SSRI immediately in patients with symptomatic hyponatremia 3

Bleeding Risk

• SSRIs increase the risk of abnormal bleeding, particularly when combined with NSAIDs, aspirin, or anticoagulants 2
• This occurs through platelet serotonin depletion affecting hemostasis 4

Seizures

• Seizures occur in approximately 0.1-0.2% of patients treated with SSRIs 3
• Introduce SSRIs with caution in patients with a history of seizures 3

Behavioral Activation and Mania

• Behavioral activation (motor restlessness, insomnia, impulsiveness, disinhibition, aggression) may occur, especially in younger children and those with anxiety disorders 2
• Mania or hypomania occurs in 0.1-0.8% of patients and may appear later in treatment 2, 3
• Screen patients for bipolar disorder risk before initiating SSRI treatment, as SSRIs can precipitate manic episodes 3

Special Population Considerations

Pregnancy

• SSRIs, particularly paroxetine, raise concerns about cardiac malformations, though recent large studies show conflicting results 1
• Late pregnancy SSRI exposure (after 20 weeks) may increase risk of persistent pulmonary hypertension of the newborn (PPHN) with a number needed to harm of 286-351 1
• Depression during pregnancy itself increases risk of premature birth and decreased breastfeeding initiation 1

Elderly Patients

• Preferred SSRIs for older adults include citalopram, escitalopram, and sertraline; avoid paroxetine and fluoxetine due to higher adverse effect rates 1
• Elderly patients face increased risk of hyponatremia, falls, and fractures 3

Patients with Medical Comorbidities

• In patients with cirrhosis, use lower or less frequent SSRI doses due to decreased clearance and prolonged elimination half-lives 3
• SSRIs have not been extensively studied in patients with recent myocardial infarction or unstable heart disease, though retrospective analysis shows no conduction abnormalities causing heart block 3
• Mean heart rate decreases by approximately 3 beats per minute with fluoxetine 3

Discontinuation Syndrome

• Gradual tapering is essential when stopping long-term SSRI therapy to avoid withdrawal symptoms 2
• Fluoxetine and norfluoxetine have exceptionally long elimination half-lives, meaning dose changes take several weeks to fully manifest in plasma levels 3
• Abrupt discontinuation can cause dizziness, nausea, headache, irritability, and flu-like symptoms 4

Drug Interactions

Critical Contraindications

• Never combine SSRIs with MAOIs due to fatal serotonin syndrome risk 3
• Fluoxetine inhibits CYP2D6 and is contraindicated with thioridazine due to QTc prolongation and risk of torsades de pointes 3

Significant Interactions

• Duloxetine is a moderate CYP2D6 inhibitor requiring dose adjustments when combined with drugs metabolized by this pathway 5
• Venlafaxine metabolism is affected by CYP2D6 inhibitors, causing significant inter-individual variation in blood levels 5

Comparative Adverse Effect Profiles

• Most second-generation antidepressants have similar overall adverse effect profiles, with specific differences in individual side effects 1
• Venlafaxine causes higher rates of nausea/vomiting than SSRIs and can elevate blood pressure at doses above 225 mg/day 1, 5
• Sertraline has higher diarrhea rates than other antidepressants 1
• Mirtazapine and paroxetine cause more weight gain than sertraline or venlafaxine 1

Clinical Monitoring Recommendations

• Monitor for suicidal ideation weekly during the first month, especially in patients under age 25 2
• Check serum sodium in elderly patients, those on diuretics, or with symptoms of confusion or weakness 3
• Assess for serotonin syndrome features when adding any serotonergic medication 3
• Monitor weight regularly during therapy 3
• Screen for sexual dysfunction proactively, as patients often do not volunteer this information 1
• Evaluate for behavioral activation, particularly in the first weeks of treatment in younger patients 2