What is the tolerance, adherence rate, discontinuation rate, and common side effects of venlafaxine (Selective Serotonin and Norepinephrine Reuptake Inhibitor - SSNRI)?

Venlafaxine Tolerability, Adherence, and Discontinuation

Overall Tolerability Profile

Venlafaxine is generally well tolerated with discontinuation rates similar to newer antidepressants (approximately 19% in clinical trials), though it carries a higher burden of side effects than SSRIs, particularly nausea and cardiovascular effects. 1, 2

The treatment discontinuation rate due to adverse events in Phase 2 and Phase 3 depression studies was 19% (537/2897 patients), which is comparable to other modern antidepressants but superior to first-generation tricyclic agents 1, 2. However, multiple meta-analyses of over 70 randomized trials involving approximately 7000 patients demonstrate that treatment discontinuation due to adverse effects occurs more commonly with venlafaxine than with SSRI antidepressants 3.

Discontinuation Rates by Specific Side Effects

The most common adverse events leading to discontinuation (>1% and approximately twice the rate of placebo) include 1:

• Nausea: 6% (vs 1% placebo) - the single most common reason for stopping treatment 4, 1
• Somnolence: 3% (vs 1% placebo) 1
• Insomnia: 3% (vs 1% placebo) 1
• Dizziness: 3% (vs <1% placebo) 1
• Nervousness: 2% (vs <1% placebo) 1
• Anxiety: 2% (vs 1% placebo) 1

In studies of hot flash management, discontinuation rates due to side effects ranged from 10-20%, which is substantially lower than the 40% discontinuation rate seen with clonidine 5.

Common Side Effects (Incidence ≥5%)

Gastrointestinal Effects

• Nausea: 37% (vs 11% placebo) - most common overall, but typically resolves within 1-3 weeks 4, 1, 2
• Constipation: 15% (vs 7% placebo) 1
• Anorexia: 11% (vs 2% placebo) 1
• Dry mouth: 22% (vs 11% placebo) 4, 1

Neurological Effects

• Somnolence: 23% (vs 9% placebo) 4, 1
• Dizziness: 19% (vs 7% placebo) 4, 1
• Insomnia: 18% (vs 10% placebo) 4, 1
• Nervousness: 13% (vs 6% placebo) 1
• Headache - common but specific incidence not dose-dependent 4
• Tremor: 5% (vs 1% placebo) 4, 1

Autonomic Effects

• Sweating/diaphoresis - occurs more frequently than with many other antidepressants 4, 1
• Blurred vision: 6% (vs 2% placebo) 1

Sexual Dysfunction

• Abnormal ejaculation/orgasm in men: 12% (vs <1% placebo) 4, 1
• Impotence: 6% (vs <1% placebo) 1
• Sexual dysfunction affects both men and women 4

Weight Changes

• Dose-dependent weight loss - 6% of patients lost ≥5% body weight (vs 1% placebo), though discontinuation for weight loss was uncommon (0.1%) 1
• Decreased appetite is common 4, 1

Critical Safety Concerns and Monitoring Requirements

Cardiovascular Effects - The Key Distinguishing Risk

Venlafaxine causes dose-dependent blood pressure elevation that may require treatment discontinuation, particularly at doses above 300 mg/day. 5, 6, 3

Blood pressure monitoring is essential 5, 6:

• 3-5% risk at ≤200 mg/day 2
• 7% risk at 201-300 mg/day 2
• 13% risk at >300 mg/day (vs 2% placebo) 2

Cardiac conduction abnormalities have been reported in a small number of patients, and venlafaxine should be prescribed with caution in patients with cardiac disease 5. QT interval prolongation can occur, potentially leading to torsades de pointes 3. A screening electrocardiogram is recommended for patients older than 40 years with cardiac risk factors 6.

Discontinuation Syndrome - Requires Mandatory Tapering

Venlafaxine must be tapered when discontinuing because a well-described withdrawal syndrome occurs, particularly with abrupt cessation. 5, 1

Discontinuation symptoms include 1:

• Agitation, anxiety, confusion
• Dizziness, vertigo, sensory disturbances (shock-like electrical sensations)
• Nausea, vomiting, diarrhea
• Headaches, fatigue, flu-like symptoms
• Insomnia, nightmares, somnolence
• Tremor, fasciculation, impaired coordination

The frequency of discontinuation symptoms increases with higher doses and longer treatment duration 1. Unlike gabapentin, venlafaxine has a significant withdrawal syndrome similar to paroxetine 5. A gradual dose reduction is recommended; if intolerable symptoms occur, resume the previous dose and taper more slowly 1.

Suicidality Risk

Increased risk of suicidal thoughts and behavior exists, particularly in children, adolescents, and young adults up to age 24 years 4.

Serotonin Syndrome

This potentially life-threatening condition can occur, especially with concomitant use of MAOIs (which is contraindicated) 4, 1.

Dose-Dependent Side Effects

Several adverse events show clear dose-dependency 5, 1:

• Blood pressure elevation (most clinically significant)
• Nausea and gastrointestinal effects
• Neurological symptoms (dizziness, somnolence)

Typically, 2-4 weeks are required to titrate to an efficacious dosage of 150-225 mg/day 5. Starting at 37.5 mg once or twice daily and increasing by 75 mg each week to a maximum of 225 mg/day over 4-6 weeks is the recommended approach 5.

Special Population Considerations

Pediatric Patients

Weight loss has been observed in children and adolescents (ages 6-17) receiving venlafaxine 1. In pooled analyses, venlafaxine-treated patients lost an average of 0.45 kg while placebo-treated patients gained 0.77 kg 1. More concerning, 18% of venlafaxine-treated patients experienced weight loss of at least 3.5% versus 3.6% of placebo patients 1. Height growth was also reduced (0.3 cm vs 1 cm in placebo over 8 weeks) 1.

Pregnancy

Exposure during the second and third trimesters increases the risk of pre-eclampsia and eclampsia 3.

Drug Interactions

In patients taking tamoxifen, venlafaxine is preferred over paroxetine and fluoxetine because it has minimal effects on CYP2D6 and does not significantly reduce endoxifen concentrations 5, 6. Venlafaxine is contraindicated with MAOIs and should be used cautiously in bipolar disorder due to risk of inducing mania 5.

Comparative Tolerability

Venlafaxine's overall tolerability exceeds that of tricyclic antidepressants but is less favorable than SSRIs 7. It has a higher incidence of nausea and vomiting than SSRIs 4. Cohort studies demonstrate that venlafaxine overdoses are more frequently fatal than SSRI overdoses 3. The seizure rate and potential for cardiac conduction changes or orthostatic hypotension are comparable to SSRIs 2.

Clinical Monitoring Algorithm

Before each refill, assess 6:

1. Blood pressure and pulse - mandatory at each visit, especially when initiating or adjusting dosage
2. Cardiovascular symptoms - new chest pain, palpitations, syncope
3. Weight changes - particularly in pediatric patients
4. Discontinuation planning - if stopping, ensure gradual taper protocol

Refills can proceed without provider contact if 6:

• Blood pressure remains stable
• Patient tolerates current dose without new cardiovascular symptoms
• No planned dose changes or discontinuation

Provider contact required before refilling if 6:

• Blood pressure is elevated
• New cardiac symptoms reported
• Patient wants to stop medication (requires taper plan)

Time Course of Side Effects

Most side effects emerge within the first few weeks of treatment 4, 8. Nausea, though the most common adverse effect, typically resolves within 1-3 weeks 2. Somnolence and other neurological effects often improve over 2-4 weeks 8. An adequate trial requires 4-6 weeks, with at least 2 weeks at maximum tolerated dosage 5.