What are the general considerations and side effects of Desvenlafaxine (serotonin-norepinephrine reuptake inhibitor) in a patient with a history of dysthymia?

Desvenlafaxine Use in Dysthymia: General Considerations and Side Effects

Desvenlafaxine is a reasonable treatment option for dysthymia, with the recommended dose being 50 mg daily, as higher doses (100 mg and above) increase side effects without proportional therapeutic benefit. 1, 2

Key Prescribing Considerations

Dosing Strategy

• Start at 50 mg once daily, which is both the starting and recommended therapeutic dose 1, 2
• Doses above 100 mg/day show incremental increases in side effects without clear additional efficacy 2
• The discontinuation rate at 50 mg (4.1%) is similar to placebo (3.8%), but rises to 8.7% at 100 mg 1

Evidence Base for Dysthymia

• While desvenlafaxine specifically has limited data in dysthymia, its parent compound venlafaxine (of which desvenlafaxine is the active metabolite) has demonstrated efficacy in multiple open-label studies 3, 4, 5
• Response rates for venlafaxine in dysthymia ranged from 73-77% in clinical trials 4, 5
• The American College of Physicians notes that evidence for second-generation antidepressants in dysthymia is mixed but supports their use 6

System-Specific Side Effects

Gastrointestinal System

• Nausea is the most common side effect and the leading cause of discontinuation (4% discontinuation rate) 1
• Constipation, diarrhea, vomiting, and decreased appetite occur commonly 6, 1
• Nausea typically occurs early in treatment and may be transient 2

Cardiovascular System

• Monitor blood pressure before and during treatment, as desvenlafaxine can cause sustained hypertension 1
• Mean increases in supine systolic BP (1.2-2.5 mm Hg) and diastolic BP (0.7-2.3 mm Hg) occur at therapeutic doses 1
• Sustained hypertension (SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits) can develop 1
• Tachycardia and increased pulse rate (1.3-4.1 bpm) may occur 1
• Weak evidence suggests SNRIs may be associated with increased cardiovascular events 6

Central Nervous System

• Dizziness (leading to 2% discontinuation), headache (2% discontinuation), and somnolence are common 1
• Insomnia occurs in 6-15% of patients (dose-dependent) 1
• Tremor, disturbance in attention, and anxiety may develop 1
• Seizures can occur, though uncommon 1
• Discontinuation syndrome is a critical concern when stopping treatment 1

Psychiatric/Behavioral Effects

• Monitor for suicidality, particularly in young adults, as SSRIs and SNRIs carry increased risk for nonfatal suicide attempts 6
• Anxiety (2-5%), nervousness, and abnormal dreams may occur 1
• Activation of mania/hypomania is possible 1
• Depersonalization and bruxism have been reported 1

Sexual Function (Critical Consideration)

• Sexual dysfunction is common and often underreported 6, 7
• In men: erectile dysfunction (3-11%), ejaculation delay (1-7%), decreased libido (4-6%), and anorgasmia (0-8%) occur in a dose-dependent manner 1
• In women: anorgasmia occurs in up to 3% 1
• If sexual dysfunction is a primary concern, consider bupropion instead, as it has the lowest risk of sexual side effects among antidepressants 7

Hematologic System

• Increased bleeding risk, particularly when combined with aspirin, NSAIDs, or anticoagulants 1
• Monitor for unusual bleeding or bruising 1

Metabolic/Endocrine Effects

• Hyponatremia can occur and may be serious or life-threatening 1
• Symptoms include headache, confusion, memory changes, weakness, unsteadiness, and in severe cases, hallucinations, seizures, or coma 1
• Blood prolactin increases have been reported 1
• Weight changes are typically modest (mean decrease of 0.4-1.1 kg) 1

Hepatic System

• Liver function test abnormalities may occur 1
• Less concern than with nefazodone, which has higher hepatotoxicity risk 6

Renal/Urinary System

• Urinary hesitation (up to 2%) and urinary retention can occur 1
• Proteinuria (≥ trace) occurs in 4-8% of patients but is generally transient and not associated with BUN or creatinine elevation 1

Ophthalmologic System

• Angle-closure glaucoma risk exists with all antidepressants including desvenlafaxine 1
• Vision changes, eye pain, blurred vision (3-4%), and mydriasis (2-6%) warrant immediate evaluation 1

Respiratory System

• Interstitial lung disease and eosinophilic pneumonia are rare but serious complications 1
• Symptoms include difficulty breathing, cough, or chest discomfort requiring immediate medical attention 1
• Yawning occurs in 1-4% of patients 1

Dermatologic System

• Hyperhidrosis (excessive sweating) is very common (10-21% in a dose-dependent manner) 1
• Rash, alopecia, photosensitivity reactions, and angioedema have been reported 1

Other Systems

• Vertigo (1-5%), tinnitus, and dysgeusia (altered taste) may occur 1
• Hot flushes affect 1-2% of patients 1
• Asthenia (weakness) and musculoskeletal stiffness have been reported 1

Critical Safety Monitoring

Discontinuation Syndrome Prevention

• Never abruptly stop desvenlafaxine, especially at higher doses 1
• Taper slowly to avoid withdrawal symptoms including: dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, electric shock sensations (paresthesia), confusion, mood changes, and seizures 1
• Reduce dose gradually over 10-14 days minimum 6

Serotonin Syndrome Risk

• Life-threatening serotonin syndrome can occur, particularly when combined with other serotonergic agents 1
• Symptoms requiring emergency evaluation: agitation, hallucinations, confusion, tachycardia, blood pressure changes, hyperthermia, muscle rigidity, tremors, loss of coordination, seizures, nausea, vomiting, diarrhea 1

Follow-up Schedule

• Assess patient status, therapeutic response, and adverse effects within 1-2 weeks of initiation 6
• Continue regular monitoring throughout treatment 6
• Check blood pressure before starting and periodically during treatment 1

Pharmacokinetic Advantages

• Desvenlafaxine is minimally metabolized via CYP450 pathway and is a weak CYP2D6 inhibitor 2
• This confers reduced risk for drug-drug interactions compared to other SNRIs 2
• Primarily excreted unchanged in urine 2

Common Pitfalls to Avoid

• Do not crush, chew, or dissolve tablets; swallow whole (empty shell may appear in stool) 1
• Avoid alcohol consumption during treatment 1
• Do not drive or operate machinery until effects are known 1
• Do not assume higher doses are more effective; 50 mg is often sufficient and better tolerated 2
• Do not overlook cardiovascular monitoring, particularly blood pressure 1