Suicide
The US Food and Drug Administration (FDA) requires all antidepressants, including venlafaxine, to carry a black box warning with a generic warning about a possible suicide risk.[41]
A 2014 meta-analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo, venlafaxine reduced the risk of suicidal thoughts and behavior.[42]
A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time, fluoxetine (Prozac) halved the suicide risk.[43]
In a study sponsored by Wyeth, which produces and markets venlafaxine, the data on more than 200,000 cases were obtained from the UK general practice research database. At baseline, patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had a significantly higher risk of suicide than the ones on fluoxetine or citalopram (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine and dothiepin which was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment, but the authors concluded that it could be due to residual confounding.[44]
An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or placebo.[45]
Venlafaxine is contraindicated in children, adolescents, and young adults. In children and adolescents with depression, venlafaxine increases the risk of suicidal thoughts or attempts.[30][31][32][33][34][35]
Serotonin syndrome
The development of a potentially life-threatening serotonin syndrome (also classified as "serotonin toxicity")[46] may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to SSRIs and SNRIs, many hallucinogens such as tryptamines and phenethylamines (e.g., LSD/LSA, DMT, MDMA, mescaline), dextromethorphan (DXM), tramadol, tapentadol, pethidine (meperidine) and triptans and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination), or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose.[47] An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150 mg per day).[48]
Miscarriage
There are few well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of miscarriage.[50][51] A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association between venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta.[52] Prospective studies have not shown any statistically significant congenital malformations.[53] There have, however, been some reports of self-limiting effects on newborn infants.[54] As with other serotonin reuptake inhibitors (SRIs), these effects are generally short-lived, lasting only 3 to 5 days,[55]
Bipolar disorder
According to the ISBD Task Force report on antidepressant use in bipolar disorder,[58] during the course of treatment for depression with those suffering from bipolar I and II, venlafaxine "appears to carry a particularly high risk of inducing pathologically elevated states of mood and behavior." Because venlafaxine appears to be more likely than SSRIs and bupropion to induce mania and mixed episodes in these patients, provider discretion is advised through "carefully evaluating individual clinical cases and circumstances."
Liver injury
A rare but serious side effect of venlafaxine is liver injury. It appears to affect both male and female patients with a median age of 44. Cessation of venlafaxine is one of the appropriate measures of management. While the mechanism of venlafaxine-related liver injury remains unclear, findings suggest that it may be related to a CYP2D6 polymorphism.[59]
Overdose
Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24 mg/L, while postmortem blood levels in fatalities are often in the 10–90 mg/L range.[60] Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.[61] It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.[24][62]
There is no specific antidote for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug.
Withdrawal syndrome
People stopping venlafaxine commonly experience SSRI withdrawal symptoms such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of electric shocks (commonly called "brain zaps"[64][65]), and sleep disturbance.[66] Venlafaxine has a higher rate of moderate to severe withdrawal symptoms relative to other antidepressants (similar to the SSRI paroxetine).[67]
The higher risk and increased severity of withdrawal symptoms relative to other antidepressants may be related to the short half-life of venlafaxine and its active metabolite.[68] After stopping venlafaxine, the levels of both serotonin and
Post-SSRI sexual dysfunction
Post-SSRI sexual dysfunction (PSSD) is an iatrogenic condition in which sexual side effects persist after discontinuation of serotonin reuptake inhibiting antidepressants, including venlafaxine.[70][71] Characteristic symptoms include genital numbness, pleasureless or weak orgasm, loss of libido, and erectile dysfunction; non-sexual symptoms such as emotional blunting and cognitive impairment may also occur.[71] The condition can arise after even brief exposure to a serotonin reuptake inhibitor and may persist indefinitely; there is currently no established treatment.[72] A case study published in 2023 specifically documented PSSD symptoms—including low libido, delayed ejaculation, and erectile dysfunction—developing after discontinuation of venlafaxine, with 5-HT1A receptor downregulation proposed as a possible mechanism.[73]
A 2023 retrospective cohort study of over 12,000 males estimated the risk of irreversible sexual dysfunction (as measured by persistent need for
Other
In rare cases, drug-induced akathisia can occur after use in some people.[78]
Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists.[79][80][81] It can also have undesirable cardiovascular effects.[82]
