The prevalence of mental disorders in the United States is approximately 30 percent. The global burden of disease statistics shows that four of the ten most important causes of disease worldwide are psychiatric in origin. The pathophysiology behind psychiatric disorders is the imbalance of the complex neurotransmitter system in the brain.  The mainstay of treatment for depression and anxiety have been therapies to modulate these neuron transmitters, including selective serotonin reuptake inhibitors (SSRI), mixed norepinephrine/serotonin reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), and Monoamine oxidase inhibitors (MAOI). This article will focus on venlafaxine, which belongs to the class of antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRIs).[1]

Venlafaxine is FDA approved to treat and manage symptoms of depression, social anxiety disorder,  and cataplexy. Off-label, venlafaxine can be used for attention deficit disorder, fibromyalgia, diabetic neuropathy, complex pain syndromes, hot flashes, migraine prevention, post-traumatic stress disorder, obsessive-compulsive disorder, and premenstrual dysphoric disorder.  Venlafaxine may be used independently or as part of combination therapy with other drugs.[2]

Venlafaxine works by increasing serotonin levels, norepinephrine, and dopamine in the brain by blocking transport proteins and stopping its reuptake at the presynaptic terminal. This action leads to more transmitter at the synapse and ultimately increases the stimulation of postsynaptic receptors. SNRIs act primarily upon serotonergic and noradrenergic neurons but have little or no effect upon cholinergic or histaminergic receptors. Venlafaxine is a bicyclic phenylethylamine compound.[3] Venlafaxine is a more potent inhibitor of serotonin reuptake than norepinephrine reuptake. Venlafaxine is essentially a selective serotonin reuptake inhibitor at 75 mg, and with higher doses such as 225 mg/day, it has significant effects on the norepinephrine transporter in addition to serotonin.

Venlafaxine is prescribed only for those 18 years and older and should not be used in children under 18. Venlafaxine should be taken with food, and patients should not take it with alcohol as combining alcohol and venlafaxine can lead to increased sedation. 

Venlafaxine comes in an oral tablet and an oral capsule. The oral tablets come in immediate-release (25 mg, 37.5 mg, 50 mg, 75 mg and 100 mg) and extended-release forms (37.5 mg, 75 mg, 150 mg, and 225 mg.) The immediate-release tablet can be cut or crushed, but the extended-release tablet may not be. Treatment for depression for the immediate release oral table typically starts at 75 mg total per day, given in two or three divided doses.[4] Dosage can increase to 150 mg per day, with a maximum dose of 375 mg per day. The extended-release oral tablet typical starting dose is 75 mg per day taken as a single dose in the morning or evening. This dose can be increased by 75 mg every four days until reaching the maximum dose of 225 mg per day.

Venlafaxine causes a lower frequency of anticholinergic, sedating, and cardiovascular side effects but a higher incidence of gastrointestinal complaints, sleep impairment, and sexual dysfunction than TCAs. Additionally, venlafaxine may impair sexual function, resulting in diminished libido, impotence, or difficulty in achieving orgasm. Sexual dysfunction frequently results in noncompliance and should be asked about specifically. Sexual dysfunction can sometimes be ameliorated by lowering the dose or instituting drug-free weekends and holidays in appropriate patients. Some patients find withdrawal symptoms uncomfortable.[5]  

Common side effects include: 

• Headache
• Nausea
• Insomnia, dizziness, hypotension, anorexia, somnolence
• Xerostomia
• Asthenia
• HTN
• Impotence, decreased libido, and/or anorgasmia
• Constipation
• Weight loss
• Abnormal dreams
• Diarrhea, abdominal pain
• Blurred vision
• Anxiety, tremor
• Hypercholesterolemia
• Hyponatremia
• Serotonin Syndrome
• Seizures

There is an FDA black box warning against venlafaxine as it can increase suicidality, cause depression exacerbation, hypomania/mania, and serotonin syndrome. Venlafaxine can also cause abnormal bleeding, altered platelet function, and anaphylaxis/anaphylactoid reaction. Venlafaxine can cause fatal skin conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Venlafaxine can also cause deterioration of glaucoma angle closure and seizures.[6] Venlafaxine has implications linking it to SIADH, HTN, arrhythmia, interstitial lung disease, eosinophilic pneumonia, pancreatitis, and hepatotoxicity. One main concern with SSRIs and SNRIs is the risk of serotonin syndrome, thought to result from hyperstimulation of brainstem 5HT-1A receptors.[7]

Contraindications to venlafaxine include concurrent use of monoamine oxidase inhibitors. Clinicians should not use venlafaxine if there is a history of anaphylaxis, and caution is necessary when combining venlafaxine with other serotonin modulators. Venlafaxine should be used cautiously with other sedating medications such as CNS depressants and alcohol use. Venlafaxine is contraindicated if it causes worsening suicidal ideation, depression, anxiety, and psychosis. Caution is advisable in heart failure patients, hyperthyroidism, and those with recent myocardial infarctions as it can raise blood pressure and increase heart rate. Venlafaxine raises the risk of seizures, and prescribers should avoid the drug in patients with a seizure disorder.[8] Venlafaxine can cause pupillary dilation and block the flow of fluid in the eye, leading to increased ocular pressure. Patients with glaucoma should have their eye pressures regularly monitored while taking venlafaxine. Venlafaxine is contraindicated in patients with uncontrolled angle-closure glaucoma.  Venlafaxine is a category C pregnancy drug. Venlafaxine can potentially pass into breast milk and cause side effects in breastfed children and should not be used in pregnancy and breastfeeding.