Continuing Education Activity

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. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, toxicity, and monitoring, of venlafaxine so providers can direct patient therapy where it is indicated as part of the interprofessional team.

Objectives:

• Identify the approved and off-label indications for venlafaxine.
• Describe the adverse effects associated with venlafaxine, including the FDA black-box warning.
• Summarize the relevant drug-drug interactions of venlafaxine.
• Explain the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care with venlafaxine therapy to improve patient outcomes for patients who have depression and related conditions for which it is indicated.

Indications

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 has 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]

Mechanism of Action

Venlafaxine works by increasing serotonin levels, norepinephrine, and dopamine in the brain by blocking transport proteins and stopping their reuptake at the presynaptic terminal. This action leads to more transmitters available 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.

Administration

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 typical starting dose of the extended-release oral tablet 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.

Adverse Effects

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 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[6]
• 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.[7] 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.[8]

Contraindications

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.[9] 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.

Monitoring

Venlafaxine can interact with many other medications, vitamins, or herbs.[10] Concurrent use of these agents can cause dangerous effects and are contraindicated with venlafaxine. The following is a brief list of drug interactions with venlafaxine:

• Patients should not take venlafaxine with monoamine oxidase inhibitors (MAOIs), linezolid, and methylene blue.  
• Caution is necessary when using venlafaxine with other drugs that can increase serotonin levels, including SSRIs, SNRIs, and tramadol, as they can lead to life-threatening serotonin syndrome. Other drugs that can raise serotonin include triptans, such as sumatriptan, rizatriptan, and zolmitriptan.
• Venlafaxine should not be combined with drugs for weight loss, such as phentermine. Using venlafaxine with drugs like phentermine may result in excessive weight loss, serotonin syndrome, and heart problems such as tachycardia and hypertension. 
• Venlafaxine with cimetidine raises the risk of high blood pressure or liver disease.
• Venlafaxine with haloperidol raises the risk of QT prolongation.[11]
• Venlafaxine taken with warfarin and anti-inflammatory drugs such as aspirin, ibuprofen, naproxen (NSAIDs) increase the risk of bleeding.
• Ritonavir, clarithromycin, or ketoconazole can inhibit the breakdown of venlafaxine leading to venlafaxine accumulation in the body.  
• Venlafaxine, taken with zolpidem, lorazepam, and diphenhydramine, can lead to increased sedation. 
• Metoprolol may be less effective when taken with venlafaxine.
• Venlafaxine can cause false positives when testing the patient’s urine for phencyclidine (PCP) and amphetamine. This effect may remain for several days after stopping venlafaxine.

Toxicity

Venlafaxine oral tablet is prescribed for long-term treatment, and it comes with serious risks if not taken as prescribed or stop it abruptly. Abrupt cessation of venlafaxine can lead to serious adverse effects such as irritability, tiredness, restlessness, anxiety,  insomnia, trouble sleeping, nightmares, headache, sweating, dizziness, tingling, or "pins and needles" feeling, shaking, confusion, nausea, vomiting, or diarrhea.  Symptoms of an overdose of venlafaxine can include: tachycardia, unusual sleepiness, dilated pupils, seizures, vomiting, cardiac arrhythmias, hypotension, muscle aches or pains, or dizziness.

Severe toxicity of venlafaxine, especially when combined with other antidepressants such as SSRI, SNRI, or MAOI, can lead to serotonin syndrome. Serotonin syndrome is a possibly life-threatening condition associated with increased serotonergic activity in the central nervous system. Serotonin syndrome may present with a spectrum of clinical findings, including autonomic hyperactivity, mental status changes, and neuromuscular abnormalities. Serotonin syndrome characteristically presents with myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, and potentially death. No laboratory tests exist to confirm the diagnosis as serotonin concentrations do not correlate clinically with symptoms. Hunter Toxicity Criteria Decision Rules can be used to form the diagnosis.[12] To meet the criteria, the patient must be taking a serotonergic agent and fulfill one of the following conditions patients must exhibit spontaneous clonus

• An inducible clonus must be present, plus agitation or diaphoresis
• The presence of ocular clonus plus agitation or diaphoresis
• Tremor with hyperreflexia
• Hypertonia with a temperature above 38 degrees C plus ocular clonus or inducible clonus

Management of serotonin syndrome involves prompt discontinuation of all serotonergic agents with supportive care aimed at normalizing hemodynamics. Patient sedation with benzodiazepines and serotonin antagonists may also be an option.[8] Cyproheptadine can be an option in the event of a failure with benzodiazepines and supportive care. Cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties, with an initial dose of 8 mg. treatment with propranolol, bromocriptine, or dantrolene is not recommended. Serotonin syndrome symptoms usually resolve within 24 hours of discontinuation of the offending agent.

Enhancing Healthcare Team Outcomes

Interprofessional healthcare team members should check the patient's blood pressure before starting the medication and, additionally, continue to monitor blood pressure while on venlafaxine. Patients on venlafaxine should also have their renal function, and lipid profiles monitored. Close monitoring of psychiatric disorders, including symptoms of suicidality, depression, mania, anxiety, or unusual behavior changes, is a necessary precaution. Exercise care when transitioning from or to monoamine oxidase inhibitors. Do not start venlafaxine within two weeks of stopping an MAOI, and MAOI therapy should not commence within seven days of stopping venlafaxine. Only through close monitoring of the patient can the adverse effects be avoided. This monitoring should have contributions from all clinicians (MDs, DOs, NPs, PAs), nursing staff, and pharmacists, who need to coordinate their activities and openly share patient information to drive therapeutic decisions, minimize adverse events, drug-drug interactions, and optimizing patient outcomes. [Level 5]