Continuing Education Activity

Venlafaxine is categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI). It is approved by the US Food and Drug Administration (FDA) to treat major depressive disorder (unipolar), social anxiety disorder, and panic disorder. In addition, venlafaxine is commonly used off-label for conditions such as attention-deficit disorder, fibromyalgia, diabetic neuropathy, complex pain syndromes, hot flashes, migraine prevention, posttraumatic stress disorder, obsessive-compulsive disorder, and premenstrual dysphoric disorder. Venlafaxine can be used either as a standalone treatment or as part of a combination therapy regimen with other medications.

Venlafaxine increases serotonin and norepinephrine levels in the central nervous system by blocking transport proteins and inhibiting their reuptake at the presynaptic terminal. This leads to a greater availability of neurotransmitters at the synapse, ultimately enhancing the activation of postsynaptic receptors. Antidepressants such as venlafaxine enhance the expression of brain-derived neurotrophic factors and promote neuroplasticity, ultimately decreasing neuroinflammation. This activity focuses on the indications, mechanism of action, administration methods, significant adverse drug reactions, contraindications, and monitoring strategies of venlafaxine in the treatment of psychiatric disorders. This activity underscores how clinicians can direct patient therapy with evidence-based guidelines to achieve optimal treatment outcomes and patient satisfaction within the interprofessional healthcare team.

Objectives:

• Identify the appropriate indications for venlafaxine therapy in the management of various psychiatric conditions based on the patient's psychiatric diagnosis and symptomatology.

• Screen patients for contraindications to venlafaxine therapy, such as hypersensitivity reactions or concurrent use of monoamine oxidase inhibitors.

• Implement appropriate dosing strategies for venlafaxine initiation, titration, and discontinuation based on patient-specific factors and treatment response.

• Communicate with other healthcare providers to coordinate comprehensive care for patients receiving venlafaxine, including monitoring vital signs and laboratory parameters.

Indications

The prevalence of mental disorders in the United States is approximately 30%. The global burden of disease statistics shows that 40% of the 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 management for depression and anxiety are therapies to modulate these neurotransmitters, including selective serotonin reuptake inhibitors (SSRIs), mixed serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Venlafaxine is categorized as an SNRI.[1]

FDA-Approved Indications

Venlafaxine is approved by the US Food and Drug Administration (FDA) to treat major depressive disorder (unipolar), social anxiety disorder, and panic disorder.[2][3][4]

Off-Label Uses

In addition, venlafaxine is commonly used off-label for conditions such as attention deficit disorder, fibromyalgia, complex pain syndromes, cataplexy, hot flashes, posttraumatic stress disorder, obsessive-compulsive disorder, premenstrual dysphoric disorder, and migraine prevention.[5] Venlafaxine can be used either as a standalone treatment or as part of a combination therapy regimen with other medications.[6] The American Academy of Neurology endorses venlafaxine for diabetic neuropathy.[7]

Mechanism of Action

Venlafaxine increases serotonin and norepinephrine in the central nervous system by blocking transport proteins and inhibiting their reuptake at the presynaptic terminal. This action leads to increased neurotransmitters available at the synapse and ultimately increases the stimulation of postsynaptic receptors. SNRIs primarily affect serotonergic and noradrenergic neurons, with little or no impact on cholinergic or histaminergic receptors. Venlafaxine is a bicyclic phenylethylamine compound.[8] Venlafaxine is a more potent serotonin reuptake inhibitor than norepinephrine reuptake. Venlafaxine inhibits serotonin reuptake at lower doses but affects both norepinephrine and serotonin reuptake at higher doses. Antidepressants such as venlafaxine increase brain-derived neurotrophic factor expression and increase neuroplasticity. Venlafaxine is also known to reduce neuroinflammation.[9][10][11]

Pharmacokinetics

Absorption: Venlafaxine is well absorbed orally (92%) but has a lower bioavailability of 45%. Peak plasma concentrations are typically attained within 2 to 3 hours for immediate-release formulations and 5.5 to 9 hours for extended-release formulations.

Distribution: Venlafaxine's plasma protein binding ranges between 27% and 30%, while its volume of distribution is 7.5 L/kg.

Metabolism: Venlafaxine is primarily metabolized by the liver, predominantly through the cytochrome P450 system, particularly the CYP2D6 enzyme.[12]

Elimination: The elimination half-life of venlafaxine varies depending on the formulation and is approximately 5±2 hours for immediate-release, 6.8±1.6 hours for extended-release besylate, and 10.7±3.2 hours for extended-release hydrochloride. However, this half-life may be prolonged in individuals with renal or hepatic dysfunction. Most venlafaxine is eliminated through urine, with about 87% of the total dose excreted through this pathway. Of this excretion, 5% is an unchanged drug, while 29% is unconjugated O-desmethyl venlafaxine and 26% as conjugated O-desmethyl venlafaxine.[13] Additionally, 27% of the total dose is excreted as minor inactive metabolites.

Administration

Available Dosage Forms and Strengths 

Venlafaxine should be taken with food, and patients should avoid combining it with alcohol to prevent increased sedation. Venlafaxine is available in both oral tablet and oral capsule forms. The oral tablets come in immediate-release dosage formulations of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg and extended-release dosage formulations of 37.5 mg, 75 mg, 150 mg, and 225 mg. Although the immediate-release tablet can be cut or crushed, the extended-release tablet cannot. Treatment for depression usually begins with immediate-release oral tablets at a total daily dose of 75 mg, divided into 2 or 3 doses.[14]

Adult Dosage

Venlafaxine is prescribed only for individuals aged 18 and older and should not be used in children aged 18 or younger. Venlafaxine should be taken with food, and patients should not take it with alcohol, as combining alcohol and venlafaxine can lead to increased sedation. The dosage can increase to 150 mg daily, with a maximum dose of 375 mg daily. The typical starting dose of the extended-release oral tablet is 75 mg daily, taken as a single dose in the morning or evening. The dose of venlafaxine can be increased by 75 mg every 4 days until the maximum dose of 225 mg daily. The FDA-approved dosing of the venlafaxine extended-release (venlafaxine hydrochloride) is given below.

• Major depressive disorder: The suggested starting dosage of venlafaxine for major depressive disorder is 37.5 to 75 mg/d, with a target dose of 75 mg/d and a maximum dosage of 225 mg/d.

• Generalized anxiety disorder: The recommended starting dosage for generalized anxiety disorder is 37.5 to 75 mg/d, with a target dosage of 75 mg/d and a maximum dose of 225 mg/d.

• Social anxiety disorder: The recommended starting and target dosage for social anxiety disorder is 75 mg/d.

• Panic disorder: The recommended starting dosage for panic disorder is 37.5 mg/d, with a target dosage of 75 mg/d and a maximum dosage of 225 mg/d.

Specific Patient Populations

Hepatic impairment: In mild-to-moderate hepatic impairment (Child-Pugh Class A or B), reduce venlafaxine's daily dose by 50%. For severe hepatic impairment (Child-Pugh Class C) or cirrhosis, decrease the total daily dose by 50% or more.

Renal impairment: Adjust the dosage based on creatinine clearance (CrCl). For mild-to-moderate impairment (CrCl 60-89 mL/min or CrCl 30-59 mL/min), reduce the total daily dose by 25% to 50%. For hemodialysis or severe impairment (CrCl <30 mL/min), decrease the daily dose by 50% or more. Due to variability in clearance, individualize dosage as needed.

Pregnancy considerations: In a case-control study involving 30,630 mothers of infants with congenital anomalies and 11,478 control mothers, associations between antidepressants and birth defects were examined. Venlafaxine exhibited associations with birth defects, emphasizing the need for further investigation to confirm these findings. When evaluating the likelihood of birth defects in women who are taking antidepressants, it is important to consider the underlying condition. This highlights the significance of making informed decisions about treatment options by weighing the risks and benefits of intervention against those of untreated depression or anxiety.[15]

Breastfeeding considerations: Infants may be exposed to venlafaxine and its active metabolite through breastmilk, with the metabolite detectable in the plasma of most breastfed infants. However, rare reports of concurrent adverse effects might exist. While some experts caution against venlafaxine use during nursing, a safety scoring system suggests it may be possible during breastfeeding. Newborns or preterm infants should be monitored for excessive sedation and adequate weight gain during lactation. Monitoring serum levels of desvenlafaxine may be considered to assess potential toxicity concerns. Bruxism has been reported in 1 infant. Neonatal adaptation syndrome, similar to that observed with other antidepressants such as SSRIs or SNRIs, may occur in newborns of mothers who took venlafaxine during pregnancy.[16]

Pediatric patients: Venlafaxine is not FDA-approved for pediatric patients. However, it has been used off-label for cataplexy.[17]

Older patients: According to the American Geriatrics Society Beers Criteria (2023), caution is recommended when using venlafaxine in older adults.[18]

Adverse Effects

Venlafaxine causes a lower frequency of anticholinergic, sedating, and cardiovascular adverse 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. Sexual dysfunction can sometimes be alleviated by lowering the dose or instituting drug-free weekends and holidays in appropriate patients.

Venlafaxine is prescribed for the long term, and it carries severe risks if not taken as directed or stopped abruptly. Abrupt cessation of venlafaxine can lead to severe 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. Some patients find withdrawal symptoms uncomfortable.[19]  Common adverse effects of venlafaxine include headache, nausea, insomnia, dizziness, somnolence, xerostomia, asthenia, hypertension, impotence, decreased libido, anorgasmia, constipation, weight loss, abnormal dreams, diarrhea, abdominal pain, blurred vision, anxiety, tremor, hypercholesterolemia, and hyponatremia. Severe adverse effects include serotonin syndrome [20] and seizures.[21]

Venlafaxine can cause depression exacerbation and hypomania/mania. 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.[22] Venlafaxine has implications linking it to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypertension, arrhythmia, interstitial lung disease, eosinophilic pneumonia, pancreatitis, and hepatotoxicity.[12]

Drug-Drug Interactions

• Venlafaxine can interact with many other medications or herbs.[23]

• Concomitant administration of desvenlafaxine with other serotonergic drugs should be avoided due to the risk of serotonin syndrome resulting from hyperstimulation of brainstem 5HT-1A receptors. Concurrent use of venlafaxine with SNRIs, SSRIs, triptans, TCAs, opioids, lithium, buspirone, amphetamines, tramadol, tryptophan, and St John's wort is not recommended. Vigilant monitoring for symptoms indicative of serotonin syndrome is imperative when venlafaxine is administered alongside these medications. If serotonin syndrome is suspected, prompt evaluation and consideration for discontinuation of venlafaxine and the other serotonergic agents involved are warranted to mitigate potential adverse effects and ensure patient safety.[24] 

• Venlafaxine should be used cautiously with sedating medications, such as central nervous system depressants and alcohol. 

• The coadministration of venlafaxine with antiplatelet or anticoagulant medications may increase the risk of bleeding. This risk is attributed to venlafaxine's potential impact on serotonin release by platelets. Close monitoring for signs of bleeding is essential when initiating or discontinuing venlafaxine in patients receiving antiplatelet or anticoagulant therapy. Clinicians should be vigilant for bleeding complications and consider appropriate interventions as necessary.

• Patients should not take venlafaxine with MAOIs, linezolid, and methylene blue. 

• Venlafaxine should not be ingested with drugs for weight loss, such as phentermine. Concurrent use of venlafaxine phentermine may cause excessive weight loss, serotonin syndrome, tachycardia, and psychosis.[25]

• The risk of bleeding may increase when taking venlafaxine with warfarin and NSAIDs such as aspirin, ibuprofen, and naproxen. 

• Clarithromycin, ritonavir, and ketoconazole can inhibit the breakdown of venlafaxine, leading to its accumulation in the body. 

• Concurrent use of venlafaxine with lorazepam zolpidem or diphenhydramine can result in increased sedation. 

• The efficacy of metoprolol is reduced when administered with venlafaxine.

• The risk of QT prolongation increases when venlafaxine and haloperidol are administered concurrently.[26]

Contraindications

Contraindications to venlafaxine include concurrent use of MAOIs. Contraindications for venlafaxine include hypersensitivity to venlafaxine, desvenlafaxine succinate, or excipients. Clinicians should not use venlafaxine if a history of anaphylaxis is evident. 

Box Warning

The FDA has issued a warning regarding antidepressants, including venlafaxine, as they have been associated with an increased risk of suicidal behaviors and thoughts in young patients. Therefore, it is crucial to closely monitor all patients receiving antidepressant treatment for any signs of clinical deterioration or the onset of such thoughts and behaviors.[27] Furthermore, it is worth noting that venlafaxine is not FDA-approved for pediatric patients.

Warning and Precautions

Caution is necessary when combining venlafaxine with other serotonin modulators. Caution is advisable in heart failure, hyperthyroidism, and those with recent myocardial infarctions, as venlafaxine 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.[28] Venlafaxine can cause pupillary dilation and block fluid flow in the eye, leading to increased ocular pressure. Patients with glaucoma should have their eye pressures regularly monitored while taking venlafaxine. Venlafaxine should be avoided in patients with uncontrolled angle-closure glaucoma. Venlafaxine is an FDA pregnancy category C drug. Venlafaxine can potentially pass into breast milk and cause adverse effects in breastfed children and should not be used in pregnancy and breastfeeding.

Monitoring

Due to venlafaxine's potential to increase blood pressure and heart rate, monitoring vital signs is imperative. Additionally, monitoring renal and hepatic function is essential to ensure accurate dosing and prevent adverse effects. Furthermore, assessing depression severity using validated tools such as the Montgomery–Asberg Depression Rating Scale and PHQ-9 (Patient Health Questionnaire-9) aids in monitoring the effectiveness of treatment and guiding therapeutic decisions.[29][30]

Toxicity

Signs and Symptoms of Overdose

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.[16] 

To meet the criteria, the patient must be taking a serotonergic agent and fulfill 1 of the following conditions:

• Spontaneous clonus
• Inducible clonus with agitation or diaphoresis
• The presence of ocular clonus plus agitation or diaphoresis
• Tremor with hyperreflexia
• Hypertonia with a temperature above 38 °C plus ocular clonus or inducible clonus

Management of Overdose

Management of serotonin syndrome involves promptly discontinuing all serotonergic agents with supportive care to normalize hemodynamics. Patient sedation with benzodiazepines and serotonin antagonists may also be an option.[24] 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.[31] 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 monitor vital signs, particularly blood pressure, during venlafaxine therapy. Additionally, venlafaxine patients should undergo regular assessments of renal function and lipid profiles. Close monitoring of psychiatric symptoms, including suicidality, depression, mania, anxiety, or unusual behavior changes, is imperative. Careful attention should be exercised during transitions between venlafaxine and MAOIs, with a recommended 2-week gap before starting venlafaxine after discontinuing an MAOI and a 7-day gap before commencing MAOI therapy after stopping venlafaxine. Collaboration among clinicians and pharmacists is essential to facilitate comprehensive monitoring, ensure patient safety, and optimize therapeutic outcomes. This approach underscores the significance of evidence-based medicine in guiding psychiatric clinical practice while tailoring care to meet individual patient needs.