Venlafaxine (Effexor)

• Venlafaxine acts on the following receptors:
  • Serotonin: at lower doses (<150 mg/day) it acts like an SSRI, and serotonergic reuptake is more prominent
  • Norepinephrine: at higher doses (≥150 mg/day) it begins to act more like an SNRI, and norepinephrine reuptake is more prominent
  • Dopamine: to a lesser degree has some mild dopaminergic activity
• Venlafaxine has no significant affinity for cholinergic, histaminergic, or α1-adrenergic receptors.

• Venlafaxine overdose causes sympathomimetic symptoms and QTc prolongation.^[1] Tachycardia, hypotension, seizures, coma, serotonin syndrome, and death can occur in severe overdoses.^[2]

• Major depressive disorder
• Generalized anxiety disorder
• Obsessive-compulsive disorder
• Posttraumatic stress disorder

• Venlafaxine comes in two oral formulations. Venlafaxine Extended Release (Effexor XR) is typically prescribed over Effexor Regular/Immediate because it is less activating and has a better side effect profile (improves tolerability, reduces nausea, and requires only once-daily dosing).

• Blood pressure (especially diastolic)
• ECG monitoring: because of venlafaxine’s association with increased diastolic blood pressure and its prominent noradrenergic activity at higher doses

Some patients may have severe problems with discontinuation of venlafaxine, compared with other antidepressants. Do not mistake withdrawal symptoms for relapse! Since venlafaxine is noradrenergic, when it is stopped abruptly, it can cause noradrenergic rebound symptoms including brain fog, dizziness, and sensations of “electric shocks.”

• Combining venlafaxine with mirtazapine has been dubbed “California Rocket Fuel” by psychopharmacologist Stephen Stahl because of the multiple mechanisms of action on neurotransmitter systems.^[4] The hypothesis is that mirtazapine increases both serotonin and norepinephrine via a different mechanism than SSRIs/SNRIs. This combination therapy was found to outperform parnate (tranylcypromine) in the landmark STAR*D trial.^[5]
• No formal randomized trials have been performed, so its evidence is largely based on expert opinion.^[6] Smaller open-label trials have been done supporting its efficacy.^{[7][8][9][10][11]}
• The maximum dosage for this combination therapy is the same as the standard dose for each respective drug (i.e. - venlafaxine ER's maximum dose is 225mg daily (IR = 375mg daily), and mirtazapine's maximum dose is 45mg daily).

• If a patient has uncontrolled narrow angle-closure glaucoma (due to its hypertensive effects)
• If a patient is taking an MAO inhibitor
• Hypersensitivity of venlafaxine

• MAOIs (serotonin syndrome)
• Inhibitors/inducers of 2D6 and 3A4
• Venlafaxine will modestly increase levels of 2D6 substrates (e.g. - aripiprazole, haloperidol)

• Due to its noradrenergic action, notable side effects include headaches, anxiety, and insomnia.
• Other common side effects include: nausea, abdominal pain, anorexia, weight loss, increased appetite, behavioural activation, sedation, irritability, hostility, asthenia, dizziness, dry mouth, nasal congestion, skin problems.
• There is also a dose-dependent increase in diastolic blood pressure (~5mmHg).

• QTc prolongation (moderate effect)
• Serotonin syndrome
• Venlafaxine-induced hypoglycemia (rare case reports of hypoglycemia in overdose)^[12][13]

• Treatment for OCD may require higher doses
• Patients on long-term venlafaxine therapy should have regular blood pressure monitoring for hypertension
• There are few studies involving venlafaxine and polysomnography, it can be activating or sedating depending on the patient, and the objective EEG findings are most similar to SSRIs.