Venlafaxine

The most important side effect to discuss with patients at the time of prescribing, not just at the time of stopping. Symptoms include dizziness, nausea, headache, irritability, insomnia, paresthesias, and "brain zaps." Can begin within 24–36 hours of a missed dose due to venlafaxine's short half-life. Taper slowly (often over weeks to months). For sensitive patients, XR capsules can be opened for bead-counting to achieve smaller dose reductions than standard strengths allow. Some clinicians bridge the final taper by switching to fluoxetine, using its long half-life for a smoother off-ramp. Discontinuation is not addiction; it is neuroadaptation.

Uncommon at lower doses. More likely above 150mg where NET blockade becomes meaningful. Monitor blood pressure and pulse at baseline and after dose increases, especially in patients with pre-existing hypertension or cardiac disease. This is the main medical safety consideration that distinguishes SNRIs from SSRIs.

The most common early side effect. Serotonergic, similar to SSRIs. Usually improves within the first 1–2 weeks. Taking with food and starting at a lower dose (37.5mg) can help.

Decreased libido, anorgasmia, delayed ejaculation. Common and often similar to SSRIs because the serotonergic mechanism drives it. The norepinephrine component does not offset the serotonergic sexual side effects. Patients who switch from an SSRI to venlafaxine specifically hoping for less sexual dysfunction are usually disappointed.

Norepinephrine-mediated. Can be clinically significant and socially distressing. Sometimes a reason for discontinuation. More pronounced at higher doses.

Some patients experience activation (insomnia, restlessness), others experience sedation. Neither is predictable before trial. Dosing time can be adjusted based on individual response.

Short-term weight loss is possible (particularly with nausea). Long-term, some patients gain weight. Overall weight effects are modest compared to mirtazapine or paroxetine but venlafaxine is not weight-neutral.

As with other antidepressants, screen for bipolar disorder before prescribing. SNRIs can precipitate mania or hypomania in susceptible patients. Consider mood stabilizer coverage when indicated.

As a potent serotonergic medication, venlafaxine increases serotonin syndrome risk when combined with MAOIs (contraindicated; follow labeling washout guidance), linezolid, tramadol, triptans, or during cross-taper transitions with other serotonergic antidepressants. Note that fluoxetine requires a longer washout than standard (due to its very long half-life) before starting an MAOI.

SIADH-mediated sodium lowering can occur with any serotonergic antidepressant, including venlafaxine. Higher risk in elderly patients and those on diuretics. Check sodium if a patient on venlafaxine develops confusion, falls, or altered mental status.