Sertraline

Most common in the first 1-2 weeks and often dose-related. This is a direct serotonergic effect. Most of the body's serotonin is in the GI tract. Starting at 25mg for the first week and taking the medication with food can reduce this significantly.

Affects a substantial proportion of patients on all SSRIs. Often underreported because patients are embarrassed and clinicians don't ask. This is the most common reason patients want to stop an otherwise effective SSRI. Among SSRIs, sertraline is neither the best nor worst for this. Paroxetine is typically the most problematic.

Some patients experience increased anxiety, restlessness, or insomnia in the first 1-2 weeks. Starting at 25mg and warning patients in advance is important. A patient who isn't warned may stop the medication, thinking it's making them worse.

Some patients report feeling less sad but also less happy, less reactive, less like themselves. This is real and likely related to serotonergic effects on emotional processing. It's worth distinguishing from residual depression (which also features anhedonia). If the patient says "I'm not depressed but I don't feel anything," consider whether this is blunting versus incomplete treatment. The distinction changes your next move.

Sertraline has moderate discontinuation risk, more than fluoxetine (whose long half-life provides a built-in taper) but less than paroxetine or venlafaxine. Always taper rather than stopping abruptly. The existence of discontinuation symptoms does not mean the medication is addictive. The mechanism is neuroplastic readjustment, not reward-pathway dependence. Sertraline's half-life is approximately 26 hours, long enough to allow gradual tapers but short enough that missed doses can produce symptoms within 1-2 days.

SSRIs inhibit serotonin uptake by platelets, which can increase bleeding risk. Worth discussing with patients on warfarin or those undergoing surgery.

Relevant combinations include MAOIs (contraindicated), linezolid, tramadol, triptans, and other serotonergic antidepressants. Always review the full medication list before initiating. Serotonin syndrome is rare with sertraline monotherapy but the risk rises meaningfully with polypharmacy.