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Alcohol consumption is generally not recommended while taking any class of antidepressant. Drugs that affect the liver may increase the levels of most antidepressants in the system, which can lead to a potentially dangerous overdose. This is particularly true for tricyclic antidepressants (TCAs).

The heartburn medication cimetidine (Tagamet) can increase the effects of many antidepressants, including desipramine, doxepin, imipramine, paroxetine and sertraline.

Smoking may reduce the effects of some TCAs. Certain TCAs may increase the sensitivity of the skin to sunlight. It is generally recommended that patients taking these medications wear sunscreen when outdoors. Some medications, such as certain antacids, may reduce the effectiveness of some  selective serotonin reuptake inhibitors (SSRIs).

SSRIs, especially fluoxetine and paroxetine, can have marked effects on the metabolism of other medications, thereby affecting the blood levels of these medications.