Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus. Common side effects include sleepiness, dry mouth, constipation, nausea, and blurry vision. Serious side effects may include increased risk of suicide in those under the age of 25, mania, and urinary retention. A withdrawal syndrome may occur if the dose is rapidly decreased. Use during pregnancy and breastfeeding is not generally recommended. Although how it works for treating depression remains an area of active inquiry, it may involve increasing the levels of norepinephrine, along with blocking histamine, acetylcholine, and serotonin. Doxepin was approved for medical use in the United States in 1969. It is available as a generic medication. In 2020, it was the 252nd most commonly prescribed medication in the United States, with more than 1million prescriptions. Medical uses Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia). As a cream it is used for short-term treatment of itchiness caused by atopic dermatitis or lichen simplex chronicus. Insomnia Doxepin is used in the treatment of insomnia. In 2016, the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence. The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar. A 2015 Agency for Healthcare Research and Quality review of treatments for insomnia had similar findings. A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxepin had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4weeks of 0.30 (95% –0.05 to 0.64). The certainty of evidence was rated as very low, and no data were available for longer-term treatment (3months). For comparison, the other sedating antihistamines assessed, trimipramine and doxylamine, had effect sizes (SMD) at 4weeks of 0.55 (95% CI –0.11 to 1.21)