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Amitriptyline was approved over half a century ago as an antidepressant and still remains popular today. Interestingly amitriptyline provides a similar degree of relief from depression as more recent additions to our armamentarium. Selecting among the various options involves considering other circumstances: medical issues, patient preference and side effect profile. Over the years, the indications for amitriptyline expanded far beyond depression and often without either formal study or specific FDA authorization. Among the conditions routinely treated with amitriptyline are fibromyalgia, chronic fatigue, diabetic neuropathy, pain lingering after shingles, insomnia and low back pain. Amitriptyline ranks among the least expensive options to prevent migraine headache and may even remedy chronic itchiness. A major issue with amitriptyline involves tiredness or fatigue. For this reason most doctors recommend taking the medicine just before retiring for the evening. In fact many physicians prescribe low doses to treat insomnia rather than larger amounts necessary to combat depression. Among the many undesirable side effects of amitriptyline are dry mouth, blurred vision, constipation, weight gain, difficulty urinating and erectile dysfunction. Problems concentrating and the potential for cardiovascular issues pose further concerns. Common to all antidepressants, the FDA mandates a warning of increased suicidal thoughts and behaviors especially among those less than age 24. Amitriptyline interacts with a significant list of other drugs. Special cautions concern triptans used to treat acute migraine attacks, Lyrica, gabapentin, tramadol and anti-psychotics now commonly employed in treating schizophrenia, mania of bipolar disorder and agitation associated with autism in children. MAO inhibitors must not be used within 2 weeks of amitriptyline. Overlap with the popular SSRIs and SNRIs such as Prozac, Celexa, Lexapro and Zoloft may risk a nasty condition known as the serotonin syndrome. Consuming alcohol while taking amitriptyline poses further risks. After a course of therapy the dose must be gradually tapered rather than abruptly discontinued. Among the antidepressants, overdose of amitriptyline poses the greatest risk of death. When used appropriately, amitriptyline continues to offer significant relief for a number of conditions of uncertain origin. Unfortunately the scientific underpinnings of how we select our therapies lags far behind our confidence level and ability to write prescriptions.