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Doxepin is not addictive, and it won’t make you “high.” Although it can cause mild to severe sedation or drowsiness, it does not have a tranquilizing effect. Doxepin is a tricyclic antidepressant, a group of drugs with three conjoined rings in their chemical structure, which is used to treat depression, anxiety, insomnia, and other mood disorders. Like imipramine and amitriptyline, it is one of the classical or first-generation antidepressants. There are two types of antidepressants that have been around since the 1950s: tricyclics (TCA) and monoamine oxidase (MAO) inhibitors. The first tricyclic antidepressant, imipramine, was approved in 1959 by the Food and Drug Administration, which established the TCA class of drugs as pharmacological treatment for depression.

What is major depressive disorder?

The most common mood disorder in the United States is major depressive disorder or MDD, a chronic, recurring, and debilitating mental disorder with a lifetime prevalence of 14.4%. MDD often occurs together with anxiety disorder, substance abuse, and impulse control disorder. The condition is most common among adult patients ages 18 to 64 years old, with 20s as median age of onset. A person may be clinically depressed if he or she has three or more of these symptoms, persisting for more than 14 days.

  • Feeling anxious, down, or “empty”
  • Unable to enjoy recreational activities, such as spending time with friends
  • May feel easily irritated, anxious, on the brink of tears
  • Feeling guilty, useless, or hopeless
  • Sleeping too much or sleeping less
  • Extreme weight loss or weight gain
  • Having low energy, feeling tired all the time
  • Easily distracted, unable to concentrate.
  • Thinking about suicide or killing oneself
  • Other physical symptoms without an underlying medical condition (stomach aches, unexplained body pains)

In treating individuals diagnosed with depression, antidepressants are the first choice of psychiatrists, in conjunction with some form of talk therapy. Some studies comparing the effectiveness of commonly used antidepressants, TCAs, MAOIs, and SSRIs, reported no difference in overall efficacy among the three drug classes. 

Antidepressant addiction and overdose

Being one of the most commonly prescribed drugs for depression—at least in the 1960s to the 1980s—TCAs are also one of the most commonly abused prescription drugs and causes more overdose deaths than any other drug. But according to Doxepin’s FDA-approved literature, euphoria is not one of its side effects. Unlike other illicit drugs that also block monoamine transporters, “doxepin has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.” Since this drug is non-addictive, tolerance does not develop.

Despite its efficacy, especially for severe type of MDD, TCA is only second to the much-celebrated SSRIs (Prozac, Zoloft, etc.) This is probably attributed to non-specific characteristic and higher toxicities of most TCAs. Instead of just acting on one target to bring beneficial effects, such as mood elevation, TCAs may target other sites in the central and peripheral nervous system.

Pharmacological effects of Doxepin

The major drawback in the use of TCAs is its side effects. Most commonly reported adverse effects at the start of treatment include irritation, jittering, unusual energy, and trouble sleeping or staying asleep. Some patients with anxiety experience worsening of existing symptoms during the first few weeks of treatment prior to the onset of positive therapeutic effects. It is unfortunate that these patients will most likely drop out of treatment before the beneficial effects of TCA can decrease their panic attacks. If you are one of these patients, your doctor may prescribe a very low starting dose of about 10–25mg per day for a few weeks. If your side effects are well tolerated at this stage, the doctor may increase the dose every 2–3 days until the negative effects disappear and your dose can be increased to the standard therapeutic dose. Increased appetite and weight gain is also a significant, possibly long-term, side effect of TCAs. Some patients reported weight gains of one pound per month, without specifying how long this increase lasts, while a number of patients may gain 20 pounds or more. Other possible side effects include increased sensitivity to the sun, postural hypotension, sleepiness, and sweating.

Serotonin and norepinephrine reuptake inhibition – causes increase of two functioning neurotransmitters in the brain, eliminating depressive symptoms.

Anticholinergic effect – blocks the neurotransmitter acetylcholine in the central and peripheral nervous system. May cause side effects such as dry mouth, blurred vision, dental problems, hyperpyrexia (feeling of overheating), and dementia-like symptoms.

Antihistaminic effect – doxepin is a potent and selective HI antagonist. It causes sedation at doses 5–25mg. This effect is beneficial for improving sleep quality and treating some cases of insomnia, but it can be bothersome for daytime use when productivity is required.