Antidepressants and Pain Control: A Historical Perspective, Tricyclic Antidepressants

By | August 14, 2011

Chemical Structure of Imipramine

Imipramine, the prototypical tricyclic antidepressant was synthesized in the early 1950's as a derivative of chlorpromazine by research chemists working at Geigy. The first clinical trials in 1955 showed the tendency to induce mild states of mania. The first clinical trials of imipramine as an antidepressant were published in 1957 by the Swiss psychiatrist Ronald Kuhn.

Tricyclic antidepressants were first developed and tested in the 1950’s and 60’s and were the first class of compounds to be widely used in the treatment of depression. Tetracyclic analogues were introduced in the 1970’s. While their mood altering effects are not as pronounced or rapid as those of opioids or amphetamines, their better side effect profile and lack of addictive potential have made them preferable to the older compounds.

Tricyclic and tetracyclic antidepressants have a number of actions within the central nervous system. They block to varying degrees the transport of all three endogenous neuroactive amines, serotonin, norepinephrine and dopamine. They also block a number of receptors for these compounds. Their relative potencies and side effect profiles are to a large extent determined by the relative binding constants for the different receptors. The fact that these compounds also block histamine receptors and muscarinic acetylcholine receptors to some extent explains some of their most common side effects, such as sedation, dry mouth and constipation.

The tricyclic compounds have now largely been displaced in the routine treatment of depression by newer drugs with better side effect profiles.  While still used for refractory cases of depression, these drugs are now used more commonly and often in sub-psychotherapeutic doses in the treatment of fibromyalgia and certain chronic pain conditions, especially neuropathic pain states.


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