Antidepressants: From MAOIs to SSRIs and more

Abstract

Byline: Chaitra. Ramachandraih, Narayana. Subramanyam, Kral. Bar, Glen. Baker, Vikram. Yeragani The era of antidepressants started with isoniazid, an antitubercular agent, which was accidentally found to have euphoric effects in patients with tuberculosis who were receiving this drug. The mood elevating property of the drug, considered to be a side effect, became the primary effect in depression and heralded the synthesis of generations of newer antidepressants. It also shifted the focus of psychiatrists from psychodynamic processes to a biological basis of the illness. [sup][1] Isoniazid belongs to a group of hydrazine compounds, which were synthesized by Fischer in the 1870's. Isonicotinyl hydrazine (isoniazid) was synthesized by Meyer and Malley at Prague from these hydrazine compounds. Forty years later it was re-synthesized by another group of scientists. By chance, it was found to be an effective antitubercular agent. In 1952, Zeller discovered that iproniazid, another hydrazine derivative, inhibited monoamine oxidase (MAO) enzyme, so named by a group of scientists led by Blaschko and Richter in 1937. The enzyme caused the oxidation of adrenaline, a monoamine and was inhibited by ephedrine. However, Mary Hare had observed similar results in 1928 with an enzyme, tyramine oxidase, which later was found to be MAO. The MAO enzyme acts on a number of endogenous and exogenous amines (serotonin, catecholamines, tyramine, beta-phenylethylamine, benzylamine). In the year 1952, Selikoff and Robidzek observed that iproniazid had greater psychostimulatory effects than isoniazid in patients with and without tuberculosis. Subsequent studies by Smith, Kamman, and del Pino found similar stimulatory effects. The effects were described as mood elevating. The patients showed increased vigor and appetite, weight gain, improved sleep, and sociability. In some cases, it caused psychomotor agitation, hypersexuality and psychoses, behavior described as "dancing in the hall". Lurie, a private psychiatrist, coined the term "antidepressant" for the psychostimulatory effects of isoniazid in depressed patients. Until then various terms such as "thymeretics" and "psychic energizers" were used to describe these effects. Kline, Loomer, and Saunders found a correlation between the effects of the antitubercular agents and their inhibitory action on MAO and used iproniazid for the first time on a group of patients with depression. They recorded significant improvement in 70% of the patients. Later studies showed that its MAO-inhibiting property increased serotonin levels in the brain similar to the effects seen with 5-hydroxytrytophan, a precursor of serotonin, which crosses the blood-brain barrier. This was also substantiated by the reversal of reserpine-induced depression by iproniazid, as reserpine depletes biogenic amines. These studies showed promising results in depression through clinical and biochemical observations, Iproniazid was launched as an antitubercular agent because of disagreements among psychiatrists and also due to its hepato and nephrotoxicity. The drug and some other hydrazine derivatives were later taken off of the market. [sup][2],[3] The above findings paved the way to the develolpment of the first class of exclusive MAO inhibitors such as isocarboxazid, tranylcypramine, phenelzine, mebanazine, nialamide, pheniprazine, and etryptamine (an indole derivative). In the meantime, the enzyme MAO was reported by Johnston, in 1968, to exist in two isomeric forms. MAO-A was found in the small intestine and MAO-B was extracted from rat brain. MAO-A deaminated adrenaline, noradrenaline, and serotonin, whereas MAO-B acted on benzylamine and [sz]-phenylethylamine. Dopamine and tyramine were the substrates for both of the isomeric forms. The classical MAO inhibitors such as tranylcypramine and phenelzine inhibited both the isoenzymes. Tranylcypramine, a derivative of cyclopropylamine, was first used in 1959 as an antidepressant, and soon MAO inhibitors became frequently prescribed antidepressants. …