Depression Treatment: Part 3 – Antidepressants


The advent of antidepressant medication was somewhat fortuitous. The first of these drugs was discovered accidentally during the aftermath of World War II. The V-2 rocket, developed in Germany, used hydrazine as one of its fuels (Valenstein, 1988). 

Subsequently, the end of the war saw a surplus of hydrazine. Alone, hydrazine is a toxic compound. However, researchers seized the opportunity to combine hydrazine with other chemicals for use as experimental treatment for tuberculosis. Two of these compounds, isoniazid and iproniazid, were found to be effective in treating tuberculosis. Shortly after these drugs began to be marketed, it came to light that tuberculosis patients were experiencing euphoria as a treatment side effect. Testing began to 


determine if isoniazid and iproniazid were effective depression treatments. However, after a short time without

 success, these experiments were discontinued.
Currently, we have the knowledge that antidepressants require several weeks to reach a steady state and are at that point therapeutically effective. Years of research producing mixed results went on for years before the effectiveness of iproniazid was established. Iproniazid, a member of a class of drugs known as monoamine oxidase inhibitors, was therefore the first antidepressant (Valenstein, 1988). 

Tricyclic antidepressants were discovered around the same time that iproniazid was showing promising results, and their discovery was also accidental (Valenstein, 1988). At the time, prolonged periods of sleep were utilized for treating psychosis. While testing a drug for sleep induction, a researcher noticed that imipramine resulted in improved energy and mood. Imipramine was tested on over five hundred patients for a period of three year. It was found that the drug improved deep depression but worsened depression with mixed features, mania, and schizophrenia. Imipramine was first marketed under the brand name Tofranil in 1958. Sales of antidepressant medication soared, and so much so that by 1980, doctors were writing ten million prescriptions a year (Valenstein, 1988).  

The development of a new class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), began in the late 1960s, when research began to emerge suggesting that serotonin was in some way involved with the presence of depressive symptoms. However, it was not until the late 1980s that the first SSRI, Prozac, was brought to market (Hillhouse & Porter, 2015). An atypical antidepressant, bupropion, obtained FDA approval in 1989. Bupropion is considered atypical because its mechanism of action impacts reuptake of dopamine and norepinephrine. It is one of six atypical antidepressants available in the U.S. Currently, antidepressants are grouped into six different classes. These include cyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and atypical antidepressants (Preston, O’Neal, & Talaga, 2013).

Antidepressants are commonly used as a first line of treatment for depression. However, decades after their invention, questions still remain as to their effectiveness. First, it is notable that while researchers have proposed mechanisms of action, no one truly knows how antidepressants work. While this is not surprising, considering that many psychiatric drugs including antidepressants were discovered by happenstance, it is perhaps remarkable considering that these drugs have been in existence for 70 years and greater clarity as to how exactly they work remains to be seen. In a meta-analysis of 522 studies involving over 100,000 participants, researchers found that antidepressants were generally more effective than the placebo, with a moderate effect size (Ciprani et al., 2018). However, 78% of the studies were funded by pharmaceutical companies, and 82% of the studies demonstrated a high risk of bias. Further, the authors found that drugs demonstrated a novelty effect, such that they appeared more efficacious when they were experimental versus when they had been established as a treatment (Ciprani et al., 2018). 

Other researchers go so far as to claim that after analysing published and unpublished data held by the pharmaceutical industry, antidepressants are no more effective than the placebo, and that further, these drugs may make people with depression more vulnerable to future relapse (Kirsch, 2014). Treatment for depression involving medication should be tailored to the needs of the individual patient, and should also include discussion with healthcare providers who demonstrate a good understanding of the current research. While the efficacy and appropriate use of antidepressants remains hotly debated, one thing remains clear: science has a long way to go before precision treatment for mental illnesses like depression become mainstream. 


Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Leucht, S., Ruhe, H. G., Turner, E. H., Higgins, J., Egger, M., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J., & Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet, 391(10128), 1357–1366. https://doi.org/10.1016/S0140-6736(17)32802-7

Hillhouse, T. M., & Porter, J. H. (2015). A brief history of the development of antidepressant drugs: From monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1), 1–21. https://doi.org/10.1037/a0038550

Kirsch, I. (2014). Antidepressants and the placebo effect. Zeitschrift fur Psychologie, 222(3), 128–134. https://doi.org/10.1027/2151-2604/a000176

Preston, J. D., O’Neal, J. H., & Talaga, M. C. (2013). Handbook of clinical psychopharmacology for therapists (7th ed.). New Harbinger Publications, Inc. 

Valenstein, E. S. (1988). Blaming the brain: The truth about drugs and mental health. The Free Press. 

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