The history of antidepressants: discovery and development

By Eva Borras

Until the 1950s, opioids and amphetamines were the common drugs used as antidepressants. Due to their addictive nature, scientists and doctors ceased their use after two specifically antidepressant drugs were discovered accidentally: iproniazid and imipramine. (Lopez-Munoz and Alamo, 2009)

In 1951, scientist Hoffman-LaRoche developed iproniazid. This drug was originally meant to be used as an anti-tuberculosis drug however it was tested to give no results in treating tuberculosis. Further research found that it was useful in other applications, such as a psychic energizer (in the words of Nathan S.Kline). At first, the side effects such as feelings of euphoria, pain relief and increased mental alertness, were not considered therapeutic as they seemed to not have consistency in results. However, a trial carried out in 1958 by Loomer, Saunders, and Kline found a significant improvement in the treatment of depressive states. (FELDSTEIN, HOAGLAND and FREEMAN, 1959) In the 1960s however, the drug was retracted as lethal liver injury was found as a side effect.

This drug works by inhibiting activity of monoamine-oxidase enzymes, to stop the breakdown of biogenic monoamines in the synaptic space and therefore increases their concentration. The theory of monoamine hypothesis of depression was developed after an alkaloid, previously used to treat hypertensive vascular disease, reserpine, was found to give rise to depression in some patients. After various experiments during the 1960s and 1970s it was found out that in order for a drug to ‘cure’ depression it would need to increase the presence of dopamine, serotonin and norepinephrine (monoamines) in the synaptic space. 

There are several monoamine-based pharmacological drug classes approved for the treatment of major depressive disorder, although the success rates are below 60%, while 34-46% of patients do not respond to treatment at all. Another major down side is that depressive symptoms often disappear after a prolonged use of antidepressants, meaning there is a delayed onset. (Hillhouse and Porter, 2015)

The other antidepressant discovered in 1950 was imipramine, the first drug in the tricyclic antidepressant family (TCA). Imipramine was molecularly modified from an antihistamine structure after a successful drug to treat schizophrenia (chlorpromazine) increased the interest of scientists to develop antipsychotic drugs. 

Usually serotonin (known for regulating emotions and moods) is reabsorbed by the postsynaptic receptor in cells after carrying out its role of neurotransmitter, carrying a message between nerve cells. The role of Imipramine is to inhibit presynaptic norepinephrine and serotonin reuptake transporters, therefore increasing the concentration of serotonin in the cleft. However, TCAs also block other postsynaptic receptors such as muscarinic, histamine H1, and adrenergic α1 and α2 receptors, which lead to unpleasant side effects such as constipation, dry mouth, dizziness and drowsiness. (Hillhouse and Porter, 2015) Therefore at the moment TCAs are not used to treat depression. (Garg and Ferguson, 2012)

In the 1980s, another revolutionary drug was introduced known as fluoxetine. This is a selective serotonin reuptake inhibitor (SSRIs) which targets more than one specific brain receptor site, and shows weak action at inhibiting postsynaptic receptors. This means SSRI’s increase serotonin by blocking reuptake rather than blocking postsynaptic receptors. In addition, it was concluded that SSRI have minimal affinity to unwanted histamine and acetylcholine postsynaptic receptors and therefore side effects are reduced, but still include nausea, insomnia, and sexual dysfunction. 

Similarly, a few years later, the first of many Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) was developed: venlafaxine. It works in a similar way as TCA; an inhibition of the reuptake of serotonin and norepinephrine in the transporters to increase levels of such. Contrary to TCAs, SNRIs have no affinity to adrenergic (α1, α2, and β), histamine (H1), muscarinic, dopamine, or postsynaptic serotonin receptors, decreasing massively the severe side effects. (Hillhouse and Porter, 2015)

In 1989, the only selective dopamine-norepinephrine reuptake inhibitor on the market, was approved as an antidepressant drug: Bupropion. It has a very low affinity to serotonin reuptake receptors and a high affinity for dopamine transporters. Therefore it works differently to the previous described antidepressants as it increases dopamine levels in the brain instead of serotonin. 

To this day, SSRIs are the most commonly  prescribed antidepressants, as they  cause less harmful side effects to the patient. According to the NHS, it takes between 2 and 4 weeks of daily dosage for the patient to feel a benefit. 

In 2017 the World Health Organization announced that more than 264 million people of all ages suffer from depression all around the world. Public Health England (PHE) reported that the rate of prescribing antidepressants in England increased from 15.8% in 2015 to 16.6% in 2018, with 930,000 patients receiving a continuous prescription from 2015 to 2018. In addition, an analysis conducted by the New York times in 2018 shows that almost 25 million adults have been taking antidepressants in the USA for at least 2 years, a 60% increase since 2010. 

Over the years, it was proved that the serotonin hypothesis accounts for 20% of the reason for depression whereas neurotransmitters GABA and glutamate account for 80%. Both latter neurotransmitters are thought to control the majority of electrical activity. In March 2019, esketamine (a nasal spray derived from ketamine) was approved by the Food and Drug Administration (FDA) for treating depression that has failed to respond to two or more antidepressants. Eskatamine works by inhibiting glutamate receptors and increasing its concentration in the brain. (Swainson et al., 2019)

In conclusion, as current antidepressants on the market are not ideal, research groups are focusing on using advances in technology to research an alternative approach to find more effective treatment, and more importantly, a possible cure.

References:

Feighner, J. and Boyer, W., 1991. Selective Serotonin Re-uptake Inhibitors. International Clinical Psychopharmacology, 6(2), p.126.

FELDSTEIN, A., HOAGLAND, H. and FREEMAN, H., 1959. Monoamine Oxidase, Psychoenergizers, and Tranquilizers. Science, 130(3374), pp.500-500.

Garg, U. and Ferguson, A., 2012. Challenges in Therapeutic Drug Monitoring of Classical Tricyclic and Newer Antidepressants. Therapeutic Drug Monitoring, pp.269-289.

Hillhouse, T. and Porter, J., 2015. A brief history of the development of antidepressant drugs: From monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1), pp.1-21.

Lopez-Munoz, F. and Alamo, C., 2009. Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today. Current Pharmaceutical Design, 15(14), pp.1563-1586.

Swainson, J., Thomas, R., Archer, S., Chrenek, C., MacKay, M., Baker, G., Dursun, S., Klassen, L., Chokka, P. and Demas, M., 2019. Esketamine for treatment resistant depression. Expert Review of Neurotherapeutics, 19(10), pp.899-911.

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