PROZAC – Perhaps the most impactful drug of all time

Major depressive disorder (MDD) is a condition characterised by persistent low mood. It also manifests itself in other symptoms, such as low self-esteem, low energy, and even unexplained chronic pain [1]. According to the UK adult psychiatric morbidity survey, 1 in 15 people attempt suicide at some point in their life, so MDD has always been an important target for drug discovery and development [2].

Perhaps the most famous anti-depressant, however, is fluoxetine – or PROZAC. This drug was developed to target the monoamine hypothesis for depression, which suggests that depression occurs due to decreased monoaminergic function in the brain [3].

Monoamines are a group of neurotransmitters. They are characterised by an aromatic ring connected to one amino group by a chain of two carbons, and include dopamine, noradrenaline and serotonin. These neurotransmitters have been proven to regulate anxiety, happiness and mood [4].

In the 1970s and earlier, there were two main treatments for depression, the first of which being monoamine oxidase inhibitors (MAOIs). Monoamine oxidase breaks down monoamines after their release, so by inhibiting this enzyme, an increased quantity of neurotransmitter remains available in the synapse, thus increasing monoaminergic function. The second was monoamine re-uptake inhibitors (MRIs). These drugs prevented monoamines from being reabsorbed by the pre-synaptic terminal, resulting in an increased quantity of neurotransmitter in the synapse, thus also increasing monoaminergic function [5].

The efficacy of these drugs strongly supports the monoamine hypothesis for depression, but the treatments were not without their weaknesses. MAOIs have low therapeutic indexes, meaning finding an efficacious dose that lacks adverse side effects for each individual is somewhat challenging [6]. Furthermore, MRIs have multiple adverse side effects, as well as being extremely dangerous in overdose. Due to this, the search for a more effective anti-depressant with fewer side effects began [7].

After the observation that the effects of these anti-depressants were enhanced when taken with tryptophan (the precursor to another monoamine, serotonin), the focus turned to the development of a serotonin-selective reuptake inhibitor. This search for this finally ended in the late 1980s, when the FDA approved Eli Lilly’s fluoxetine. This serotonin-selective reuptake inhibitor was and still is a massive success, with annual sales peaking at $2.6 billion – making it one of the best-selling drugs of all time.

Since its approval for MDD, fluoxetine has also been approved as a treatment for obsessive-compulsive disorder (OCD), alcohol dependence, premenstrual dysphoric disorder, panic disorder, post-traumatic stress disorder (PTSD), and bulimia nervosa, among others. Supplementary to its once-inconceivable therapeutic value, the success of fluoxetine reaffirmed the importance of serotonin in MDD, which pathed the way to the development of many other treatments, including more SSRIs, for example, citalopram and sertraline.

The number of deaths by suicide has significantly decreased in the UK since the launch of fluoxetine; it may never be clear how much the drug has contributed to this, but what is absolutely certain, is that it has rescued a huge number of lives from the symptoms and repercussions of MDD.

Chas Alexander Smith

References

1. National Institute of Mental Health. (2019).Depression. [online] Available at: https://www.nimh.nih.gov/health/topics/depression/index.shtml
2. McManus, S., Bebbington, P. and Jenkins, R. (2019).Adult Psychiatric Morbidity Survey: Mental Health and Wellbeing, England, 2014. [online] GOV.UK. Available at: https://www.gov.uk/government/statistics/adult-psychiatric-morbidity-survey-mental-health-and-wellbeing-england-2014
3. Tobe, E. (2014). Monoamine Oxidase Inhibitor Therapy and the Catecholamine Hypothesis of Depression Revisited.Psychiatric Annals, 44(11), pp.524-529.
4. Wehmeier, P., Kluge, M., Maras, A., Riemann, D., Berger, M., Kohnen, R., Dittmann, R. and Gattaz, W. (2005). Fluoxetine Versus Trimipramine in the Treatment of Depression in Geriatric Patients.Pharmacopsychiatry, 38(01), pp.13-16.
5. Schildkraut, J. (1965). The catecholamine hypothesis of depressive disorders: A review of supporting evidence.American Journal of Psychiatry, 122(5), pp.509-522.
6. Gillette, J., Dingell, J., Sulser, F., Kuntzman, R. and Brodie, B. (1961). Isolation from rat brain of a metabolic product, desmethylimipramine, that mediates the antidepressant activity of imipramine (Tofranil).Experientia, 17(9), pp.417-418.
7. Wong, D., Perry, K. and Bymaster, F. (2005). The Discovery of Fluoxetine Hydrochloride (Prozac).Nature Reviews Drug Discovery, 4(9), pp.764-774.