Depression is a mental state disorder that often leads to poor quality of life and impaired role functioning. It is an emotional state “marked by feelings of low self-worth or guilt and a reduced ability to enjoy life.”1 The International Classification of Disease, 10th Revision classified depression under mood (affective) disorders2. According to the World Health Organization (WHO), this disorder is characterized by persistent sadness and a lack of interest or pleasure in previously rewarding or enjoyable activities.3,4 Depression is a leading cause of disability around the globe. The WHO, ~3.8% of the population worldwide, that is, 280 million people around the world have depression3. Despite all the controversies around the use of selective serotonin reuptake inhibitors (SSRIs), they are prescribed as the first line of treatment for depression5. The prescription of SSRIs for depression has shown a massive surge in recent years. This presents an intriguing insight and remains a matter of interest as to why the use of SSRIs is skyrocketing and is still being advertised and prescribed to the general masses. Of the antidepressant medications dispensed, the number of SSRIs increased by 35.2% from 33.3 million items in 2015/2016 to 45.0 million items in 2021/20226. The United Kingdom (UK), the United States of America (USA), Asia, and Australia have reported a 2- to 3-fold increase in SSRI prescriptions in the last decade7.
SSRIs inhibit the transporter proteins from transporting serotonin from the synaptic cleft back into the presynaptic neuron, thereby increasing the availability and activity of synaptic serotonin. SSRIs are predicated on the serotonin hypothesis of depression, which maintains that an imbalance of serotonin levels resulting from a deficiency in serotonin availability can cause depressive symptoms. The acclaimed serotonin hypothesis has its origin in a study in the 1960s. This study suggested that disturbance of the serotonin pathway plays a pivotal role in the pathophysiology of depression8. These pathophysiological effects are known to be induced either by decreased levels of serotonin in the brain or a defect in receptor activity. This hypothesis got overwhelming recognition and remained a foundation for research in the field of neuroscience. With standard curricular textbooks certifying it, leading researchers endorsing it, and ads advertising it, it is very popular among the masses.9,10 We therefore write this correspondence to initiate a discussion regarding the current trends in the treatment of depression, as well as to explore recent research and the potential of alternative medications other than SSRIs for its treatment.
The effectiveness of SSRIs for the management of depression, however, is still uncertain. Therefore, the principal hypothesis, which regards the brain monoamine levels to have a direct contribution to depression, has been revised through considerable research in the preceding years. An umbrella review by Moncrief and colleagues identified and collated existing overviews of research on serotonin and depression, including systematic reviews and meta-analyses, the results of which were published in Molecular Psychiatry11. Their findings suggested that there is no convincing evidence that depression is associated with, or caused by lower serotonin concentrations or activity and calls into question the basis for the use of antidepressants12. In addition, the use of antidepressants has also been questioned by numerous researchers who have shown that the differences between antidepressants and placebo are minute and more likely to be clinically insignificant13. The effect size of antidepressants over placebo has been estimated to be around 0.30 in clinical trials, which is not remarkable14. Similarly, the curative effect of antidepressants is influenced by the expectation bias of the placebo effect. In a study, increasing the level of blinding decreased the differences between the results of treatment and placebo12. SSRIs also increase the risk of both serious and nonserious adverse events. The most troubling adverse effects of SSRIs during long-term use seem to be gastrointestinal problems, sleep disturbances, and sexual dysfunction, along with an increased risk of birth defects in infants of women treated with some SSRIs during pregnancy15. Since the proof of serotonin deficiency in depression is missing, the use of SSRIs presumed to act via the effects of serotonin is thus highly contested. Nonetheless, it does not imply that SSRIs are ineffective. It, however, stresses the necessity of the upgradation of guidelines for treating depression.
Novel pharmacological options are now emerging with a safer side effect profile and a long history of safe use in medicine. The recent Food and Drug Administration approval of Esketamine nasal spray after the discovery of the antidepressive properties of ketamine is an important breakthrough15. It is first of its kind noncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist available as a nasal spray that provides fast-acting relief in depressive patients. Dextromethorphan/bupropion is another NMDAR antagonist recently recognized by Food and Drug Administration for depression as an extended relief oral tablet16. Current research practices are focused on targeting specific receptors and receptor families that have involvement in the pathophysiology of depression. Opioid receptors, NMDAR, metabotropic glutamate receptors, and galanin receptors are explored for novel treatment options15.
Having highlighted some of these gaps, we therefore recommend further research and studies to be conducted by psychiatrists in the world for possible exploration of the underlying cause of depression and to confirm the originality of the serotonin hypothesis. Larger randomized trials at a low risk of bias should be conducted by researchers to investigate the efficacy and assess the harmful effects of SSRIs in the long term. With new treatment options surfacing, the upgradation of standard treatment practices for depression is required. Hence, this will improve the gaps in the knowledge, attitude, and perception of clinicians worldwide in the understanding of depression and will bridge the conflict between modern research and the physicians’ prescription of patients with depression.
Sources of funding
S.S. and A.M.K.: conceptualization; C.M.V.S.: funding acquisition; M.O.A.: investigation:, A.M.K.: project administration; S.S. and A.M.K.: resources; A.M.K.: software; M.O.O.: supervision; A.M.K.: validation; M.O.O.: visualization; S.S.: writing—original draft; A.M.K. and S.G.: M.O.O.: writing—review and editing; All authors: final approval of manuscript for publication.
Conflict of interest disclosures
The authors declare that they have no financial conflict of interest with regard to the content of this report.
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Che Mbali Valentina Sih.
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The authors thank Malik Olatunde Oduoye, the West-African Regional Director at Oli Health Magazine Organization, Kigali, Rwanda, [email protected], for the guidance and mentorship.
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