Antidepressants are a cornerstone of psychiatric treatment. With the huge burden that depression places on society, it’s understandable that a plethora of research and development has been focused on these medications.

The year 2022 saw significant advances in the research and development of antidepressants. Intriguingly, some of these findings turned modern conceptions of antidepressants on their head.

 

Effect on quality of life

The National Institute of Mental Health reported that more than 17 million American adults experienced at least one major depressive episode in 2017, according to research published by PLOS ONE.

Almohammed OA, Alsalem AA, Almangour AA, et al.Antidepressants and health-related quality of life (HRQoL) for patients with depression: Analysis of the medical expenditure panel survey from the United States. PLOS One. 2022;17(4):e0265928.

 

Furthermore, patients with chronic comorbidities are more likely to experience major depression, with symptoms including anhedonia, sadness, poor concentration, and mood disturbance.

Depression upends health-related quality of life (HRQoL) in people who are affected. In a comparative cohort, the PLOS ONE researchers performed a secondary database analysis to assess the impact of pharmacologic treatment on HRQoL in US adults with patients.

They found that 58% of the cohort received antidepressant medications, with the use of the drugs improving the mental—but not physical—components of HRQoL. These findings represented only a trend and were not significant compared with patients who were not taking antidepressants.

The real-world effect of using antidepressant medications does not continue to improve patients’ HRQoL over time.

“Future studies should not only focus on the short-term effect of pharmacotherapy, [they] should rather investigate the long-term impact of pharmacological and non-pharmacological interventions on these patients’ HRQoL,” the PLOS ONE authors concluded.

 

 

Way-off-label indications

The efficacy of fluvoxamine in treating COVID-19 may seem questionable, but this topic is one of high clinical interest. Fluvoxamine is an SSRI and σ-1 receptor (S1R) agonist that may exhibit anti-inflammatory and antiviral effects.

Publishing in the Lancet Global Health, Brazilian researchers found that 100 mg of fluvoxamine BID decreased the necessity for hospitalization in outpatients with early COVID-19.

Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022;10(1):e42–e51.

 

However, researchers who published pre-print in medRxiv (and are awaiting peer review and journal publication as of this writing) found that taking 50 mg fluvoxamine BID for 10 days did not reduce recovery time versus placebo in patients with mild to moderate COVID-19.

McCarthy MW, Naggie S, Boulware DR, et al. Fluvoxamine for outpatient treatment of COVID-19: A decentralized, placebo-controlled, randomized, platform clinical trial. medRxiv. Published online November 1, 2022:2022.10.17.22281178.

 

 

 

Is serotonin sus?

The association between lower serotonin levels and depression was first floated in the 1960s, and by the 1990s, SSRIs had made their way into the market.

According to the authors of an umbrella review published in Molecular Psychiatry, “Although it has been questioned more recently, the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support, leading researchers endorsing it, and much empirical research based on it.”

Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: A systematic umbrella review of the evidence. Mol Psychiatry. Published online July 20, 2022:1–14.

 

Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance.’ Many general practitioners also subscribe to this view and popular websites commonly cite the theory.

Despite this theory being widely accepted, however, the authors found that the principal areas of serotonin research showed no consistent evidence of a link between serotonin and depression, along with no evidence that low serotonin activity mediates depression. In fact, there is some data that indicates long-term antidepressant use decreases serotonin concentrations.

 

 

Effects in a flash

The brass ring in modern antidepressant development is an agent that lacks undesirable adverse effects and addictive properties, and also reportedly acts quickly.

Publishing in Science, Chinese researchers detailed the discovery of an agent that parses the serotonin transporter from nitric oxide synthase, thus decreasing intercellular serotonin concentrations in the dorsal raphe nucleus.

Sun N, Qin YJ, Xu C, et al. Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN. Science. 2022;378(6618):390–398.

 

This action improves serotonergic neuron activity and bolsters serotonin release to elicit faster onset. It should be noted that this small-molecule blocker of the nitric oxide synthase-serotonin transporter interaction has yet been tested only in animal models.

“Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits,” the authors wrote. “We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects.”

This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD [major depressive disorder].