Blocking 5-HT2C Receptors to Reduce Side Effects and Potentiate Efficacy of SSRI Antidepressants

Serotonin selective reuptake inhibitors (SSRIs) have been the first-line treatment for depression and anxiety disorders for over two decades. However, less than half of patients respond to SSRIs. Furthermore, even when SSRIs are effective, patients sometimes discontinue treatment because of intolerable side effects. In a new Molecular Psychiatry report, researchers at Columbia University Irving Medical Center (CUIMC) have identified a likely culprit, the blockade which improves not only the side effect profile but also the therapeutic impact of SSRIs.

Why the study is important

Depression is a very prevalent mental disorder, considered by the World Health Organization (WHO) to be the leading cause of disability worldwide. Improving the efficacy and alleviating the side effects of the first-line treatment for depression disorders will reduce overall global burden of disease and save lives.

Background

Globally, more than 300 million people suffer from depression. At its worst, depression can lead to suicide, a leading cause of death worldwide.

The first SSRI, fluoxetine, was clinically introduced in 1987 and revolutionized pharmacotherapy for depression. The way SSRIs work is at first glance very simple: SSRIs selectively target and block the serotonin transporter, thereby reducing the reuptake of serotonin by neurons. However, as a consequence of this transporter-blockade, released serotonin levels accumulate and lead to the activation of many different types of serotonin receptors—at least 14—throughout the brain. Hence, the SSRI then acts like a cocktail of 14 drugs, each of them selectively targeting the different types of serotonin receptors. The net effect of this complex activation results in antidepressant effects, but only in a subset of the patient population, and often accompanied by unwanted side effects.

It stands to reason that SSRI-based therapy could be improved through two approaches. If we could identify which of the 14 receptors are responsible for the clinically beneficial (antidepressant) effect of SSRIs, we could then target those receptors with selective agonists, allowing the receptors to be directly activated. Or, if we could identify which of the 14 receptors cause the undesirable side effects of SSRIs, those receptors could be directly targeted with selective antagonists to prevent receptor activation, along with classic SSRI treatment.

What the researchers did

The Columbia team followed the latter strategy, setting out to identify the receptor and neuronal circuit mechanism responsible for a group of SSRI-induced side effects associated with reduced dopamine function: apathy, emotional blunting, reduced libido, an inability to experience pleasure, akathisia, and extrapyramidal motor symptoms (movement disorders including tremors and muscles spasms). These side effects are not directly life-threatening, but they can counteract the antidepressant efficacy and result in discontinuation of medication in patients even when depression is in remission. The researchers studied mice after the team previously reported behavioral consequences of hypo-dopaminergic function in a mouse model of chronic SSRI treatment (Morelli et al., 2011).

Now the team reports that the 5-HT2C receptor is the main player in reducing dopaminergic activity due to SSRI treatment. SSRI-induced negative behavioral consequences, such as impaired motor function, were reversed when SSRI treatment was accompanied by a 5-HT2C receptor blockade. Importantly, SSRI-induced positive behavioral consequences—for example, reduced anxiety and depressive behavior—improved in mice treated with both the SSRI and the 5-HT2C receptor blockade. Using modern techniques to probe and deconstruct neurocircuitry, the research team identified and characterized the neuronal connections behind this inhibitory control of serotonin on dopamine via the 5-HT2C receptor.

What the findings mean

“We think it’s highly likely that 5-HT2C receptor blockade is a viable strategy to increase efficacy and improve side effect profiles of SSRI-based pharmacotherapy,” says Mark Ansorge, PhD, Assistant Professor of Clinical Neurobiology (in Psychiatry) at Columbia University Vagelos College of Physicians and Surgeons. “Furthermore, because 5-HT2C receptors are functioning at a critical basal ganglia juncture that provides feedback regulation into the main dopaminergic centers, engagement of this target can potentially be leveraged to treat ailments other than depression.” For example, dopaminergic hypo-function of other causes, such as Parkinson’s Disease, might be counteracted by 5-HT2C receptor antagonist treatment, which would again lead to disinhibition of dopaminergic neuronal activity. Conversely, dysfunction with increased dopaminergic activity and excessive activation of basal ganglia loops could be counteracted by 5-HT2C receptor activation. Disorders with such dysfunction include Obsessive Compulsive Disorder and Tourette Syndrome–and indeed, SSRIs are effectively used to treat patients suffering from impaired behavioral inhibition.

“To test our translational hypotheses, it will now be important to evaluate pharmacodynamic and pharmacokinetic parameters for chronic 5-HT2C receptor-targeted treatments and assess potential 5-HT2C antagonism-related side effects, such as excessive weight gain. Our goal is to guide drug development on the way to improve treatment approaches for emotional, motivational, and motor symptoms in psychiatric and neurological disorders.”

Study details

The authors of this paper are Elena Y. Demireva (CUIMC), Deepika Suri (CUIMC), Emanuela Morelli (CUIMC), Darshini Mahadevia (CUIMC), Nao Chuhma (CUIMC), Catia M. Teixeira (CUIMC), Annette Ziolkowski (CUIMC), Marc Hersh (CUIMC), James Fifer (CUIMC), Sneha Bagchi (CUIMC), Alexei Chemiakine (CUIMC), Holly Moore (CUIMC), Jay A. Gingrich (CUIMC), Peter Balsam (CUIMC), Stephen Rayport (CUIMC), and Mark S. Ansorge (CUIMC).

The authors declare that they have no conflict of interest.

This work was supported by The Sackler Institute for Developmental Psychobiology, a Sackler Award (M.S.A.), and the National Institute of Mental Health (R01 MH099118, R01 MH068073). Correspondence should be addressed to Mark S. Ansorge, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032. ma2362@cumc.columbia.edu.