Abstract
Major depressive disorder (MDD) is the most prevalent mental illness contributing to global disease burden. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the first-line treatment for MDD, but are only fully effective in 30% of patients and require weeks before improvement may be seen. About 30% of SSRI-resistant patients may respond to augmentation or switching to another antidepressant, often selected by trial and error. Hence a better understanding of the causes of SSRI resistance is needed to provide models for optimizing treatment. Since SSRIs enhance 5-HT, in this review we discuss new findings on the circuitry, development and function of the 5-HT system in modulating behavior, and on how 5-HT neuronal activity is regulated. We focus on the 5-HT1A autoreceptor, which controls 5-HT activity, and the 5-HT1A heteroreceptor that mediates 5-HT actions. A series of mice models now implicate increased levels of 5-HT1A autoreceptors in SSRI resistance, and the requirement of hippocampal 5-HT1A heteroreceptor for neurogenic and behavioral response to SSRIs. We also present clinical data that show promise for identifying biomarkers of 5-HT activity, 5-HT1A regulation and regional changes in brain activity in MDD patients that may provide biomarkers for tailored interventions to overcome or bypass resistance to SSRI treatment. We identify a series of potential strategies including inhibiting 5-HT auto-inhibition, stimulating 5-HT1A heteroreceptors, other monoamine systems, or cortical stimulation to overcome SSRI resistance.
Highlights
Major depressive disorder (MDD) has a high incidence and low remission rate with the current therapeutic strategies
In this review we focus mechanisms of resistance to SSRIs involving altered activity of 5-HT neurons via 5-HT1A autoreceptors and how these changes can be overcome by targeting 5-HT1A receptors, non-5-HT mechanisms or activityinduced neuroplasticity
These results suggest a reduced activity of the 5-HT system driven by increased 5-HT1A autoreceptors and/or reduced 5-HT1A heteroreceptors may predispose to MDD
Summary
Major depressive disorder (MDD) has a high incidence and low remission rate with the current therapeutic strategies. Major depression is the largest contributor to global disability by years lived with disability, and anxiety disorders rank sixth (World Health Organization [WHO], 2017). The annual prevalence of depression is 4.4% overall, 3.6% in men and 5.1% in women (Baxter et al, 2014; World Health Organization [WHO], 2017). Major depression is diagnosed by persistent symptoms such as sadness, irritability, anhedonia or changes in appetite or sleep patterns that could result in suicidal thoughts and attempts (Kessler and Bromet, 2013). Genetic or biomarkers for major depression remain elusive, and current genome-wide association studies indicate that individual genetic polymorphisms contribute only a small increase in risk for depression
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