A Neurobiological Hypothesis of Treatment-Resistant Depression – Mechanisms for Selective Serotonin Reuptake Inhibitor Non-Efficacy

Abstract

First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying “treatment resistant depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by “flooding” 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario – presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder – each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD.

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

“…Major depressive disorder (MDD) is a disabling mental illness with poorly understood pathophysiology and high rates of inadequate treatment response (1, 2). Accumulating evidence over the past 2 decades strongly implicated glutamate neurotransmission alterations in the pathophysiology and treatment of MDD (3, 4), particularly the exciting discovery of rapid acting antidepressant effects induced by subanesthetic doses of ketamine, a glutamate modulator (5–8).…”

Biomarkers for Depression: Recent Insights, Current Challenges and Future Prospects

“…A recent review sets out this theory and suggests that in TRD, this could be reversed (and 5-HT restored) through multimodal treatment targeting multiple neurotransmitters. 99 Interestingly, increases in serotonin do not always occur conjunctively with therapeutic antidepressant benefits. 100 Despite this, neurotransmitter metabolites such as 3-methoxy-4-hydroxyphenylglycol, of noradrenaline, or homovanillic acid, of dopamine, have often been found to increase alongside reduction in depression with antidepressant treatment 101,102 or that low levels of these metabolites predict a better response to SSRI treatment.…”

Investigational drugs in recent clinical trials for treatment-resistant depression

“…TRD is a complex, multifactorial, and heterogeneous group of disorders, integrating neurobiological and environmental factors, which reduces the sensitivity to selective serotonin reuptake inhibitors (SSRIs) and second-line antidepressants [10–12]. Among these factors, converging lines of evidence indicate an important pathophysiological role of the glutamatergic system [13,14].…”