Mechanisms underlying the antidepressant response and treatment resistance

Abstract

Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment-resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance.

Keywords: SSRI; antidepressants; depression; mood; mouse models; treatment resistance.

Figure 1

A potential hippocampus-based neural circuit for TRD. Several distinct neural circuits likely underlie resistance to traditional antidepressants. This is one potential hippocampus-based circuit. The hippocampus regulates the HPA axis (mpPVN > Anterior Pituitary Gland > Adrenal Cortex) through multiple brain nuclei. Medial parvocellular paraventricular nucleus (mpPVN) neurons receive inhibitory inputs from the bed nucleus of the stria terminalis (BNST), the dorsomedial hypothalamus (dmHYP), the preoptic area (POA), and the nucleus of the solitary tract (NTS). In turn, these areas receive excitatory inputs from the ventral subiculum (vSUB) and the medial prefrontal cortex (mPFC). The ventral hippocampus innervates and regulates the ventral subiculum (vSUB) and the medial prefrontal cortex (mPFC). Importantly, this is a feedback loop as corticosterone produced in the adrenal cortex regulates a large population of receptors in the dentate gyrus of the hippocampus. In addition, the ventral hippocampus (vHIP) regulates the nucleus accumbens (NAc) through the ventral subiculum (vSUB) and the subgenual cingulate (SGC) through the ventral subiculum (vSUB) and the Papez circuit. Identification of mechanisms underlying treatment resistance in this circuitry may result in novel therapeutic avenues.