Harmonizing the Neurobiology and Treatment of Obsessive-Compulsive Disorder

Abstract

Obsessive-compulsive disorder (OCD) is a common, chronic, and oftentimes disabling disorder. The only established first-line treatments for OCD are exposure and response prevention, and serotonin reuptake inhibitor medications (SRIs). However, a subset of patients fails to respond to either modality, and few experience complete remission. Beyond SRI monotherapy, antipsychotic augmentation is the only medication approach for OCD with substantial empirical support. Our incomplete understanding of the neurobiology of OCD has hampered efforts to develop new treatments or enhance extant interventions. This review focuses on several promising areas of research that may help elucidate the pathophysiology of OCD and advance treatment. Multiple studies support a significant genetic contribution to OCD, but pinpointing the specific genetic determinants requires additional investigation. The preferential efficacy of SRIs in OCD has neither led to discovery of serotonergic abnormalities in OCD nor to development of new serotonergic medications for OCD. Several lines of preclinical and clinical evidence suggest dysfunction of the glutamatergic system in OCD, prompting testing of several promising glutamate modulating agents. Functional imaging studies in OCD show consistent evidence for increased activity in brain regions that form a cortico-striato-thalamo-cortical (CSTC) loop. Neuromodulation treatments with either noninvasive devices (e.g., transcranial magnetic stimulation) or invasive procedures (e.g., deep brain stimulation) provide further support for the CSTC model of OCD. A common substrate for various interventions (whether drug, behavioral, or device) may be modulation (at different nodes or connections) of the CSTC circuit that mediates the symptoms of OCD.

Keywords: Deep Brain Stimulation; Exposure Response Prevention; Genetics; Genomics; Glutamate; Neurobiology; Neurostimulation; OCD; PANDAS; Serotonin; Transcranial Magnetic Stimulation.

FIGURE 1.. Schematic of cortico-striato-thalamo-cortical (CSTC) circuit model for obsessive-compulsive disorder (OCD)^a

^a CSTC loops engage functionally related regions of the cortex, striatum, and thalamus relevant to a particular behavior. Cortical regions relevant for OCD pathophysiology span regions of the prefrontal cortex (PFC), including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventromedial PFC (vmPFC), and dorsolateral PFC (dlPFC). The direct pathway is net excitatory and tends to facilitate behavior, whereas the indirect pathway is net inhibitory and tends to restrain behavior. Over-activity of the direct pathway is a hypothesized feature of the pathogenesis of OCD. This hyperactivity is denoted by a thick line of excitatory input from the cortex to striatum. The striatum in turn has increased inhibitory tone (thick line) on the globus pallidus interna/substantia nigra pars reticulata complex (GPi/SNr), which causes decreased inhibition (thin line) of the thalamus. The thalamus is thereby disinhibited and increases its excitatory input (thick line) to the cortex. The net effect is therefore increased symptomatic behavior. A more recently highlighted “hyperdirect” pathway bypasses the striatum and synapses directly on the subthalamic nucleus (STN). Modulating this pathway has gained in prominence as a mechanism for therapeutic intervention. GPe=globus pallidus externa.