Obsessive–compulsive disorder: an integrative genetic and neurobiological perspective

Key Points Obsessive–compulsive disorder (OCD) is a phenotypically complex multidimensional neuropsychiatric disorder. Family and twin studies provide definitive evidence that genetic and environmental factors can increase risk of the disorder. Candidate gene and genome-wide association studies provide strong suggestive evidence that genes in the serotonergic, dopaminergic and glutamatergic systems confer risk for the manifestation of OCD. Imaging studies as well as neuropsychological and treatment studies have implicated frontal–subcortical circuits in the pathophysiology of OCD. A cortico–striato–thalamo–cortical circuit is the prevailing model regarding the neural and pathophysiological underpinnings of OCD. The prevailing treatments include both pharmacological agents (selective serotonin-reuptake inhibitors) and cognitive behavioural therapy (CBT), with CBT and/or a combination of pharmacological and CBT being the most efficacious. Animal studies provide strong evidence for the involvement of the glutamatergic system in the expression of OCD-like behaviours. A model incorporating both genetic and epigenetic mechanisms in the manifestation of OCD is suggested as a heuristic for the pathophysiology of OCD. Obsessive–compulsive disorder has been scrutinized in many genetic, neuropsychological and neuroimaging studies. Pauls and colleagues provide an overview of our current understanding of the vulnerability factors, triggers and mechanisms underlying this devastating condition. Obsessive–compulsive disorder (OCD) is characterized by repetitive thoughts and behaviours that are experienced as unwanted. Family and twin studies have demonstrated that OCD is a multifactorial familial condition that involves both polygenic and environmental risk factors. Neuroimaging studies have implicated the cortico–striato–thalamo–cortical circuit in the pathophysiology of the disorder, which is supported by the observation of specific neuropsychological impairments in patients with OCD, mainly in executive functions. Genetic studies indicate that genes affecting the serotonergic, dopaminergic and glutamatergic systems, and the interaction between them, play a crucial part in the functioning of this circuit. Environmental factors such as adverse perinatal events, psychological trauma and neurological trauma may modify the expression of risk genes and, hence, trigger the manifestation of obsessive–compulsive behaviours.