Depression, substance abuse and chronic pain are recurrent neuropsychiatric disorders that commonly occur comorbidly. Recent human neuroimaging studies have identified dysregulation of similar brain regions across these conditions, implicating structures not only involved in sensory processing such as the primary and secondary somatosensory cortices and thalamus, but also those regulating cognitive appraisal, valence and reward, such as the anterior cingulate cortex, medial prefrontal cortex, amygdala and nucleus accumbens. In addition, alterations of the default mode network  characterized by deficits in cognitive flexibility have been demonstrated in patients with the depression-substance abuse-chronic pain triad. Several neurotransmitter systems have been implicated on a molecular level, particularly those involved in neuroplastic mechanisms including glutamate, serotonin, dopamine and endocannabinoids. These findings suggest a shared pathophysiology related to reduced homeostatic capacity in the context of chronic physical and/or psychological adversity, and as such, provide a conceptual framework to identify potential novel pharmacological targets across these disorders.

Therapeutic outcomes when treating depression, substance abuse and chronic pain as distinct entities are modest, and deteriorate markedly when occurring comorbidly. A mechanism-based, cross-diagnostic approach, as opposed to the conventional syndrome-based, categorical model, could potentially improve therapeutic outcomes. This session aims to provide an overview of potential novel pharmacological targets that may contribute to restoration of CNS homeostasis in patients presenting with the  depression-substance abuse-chronic pain triad.