Here we review our recent body of work on the impact of mood and comorbid anxiety disorders, alcohol dependence, and their treatments on heart rate variability (HRV), a psychophysiological marker of mental and physical wellbeing. We have shown that otherwise healthy, unmedicated patients with these disorders display reduced resting-state HRV, and that pharmacological treatments do not ameliorate these reductions. Other studies highlight that tricyclic medications and the serotonin and noradrenaline reuptake inhibitors in particular may have adverse cardiovascular consequences. Reduced HRV has important functional significance for motivation to engage social situations, social approach behaviours, self-regulation and psychological flexibility in the face of stressors. Over the longer-term, reduced HRV leads to immune dysfunction and inflammation, cardiovascular disease and mortality, attributable to the downstream effects of a poorly functioning cholinergic anti-inflammatory reflex. We place our research in the context of the broader literature base and propose a working model for the effects of mood disorders, comorbid conditions, and their treatments to help guide future research activities. Further research is urgently needed on the long-term effects of autonomic dysregulation in otherwise healthy psychiatric patients, and appropriate interventions to halt the progression of a host of conditions associated with morbidity and mortality.