Opioid agents for treatment-resistant depression

Treatment-resistant depression (TRD) is a major public health problem in terms of prevalence, individual suffering, and cost for society, and it is commonly associated with significant disability and psychosocial impairment worldwide. Despite recent advances in the effort to identify the neurobiological correlates of TRD, the pathophysiology of this condition still remains unclear. The opioid system is known to be involved in stress responses, mood, reward, and hedonic responses. Relevantly, this system is important for modulating dopaminergic (DA), serotonergic (5-HT) and noradrenergic (NA) systems, synaptic plasticity, neurogenesis in the hippocampus, hypothalamic-pituitary-adrenal gland (HPA) axis functioning, and brain-derived neurotrophic factor (BDNF) activity; and it is dysregulated in depressive disorders, as well. Emerging approaches to address endogenous opioid dysregulation in MDD may yield novel therapeutics associated with reduced or absent risk of abuse or addiction. The present chapter illustrates the psychoactive medications related to the opioid system which may be considered in treating TRD, their mechanisms of action, pharmacokinetics, efficacy, and adverse effects. The most relevant clinical studies of all these drugs have been here summarized with a particular focus on efficacy and safety of these drugs.