Depression as a Neuroendocrine Disorder: Emerging Neuropsychopharmacological Approaches beyond Monoamines

Abstract

Depression is currently recognized as a crucial problem in everyday clinical practice, in light of ever-increasing rates of prevalence, as well as disability, morbidity, and mortality related to this disorder. Currently available antidepressant drugs are notoriously problematic, with suboptimal remission rates and troubling side-effect profiles. Their mechanisms of action focus on the monoamine hypothesis for depression, which centers on the disruption of serotonergic, noradrenergic, and dopaminergic neurotransmission in the brain. Nevertheless, views on the pathophysiology of depression have evolved notably, and the comprehension of depression as a complex neuroendocrine disorder with important systemic implications has sparked interest in a myriad of novel neuropsychopharmacological approaches. Innovative pharmacological targets beyond monoamines include glutamatergic and GABAergic neurotransmission, brain-derived neurotrophic factor, various endocrine axes, as well as several neurosteroids, neuropeptides, opioids, endocannabinoids and endovanilloids. This review summarizes current knowledge on these pharmacological targets and their potential utility in the clinical management of depression.

Figure 1

Expanding views on the neurobiology of depression. GABA: γ-aminobutyric acid; BDNF: brain-derived neurotrophic factor. Current neuropsychopharmacological approaches to depression are centered on the monoamine hypothesis. Nevertheless, the imperfect results obtained in clinical practice with currently available antidepressant drugs have propelled the discovery of various potential pharmacological targets beyond noradrenaline, dopamine, and serotonin.

Figure 2

Effects of ketamine on the glutamatergic synapse. Ketamine acts as an NMDA antagonist on GABAergic interneurons, as well as on postsynaptic glutamatergic neurons. Antagonism in the former results in disinhibition of presynaptic glutamatergic neurons, thus favoring activation of AMPAR in postsynaptic glutamatergic neurons. This, along with activation of voltage-dependent calcium channels, results in activation of the PI3K pathway which leads to increased mTOR activity. Furthermore, antagonism of NMDAR leads to inhibition of the nitric oxide pathway, which in turn leads to Rheb stabilization and mTOR pathway potentiation. mTOR increases p70s6K activity, which promotes BDNF signaling. BDNF activity is also favored by the inactivation of eEf2K secondary to NMDAR antagonism.

Figure 3

Neuropeptide pharmacotherapeutic targets in depression. OXT: oxytocin; LHA: lateral nucleus; PVH: paraventricular nucleus; DMH: dorsomedial nucleus; VMH: ventromedial nucleus; ARC: arcuate nucleus; AVPR1B: arginine vasopressin receptor 1B; NK1: neurokinin 1. Key findings regarding the current knowledge on neuropeptides in the neuropsychopharmacology of depression include the following: (1) Abundant preclinical and clinical evidence suggests oxytocin may significantly contribute to the improvement of depression-related symptoms such as sexual dysfunction, anhedonia, and sleep disturbances. (2) AVPR1B antagonists appear to reduce symptoms of anxiety and depression in both animal and human models. (3) Several modulators of neuropeptide signaling have shown antidepressant activity; however, further research is required to characterize their significance and utility.

Figure 4

Pharmacotherapeutic targets for depression in reward neurocircuits. ^∗Agonist. ^∗∗Antagonist. ^∗∗∗Modulator. μ: µ-opioid receptor. δ: δ-opioid receptor. κ: κ-opioid receptor. CB1: cannabinoid receptor 1. CB2: cannabinoid receptor 2. TRPV1: transient receptor potential cation channel V1. Research on pharmacotherapeutic targets for depression in the reward system remains principally preclinical. Currently available results presume some potential clinical utility for these substances for the treatment of depression, with varying degrees of efficacy and differing pharmacological profiles.