Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

Abstract

The monoamine hypothesis has been the prevailing hypothesis of depression over the last several decades. It states that depression is associated with reduced monoamine function. Hence efforts to increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters has been a central theme in depression research since the 1960s. The selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are currently first line treatment options for major depressive disorder (MDD). One of the recent trends in antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic receptors and additional transporters (e.g. with multimodal drugs and triple re-uptake inhibitors) or by adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses of depression have been brought forward in pre-clinical and clinical research based on biological hallmarks of the disease and efficacy of pharmacological interventions. A central strategy has been to target glutamate receptors (for example, with intravenous infusions of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine). Other strategies have been based on modulation of cholinergic and γ-aminobutyric acid (GABA)ergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal(HPA)-axis, the reward system and neuroinflammation. Here we review the pharmacological profiles of compounds that derived from these strategies and have been recently tested in clinical trials with published results. In addition, we discuss putative treatments for depression that are being investigated at the preclinical level and outline future directions for antidepressant research.

NMR-based metabonomic analysis of normal rat urine and faeces in response to (±)-venlafaxine treatment

“…This chemical shift was confirmed by a direct 1D 1 Tables S3-S4. For urine, all the models were 389 significant, while for faecal water only the pairwise comparison models between control 390 and high-dose group were significant.…”

“…Since this disorder is varied and complex, its etiology and pathology remain 62 unknown, as do the mechanisms of action of the antidepressants currently used. Among 63 the various hypotheses about depression, the most relevant is the monoamine hypothesis 64 [1]. Since this disorder is multifactorial, its study requires a multidisciplinary approach that 65 can only be carried out with the use of recent technological advances such as genomics, 66 proteomics and metabonomics.…”

“…Plots of the PLS BP scores for the two vectors (t [1] and t[2]) were mapped to generate a 308 time-course trajectory plot describing the different phases of the dominant metabolic 309 perturbations with time. The xenometabolic trajectory plot was calculated using the mean 310…”

“…However, the exact mechanisms 342 of action are still unknown, as is the case with other types of antidepressants and more 343 generally with the etiology and pathology of depression. Moreover, the reason for the time 344 lag of response to treatment is also unclear, although it is related to pre-and post-synaptic 345 adaptive mechanisms and/or neurogenesis [1]. Table S1 and Figures S1-S3).…”

Prevalence and structure of anxiety-depression in an Australian community sample

“…Combinations of pharmacological and psychological therapies have been shown to be effective, as has exercise [51], with recent recommendations that the choice of treatment should be based on patient preferences and possible interactions or contraindications of various treatment options [51]. Treatment of depression also consists of pharmacological [52] and psychological therapies [53,54], with recent recommendations that there is a need to acknowledge patients' needs and treatment sensitivities [55]. There is emerging evidence that computer-based delivery of psychological treatments can be successful for depression [56] and that stimulation of brain activity is also successful for some patients [57].…”