Major Depressive Disorder (MDD) and Schizophrenia– Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review

Abstract

Second-generation antipsychotics are common candidates for the adjunctive treatment of major depressive disorder and for the treatment of schizophrenia. However, unmet needs remain in the treatment of both disorders. Considering schizophrenia, antipsychotics are the most common treatment and have demonstrated good efficacy. Still, side effects of these treatments are commonly reported and may impact adherence to the medication and functioning in patients with schizophrenia. Regarding major depressive disorder, despite the availability of several classes of antidepressants, many patients do not achieve remission. Adjunctive treatment with antipsychotics may improve clinical and functional outcomes. Compared with dopamine D2 receptor antagonism that is exhibited by most antipsychotics, partial agonism may result in improved outcomes in major depressive disorder and in schizophrenia. Aripiprazole, cariprazine, and brexpiprazole have partial agonism at the dopamine D2 receptor and could potentially overcome limitations associated with D2 antagonism. The objectives of this review were (1) to discuss the goal of treatment with second-generation antipsychotics in major depressive disorder and schizophrenia, and the clinical factors that should be considered, and (2) to examine the short- and long-term existing data on the efficacy and safety of D2 receptor partial agonists (aripiprazole, cariprazine, and brexpiprazole) in the adjunctive treatment of major depressive disorder and in the treatment of schizophrenia.

2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation

“…These drugs can be categorized into three generations: the first-generation dopamine D 2 receptor (D 2 R) antagonists, the second-generation D 2 R/5-HT 2A dual antagonists, and the third-generation D 2 R partial agonists . Although other emerging targets for the treatment of schizophrenia have been actively pursued, − D 2 R partial agonism has shaped the recent discovery efforts of novel antipsychotics. − Compared to the first- and second-generation drugs, D 2 R partial agonists can better address the negative and cognitive symptoms of schizophrenia while showing less side effects …”

Dysregulation of brain dopamine systems in major depressive disorder

“…46 For example, lurasidone and aripiprazole/brexpiprazole are new agents with DA receptor modulating effects that are both effective in treating depressive symptoms. [46][47][48][49] Rodent models of MDD also implicate and replicate DAergic contributions to MDD-induced cellular and regional pathologies and maladaptations (Table 1; see also the following excellent reviews focused on this topic [50][51][52] ). Anhedonia, again, takes center stage, and this can be assessed through a variety of assays with distinct strengths and limitations, ranging from simple sucrose consumption assays to complex operant models of decisional anhedonia.…”

“…46 For example, lurasidone and aripiprazole/brexpiprazole are new agents with DA receptor modulating effects that are both effective in treating depressive symptoms. 46–49…”

A New Perspective on Hippocampal Synaptic Plasticity and Post-stroke Depression

“…The use of antidepressants such as fluoxetine, acetylcholine, and pioglitazone can reverse hippocampal neural damage, counteract dopaminergic neuron-induced apoptosis of neurons in various brain regions, and exert antidepressant effects (Bonato et al 2018;Dallé et al 2020;Singh et al 2017). Thus, similar to the 5-HT system, the dopaminergic system is involved in depression-like behavior by modulating hippocampal neurogenesis (Mallet et al 2019). Overall, the antidepressant effects of selegiline may be attributed to its ability to enhance dopaminergic neurotransmission in the hippocampus and reduce hippocampal LTP impairment independent of its MAO-A inhibition.…”