Investigational Drugs for the Treatment of Depression (Part 1): Monoaminergic, Orexinergic, GABA-Ergic, and Anti-Inflammatory Agents

Abstract

Therapeutic management of depression has currently important limitations, and its low efficacy is reflected in high rates of non-response even after multiple trials of antidepressants. Almost two-thirds of the patients diagnosed with major depression who received a 4–6 weeks trial of antidepressant could not reach remission, and more than 30% of these patients are considered treatment-resistant. In bipolar depression, the situation is also discouraging if we analyze the high suicide rate, the risk for the treatment-emergent affective switch when antidepressants are added, the high rate of treatment resistance (up to 25%), and the severe functional impairments associated with these episodes. Therefore, new therapeutic agents are needed, as well as new pathogenetic models for depression. The vast majority of the currently approved antidepressants are based on the monoamine hypothesis, although new drugs exploiting different neurotransmitter pathways have been recently approved by FDA. Brexanolone, an allopregnanolone analog, is an example of such new antidepressants, and its approval for post-partum depression inspired the search for a new generation of neurosteroids and GABA-ergic modulators, with an easier way of administration and superior tolerability profile. Orexin receptors antagonists are also extensively studied for different psychiatric disorders, depression included, in phase II trials. Antiinflammatory drugs, both cyclo-oxygenase 2 inhibitors and biological therapy, are investigated in patients with depressive disorders based on the proven correlation between inflammation and mood disorders in preclinical and clinical studies. Also, a new generation of monoamine-based investigational drugs is explored, ranging from triple reuptake inhibitors to atypical antipsychotics, in patients with major depression. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost seven decades, that new pathogenetic pathways should be targeted to increase these patients’ response rate.

Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders

“…Currently, many depressed patients become insensitive to medication and even further exhibit refractory depression [ 9 , 10 ]. Because there is no systematic theoretical guidance, the diagnosis and treatment often face a dilemma [ 11 ]; antidepressant treatment options are limited and, in some cases, ineffective [ 12 ].…”

Third-generation antipsychotics in patients with schizophrenia and non-responsivity or intolerance to clozapine regimen: What is the evidence?

“…The safety profile of lumateperone was evaluated in large clinical trials as good, with no clinically significant motor, endocrine, or cardiometabolic adverse events, which allows for optimism in the case of patients with schizophrenia and comorbid metabolic diseases, either primary or secondary to antipsychotic medication (64). Also, the possible use of lumateperone for major depression or bipolar depression is undergoing investigation in clinical trials, and this may bring a new perspective to the treatment of mood symptoms in schizoaffective disorder (65)(66)(67). No trial or case report regarding the use of lumateperone either as monotherapy or added to clozapine in patients with URS has been found during this search.…”

The pharmacogenetics of the new-generation antipsychotics – A scoping review focused on patients with severe psychiatric disorders

“…For the purpose of this scoping review, the category of “new generation antipsychotics” included the D2/D3 receptors partial agonists (cariprazine, brexpiprazole, aripiprazole), but also lumateperone (which possesses D2 presynaptic partial agonism and postsynaptic antagonism), and pimavanserin (an antipsychotic agent with a very specific pharmacodynamic profile) ( 62 – 65 ).…”