Predominant Mechanisms of Action in Investigational Schizophrenia Drugs

Three Most Common Mechanisms in Trials

Based on the available information, the three most common mechanisms of action in trials for drugs not yet approved for schizophrenia are:

1. Dopamine receptor downregulation: This mechanism represents an alternative strategy to address dopaminergic hyperactivity implicated in schizophrenia. Unlike traditional antipsychotics that block dopamine receptors, this approach involves processes such as receptor proteolysis, modulation of receptor gene transcription, and affecting RNA stability. These processes cause a decrease of existing receptors and reduction of receptor synthesis. This mechanism could explain the antipsychotic effects of dopamine agonists or partial agonists like aripiprazole. D2 receptor partial agonist antipsychotic agents are preferred in the early phase of treatment of psychotic disorders.

2. Antioxidant mechanisms: Antioxidants are gaining importance in trials for treating negative symptoms of schizophrenia. This represents a growing area of investigation, particularly as traditional treatments often fail to adequately address negative symptoms which "persist despite treatment." N-acetylcysteine is specifically mentioned as one of the few new pharmacological treatment options being evaluated in early-onset schizophrenia (EOS).

3. mTOR inhibition: The mammalian target of rapamycin (mTOR) inhibitor everolimus has shown effectiveness in different tumor entities and might have applications in schizophrenia treatment. Studies showed that everolimus significantly reduced mTOR expression and decreased AREG expression regardless of HPV status.

Additional Investigational Mechanisms and Targets

Beyond these three primary mechanisms, several other approaches are being investigated:

• Multi-target receptor approaches: Compounds like D2AAK3 target multiple receptors simultaneously, including D2, 5-HT1A, and 5-HT2A receptors. G-protein-coupled receptors (GPCRs) are important targets for new antipsychotics.

• Sodium channel inhibition: This mechanism is being investigated specifically for treating cognitive symptoms of schizophrenia. Two new structurally diverse sodium channel blockers (GSK2 and GSK3) with potent anticonvulsant activity have shown potential in preventing cognitive deficits in preclinical models.

• Glutamatergic and GABAergic systems: Drugs targeting glutamatergic receptors (GRIN2A and GRM3), calcium channels (CACNA1C and CACNB2), and GABA receptor (GABBR2) are being investigated.

• Multityrosine kinase inhibition: Drugs like sorafenib and sunitinib are multityrosine kinase inhibitors that might have potential applications in schizophrenia treatment.

• Novel compounds for positive symptoms: Several promising compounds are being investigated, including lamotrigine, pro-cognitive compounds (donepezil, idazoxan, piracetam), anti-inflammatory drugs (celecoxib, methotrexate), cardiovascular compounds (L-theanine, mononitrate isosorbide, propentofylline, sodium nitroprusside), and metabolic regulators (diazoxide, allopurinol).

• Hormonal approaches: Oxytocin is being evaluated in early-onset schizophrenia, and raloxifene is being investigated specifically in women.

• Systems outside the CNS: Biological systems outside the central nervous system, such as immunity or metabolism, are emerging as potential targets for positive symptoms.

These diverse investigational approaches reflect the need for new pharmacological strategies, as about one-third of schizophrenia patients only partially respond to treatment with available antipsychotics, and current research has contributed little to progress in treating negative symptoms of schizophrenia.