Schizophrenia - Emerging treatments

Xanomeline/trospium

It has been postulated that the muscarinic cholinergic system contributes to the pathophysiology of schizophrenia. A proprietary combination formulation of xanomeline (a muscarinic receptor agonist at M1 and M4 receptors in the central nervous system) and trospium (a muscarinic receptor antagonist that reduces the unwanted peripheral cholinergic effects of xanomeline) has been approved in the US for the treatment of schizophrenia in adults. Two 5-week phase 3 trials have demonstrated the beneficial effects of xanomeline/trospium on schizophrenia symptoms.[239] The drug was generally well tolerated.[240][241] The results of two 52-week, open-label trials to assess longer-term efficacy and safety have not been published yet. Xanomeline/trospium is not approved in Europe as yet.

Trace amine-associated receptor 1 (TAAR1) agonists

TAAR1 has emerged as a novel therapeutic target for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor expressed in various dopamine-rich regions of the brain that are associated with schizophrenia. By activating TAAR1, TAAR1 agonists appear to modulate the signaling of multiple neurotransmitter systems that are dysregulated in schizophrenia, including the dopaminergic, serotonergic, and glutamatergic systems.[242] Ulotaront is the first TAAR1 agonist to enter phase 3 trials. A 4-week phase 2 trial and a 26-week open-label extension of this trial have demonstrated beneficial effects of ulotaront on positive and negative symptoms of schizophrenia; there were no significant changes in metabolic parameters in participants taking ulotaront.[243][244] Ralmitaront, a TAAR1 partial agonist, is under investigation in phase 2 trials.[245]

Iclepertin

Dysfunction of glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors is implicated in the causes of schizophrenia. One strategy to enhance glutamatergic transmission is to inhibit glycine transporter-1 and therefore increase synaptic levels of glycine, which is a coagonist required for NMDA receptor-mediated signaling.[246] A 12-week phase 2 trial found that iclepertin, a glycine transporter-1 inhibitor, improved cognition in patients with schizophrenia; the number of patients with adverse events was similar between the treatment and placebo groups.[247] Ongoing phase 3 trials are investigating the effects of adjunct treatment with iclepertin on cognition and functional improvement.

Dexmedetomidine

A sublingual formulation of dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, has been approved by the Food and Drug Administration (FDA) for the acute treatment of agitation associated with schizophrenia in adults. This orally-dissolving sublingual/buccal film can be self-administered and has a rapid onset of action. The FDA approval is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group phase 3 trials.[248][249] While sublingual dexmedetomidine did not exhibit any treatment-related serious adverse effects, it may cause dose-dependent adverse effects including hypotension, orthostatic hypotension, and bradycardia.[248][249] Dexmedetomidine should not be used in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope.

Metacognitive training (MCT)

MCT for psychosis may help patients with schizophrenia learn to question unfounded assumptions, known as cognitive biases, that contribute to their symptoms. Studies have suggested that MCT may reduce delusions and hallucinations, and improve self-esteem and functioning in patients with schizophrenia.[250] However, implementation and cost-effectiveness trials are still needed to examine its utility in real-world clinical settings.[251]

Complementary and alternative therapies

There is limited evidence to support the use of complementary and alternative therapies in patients with schizophrenia. Physical exercise offers added value in the multidisciplinary care of people with schizophrenia; it is associated in particular with improvements in cognitive function.[252][253][254] Yoga, mindfulness-based therapy, and creative art therapies, including drama therapy and music therapy, might be beneficial.[255][256][257][258][259][260][261][262] However, more research is needed to further examine the efficacy of these therapies. [ ]