Schizophrenia - Emerging treatments

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 co-agonist required for NMDA receptor-mediated signalling.[143] 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.[144] Ongoing phase 3 trials are investigating the effects of adjunct treatment with iclepertin on cognition and functional improvement.

Xanomeline/trospium

The muscarinic cholinergic system has been implicated in the pathophysiology of schizophrenia.[145] A combination of xanomeline (a muscarinic receptor agonist) and trospium (a muscarinic receptor antagonist that reduces the unwanted peripheral cholinergic effects of xanomeline) is under investigation as a potential treatment for schizophrenia.[146] A 5-week phase 2 trial demonstrated the beneficial effects of xanomeline/trospium on positive and negative symptoms.[147] Another 5-week phase 3 trial reported xanomeline/trospium was effective in reducing positive and negative symptoms of schizophrenia and was generally well tolerated.[148] Results from additional trials, including 52-week open-label trials, will provide additional information on the efficacy and safety of xanomeline/trospium.

Emraclidine

Emraclidine is a highly selective modulator of cholinergic muscarinic (M4) receptors. This results in reduced dopaminergic activity without direct dopamine receptor antagonist activity, which could minimise the side effects commonly linked to other antipsychotics.[149] A randomised, double-blind, placebo-controlled phase 1b trial in adults demonstrated a favourable safety and tolerability profile and significant improvement in psychotic symptoms, as reflected by a reduction in the Positive and Negative Syndrome Scale (PANSS) total score.[150] The most common adverse event was headache.[150] Modest, transient increases in blood pressure and heart rate observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6.[150] Three phase 2 clinical trials are ongoing to confirm the efficacy, safety, and tolerability of emraclidine.[149]

Oestrogen-related treatments

Treatment with oestrogen may improve symptoms of schizophrenia in women. However, this improvement must be balanced against the risk of excess exposure of peripheral tissue to oestrogen. Raloxifene hydrochloride is a selective mixed oestrogen agonist/antagonist with potential neuroprotective effects and fewer oestrogenic adverse effects than other types of oestrogen treatment. One double-blind, placebo-controlled, randomised study reported that raloxifene reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia.[151] A second double-blind, randomised, placebo-controlled found that transdermal oestradiol improved positive and negative symptoms of schizophrenia in women of childbearing age.[152]

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 signalling of multiple neurotransmitter systems that are dysregulated in schizophrenia, including the dopaminergic, serotonergic, and glutamatergic systems.[153] 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 the beneficial effects of ulotaront on positive and negative symptoms of schizophrenia; no significant changes in metabolic parameters were found in participants taking ulotaront.[154][155] Ralmitaront, a TAAR1 partial agonist, is under investigation in phase 2 trials.[156]

Olanzapine/samidorphan

Olanzapine co-formulated with the opioid antagonist samidorphan results in less weight gain than using olanzapine alone.[157] The risk of orthostatic hypotension should be assessed for patients who require repeated doses of intramuscular olanzapine.

Lumateperone

Lumateperone is a potent serotonin 5-HT2A receptor antagonist and dopamine modulator.[158] It was well-tolerated in two randomised, double-blind, placebo-controlled trials with a low risk of cardiometabolic and extrapyramidal adverse effects during short-term follow-up.[159][160][161]

Inhaled loxapine

Loxapine is a dibenzoxazepine antipsychotic. The inhaled formulation option has a rapid onset of action, is well tolerated, is easy to administer, and may be better accepted (by patients and carers) compared with oral or intramuscular antipsychotics.[162]