Table 1 Summary of medications targeting interacting systems with relevance to the corticolimbic system in Schizophrenia Spectrum Disorders (SSD).

From: Corticolimbic circuitry as a druggable target in schizophrenia spectrum disorders: a narrative review

Medications (Mechanism)

Corticolimbic pharmaco-neuroimaging

Impact on symptoms

Endocannabinoid

Cannabidiol (multiple targets)

• Healthy Participants- Decreased corticolimbic activity in healthy individuals [237, 238].

• SSD- Decreased hippocampal and parahippocampal activity. Normalised hippocampal-striatal functional connectivity during verbal memory recall [239].

• CHR-P- not effective when given for short durations. Longer durations may be needed [240, 241].

• SSD- improvements in PANSS positive scale and clinician’s overall impression (CGI-I) with 6 weeks adjunctive treatment [242].

Acetylcholine

Xanomeline (muscarinic M1 and M4 agonist)

• Rodents - Dose-dependently attenuated ketamine-induced brain activation [243]. Increased neocortical-striatal connectivity and attenuated corticolimbic response and frontal-hippocampal hyperconnectivity induced by PCP [244].

• SSD- Lower [3H]pirenzepine binding in the cortex, hippocampus and striatum [245].

• SSD- pilot study (N = 20) improved BPRS and total PANSS scores [246]. High rates of adverse effects.

KarXT (xanomeline-trospium)

N/a

• SSD- Phase II studies- improved PANSS total scores [247]. Phase III studies- improved PANSS total score at 5 weeks [248] Ongoing studies (NCT05145413, NCT04738123, and NCT04659174).

Emraclidine CVL-231 (M4 positive allostatic modulator)

N/a

• SSD- Phase 1B study- decreased total and negative PANSS [249]. Phase II ongoing (NCT05227690).

EVP-6124, AVL-3288 (α7 nicotinic receptor partial agonists/positive allostatic modulator)

N/a

• SSD- Phase 1b study- non-significant worsening in RBANS scores [250]. Phase III study- no significant benefit on cognitive symptoms [251]. Metanalysis- not effective for cognitive symptoms and small effect for negative symptoms [252].

Serotonin

Pimavanserin/ ACP-103 (inverse agonist/ antagonist 5-HT2A receptors)

• Rodents- Increased dopamine release in mPFC [253].

• SSD- Adjunctive use with low dose risperidone improved PANSS total score [254]. Phase II study - improved negative symptoms [255]. Phase III study - no significant difference in PANSS total scores [256].

Roluperidone/ MIN‐101 (5‐HT2A and sigma‐2 antagonist)

N/a

• SSD- Phase II study- no significant reduction in PANSS total or cognitive symptoms [257]. Phase III study- improvements in negative symptoms (NSFS) [258].

  1. Evidence from schizophrenia spectrum disorders (SSD), clinical high risk for psychosis (CHR-P), healthy participants and rodents. Scales- positive and negative syndrome scale (PANSS), The clinical global impressions scale- improvement (CGI-I), brief psychiatric rating scale (BPRS), repeatable battery for the assessment of neuropsychological status update (RBANS) and negative symptom factor scale (NSFS).
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