Alternative pharmacologic targets for the treatment of schizophrenia.Curr Opin Psy.March.2013.


All effective antipsychotics  act on dopamine receptors. There is not much difference in efficacy between these agents. Alternative pharmacologic targets need to be pursued to see whether different approaches will provide better response either in global symptoms or in specific symptoms ( like cognitive symptoms).

Seiya Miyamotoa, Lars F. Jarskogb, and W. Wolfgang Fleischhackerd reviews the results from phase 1 and phase 2 trials of novel agents acting on targets other than Dopamine receptors.

Serotonin receptors: Selective 5-HT2C receptor agonists have shown antipsychotic effect in animal models.A 6-week placebo and olanzapine-controlled phase II study with the full 5-HT2C agonist vabicaserin showed a significant improvement over placebo for the 200 mg/day dose . 400mg dose was not different from placebo.

GABA receptors:  GABAergic interneurons inhibit neuronal output of glutamatergic pyramidal cells in the prefrontal cortex  through activation of GABA type A (GABAA) receptors containing a2 subunits. BL-1020 has strong affinity to GABA receptor. A 6-week phase II open- label trial, BL-1020  showed  reduction in psychotic symptoms in 36 patients with chronic schizophrenia.MK-0777 is a relatively weak GABAA a2 partial agonist,and most recent study did not show any benefit on cognitive symptoms.

Glycine receptors: blockade of GlyT1 can  increase NMDA-R-mediated transmission. Sarcosine (N-methylglycine), a potent GlyT1 inhibitor prototype, has shown benefits when added to antipsychotics.2g/day is shown to be of benefit in an RCT. Another GlyT1 inhibitor, bitopertin, significantly improved negative  symptoms.However  GlyT1 inhibitor Org 25935 was not effective.

Metabotropic glutamate receptors:These are  located presynaptically on glutamate terminals and act as autoreceptors to inhibit glutamate release. Few  agonist agents in this   group have been studied, none have come out with promising results.

Nicotinic receptors: 1. Alpha 7 receptor: There is considerable evidence for altered alpha 7 nAChR levels and function in schizophrenia. At least 4 different agents ( agonists) have been successfully tried  so far.Cognitive symptoms tend to improve with these agents.2. a4 b2  nicotinic receptor. Agonists at this receptor is reported to improve cognition when given as adjunctive agents.

Cannabinoid receptors:  selective CB1 receptor antagonist rimonabant was withdrawn due to psychiatric side effects.Cannabidiol (CBD), a cannabis constituent with no action on CB1 receptors, showed equivalent efficacy to amisulpride in 42 patients with acutely exacerbated schizophrenia.

Minocycline: Studies suggest that this can improve cognitive symptoms.It has antioxidant, anti- inflammatory, and neuroprotective properties.

Oxytocin: Single-dose intranasal oxytocin can increase interpersonal trust, eye contact, face emotion recognition and social reciprocity in healthy and autistic individuals . Three small studies show improvements in social cognition and verbal memory.

Erythropoietin: This has direct neuroprotective effects. Weekly intravenous administration of adjunctive high-dose recombinant human EPO (rhEPO) produced significantly greater cognitive improvement as compared with placebo in 39 patients with chronic schizophrenia on stable antipsychotics.

Conclusions:The results are promising  from phase II trials of GlyT1 inhibitors, selective alpha 7 nAChR agonists, minocycline, oxytocin, and Erythropoietin. If these agents show to be effective in phase 3 trials, we would have the third generation antipsychotics to improve the lives of our patients.

Summary of the article:

Alternative pharmacologic targets for the treatment of schizophreniaresults from phase I and II trials.Miyamoto S, Jarskog LF, Fleischhacker WW.Curr Opin Psychiatry. 2013 Mar;26(2):158-65.

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