Clinical Overview: Updates in Pharmacologic Options for the Treatment of Schizophrenia, Bipolar Disorder

Schizophrenia is a mental condition in which reality is difficult to interpret. This can be due to multi-faceted hallucinations or other behaviors that impact quality of life.

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Schizophrenia occurs in 1 in 300 people worldwide, with onset most commonly occurring in teenage years and persisting for life. There is no cure and it is usually treated with a first or second generation antipsychotic.

Xanomeline-trospium (Karxt) is a combination medication with a novel mechanism of action for the treatment of schizophrenia. Low acetylcholine levels in the brain may theoretically impact sensory gating deficit and visual or auditory hallucinations associated with schizophrenia.

It is hypothesized that increasing available acetylcholine in the brain might alleviate the aforementioned symptoms. Xanomeline is an oral muscarinic cholinergic receptor agonist that stimulates M1 and M4 muscarinic cholinergic receptors, which are known to impact the pathophysiology of schizophrenia.

Trospium is an oral pan-muscarinic receptor antagonist whose structure prevents it from reaching the cerebrospinal fluid, and therefore, should not cause central nervous system adverse effects (AEs). Using both together may stimulate brain muscarinic receptors with therapeutic antipsychotic doses of xanomeline while minimizing AEs.

It would be the only medication approved to treat the negative symptoms of schizophrenia. The medications currently used for schizophrenia are solely antipsychotics and this new mechanism of action may be impactful on patient outcomes.

Risperidone is an antipsychotic that is commonly used treat schizophrenia. Rykindo (risperidone) is a new long-acting intramuscular (IM) formulation of this antipsychotic.

The ease of administration with an injection is advantageous because this patient population is commonly agitated and difficult to administer oral medications to. The long duration (2 weeks) of effectiveness with Rykindo will be useful in this population in whom compliance is frequently an issue.

There are other IM injections of antipsychotics, and even another existing injection formulation of risperidone, such as Risperidal Consta (risperidone). Rykindois a microsphere and, like Risperdal Consta, requires an overlap with oral risperidone while the IM takes effect.

Both are administered every 2 weeks but Rykindo is unique because it only takes 7 days to see the effect verses the 3 weeks required for Risperdal Consta. Perserisis the subcutaneous (SQ) form, which does not require oral overlap, but is administered monthly.

The preference in the available formulations will likely be patient specific. Rykindo is not only approved for adults with schizophrenia as monotherapy but also as an adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults.

Lumateperone(Caplyta) is another agent newly approved for adults with schizophrenia and bipolar depression as monotherapy and adjunctive therapy. Lumateperone acts on serotonin receptors like the other second-generation antipsychotics, alpha-2 agonists, and SSRIs.

Unlike other antipsychotics, it has low affinity for the dopamine D2 receptor. Most antipsychotics have an occupancy of greater than 60% at this receptor. Of these, quetiapine and cloazapine’s occupancy are the closest to 60%; however, lumateperone has a 39% occupancy.

This translates to better tolerability with a lower rate of akathisia and extrapyramidal AEs in both schizophrenia and bipolar disorder. Lumateperone is unique because it allows for the treatment of bipolar I and II depression as adjunctive or monotherapy.

Other agents in this class for the treatment of bipolar I (lurasidone and cariprazine) and bipolar I and II (quetiapine) can only treat monotherapy. Lurasidone can do both monotherapy and adjunctive therapy but only for bipolar I.

Sublingual dexmedetomidine (Igalmi) was approved last year for acute agitation in adult patients with schizophrenia or bipolar I or II disorder. Keep a look out for these medications, as xanomeline-trospium will be coming in 2023 and lumateperone, Rykindo, and Igalmi have been FDA-approved within the past year.

References

1. Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs. . UpToDate. Accessed June 1, 2023. https://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-long-acting-injectable-antipsychotic-drugs#.
2. Bipolar major depression in adults: Choosing treatment. . UpToDate. Accessed June 1, 2023. https://www.uptodate.com/contents/bipolar-major-depression-in-adults-choosing-treatment?search=bipolar+treatment§ionRank=1&usage_type=default&anchor=H2681143167&source=machineLearning&selectedTitle=2~150&display_rank=2#.
3. Schizophrenia. Mayo Clinic. January 7, 2020. Accessed June 1, 2023. https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443.
4. What is acetylcholine? Mental Health America. Accessed June 1, 2023. https://mhanational.org/what-acetylcholine.
5. Schizophrenia. World Health Organization. Accessed June 1, 2023. https://www.who.int/news-room/fact-sheets/detail/schizophrenia.
6. Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. New England Journal of Medicine. Accessed June 1, 2023. https://www.nejm.org/doi/full/10.1056/NEJMoa2017015.
7. Dosing and administration of long-acting injectable antipsychotics for schizophrenia in adults. UpToDate. Accessed June 1, 2023. https://www.uptodate.com/contents/image?imageKey=PSYCH%2F59201. Highlights of prescribing information Caplyta. FDA Approvals. (n.d.). Retrieved October 2, 2022, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209500s000lbl.pdf
8. For healthcare professionals - CAPLYTA® (lumateperone) for Bipolar depression. For Healthcare Professionals - CAPLYTA® (lumateperone) for Bipolar Depression. (n.d.). Retrieved October 2, 2022, from https://www.caplytahcp.com/?gclid=Cj0KCQjwyOuYBhCGARIsAIdGQRNzFoC-Oy75Op9kFr6fBxpkOoPh4yIGiE-y1fPSjd5jaABrcE1h8CgaAsb5EALw_wcB&gclsrc=aw.ds
9. BioXcel Therapeutics announces FDA approval of IGALMI™ (dexmedetomidine) sublingual film for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults. BioXcel. News release. https://ir.bioxceltherapeutics.com/news-releases/news-release-details/bioxcel-therapeutics-announces-fda-approval-igalmitm