Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores

Kappel, Djenifer B.; Legge, Sophie E.; Hubbard, Leon; Willcocks, Isabella; O’Connell, Kevin; Smith, Robert L.; Molden, Espen; Andreassen, Ole A.; King, Adrian; Jansen, John A.; Helthuis, Marinka; O’Donovan, Michael; Walters, James; Pardiñas, Antonio F.

doi:10.1016/j.biopsych.2022.07.014

Cited by 15 publications

(16 citation statements)

References 39 publications

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“…For example, in patients with SCZ, a negative correlation ( r = -0.05[95%CI: -0.09 – -0.01]) was found between PGSSCZ and response to second generation antipsychotics (olanzapine, aripiprazole, risperidone, quetiapine, haloperidol, ziprasidone, perphenazine) following six weeks treatment 34 . Kappel et al(2023) observed a positive correlation ( β =12.21; 95%CI: 4.81 – 19.62) between PGSSCZ and high clozapine dosing (>600 mg/day) suggesting that individuals with a higher PGSSCZ may require increased doses of clozapine to achieve effective treatment response 33 . In patients treated with risperidone, those who had a higher PGSSCZ reported more depressive symptoms 45 , and worsened positive and negative psychotic symptoms 46 .…”

Section: Resultsmentioning

confidence: 99%

“…Several studies (20 studies) revealed that individuals with higher genetic loading for SCZ had a poorer treatment outcome to psychiatric medications [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] , while the remaining studies didn't find significant associations. For example, in patients with SCZ, a negative correlation (r = -0.05[95%CI: -0.09 --0.01]) was found between PGSSCZ and response to second generation antipsychotics (olanzapine, aripiprazole, risperidone, quetiapine, haloperidol, ziprasidone, perphenazine) following six weeks treatment 34 dosing (>600 mg/day) suggesting that individuals with a higher PGSSCZ may require increased doses of clozapine to achieve effective treatment response 33 . In patients treated with risperidone, those who had a higher PGSSCZ reported more depressive symptoms 45 , and worsened positive and negative psychotic symptoms 46 .…”

Section: The Association Of Pharmacogenomic Scores With Treatment Out...mentioning

confidence: 99%

“…Validation of polygenic models: Given the complexity of pharmacogenetic models, current sampling issues and the associated risks of false discovery and poor generalizability across different populations, external replication and validation of these models is critical for future implementation 25,[112][113][114] . Only 26.4% of studies included in this systematic review employed external validation 31,33,34,36,37,43,45,46,55,56,59,62,64,115 .…”

Section: Future Directions In Pgx-score Researchmentioning

confidence: 99%

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Pharmacogenomic scores in psychiatry: Systematic review of existing evidence

Sharew,

Clark,

Schubert

et al. 2024

Preprint

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In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment: poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice. Keywords: Polygenic score, Pharmacogenomics, Psychiatric disorders, Psychotropic drugs, treatment outcomes

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Section: Resultsmentioning

confidence: 99%

Section: The Association Of Pharmacogenomic Scores With Treatment Out...mentioning

confidence: 99%

Section: Future Directions In Pgx-score Researchmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacogenomic scores in psychiatry: Systematic review of existing evidence

Sharew,

Clark,

Schubert

et al. 2024

Preprint

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“… 25 A high genetic load for schizophrenia appears to increase the risk for a poor treatment response. 33 , 449 Compared with TRS, CRS is characterized by later clozapine initiation and associated with higher mortality rates. 127 , 350 Importantly, clozapine should not be discontinued in patients with CRS, but rather augmented ( Table 3 ).…”

Section: Management Of Clozapine-resistant Schizophreniamentioning

confidence: 99%

“…These cases are classified as ultra-treatment resistant or clozapine-resistant schizophrenia (CRS) 25 . A high genetic load for schizophrenia appears to increase the risk for a poor treatment response 339 . Compared to TRS, CRS is characterized by later clozapine initiation and associated with higher mortality rates 124,338 .…”

Section: Management Of Clozapine-resistant Schizophreniamentioning

confidence: 99%

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Qubad

Bittner

2023

Therapeutic Advances in Psychopharmacology

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Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine’s wide-ranging superior efficacy – for treatment-resistant schizophrenia (TRS) and beyond – and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients’ benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine’s unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine’s full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

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