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. 2020 Apr 2;30(Suppl 1):229–240. doi: 10.18865/ed.30.S1.229

Exploring Biologic Predictors Response Disparities to Atypical Antipsychotics among Blacks: A Quasi-Systematic Review

Rebecca N Jerome 1,✉, Jill M Pulley 1, Nila A Sathe 2,3, Shanthi Krishnaswami 2, Alyssa B Dickerson 1, Katherine J Worley 1,2, Consuelo H Wilkins 4
PMCID: PMC7138445  PMID: 32269465

Abstract

Purpose

Management of schizophrenia among Blacks in the United States is affected by persistent disparities. This review explored response to atypical antipsychotics among Blacks compared with other groups to assess systematic variation that may contribute to disparities.

Methods

We conducted a quasi-systematic review of studies reporting response to atypical antipsychotics among Blacks compared with other groups, including effects of genetic variation.

Results

Of 48 identified research articles, 29 assessed differences in outcomes without inclusion of genetic variation and 20 explored effects of genetic variation; of note: one article included both types of data. Analysis of the 29 papers with clinical outcomes only suggests that while data on efficacy and risk of movement disorders were heterogeneous, findings indicate increased risk of metabolic effects and neutropenia among Blacks. Of the 20 articles exploring effects of genetic variation, allelic or genotypic variations involving several genes were associated with altered efficacy or safety among Blacks but not Whites, including risk of decreased response involving variation in DRD4 and DRD1, and improved efficacy associated with variants in DRD2, COMT, and RGS4. Others showed significant improvement in treatment response only among Whites, including variation in DTNBP1, DRD4, and GNB3.

Conclusions

The current analysis can help tailor management among Blacks using an atypical antipsychotic. Heterogeneity in genetic variation effects and response allele frequency suggests that pharmacogenetics approaches for atypical antipsychotics will need to explicitly incorporate race and ethnicity.

Keywords: Atypical Antipsychotics, Schizophrenia, Blacks, Disparities, Pharmacogenetics

Introduction

Diagnosis and management of mental health conditions among Blacks in the United States remains complex and affected by significant disparities, particularly in those with more severe disease. Blacks may be 2-5 times more likely to be diagnosed with schizophrenia as compared with Whites1; further, research indicates differences in prescribing, including overuse of lower efficacy, higher-risk first generation antipsychotics in this group.2 In addition to these striking disparities in disease management, any unrecognized systematic variations in response to atypical antipsychotic therapy could be significantly contributing to disparities among Blacks living with schizophrenia.

While the growing body of pharmacogenomics research has significant potential for guiding treatment decisions, the persistent heterogeneity of observed treatment responses in many clinical situations suggests that additional genetic and other biologic factors may contribute to the success, or failure, of a given treatment approach in individuals of different racial and ethnic backgrounds. Notable patterns of altered safety and efficacy in Blacks, for example, as compared with other demographic groups include: a CCR5 genotype associated with response to highly active antiretroviral therapy, further modified by strength of African ancestry,3 and an altered risk profile in Black severe heart failure patients receiving spironolactone.4 Such differences may significantly contribute to ongoing health disparities, particularly as they relate to potential decreased therapeutic efficacy or increased risk of side effects.

The published literature, as a body of existing data, represents an important opportunity for employing analytic approaches to understanding safety and efficacy patterns that may further inform clinical practice and future research related to the care of individuals of different racial and ethnic backgrounds. To begin to explore potential biologic factors that may affect response to atypical antipsychotic agents, including potential differences in safety and efficacy, we used a quasi-systematic literature review approach. The goals of this analysis included: 1) to inform treatment planning when feasible and appropriate; and 2) to enrich hypothesis formation for future research to develop deeper understanding of the biologic explanations underpinning some of these results.

Methods

Information Sources and Eligibility Criteria

This pilot review employed data aggregated by IMS Institute for Healthcare Informatics to identify the most prescribed brand name and generic drugs in the United States,5 prioritizing agents with FDA-approved indications for treatment of conditions with known health or treatment response disparities6 affecting Blacks. For this review, we used this information as well as clinical input and focused on the atypical antipsychotics, commonly used to treat schizophrenia and related disorders. Our quasi-systematic review protocol, PRISMA diagram, and detailed evidence extraction files are archived at https://rocket.app.vumc.org/index.php?doc_id=21299.

We searched MEDLINE via PubMed for articles published from January 2000 to November 2016 using a combination of controlled vocabulary and key terms related to atypical antipsychotics, African ancestry, and genetic or drug response variation. We selected the year 2000, when the first draft of the human genome was completed, as a starting date given that the majority of evidence related to our pharmacogenomics objective would be published after this time.7 To ensure that our analysis incorporated the most current literature, we completed a final manual search of citations in PubMed published from November 2016 through August 2019. We did not include EMBASE searches due to exploration indicating that this resource was duplicative of the citations retrieved using PubMed. In parallel, we developed inclusion criteria in consultation with team experts and informed by our preliminary review of response variability information.

We sought studies assessing any differential response to drugs of interest and those identifying genetic polymorphisms related to drug response variability or modification. We included: 1) empirical studies of any design and pooled trial analyses, systematic reviews, and meta-analyses addressing variation in effectiveness or safety of atypical antipsychotics among Blacks compared with another racial/ethnic group; and 2) original research studies evaluating genetic variations that may affect drug response in Blacks compared with other ethnic groups. We limited inclusion to English language studies. Four reviewers (RJ, SK, NS, KW) independently screened titles/abstracts and the full text of studies using predetermined criteria, with discrepancies between reviewers resolved through discussion to reach consensus.

Data Extraction and Analysis

We extracted study design, key study population characteristics, methodologic characteristics (study design), and outcome data on constructs of interest (race/ethnicity, allelic variations, efficacy measures, safety data) from eligible studies. To accommodate the heterogeneous terminology used among studies to refer to subgroups by race and ethnicity, we use the term Black throughout this analysis to refer to any subgroup defined within studies as Black, African, African American, or of African ancestry, and use the term White to refer to subgroups defined within studies as White, Caucasian, European American, or of European ancestry. Other less commonly compared groups in this literature are described using the definition used in the original studies (eg, Mexican, Puerto Rican, Latin American, Asian).

We synthesized studies qualitatively and report descriptive statistics in summary tables. As this was a pilot review, we did not formally assess the methodologic quality of studies. To assess relative population frequency of variants with significant allelic or genotypic effects on efficacy and/or safety, we explored minor allele frequency (MAF) among the subgroups using SNP prevalence data in gnomAD.8

Results

Article Selection and Overview

Of the 3158 articles retrieved by our searches, 48 papers describing antipsychotics outcome data met inclusion criteria. While our search focused on atypical antipsychotic agents, we summarize data regarding typical antipsychotics when also present in an included study.

Studies focusing on adult participants predominated in this literature. Whites were the most common group compared with Blacks, with only a few studies analyzing a Hispanic or Latin American group for comparison. Most studies categorized race and ethnicity based on participant self-report or did not share their approach for categorizing race and ethnicity; a limited number of analyses incorporated genetic ancestry markers. Almost all articles focused on antipsychotic therapy for treatment of disorders on the schizophrenia spectrum; a limited number described other uses, such as management of agitation in the pediatric psychiatric unit setting.

Antipsychotics: General Efficacy or Safety Effects by Race/Ethnicity

We identified 29 articles assessing potential differences in efficacy and/or safety of atypical antipsychotic agents in Blacks as compared with other racial or ethnic groups, including those studies exploring subgroup effects within clinical data without analysis of genomic variant effects. These studies included a range of approaches for defining the Black subgroup, including self-report in three,9–11 self-report plus participant-reported race/ethnicity of biologic parents and grandparents in two,12,13 and the medical record or a registry/database in six;14–19 an approach was not reported in 17 articles20–36 and one meta-analysis used existing categorization from included studies.37 One study using self-reported Black race also included estimation of geographic ancestry using the STRUCTURE software.12

Efficacy

Ten studies analyzed potential differences in efficacy outcomes associated with antipsychotic therapy in Blacks as compared with other racial or ethnic groups (Table 1).9,10,12,14,20–23,35,36 Three pooled analyses of antipsychotics trial data found equal clinical efficacy of these agents in Blacks as compared with other groups.10,12,20 ANCOVA subgroup analyses of two randomized controlled trials (RCTs) of atypical antipsychotics found no significant treatment interactions with race and ethnicity.35,36 A fourth pooled analysis of trial data from South Africa found improved efficacy of antipsychotic therapies in Black and mixed descent participants as compared with White participants (P=.002 for group difference in incidence of > 40% reduction in Positive and Negative Syndrome Scale (PANSS) total scores).23

Table 1. Atypical antipsychotic studies reporting efficacy outcomes (without genetic data).

Author, year Design Black N/Total N Condition(s)a; Drug(s)b Efficacy among Blacksc
Arnold 20139 RCT 506/1398 Sz; O,Q,R,Z,P ↑
Chan 201312 Pooled trials 30/237 Sz; C,O,R,H =
Loebel 201335 RCT 95/524 Sz; L,Q =
Meltzer 201136 RCT 160/548 Sz; L,O =
Stauffer 201020 Pooled trials 375/980 Sz,Sp,Sa; O =
Lawson 200910 Pooled trials 267/955 Sz; Z,H =
Barzman 200714 Case series 33/69 Ag; Z =
Patel 200622 Case series 38/105 Szspec; R ↑
Ciliberto 200521 RCT, post-hoc 174/439 Sz,Sz; R = Total PANSS, θ 2 subscales
Emsley 200223 RCT, post hoc 50/129 Sz,Sp; NS ↑
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Key: ↑ increased efficacy; ↓ decreased efficacy; = similar efficacy among groups; θ efficacy found in another group but not found among Blacks; RCT, randomized controlled trial; post hoc, secondary analysis of trial data.

a. Sa, schizoaffective disorder; Sp, schizophreniform disorder; Sz, schizophrenia; Szspec, schizophrenia spectrum disorders.

b. C, clozapine; H, haloperidol; L, lurasidone; NS, specific agents not detailed; O, olanzapine; P, perphenazine; Q ,quetiapine; R, risperidone; Z, zuprasidone.

c. Compared with other racial and/or ethnic groups.

In a secondary analysis of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data by Arnold et al, investigators found that White adults discontinued olanzapine and risperidone for lack of efficacy at higher rates than Black or Hispanic participants (P=.04), while Hispanic participants discontinued perphenazine and ziprasidone for lack of efficacy at higher rates than Whites or Blacks (P≤05).9 In another secondary analysis of RCT data, Ciliberto et al found no effect of race on total PANSS scores in risperidone-treated adults; however, White participants improved on all five PANSS subscales while Blacks improved on only three, failing to show improvements in disorganized thought and uncontrolled hostility/excitement.21

The two retrospective case series included children and adolescents and found differing results. Patel et al found greater improvement in challenging behaviors during risperidone therapy among Black as compared with Hispanic adolescents with schizophrenia,22 while Barzman et al found no effect of ethnicity on ziprasidone efficacy for management of agitation in the pediatric psychiatric unit setting.14

Safety

Potential differences in various antipsychotics-related safety outcomes among Blacks as compared with other groups were identified in 23 articles (Table 2); adverse events included metabolic effects (16 articles),10,12,13,15,16,20,21,24–31,37 movement disorders (8 articles),9,11,12,20,21,32,37,38 neutropenia (4 articles),17–19,33 bone mineral density (1 article),34 and general side effects (1 article).21

Table 2. Atypical antipsychotic studies reporting safety outcomes (without genetic data).

Author, year Design Black/Total N Condition(s)a; Drug(s)b Safety among Blacksc
DC MV N MT B
Demler 201633 Case series NR/193 Sz; C ↓
Kane 201430 RCT 223/340 Sz; A ↓
Su 201411 Case control 135/492 Spsy,Ba,Sa, D;Mult ↓
Arnold 20139 RCT 506/1398 Sz; O,Q,R,Z,P = ↑
Chan 201312 Pooled trials 30/237 Sz; C,O,R,H = ↓
Maher 201318 Case series 28/88 Sz,Sa; C ↓
Nowrouzi 201331 Pooled studies 56/139 Sz; C,O,R,H ↓
Muller 201213 Pooled studies 58/186 Sz,Sa; C,O,R,H ↓
Stauffer 201020 Pooled trials 375/980 Sz,Sp,Sa; O = = ↓
Krakowski 200927 RCT, post hoc 56/93 Sz,Sa; C,O,H ↓
Lawson 200910 Pooled trials 267/955 Sz; Z,H ↓ =
Lipkovich 200929 Pooled trials 399/3826 Szspec,Bp,Br;O ↓
Rahman 200919 Case series 25/133 NR;Q ↓
Ormerod 200837 Meta-analysis 287/844 Ps,D; Mult = =
de Leon 200726 RCT, post hoc 7/50 Sz,Sa; C ↓
Kelly 200717 Case series 588/1875 Sz,Sa; C ↓
Nihalani 200725 Case series NR/49 Sz,Sa,Dd, Bp; C ↓
Wonodi 200732 Case series 62/114 NR; Mult ↓
Ciliberto 200521 RCT, post-hoc 174/439 Sz,Sa; R = =
Henderson 200528 Case series 6/96 Sz,Sa; C ↓
Howes 200534 Cross sectional 55/102 NR;Mult ↓
Lambert 200515 Registry 3111/18182 Sz; O,C,R,Q ↓
Lambert 200516 Registry 2174/12637 Sz; O,C ↓
Rosenheck 200024 RCT, post hoc 125/423 Sz; C,H ↓
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Key: ↑ increased safety; ↓ decreased safety; = similar safety among groups; RCT, randomized controlled trial; post hoc, secondary analysis of trial data; DC, all cause discontinuation; MV, movement disorders; MT, metabolic dysfunction; N, neutropenia; BN, bone mineral density changes.

a. Ba, bipolar affective disorder; Bp, bipolar disorder; Br, borderline personality disorder Dd, delusional disorder; D, depression; NR, not reported; Ps, psychosis; Sa, schizoaffective disorder; Sp, schizophreniform disorder; Spsy, schizophrenia psychosis; Sz, schizophrenia; Szspec, schizophrenia spectrum disorders.

b. A, aripiprazole; C, clozapine; H, haloperidol; Multi, multiple atypical antipsychotics; NS, specific agents not detailed; O, olanzapine; Q, quetiapine; R, risperidone; Z, zuprasidone.

c. Compared with other racial and/or ethnic groups.

Results of analyses exploring the risk of metabolic adverse effects among Blacks exposed to atypical antipsychotic agents were varied but seem to indicate a general trend toward increased risk of metabolic side effects in this group as compared with other groups. Eight analyses indicated increased risk of weight gain in Blacks using various antipsychotic agents, including two pooled analyses of olanzapine trial data,20,29 two secondary analyses of individual clozapine RCTs,26,39 one RCT of aripiprazole,30 two pooled analysis of studies involving multiple antipsychotics,13,31 and one secondary analysis of an RCT including multiple antipsychotic agents.27 Yet, three additional studies found no effect of race on this outcome; studies included a risperidone trial,21 a pooled analysis of ziprasidone RCTs,10 and a meta-analysis of data on multiple antipsychotics.37 Increased risk of new-onset diabetes and/or increased serum glucose was also observed among Blacks in an olanzapine registry study15 and a clozapine case series28; increased risk of diabetic ketoacidosis among Blacks was also noted in one case series.25 However, three analyses failed to find a significant effect of race on glucose and/or diabetes, including two pooled analyses of ziprasidone and olanzapine RCT data10,20 and a meta-analysis of multiple antipsychotics.37 Two studies also found Blacks to be at greater risk of increased lipid levels during antipsychotic therapy as compared with other groups, including a registry study of olanzapine16 and a secondary analysis of an RCT including multiple antipsychotics,27 though two additional studies failed to find a significant effect of race on lipids in patients treated with olanzapine20 or ziprasidone,10 respectively.

Among the eight articles examining variation in risk for antipsychotic-associated movement disorders by race and ethnicity, results were heterogeneous. Three analyses found no significant effect of race and ethnicity on incidence of movement adverse events (AEs) among adults, including a pooled analysis of RCTs of olanzapine,20 a secondary analysis of a risperidone RCT,21 and a pooled analysis of RCTs involving multiple antipsychotic agents.12 Three studies indicated increased risk of movement AEs in Blacks as compared with other groups, including a pooled analysis of adult data from ziprasidone RCTs,10 a case control study including multiple antipsychotics in adult participants,11 and a pediatric case series including multiple antipsychotics.32 Conversely, two studies found reduced risk of movement AEs among Black adults as compared with adults from other subgroups; these included a pooled analysis of haloperidol RCT data10 and a secondary analysis of an RCT including multiple antipsychotic agents.9

Four retrospective case series assessed neutropenia during antipsychotic therapy in Blacks as compared with other groups, three examining clozapine17,18,33 and one assessing quetiapine.19 Two of these papers included adults17,33 and two focused on children/adolescents.18,19 All four analyses indicated increased risk of various neutropenia-related events among Blacks as compared with others; these risk signals varied and included higher incidence of moderate neutropenia/leukopenia/granulocytopenia,19,33 higher incidence of discontinuation due to leukopenia,17 and increased risk of neutropenia.18

One study in the UK assessed bone mineral density (BMD) in patients taking various antipsychotics, finding no evidence of reduced BMD among White participants and Black women at the total spine, total hip, and femoral neck, while Black men showed reduced BMD at total spine but not at the hip or femoral neck.34 Finally, the one article assessing overall incidence of side effects in patients receiving risperidone found no significant effect of race and ethnicity on this general outcome.21

Antipsychotics: Genetic Variants and Response

Building upon the subgroup effects detected in studies limited to subgroup analyses of clinical data, we next assessed the 20 articles assessing effects of interaction between genomic variation and race on response to antipsychotic therapy (Table 3 and Table 4), with analyzed outcomes including efficacy (12 articles),40–51 incidence of any adverse effects (1 article),52 risk of weight gain (5 articles),13,53–56 risk of movement disorders (3 articles),52,57,58 and drowsiness (1 article).54 These studies included a range of approaches for defining the Black subgroup, including self-report in three,49,57,58 self-report plus participant-reported race/ethnicity of biologic parents and grandparents in three,13,55,56 principal component analysis comparing participants with 1000 Genome Phase 1 data,50,51 and estimation of geographic ancestry using the STRUCTURE program41; the approach for defining the Black subgroup was not reported in 11 articles.40,42–48,52–54

Table 3. Atypical antipsychotic studies: genetic associations with efficacy outcomes.

Author, year Design Black/Total N Condition(s)a Drug(s)b Variants and relative directionality of effect on efficacy among Blacksc
Li 201850 Pooled trials 219/587 Sz; L ↑ (STXBP5L variants);↓Eff (CTNNA2 SNP)
Li 201851 Pooled trials 195/429 Sz; L = (multiple genes and SNPs)
Hwang 2012, 2011, 2010, 2007, 2006, 200542–47 Pooled studies 98/426 Sz; C,O,R,H ↓ (120-bp repeat and (G)n repeat, DRD4); θ (48-bp repeat, DRD4; DRD1 haplotype); ↑ (DRD1 genotype and haplotype; SNPs and haplotypes, DRD2)
Fijal 200948 RCT, post hoc 78/153 Sz,Sa; R ↑ PANSS negative symptom change (COMT SNP); = PANSS total score change (GRM3 SNP); θ PANSS positive symptom change (GRM3 SNP)
Zuo 200941 RCT 54/181 Sz; H,C θ (DTNBP1 haplotype, diplotype); ↑ (clozapine; DTNBP1 SNP); ↑ (haloperidol; DTNBP1 SNP)
Campbell 200849 RCT, post hoc 198/678 Sz;P,Z,O,R,Q ↑ (RGS4 SNP)
Muller 200540 Pooled cohorts 57/145 Sz; C,H,O,R θ (GNB3 SNP)
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Key: ↑ increased efficacy; ↓ decreased efficacy; =equal efficacy; θ genetic effect on efficacy found in another group not found among Blacks; bp, base pair; PANSS, Positive and Negative Syndrome Scale; RCT, randomized controlled trial; SNP, single nucleotide polymorphism.

a. Sa, schizoaffective disorder; Sz, schizophrenia.

b. A, aripiprazole; C, clozapine; H, haloperidol; L, lurasidone; O, olanzapine; P, perphenazine; Q, quetiapine; R, risperidone; Z, zuprasidone.

c. Compared with other racial and/or ethnic groups.

Table 4. Atypical antipsychotic studies: genetic associations with safety outcomes.

Author, year Design Black/Total N Condition(s)a Drug(s)b Outcome type and relative directionality of effect among Blacksc
Greenbaum 201257 Cross-sectional 111/178 Sz; R,O,C =movement disorders (ZFPM2 SNP)
Muller 201213 Pooled studies 58/186 Sz,Sa; C,O,R,H =weight gain (DRD2 SNP); θ different variants affecting weight gain in Blacks and Whites (DRD2 and DRD3 SNPs)
Tiwari 201055 RCT 57/217 Sz; C,O ↓metabolic dysfunction (CCKBR SNP)
Tiwari 201056 RCT 54/154 Sz, C,O =metabolic dysfunction (INSIG2 SNP)
Greenbaum 200958 Cross-sectional 115/184 Sz; R,O,C =movement disorders (RGS2 SNPs)
Sickert 200953 Pooled studies 54/129 Sz; C,O,R,H θ metabolic dysfunction (ADRA2A SNP)
Cashman 200854 Pooled cohorts 240/844 Sz; O θ metabolic changes; drowsiness (FMO3 SNPs)
Grossman 200852 RCT, post hoc 211/708 Sz; O,Q,R,Z,P ↓discontinuation due to ADR (FMO3 SNPs)
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Key: ↑ increased safety; ↓ decreased safety; = similar safety among groups; θ genetic effect on safety found in another group not found among Blacks; RCT randomized controlled trial; SNP single nucleotide variant.

a. Sz, schizophrenia.

b. C, clozapine; H, haloperidol; O, olanzapine; P, perphenazine; Q, quetiapine; R, risperidone; Z, zurasidone.

c. Compared with other racial and/or ethnic groups.

Genetic Variants and Efficacy of Antipsychotic Therapies

Twelve articles yielded data examining possible genetic modifiers of response to antipsychotic therapy in Blacks as compared with other groups (Table 3). One study identified a GRM3 genotype associated with significantly improved response to atypical antipsychotic treatment in both Whites and Blacks;48 the response-associated allele is more prevalent among Blacks as compared with Whites.8

A number of detected effects were associated with influence on efficacy in Blacks without significant effects in Whites. Of these, nonresponse or lower response to treatment was associated with a 120 bp tandem repeat in DRD4,42 a G(n) mononucleotide repeat in DRD4,42(p4) and a DRD1 genotype45; the variant in the DRD1 genotype is also more than twice as prevalent among Blacks as compared with Whites.8 STXBP5L was found to be a key locus in association with lurasidone response among Blacks but not Whites in a GWAS of pooled data three trials, while CTNNA2 variation was associated with reduced lurasidone response in both groups (though separate variants in Blacks compared with Whites).51 Another GWAS, involving two of these lurasidone trials, failed to find any variants of genome-wide significance.50

Potential pharmacogenetic markers associated with improved efficacy of atypical antipsychotics among Blacks without a similar association among Whites included two DRD2 variants,46 one DRD2 genotype,47 two DRD2 haplotypes,46,47 a COMT genotype,48 and three variants in RGS4.49 In terms of pharmacogenetic markers predicting improved response to specific therapeutics in Blacks but not Whites, a DTBNP1 SNP was associated with better clozapine response,41 a DTNBP1 genotype associated with improved haloperidol response,41 and a RGS4 genotype associated with duration of treatment continuation as well as specific agent efficacy.49 Several of these variants also differ in prevalence between subgroups; as compared with Whites, the response-associated allele for significant SNPs was at least 10% more prevalent among Blacks for two variants, at least 10% less prevalent for five variants, and roughly similar for two variants.8

Several genetic markers were significantly associated with treatment response in White but not Black participants, including improved treatment response associated with diplotype and haplotype effects in DTNBP1,41 a 48 bp repeat in DRD4,42 and a GNB3 genotype.40

Finally, one study found a DRD1 haplotype predicting lower treatment response among Whites, while a different haplotype in this gene was associated with improved treatment response among Blacks.45

Genetic Variants and Safety of Antipsychotic Therapies

We identified eight studies that included analysis of the potential impact of genetic variation on adverse effects of atypical antipsychotic use among Blacks as compared with other subgroups (Table 4).13,52–58 One secondary analysis of RCT data examined treatment discontinuation due to adverse drug reaction, finding that this outcome correlated significantly with lower activity variants in the FMO3 gene among Blacks treated with olanzapine (P=.01); no similar effect of these variants was observed in the overall cohort or the White subgroup.52 One of these variants has similar prevalence between Blacks and Whites, while the other is more than 10% less prevalent among Blacks.8

Of the four analyses assessing potential genetic variants modifying antipsychotic-associated weight gain, one study indicated increased risk of a DRD2 variant on weight gain among both Whites and Blacks, though the variant is much less prevalent among Blacks.13 Three analyses found significant weight gain risk alleles in Whites that failed to have a significant effect among Blacks, including variants in ADRA2A (both allele and genotype effects),53 FMO3,54 DRD2,13 and TaqIA.13 Three of these risk alleles are less prevalent among Blacks and one is of similar prevalence between Blacks and Whites.8 One study found significantly increased weight gain/appetite among Latin Americans carrying the p.Glu308Gly (rs2266780) FMO3 variant, not observed among Blacks or other subgroups;54 this variant is more common among Latin Americans as compared with Blacks.8

One study found significantly increased risk of weight gain in association with a DRD3 allele13 among Black participants with no significant effect in Whites; the DRD3 allele is also almost two times more prevalent among Blacks. Intriguingly, one study found opposite directionality of effect on weight gain for a variant in CCKBR, identifying increased risk of weight gain with this allele in Blacks but decreased risk of weight gain among Whites55; the risk allele is also >20% less prevalent among Blacks as compared with Whites.8 This same dataset did not find any effect of INSIG2 alleles in either group.56

Of the three articles exploring multiple antipsychotic agents and potential genetic modifiers of risk of antipsychotic-induced movement disorders, one study failed to find significant associations in either Blacks or Whites, including CYP2D6 or CYP1A2*1F effects on risk of tardive dyskinesia.52 Two studies focused on antipsychotic-induced parkinsonism (AIP) and found both an AIP susceptibility allele (G allele of intronic variant g.105503826C>G (rs12678719) in ZFPM2) and a protective allele (G allele of g.192812042C>G (rs4606) in the 3’ untranslated region of RGS2); both variants had significant effects in both the Black subgroup and the overall cohort,57,58 with one being similar prevalence between Blacks and Whites and one >2 times more prevalent among Blacks.8

One study assessed the potential contribution of FMO3 variants to risk of drowsiness during olanzapine therapy; p.Val257Met was associated with risk in the Latin American subgroup (P=.042) but not among Blacks, Whites, or Asians.54

Discussion

This quasi-systematic review mined the literature to assess potential disparities in efficacy- and safety-related characteristics in Blacks compared with other racial or ethnic groups in response to use of atypical antipsychotic agents. We found notable differences in efficacy and safety outcomes between Blacks and other groups for this type of agent. In addition to variability in treatment response, our review detected signals related to increased risk of safety issues in Blacks, such as metabolic issues including weight gain and treatment-associated diabetes, and movement-related adverse effects. While increased risks of these side effects with use of an atypical antipsychotic agent are generally well-known and also acknowledged to be relevant issues in the care of Black patients, disparately increased risks in this subgroup do not appear to be prominently noted in the biomedical literature and may have important clinical implications.

Qualitative analysis of the data also indicates increased risk of neutropenia in Blacks as compared with Whites; given that 25%-50% of Blacks are affected by benign ethnic neutropenia (BEN) and mandatory clozapine monitoring includes specific reference ranges and requirements for this group,59 baseline and periodic laboratory testing may present a particularly key component of safety monitoring in Blacks using an atypical antipsychotic. However, a 2016 systematic review of patients with BEN treated with clozapine indicated no signs of impaired phagocytosis and infection parameters (frequency, severity, outcome) similar to those without BEN; these authors suggested that a neutrophil count >1,000/mm3 is safe for initiation or resumption of clozapine therapy.60 Awareness of these issues can inform clinicians’ approach to monitoring and concomitant interventions in Blacks taking atypical antipsychotics.

Pharmacogenomics analyses illuminated potential genetic contributors to the effects noted above; for example, the same allele associated with decreased risk of weight gain in Whites was associated with increased weight gain among Blacks using antipsychotic therapy.55 Investigators note that this finding may represent a “flip flop” phenomenon, potentially caused by altered linkage disequilibrium between the causal locus and the variants analyzed or underlying variation in frequency of the causal locus in the two populations.55 Further, in two additional studies, the variants associated with increased efficacy among Blacks and Whites differed, with unique variants in each group, suggesting that different polymorphisms contributing to efficacy in these groups.40,48 While potentially an issue of underpowered samples, a number of variants with significant effects among Whites failed to exhibit significant effects among Blacks.

We also observed notable variability in the underlying population frequency of alleles with significant effects among included studies. Blacks’ exposure to some significant alleles, as measured by MAF reported in gnomAD,8 is higher by an absolute 10% or more as compared with Whites, while Blacks’ exposure to other response alleles is lower by 10% or more. This underlying variability in allele carriage was observed in both treatment response- and adverse effect- associated variants. These observations strongly suggest that future pharmacogenomics studies and strategies will need to be intentionally diverse as well as explicitly incorporate consideration of race and ethnicity, rather than simply extrapolating results from Whites to other subgroups.

Study Limitations

Several limitations apply to this pilot review. Included articles exploring racial disparities in safety and efficacy of atypical antipsychotics, as well as genetic modifiers, are affected by relatively low sample sizes especially within subgroups, suggesting that their power to detect the full spectrum of predictors of efficacy and safety among Blacks is somewhat limited. Our search focused on studies analyzing the efficacy or safety of atypical antipsychotics by race and ethnicity; though we identified a number of RCT analyses, there may be additional subgroup analyses in the larger atypical antipsychotic literature that our search and review approach did not capture. As this was a quasi-systematic review, the current approach did not incorporate some systematic review steps that may help mitigate bias, such as risk of bias scoring. Also of note, a significant subset of the studies analyzing atypical antipsychotic effects included multiple reuse and recombination of the same datasets, with unknown impact on risk of false positive signals in the associated analyses. Heterogeneity of atypical antipsychotic agents considered among various studies also precluded quantitative analysis of results beyond the pooled analyses included in this review; additionally, many articles did not detail their approach for defining the Black subgroup of participants, introducing the possibility of further variability that is difficult to estimate. The limited amount of pediatric data also precludes substantive conclusions regarding implications for care of children and adolescents. Further, while analyses of the effects of SNPs and, to a lesser extent haplotypes, seem to predominate in this literature, other related signals such as protein-protein interactions and epigenetics may also hold great promise as the literature evolves. Finally, though this review focused on response disparities among Blacks, we note incidental findings of variability in treatment response and adverse effect among Hispanic and Latino patients reported in some studies, suggesting that additional systematic assessment would be valuable in supporting tailoring of atypical antipsychotic therapy in this subgroup as well.

Conclusions

This review demonstrates an approach for synthesizing existing data to illuminate differential treatment efficacy and safety signals among Blacks as compared with other subgroups. The current analysis can help inform clinician tailoring of patient education and monitoring among Blacks using an atypical antipsychotic agent, including framing a plan for surveillance for neutropenia and potential metabolic issues.

Given the variability in allelic, genotypic, and haplotype-associated effects observed in studies evaluating the effects of this potential modifiers on safety and efficacy of the atypical antipsychotics, this literature further suggests that any pharmacogenetics-based strategies for tailoring selection of a therapeutic will need to explicitly incorporate consideration of race and ethnicity, as different variation characteristics appear to influence treatment efficacy and safety in Blacks as compared with other groups. The wide differences observed in minor allele frequency for some variants, further suggest that the need for development and validation of pharmacogenetic strategies informed by race and ethnicity will be an essential component of future strategies to ensure safety and efficacy of atypical antipsychotic therapy in individual patients.

Future research into hypotheses informed by the signals identified in this review will allow us to better understand biologic underpinnings of variable safety and efficacy of antipsychotics among Blacks, including the import of these effects within each individual’s treatment plan. Such approaches, when applied to appropriately powered datasets, will allow us to continue to advance the ability of precision medicine to truly be applied clinically across the rich diversity of our patient population.

Acknowledgments

This project described was supported by grant U54MD010722 from the National Institute on Minority Health and Health Disparities and the National Human Genome Research Institute and by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Institute on Minority Health and Health Disparities, the National Human Genome Research Institute, the National Center for Advancing Translational Sciences, or the National Institutes of Health.

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