Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Apr 1.
Published in final edited form as: Community Ment Health J. 2021 May 29;58(3):517–525. doi: 10.1007/s10597-021-00847-0

A Comparison of Attitudes, Comfort, and Knowledge of Clozapine Among Two Diverse Samples of US Psychiatrists

Robert O Cotes 1, A Umair Janjua 1, Beth Broussard 1, David Lazris 1, Ayesha Khan 2, Yunshen Jiao 3, Sarah L Kopelovich 4, David R Goldsmith 1
PMCID: PMC9112232  NIHMSID: NIHMS1803186  PMID: 34052963

Abstract

Considerable variation in clozapine utilization exists across the United States, and little is known about the perspective of psychiatrists in states with low clozapine use. To better understand clozapine practices, attitudes, and barriers, a survey was administered to a group of southeastern state conference attendees (SSCA; N = 86). The same survey was administered to psychiatrists belonging to a national community psychiatry organization (AACP; N = 57), and differences were analyzed across the two samples. In comparison to the AACP, the SSCA group felt less comfortable, perceived clozapine as less safe and effective, had fewer patients on clozapine, and were more likely to prefer antipsychotic polypharmacy to clozapine use. Across the sample, use of a myocarditis screening protocol was rare (N = 14/76; 18%) and less than half used plasma antipsychotic levels to guide dosage (N = 60/129; 47%). Continuing professional education on clozapine are needed for psychiatrists who see individuals with psychotic disorders.

Keywords: Clozapine, Prescriber, Attitudes, Schizophrenia

Introduction

Treatment resistant schizophrenia (TRS) is a significant public health concern occurring in approximately 20–30% of individuals with schizophrenia (Conley & Kelly, 2001). In the US, annual costs for individuals with TRS are 3–11 times higher than those with schizophrenia, and TRS contributes more than $34 billion in annual direct medical costs (Kennedy et al., 2014). Clozapine is the only medication approved by the Food and Drug Administration for TRS in patients with schizophrenia (Mylan Pharmaceuticals, 2020). Studies have demonstrated that clozapine may benefit a person’s quality of life, satisfaction with treatment, overall mood, and social abilities (Qurashi et al., 2015; Waserman & Criollo, 2000) as well as reduce aggressive behavior (Krakowski et al., 2006). Most prescribers believe clozapine to be the most effective antipsychotic (Leung et al., 2019).

Despite its superior efficacy in TRS (Kane et al., 1988; McEvoy et al., 2006; Stroup et al., 2016), clozapine remains underutilized in the US. For Medicaid recipients in 2002–2005, clozapine accounted for only 2.5% of antipsychotic prescriptions for individuals with schizophrenia, and 5.5% for individuals with evidence of treatment resistance (Stroup et al., 2014). In a subsequent analysis of Medicaid programs from 2006 to 2009, clozapine accounted for 4.8% of antipsychotic prescriptions for people with schizophrenia (Olfson et al., 2016). In another publicly insured US sample, the proportion of clozapine prescriptions among individuals prescribed antipsychotic medications significantly decreased from 2005 to 2014, while other nations such as Canada, Finland, and Germany reported an increase over a similar period (Bachmann et al., 2017).

Several surveys of prescribers have been developed to better understand the barriers to clozapine use. Reasons for clozapine’s underuse are multifactorial and can be divided into administrative, patient-related, and prescriber-related barriers. Please refer to Fig. 1 for a schematic of barriers to clozapine use. Regarding patient-related barriers, patient reluctance about regular blood work and concerns about side effects are some of the most frequently cited barriers (Gee et al., 2014; Nielsen et al., 2010; Tungaraza & Farooq, 2015). The main barriers for physicians include a lack of prescribing experience, comfort, and training with the medication (Kelly et al., 2018; Nielsen et al., 2010; Verdoux et al., 2018). Physicians who have never prescribed clozapine tend to overestimate the significance of barriers to prescribing in comparison to current prescribers (Kelly et al., 2018). A lack of prescriber comfort with clozapine may postpone a trial in favor of antipsychotic polypharmacy or other treatment options that are not supported by the evidence (Leung et al., 2019).

Fig. 1.

Fig. 1

Open in a new tab

Barriers to clozpaine utlization

There is considerable regional and state by state variation in the use of clozapine in the US. In an analysis of Medicaid recipients with schizophrenia from 2006 to 2009, the percentage of individuals on clozapine varied widely from the state that used clozapine most frequently (16%) to the states that used it least frequently (2%) (Treatment Advocacy Center, 2015). This same analysis demonstrated that the state variation of individuals on clozapine was not a function of people per psychiatrists in that state, and suggested instead that perhaps prescriber attitudes contributed to clozapine’s underutilization (Treatment Advocacy Center, 2015). The vast majority of US surveys examining perspectives on clozapine use and interventions to increase clozapine use have taken place in states that use clozapine either at or above the national average, leaving a gap in the literature about the perspectives of prescribers from low prescribing clozapine states. We therefore sought to examine attitudes, experiences of training, knowledge, and perceived barriers about clozapine from psychiatrists practicing in a low-clozapine prescribing state. Furthermore, we wanted to compare those perspectives with a group of psychiatrists from a guild community psychiatry organization that we hypothesized would be more familiar with using clozapine. Insights from these cohorts will help us better target educational interventions for prescribers who treat people with psychosis, and promote greater clozapine use.

Methods

Sample

The clozapine prescriber survey consisted of a total of 31 items querying personal and professional demographics, clozapine prescribing practices, formal clozapine training or education, knowledge about clozapine, and perceptions of clozapine’s safety and efficacy. Responses were a combination of multiple-choice, Likert scale, and open-ended. The complete survey can be found in the supplemental materials. The survey was sent out to the American Association of Community Psychiatrists (AACP) listserv in three waves (11/10/2015, 12/8/2015, and 8/8/2016). As of 8/29/2016, the AACP had 550 active email members. Fifty-seven surveys were collected, yielding a response rate of 10.3%. In addition, the survey was administered in paper-and-pencil form to attendees of a southeastern state’s semi-annual psychiatric conference in 2015. The group of southeastern state conference attendees (SSCA) completed 98 surveys. Prescribers who said they did not work with individuals with psychotic disorders were excluded from the analysis (SSCA N = 11; AACP N = 0). In total, 143 surveys were included in the final analysis (SSCA N = 86; AACP N = 57). No compensation was offered to either group. Informed consent was obtained from each of the participants and the study was deemed exempt by the Emory University Institutional Review Board.

Statistical Methods

Statistical analyses were conducted using IBM SPSS Statistics version 26 (Chicago, IL). Results are reported with descriptive statistics where appropriate. Student’s t-tests were used for normally distributed continuous variables, and Chi-square or Fisher’s exact tests were used for categorical variables. All authors certify responsibility for the contents herein.

Results

Demographic Characteristics

The AACP and SSCA groups were compared across demographic variables, areas of expertise, and practice characteristics (Table 1). Between the two groups, there was no difference between the mean respondent age and mean number of years after training. AACP respondents were more likely to work in an outpatient setting [X2 (1, N = 143) = 20.99, p < 0.001], were more likely to report having a majority of their caseloads comprised of people with psychotic disorders [X2 (1, N = 101) = 11.86, p = 0.001], and were more likely to endorse clinical expertise in schizophrenia spectrum disorders [X2 (1, N = 143) = 11.35, p = 0.001]. There were fewer trainees in the SSCA group (p = 0.028). Regarding primary payer source, the AACP group was more likely to work with individuals receiving Medicaid/Medicare [X2 (1, N = 143) = 44.91, p < 0.001], whereas the SSCA group was more likely to see people with commercial insurance [X2 (1, N = 143) = 5.65, p = 0.017] or see people who pay for services out-of-pocket [X2 (1, N = 143) = 10.31, p = 0.001]. Less than half of the respondents in each group (43% SSCA, 48% AACP) had access to on-site phlebotomy, and this proportion was not significantly different across the two groups.

Table 1.

Characteristics of respondents, stratified by group

Variable AACP (N = 57) SSCA (N = 86) p-valuea
Male (N, %) 31 (54.4%) 48 (55.8%) .866
Age (years; M, SD) 50.7 ± 13.9 55.2 ± 13.9 .066
Trainee (N, %) 8 (14.0%) 3 (3.5%) .028b
Years post residency (M, SD) 18.8 ± 13.6 21.6 ± 14.3 .113
Area of clinical expertise
  Child and adolescent (N, %) 7 (12.3%) 31 (36.0%) .002
  Forensic (N, %) 1 (1.8%) 11 (12.8%) .028b
  General adult (N, %) 50 (87.7%) 75 (87.2%) .928
  Mood and anxiety (N, %) 12 (21.1%) 30 (34.9%) .075
  Psychotherapy (N, %) 4 (7.0%) 15 (17.4%) .072
  Schizophrenia (N, %) 28 (49.1%) 19 (22.1%) .001
Practice setting
  Forensic (N, %) 1 (1.8%) 2 (2.3%) 1.000b
  Inpatient (N, %) 15 (26.3%) 21 (24.4%) .798
  Outpatient (N, %) 54 (94.7%) 52 (60.5%) < .001
Primary payer source
  Commercial insurance (N, %) 9 (15.8%) 29 (33.7%) .017
  Medicaid/medicare (N, %) 51 (89.5%) 28 (32.6%) < .001
  Out of pocket (N, %) 4 (7.0%) 25 (29.1%) .001b
  Uninsured (N, %) 18 (31.6%) 18 (20.9%) .272
  Majority pts psychotic d/o (N, %)c 30 (53.6%) 9 (20.0%) .001
Open in a new tab

AACP American Association of Community Psychiatrists; SSCA southeastern state conference attendees; pts patients; D/o disorder

a

p-values Pearson Chi-Square for categorical variables, two two-tailed t-test for continuous variables

b

Fisher’s exact test

c

Denominator for AACP group 56 and SSCA group 45

Clozapine Perceptions and Use

When comparing the two groups, we found key differences in perceptions and use of clozapine. In two separate questions, respondents were asked to rate the safety and efficacy of clozapine on a scale of 0–10 (10 being most safe and effective). The SSCA group rated clozapine lower on safety (M = 6.29, SD = 1.94) than the AACP group (M = 7.04, SD = 1.71), t(136) = 2.32, p = 0.022. The SSCA group also rated clozapine lower on efficacy (M = 8.51, SD = 1.11) than the AACP group (M = 8.98, SD = 1.02), t(137) = 2.57, p = 0.011. About two-thirds (64%) of the SSCA group felt “somewhat comfortable” or “comfortable” with clozapine, whereas nearly all (95%) members of the AACP group reported feeling “somewhat comfortable” or “comfortable” with clozapine, X2 (1, N = 141) = 17.57, p < 0.001. There was not a significant difference on how the two groups viewed their patients’ satisfaction on clozapine, as 72% of the SSCA group and 75% of the AACP group felt that their patients were more satisfied on clozapine compared to other antipsychotic medication. Members of the SSCA group reported treating fewer patients with clozapine (M = 1.79, SD = 3.22) than AACP members (M = 11.09, SD = 17.85), t(54) = 3.75, p < 0.001.

Clinical Practice Patterns with Clozapine

Prescribers were asked about practice patterns and adherence to evidence-based practices regarding clozapine (Table 2). When prescribers were asked if they would rather use clozapine versus combine two antipsychotic medications, 79% of the AACP group would rather use clozapine, whereas 48% of the SSCA group would rather use clozapine, X2 (1, N = 130) = 13.00, p < 0.001. Nearly two-thirds (63%) of the AACP group would opt for clozapine after two or fewer failed antipsychotic trials, while only one-third (33%) of the SSCA group would prescribe clozapine after two or fewer failed antipsychotic trials, X2 (1, N = 139) = 12.40, p < 0.001. If a patient were suicidal, 43% of the AACP group would prescribe clozapine after one other antipsychotic failure, versus 26% of the SSCA group, X2 (1, N = 132) = 3.97, p = 0.046. The AACP group was more likely to use plasma clozapine levels to guide dosing than the SSCA group (64% vs 33%), X2 (1, N = 129) = 12.57, p < 0.001. Additionally, the AACP group was more likely to start clozapine in the outpatient setting in comparison to the SSCA group (88% vs 71%), X2 (1, N = 130) = 5.15, p = 0.023. The SSCA group was more likely to use a myocarditis screening protocol than the AACP (18% vs 8%) but this difference was not statistically significant. When asked about the maximum daily dose of clozapine used (mg), members of the AACP group would use a higher dose (M = 736.96, SD = 215.36) than the SSCA group (M = 590.53, SD = 226.68), t(91) = 3.2, p < 0.002.

Table 2.

Clozapine clinical practice patterns of respondents, stratified by group

Variable Total AACP SSCA p-valuea
Rather use clozapine than combine two antipsychotic drugs (N, %) 80 (61.5%) 35 (47.9%) 45 (78.9%) < .001
Uses clozapine after two or fewer antipsychotic failures (N, %) 63 (45.3%) 36 (63.2%) 27 (32.9%) < .001
Would use clozapine after one antipsychotic failure with a suicidal patient (N, %) 44 (33%) 24 (42.9%) 20 (26.3%) .046
Uses plasma clozapine levels to guide dosing (N, %) 60 (46.5%) 36 (64.3%) 24 (32.9%) < .001
Would start clozapine in an outpatient setting (N, %) 102 (78.5%) 50 (87.7%) 52 (71.2%) .023
Uses a myocarditis screening protocol (N, %) 19 (14.3%) 5 (8.8%) 14 (18.4%) .116
Maximum dose of clozapine used, mg (M, SD) 662 ± 231 737 ± 215 590 ± 226 .002
Open in a new tab

AACP American Association of Community Psychiatrists; SSCA southeastern state conference attendees

a

Comparison between AACP and SSCA groups. p-values Pearson Chi-Square for categorical variables, two two-tailed t-test for continuous variables

When allowing a correct answer for the one-year incidence of agranulocytosis as a range of 0.018–2%, 87% of the AACP group answered this correctly versus 36% of the SSCA group, X2 (1, N = 111) = 29.21, p < 0.001). For the SSCA group, 50% overestimated the rate of agranulocytosis, 6% underestimated the rate, and 8% reported they did not know the rate of agranulocytosis. Within the AACP group, 11% overestimated the risk of agranulocytosis and 2% underestimated the risk.

Active versus Inactive Clozapine Prescribers

Active clozapine prescribers were defined as prescribers who prescribed clozapine in the past month. Respondents who prescribed clozapine in the past month thought clozapine was safer (M = 6.93, SD = 1.70) versus those who did not (M = 6.07, SD = 2.04), t(136) = 2.67, p < 0.009. Additionally, respondents who prescribed clozapine in the past month thought clozapine was more effective (M = 8.88, SD = 1.13) than those who did not [M = 8.42, SD = 0.98), t(137) = 2.48, p = 0.014. Nearly all (95%) active clozapine prescribers rated themselves as “somewhat comfortable” or “comfortable” with clozapine, whereas about half (48%) of those who were not active prescribers rated themselves as either “somewhat comfortable” or “comfortable”, X2 (1, N = 141) = 41.74, p = < 0.001]. There was no difference in age for individuals who prescribed clozapine in the past month versus those who did not, nor in number of years post-residency training.

Members of the AACP group were more likely to be active prescribers of clozapine than the SSCA group (90% vs 40%), X2 (1, N = 143) = 35.46, p < 0.001. Of active prescribers, the SSCA group prescribed clozapine to a mean of 3.94 (SD = 4.21) patients, while the AACP prescribed clozapine to a mean of 11.98 (SD = 18.30) patients, t(56) = 2.96, p = 0.005. Both AACP and SSCA groups felt that their patients were more satisfied being treated with clozapine in comparison to other antipsychotic medications (78% and 94%). No one in either group of active prescribers responded that their patients were less satisfied on clozapine when compared to other antipsychotics.

Impact of Clozapine Training During Residency

Overall, just over one-fifth of respondents (22%) received formal training in clozapine during residency. SSCA respondents were more likely than AACP respondents to received clozapine training in residency (26% vs 15%) but the difference was not statistically significant. For those that received residency training in clozapine, there was no difference in usage of clozapine within the past month, perceptions about clozapine’s safety or efficacy, comfort with clozapine, or knowledge about clozapine in comparison to those who did not receiving training in residency. Among our small sample of trainees (N = 11), 91% reported feeling “somewhat comfortable” or “comfortable” using clozapine. Trainees were more likely to receive specialized training in clozapine in comparison to non-trainees (50% versus 20%) but the difference was not statistically significant.

Clozapine Barriers

Respondents were asked to rank the top three barriers to prescribing clozapine as a free text response, assigning 1 to the most significant, 2 to the second most significant, and 3 to the third most significant (Fig. 2). If a participant assigned a 1, 2, or 3 to a barrier it was classified as a top three barrier. For the total sample, the most common barrier that appeared in the top three of respondents’ selections was obtaining routine hematologic monitoring (74%). Just under half (44%) of the sample identified hematologic monitoring as the most significant barrier. Side effects and medication adherence were the second and third most common barriers that appeared in the top three (47% and 19%, respectively).

Fig. 2.

Fig. 2

Open in a new tab

Barriers to clozapine use. Respondents (N = 138) were asked to rank their top three most significant barrier with rank 1 being the most significant

When comparing the AACP and SSCA perceptions of barriers, labs and side effects were the number one and number two most commonly reported barriers for both groups. There were some differences in perceptions of the barriers between the two groups when looking at the top three barriers identified. The AACP group was more likely to report routine hematologic monitoring (89% vs 65%, X2 (1, N = 138) = 9.73, p = 0.002), issues with the registry (13% vs 4%, p = 0.044), and agreement from the client to take the medication as barriers than the SSCA group (17% vs 6%, X2 (1, N = 138) = 4.41, p = 0.036). The SSCA group was more likely to report not seeing that patient population than the AACP group (18% vs 0%, X2 (1, N = 138) = 10.49, p = 0.001).

Discussion

We surveyed members of a community psychiatry guild organization (AACP) and cohort of psychiatrists in a low-clozapine prescribing state (SSCA) to better understand clozapine prescribing patterns, perceived barriers to its use, and knowledge about the medication. Administration of the same survey to two different groups revealed a stark contrast in perspectives. In comparison to the SSCA, the AACP group reported greater comfort prescribing clozapine, felt clozapine was safer and more effective, had more clients on clozapine on average, and was more likely to prescribe clozapine in accordance with evidence-based practices.

The AACP group was more likely than the SSCA to utilize clozapine after two antipsychotic failures, a recommendation that is supported by US and international guidelines (American Psychiatric Association, 2020; Howes et al., 2017; National Institute for Health & Care Excellence, 2014). In our total sample, only 44% of respondents indicated they would use clozapine after two antipsychotic failures, which may be relevant for when, or if, individuals are started on clozapine. Delaying a trial of clozapine could have considerable clinical ramifications. There is limited evidence available from North American settings which detail the length of time until clozapine initiation. However, in a Canadian sample, the median length of treatment prior to clozapine use was 8.9 years in males and 7.7 years in females, with 68% of patients having tried three or more antipsychotics prior to clozapine (Alessi-Severini et al., 2013). Early identification of TRS may have implications for how individuals may respond to clozapine, as in a Danish registry study, each prior antipsychotic trial resulted in a 8–11% lower likelihood of response to clozapine (Nielsen et al., 2012).

Underutilization of clozapine and overutilization of antipsychotic polypharmacy without justification may be an indicator for poor quality of care (The Joint Commission, 2020). Over half (52%) of SSCA respondents would prefer to combine two antipsychotics instead of using clozapine. Antipsychotic polypharmacy is common among individuals with schizophrenia and is widespread in the southeastern US (Cotes et al., 2018). Although there may be situations where antipsychotic polypharmacy may be a consideration (Foster & King, 2020), about two-thirds of patients receiving two antipsychotics may safely be converted to a single antipsychotic (Essock et al., 2011). For people with TRS, antipsychotic polypharmacy should not be attempted without a trial of clozapine monotherapy. Prescribers who preferentially combine non-clozapine antipsychotics may be a key group to target with educational initiatives.

Regarding prescribing practices, a myocarditis screening protocol was infrequently used by members of either group. Significant variation exists in myocarditis case detection rates around the world, generally with a higher incidence and mandatory screening in Australia (Dawson et al., 2018). Some have called for a screening protocol to be used during clozapine initiation (Goldsmith & Cotes, 2017; Ronaldson et al., 2011), yet recommendations still vary about what measures this protocol should entail (Knoph et al., 2018). In the last five years, more research has been published about myocarditis, potentially increasing awareness, and psychiatrist screening practices may have changed since the time the survey was administered. Therapeutic drug monitoring was used significantly more frequently by the AACP group and may also reflect a measure of comfort and familiarity with the medication. Both US and international guidelines support using therapeutic drug monitoring for clozapine (American Psychiatric Association, 2020; Hiemke et al., 2018) to guide dosing adjustments and to monitor for adherence.

Only a minority of respondents received specialized training during residency on clozapine. Training in residency was not associated with clozapine comfort, number of patients on clozapine, perceptions on clozapine’s safety or efficacy, or clozapine knowledge. We caution over-interpretation of this association, which could be explained by differences in practice settings, recall bias, and a small sample size (only 29 respondents received training). Many prescribers without formal training in residency were able to utilize clozapine effectively, with confidence, and prescribed clozapine to many individuals. Given that our respondents were, on average, approximately 20 years post-residency, it is possible that many had engaged in self-directed learning or formal continuing education on clozapine. Among our small sample of trainees, nearly all reported feeling “somewhat comfortable” or “comfortable” using clozapine, which may reflect the increasing prevalence of clozapine education and training in residency programs in the US. In their report, “Clozapine Utilization: Addressing Barriers,” the National Association of State Mental Health Program Directors advocated for psychiatry residents to receive clozapine didactics, a requirement to be registered with REMS, and to also have clinical experiences treating and monitoring individuals on clozapine (2016). However, a recent sample of 164 psychiatry residents found 59% of the individuals surveyed felt either very uncomfortable or somewhat uncomfortable with clozapine, and 38% endorsed inadequate training on how to use clozapine as the main factor in delaying clozapine initiation (Singh et al., 2020). This variability in self-perceived comfort in clozapine prescribing across samples affirms the prioritization of clozapine education during residency training.

The main barriers reported by both groups, routine hematologic monitoring and side effects, were consistent with common barriers reported elsewhere (Gee et al., 2014; Verdoux et al., 2018). Although the perception of barriers between the two different groups did not vary dramatically, compared to the national sample of community psychiatrists, the state-based sample were more likely to endorse inaccessibility of their patients, patient non-consent to clozapine, and labs as barriers to clozapine prescribing. These responses may reflect patient and administrative barriers in this low-prescribing state but cannot be disentangled from the provider’s perception about the medication itself (i.e. less confidence in the medication, greater perception of barriers). Although only respondents who indicated they saw individuals with psychotic disorders were included in the analysis, when asked about barriers, 11% of the SSCA group said not treating the patient population was a barrier to clozapine use. If up to a third of people with schizophrenia have TRS, any prescriber who sees individuals with psychotic disorders should be prepared for the possibility of seeing someone who would benefit from clozapine.

A number of approaches have been utilized to overcome barriers and expand clozapine use, which may be of importance to mental health administrators, especially in low-prescribing states. In one large-scale initiative, New York State developed manuals for clinicians, made statewide grand round presentations, and had telephone consultation services during weekday business hours, and demonstrated a 40% increase in clozapine use among patients with a diagnosis of schizophrenia (Carruthers et al., 2016). The development of clozapine clinics can play a role in consolidating knowledge, streamlining processes, offering trainees an opportunity to use clozapine in residency, and can help individuals and families with psychoeducation (Hughes & Singh, 2016). Prescriber education should expand beyond residents and should include psychiatrists who identify as general practitioners who see clients with psychotic disorders. Coordination should occur with psychiatric pharmacists (Kelly & Love, 2019) and between inpatient and outpatient settings. Strategies such as audit and feedback have been employed successfully to increase clozapine use and improve antipsychotic prescribing (Wheeler et al., 2009).

Limitations

This study has a number of weaknesses including a cross-sectional design. Several key characteristics between the two samples could contribute to the differences in clozapine perceptions, utilization, and comfort. For example, the AACP group was far more likely to work with a caseload that included the majority of people who had a diagnosis of a psychotic disorder. By seeing more individuals with psychotic disorders, it is possible the AACP group saw a wider range of presentations of psychotic disorders, were more familiar identifying and treating individuals with TRS, and could better identify clozapine candidates. In contrast, the SSCA group was more likely to have an area of expertise working with children and adolescents, a setting where schizophrenia may be encountered less frequently, and prescribers have less familiarity with clozapine. Additional limitations of this study include a small sample size in comparison to other studies conducted on prescriber attitudes on clozapine. There was a low participation rate in the AACP sample, which was recruited through listserv emails. Different recruitment methods, such as the pencil and paper method used for the SSCA could be used in future studies in an effort to increase participation. The SSCA group represents about a fifth of the state’s psychiatrists and it is unclear how these attitudes translate to the rest of the state’s psychiatrists whose perspectives were not captured. We cannot exclude the possibility that prescribers in either group may have over or underestimated their clozapine prescribing in the self-report survey. Further research could consider matching prescriber perceptions with data pulled from the electronic medical record about clozapine utilization or how often appropriate monitoring took place. Despite these limitations, however, the current study still adds important evidence to the growing literature.

Conclusions

The national sample of community psychiatrists were significantly more knowledgeable and more likely to engage in evidence-based prescribing practices than the sample of prescribers from a low-utilization clozapine state. Focused educational efforts are still needed to help prescribers identify appropriate clozapine candidates and use the medication with confidence.

Supplementary Material

Supplementary Material

Acknowledgements

The authors would like to thank the survey participants. The authors would also like to acknowledge Maya Sternberg for her contribution to the data analysis of this project.

Funding

No funding was received for conducting the study. Outside of this work, Dr. Cotes received research funding from Otsuka, Roche, Alkermes, and Lundbeck Pharmaceuticals, and is a consultant to Saladax Biomedical. The remaining authors have nothing to disclose.

Footnotes

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s10597-021-00847-0.

References

  1. Alessi-Severini S, Le Dorze J-A, Nguyen D, Honcharik P, & Eleff M (2013). Clozapine prescribing in a Canadian outpatient population. PLoS ONE, 8(12), e83539–e83539. 10.1371/journal.pone.0083539 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. American Psychiatric Association. (2020). The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia, third edition. https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines
  3. Bachmann CJ, Aagaard L, Bernardo M, Brandt L, Cartabia M, Clavenna A, & Taylor D (2017). International trends in clozapine use: A study in 17 countries. Acta Psychiatrica Scandinavica, 136(1), 37–51. 10.1111/acps.12742 [DOI] [PubMed] [Google Scholar]
  4. Carruthers J, Radigan M, Erlich MD, Gu G, Wang R, Frimpong EY, Essock SM, Olfson M, Castillo EG, Miller GA, Sederer LI, & Stroup TS (2016). An initiative to improve clozapine prescribing in New York state. Psychiatric Services, 67(4), 369–371. 10.1176/appi.ps.201500493 [DOI] [PubMed] [Google Scholar]
  5. Conley RR, & Kelly DL (2001). Management of treatment resistance in schizophrenia. Biological Psychiatry, 50(11), 898–911. 10.1016/s0006-3223(01)01271-9 [DOI] [PubMed] [Google Scholar]
  6. Cotes RO, Goldsmith DR, Kopelovich SL, Lally CA, & Druss BG (2018). Characteristics of medicaid recipients receiving persistent antipsychotic polypharmacy. Community Mental Health Journal, 54(6), 699–706. 10.1007/s10597-017-0183-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dawson JL, Clark SR, Sluggett JK, Procter NG, & Bell JS (2018). Is the higher incidence of clozapine induced myocarditis in Australia due to awareness and monitoring? Schizophrenia Research, 201, 426–427. 10.1016/j.schres.2018.05.044 [DOI] [PubMed] [Google Scholar]
  8. Essock SM, Schooler NR, Stroup TS, McEvoy JP, Rojas I, Jackson C, & Covell NH (2011). Effectiveness of switching from antipsychotic polypharmacy to monotherapy. American Journal of Psychiatry, 168(7), 702–708. 10.1176/appi.ajp.2011.10060908 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Foster A, & King J (2020). Antipsychotic polypharmacy. Focus, 18(4), 375–385. 10.1176/appi.focus.20190047 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gee S, Vergunst F, Howes O, & Taylor D (2014). Practitioner attitudes to clozapine initiation. Acta Psychiatrica Scandinavica, 130(1), 16–24. 10.1111/acps.12193 [DOI] [PubMed] [Google Scholar]
  11. Goldsmith DR, & Cotes RO (2017). An unmet need: A clozapine-induced myocarditis screening protocol. The Primary Care Companion for CNS Disorders. 10.4088/PCC.16l02083 [DOI] [PubMed] [Google Scholar]
  12. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J , Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Gründer G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T,…Baumann P (2018). Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry, 51(1-02), 9–62. 10.1055/s-0043-116492 [DOI] [PubMed] [Google Scholar]
  13. Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA , Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P,…Correll CU (2017). Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. American Journal of Psychiatry, 174(3), 216–229. 10.1176/appi.ajp.2016.16050503 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hughes A, & Singh B (2016). Clozapine clinic: The need of the hour. American Journal of Psychiatry Residents Journal, 11(7), 3–3. 10.1176/appi.ajp-rj.2016.110702 [DOI] [Google Scholar]
  15. Kane J, Honigfeld G, Singer J, & Meltzer H (1988). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry, 45(9), 789–796. [DOI] [PubMed] [Google Scholar]
  16. Kelly DL, Ben-Yoav H, Payne GF, Winkler TE, Chocron SE, Kim E, Kitchen C, Stock V, Vyas G, Love RC, Wehring HJ, Sullivan KM, Feldman S, Liu F, McMahon RP, & Ghodssi R (2018). Blood draw barriers for treatment with clozapine and development of a point-of-care monitoring device. Clinical Schizophrenia & Related Psychoses, 12(1), 23–30. 10.3371/csrp.Kebe.070415 [DOI] [PubMed] [Google Scholar]
  17. Kelly DL, & Love RC (2019). Psychiatric pharmacist’s role in overcoming barriers to clozapine use and improving management. Mental Health Clinician, 9(2), 64–69. 10.9740/mhc.2019.03.064 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kennedy JL, Altar CA, Taylor DL, Degtiar I, & Hornberger JC (2014). The social and economic burden of treatment-resistant schizophrenia: A systematic literature review. International Clinical Psychopharmacology, 29(2), 63–76. 10.1097/YIC.0b013e32836508e6 [DOI] [PubMed] [Google Scholar]
  19. Knoph KN, Morgan RJ 3rd., Palmer BA, Schak KM, Owen AC, Leloux MR, Patel M, & Leung JG (2018). Clozapine-induced cardiomyopathy and myocarditis monitoring: A systematic review. Schizophrenia Research, 199, 17–30. 10.1016/j.schres.2018.03.006 [DOI] [PubMed] [Google Scholar]
  20. Krakowski MI, Czobor P, Citrome L, Bark N, & Cooper TB (2006). Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry, 63(6), 622–629. 10.1001/archpsyc.63.6.622 [DOI] [PubMed] [Google Scholar]
  21. Leung JG, Cusimano J, Gannon JM, Milgrom O, Valcourt SC, Stoklosa JB, Kemp M, Olsufka W, Vickery PB, Nichols SD, Crouse EL, Paxos C, Johnson EK, & Palmer BA (2019). Addressing clozapine under-prescribing and barriers to initiation: A psychiatrist, advanced practice provider, and trainee survey. International Clinical Psychopharmacology, 34(5), 247–256. 10.1097/YIC.0000000000000269 [DOI] [PubMed] [Google Scholar]
  22. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK, & CATIE Investigators. (2006). Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. American Journal Psychiatry, 163(4), 600–610. 10.1176/appi.ajp.163.4.600 [DOI] [PubMed] [Google Scholar]
  23. Mylan Pharmaceuticals. (2020). Clozapine drug label information. Retrieved December 11, 2020, fromhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=883b5d43-0339-7dc1-f775-93791fb9b978.
  24. National Association of State Mental Health Program Directors. (2016). Clozapine underutilization: Addressing the barriers. Retrieved December 11, 2020, from https://www.nasmhpd.org/sites/default/files/Assessment%201_Clozapine%20Underutilization.pdf
  25. National Institute for Health and Care Excellence. (2014). Psychosis and schizophrenia in adults: Prevention and management. Retrieved December 21, 2020, from https://www.nice.org.uk/guidance/cg178/chapter/1-Recommendations#subsequent-acute-episodes-of-psychosis-or-schizophrenia-and-referral-in-crisis-2 [PubMed]
  26. Nielsen J, Dahm M, Lublin H, & Taylor D (2010). Psychiatrists’ attitude towards and knowledge of clozapine treatment. Journal of Psychopharmacology, 24(7), 965–971. 10.1177/0269881108100320 [DOI] [PubMed] [Google Scholar]
  27. Nielsen J, Nielsen RE, & Correll CU (2012). Predictors of clozapine response in patients with treatment-refractory schizophrenia: Results from a Danish Register Study. Journal of Clinical Psychopharmacology, 32(5), 678–683. 10.1097/JCP.0b013e318267b3cd [DOI] [PubMed] [Google Scholar]
  28. Olfson M, Gerhard T, Crystal S, & Stroup TS (2016). Clozapine for schizophrenia: State variation in evidence-based practice. Psychiatric Services, 67(2), 152. 10.1176/appi.ps.201500324 [DOI] [PubMed] [Google Scholar]
  29. Qurashi I, Stephenson P, Chu S, Duffy C, Husain N, & Chaudhry I (2015). An evaluation of subjective experiences, effects and overall satisfaction with clozapine treatment in a UK forensic service. Therapeutic Advances in Psychopharmacology, 5(3), 146–150. 10.1177/2045125315581996 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, & McNeil JJ (2011). A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Australian and New Zealand Journal of Psychiatry, 45(6), 458–465. 10.3109/00048674.2011.572852 [DOI] [PubMed] [Google Scholar]
  31. Singh B, Hughes AJ, & Roerig JL (2020). Comfort level and barriers to the appropriate use of clozapine: A preliminary survey of US psychiatric residents. Academic Psychiatry, 44(1), 53–58. 10.1007/s40596-019-01134-7 [DOI] [PubMed] [Google Scholar]
  32. Stroup TS, Gerhard T, Crystal S, Huang C, & Olfson M (2014). Geographic and clinical variation in clozapine use in the United States. Psychiatric Services, 65(2), 186–192. 10.1176/appi.ps.201300180 [DOI] [PubMed] [Google Scholar]
  33. Stroup TS, Gerhard T, Crystal S, Huang C, & Olfson M (2016). Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. American Journal of Psychiatry, 173(2), 166–173. 10.1176/appi.ajp.2015.15030332 [DOI] [PubMed] [Google Scholar]
  34. The Joint Commission. (2020). Hospital-based inpatient psychiatric measures. Retrieved December 31, 2020, from https://www.jointcommission.org/measurement/measures/hospital-based-inpatient-psychiatric/
  35. Treatment Advocacy Center. (2015). Clozapine for treating schizophrenia: A comparison of the states. Retrieved December 14, 2020, from http://www.treatmentadvocacycenter.org/storage/documents/clozapine-for-treating-schizophrenia.pdf
  36. Tungaraza TE, & Farooq S (2015). Clozapine prescribing in the UK: Views and experience of consultant psychiatrists. Therapeutic Advances in Psychopharmacology, 5(2), 88–96. 10.1177/2045125314566808 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Verdoux H, Quiles C, Bachmann CJ, & Siskind D (2018). Prescriber and institutional barriers and facilitators of clozapine use: A systematic review. Schizophrenia Research, 201, 10–19. 10.1016/j.schres.2018.05.046 [DOI] [PubMed] [Google Scholar]
  38. Waserman J, & Criollo M (2000). Subjective experiences of clozapine treatment by patients with chronic schizophrenia. Psychiatric Services, 51(5), 666–668. 10.1176/appi.ps.51.5.666 [DOI] [PubMed] [Google Scholar]
  39. Wheeler A, Humberstone V, Robinson E, Sheridan J, & Joyce P (2009). Impact of audit and feedback on antipsychotic prescribing in schizophrenia. Journal of Evaluation in Clinical Practice, 15(3), 441–450. 10.1111/j.1365-2753.2008.01032.x [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material
NIHMS1803186-supplement-Supplementary_Material.doc (67KB, doc)

RESOURCES