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Insulin resistance of unknown mechanism was first reported in patients with schizophrenia 55 years ago.[[1]] Modern atypical antipsychotics further increase the risk of diabetes through multiple mechanisms, but principally weight gain via central actions causing changes to leptin, adiponectin and ghrelin levels, and peripheral inhibition of glucose transport.[[2,3]] Clozapine and olanzapine are the atypical antipsychotics with the highest risk of causing diabetes.[[4]] Clozapine is unique in that it has superior efficacy for treatment resistant schizophrenia (failure to respond to at least two antipsychotic medications over at least six weeks each), and it is the only antipsychotic associated with decreased risk of attempted and completed suicide.[[5]] Meta-analysis shows lower long-term all-cause mortality compared with other antipsychotics, despite increased metabolic syndrome.[[6]] Furthermore, all patients on clozapine require long-term monthly lab tests to check for the rare, but potentially fatal, idiosyncratic side effect of neutropenia.[[7]] In New Zealand, a database is maintained to ensure all patients are monitored; therefore, all patients on clozapine in our region, Northland, New Zealand, are captured. As well as monthly full blood count, the recommendation is that patients on clozapine are screened for diabetes with HbA1c at baseline, three and six months after commencement of clozapine and then yearly.

Methods

We evaluated all Northland, New Zealand patients receiving clozapine in September 2021. We used the clozapine database that is an accurate record of all patients prescribed clozapine in our region, hospital and general practice records to obtain demographic data, including age, sex, ethnicity, duration of treatment; when available body mass index (BMI) and change of BMI using the formula BMI=kg/m[[2]], where kg is a person’s weight in kilograms, and m[[2]] is their height in meters squared; co-administration of other antipsychotics; HbA1c results close to commencement of clozapine and most recent HbA1c. In New Zealand, diabetes is diagnosed with HbA1c of 50mmol/mol or greater on two occasions unless symptomatic: pre-diabetes HbA1c 41–49 mmol/mol. The data analysis was performed in the R programming software. Results are reported as mean (range; standard deviation). Analysis of variance (ANOVA) and Pearson correlation coefficient was used to compare between two or more groups for any quantitative data.

Results

Two hundred and eighty-seven Northland patients with schizophrenia were prescribed clozapine at the time of the audit. Sixty-five point eight five percent were NZ Māori (Māori make up 35.8% of general Northland population), and 30.66% NZ European; 66.89% were male. Māori were younger—mean age 42 years (range 19–74; standard deviation (SD) 12)—compared to NZ Europeans—mean age 49 years (range 17-82; SD 15). Only 5.23% of the cohort had not obtained an HbA1c within the preceding two years. The majority of tests were requested by hospital mental health providers rather than through primary care.

The average current HbA1c of the entire cohort was 45mmol/mol (range 27–117, SD 17); in Māori the average current HbA1c was 48, in NZE 40mmol/mol (Figure 1).

Figure 1: The box plot representing the HbA1c results in relation to each ethnicity. The dashed line represent the average HbA1c results of the entire sample (n =287).

The average HbA1c remained higher for females in the ethnicity group compared to males (Table 1, Figure 2).

Figure 2: Average HbA1c in relation to each ethnicity based on gender.

Twenty-six point four eight percent of the cohort had diabetes: one patient had type one diabetes diagnosed before commencement of clozapine and 75 type two diabetes; an additional 42 patients (14.63 %) had pre-diabetes. In Northland’s general population, approximately 6% have known diabetes.

Of the 118 patients with dysglycaemia, 19 (16.10 %) had diabetes or pre-diabetes at the time of commencement of clozapine; all those with pre-clozapine diabetes had a confirmed diagnosis. For the remaining 99 patients, diabetes/pre-diabetes was diagnosed 1–26 years after starting treatment (median six years; only six patients within the first year). For those with diabetes, 85.53% were Māori; control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41–117).

BMI data was available for 92% patients with diabetes/pre-diabetes. The average BMI was 37kg/m[[2]] for Māori compared to 32kg/m[[2]] in NZ Europeans (range 21–63, SD 8) (Figure 3).

Figure 3: The box plot representing BMI between Māori and NZ Europeans.

There was a moderate relationship between clozapine use and increasing BMI (Pearson’s correlation coefficient of 0.74); however, further studies are needed to establish a consistent relation between increase in BMI with clozapine for the Northland population.

Forty point four two percent of the entire cohort were co-prescribed an additional antipsychotic agent. Limitations in analysis did not determine whether the antipsychotic polypharmacy was as part of a time limited strategy or a maintenance regime. Of concern for 23 patients, olanzapine was prescribed with clozapine. Olanzapine has a high rate of weight gain and increased risk of diabetes. Of the patients prescribed both olanzapine and clozapine, four had diabetes, five pre-diabetes which was not an increased risk for dysglycaemia compared to the whole cohort.

Discussion

Forty-one percent of Northland schizophrenia patients on clozapine have either diabetes or pre-diabetes. The majority have type two diabetes, are obese and have poor glycaemic control. Māori are vastly over-represented and develop diabetes at a younger age than NZ Europeans. Given these results, the choice of clozapine does not appear to be influenced by pre-existing metabolic status, but rather on psychiatric indications. Our results are similar to a 21-year American study of 96 patients that showed a 43% rate of diabetes particularly in Hispanic and African Americans on clozapine.[[8]]

There are challenges to ensuring appropriate physical healthcare for patients with severe schizophrenia. Persistent psychotic symptoms can impact on the ability of patients to trust and engage with healthcare providers. The symptoms can also have an impact on the ability of the patients to engage with healthy lifestyle advice, or follow treatment plans involving adherence to complex medication regimes or monitoring blood glucose levels at home.

Working with primary care to try and ensure all patients on clozapine have a general practitioner is imperative. Unfortunately, a significant number of patients prescribed clozapine either are not enrolled in primary care or have not seen a general practitioner for over one year. Currently a pilot project is occurring with a community support worker attached to Te Roopu Whitiora, Māori mental health team Whangārei to try and practically help people with severe mental illness enrol and attend primary care and other specialists’ reviews. Health improvement practitioners are attached to some primary care practices, and have a very broad brief involving health and wellbeing when a general practitioner wants additional support for a patient with mental health concerns.  These could be an avenue to improve outcomes for people on clozapine who are engaged with primary care.

Northland nationally has a high proportion of people who are classified as being in the most deprived economic conditions. This directly impacts on access to healthy food options and primary care.[[9]] Māori and people with severe mental illness are more likely to experience social and economic deprivation.

Prevention of weight gain and weight loss strategies remain the priority for dealing with the adverse metabolic effects of clozapine and targeted intervention is required. GLP-1 agonists have only recently become funded in New Zealand and studies have shown they are likely to be the agent of choice after metformin.[[10]]

The increased percentage of Māori versus non-Māori prescribed clozapine can be seen as a proxy measure for an increased risk of severe schizophrenia in the Māori population. Although treatment resistant illness is associated with an increased risk of certain copy number variants there are also environmental risk factors associated with social deprivation that disproportionately affect Māori. Duration of untreated psychotic illness and the number of severe acute relapses contribute to persistent psychotic symptoms which require clozapine.

Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of people with treatment-resistant schizophrenia are required. This is consistent with Māori models of healthcare such as Te Whare Tapa Whā.[[11]] Determining successful local strategies to optimally manage the physical health of this vulnerable group will involve review of “successful” patients who have managed to avoid weight gain and the development of dysglycaemia.

Summary

Abstract

Aim

Clozapine is a unique atypical anti-psychotic agent with best efficacy for treatment resistant schizophrenia compared to other agents, but with increased metabolic adverse effects. We sought to audit the prevalence of diabetes and pre-diabetes in Northland, New Zealand patients on clozapine.

Method

We captured all 287 patients in Northland, New Zealand who were prescribed clozapine in September 2021 and obtained demographic, clinical and laboratory data.

Results

We discovered that 26.48% had diabetes (one patient type one, 75 type two diabetes) and 14.63% had pre-diabetes that developed after a median of six years’ clozapine treatment. Diabetes prevalence is approximately 6% in the general population. NZ Māori made up 65.85% of the entire cohort (35.8% of the general population) and 85.53% of the diabetes patients. NZ Europeans represented most of the remaining 30.66% on clozapine, consistent with the largely bicultural ethnic mix of our region. Māori on clozapine were younger: mean age 42 years, compared to NZ Europeans, mean age 49 years. The average BMI was 37kg/m[[2]] for Māori, 32 for Europeans (range 21–63, SD 8); there was a moderate relationship between clozapine use and increasing BMI (correlation coefficient of 0.74). For the diabetes patients, glycaemic control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41–117).

Conclusion

Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of Northland, New Zealand people with treatment-resistant schizophrenia on clozapine are required to reduce the 41% rate of dysglycaemia in this predominantly Māori group.

Author Information

Nicole M McGrath: Physician, Department of Medicine, Northland District Health Board, Whangārei. Verity Humberstone: Psychiatrist, Department of Psychiatry, Northland District Health Board, Whangārei. Ashley C Abraham: Clinical Audit Facilitator, Northland District Health Board, Whangārei.

Acknowledgements

Correspondence

Nicole M McGrath: Physician, Department of Medicine, Northland District Health Board, Private Bag 9748, Whangārei. 09 434100.

Correspondence Email

Nicole.mcgrath@northlanddhb.org.nz

Competing Interests

Nil.

1) Martin FI. Alford FP. Insulin sensitivity in schizophrenia. Br Med J 1970; 2:50.

2) De Hert M, Detraux J, Van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol [Internet]. 2012 Feb.

3) Singh R, Bansal Y, Medhi B, Kuhad A. Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives. Eur J Pharmacol. 2019 Feb 5;844:231-240.

4) Melkersson K, Dahl M-L. Adverse Metabolic Effects associated with Atypical antipsychotics: literature review and clinical implications. Drugs 2004;64(7):701-23.

5) Taipale H, Lähteenvuo M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J. Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia. Schizophr Bull [Internet]. 2021 Jan 23 [cited 2021 Aug 23];47(1):23–30.

6) Vermeulen JM, Van Rooijen G, Van De Kerkhof MPJ, Sutterland AL, Correll CU, De Haan L. Clozapine and Long-Term Mortality Risk in Patients with Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years. Schizophr Bull [Internet]. 2019 Mar 7 [cited 2021 Aug 23];45(2):315–29.

7) New Zealand data sheet CLOZARIL. Medsafe.govt.nz Available at: https://www.medsafe.govt.nz/profs/datasheet/c/Clozariltab.pdf [Accessed 12 January 2022].

8) Nemani KL, Greene C and Henderson DC. Clozapine, diabetes mellitus, cardiovascular risk and mortality: results of a 21-year naturalistic study in patients with schizophrenia and schizoaffective disorder. Clin Schizophr Relat Psychoses 2019;12(4): 168-176.

9) Population of Northland DHB. Ministry of Health NZ. 2021. Available at: https://www.health.govt.nz/new-zealand-health-system/my-dhb/northland-dhb/population-northland-dhb [Accessed 12 January 2022].

10) Cernea S, Dima L, Correll CU, Manu P. Pharmacological Management of Glucose Dysregulation in Patients Treated with Second-Generation Antipsychotics. Drugs [Internet]. 2020 Nov 1 [cited 2021 Aug 23];80(17):1763–81.

11) Durie M. 2001 Mauri ora: The dynamics of Māori health. Oxford University Press.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Insulin resistance of unknown mechanism was first reported in patients with schizophrenia 55 years ago.[[1]] Modern atypical antipsychotics further increase the risk of diabetes through multiple mechanisms, but principally weight gain via central actions causing changes to leptin, adiponectin and ghrelin levels, and peripheral inhibition of glucose transport.[[2,3]] Clozapine and olanzapine are the atypical antipsychotics with the highest risk of causing diabetes.[[4]] Clozapine is unique in that it has superior efficacy for treatment resistant schizophrenia (failure to respond to at least two antipsychotic medications over at least six weeks each), and it is the only antipsychotic associated with decreased risk of attempted and completed suicide.[[5]] Meta-analysis shows lower long-term all-cause mortality compared with other antipsychotics, despite increased metabolic syndrome.[[6]] Furthermore, all patients on clozapine require long-term monthly lab tests to check for the rare, but potentially fatal, idiosyncratic side effect of neutropenia.[[7]] In New Zealand, a database is maintained to ensure all patients are monitored; therefore, all patients on clozapine in our region, Northland, New Zealand, are captured. As well as monthly full blood count, the recommendation is that patients on clozapine are screened for diabetes with HbA1c at baseline, three and six months after commencement of clozapine and then yearly.

Methods

We evaluated all Northland, New Zealand patients receiving clozapine in September 2021. We used the clozapine database that is an accurate record of all patients prescribed clozapine in our region, hospital and general practice records to obtain demographic data, including age, sex, ethnicity, duration of treatment; when available body mass index (BMI) and change of BMI using the formula BMI=kg/m[[2]], where kg is a person’s weight in kilograms, and m[[2]] is their height in meters squared; co-administration of other antipsychotics; HbA1c results close to commencement of clozapine and most recent HbA1c. In New Zealand, diabetes is diagnosed with HbA1c of 50mmol/mol or greater on two occasions unless symptomatic: pre-diabetes HbA1c 41–49 mmol/mol. The data analysis was performed in the R programming software. Results are reported as mean (range; standard deviation). Analysis of variance (ANOVA) and Pearson correlation coefficient was used to compare between two or more groups for any quantitative data.

Results

Two hundred and eighty-seven Northland patients with schizophrenia were prescribed clozapine at the time of the audit. Sixty-five point eight five percent were NZ Māori (Māori make up 35.8% of general Northland population), and 30.66% NZ European; 66.89% were male. Māori were younger—mean age 42 years (range 19–74; standard deviation (SD) 12)—compared to NZ Europeans—mean age 49 years (range 17-82; SD 15). Only 5.23% of the cohort had not obtained an HbA1c within the preceding two years. The majority of tests were requested by hospital mental health providers rather than through primary care.

The average current HbA1c of the entire cohort was 45mmol/mol (range 27–117, SD 17); in Māori the average current HbA1c was 48, in NZE 40mmol/mol (Figure 1).

Figure 1: The box plot representing the HbA1c results in relation to each ethnicity. The dashed line represent the average HbA1c results of the entire sample (n =287).

The average HbA1c remained higher for females in the ethnicity group compared to males (Table 1, Figure 2).

Figure 2: Average HbA1c in relation to each ethnicity based on gender.

Twenty-six point four eight percent of the cohort had diabetes: one patient had type one diabetes diagnosed before commencement of clozapine and 75 type two diabetes; an additional 42 patients (14.63 %) had pre-diabetes. In Northland’s general population, approximately 6% have known diabetes.

Of the 118 patients with dysglycaemia, 19 (16.10 %) had diabetes or pre-diabetes at the time of commencement of clozapine; all those with pre-clozapine diabetes had a confirmed diagnosis. For the remaining 99 patients, diabetes/pre-diabetes was diagnosed 1–26 years after starting treatment (median six years; only six patients within the first year). For those with diabetes, 85.53% were Māori; control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41–117).

BMI data was available for 92% patients with diabetes/pre-diabetes. The average BMI was 37kg/m[[2]] for Māori compared to 32kg/m[[2]] in NZ Europeans (range 21–63, SD 8) (Figure 3).

Figure 3: The box plot representing BMI between Māori and NZ Europeans.

There was a moderate relationship between clozapine use and increasing BMI (Pearson’s correlation coefficient of 0.74); however, further studies are needed to establish a consistent relation between increase in BMI with clozapine for the Northland population.

Forty point four two percent of the entire cohort were co-prescribed an additional antipsychotic agent. Limitations in analysis did not determine whether the antipsychotic polypharmacy was as part of a time limited strategy or a maintenance regime. Of concern for 23 patients, olanzapine was prescribed with clozapine. Olanzapine has a high rate of weight gain and increased risk of diabetes. Of the patients prescribed both olanzapine and clozapine, four had diabetes, five pre-diabetes which was not an increased risk for dysglycaemia compared to the whole cohort.

Discussion

Forty-one percent of Northland schizophrenia patients on clozapine have either diabetes or pre-diabetes. The majority have type two diabetes, are obese and have poor glycaemic control. Māori are vastly over-represented and develop diabetes at a younger age than NZ Europeans. Given these results, the choice of clozapine does not appear to be influenced by pre-existing metabolic status, but rather on psychiatric indications. Our results are similar to a 21-year American study of 96 patients that showed a 43% rate of diabetes particularly in Hispanic and African Americans on clozapine.[[8]]

There are challenges to ensuring appropriate physical healthcare for patients with severe schizophrenia. Persistent psychotic symptoms can impact on the ability of patients to trust and engage with healthcare providers. The symptoms can also have an impact on the ability of the patients to engage with healthy lifestyle advice, or follow treatment plans involving adherence to complex medication regimes or monitoring blood glucose levels at home.

Working with primary care to try and ensure all patients on clozapine have a general practitioner is imperative. Unfortunately, a significant number of patients prescribed clozapine either are not enrolled in primary care or have not seen a general practitioner for over one year. Currently a pilot project is occurring with a community support worker attached to Te Roopu Whitiora, Māori mental health team Whangārei to try and practically help people with severe mental illness enrol and attend primary care and other specialists’ reviews. Health improvement practitioners are attached to some primary care practices, and have a very broad brief involving health and wellbeing when a general practitioner wants additional support for a patient with mental health concerns.  These could be an avenue to improve outcomes for people on clozapine who are engaged with primary care.

Northland nationally has a high proportion of people who are classified as being in the most deprived economic conditions. This directly impacts on access to healthy food options and primary care.[[9]] Māori and people with severe mental illness are more likely to experience social and economic deprivation.

Prevention of weight gain and weight loss strategies remain the priority for dealing with the adverse metabolic effects of clozapine and targeted intervention is required. GLP-1 agonists have only recently become funded in New Zealand and studies have shown they are likely to be the agent of choice after metformin.[[10]]

The increased percentage of Māori versus non-Māori prescribed clozapine can be seen as a proxy measure for an increased risk of severe schizophrenia in the Māori population. Although treatment resistant illness is associated with an increased risk of certain copy number variants there are also environmental risk factors associated with social deprivation that disproportionately affect Māori. Duration of untreated psychotic illness and the number of severe acute relapses contribute to persistent psychotic symptoms which require clozapine.

Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of people with treatment-resistant schizophrenia are required. This is consistent with Māori models of healthcare such as Te Whare Tapa Whā.[[11]] Determining successful local strategies to optimally manage the physical health of this vulnerable group will involve review of “successful” patients who have managed to avoid weight gain and the development of dysglycaemia.

Summary

Abstract

Aim

Clozapine is a unique atypical anti-psychotic agent with best efficacy for treatment resistant schizophrenia compared to other agents, but with increased metabolic adverse effects. We sought to audit the prevalence of diabetes and pre-diabetes in Northland, New Zealand patients on clozapine.

Method

We captured all 287 patients in Northland, New Zealand who were prescribed clozapine in September 2021 and obtained demographic, clinical and laboratory data.

Results

We discovered that 26.48% had diabetes (one patient type one, 75 type two diabetes) and 14.63% had pre-diabetes that developed after a median of six years’ clozapine treatment. Diabetes prevalence is approximately 6% in the general population. NZ Māori made up 65.85% of the entire cohort (35.8% of the general population) and 85.53% of the diabetes patients. NZ Europeans represented most of the remaining 30.66% on clozapine, consistent with the largely bicultural ethnic mix of our region. Māori on clozapine were younger: mean age 42 years, compared to NZ Europeans, mean age 49 years. The average BMI was 37kg/m[[2]] for Māori, 32 for Europeans (range 21–63, SD 8); there was a moderate relationship between clozapine use and increasing BMI (correlation coefficient of 0.74). For the diabetes patients, glycaemic control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41–117).

Conclusion

Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of Northland, New Zealand people with treatment-resistant schizophrenia on clozapine are required to reduce the 41% rate of dysglycaemia in this predominantly Māori group.

Author Information

Nicole M McGrath: Physician, Department of Medicine, Northland District Health Board, Whangārei. Verity Humberstone: Psychiatrist, Department of Psychiatry, Northland District Health Board, Whangārei. Ashley C Abraham: Clinical Audit Facilitator, Northland District Health Board, Whangārei.

Acknowledgements

Correspondence

Nicole M McGrath: Physician, Department of Medicine, Northland District Health Board, Private Bag 9748, Whangārei. 09 434100.

Correspondence Email

Nicole.mcgrath@northlanddhb.org.nz

Competing Interests

Nil.

1) Martin FI. Alford FP. Insulin sensitivity in schizophrenia. Br Med J 1970; 2:50.

2) De Hert M, Detraux J, Van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol [Internet]. 2012 Feb.

3) Singh R, Bansal Y, Medhi B, Kuhad A. Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives. Eur J Pharmacol. 2019 Feb 5;844:231-240.

4) Melkersson K, Dahl M-L. Adverse Metabolic Effects associated with Atypical antipsychotics: literature review and clinical implications. Drugs 2004;64(7):701-23.

5) Taipale H, Lähteenvuo M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J. Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia. Schizophr Bull [Internet]. 2021 Jan 23 [cited 2021 Aug 23];47(1):23–30.

6) Vermeulen JM, Van Rooijen G, Van De Kerkhof MPJ, Sutterland AL, Correll CU, De Haan L. Clozapine and Long-Term Mortality Risk in Patients with Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years. Schizophr Bull [Internet]. 2019 Mar 7 [cited 2021 Aug 23];45(2):315–29.

7) New Zealand data sheet CLOZARIL. Medsafe.govt.nz Available at: https://www.medsafe.govt.nz/profs/datasheet/c/Clozariltab.pdf [Accessed 12 January 2022].

8) Nemani KL, Greene C and Henderson DC. Clozapine, diabetes mellitus, cardiovascular risk and mortality: results of a 21-year naturalistic study in patients with schizophrenia and schizoaffective disorder. Clin Schizophr Relat Psychoses 2019;12(4): 168-176.

9) Population of Northland DHB. Ministry of Health NZ. 2021. Available at: https://www.health.govt.nz/new-zealand-health-system/my-dhb/northland-dhb/population-northland-dhb [Accessed 12 January 2022].

10) Cernea S, Dima L, Correll CU, Manu P. Pharmacological Management of Glucose Dysregulation in Patients Treated with Second-Generation Antipsychotics. Drugs [Internet]. 2020 Nov 1 [cited 2021 Aug 23];80(17):1763–81.

11) Durie M. 2001 Mauri ora: The dynamics of Māori health. Oxford University Press.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Insulin resistance of unknown mechanism was first reported in patients with schizophrenia 55 years ago.[[1]] Modern atypical antipsychotics further increase the risk of diabetes through multiple mechanisms, but principally weight gain via central actions causing changes to leptin, adiponectin and ghrelin levels, and peripheral inhibition of glucose transport.[[2,3]] Clozapine and olanzapine are the atypical antipsychotics with the highest risk of causing diabetes.[[4]] Clozapine is unique in that it has superior efficacy for treatment resistant schizophrenia (failure to respond to at least two antipsychotic medications over at least six weeks each), and it is the only antipsychotic associated with decreased risk of attempted and completed suicide.[[5]] Meta-analysis shows lower long-term all-cause mortality compared with other antipsychotics, despite increased metabolic syndrome.[[6]] Furthermore, all patients on clozapine require long-term monthly lab tests to check for the rare, but potentially fatal, idiosyncratic side effect of neutropenia.[[7]] In New Zealand, a database is maintained to ensure all patients are monitored; therefore, all patients on clozapine in our region, Northland, New Zealand, are captured. As well as monthly full blood count, the recommendation is that patients on clozapine are screened for diabetes with HbA1c at baseline, three and six months after commencement of clozapine and then yearly.

Methods

We evaluated all Northland, New Zealand patients receiving clozapine in September 2021. We used the clozapine database that is an accurate record of all patients prescribed clozapine in our region, hospital and general practice records to obtain demographic data, including age, sex, ethnicity, duration of treatment; when available body mass index (BMI) and change of BMI using the formula BMI=kg/m[[2]], where kg is a person’s weight in kilograms, and m[[2]] is their height in meters squared; co-administration of other antipsychotics; HbA1c results close to commencement of clozapine and most recent HbA1c. In New Zealand, diabetes is diagnosed with HbA1c of 50mmol/mol or greater on two occasions unless symptomatic: pre-diabetes HbA1c 41–49 mmol/mol. The data analysis was performed in the R programming software. Results are reported as mean (range; standard deviation). Analysis of variance (ANOVA) and Pearson correlation coefficient was used to compare between two or more groups for any quantitative data.

Results

Two hundred and eighty-seven Northland patients with schizophrenia were prescribed clozapine at the time of the audit. Sixty-five point eight five percent were NZ Māori (Māori make up 35.8% of general Northland population), and 30.66% NZ European; 66.89% were male. Māori were younger—mean age 42 years (range 19–74; standard deviation (SD) 12)—compared to NZ Europeans—mean age 49 years (range 17-82; SD 15). Only 5.23% of the cohort had not obtained an HbA1c within the preceding two years. The majority of tests were requested by hospital mental health providers rather than through primary care.

The average current HbA1c of the entire cohort was 45mmol/mol (range 27–117, SD 17); in Māori the average current HbA1c was 48, in NZE 40mmol/mol (Figure 1).

Figure 1: The box plot representing the HbA1c results in relation to each ethnicity. The dashed line represent the average HbA1c results of the entire sample (n =287).

The average HbA1c remained higher for females in the ethnicity group compared to males (Table 1, Figure 2).

Figure 2: Average HbA1c in relation to each ethnicity based on gender.

Twenty-six point four eight percent of the cohort had diabetes: one patient had type one diabetes diagnosed before commencement of clozapine and 75 type two diabetes; an additional 42 patients (14.63 %) had pre-diabetes. In Northland’s general population, approximately 6% have known diabetes.

Of the 118 patients with dysglycaemia, 19 (16.10 %) had diabetes or pre-diabetes at the time of commencement of clozapine; all those with pre-clozapine diabetes had a confirmed diagnosis. For the remaining 99 patients, diabetes/pre-diabetes was diagnosed 1–26 years after starting treatment (median six years; only six patients within the first year). For those with diabetes, 85.53% were Māori; control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41–117).

BMI data was available for 92% patients with diabetes/pre-diabetes. The average BMI was 37kg/m[[2]] for Māori compared to 32kg/m[[2]] in NZ Europeans (range 21–63, SD 8) (Figure 3).

Figure 3: The box plot representing BMI between Māori and NZ Europeans.

There was a moderate relationship between clozapine use and increasing BMI (Pearson’s correlation coefficient of 0.74); however, further studies are needed to establish a consistent relation between increase in BMI with clozapine for the Northland population.

Forty point four two percent of the entire cohort were co-prescribed an additional antipsychotic agent. Limitations in analysis did not determine whether the antipsychotic polypharmacy was as part of a time limited strategy or a maintenance regime. Of concern for 23 patients, olanzapine was prescribed with clozapine. Olanzapine has a high rate of weight gain and increased risk of diabetes. Of the patients prescribed both olanzapine and clozapine, four had diabetes, five pre-diabetes which was not an increased risk for dysglycaemia compared to the whole cohort.

Discussion

Forty-one percent of Northland schizophrenia patients on clozapine have either diabetes or pre-diabetes. The majority have type two diabetes, are obese and have poor glycaemic control. Māori are vastly over-represented and develop diabetes at a younger age than NZ Europeans. Given these results, the choice of clozapine does not appear to be influenced by pre-existing metabolic status, but rather on psychiatric indications. Our results are similar to a 21-year American study of 96 patients that showed a 43% rate of diabetes particularly in Hispanic and African Americans on clozapine.[[8]]

There are challenges to ensuring appropriate physical healthcare for patients with severe schizophrenia. Persistent psychotic symptoms can impact on the ability of patients to trust and engage with healthcare providers. The symptoms can also have an impact on the ability of the patients to engage with healthy lifestyle advice, or follow treatment plans involving adherence to complex medication regimes or monitoring blood glucose levels at home.

Working with primary care to try and ensure all patients on clozapine have a general practitioner is imperative. Unfortunately, a significant number of patients prescribed clozapine either are not enrolled in primary care or have not seen a general practitioner for over one year. Currently a pilot project is occurring with a community support worker attached to Te Roopu Whitiora, Māori mental health team Whangārei to try and practically help people with severe mental illness enrol and attend primary care and other specialists’ reviews. Health improvement practitioners are attached to some primary care practices, and have a very broad brief involving health and wellbeing when a general practitioner wants additional support for a patient with mental health concerns.  These could be an avenue to improve outcomes for people on clozapine who are engaged with primary care.

Northland nationally has a high proportion of people who are classified as being in the most deprived economic conditions. This directly impacts on access to healthy food options and primary care.[[9]] Māori and people with severe mental illness are more likely to experience social and economic deprivation.

Prevention of weight gain and weight loss strategies remain the priority for dealing with the adverse metabolic effects of clozapine and targeted intervention is required. GLP-1 agonists have only recently become funded in New Zealand and studies have shown they are likely to be the agent of choice after metformin.[[10]]

The increased percentage of Māori versus non-Māori prescribed clozapine can be seen as a proxy measure for an increased risk of severe schizophrenia in the Māori population. Although treatment resistant illness is associated with an increased risk of certain copy number variants there are also environmental risk factors associated with social deprivation that disproportionately affect Māori. Duration of untreated psychotic illness and the number of severe acute relapses contribute to persistent psychotic symptoms which require clozapine.

Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of people with treatment-resistant schizophrenia are required. This is consistent with Māori models of healthcare such as Te Whare Tapa Whā.[[11]] Determining successful local strategies to optimally manage the physical health of this vulnerable group will involve review of “successful” patients who have managed to avoid weight gain and the development of dysglycaemia.

Summary

Abstract

Aim

Clozapine is a unique atypical anti-psychotic agent with best efficacy for treatment resistant schizophrenia compared to other agents, but with increased metabolic adverse effects. We sought to audit the prevalence of diabetes and pre-diabetes in Northland, New Zealand patients on clozapine.

Method

We captured all 287 patients in Northland, New Zealand who were prescribed clozapine in September 2021 and obtained demographic, clinical and laboratory data.

Results

We discovered that 26.48% had diabetes (one patient type one, 75 type two diabetes) and 14.63% had pre-diabetes that developed after a median of six years’ clozapine treatment. Diabetes prevalence is approximately 6% in the general population. NZ Māori made up 65.85% of the entire cohort (35.8% of the general population) and 85.53% of the diabetes patients. NZ Europeans represented most of the remaining 30.66% on clozapine, consistent with the largely bicultural ethnic mix of our region. Māori on clozapine were younger: mean age 42 years, compared to NZ Europeans, mean age 49 years. The average BMI was 37kg/m[[2]] for Māori, 32 for Europeans (range 21–63, SD 8); there was a moderate relationship between clozapine use and increasing BMI (correlation coefficient of 0.74). For the diabetes patients, glycaemic control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41–117).

Conclusion

Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of Northland, New Zealand people with treatment-resistant schizophrenia on clozapine are required to reduce the 41% rate of dysglycaemia in this predominantly Māori group.

Author Information

Nicole M McGrath: Physician, Department of Medicine, Northland District Health Board, Whangārei. Verity Humberstone: Psychiatrist, Department of Psychiatry, Northland District Health Board, Whangārei. Ashley C Abraham: Clinical Audit Facilitator, Northland District Health Board, Whangārei.

Acknowledgements

Correspondence

Nicole M McGrath: Physician, Department of Medicine, Northland District Health Board, Private Bag 9748, Whangārei. 09 434100.

Correspondence Email

Nicole.mcgrath@northlanddhb.org.nz

Competing Interests

Nil.

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