Prescribing patterns of long-acting injectable antipsychotics in a community setting in South Africa

Background Long-acting injectable antipsychotics (LAI – APs) improve adherence to antipsychotics and decrease functional decline in schizophrenia. Yet they are prescribed late, in patients with established functional decline. Although LAI – APs are widely prescribed in South Africa, there is a paucity of research regarding the prescription profile for LAI – APs. Aim This study aimed to describe prescribing practices for LAI – APs at psychiatric clinics. Setting Community psychiatric clinics in South Africa. Methods A retrospective review of the psychiatric files of all patients on LAI – APs attending the clinics over the study period was conducted. Sociodemographic, clinical and pharmacological information regarding the LAI – AP prescribed was extracted from the files. Results A total of 206 charts were examined. The mean age of the study population was 46 (SD ± 12) years. Significantly more patients were male (n = 154; 74.8%), single (n = 184, 89.3%) and unemployed (n = 115; 55.8%) (p < 0.001). Approximately half had a comorbid substance use disorder (47.6%). The most common indication for the prescription of a LAI – AP was non-adherence (66%). Only 9.7% of the patients were prescribed a LAI – AP alone. No significant socio-demographic or clinical characteristic was associated with this prescribing habit. A LAI – AP was prescribed in combination with an oral antipsychotic, mood stabiliser or antidepressant in 53.9%, 44.7% and 7.8% of patients, respectively. Conclusion Long-acting injectable antipsychotics were prescribed mainly following noncompliance with oral antipsychotics and may represent a missed opportunity to prevent functional decline. The high prevalence of LAI – AP polypharmacy has been highlighted.


Introduction
The introduction of oral antipsychotic medication in the early 1950s transformed the treatment of schizophrenia globally. 1 However, the problem of nonadherence or partial adherence to oral antipsychotic medications is common. Up to 50% of patients with schizophrenia do not take their oral medication as prescribed, resulting in a four-fold higher risk of relapse. 2,3 Although most of the evidence regarding adherence to antipsychotic medication is derived from studies in patients with schizophrenia, the goal of treatment for any of the disorders in the schizophrenia spectrum and related disorders section of DSM 5 4 is to prevent relapses, because relapses are associated with serious psychosocial, biological and economic consequences. 5 After each relapse, it takes longer to achieve remission, there is a risk of treatment failure and there is evidence of progressive structural damage to the brain. Although the time taken to relapse after treatment discontinuation is variable, relapse is inevitable in the vast majority of patients after a period of approximately 2 years. 2,3,5,6 Therefore, research to identify factors associated with nonadherence to antipsychotic medication is important. 3 Several patient, provider and medication-related factors are associated with nonadherence or partial adherence to antipsychotic medication. 3 One such medication-related factor, the prescribing of long-acting injectable formulations of antipsychotic medication, has been shown to improve adherence to antipsychotic medication. 3,7 Long-acting injectable antipsychotics (LAI -APs) decrease the potential for missed doses because they are administered either once or twice per month, compared with the daily ingestion of an oral antipsychotic. Long-acting injectable antipsychotics also provide continuous drug delivery with a more favourable pharmacokinetic profile, higher bioavailability and stable receptor occupancy. 8 Several studies have shown a definite advantage of LAI -APs in reducing relapses. 9,10,11 However, some of the early studies in favour of LAI -APs over oral medications were called into question and some subsequently conducted randomised control trials (RCTs) failed to confirm a clear advantage of LAI -APs over oral antipsychotics. 12,13 A possible explanation for these inconsistent findings is the methodological differences and bias associated with observational studies compared with RCTs. Compared with oral antipsychotics, the improved adherence associated with the prescription of LAI -APs has been shown to decrease the relapse rate 11 and the number and duration of hospitalisations 14 with a consequent decrease in the cost of care. 15 Despite the improved adherence and the subsequent benefits conferred by LAI -APs, they are on average only prescribed in 20% -37% of patients with schizophrenia. 7,16,17 Various sociodemographic and clinical factors have been associated with the prescribing of LAI -APs. These factors include the duration of illness, 18 gender, 18,19,20,21 ethnicity, 22,23 education, 23 socio-economic status, 21,23,24,25 comorbid substance use disorders, 23 inpatient versus outpatient care, 20 acceptability to patients, 26 adherence to antipsychotic medication 3,7 and attitude of psychiatrists towards LAI -APs. 27 A key advantage of LAI -APs over oral antipsychotics is that they improve adherence to antipsychotic medication because they do not have to be taken daily. Yet, it is reported internationally that the concurrent prescription of oral psychotropic medication is frequent, with 46% -75% of patients on LAI -APs also receiving concurrent prescriptions of an oral psychotropic. 23,26,28,29,30,31 It is important to examine rational drug utilisation, because inappropriate prescription of medication contributes to poor health outcomes. Rational prescription of psychotropic medication is especially relevant in low-income and middleincome countries to prevent wastage of precious mental health resources. 32 Despite over two decades of research on prescribing practices for LAI -APs globally, 24 there remains a gap in the literature concerning the prescription patterns for LAI -APs in South Africa (SA). Only a few local studies have included information on the prescription of LAI -APs, and these were either limited to patients of only one ethnic group, 33 patients recently discharged from a psychiatric hospital 34 or outpatients attending tertiary psychiatric hospital clinics. 26 Hence, the aim of this study was to examine the prescribing practices for LAI -APs in patients attending community psychiatric clinics in Johannesburg, SA. The general objective was to describe the sociodemographic characteristics, clinical characteristics, types, dosages and frequency of the LAI -APs that were prescribed. The specific objective was to determine the prevalence of concurrent prescriptions of LAI -APs and oral psychotropic medications and to determine if any significant sociodemographic and clinical characteristic were associated with these prescriptions.

Method
This retrospective chart review was conducted at three psychiatric clinics based in the Chiawelo, Westbury and Lenasia South Community Health Centres. These clinics were randomly selected from the 23 clinics in the Johannesburg Metropolitan Health District. Three clinics were chosen because together they yielded a sufficient sample size. Each clinic in the district was assigned a number and three numbers were randomly drawn. The numbers drawn corresponded to the clinics included in this study. The psychiatric clinics are staffed by psychiatric nurses and medical officers or registrars in training for psychiatry. The psychiatric clinics' patient records are filed separately from the community health center's clinical records.
All adult patients (aged 18 and older) attending the clinics who had received a LAI -AP over a 1-month period were included in the study. There were no exclusion criteria.
Each clinic's nursing staff maintains a monthly register of all patients for whom a LAI -AP is administered. The principal investigator accessed the clinical files of the patients who met the inclusion criteria and used a data collection form to manually record the following sociodemographic, clinical and treatment variables from the clinical notes: age, gender, population group, relationship status, the highest level of education achieved, employment status, primary psychiatric diagnosis, duration of illness, family history of mental illness, comorbid illnesses (psychiatric, medical and substance use), prescription of oral medication and details of the LAI -AP prescribed (the main indication for initiation, the date of initiation of the LAI -AP prescribed, the frequency of administration and the dose).
All records made on the data collection sheet were kept confidential. The name and patient numbers were anonymised on the populated databases in Microsoft Excel and raw data were only viewed by the principal investigator.

Data analysis
A descriptive analysis of the sociodemographic and clinical variables was performed. All statistical analyses were conducted using R software (version 3.50, http://www.Rproject.org). All tests were two-tailed probability values, and statistical significance was accepted when p ≤ 0.05. The data set for this study was generated from assessments of categorical scores. Categorical data are usually non-normal. Thus, nonparametric chi-squared contingency tests were used to analyse count data per variable.
For the purposes of meaningful statistical analysis, the patients were subsequently divided into two groups, namely those on LAI -AP alone and those on LAI -APs combined with oral antipsychotic medication, and the categories of some of the variables were collapsed. The chi-square test or Fisher's exact test was applied to the categorical variables to determine if there was a significant relationship between the sociodemographic and clinical characteristics in patients receiving LAI -APs only versus those receiving concurrent prescriptions of LAI -APs and oral psychotropic medications. In the few cases of continuous data, these were tested for normality using QQ-plots and then analysed using t-tests for comparisons between the two groups. Multivariate logistic regression analysis was performed with 95% confidence intervals to adjust for relevant covariates.

Ethical considerations
Ethical approval was obtained from the University of the Witwatersrand Human Research Ethics Committee (reference number: M181062). Permission to conduct the study was obtained from the research committee of Johannesburg Health District. All records made on the data collection sheet were kept confidential. The name and patient numbers were anonymised in the populated databases in Microsoft Excel and raw data were only viewed by the principal investigator.
Significantly, more patients had a primary psychiatric diagnosis from the schizophrenia spectrum and related disorders chapter of the DSM 5 (n = 144; 69.9%) and a duration of illness of > 5 years (n = 180; 87.3%) (p < 0.001). A comorbid psychiatric illness and medical illness was present in 20.4% (n = 42) and 33% (n = 68) of the patients on a LAI -AP, respectively. The prevalence of comorbid substance abuse was 47.6% (n = 108) ( Table 1).
Of the 206 patients in the study population, only 9.7% (n = 20) were prescribed a LAI -AP alone. The other 90.3% (n = 186) was prescribed some oral psychotropic medication in addition to the LAI -AP. In more than half of these patients, it was an oral antipsychotic (n = 111, 53.9%). A mood stabiliser  (Table 3).
The sociodemographic and clinical characteristics of the patients on a LAI -AP only were compared with those on a LAI -AP combined with and an oral antipsychotic. There were no statistically significant differences between the group that was on LAI -AP alone compared with the group that was on LAI -AP combined with an oral antipsychotic with respect to gender (x 2 = 0.435; p = 0.5), age (x 2 = 3.845; p = 0.1), the mean age (t = −1.12, p = 0.  Table 4). There was a statistically significant difference with regard to comorbid medical illness (x 2 = 4.979, p = 0.03) ( Table 4). However, on multivariate analysis, the p-value was 0.6.
The treatment characteristics of the patients on a LAI -AP only were compared with those on a LAI -AP combined with an oral antipsychotic. There was also no statistically significant difference between the two groups with regard to the specific LAI -AP prescribed (x 2 = 0.027; p = 0.87), the mean duration of the LAI -AP prescribed (t = 1.8; p = 0.07), the mean dose of flupenthixol (t = 0.96; p = 0.3), the mean dose of zuclopenthixol (t = 0.49; p = 0.6), the injection interval (p = 1.000) and the indications for LAI -AP prescription (p = 0.912) ( Table 5).

Discussion
The prescription pattern for LAI -APs in this study is in keeping with the traditional profile of patients for whom LAI -APs are prescribed globally. 25,35 Long-acting injectable     antipsychotics have long been prescribed for patients who are older, male, not compliant with oral medication, inclined to relapse frequently and potentially posing a danger to others. 17 In this study, LAI -APs were prescribed mostly for patients who were over the age of 40 (64.1%), male (74.8%), single (89.3%), unemployed or in receipt of a social grant (96.1%), diagnosed with a condition from the schizophrenia and related disorders chapter of DSM 5( 69.9%) and experiencing a duration of illness greater than 5 years (88.4%). Flupenthixol decanoate was the most frequently prescribed LAI -AP (64.1%), and the main indication for a LAI -AP was nonadherence to oral antipsychotic medication (66%). Polypharmacy was common; 90% of the patients were on a LAI -AP combined with an oral psychotropic.

Duration of illness
The mean age of the patients in this study was 46 years. This is in keeping with a systematic review that reported a mean age at treatment with LAI -APs ranging from 38.5 years in the 1970s to 39.5 years in the 2000s, 25 a study conducted across six East Asian countries, 18 and similar to three publications from Italy, 35 the United States of America (USA) 36 and Australia. 37 Three-quarters of the patients on LAI -APs in this study were males. Although gender disparity in the prescription of LAI -APs is a consistent finding in the literature, 25 the proportion of males receiving a LAI -AP was higher than that reported by Lindstrom et al. (58%) 19 and Sim et al. (56%). 18 A possible explanation may be the high frequency (66%) of nonadherence as the indication for initiation of the LAI -AP in this study. Women generally have higher adherence rates to psychotropic medications than men. 38 It is also possible that prescribers utilise coercive treatment for male patients more readily.
Only 1.5% of patients who were prescribed a LAI -AP in this study had a tertiary level of education and 3.9% were employed. This is in stark contrast to a study from Europe, where 44% of patients on a LAI -AP had a university degree and 22% were employed. 35 However, this is most likely a reflection of the high rate of unemployment amongst patients with mental illness in SA 34 and because most of these higher functioning patients were receiving second-generation antipsychotic (SGA) LAI -APs.
The diagnostic indication for a LAI -AP in this study was consistent with several studies that reported that LAI -APs are most frequently prescribed for patients with schizophrenia. 9,18,27,35,36 Schizophrenia is a chronic mental illness that is associated with poor adherence to oral medication resulting in a high risk of relapse and admission to hospital. 3,38 Adherence to antipsychotic medication is critical for the recovery and restoration of occupational and social dysfunction in schizophrenia. 3 Several studies have confirmed that prescribing LAI -APs is an effective strategy to improve treatment adherence in schizophrenia. 10,24 Consequently, several international schizophrenia management guidelines 10,17,39 and the Standard Treatment Guidelines and Essential   Medicines List for SA 40 recommend the prescription of LAI -APs in schizophrenia. Hence, the prescribing of LAI -APs was therefore rational and in accordance with these guideline recommendations and the manufacturer's labelled indication for LAI -APs. 41 Approximately 10% of the patients who were prescribed LAI -APs in this study had a primary diagnosis of bipolar disorder. This figure is similar to the range of 4.8% -8.0% reported in other studies 22,30,37 but lower than the 18% reported by Ostuzzi et al. 35 Bipolar disorder is a potentially lifelong chronic mental illness and adherence to medication is also critical for effective control of symptoms, prevention of relapse and rehospitalisation. 42,43 Recently, the indications for LAI -APs have been expanded beyond schizophrenia to include approval for use in the maintenance phase of bipolar disorder. It has been shown that LAI -APs are also effective in reducing relapse rates in patients with bipolar disorder who are poorly adherent to medication. 43 Consequently, the prescription of LAI -APs as both monotherapy and adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar disorder has been approved by some guidelines, including that of the Canadian Network for Mood and Anxiety Treatments, 44 the United States Food and Drug Administration and the European Medical Agency. 43 However, it is only the SGA LAI -APs, and not the firstgeneration (FGA) LAI -APs, that are approved for use in bipolar disorder. 42 Yet, in this study, FGA LAI -APs were prescribed for bipolar disorder. As previously discussed, because of the lack of availability of SGA LAI -APs on The South African National Department of Health Standard Treatment Guidelines and Essential Medicines List, it is likely that first-generation LAI -APs became the only available pharmacological option for patients with bipolar disorder who were not adherent to oral medication.

Indication for prescription
Only 12% of the patients on a LAI -AP in this study had a duration of illness that was less than 5 years. The first 5 years after the onset of the illness has been called the 'critical period' because most of the clinical and psychosocial decline occurs within this period. 45 There is little doubt that nonadherence to treatment is a predictor of symptom recurrence in patients with a first episode of psychosis. 6 Several authors have therefore suggested that LAI -APs should be prescribed in patients with a first episode of psychosis, because the prescription of LAI -APs in younger patients after a first episode of schizophrenia has been shown to improve adherence, prevent relapses, reduce hospitalisations and result in better overall long-term outcomes. 7,10,17,46,47 It is possible that doctors' reluctance to prescribe LAI -APs in patients with a first episode psychosis in this study may have been influenced by their attitudes towards LAI -APs. A study from the United Kingdom found that individual psychiatrists were reluctant to prescribe LAI -APs because they viewed LAI -APs as coercive, stigmatising and less acceptable to patients. 27 Even in Africa, where medical paternalism is common, some psychiatrists still viewed LAI -APs as coercive. 48 A comorbid substance use disorder was present in almost half of the patients (48%) on LAI -APs in this study. There is little doubt that individuals with comorbid substance use have a consistently higher prevalence of nonadherence to antipsychotic medication than those without. 3,38 Although the evidence is not robust, there is proof of improved adherence and symptom control in patients on LAI -APs with dual diagnoses, 46 with better outcomes for SGA LAI -APs compared with FGA LAI -APs. 49 Flupenthixol decanoate was prescribed more frequently than zuclopenthixol decanoate in this study (64% vs. 36%). This preference for flupenthixol over zuclopenthixol was also reported in New Zealand, 50 Australia 51 and Nigeria. 31 Although earlier studies reported that zuclopenthixol decanoate had greater antiaggressive efficacy and flupenthixol decanoate had greater antidepressant properties, 24 subsequent systematic reviews found no real differences in global outcome measures or adverse events between them. 52 The choice of prescription between the two LAI -APs in this study was therefore most probably because of a local prescribing habit, general availability and familiarity with the drug. 36 In the public sector of SA, only FGA LAI -APs are available on the national formulary. 40 Second-generation antipsychotic LAI -APs are obtainable on a named patient basis, by prior motivation through a buy-out process. However, a recent systematic review and meta-analysis found no difference in efficacy and discontinuation rates between first-generation compared with second-generation LAI -APs in the management of schizophrenia. 53 The main indication for using LAI -APs was nonadherence to oral psychotropic medication. Yet, this study found that only 9.7% of the patients were prescribed a LAI -AP alone. The remaining 90.3% were prescribed an oral psychotropic medication (another antipsychotic and a mood stabiliser and an antidepressant) in combination with the LA -AP.
In approximately half of the patients, the other oral psychotropic medication coprescribed was an antipsychotic. Similar high prescription rates have been reported in clinical practice globally, including several studies from the United States of America, 23,28,29,30,54 Nigeria, 31 SA 26 and Korea. 55 The authors explain that some of the patients in these studies had recently been discharged from psychiatric institutions and that either the oral antipsychotic supplementation was used to augment the LAI -AP during the period of stabilisation or that they were being 'weaned off' oral antipsychotics that had been initiated during hospitalisation. 23,30,54 However, our finding is significant because ours was a community clinicbased sample of patients, many of whom had been prescribed this combination for prolonged periods.
Antipsychotic polypharmacy (combining two antipsychotic medications, i.e. LAI -APs with oral antipsychotic medication) is a questionable prescribing habit because it argues against the main indication of nonadherence and increases the potential for drug-drug interactions, a range of side effects and cost of care. 16 However, because the practice is so widespread in real-world settings, it is possible that the response to LAI -APs monotherapy in published clinical trials is overestimated. It may also be a reflection of the illness severity and complexity in patients for whom LAI -APs are prescribed. 28 Our study did not find any significant sociodemographic and clinical characteristics associated with this prescribing habit.
Similar to the high rate of concurrent oral antipsychotic prescriptions, approximately half of the patients in this study (44.7%) were prescribed a mood stabiliser in addition to the LAI -AP. Our figure is in keeping with those in previous reports of concurrent mood stabiliser coprescriptions ranging from 19% 28 to 47%. 54 It is possible that in our study, the mood stabiliser was used to augment the LAI -AP in patients with treatment resistance who had a poor response to antipsychotic medication 56 or that LAI -APs were used in nonadherent patients with bipolar disorder because an injectable mood stabiliser is not yet available or for the treatment of the bipolar phase of schizoaffective disorder.
About 8% of the study population was prescribed an antidepressant in addition to the LAI -AP. Although Joo et al. 55 and Olfson et al. 54 also reported similar prescribing patterns, the findings cannot be directly compared with our study because concurrent antidepressant use in their studies was in the first few months after initiation of a LAI -AP only.
This study was unable to establish any significant sociodemographic and clinical characteristics that were associated with the prescribing of LAI -AP combined with oral psychotropic medication. There is a paucity of published research regarding this comparison with Doshi et al. 29 also having reported no association. However, Aggarwal et al. 28 reported that patients taking concomitant LAI -APs and oral psychotropic medications were more likely to abuse alcohol. The authors could not account for this finding, except to note that prescribers may have thought that patients with alcohol abuse were more likely to be unreliable and have cognitive impairment.

Limitations
Limitations of our study include the lack of generalisability to other community clinics in SA, incomplete clinical records and the cross-sectional study design. The lack of information regarding the prescription of LAI -APs for specific diagnoses such as schizoaffective disorder and symptom severity is a further limitation, because this could have been a possible explanation for the high prevalence of polypharmacy.
To the best of our knowledge, this is the first report of prescription patterns for LAI -APs in a community health setting in SA. Globally, there is minimal information regarding prescription patterns of LAI -APs in community health settings. 36 Therefore, the strengths of the study are the community clinic setting and the information on real-world patients in usual care, given the general lack of data on antipsychotic utilisation in clinical practice from Africa. 57 Furthermore, this study provides some information on the prevalence of combining LAI -APs and oral psychotropic treatment, which is not well established in low-income and middle-income countries with restricted formularies.

Conclusions
The results of this study confirm that despite calls for the increased utilisation of LAI -APs in the earlier phases of schizophrenia, 7,10,17,46 LAI -APs in SA were prescribed mainly for older male patients who were not gainfully employed, with dual diagnoses and who were not adherent to oral medication. The authors highlight the high prevalence of polypharmacy in patients receiving LAI -APs and the lack of SGA LAI -APs in community psychiatric clinics in Johannesburg. Further research is needed to establish the prescribing habits for LAI -APs in other provinces in SA and to investigate the adherence and quality of life of patients on LAI -APs compared with oral antipsychotics.