|Year : 2020 | Volume
| Issue : 1 | Page : 30-36
Antipsychotic prescription and polypharmacy among outpatients with schizophrenia in a Nigerian hospital
Ihechiluru Goodnews Anozie, Bawo O James, Joyce O Omoaregba
Department of Clinical Services, Federal Neuropsychiatric Hospital, Benin-City, Nigeria
|Date of Submission||17-Jun-2019|
|Date of Acceptance||23-Oct-2019|
|Date of Web Publication||14-Jan-2020|
Dr. Ihechiluru Goodnews Anozie
Department of Clinical Services, Federal Neuropsychiatric Hospital, P.M.B 1108, Benin-City
Source of Support: None, Conflict of Interest: None
Background: International guidelines recommend antipsychotic monotherapy as the ideal treatment option in pharmacotherapy for schizophrenia, though this yields modest outcomes in a third of patients. Antipsychotic polypharmacy (APP) has been tried in many patients with schizophrenia to improve outcomes in those with poor treatment response. Objectives: This study examined the pattern of antipsychotic prescription and polypharmacy among outpatient attendees with schizophrenia in a Nigerian psychiatric hospital. Methods: A cross-sectional study of 320 attendees with schizophrenia at the consultant outpatient department was undertaken. We administered a socio-demographic questionnaire, antipsychotic medication and health questionnaire to record the general health indices and the prescribed antipsychotic medication of participants and the Mini-International Neuropsychiatric Interview (MINI) Version 6.0 (psychosis module). Results: Oral second-generation antipsychotics (SGAs) monotherapy was most commonly prescribed. The prevalence of APP was 50.9%. Participants on simultaneous anticholinergic agents (P < 0.001), a twice-daily antipsychotic dosing interval (P < 0.001,) alcohol use (P = 0.02), antidepressant use (P = 0.02) and a current episode of schizophrenia on the MINI (P < 0.001) were more likely to be on an APP regimen. Conclusion: Although a preference for SGA monotherapy was observed, the prevalence of APP remained high. Clinicians, therefore, should be cautious regarding the clinical utility of APP and discourage its persistent use.
Keywords: Antipsychotics, Nigeria, polypharmacy, prescription, schizophrenia
|How to cite this article:|
Anozie IG, James BO, Omoaregba JO. Antipsychotic prescription and polypharmacy among outpatients with schizophrenia in a Nigerian hospital. Niger Postgrad Med J 2020;27:30-6
|How to cite this URL:|
Anozie IG, James BO, Omoaregba JO. Antipsychotic prescription and polypharmacy among outpatients with schizophrenia in a Nigerian hospital. Niger Postgrad Med J [serial online] 2020 [cited 2020 Feb 26];27:30-6. Available from: http://www.npmj.org/text.asp?2020/27/1/30/275812
| Introduction|| |
Schizophrenia is a chronic debilitating illness of the mind with far-reaching consequences on social, interpersonal and occupational functioning in those affected. It significantly contributes to the global burden of disease. Antipsychotic medications, which are the mainstay of treatment, yield modest outcomes as they improve positive symptoms but are less effective on negative and cognitive symptoms. About a third of patients with schizophrenia achieve symptomatic and functional improvement with antipsychotic monotherapy, such that 'poor responders' may require other treatment options to improve outcomes.
Over the past decade, research evidence suggests that clinicians currently prefer prescribing atypical antipsychotic agents to typical antipsychotics, resulting in the reduction of typical-atypical prescription ratios in developing countries and reversal in developed countries.,,, International guidelines and expert consensus documents recommend monotherapy as the ideal treatment option., However, due to the overall poor prognosis of schizophrenia and the desire to improve outcomes, antipsychotic polypharmacy (APP), described as the simultaneous use of two or more antipsychotics, has been tried in many patients with schizophrenia., This trend of APP prescription has persisted in clinical practice to date., Higher rates of APP is associated with treatment resistance, management of acute exacerbation of psychosis, avoiding the use of high-dose monotherapy and arrested medication switch. Other associated factors include in-patient treatment, anticholinergic use, the worsening severity of illness and the use of depot medications.,,
We set out to study the pattern of antipsychotic prescription and polypharmacy among outpatient attendees with schizophrenia at the Federal Neuropsychiatric Hospital (FNPH), Benin-City, Nigeria, given that available evidence from Nigeria are few and psychopharmacotherapy is the main thrust of treatment in this environment.
| Methods|| |
Ethical clearance and approval was obtained from the Ethics and Research Committee of the FNPH, Benin-City, Edo State, Nigeria, on November 11, 2016 (Protocol Number: PH/A.864/Vol. X/55). No identifying information was collected during the review.
Study design and location
We carried out a descriptive, cross-sectional study of service users of the consultant outpatient department of the FNPH, Benin-City, Nigeria. The hospital is a 270-bed facility which provides a wide range of psychological services and interventions, including emergency and general medical in-patient services, outpatient care and emergency services to persons with psychological disorders.
A total of 320 participants were recruited for the study. To be included in the study, a patient must be within the age range of 18–65 years, diagnosed with schizophrenia by an attending consultant psychiatrist according to the tenth edition of the International Classification of Diseases-10 criteria and had provided written informed consent to participate in the study. We excluded patients who were acutely ill at the time of recruitment, unable to understand the essence of the study or had not received antipsychotic treatment at least 6 months before recruitment.
Sample size calculation and sampling
This report is a part of a wider study that explored the prevalence and correlated of APP and high dose antipsychotic prescriptions among outpatients with schizophrenia. Using the prevalence of 38% and the sample size for this cross-sectional study were calculated using  After adjusting for a population <10,000, an inflationary rate of 10% was included to boost the power of the study, resulting in a total of 320 participants. We used the systematic random sampling method in the recruitment of the participants.
A working definition of polypharmacy
This study defined APP as outpatients who were on two or more antipsychotics at the time of the study, regardless of the form of combination or route of the administration of the medication.
A proforma designed by the researcher was used to obtain data on age, gender, employment, educational and marital status.
Antipsychotic medication and health questionnaire
This questionnaire was designed to capture data regarding the current prescription of antipsychotics (oral and depot antipsychotics), dosing regimen, use and the dose of anticholinergic agents. Data on illness characteristics, including duration of illness, duration of treatment and cost of medication as well as the presence of physical comorbidity, were also collated.
The Mini-International Neuropsychiatric Interview Version 6.0 (psychosis module)
The Mini-International Neuropsychiatric Interview (MINI), a structured diagnostic interview schedule, was used in the confirmation of the diagnosis of schizophrenia.
The study spanned 17 weeks (July–October 2017). We recruited patients with schizophrenia who satisfied the study criteria within this timeframe to participate in the study. A total of 320 outpatients with schizophrenia consented to participate. The study participants were interviewed by one of the researchers who administered the socio-demographic, antipsychotic medication and health questionnaires and the MINI.
The Statistical Package for the Social Sciences, SPSS version 23 (IBM Corp, Armonk, NY, USA), was used to analyse the collated data. The results are presented in tables. For bivariate analyses, the outcome variable was the proportion of patients with APP. Relationships between categorical and continuous variables and APP were tested using the Chi-square test and Student's t-test, respectively. Statistical significance was set at P < 0.05.
| Results|| |
Socio-demographic and clinical characteristics of participants
There were 167 (52.2%) female, with the age range of 31–40 years (38.8%) having the highest number of respondents. About two-thirds (68.1%) of the participants were 'single', while a third of the respondents (n = 112, 35%) were employed, with slightly less than half of the employed respondents (45.5%) earning below the monthly national minimum wage of N18000 ($50). A third (34.4%) of the respondents had a post-secondary level of education. [Table 1] shows the clinical characteristics of the participants. Paranoid schizophrenia (n = 232, 72.5%) was the most common diagnosis, followed by undifferentiated schizophrenia (20.3%). Nearly half (49.7%) had a current psychotic episode at the time of the study. Using the body mass index protocol, more than a third (36.9%) were either overweight or obese. In addition, 7.2% and 2.2% had comorbid hypertension and diabetes, respectively.
Pattern of antipsychotic prescribing and polypharmacy
The pattern of antipsychotic prescription to the respondents is shown in [Table 2]. Oral second-generation antipsychotics (SGAs) were more commonly prescribed than oral first-generation antipsychotics (FGAs), either as monotherapy or in combinations with long-acting injections (LAI). Olanzapine (33.1%) was the most commonly prescribed oral agent, followed by risperidone (24.4%) and aripiprazole (1.3%), respectively. Regarding oral FGAs, trifluoperazine (21.6%) and chlorpromazine (14.7%) prescriptions were more common than haloperidol prescriptions (7.5%). A total of 168 participants were on depot antipsychotics, mostly in combination with oral antipsychotics, particularly long-acting fluphenazine decanoate injections.
For participants on monotherapy, two-third (69%) of the respondents received SGA prescriptions, a sharp contrast to nearly a third (31%) of the participants on FGAs. In addition, olanzapine (40.5%) was the most common prescribed SGA, followed by risperidone (25.9%). Among the typical antipsychotic agents, 14.6% of the participants were on trifluoperazine, while 8.2% received chlorpromazine. Only 8 (2.5%) respondents were on depot antipsychotics as monotherapy.
Regarding the pattern of prescription for polypharmacy as seen in [Table 3] (n = 163), nearly all (98.2%) combinations included an LAI. The common combinations were intramuscular fluphenazine + trifluoperazine (22.7%), intramuscular fluphenazine + risperidone (20.2%) and intramuscular fluphenazine + olanzapine (19%) combinations. The simultaneous prescriptions of 3 different antipsychotics, consisting of one LAI with two oral preparations, were noted in 8% of the respondents. A large majority (90.8%) of participants received a single oral and depot combination. When polypharmacy was classified based on the generation of the antipsychotic agents, 52.1% of the respondents received typical + atypical antipsychotic combinations, while 47.9% had two typical antipsychotic combinations.
Twothirds of the participants on polypharmacy received polypharmacy prescriptions for augmentation/maintenance, with a further 18.4% on polypharmacy from the commencement of treatment. Twenty-one (12.9%) participants received combination regimes due to the worsening severity of the illness. Only two respondents were on polypharmacy following a failed clozapine trial.
Correlates of antipsychotic polypharmacy
Males were significantly more likely to receive APP than females (P = 0.01, odds ratio [OR] =1.75 [1.12–2.72]). Respondents who were categorized as unmarried were nearly twice as likely to be receiving APP compared to the married group (P = 0.04, OR = 1.80 [1.00–3.27]). Furthermore, participants with a longer duration of illness were more likely to be on APP when compared to those with shorter illness duration (t = 2.03, P = 0.04).
As shown in [Table 4], respondents who had concurrent anticholinergic use (P < 0.001, OR: 40.24 [20.66–78.36]), alcohol use (P = 0.02, OR = 3.31 [1.21–9.05]), antidepressant use (P = 0.02, OR = 4.02 [1.10–14.69]), twice daily dosing interval of antipsychotics (P < 0.001, OR = 3.90 [1.92–7.91]) and current episode of schizophrenia (P < 0.001, OR = 3.86 [2.43–6.1]) were more likely to receive APP.
|Table 4: Comparison of clinical related characteristics of participants and antipsychotic polypharmacy|
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| Discussion|| |
The pattern of antipsychotic prescription
The current trend in the prescription of atypical agents, either as monotherapy or alongside LAI indicates a shift in prescribing the practice, as previous evidence from the same study setting showed a preference for FGAs to SGAs. Furthermore, other relevant research findings show that atypical antipsychotic prescriptions are now more common than typical antipsychotic prescriptions, with olanzapine being the most commonly prescribed single oral agent., Hence, the changing direction of evidence in the prescribing trends of antipsychotics may reflect the prescriber's efforts to reduce the impact of undesirable adverse effects of FGAs, given that brands of SGAs are now more locally available and affordable.
In Nigeria, the historical use of LAIs in Nigeria has been well highlighted. James et al. reported that Nigerian psychiatrists estimate that 40% of their patients with psychosis were on depot preparations, as clinicians viewed the use of these long-acting preparations as a way of garnering healthy engagement and patient participation in their treatment, given that it appears culturally acceptable to presume enhanced potency of intramuscular preparations. Similarly, Kenicer et al., in their survey of psychiatrists to identify trends in antipsychotics prescribing preferences, reported that more experienced psychiatrists were more likely to prescribe depot preparations at different stages of management due to poor response, tolerability of preparations and patient's preferences.
Regarding polypharmacy combinations, our findings compare favourably with reports of Armstrong and Temmingh in which FGA + FGA accounted for 55.49% of APP prescriptions, FGA + SGA combinations were 35.97% and SGA + SGA agents were 5.49%, but differ significantly from the report of Kim et al. in which only 6.4% had typical antipsychotic combinations, 46.82% received typical-atypical antipsychotic combinations, while atypical antipsychotic combinations were prescribed to another 46.82%., The observed differences may be to attributed to the significant impact of the Korea Medication Algorithm Project for Schizophrenia which recommended atypical antipsychotic use as a first-line medication, even without any prior typical antipsychotic trial in such patients, as well as the reduced propensity of atypical agents to cause extrapyramidal side effects (EPSEs). Globally, low rates of atypical APP may result from the higher cumulative cost of combining two SGAs., Furthermore, the global cost of Risperdal Consta®, an SGA depot occasionally available for use in Nigeria is highly prohibitive, whether for single or combination use, given the out-of-pocket payment system and the high foreign exchange rates.
The proportion of patients with a prescribed combination of three antipsychotic drugs was 8%, all involving one LAI and two oral formulations. This mirrors the report of Rittmannsberger but is much lower when compared with 31.8% reported by Zaraa et al., In their work, Zaraa et al. inferred that the increased rate of antipsychotic combination use in the management of patients with schizophrenia indicated a poor level of compliance with standards and safety protocol, in addition to the likelihood of increased risk of adverse effects. However, they also observed that most of the doses of the added antipsychotic agents where prescribed below the minimum effective dose necessary for therapeutic response, suggesting that their role may be additive rather than for symptomatic improvement. Furthermore, we observed that the most common polypharmacy combination was depot fluphenazine + tablet trifluoperazine (22.7%), followed by depot fluphenazine + risperidone (20.2%) and depot fluphenazine + olanzapine combinations (19%), which differed from other reports because of differences in availability of antipsychotic agents at different locations and the peculiarities of prescribers' preferences.,
Prevalence of antipsychotic polypharmacy
The prevalence of APP was found to be 50.9% in this study, which revealed a significant drop from 70.4%, as reported by Igbinomwanhia et al. This significant reduction may not be unconnected to efforts geared towards promoting compliance with international treatment standards among clinicians. Globally, the reported prevalence rates of APP vary significantly due to methodological differences used in the study design. Gallego et al., in their comprehensive review on global and regional trends in the prevalence of APP, reported a varying prevalence range from 16% to 32%. Asian researchers reported a prevalence of 27% in Hong Kong, 20.4% in Korea, indicating the possibility of a specific pharmacokinetic ability of Asians to respond to low doses of antipsychotics and consequently having lower rates of APP.,,
International treatment protocols recommend that clozapine therapy should be commenced after two failed trials of monotherapy rather than polypharmacy., However, only two patients were on a combination regimen following an unsuccessful clozapine trial, in line with international guidelines. This parallels the finding of Tapp et al. who reported that only 4.3% of their respondents had received APP after failed clozapine therapy. This presupposes that there is a greater degree of noncompliance with standard treatment protocols, as evidence show that there has not been a significant reduction in the time taken by clinicians to initiate clozapine therapy after failed trials of monotherapy, given the widespread acceptance of anecdotal practice of polypharmacy. Locally, clinicians may prefer the use of polypharmacy to a trial of clozapine after unsuccessful monotherapies due to the difficulties involved in the outpatient weekly measurements of granulocytes as is recommended in the clozapine therapy protocol.
Correlates of antipsychotic polypharmacy
Males and 'single' individuals were more likely to have received APP compared to females and the married group, respectively. However, Igbinomwanhia et al. did not report any significant association between socio-demographic variables and APP, while some other researchers have reported associations between APP and socio-demographic variables.,, These conflicting reports may suggest that the level of evidence linking socio-demographic variables and APP may be regarded as weak or modest at best, thereby creating an opportunity for further investigations. However, males had higher rates of APP than females, and these may not be unconnected with the need to manage aggression and greater illness severity in these individuals.
APP was found to be significantly associated with subjects who use alcohol without other psychoactive substances. Other research works have mixed reports regarding this association, as such findings may be due to differences in disclosure of substance use by participants or how substance use was assessed among participants. Furthermore, poor treatment response rates among patients with schizophrenia have been associated with co-occurring substance use disorders. The significant association between the use of anticholinergic agents and APP may reflect the risk of EPSEs in this cohort. In addition to the side effects of antipsychotics themselves, anticholinergic agents also contribute significantly to the overall side effect burden and could worsen cognition and sedation.,
The use of depot antipsychotic medication was strongly associated with APP, mostly in FGA + SGA combinations as was also reported by Gallego et al. Xiang et al. noted that due to the lack of flexibility of depot preparations, one can justify the addition of oral antipsychotic agents to such a regimen. Other plausible reasons for the high use of oral-depot combinations could be due to affordability, presumed higher effectiveness and medication non-adherence. Furthermore, depot preparations, when used in combination with oral agents, often result in high dose prescriptions, with numerous challenges and clear drawbacks. The arrangement of scheduled depot clinics and adherence counselling may help in reducing APP prescribing, particularly depot-oral combinations, among patients with schizophrenia.
The strength of this study is that it adds to available research evidence on APP, which is a major area of concern in psychopharmacology. The limitations are that the findings of APP among outpatients may not be generalisable to inpatients, who may have higher doses of APP. Furthermore, the cross-sectional design may not be suitable in identifying probable causality between APP and its correlates. Third, participants who may have treatment-resistant schizophrenia for which APP was prescribed were not considered in the design of the study. Finally, a comprehensive view of prescribers' reasons for APP was not explored in this study.
In conclusion, this research shows the changing trend of the pattern of antipsychotic prescription in favour of SGA monotherapy as well as contributing evidence on the relatively high prevalence of APP. APP is associated with the use of depot medications, concurrent use of anticholinergic agents, as well as a current psychotic episode of schizophrenia. The identified gaps in this study can be further evaluated by employing a longitudinal design.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]