Antipsychotic Medication in Sub-Saharan Africa: A Systematic Literature Review

Abstract

Objective:

Schizophrenia is a treatable psychiatric condition affecting millions of people worldwide. However, there is limited evidence on the use of antipsychotic medications in certain areas of the world, such as Sub-Saharan Africa (SSA). The aims of this systematic literature review were to find papers focused on the use of antipsychotic drugs for treatment of individuals with primary psychotic disorders in SSA, to describe the origin and timeline of published reports, to assess the methodological quality of intervention outcome studies, to summarize the intervention strategies, to examine patient level outcomes, and to analyze temporal trends in study methodology over the observation window.

Methods:

Pubmed, PsychInfo, Cochrane Collaboration, and CINAHL databases were searched to locate studies conducted in SSA that focused on antipsychotic medication treatment for primary psychotic disorders and that investigated at least one patient level outcome. Articles written in English and published in peer-reviewed journals before April 2019 were included. Epidemiological studies, drug discontinuation studies, studies with drugs other than antipsychotics, and multi-center studies that did not specify SSA results were excluded. The authors used a standardized instrument to rate studies’ methodological quality.

Results:

Twenty six articles were reviewed. Based on studies’ methodological quality, three levels of evidence were found: single-group reports, quasi-experimental studies, and randomized controlled trials. Studies chosen analyzed the associations of antipsychotics with either improvement in psychiatric symptoms, presence of side effects, rates of remission, or improvement in functional status. Nine studies reported improvements in psychiatric symptoms associated with receiving an antipsychotic medication. Seven studies investigating side effects of antipsychotics found that they were associated with an increase in metabolic syndrome. Two studies reported that remission was achieved in the majority of subjects treated with antipsychotics, and one study reported improvements in functional status associated with receiving an antipsychotic.

Conclusions:

Although the results suggest that, despite side effects, treatment with antipsychotic medications may be beneficial for individuals with primary psychotic disorders in SSA, several gaps were identified in the current literature. There is a scarcity of research on antipsychotics from countries in sub-Saharan Africa apart from South Africa. Moreover, the underrepresentation of persons from racial or ethnic minority groups in this literature limits its generalizability. The implications for research and practice are discussed.

INTRODUCTION

Schizophrenia affects more than 20 million people worldwide and people with schizophrenia are 2-3 times more likely to die prematurely compared to the general population.¹ Schizophrenia and other psychotic disorders are defined by abnormalities which affect quality of life such as delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior and negative symptoms.² According to the World Health Organization, more than 69% of people with schizophrenia are not receiving appropriate care and 90% of people with untreated schizophrenia live in low- and middle- income countries, such as the countries in Sub-Saharan Africa (SSA). Lack of access to mental health services is an important issue in SSA and lower-and middle income countries more broadly.¹

In spite of the existing level of burden in many settings, schizophrenia is a treatable condition responsive to evidence-based treatments such as antipsychotic medications. There is however, a limited evidence base on the use of antipsychotic treatment for schizophrenia in SSA. Past reviews of the literature have focused mainly on the different types of treatment available. In a 2017 literature review of forty studies from eight countries, Chidarikire et al. concluded that people living with schizophrenia in SSA were mainly treated by faith, traditional healers and modern psychiatry, if treated at all.³ A 2015 literature review by Burns et al. found that approximately half of individuals seeking formal health care for mental disorders in Africa from 1990 to 2004 chose traditional and religious healers as their first-line treatment.⁴ There is a paucity of information that identifies and characterizes use of antipsychotic medications and their effects on patients with schizophrenia or other psychotic disorders in SSA. This systematic literature review of original research articles focused on the use of antipsychotic drugs for treatment of individuals with schizophrenia/primary psychotic disorders in SSA describes the origination and timeline of published reports, assesses the methodological quality of antipsychotic intervention outcome studies, summarizes the intervention strategies, examines patient level outcomes including information on racial and ethnic minority sub-groups and analyzes temporal trends in study methodology over the observation window.

METHODS

Study Selection

We searched the Pubmed, PsychInfo, Cochrane Collaboration and CINAHL databases for original antipsychotic outcome studies and clinical trials published up until April 2019. Our search strategy included combinations of the following key words: schizophrenia, schizoaffective disorder, psychosis, severe mental illness, chronic psychotic conditions, antipsychotic medication, antipsychotic, medication treatment, clinical trial, sub-Saharan Africa, and the individual countries of sub-Saharan Africa. We also did an African Journals Online search using the syntax schizophrenia for the first term and treatment, antipsychotic medication, antipsychotic, clinical trial, or medication treatment for the second term.

Our search yielded a total of 883 results, with a new total of 709 articles after removing 174 duplicates. The first two authors (SK and SS) screened all abstracts for relevance and found 129 pertinent articles. We then narrowed down the inclusion criteria to studies investigating primary psychotic disorders (including schizophreniform, schizoaffective, schizophrenia, and bipolar disorder), primary treatment with one or more antipsychotic medications, and at least one patient level outcome (for example, psychiatric symptoms, functional status, adherence, and side effects). We excluded epidemiological studies, drug discontinuation studies, studies with drugs other than antipsychotics, and multi-center studies that did not specify SSA results.

To ensure that the inclusion/exclusion criteria were being applied in the same way, three of the authors performed a dry run of abstract review. The first ten abstracts from PubMed and PsychInfo each were compiled into an Excel spreadsheet and the authors decided independently whether or not to include the articles. We compared our decisions and came to a consensus regarding any discrepancies. We then applied these uniform criteria to the rest of the articles, excluding 84 articles. Forty-five full text articles were screened to remove non-prospective studies and confirm the location of the studies. In total, 26 articles were included in the review. Figure 1 shows the publication review process.

Figure 1:

PRISMA Flowchart for Publication Review Process

Analytical Strategies

A data extraction checklist was developed to systematically code study characteristics including author, year, country, study design, sample description, control group, treatment, outcome measurement, and results.⁵ To rate the methodological quality of studies, we employed a modified version of the Methodological Quality Rating Scale (MQRS).⁶ This rating scale assesses the methodological quality of studies across 12 different dimensions (for example, study design and follow-up length). Cumulative MQRS scores for each study range from 1, poor quality, to 16, high quality. Working together, the first two authors (SK and SS) used the modified MQRS to rate the methodological rigor of each of the 26 studies included in this review.

RESULTS

Overview

Table 1 displays the characteristics of the 26 studies included in the final review. Study samples ranged in size from 12 to 207, with an average sample size of 207. 12 studies had a sample size between 12 and 50, 9 studies had a sample size between 51 and 150, and 5 studies had a sample size between 151 and 207.

Table 1:

Characteristics of Studies Included in Review

Author/Year	Country	Study Design	Sample Description	Control	Treatment	Outcome Measurement	Results
Luckhoff et al. 2019	South Africa	Prospective Cohort	106 minimally treated or antipsychotic-naive patients		flupenthixol decanoate over 12 months	Psychopathology evaluated using the Positive and Negative Syndrome Scale (PANSS)	treatment duration predicted improvement in psychopathology independent of age, sex, ethnicity, substance use
Ojagbemi et al. 2018	South Africa and Nigeria	Prospective Cohort	99 Xhosa (South Africa) and Yoruba (Nigeria)		flupenthixol decanoate for 3 months	Neurological soft signs (NSS) and extrapyramidal symptoms (EPS)	EPS recorded in 34 patients (38.6%). Akathisia in patients with a longer duration of untreated psychosis (r = 0.75, β = 0.70, p = 0.008). Association specific for parkinsonism (r = 0.75, β = 0.85, p = 0.008) and dyskinesia (r = 0.75, β = 1.70, p = 0.008).
Ezeme et al. 2017	Nigeria	Prospective Cohort	172 patients with schizophrenia		antipsychotics for 6 weeks	Improvement defined as ≥ 20% reduction in PANSS	Better response associated with medication adherence, good premorbid functioning, fewer negative symptoms, less cognitive impairment, less co-morbidity, and short duration of untreated psychosis.
Ezeme et al. 2016	Nigeria	Prospective Cohort	172 patients with schizophrenia		antipsychotics for 6 weeks	Improvement defined as ≥ 20% reduction in PANSS	68% had a good response while 32% had poor response.
Olose et al. 2017	Nigeria	Prospective Cohort	60 antipsychotic naive patients with schizophrenia	60 first-degree relatives matched for gender and age	antipsychotics for 12 weeks	Fasting lipid profiles at baseline and after 12 weeks	Mean endpoint of total cholesterol/lipids significantly higher than initial values. Prevalence of dyslipidemia 13%. Patients on atypical antipsychotics had higher risk for dyslipidemia.
Emsley et al. 2017	South Africa	Prospective Cohort	126 patients with first-episode psychotic disorder		standardized antipsychotics for 12 months	Neurological Evaluation Scale (NES); State- and trait-related associations with psychopathology, and functionality	Significant effects for all NSS domains. Improvements in sensory integration predicted by working memory (p=0.01); Improvements in motor sequencing predicted by working memory (p=0.005) and functionality (p=0.005); NES total change predicted by disorganised symptoms (p=0.02). More substantial associations between trait-related vs. state-related change.
Chiliza et al. 2015	South Africa	Prospective Cohort	126 patients with chronic psychotic disorders		flupenthixol decanoate for 12 months	Psychiatric Symptoms	12% non-responders. Non-responders were younger, had more disorganised symptoms, poorer functioning, lower quality of life, more prominent neurological soft signs (NSS) and lower BMI.
Chiliza et al. 2016	South Africa	Prospective Cohort	207 patients with first episode schizophrenia		flupenthixol decanoate for 12 months	Adherence, Psychiatric Symptoms, Functional Status; Quality of life, Medication tolerability	72% completed 12 months of treatment. Good acceptance, tolerability and adherence to depot. 82% responded to treatment, 60% remitted. Relapse in 19%, and 5% were treatment resistant.
Emsley et al. 2013	South Africa	Prospective Cohort	31 patients treated for first and second episodes of psychosis		2-year treatment with risperidone long-acting injection (RLAI) for a first episode and 2-year further treatment phase for a recurrence episode	PANSS	PANSS and overall response rates similar for the 2 treatment periods. 55% second episode patients discontinued the study compared with 28% first episode, suggesting reduced effectiveness after illness recurrence. Non-responsiveness in 16%, consistent with the hypothesis that relapse may be biologically harmful in a subset of patients.
Emsley et al. 2008	South Africa	Prospective Cohort	50 newly diagnosed patients with schizophrenia or schizophreniform disorder aged 16 to 43		long-acting injectable risperidone for 2 years	Remission	Remission achieved in 64%. Of those achieving remission, 97% maintained this status until study completion.
Emsley et al. 2008	South Africa	Prospective Cohort	50 patients aged 15 to 43 years with newly diagnosed schizophreniform disorder or schizophrenia		long-acting injectable risperidone for 2 years	Remission; EPS; prolactin levels	36 patients (72%) completed the trial. Of 39 (78%) who showed clinical response of 50%, 4 relapsed. 32 (64%) remitted. 10 patients required anticholinergic medication, 1 developed dyskinesia. Prolactin levels were elevated in 18 (50%). Mean increase in BMI was 4.8 kg/m (SD, 3.8 kg/m).
Oosthuizen et al. 2003	South Africa	Prospective Cohort	57 subjects with first-episode psychosis		haloperidol for 12 months	Psychiatric Symptoms; Side Effects	Twelve-month incidence of tardive dyskinesia (TD) was 12.3% (N = 7). TD patients were older (p = .01) and received higher doses of haloperidol (p = .004). Age (p = .031), negative symptoms (p = .028), and dose of haloperidol (p = .016) were predictors of TD risk.
Brook S. 2000	South Africa	Prospective Cohort	12 patients with acute exacerbation of schizophrenia		Short term intramuscular (IM) ziprasidone (3 days) transitioned to oral ziprasidone (days 4 and 5)	Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI); EPS	Improvements in BPRS and CGI maintained on days 4 and 5. No extrapyramidal syndrome or serious adverse events. The transition from IM to oral ziprasidone was well tolerated.
Oosthuizen et al. 2001	South Africa	Prospective Cohort	35 patients with a first episode of psychosis		haloperidol for 12-weeks	PANSS; EPS	Mean reduction in PANSS was 30.3% (SD 20.9%) at 6 weeks and 41.4% (SD 16.6%) at 12 weeks. No significant changes in mean extrapyramidal symptoms.
M. R. Olivier et al. 2015	South Africa	Prospective Case Control	92 patients with first episode schizophrenia	100 healthy controls	flupenthixol decanoate for 12 months	PANSS; MATRICS Cognitive Consensus Battery (MCCB) composite score over 12 months	Significant group × time effect (p ≤ 0.0001) for the MCCB composite score. For other MCCB domains there were significant group × time effects for attention and vigilance (p ≤ 0.0001), visual learning (p ≤ 0.0001), verbal learning (p = 0.005) and working memory (p ≤ 0.0001). Moderate correlations between change in MCCB composite score and change in symptomatology.
Kaminga et al. 2018	Malawi	Prospective Cohort	126 first episode psychosis patients (aged 18-65)		antipsychotic for 18 months	Remission in positive and negative symptoms defined by the Remission in Schizophrenia Working Group criteria	98 (78%) completed follow-up, 70 (71.4%) remitted within mean duration of 8.05 (4.54) months. Long DUP, poor insight, being separated/divorced/widowed, deteriorating premorbid functioning, family history of psychiatric disorders, and male gender delayed remission.
Saloojee et al. 2017	South Africa	Prospective Cohort	67 antipsychotic naive patients with a first episode of severe mental illness	67 controls	antipsychotic for 12 months	Side Effects: Metabolic Syndrome measured using the 2009 Joint Interim Statement criteria (Albert et al. 2009)	Of 64 study subjects without baseline metabolic syndrome, only 36 completed the 12-month follow-up (response rate 56.3%). The incidence of metabolic syndrome was 5.5%.
B. Chiliza et al. 2015	South Africa	Prospective Cohort	107 largely antipsychotic naïve, first-episode schizophrenia patients		flupenthixol decanoate for 12 months	Side Effects: metabolic syndrome, body mass, fasting blood glucose and lipids	Significant increases in BMI (P < .0001), waist circumference (P = 0.0006) and triglycerides (P = 0.03) and decrease in HDL (P = 0.005). Change in BMI was only correlated with change in triglycerides (P = .008). Only significant predictor of BMI increase was lack of substance abuse (P = .002).
Emsley et al. 2015	South Africa	Prospective Cohort	22 never-treated, non-substance-abusing patients with first-episode schizophrenia or schizophreniform disorder	23 healthy controls	risperidone or flupenthixol long acting injection	Side effects: brain volume changes on MRI, psychopathology, insight, functionality, cognitive performance, and motor symptoms	Caudate but not putamen sizes were larger in patients at baseline. No significant group x time interactions were found for any MRI regions.
Emsley et al. 2017	South Africa	Prospective Cohort	23 previously antipsychotic naive patients with a first episode of schizophrenia or schizophreniform disorder	53 matched healthy individuals	lowest possible dose of flupenthixol decanoate depot formulation	Side effects: brain volume changes, EPS, weight gain	Excessive cortical volume reductions were observed in patients, with no significant group differences for changes in subcortical grey matter and white matter volumes. In multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p= 0.04). No significant association between cortical volume changes and psychopathology, functionality, and extrapyramidal symptoms or age, gender, and duration of untreated psychosis.
Emsley et al. 2015	South Africa	Prospective Cohort	22 antipsychotic naive patients with first episode schizophrenia	23 healthy volunteers	risperidone long acting injection or flupenthixol decanoate for 13 weeks	Brain volume on MRI	Ventral diencephalon volume reduction correlated bilaterally with body mass increase and HDL-cholesterol reductions, and unilaterally with blood glucose elevation.
Emsley et al. 2005	South Africa	Prospective Randomized Parallel Group Study	45 clinically stable patients with schizophrenia		quetiapine and haloperidol for 52 weeks	Side Effects: change in BMI and glycosylated haemoglobin (HBA1c) levels	No between-group differences for BMI (F=1.90, p=0.1) and HBA1c (F=1.17, p=0.3) values, and there were no significant changes in BMI for either group. HBA1c levels decreased for the haloperidol group (−1.5%, p=0.04), but not for the quetiapine group (−0.3%, p=0.5).
Oosthuizen et al. 2004	South Africa	Prospective Randomized Controlled Study	40 subjects with first-episode psychosis		2 vs. 8 mg/d of haloperidol for 6 weeks	Psychiatric Symptoms: PANSS; Side Effects: extrapyramidal side effects	Both treatments were equally effective in reducing the PANSS. Low dose haloperidol was better tolerated, with fewer extrapyramidal effects, less frequent use of anticholinergic medication and smaller prolactin elevations.
Landmark et al. 1994	South Africa	Prospective Randomized Controlled Study	93 South African Xhosa patients with schizophrenia		fluphenazine decanoate depot injection used alone or fluphenazine decanoate with fluphenazine HCl IM	Length of hospital stay	The combined treatment significantly shortened the length of hospital stay. The combined treatment group also obtained significantly higher symptom improvement.
Emsley et al. 2004	South Africa	Prospective Randomized (Active) Controlled Study	45 patients aged 18 to 65 w/ tardive dyskinesia with either schizophrenia or schizoaffective disorder		quetiapine (N = 22) or Haloperidol (N=23) for 12 months	Side effects: changes in tardive dyskinesia	The quetiapine group showed significantly greater improvements in dyskinesia (6 and 9 months [p ≤ .01]) and CGI dyskinesia. Response rate (≥ 50% symptom reduction) was greater with quetiapine than haloperidol (64% [9/14] and 37% [6/16] at 6 months; 55% [6/11] and 28% [4/14] at 12 months). Serum prolactin differed significantly between groups (p=.005), with elevation for haloperidol.
S. Brook et. al. 1998	South Africa	Prospective Randomized (Active) Controlled Study	44 patients age 18 - 65 with schizophrenia, schizophreniform disorder and substance induced psychotic disorder who required acute neuroleptic treatment		parenteral zuclopenthixol acetate (N=24) or haloperidol (N=20) parenterally than orally for 28 days	Psych Symptoms: Brief Psychiatric Rating Scale (BPRS), Clinical Global Improvement Scale (CGI) and the Simpson Angus Scale (SAS)	No significant differences between the two agents in efficacy and tolerability.

Studies were from Nigeria (n=3), South Africa (n=21), Malawi (n=1), and 1 multi-center study in Nigeria and South Africa. Most studies were published between 2015 and 2019, with 5 studies published in 2015 and 2017 (Figure 2).

Figure 2:

Number of Publications Published per Year

Designs

Out of 26 total studies, 15 were single group pre-test post-test studies, 5 were quasi-experimental studies with non-equivalent control groups, and 6 were randomized controlled studies. There were 5 studies that compared two different antipsychotic medications to each other, and those were considered randomized controlled studies in our analysis. S. Brook et al. 1998 compared haloperidol to zuclopenthixol acetate while Emseley et al. 2004 and Emsley et al. 2005 compared haloperidol to quetiapine.^7,8,9 Emsley et al. 2015 compared risperidone to flupenthixol decanoate in 2 different studies.^22,23 In addition, there was 1 study, Landmark et al. 1994, that compared fluphenazine decanoate depot alone to fluphenazine decanoate with HCl, which was also considered a randomized controlled study in our analysis.¹⁰

Out of 26 total studies, 9 studies were blinded and 25 were single site studies. The only multisite study was Ojagbemi et al. 2018 which involved data from both South Africa and Nigeria.¹¹

Funding

The top three sponsors for the studies in this review were the Medical Research Council of South Africa, the New Partnership for Africa’s Development (NEPAD), and Lundbeck International. Out of 26 total studies, 12 received funding from the Medical Research Council of South Africa; 10 received funding from NEPAD; and 6 received funding from Lundbeck International. There were 2 studies that were funded completely by their authors, and 2 studies that were funded by an academic institution, the University of Stellenbosch. A variety of pharmaceutical companies provided funding, such as Janssen (for 2 studies), Pfizer Incorporated (for 1 study), and Bristol Myers Squibb (for 1 study). With regard to government funding, there was 1 study that assessed patients in a federal government funded hospital in the South-East region of Nigeria, and another study that was provided funding from the Office of the US Global AIDS Coordinator and the US Department of Health and Human Services. The National Research Foundation of South Africa and the Discovery Foundation provided funding for 1 study each. In addition, Harry Crossley and MATRICS Assessment Inc. provided funding for 1 study each. Lastly, 1 study stated that the authors received no specific grant from any funding agency, commercial or not-for-profit sector.

Populations

Gender

All of the studies reported the gender make-up of the sample groups. The samples were predominantly male, and two studies consisted of a sample with a female majority.^12,13

Racial and Ethnic Groups

17 (65.4%) studies reported the racial demographics of the samples. The total sample size across these 17 studies was 1158: 263 (22.7%) were black, 769 (66.4%) were mixed, and 126 were white (10.9%).

2 studies listed the ethnic makeup of their samples. Landmark’s sample consisted of 93 Xhosa patients whereas Ojagbemi had 81 Yoruba patients and 18 Xhosa patients.^10,11

Racial and ethnic differences in treatment outcomes were not examined in any of the studies.

Diagnosis

Out of 26 total studies, 24 had samples with patients who were diagnosed with either schizophrenia or schizophreniform disorder. Three of these studies also included patients with bipolar disorder. 2 studies stated that their sample patients experienced first-episode psychosis and didn’t identify a specific psychotic disorder.

Antipsychotics

Out of 26 total studies, 6 did not clarify which antipsychotics were administered. Ten studies utilized flupenthixol decanoate, 5 studies utilized risperidone, 6 studies utilized haloperidol, 2 studies utilized quetiapine, 1 study utilized zuclopenthixol acetate, and 1 study utilized ziprasidone.

Outcomes

Psychiatric Symptoms

9 studies looked at psychiatric symptoms as an outcome measure of antipsychotics, with 6 studies specifying using the Positive and Negative Syndrome Scale (PANSS), 1 study using the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression of Severity (CGS)¹⁴, and the other 2 studies not specifying the measure used. In a prospective cohort study by Oosthuizen in 2001, 35 patients with a first episode of psychosis were treated with Haloperidol for 12 weeks, restricting the dose to 1 mg for the first 4 weeks.¹⁵ The mean percentage reduction in Positive and Negative Symptom Scale score between baseline and 6 and 12 weeks was 30.3% (SD 20.9%) and 41.4% (SD 16.6%), respectively.¹⁵ In a prospective cohort study by Ezeme et al, out of 172 schizophrenia patients treated with typical and atypical antipsychotics for 6 weeks, 68% had a 20% or more reduction in PANSS.¹³

Studies comparing different treatments found no difference in PANSS between 2 mg and 8 mg of haloperidol¹⁶ and no difference in BPRS and CGS scores between haloperidol and zuclopenthixol acetate.⁷ One particular study found that treatment reduction was associated with reduction of psychiatric symptoms.¹⁷ In a prospective cohort study conducted in South East Nigeria, good medication adherence, good premorbid functioning, fewer negative symptoms, less cognitive impairment, absence of comorbid personality disorder, and short duration of untreated psychosis were associated with a greater reduction in psychiatric symptoms.¹⁸ In another prospective cohort study by Emsley, 31 patients were treated with long acting risperidone injectable for a first and second episode of schizophrenia, and no difference in PANSS was found between the two treatments.¹⁹

Side Effects

Eight studies investigated side effects as an outcome of antipsychotics, primarily looking at metabolic syndrome and extrapyramidal symptoms. Most studies found that antipsychotics were associated with an increase in metabolic syndrome, but a prospective randomized parallel group study by Emsley et al comparing quetiapine and haloperidol found no significant metabolic changes from baseline in either group.⁹ A prospective cohort study by Chiliza that looked at 107 largely antipsychotic naive first episode schizophrenia patients found significant increases in BMI (p<.0001), waist circumference (p=.0006), and triglycerides (p=0.03) and a significant decrease in HDL (p=.005). However, no changes were seen in systolic and diastolic pressure, glucose, and cholesterol values over time. Furthermore, the change in BMI was correlated with the change in triglycerides.²⁰

Studies specifying tardive dyskinesia as a side effect found that patients with tardive dyskinesia were older and received higher mean doses of haloperidol²¹ and that between quetiapine and haloperidol, treatment with quetiapine was associated with a significantly greater improvement in tardive dyskinesia.⁸ An early prospective cohort study by Oosthuizen suggests that the dose of haloperidol is important in determining side effects. Oosthuizen found that there was no significant difference in EPS from baseline in patients treated with 1 mg of haloperidol over 12 weeks.¹⁵ A 2004 study by Oosthuizen further clarified that a 2 mg dose of haloperidol over 6 weeks was associated with fewer extrapyramidal side effects (EPS) than a 6 mg dose.¹⁶ Lastly, a prospective cohort study that looked at treatment with low dose flupenthixol decanoate for 3 months recorded treatment induced EPS in 38.6% of patients, and found that spontaneous EPS was associated with treatment emergent akathisia in patients with a longer duration of untreated psychosis.¹¹

Between 2015 and 2017, Emsley et al published three studies looking at changes in brain volume on MRI as a side effect of antipsychotic medication. No other publication mentioned brain volume as a possible side effect. When comparing 22 never-treated patients with a first episode of schizophrenia who were treated with risperidone or flupentixol decanoate with 23 matched healthy controls over 13 weeks, Emsley found that caudate sizes were larger at baseline in patients and that there was no significant association between caudate volume and improvement in psychotic symptoms.²² Another paper published in the same year conducted different analyses on the data and noted that ventral diencephalon volume reduction was strongly correlated bilaterally with body mass increase and HDL-cholesterol reductions, and unilaterally with blood glucose elevation; there were no significant changes in pre-cortical thickness.²³ However in 2017, in another prospective cohort study comparing 23 first episode patients on flupentixol decanoate with 53 healthy controls, Emsley observed excessive cortical volume reductions in patients [−4.6 (6.6)%] v. controls [−1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. Furthermore, there was no significant association between cortical volume changes and psychopathology, functionality, duration of untreated psychosis or EPS.²⁴

Remission

3 studies considered remission as a possible outcome.^19,25,26 A prospective cohort study in Malawi looked at outcomes in 126 first episode psychosis patients treated with antipsychotic medication for 18 months. Using the Remission in Schizophrenia Working Group criteria, 71.4% of patients achieved symptomatic remission with a mean duration of 8.05 months. A number of factors delayed symptomatic remission, including being male, family history of psychiatric disorders, deteriorating premorbid functioning, and being separated/divorced/widowed.²⁵ In Emsley’s prospective cohort study looking at treatment of 50 newly diagnosed patients with ILAR for 2 years, 64% of the patients achieved remission.²⁶ In a 2013 study by Emsley looking at 2 different treatment periods of 31 patients, remission rates were similar for both treatment periods.¹⁹

Functional Status

Only one study primarily investigated functional status. Olivier et al analyzed changes in the MATRICS Cognitive Consensus Battery (MCCB) score over 12 months between 92 patients with first episode schizophrenia and 100 healthy controls. Using a mixed-effects model, patients had a greater change in MCCB composite score than controls. There were significant group x time effects for attention and vigilance, visual learning, verbal learning, and working memory.²⁷

DISCUSSION

Aims of Study

Sub-Saharan Africa has a high burden of mental illness, and antipsychotic medications are essential in treatment. The goal of this study was to provide a systematic literature review of antipsychotic medications tested in sub-Saharan Africa. We found 26 studies, focusing our review on a few key aspects.

Our first aim was to study the origination and timeline of published reports. While the majority of reports were from South Africa, perhaps not surprising given that South Africa is a higher-income nation, only three (11.5%) reports included countries outside of South Africa. A review of poverty and common mental disorders in 2010 looked at several low and middle income countries, including many in SSA, and found positive associations between poverty and mental illness.²⁸ Thus, the paucity of research on antipsychotics from other countries in sub-Saharan Africa is surprising, and suggests a gap in evidence that needs to be addressed.

Another aim was to examine the inclusion of people from racial and ethnic minority groups. Only two studies mentioned ethnic groups among Black South Africans, mentioning Xhosa patients. While both studies used interviewers speaking Xhosa, no other ethnic groups were specified. South Africa is home to people of various ethnicities such as Zulu, Basotho, and Bapedi,²⁹ and thus attention to cultural elements when implementing an antipsychotic intervention can affect outcomes.

Our third aim was to rate studies’ methodological quality. The findings from the MQRS ratings suggest three levels of evidence corresponding to the degree of internal validity of the studies. At the lowest level were the fifteen uncontrolled studies that relied on single-group pre-post designs. These studies tended to not be blinded (N=87%). At the second level of evidence were the five studies that utilized quasi-experimental methods. More than half of these quasi-experimental studies (N=60%) didn’t enumerate the number of dropouts. Similar to the uncontrolled trials in level 1, most of the studies were not blinded (N=80%).

At the highest level of methodological quality were three randomized controlled studies. The three studies that score the highest number of points were Emsley et al. 2005, Emsley et al. 2004, and Brook et al. 1998.^7,8,9 These blinded studies all had 44-45 patients, all used standardized interventions, and treatment ranged from 4 weeks to 52 weeks. Two major limitations of these randomized controlled trials was that two had follow up rates less than 70% and all three studies failed to use collateral verification of patient’s self reports. Future randomized controlled trials in this area should consider employing techniques to improve follow up rate. In addition, future studies should acquire objective measures to verify patient reports to strengthen the validity of the results.

Our fourth aim was to analyze how the types of studies being conducted in SSA have changed over time. Firstly, sample size generally increased. Secondly, earlier studies seem to focus on psychological symptoms as outcome measures, using BPRS and PANSS as standardization for these symptoms. Later studies focused more explicitly on side effects, such as extrapyramidal symptoms. This might be related to the fact that some side effects, such as weight gain or metabolic syndrome might be more likely to become obvious with longer exposure to treatment and greater clinician (and researcher) awareness of these side effects. That being said, the treatment follow-up length for the studies we reviewed has stayed relatively consistent over time with 15 studies lasting 12 months or longer and 10 studies lasting less than 6 months. There does not appear to be any significant trend towards conducting studies with longer treatment follow-up times.

Our final aim was to examine intervention strategies. Across the studies reviewed, the goal of antipsychotic intervention was to treat schizophrenia, schizophreniform disorder, or first episode psychosis. Interventions included first generation antipsychotic medications such as haloperidol, zuclopenthixol, and flupenthixol decanoate; and second generation antipsychotic medications such as quetiapine, ziprasidone, risperidone. There were 5 studies that compared two different antipsychotic interventions. Brook et al. 1998 compared haloperidol to zuclopenthixol acetate and found that there were no significant differences between the two agents in efficacy or tolerability.⁷ Emsley et al. 2004 compared haloperidol to quetiapine and found that quetiapine resulted in greater improvements in dyskinesia and fewer EPS.⁸ Emsley et al. 2005 compared the same two medications and found that there were no differences in BMI or HBA1c between the two medications; BMI and HBA1c are measures of metabolic syndrome, a common side effect of antipsychotics.⁹ Emsley et al. 2015 compared risperidone to flupenthixol decanoate in 2 different studies and no differences between the two were found with regards to brain volume on MRI.^22,23 Landmark et al. 1994, compared fluphenazine decanoate depot alone to fluphenazine decanoate with HCl, and found that the combined treatment significantly shortened the length of hospital stay from a mean of 40.7 days to a mean of 30.5 days; the combined treatment group also obtained significantly higher improvement ratings one week after the start of treatment than the single treatment patients.¹⁰

Limitations

Our review has several limitations. Since one of the inclusion criteria in this review was that reports be published in English, key findings in other languages may not have been captured. Moreover, the difference in outcome measures (especially with psychiatric symptoms and extrapyramidal symptoms), small samples, and different antipsychotics used prevented us from conducting a meta-analysis. In any systematic literature review, there is the possibility of missing published studies that meet the preset inclusion criteria, so we utilized multiple databases and manual searches to reduce this possibility. Finally, it is important to note that no measurement technique is free of error. To minimize errors in our ratings of the studies’ methodological qualities, we used an established measuring system, MQRS scoring, and rated all studies together, resolving any disagreements in a standardized manner.

CONCLUSIONS

In conclusion, there is a very limited literature on antipsychotic treatment for chronic psychotic disorders in SSA. While symptoms are reduced with both first and generation drug treatments, side effects can be substantial and rates of adherence are often sub-optimal. Given the extensive burden of chronic psychosis on patients and families there is a critical need for additional studies that identify best practices and therapeutic options in this setting.

Highlights:

• This paper reviews 26 studies conducted in SSA that focused on antipsychotic medication treatment for primary psychotic disorders and that investigated at least one patient level outcome.

• Studies chosen analyzed the associations of antipsychotics with either improvement in psychiatric symptoms, presence of side effects, rates of remission, or improvement in functional status.

• Nine studies reported improvements in psychiatric symptoms associated with receiving an antipsychotic medication; seven studies investigating side effects of antipsychotics found that they were associated with an increase in metabolic syndrome; two studies reported that remission was achieved in the majority of subjects treated with antipsychotics; and one study reported improvements in functional status associated with receiving an antipsychotic.

• Antipsychotic medications may be beneficial for individuals with primary psychotic disorders in SSA, however there is a scarcity of research on antipsychotics from countries in sub-Saharan Africa apart from South Africa.