With the revision of the National Essential Medicines List in South Africa, quetiapine is only available at the discretion of individual institutions in the public health sector. However, quetiapine is effective in managing all aspects of bipolar disorder, including preventative treatment of depressive episodes, and may be a cost-effective option in severe illness.
To present the first retrospective review of quetiapine use in a peri-urban health district of South Africa, describing the patient profile, clinical response and prescribing patterns.
The clinical files of all patients in Sedibeng District who received quetiapine over a defined 3-year period (2011–2013) were reviewed. A positive clinical response was defined as both symptomatic and functional improvement. Demographic and clinical characteristics of responders were compared with that of non-responders. Pre- and post-quetiapine scripts of the responders were audited and costed.
Patients who received quetiapine (
Quetiapine use was associated with a highly significant improvement in functioning; however, it came at a 52% increase in medicine cost. Pre-quetiapine treatments, though, did not achieve an optimal level of functioning, and overall costs may be reduced by more rational prescribing habits.
Cost awareness on the part of doctors is essential in Africa with its scarce resources and high disease burden, yet medical practitioners rarely audit the cost of the treatment they prescribe.
However, with the availability of generic medication, an argument has been made for the wider use of SGAs in LMICs in the treatment of BD.
In South Africa, with the revision of the National Essential Medicines List (NEML) to allow for universal health coverage,
In the management of BD, the range of efficacious medicines for the treatment of depressive episodes is considerably more limited than that for mania.
Although not on the NEML, quetiapine is currently available in the public health sector
The aim of this study was to evaluate the use of quetiapine over a 3-year period in the community psychiatric clinics of the Sedibeng district of Gauteng, where the extended-release (XR) form of quetiapine has been available.
The first objective was to describe the patient population for whom quetiapine XR was prescribed, to describe the clinical response; and to compare those who responded to quetiapine (responders) with those who did not (non-responders) in terms of demographic and clinical profile, polypharmacy and side-effect burden. The second objective was to make an assessment of the direct pharmaceutical cost implications for those in whom a positive clinical response to quetiapine was evident in the clinical records. The third objective was to ascertain whether the use of quetiapine was judicious according to approved indications, current evidence and treatment guidelines.
A retrospective record review of all patients who received quetiapine XR in the Sedibeng district psychiatry clinics between January 2011 and December 2013 was performed. The clinical records were examined up to the end of July 2014 in order to allow time for a sustained clinical response.
Sedibeng is a peri-urban district in Southern Gauteng with a total population of 916 484 as of 2011.
All patients for whom quetiapine was prescribed between January 2011 and December 2013 were included in the study. Those in whom a positive clinical response was evident from the clinical records were included in the pre- and post-quetiapine costing assessment.
A list of patients who were prescribed quetiapine during the study period was obtained from the district pharmacy. Clinic registers were also checked to ensure that no patients were missed. The clinical records of each patient were then examined for demographic details, response to quetiapine, clinical diagnosis and prescribing patterns.
The clinical response to quetiapine was ascertained retrospectively from clinical notes and nursing records. As rating scales are not used routinely in the district psychiatric clinics, one had to be applied retrospectively in order to assess the response to treatment in an objective and quantifiable manner. The Global Assessment of Functioning (GAF) Scale was used as clinical records are a recognised source of information for the GAF Scale, it is simple, it provides an overall measure of both symptoms and impairment across all psychiatric disorders, and it may be used to reflect a change in the patient’s condition over time.
Although the two dimensions of the scale have been shown to be valid in terms of reflecting both symptomatic distress and social functioning, its reliability has been questioned, especially in the routine clinical setting with different raters of varying experience using different sources of information for the same patient. Although it may be more reliable when applied retrospectively in an objective manner by one investigator, its validity is dependent on the quality and accuracy of the available notes. Therefore, all clinical notes, including those made by the nursing staff, social workers, allied professionals and referring doctors, were used to determine which of the 10 anchor points was most applicable prior to quetiapine initiation (pre-quetiapine) and at July 2014 or at quetiapine discontinuation if this had occurred (post-quetiapine). A positive clinical response was defined as an improvement of at least one decile in the GAF Scale, taking the lower of the two dimensions as the reference point for the pre- and post-quetiapine measures.
For those with a positive clinical response, the pre- and post-quetiapine prescriptions were costed. The costing analysis was performed on the script immediately before quetiapine was prescribed, being the treatment which was deemed clinically necessary to change because of poor response and/or adverse effects, and the last script on quetiapine before the analysis ended, being the medication which had resulted in improved functioning. For consistency in cost comparison, the average monthly cost per medicine and per script was calculated using prices from the national procurement catalogue of June 2015, being the prices at the time of the analysis. Only medicine costs were determined. Depending on dosage, costs of quetiapine XR 50 mg, 200 mg, 300 mg and 400 mg were used. Scripts for non-responders were not included in the costing analysis as quetiapine would have been stopped and alternative clinical decisions would have been made.
Data analysis was carried out using Statistical Analysis Software (SAS) Version 9.3 for Windows. The 5% significance level (
Ethics approval was granted by the Human Research Ethics Committee of the University of the Witwatersrand.
Only 40 patients in the Sedibeng district psychiatric clinics received quetiapine over the 3 years. Demographic data are presented in
Demographic profile of the overall group (
Variable | % | |
---|---|---|
Female | 32 | 80.0 |
Male | 8 | 20.0 |
Black | 22 | 55.0 |
White | 15 | 37.5 |
Indian | 2 | 5.0 |
Coloured |
1 | 2.5 |
Single | 27 | 67.5 |
In a relationship | 13 | 32.5 |
Unemployed | 25 | 62.5 |
Employed | 11 | 27.5 |
Student (tertiary institution) | 3 | 7.5 |
Scholar | 1 | 2.5 |
Primary | 1 | 2.5 |
Secondary | 13 | 32.5 |
Matric | 19 | 47.5 |
Tertiary | 7 | 17.5 |
, the South African national census uses the term ‘Coloured’, instead of Mixed race.
HLOE, highest level of education.
The pre- and post-quetiapine GAF scores of the sample are illustrated in
Global assessment of functioning score before (
Of the 40 patients, 13 (32%) were grouped as non-responders and 27 (68%) as responders (including the three referred from the private sector mentioned above). Four patients were designated non-responders despite improvement on the functional dimension of the GAF scale. Two of these patients had persistent distressing psychotic symptoms resulting in a lower overall GAF score despite an improvement in mood and level of function. In the other two, the better functioning was deemed from the records to be because of psychosocial interventions rather than medication, and quetiapine use had been stopped in both. Although this could be considered to be inconsistent with the criteria, as the overall GAF score had improved, they could not be included as responders as evidence in the notes revealed otherwise. One patient (a 63-year-old with dementia) was grouped as a non-responder despite a symptomatic response as there was no improvement on the functional dimension.
Of those in whom the GAF score was ascertained, 95% of patients were seriously ill and/or functionally impaired with scores of 41–50 and below prior to quetiapine use. Post-quetiapine use, 61% of patients had a GAF score of 51–60 or above, a level of functioning at which an individual may sustain employment or care for children. The GAF score improved significantly overall and for the responder group (
There were no significant differences between responders and non-responders regarding the demographic profile, age of onset, duration of illness, pre-quetiapine GAF score or number of hospitalisations. A history of repeated hospitalisation was common, with about half (51%) of the 40 patients having had three or more admissions and one-third of the patients having five or more admissions before initiation on quetiapine. After quetiapine use, over a time range of 5–48 months, there was one admission amongst the responders, which was related to HIV infection, and three amongst the non-responders. Because of the disparate time periods it was not possible to do a before and after comparison for hospitalisations.
Primary and co-morbid diagnoses are summarised in
Primary and comorbid diagnoses.
Category | Overall |
Non-responders |
Responders |
|||
---|---|---|---|---|---|---|
% | % | % | ||||
BD II | 12 | 30 | 1 | 8 | 11 | 41 |
BD I | 11 | 28 | 2 | 15 | 9 | 33 |
MDD | 6 | 15 | 4 | 31 | 2 | 7 |
Schizoaffective disorder | 6 | 15 | 2 | 15 | 4 | 15 |
Mood and/or psychosis due to AMC | 3 | 8 | 2 | 15 | 1 | 4 |
Schizophrenia | 1 | 3 | 1 | 8 | 0 | 0 |
None (V code: Malingering) | 1 | 3 | 1 | 8 | 0 | 0 |
Clinical features of psychotic depression | 22 | 55 | 5 | 38 | 17 | 63 |
GAD | 8 | 20 | 3 | 23 | 5 | 19 |
PTSD | 2 | 5 | 1 | 8 | 1 | 4 |
Social anxiety disorder | 1 | 3 | 0 | 0 | 1 | 4 |
OCD | 1 | 3 | 0 | 0 | 1 | 4 |
Benzodiazepine use disorder | 5 | 13 | 3 | 23 | 2 | 7 |
Cannabis use disorder | 3 | 8 | 2 | 15 | 1 | 4 |
Alcohol use disorder | 1 | 3 | 0 | 0 | 1 | 4 |
Cocaine use disorder | 1 | 3 | 1 | 8 | 0 | 0 |
Heroin use disorder | 1 | 3 | 0 | 0 | 1 | 4 |
Bereavement | 3 | 8 | 2 | 15 | 1 | 4 |
Malingering | 1 | 3 | 1 | 8 | 0 | 0 |
Cluster B | 10 | 25 | 4 | 31 | 6 | 22 |
Cluster C | 9 | 23 | 4 | 31 | 5 | 19 |
Hypertension | 5 | 13 | 0 | 0 | 5 | 19 |
Hypercholesterolaemia | 4 | 10 | 1 | 8 | 3 | 11 |
Hypothyroidism | 4 | 10 | 1 | 8 | 3 | 11 |
HIV | 3 | 8 | 0 | 0 | 3 | 11 |
Peptic ulcer disease | 2 | 5 | 0 | 0 | 2 | 7 |
Ulcerative colitis | 2 | 5 | 0 | 0 | 2 | 7 |
Cardiac failure | 1 | 3 | 1 | 8 | 0 | 0 |
Dementia | 1 | 3 | 1 | 8 | 0 | 0 |
Diabetes mellitus | 1 | 3 | 0 | 0 | 1 | 4 |
Epilepsy – idiopathic | 1 | 3 | 0 | 0 | 1 | 4 |
Neurocysticercosis with epilepsy | 1 | 3 | 0 | 0 | 1 | 4 |
TBI with epilepsy | 1 | 3 | 1 | 8 | 0 | 0 |
BD II, bipolar II disorder; BD I, bipolar I disorder; MDD, major depressive disorder; AMC, another medical condition; GAD, generalised anxiety disorder; PTSD, post-traumatic stress disorder; OCD, obsessive compulsive disorder; HIV, human immunodeficiency virus; TBI, traumatic brain injury.
All but two patients were initiated on quetiapine as outpatients, during maintenance treatment. Most had previously received multiple trials of medication (
Percentage of patients who had received previous medication trials.
Medication | Overall |
Non-responders |
Responders |
|||
---|---|---|---|---|---|---|
% | % | % | ||||
Antipsychotic | 33 | 83 | 13 | 100 | 20 | 74 |
≥ 3 trials of different antipsychotics | 9 | 23 | 5 | 38 | 4 | 15 |
Risperidone | 32 | 80 | 13 | 100 | 19 | 70 |
Haloperidol/typical LAI | 13 | 33 | 7 | 54 | 6 | 22 |
Olanzapine | 12 | 30 | 2 | 15 | 10 | 37 |
Clozapine | 4 | 10 | 2 | 15 | 2 | 7 |
Chlorpromazine | 2 | 5 | 0 | 0 | 2 | 7 |
Sulpiride | 1 | 3 | 0 | 0 | 1 | 4 |
Antidepressant | 31 | 78 | 11 | 85 | 20 | 74 |
≥ 3 trials of different antidepressants | 10 | 25 | 2 | 15 | 8 | 30 |
SSRI | 30 | 75 | 10 | 77 | 20 | 74 |
Amitriptyline | 11 | 28 | 3 | 23 | 8 | 30 |
SNRI (venlafaxine) | 9 | 23 | 2 | 15 | 7 | 26 |
Anticonvulsant | 28 | 70 | 9 | 69 | 19 | 70 |
≥ 3 trials of different anticonvulsants | 2 | 5 | 0 | 0 | 2 | 7 |
Valproate | 19 | 48 | 5 | 38 | 14 | 52 |
Lamotrigine | 18 | 45 | 5 | 38 | 13 | 48 |
Carbamazepine | 4 | 10 | 1 | 8 | 3 | 11 |
Gabapentin | 1 | 3 | 0 | 0 | 1 | 4 |
Lithium (missing: |
15 | 38 | 3 | 23 | 12 | 44 |
ECT | 3 | 8 | 0 | 0 | 3 | 11 |
Missing data | 3 | 8 | 0 | 0 | 3 | 11 |
LAI, long acting injectable; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin noradrenaline reuptake inhibitor; ECT =, electroconvulsive therapy.
The median quetiapine dose was 300 mg (IQR 200 mg–400 mg; range 50 mg–800 mg), with no significant difference in dose between responders and non-responders (
For responders, the mean duration of quetiapine use, and duration of improved function, was 23 months (range of 5–48 months, s.d. = 11). None of the responders discontinued quetiapine during the study period, apart from one patient who stopped treatment at only 5 months, after having started a new job. This appeared to be related to stigma and insufficient psychosocial support. The duration of quetiapine prescriptions in non-responders was significantly lower (
Adverse effects were noted most frequently with typical antipsychotics and least commonly with antidepressants and lamotrigine (
Percentage of patients on a medication who reported side effects.
Evaluated as the number of different psychotropic and related medications per day, excluding medications for comorbid medical illness, polypharmacy was greater amongst responders than amongst non-responders (
Average pre-and post-quetiapine medication cost per patient (responder).
Medication | Pre-quetiapine |
Post-quetiapine |
||
---|---|---|---|---|
Number of scripts | Average cost/script/month | Number of scripts | Average cost/script/month | |
Quetiapine | 0 | 25 | R119.58 | |
Haloperidol/Typical LAI | 3 | R21.32 | 0 | |
Risperidone | 10 | R10.96 | 1 | R9.42 |
Olanzapine | 3 | R50.16 | 0 | |
Chlorpromazine | 1 | R20.40 | 0 | |
SSRI | 14 | R9.42 | 6 | R6.95 |
SNRI (venlafaxine) | 3 | R133.41 | 2 | R108.32 |
TCA | 7 | R5.45 | 3 | R6.30 |
Valproate | 10 | R63.39 | 6 | R72.41 |
Lamotrigine | 5 | R23.90 | 10 | R22.01 |
Carbamazepine | 1 | R25.18 | 0 | |
Lithium | 9 | R55.70 | 4 | R66.87 |
Benzodiazepine | 13 | R47.72 | 9 | R85.32 |
Thyroxine | 2 | R5.35 | 4 | R4.51 |
Other | 16 | R43.22 | 1 | R25.65 |
LAI, long acting injectable; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; s.d., standard deviation.
As quetiapine is both sedating and anxiolytic, reduced use of benzodiazepines had been anticipated but did not materialise. The number of benzodiazepine scripts decreased insignificantly from 13 to 9, but the average cost per patient almost doubled. The cost increase post-quetiapine was because of an increased dosage in four prescriptions and a reduced dosage to the more expensive 0.5 mg tablets of clonazepam in only two scripts. Of note, two patients were initiated on benzodiazepines simultaneously with the quetiapine prescription. Hence, of the original 13 scripts, the benzodiazepine was discontinued in 6 patients but commenced in 2 others.
The cost implications of using quetiapine to achieve the improvement in GAF score amongst those who responded are summarised in
Given that BD affects at least 1% of the general adult population,
Overall, quetiapine use appears to have been judicious according to approved indications and treatment guidelines, a working differential diagnosis of bipolar depression and a median dose of 300 mg, the recommended dose for prevention of relapse into a depressive episode in BD.
Responders differed significantly from non-responders only in polypharmacy, both pre- and post- quetiapine. Although possible clinical reasons for the greater polypharmacy could not be deduced from this study, it may reflect difficulty in managing BD, which accounted for 74% of primary diagnoses in the responder group. The use of risperidone, typical antipsychotics and antidepressants instead of mood stabilisers or antipsychotics with mood stabilising properties is consistent with the literature, which describes ongoing use of these medications in response to psychotic and depressive symptoms in bipolar depression.
The use of benzodiazepines prior to quetiapine may reflect persistent anxiety and insomnia despite existing pharmacotherapy. However, long-term use is associated with serious morbidity and dependency.
Although the 52% cost increase appears high for South Africa, the pre-quetiapine average cost of R132.00 per patient per month achieved a level of functioning in most patients below that required to attend to a child or keep a job, accompanied by residual psychiatric symptoms and a higher pill burden. An increase of R68.37 per patient per month may well be justified through improved clinical outcomes and reduced utilisation of the healthcare system, as has been shown in international health economics analyses.
A major limiting factor of this paper is the retrospective study design and dependence on routine clinical records, which may have affected the reliability of the findings. Regarding the GAF Scale, some subjectivity in allocation of a score is unavoidable. In addition, a disadvantage of only using the lower score of the two dimensions, as opposed to both a symptom and a function score, may have caused some responders (or partial responders) to have been labelled as non-responders. Regarding the previous trials of medication, the study design precluded accurate analysis of the adequacy of each trial. Finally, to give a true reflection of expenses, the costing exercise could have included the cost of quetiapine use in non-responders as ‘wasted resources’.
Notwithstanding these limitations, this paper highlights the need for clinicians to audit prescribing patterns and increases awareness of the medication costs in patient care. In addition, it contributes to the literature regarding the treatment of bipolar depression in South Africa, for which there is a marked paucity of literature. Further studies on cost-effective maintenance treatment of BD in South Africa are recommended to inform both patient care and the NEML.
Quetiapine use was associated with a highly significant improvement in functioning in our sample of patients. However, it came at a 52% increase in medicine cost. Pre-quetiapine treatments, though, did not achieve an optimal level of functioning, and overall costs may be reduced by more rational prescribing habits. Simply creating awareness of the medicine costs of managing such patients may improve resource utilisation and reduce inappropriate prescribing.
The authors thank Data Management and Statistical Analysis for the data analysis.
The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.
L.J.R. designed the study and was the principal investigator; J.K.M. assisted with the interpretation of results, cost assessment and write-up; B.J.v.R. assisted with the protocol and the write-up.