En Afrique subsaharienne, l'épilepsie reste un problème de santé publique majeur. En plus d'un manque de ressources en soins de santé, le déficit thérapeutique dans la prise en charge de l'épilepsie est très élevé. Seuls quelques antiépileptiques de première ligne sont disponibles et leur qualité pose question. Actuellement, quelques données sont disponibles sur la question de la qualité des antiépileptiques dans les pays en développement. Deux études ont montré une proportion de mauvaise qualité allant de 13,7% pour le phénobarbital en Mauritanie à 65,0% pour la phénytoïne, la carbamazépine et le valproate de sodium au Vietnam. L'objectif de cette étude était d'évaluer les déterminants du déficit thérapeutique des personnes vivant avec l'épilepsie dans les pays en développement. Les objectifs de recherche étaient d'identifier et de décrire les programmes d'intervention visant à améliorer la prise en charge médicamenteuse, d'identifier les déterminants sociaux du déficit thérapeutique, d'évaluer la qualité des antiépileptiques disponibles en Afrique subsaharienne et d’en mesurer la disponibilité, le coût et l’accessibilité financière. Le schéma d'étude pour l'évaluation des interventions et des déterminants sociaux était une revue systématique de la littérature. Pour les questions de qualité, de disponibilité, de coût et d'accessibilité, une étude transversale multicentrique a été réalisée dans 9 pays d’Afrique ubsaharienne. Dans chaque pays, les zones urbaines et rurales ont été systématiquement étudiées de la même manière, en explorant la chaîne d'approvisionnement officielle et le secteur illicite. Les soins communautaires et le personnel paramédical ont été des facteurs de succès dans ces pays où les ressources médicales sont limitées. L'adhésion thérapeutique était l’une des pierres angulaires dans la prise en charge médicamenteuse des personnes vivant avec l'épilepsie, souvent mal ou peu maitrisée. L'éducation thérapeutique était une dimension prometteuse à développer. Au total, 32,3 % des antiépileptiques étaient de mauvaise qualité. La carbamazépine (38,7 % [intervalle de confiance à 95 % (IC 95 %)] : 21,8 - 57,8) et la phénytoïne 83,3 % (IC 95 % : 35,8 - 99,5) présentaient la proportion la plus élevée de substandards, principalement en raison d’une mauvaise dissolution. Le valproate de sodium était l’antiépileptique avec la qualité la plus mauvaise (32,1 % ; IC à 95 %, 15,8 - 42,3). Le phénobarbital (94,1 % ; IC à 95 %, 80,3 - 99,2) possédait la meilleure qualité. La prévalence d’antiépileptiques de mauvaise qualité augmentait pour les échantillons distribués par une structure publique (Odds Ratio OR, 9,9 ; IC à 95 %, 1,2-84,1 ; p<0,04) ainsi que ceux fabriqués en Chine (OR, 119,8 ; IC 95 %, 8,7-1651,9 ; p<0,001). De même cette prévalence augmentait lorsqu'ils étaient stockés dans de mauvaises conditions (OR, 5,4 ; IC à 95 %, 1,2-24,1 ; p<0,03). Aucune contrefaçon n'a été observée dans cette étude. Le phénobarbital et les formes génériques étaient les plus accessibles mais les moins disponibles, principalement dans le secteur privé, chaîne d'approvisionnement ayant le plus grand réseau de distribution dans ces pays.Le rôle du pharmacien et du personnel paramédical devrait être renforcé. Des conditions de stockage inadéquates, comprenant le manque de contrôle de la température et de l'humidité, sont susceptibles de conduire à des médicaments inefficaces voire dangereux. Le déconditionnement, pratique courante et potentiellement dangereuse, doit être supervisée et sécurisée. La production locale d’antiépileptiques a plusieurs aspects positifs pour diminuer le déficit thérapeutique en agissant sur l'accessibilité géographique, financière et sur la qualité. Le programme de pré-qualification de l'OMS a permis d'améliorer considérablement la qualité des médicaments dans les pays en développement. L'inclusion des antiépileptiques dans ce programme constituerait une amélioration certaine pour le traitement de l'épilepsie. / In sub-Saharan Africa, epilepsy remains a neglected public health issue. In addition to a lack of trained healthcare resources, including staff and infrastructure, the high epilepsy treatment gap has been a source of concern. Only a few major first-line antiepileptic drugs are readily available and the quality of these drugs could pose further issues. Currently, there are a few data available to address the question of the quality of antiepileptic drugs in low- and middle-income countries. Two studies have shown the proportion of poor-quality drugs to range from 13.7% for phenobarbital in Mauritania to 65,0% for phenytoin, carbamazepine, and sodium valproate in Vietnam. The aim of this study was to assess the determinants of the treatment gap of people living with epilepsy in low- and middle-income countries. Research objectives were to identify and describe intervention programmes aimed at improving drug management, to extract social determinants of the treatment gap, to evaluate the quality of antiepileptic drugs available in sub-Saharan Africa and to measure the availability, cost and affordability of antiepileptic drugs in sub-Saharan Africa.The study design for intervention and social determinants assessment was a systematic literature review. For quality, availability, cost and affordability issues a multicentre cross-sectional study has been carried out in 9 sub-Saharan Africa countries with an identical data and sample collection protocol. In each country, urban and rural areas have been systematically investigated in the same manner, exploring both the official supply chain and the illicit system in each setting. All the structures where a patient could buy or obtain antiepileptic drugs have been investigated. Community-based care and allied health staff were success factors in resource limited settings. Adherence to treatment has been pointed out to be a corner stone of people living with epilepsy drug management, poorly and slightly controlled. Therapeutic patient education was a promising dimension to be developed. Overall 32.3% of the tablets were of poor quality, but no statistical difference was observed across the sites. Carbamazepine (38.7% [95% Confidence Interval (95%CI)]: 21.8 – 57.8) and phenytoin 83.3% (95% CI 35.8 – 99.5) had the highest proportion of substandard quality, mainly due to dissolution failure. Sodium valproate was the antiepileptic drug with the poorest quality (32.1%; 95% CI 15.8 – 42.3). Phenobarbital (94.1%; 95% CI 80.3 – 99.2) had better quality. Prevalence of substandard quality increased in samples supplied from a public structure (Odds Ratio (OR), 9.9; 95% CI 1.2-84.1; p<.04) as well as those manufactured in China (OR, 119.8; CI 8.7-1651.9; p<.001). The prevalence of antiepileptic drugs with bad quality increased when improperly stored (OR, 5.4; 95% CI 1.2-24.1; p<.03). Phenobarbital and generic formulations remained the most affordable antiepileptic drugs but the least available mainly in the private sector, the supply chain with the largest distribution network in countries.The role of pharmacist and other allied staffs should be enhanced. No counterfeiting has been observed for antiepileptic drugs in this study. However, inadequate storage conditions, including the lack of temperature and humidity control, are likely to lead to ineffective and maybe dangerous antiepileptic drugs, even when good quality antiepileptic drugs are initially imported. Unpacking practice, common and potentially dangerous, must be supervised and secured. Local production of antiepileptic drugs has several positive aspects for decreasing treatment gap by enhancing geographical, financial accessibility and quality of drugs. WHO prequalification program has produced great improvement in diseases management in developing countries. Inclusion of antiepileptic drugs in this program may be highly profitable for people living with epilepsy.

Background The World Health Organization (WHO) defines health as a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. Despite its importance, mental health provisions are often limited. In 2015, Indonesia had only 773 psychiatrists for 250 million residents. This shortage of specialist mental health professionals is shared by most Low- and Middle-Income Countries (LMICs) and is reflected in the Treatment Gaps in this region indicating the very small proportion of people who receive adequate mental health care for their needs. While the median worldwide Treatment Gap for psychosis is 32.2% (Kohn et al., 2004), in Indonesia it is more than 90%. Experts suggested integrating mental health care into primary care, to help bridge this gap (Mendenhall et al., 2014). The systematic introduction of the World Health Organization Mental Health Gap Action Programme into primary care clinics across Indonesia and the presence of a 15-year-old co-location of Clinical Psychologists in Yogyakarta province's primary care clinics presented an opportunity to assess the clinical and cost-effectiveness of both frameworks. Methods This research ("the trial") set out to develop an approach, and then implement it, to compare the adapted WHO mhGAP framework with the existing specialist framework within primary mental health services in Yogyakarta, Indonesia, through a pragmatic, two-arm cluster randomised controlled non-inferiority trial. This design enabled an examination of patients derived from whole populations in a 'real world' setting. The trial involved two phases: a pilot study in June 2016 with the objectives to refine data collection procedures and to serve as a practice run for clinicians involved in the trial; as well as a substantive trial beginning in December 2016. The 12-item General Health Questionnaire (GHQ-12) was established as a 'fairly accurate' screening tool using a Receiver Operating Curve study. Using the GHQ scoring method of 0-0-1-1, a threshold of 1/2 was identified for use in clinical setting, i.e. the context of the trial. The primary outcome was the health and social functioning of participants as measured by the Health of the Nation Outcome Scale (HoNOS) and secondary outcomes were disability as measured by WHO Disability Assessment Schedule 2.0 (WHODAS 2.0), quality of life as measured by European Quality of Life Scale (EQ‐5D-3L), and cost of intervention evaluated from a health services perspective, which aimed to determine the clinical effectiveness and cost-effectiveness of both frameworks at six months. Results During the recruitment period, 4944 adult primary care patients attended 27 participating primary care centres. Following screening (n=1484) and in-depth psychiatric interviews (n=394), 174 WHO mhGAP arm and 151 Specialist arm participants received a formal diagnosis and were recruited into the trial. The number of required participants per treatment arm, to provide statistical power of 0.80 and statistical bilateral significance value of 0.05 was estimated to be 96. A total of 153 participants of the WHO mhGAP arm and 141 of the Specialist arm were followed-up at six months, representing 90.8% of all participants diagnosed. At follow-up, 82% (n=126) participants of the WHO mhGAP arm indicated they had attended at least one treatment session during the trial, significantly more than in the Specialist Arm (69%; n=97), 2 = 7.364, p=0.007. The WHO mhGAP arm was proven to be statistically not inferior to the Specialist arm in reducing symptoms of social and physical impairment, reducing disability, and improving health-related quality of life at six months. Cost-effectiveness analyses show that the Specialist arm was dominant for a unit of improvement in patient outcomes at six months. While the framework is more expensive for the Health System, participants in the Specialist arm were found to have larger improvements. Conclusion Given that both frameworks yielded positive patient outcomes, there is no immediate need to increase the absolute number of specialist mental health professionals in community psychiatry (i.e. replicate the specialist framework outside Yogyakarta). As most psychologists and psychiatrists in Indonesia reside in large cities, the current systematic roll-out of the adapted WHO mhGAP framework might address the need to strengthen non-stigmatising mental health care within community contexts, reflecting the preferences of primary care patients. In districts or provinces which could afford the additional cost, however, the Specialist framework was shown to be better at improving patient outcomes than the adapted WHO mhGAP framework. Existing resources for specialist care can be arranged in a hub-and-spoke (step-up care) model where higher-level interventions are provided for those with greater needs. The proposed model would free-up resources for advanced clinical training of the specialist workforce in key areas of need while keeping specialist services accessible. Trial Registration This trial has been registered with clinicaltrials.gov since 25 February 2016, NCT02700490. Ehical Standards Full ethics approval from the University of Cambridge, UK was received on 15 December 2015 (PRE.2015.108) and from Universitas Gadjah Mada, Indonesia on 14 April 2016 (1237/SD/PL.03.07/IV/2016). A condition of ethics approval from the University of Cambridge is that the investigator is covered by indemnity insurance and that participants are insured for the period of their participation. This was provided by the University of Cambridge Trial Insurance Office (609/M/C/1510). Ethics approval from all the clusters was not required as each cluster (Puskesmas) is a local GP surgery which does not have its own ethics committee. Instead, approval to conduct research at the province of Yogyakarta including all five districts: Kota Yogyakarta, Sleman, Gunung Kidul, Kulon Progo, Bantul Districts was obtained from the Provincial Government Office (070/REG/V/625/5/2016) following ethics approvals. Written consent to participate was obtained from clinicians taking part as well as all patient-participants.