The Expert Committee considered that long-acting injectable antipsychotic medicines are a valuable treatment option to increase adherence to treatment and reduce relapse in adults with schizophrenia and related psychotic disorders. The Committee also noted with concern the uncertainty of current and future availability of fluphenazine injection, which is the only long-acting injectable antipsychotic medicine included on the EML at the moment, and considered that the availability of alternative medicines would be important to meet the public health need for such treatments. The Committee noted that long-acting injectable antipsychotic medicines are an established treatment option for schizophrenia and are recommended in existing WHO (mhGAP) guidelines. In particular, the Committee acknowledged that long-acting injectable antipsychotic medicines are useful in low-resource settings, where many factors might impede regular monitoring and follow-up of patients. The Committee noted that the available data suggest benefits of long-acting injectable antipsychotic medicines versus oral antipsychotic medicines in preventing hospitalization or relapse, especially in populations with low treatment adherence. The effectiveness and overall safety of first-generation and second-generation antipsychotic medicines are similar. The availability of agents with different side-effect profiles may support the selection of one treatment over another given a patient’s clinical status and vulnerabilities. The Expert Committee therefore recommended the addition of paliperidone palmitate 1-month long-acting injection to the core list of the EML for maintenance treatment of schizophrenia in adults stabilized on oral therapy. The listing is recommended with a square box specifying risperidone long-acting injection as a therapeutic alternative. The Committee also noted and welcomed the planned comprehensive review by the WHO Department of Mental Health and Substance Use of the mental health sections of the EML and EMLc to achieve optimal alignment between the Model Lists and recommendations of the WHO mental health treatment guidelines.

Currently, the only long-acting injectable antipsychotic medicine included on the EML is fluphenazine (decanoate or enantate), with a square box as representative of unspecified alternatives within the same pharmacological class. The availability of fluphenazine globally is erratic, representing a major threat for people requiring regular treatment over long periods.

Globally, 20 million people, or about 0.9% of the world’s population, are estimated to have schizophrenia (2). As estimated by the Global Burden of Disease (GBD) study 2017, schizophrenia contributes 12.66 million disability-adjusted life years (DALYs) to the global burden of disease (3). More than 50% of individuals who receive a diagnosis of schizophrenia have intermittent but long-term psychiatric problems, and about 20% have chronic symptoms and disability (4). Regular pharmacological treatment from the early stages of the disease may be key to preserving neurocognitive abilities, preventing structural brain changes, and delaying progression to chronic functional deterioration, resulting in better quality of life and increased survival (5). Life expectancy in people with schizophrenia is about 14 years shorter than the general population (6). Adherence to treatment is an important issue with only one in three people with schizophrenia fully adhering to antipsychotic treatment (7,8). Together with other factors, non-adherence to medication is a predictor of relapse (9). Long-acting injectable antipsychotic medicines were developed with the primary aim of reducing non-adherence. Median treatment coverage for schizophrenia in low- and middle-income countries is estimated to be about 30%. Almost two thirds of people with schizophrenia and related disorders in low- and middle-income countries do not receive adequate treatment. The treatment gap for schizophrenic disorders was larger in lower-income countries (89%) than in lower-middle-income (69%) and upper-middle-income countries (63%). The size of the treatment gap shows a significant negative association with: the prevalence of schizophrenic disorders in the general population; gross national income; the availability of psychiatric hospital beds; the number of psychiatrists per 100 000 population; and the number of nurses in mental health facilities per 100 000 population (10).

The application presented the results of a systematic review and network meta-analysis of 78 randomized controlled trials (11 505 participants) evaluating the comparative efficacy, acceptability and tolerability of long-acting antipsychotic medicines in adults with chronic non-affective psychosis (11). The primary outcomes were relapse rate and all-cause discontinuation of the medication (the latter as a measure of “acceptability”). Secondary outcomes included: efficacy measured as mean change in scores on validated rating scales measuring psychopathology and quality of life; functioning; and hospitalizations. Relapse rate Sixty-nine studies (11 176 participants) contributed data for this outcome. Various long-acting antipsychotic injections were significantly more effective than placebo in preventing relapse, including: paliperidone 3-month (risk ratio (RR) 0.27, 95% confidence interval (CI) 0.17 to 0.42), fluphenazine (RR 0.34, 95% CI 0.24 to 0.48), risperidone (RR 0.34, 95% CI 0.23 to 0.52) and paliperidone 1-month (RR 0.39; 95% CI 0.30 to 0.50). Head-to-head comparisons showed paliperidone 3-month, aripiprazole and fluphenazine were more effective than haloperidol. Results of the network meta-analysis were consistent with results from pairwise meta-analyses, with the exception of haloperidol versus placebo (favouring placebo in the direct estimate) and fluphenazine versus haloperidol (not significant in the direct estimate). Paliperidone 3-month ranked best based on the mean surface under the cumulative ranking curve. Compared to placebo, the certainty of evidence was rated as high for paliperidone 3-month and paliperidone 1-month, and moderate for risperidone. Acceptability (all-cause discontinuation) Seventy-four studies (11 385 participants) contributed data for this outcome. Most long-acting antipsychotic injections were significantly more acceptable than placebo, including paliperidone 3-month (RR 0.60, 95% CI 0.43 to 0.84), haloperidol (RR 0.64, 95% CI 0.50 to 0.81), fluphenazine (RR 0.67, 95% CI 0.55 to 0.81), risperidone (RR 0.70, 95% CI 0.57 to 0.85) and paliperidone 1-month (RR 0.70, 95% CI 0.58 to 0.85). Head-to-head comparisons showed aripiprazole to be significantly superior to fluphenazine, paliperidone 1-month and risperidone, among others. Results of the network meta-analyses were consistent with those from pairwise meta-analyses, with some exceptions, including aripiprazole versus paliperidone 1-month (not significant in the direct estimate). Zuclopenthixol, clopenthixol, aripiprazole and paliperidone 3-month ranked best based on the mean surface under the cumulative ranking curve. Compared with placebo, the certainty of evidence was rated as high for paliperidone 3-month, and moderate for fluphenazine and paliperidone 1-month. For most of the head-to-head comparisons, the certainty of evidence was rated low or very low due to within-study bias and imprecision. Efficacy measured as mean change in scores on validated rating scales Risperidone (standardized mean difference (SMD) 0.82, 95% CI 0.34 to 1.30) and paliperidone 1-month (SMD 0.49, 95% CI 0.12 to 0.86) were among the second-generation antipsychotic medicines found to be significantly better than placebo for this outcome. No significant differences were observed in the head-to-head comparisons. Quality of life Data were available only for aripiprazole, risperidone and paliperidone 1-month for this outcome (placebo was not included). In head-to-head comparisons, aripiprazole was superior to paliperidone 1-month. Hospitalization Compared with placebo, treatment with aripiprazole, paliperidone 3-month, haloperidol, fluphenazine and paliperidone 1-month resulted in significantly lower hospitalization rates. Functioning In pairwise meta-analyses, no significant differences between treatments were seen for patient functioning, except for paliperidone 3-month which resulted in better patient functioning than placebo based on results of one study. A network meta-analysis could not be carried out. With respect to the formulations proposed for listing (paliperidone 1-month and risperidone) head-to-head comparisons in the network meta-analysis showed that these medicines are: • superior to placebo in reducing the risk of relapse, with effect sizes similar to those of other long-acting antipsychotic medicines included in the analysis, and high (paliperidone 1-month) and moderate (risperidone) certainty of evidence. No statistically significant differences emerged when compared head-to-head with other long-acting antipsychotic medicines. • more acceptable than placebo in terms of overall dropouts (a pragmatic measure of the balance between efficacy and tolerability), with effect sizes similar to those of other long-acting antipsychotic medicines included in the analysis, and moderate (paliperidone 1-month) and low (risperidone) evidence. No statistically significant differences emerged when compared head-to-head with other long-acting antipsychotic medicines, except for aripiprazole, which showed a better acceptability profile compared with both paliperidone 1-month and risperidone. According to a large Swedish database study (12), in which 29 823 adults with a diagnosis of schizophrenia were followed between 2006 and 2013, both paliperidone 1-month and risperidone appeared effective in preventing psychiatric rehospitalization compared with no use of antipsychotic medicines (paliperidone: hazard ratio (HR) 0.51, 95% CI 0.41 to 0.64; risperidone: HR 0.61, 95% CI 0.55 to 0.68), and compared with oral olanzapine (paliperidone: HR 0.72, 95% CI 0.62 to 0.83; risperidone: HR 0.80, 95% CI 0.73 to 0.87). The effect size was comparable to those of other long-acting antipsychotic medicines. Although comparability of oral and long-acting antipsychotic medicines is debated, two systematic reviews and meta-analyses of randomized trials failed to detect significant differences between these two formulations in terms of efficacy, overall acceptability, tolerability and common adverse events (13,14).

The systematic review and network meta-analysis presented in the application considered dropouts as a result of adverse events (as a measure of “tolerability”), weight gain, hyperprolactinaemia, extrapyramidal symptoms and QTc prolongation, and sedation (11). Dropouts due to adverse events Paliperidone 1-month was less tolerable than placebo (RR 1.87, 95% CI 1.02 to 3.40), while for other long-acting antipsychotic medicines, no significant differences were observed compared with placebo. Weight gain Significantly higher weight gain occurred with aripiprazole, paliperidone 1-month and paliperidone 3-month, compared with placebo. Hyperprolactinaemia The risk of hyperprolactinaemia was significantly higher for olanzapine, paliperidone 1-month and paliperidone 3-month compared with placebo. Extrapyramidal symptoms No long-acting antipsychotic medicine showed a significantly higher risk of extrapyramidal symptoms compared with placebo. QTc prolongation and sedation In pairwise meta-analyses, no significant differences between treatments emerged, except for paliperidone 3-month which showed a lower risk of QTc prolongation than paliperidone-LAI 1-month, based on the results of one study. Previous systematic reviews and meta-analyses found no relevant differences between the oral and long-acting injection formulations of the same antipsychotic medication (13,14). A network meta-analysis (15) showed that both oral risperidone and paliperidone were worse than placebo in terms of: • weight gain: paliperidone (mean difference (MD) 1.49 kg, 95% CI 0.98 to 2.00 kg; 1536 participants; high-certainty evidence) and risperidone (MD 1.44 kg, 95% CI 1.05 to 1.83 kg; 2521 participants; high-certainty evidence); • use of antiparkinson medications: paliperidone (RR 1.61, 95% CI 1.17 to 2.10; 1355 participants; very low-certainty evidence) and risperidone (RR 1.80, 95% CI 1.40 to 2.38; 2174 participants; low-certainty evidence); • prolactin increase: paliperidone (MD 48.51 ng/mL, 95% CI 43.52 to 53.51 ng/mL; 1067 participants; moderate-certainty evidence) and risperidone (MD 37.98 ng/mL, 95% CI 34.64 to 41.38 ng/mL; 1761 participants; moderate-certainty evidence). Another systematic review and meta-analysis assessed the risk of death associated with long-acting injectable and oral antipsychotic medicines in people with schizophrenia (16). Up to 52 randomized controlled trials were included (17 416 participants). Neither pooled nor individual long-acting injectable antipsychotic medicines (aripiprazole, fluphenazine, olanzapine, paliperidone and risperidone) differed from placebo regarding the incidence of all-cause death (overall RR 0.64, 95% CI 0.24 to 1.70; 18 studies; 5919 participants). Similarly, pooled long-acting injectable antipsychotic medicines (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone and zuclopenthixol) did not differ from pooled oral antipsychotic medicines with regard to all-cause death (overall RR 0.71, 95% CI 0.38 to 1.34; 24 studies; 7879 participants). Secondary analyses showed no differences between long-acting injectable antipsychotic medicines and both placebo and oral antipsychotic medicines in terms of suicide. The risk of death was similar for individual long-acting injectable antipsychotic medicines and oral antipsychotic medicines.

Costs and worldwide availability of long-acting injectable antipsychotic medicines vary. Although currently both risperidone and paliperidone 1-month long-acting injections are marketed by the innovator company Janssen, most of the patents that prevent the marketing of generics have already expired, and most of the remaining will expire soon. A 1-year mirror-image study conducted in the United Kingdom, including 30 people receiving aripiprazole long-acting injection and 84 receiving paliperidone 1-month long-acting injection, showed a significant reduction in both bed occupancy and hospital admission compared with the period before the introduction of the treatment. Estimated minimum savings were £ 14 175 for aripiprazole and £ 13 750 for paliperidone (19). Similarly, a mirror-image study conducted in Spain, including 71 outpatients starting paliperidone 1-month long-acting injection, showed that fewer hospitalizations, shorter hospitalization days, fewer emergency assists and a decrease in the mean number of antipsychotic medicines used per patient were associated with the long-acting treatment. These reductions led to an overall reduction in inpatient spending (savings of € 175 766) and a 32% increase in spending on antipsychotic medicines (equivalent to € 151 127) after 1 year of treatment (20). The cost–effectiveness of paliperidone versus haloperidol decanoate in the maintenance treatment of schizophrenia was evaluated in the ACLAIMS trial (21). This trial included 311 participants allocated to haloperidol decanoate and paliperidone. Paliperidone had a better efficacy profile in terms of quality-adjusted life years (QALY) but also greater average quarterly inpatient, outpatient and medications costs. The incremental cost–effectiveness ratio for paliperidone was US$ 508 241 per QALY. Overall, haloperidol decanoate was more cost-effective than paliperidone palmitate, and the markedly higher on-patent costs of paliperidone were not justified by its slightly greater benefits (21). Table 9 compares costs of long-acting injection formulations of various antipsychotic medicines in different countries. <Refer to the WHO Technical Report Series, No. 1035>

According to WHO guidelines, people with psychotic disorders (including schizophrenia), who require long-term antipsychotic treatment, can be offered depot antipsychotic medicines instead of oral medications as part of a treatment plan. The guidelines also recommend that patients and carers should be offered clear and accessible information in a suitable format about the use and possible side-effects of oral versus depot preparations (17,18).

Risperidone long-acting injection has been approved by the US Food and Drug Administration for the treatment of schizophrenia, and as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder. Risperidone long-acting injection has also been approved by the European Medicines Agency for the maintenance treatment of schizophrenia in people currently stabilized with oral antipsychotic medicines. Paliperidone long-acting injection 1-month has been approved by the US Food and Drug Administration: for treatment of schizophrenia; for treatment of schizoaffective disorder as monotherapy; and as an adjunct to mood stabilizers or antidepressants. It is also approved by the European Medicines Agency for the maintenance treatment of schizophrenia in adults whose disease has already been stabilized on treatment with paliperidone or risperidone. Paliperidone long-acting injection 3-month has been approved by the US Food and Drug Administration for the treatment of schizophrenia in patients after they have been adequately treated with paliperidone long-acting injection 1-month for at least 4 months, and by the European Medicines Agency for maintenance treatment of schizophrenia in adult patients who are clinically stable on paliperidone long-acting injection 1-month. According to the manufacturer Janssen, paliperidone long-acting injection 1-month and 3-month are currently approved in 103 and 91 countries, respectively, including the USA, countries of the European Union, Japan, Ghana and South Africa. Risperidone long-acting injection is currently licensed in 59 countries. The 12.5 mg dose is used as the titration/starting dose only and is currently only available in Canada and the USA.

Although paliperidone palmitate 3-month long-acting injection was shown to be effective and acceptable, the applicants decided not to consider this medication for the present proposal for the following reasons. • It has been available only in relatively recent times (approved by the European Medicines Agency in 2016), it not yet commonly used in clinical practice and worldwide its availability may be limited. • Some concerns had been raised about the randomized study comparing paliperidone palmitate 3-month and placebo (22). Study participants underwent a stabilization phase with paliperidone 1-month before randomization which might have inflated the effect size in favour of paliperidone. • More research is needed to rule out possible unintended consequences of this formulation of paliperidone, including the effects of reduced doctors’ visits due to the longer dosing interval. In addition, the cumulative monthly dose of paliperidone 3-month is slightly higher than that of paliperidone 1-month and this may affect toxicity and tolerability (23). In general, injectable long-acting antipsychotic medicines are administered by health care professionals and require some technical precautions. Paliperidone is supplied in prefilled syringes and can be stored at room temperature, risperidone requires reconstitution and cold chain storage. If cold chain storage is not available, it can be stored at room temperature so long as the temperature does not exceed 25 °C (77 °F), and it is used within 7 days. In some low- and middle-income countries and in humanitarian emergency settings, these logistical constraints and the need for trained health care workers may prevent the use of long-acting risperidone. The Department of Mental Health and Substance Use provided comments on the application. It noted that the department had been approached on multiple occasions by various organizations (e.g. Médecins Sans Frontières, United Nations High Commissioner for Refugees and Christian Blind Mission) about the uncertainty of the future availability of fluphenazine, currently the only long-acting injectable antipsychotic on the EML. Long-acting injectable antipsychotic medicines are an established treatment option for schizophrenia and are recommended in existing guidelines of the WHO Mental Health Gap Action Programme (mhGAP). The Department’s comments also highlighted a recently published new systematic review by a different research group that showed significant benefits of long-acting injectable antipsychotic medicines versus oral antipsychotic medicines in preventing hospitalization or relapse (1), providing further evidence of the importance of having long-acting injectable antipsychotic medicines available in health services around the world.