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      Long-acting injectable antipsychotics treatment during COVID-19 pandemic – A new challenge

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      a , b , * , a , a , b
      Schizophrenia Research
      Elsevier B.V.

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          Abstract

          Non-adherence is an important factor in therapeutic failure, which is frequently correlated with disease progression. This phenomenon is common in most diseases that require chronic treatment (cardiovascular, metabolic, degenerative, etc.) (Timmerman et al., 2016). In the case of mental illness and schizophrenia in particular, non-adherence (total or partial) reaches up to 75% of cases, being rather the rule than the exception (Kane et al., 2013a; Dobber et al., 2018; Kishimoto et al., 2013a). Medication non-adherence is associated with poor outcomes, more hospital readmissions, and increased costs of care in schizophrenia (Winton-Brown et al., 2017; Haddad et al., 2014). Poor medication adherence is multifactorial, is caused by the lack of insight (the individual does not want to be treated because he/she does not consider himself/herself ill), or persistent psychotic symptoms. In contrast, cognitive deficits and causes related to the evolution of the disease are important factors in the individual's motivation for taking medication (Lacro et al., 2002). Strong evidence of the superiority of long-acting injectable antipsychotics (LAIs) over oral antipsychotics (OA) in relapse prevention and reducing mortality in schizophrenia is demonstrated in many studies (Taipale et al., 2018). LAIs have been shown to be more effective in persons under 35 years of age. Avoiding treatment abandon, LAIs determined more frequently remission and recovery than OA (Kishimoto et al., 2013b; Kane et al., 2013b). Efficiency has been proven in the prevention of relapses also in the catatonic forms (Ifteni and Teodorescu, 2017). Experts considered that LAIs should be introduced as early as possible for better outcome in schizophrenia (Stahl, 2014). Despite its proven effectiveness and favorable cost-benefit ratio, LAIs are still underused world-wide due to different reasons including economic (high cost), mistrust, fear, stigma and outdated concepts (Taylor et al., 2018). On the part of the patients, the refusal is related in particular to the mode of administration (injection), the control of the treatment (the feeling that they no longer decide), the administration protocols (in specialized centers, post injection monitoring in the case of olanzapine pamoate, etc.) (Yeo et al., 2017). To all these, new restrictions or limitations of prescription and administration caused by COVID-19 pandemic are now are added. In order to limit the possibility of contamination, authorities in many countries, including Romania, have recommended limitation or restriction of access to hospitals, which remain strictly intended for emergencies only. General practitioners, but also psychiatrists, have limited the number of interactions with patients and have started a difficult process for online consultations. In addition to benefits, issues regarding ethics, confidentiality, accessibility, etc. are present. Online consultations cannot capture many aspects of psychiatric pathology and are often impossible in cases with low income or in rural or isolated areas. Delayed supply in pharmacies caused by the restriction or cancellation of the export of medicines or sanitary equipment in the context of a COVID-19 is another barrier. As a result, a significant number of patients with schizophrenia have been (or will soon be) undergoing treatment with less expensive, easy-to-obtain, and manageable oral antipsychotics. In our psychiatric setting (public hospital with 150 beds for acute patients), the number of LAIs prescriptions decreased dramatically (49% for risperidone LAI and 90% for olanzapine LAI) from December 2019 to March 2020 (Table 1 ). Table 1 The evolution of LAIs prescription before and after declaration of COVID-19 pandemic. Table 1 Type of LAIs Number of prescriptions before WHO declared COVID-19 pandemic Number of prescriptions after WHO declared COVID-19 pandemic Reduction of LAIs prescriptions December 2019 January 2020 February 2020 3 months average March 2020 aripiprazole 30 33 35 32.66 10 70% paliperidone 22 27 30 26.33 5 81% olanzapine 19 21 20 20.00 2 90% risperidone 35 41 40 38.66 20 49% The switch from LAIs to OA was requested by patients or caregivers to reduce the number of trips to pharmacies, medical offices or public mental health centers. For most forms of intramuscular administration, manufacturers and experts have recommended that the treatment be done by specialized medical personnel (physicians or nurses) in centers with experience to avoid any problems. Administration at home is not recommended. Human natural anxiety related to this unique phenomenon in the last hundred years is added. Conspiracy theories in media have a major impact on patients with schizophrenia but not only. We will probably see in the coming days or weeks many patients in clinical remission switched from LAI to OA. Future mirror-image studies will show the consequences of this switch. The effect size will be directly proportional with duration of the pandemic and the restrictions imposed. No-one can anticipate the duration of COVID-19 pandemic and this situation can be prolonged. What can we do to prevent relapses with its dramatic consequences, especially in patients who have been undergoing LAIs for years and have not experienced relapses for a long time, some even considering themselves to be “cured”? What would be the best standard of care in these situations? Proposed measures such as increasing the dose, delaying the next injection, or administration by the pharmacists or family members imposed important risk: stress, pain, too superficial or too profound injection, inadequate site of injection (deltoid or gluteal), etc. We must continue to advocate for improved access to long-acting antipsychotics for the people with previous non-adherence as well as for the young patients at the early stages of schizophrenia, even in this difficult period. Role of funding source None. Declaration of competing interest None of the authors have conflicts to report.

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          Most cited references12

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          Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies.

          Although non-adherence is common across all branches of medicine, psychotic disorders pose additional challenges that increase its risk. Despite the importance of non-adherence, clinicians generally spend too little time on assessing and addressing adherence attitudes and behaviors. Importantly, how adherence is measured significantly impacts the findings, and the most frequently employed methods of asking patients or judging adherence indirectly based on efficacy or tolerability information have poor validity. Novel technologies are being developed that directly assess adherence and that can also be used to both provide real-time feedback to clinicians and serve as an intervention with patients. Several treatments are available that can positively impact adherence. Among psychosocial interventions, those combining multiple approaches and involving multiple domains seem to be most effective. Although long-acting injectable antipsychotics are theoretically a very powerful tool to assure adherence and signal non-adherence, recent results from randomized controlled trials failed to show superiority compared to oral antipsychotics. These data are in contrast to nationwide cohort studies and mirror-image studies, which arguably include more representative patients receiving long-acting antipsychotics in clinical practice. This disconnect suggests that traditional randomized controlled trials are not necessarily the best way to study interventions that are thought to work via reducing non-adherence. Clearly, non-adherence is likely to remain a major public health problem despite treatment advances. However, increasing knowledge about factors affecting adherence and leveraging novel technologies can enhance its early assessment and adequate management, particularly in patients with psychotic disorders.
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            Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies.

            Recent, large, randomized controlled trials (RCTs) showed no benefit of long-acting injectable (LAI) antipsychotics over oral antipsychotics in preventing relapse in schizophrenia, nor did a recent meta-analysis incorporating these studies. However, RCTs might enroll a disproportionate number of patients with better treatment adherence and lower illness severity. Mirror-image studies, which compare periods of oral antipsychotic versus LAI treatment in the same patients, might therefore better reflect the real-world impact of LAIs.
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              Is Open Access

              Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia

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                Author and article information

                Contributors
                Journal
                Schizophr Res
                Schizophr. Res
                Schizophrenia Research
                Elsevier B.V.
                0920-9964
                1573-2509
                27 April 2020
                27 April 2020
                Affiliations
                [a ]Transilvania University of Brasov, Romania
                [b ]Clinical Hospital of Psychiatry and Neurology Brasov, Romania
                Author notes
                [* ]Corresponding author at: Transilvania University of Brasov, Romania. petru.ifteni@ 123456unitbv.ro
                Article
                S0920-9964(20)30237-1
                10.1016/j.schres.2020.04.030
                7185008
                32349886
                f1e18a12-e163-4766-a298-3423cf98b65e
                © 2020 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 8 April 2020
                : 13 April 2020
                : 22 April 2020
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                Neurology
                Neurology

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