Journal of Mental Health

ISSN: 0963-8237 (Print) 1360-0567 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmh20

Oral depot antipsychotic drugs: time for a paradigm shift? Harpal Singh Nandhra & Akeem Sule To cite this article: Harpal Singh Nandhra & Akeem Sule (2015): Oral depot antipsychotic drugs: time for a paradigm shift?, Journal of Mental Health, DOI: 10.3109/09638237.2014.973102 To link to this article: http://dx.doi.org/10.3109/09638237.2014.973102

Published online: 12 Feb 2015.

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Date: 03 October 2015, At: 17:17

http://informahealthcare.com/jmh ISSN: 0963-8237 (print), 1360-0567 (electronic) J Ment Health, Early Online: 1–2 ! 2014 Shadowfax Publishing and Informa UK Limited. DOI: 10.3109/09638237.2014.973102

EDITORIAL

Oral depot antipsychotic drugs: time for a paradigm shift? Harpal Singh Nandhra1 and Akeem Sule2,3 Coventry and Warwickshire Parnership Trust, Ashton House, Leamington Spa, Warwickshire, UK, 2Springhouse CMHT, Biggleswade Hospital, Bigglesewade, Bedfordshire, UK, and 3Wolfsan College, University of Cambridge, Cambridge, UK

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Meta-analysis of placebo controlled trials shows that antipsychotic drugs (APDs) are highly effective in reducing rates of relapse and rehospitalisation in people with schizophrenia (Leucht et al., 2012). In clinical practice, the effectiveness of maintenance treatment is often undermined by poor adherence. In one study, over a third of patients had an annual medication possession ratio of less than 80% (Valenstein et al., 2006), a measure often adopted to indicate poor adherence and other studies have reported comparable rates. Poor medication adherence is a consistent predictor of poorer outcomes in schizophrenia (Novick et al., 2010) and improving adherence is an important clinical focus. Strategies to improve adherence need to be patient specific and reflect the underlying factors (NICE, 2009). Involving the patient in treatment decisions and modifying dysfunctional health beliefs are important particularly when non adherence is intentional. Adherence aids and antipsychotic long acting injections (LAIs) can assist some individuals. In the UK depending on the clinical setting one quarter to one third of patients receive LAIs. The relative effectiveness of oral APDs and LAI APDs is partly dependant on trial design (Haddad et al., 2006; Kirson et al., 2013). Observational studies tend to report superior outcomes for LAIs in terms of continuation or rehospitalisation whereas meta-analysis shows equivalent relapse rates for oral and LAI APDs (Kishimoto et al., 2014). Their use varies considerably geographically. LAI APDs have the advantage of knowing that the patient has had the medication administered with the date and dose known. The dosing is infrequent and the patient does not have to remember to take it. Unfortunately for many patients, LAI administration has many disadvantages (Gray et al., 2009). They are invasive, have injection site problems, carry a risk of needlestick injury and needle phobia is often cited as a reason not to have LAI. The process can also be perceived as coercive, an affront to dignity and consequently lead to further disengagement which is a crucial hindrance to long term success. Monitoring daily administration of medication is often perceived as excessively intrusive into pts lives and in

Correspondence: Harpal Singh Nandhra, Coventry and Warwickshire Parnership Trust, Ashton House, Leamington Spa, Warwickshire, UK. E-mail: [email protected]

resource limited settings is not a viable long term option. Covert secretion by the pt can also occur in time pressured situations. As oral depots are administered less often than daily more care can be taken to ensure ingestion. Oral depots have the potential to overcome all these problems when adherence is problematic. This could be under a CTO if medication refusal is the primary issue. Penfluridol is the archetypal oral depot and there are two other drugs which could be used in this way. Penfluridol never licensed in the UK is administered once a week orally. It does have licenses in some countries including India, USA and the Netherlands. Aripiprazole has been used by one of the authors (HSN) three days a week with excellent results and tolerability. Pimozide has been used on alternate days. Penfluridol, a white micro-crystalline tertiary amine, belonging to the diphenylbutylpiperidine group was first synthesized in 1968. Following oral administration it is deposited in fatty tissue from which it is slowly released, resulting in a prolonged duration of action with a half-life of 70 h. It is primarily excreted unchanged in the faeces with some hepatic metabolism and enterohepatic recycling (Janssen, 1972). Soares & Lima (2006) completed a Cochrane review of Penfluridol. They found Penfluridol was superior to depot typical antipsychotics in stopping the patients ‘‘leaving the study early’’ (n ¼ 218, 5RCTs, RR 0.55, CI 0.3 to 0.97, NNT 6, CI 3.4 to 50). There were no differences in efficacy and safety measures. Pimozide also a diphenylbutylpiperidine has a mean serum elimination half-life of approximately 55 h. This is highly variable and may be as long as 150 h in some individuals. Theoretically, it could be used with once weekly dosing in slow metabolisers and twice a week in fast metabolisers. The mean elimination half-lives for aripiprazole (a second generation antipsychotic) are approximately 75 h in extensive metabolisers of CYP2D6 and approximately 146 h in poor metabolisers of CYP2D6. Theoretically, it could be used with once weekly dosing. Theoretically, peak dose side effects could be worsened with oral depots, but this was not observed in the systematic review by Soares et al. and has not been observed in the clinical experience of the authors. Nevertheless, this should be closely clinically monitored and would be an important

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endpoint in randomised controlled trials. With pimozide this could be QTc prologation and extrapyramidal side effects, and with aripiprazole could be akathisia. There is further hope for the future with the development of microsphere nanotechnology. Anti-tubercular drugs have been produced in a formulation which allows weekly administration (Pandey & Khuller, 2004), and microsphere cancer therapy is being used (Cummings, 1998). Oral depots have considerable advantages over daily oral administration and LAI without any of their drawbacks. They represent an underused weapon in a psychiatrist’s armamentarium. It is time for rigorous trials to demonstrate that their theoretical benefits are reproduced in the real life situation.

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References Cummings J. (1998). Microspheres as a drug delivery system in cancer therapy. Expert Opin Therapeut Patents, 8, 153–71. Gray R, Spilling R, Burgess D, Newey T. (2009). Antipsychotic longacting injections in clinical practice: Medication management and patient choice. Br J Psychiat, 195, S51–6. Haddad PM, Taylor M, Niaz OS. (2006). First-generation antipsychotic long-acting injections v. oral antipsychotics in schizophrenia: Systematic review of randomised controlled trials and observational studies. Br J Psychiat, 52, S20–8.

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Janssen PAJ. (1972). Long-acting neuroleptics and other psychoactive drugs on the future. Clin Med, 79, 12–14. Kirson NY, Weiden PJ, Yermakov S, et al. (2013). Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: Synthesizing results across different research designs. J Clin Psychiat, 74, 568–75. Kishimoto T, Robenzadeh A, Leucht C, et al. (2014). Longacting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A meta-analysis of randomized trials. Schizophr Bull, 40, 192–213. Leucht S, Tardy M, Komossa K, et al. (2012). Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: A systematic review and meta-analysis. Lancet, 379, 2063–71. NICE. (2009). Medicines adherence: Involving patients in decisions about prescribed medicines and supporting adherence. Clin Guidelines, CG76. Novick D, Haro JM, Suarez D, et al. (2010). Predictors and clinical consequences of non-adherence with antipsychotic medication in the outpatient treatment of schizophrenia. Psychiat Res, 176, 109–13. Pandey R, Khuller GK. (2004). Chemotherapeutic potential of alginatechitosan microspheres as anti-tubercular drug carriers. J Antimicrob Chemother, 53, 635–40. Soares BG, Lima MS. (2006). Penfluridol for schizophrenia. Cochrane Database Syst Rev, 19, CD002923. Valenstein M, Ganoczy D, McCarthy JF, et al. (2006). Antipsychotic adherence over time among patients receiving treatment for schizophrenia: A retrospective review. J Clin Psychiat, 67, 1542–50.

Oral depot antipsychotic drugs: time for a paradigm shift?

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