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Is antipsychotic depot treatment an underutilised gold
standard in the long-term treatment of schizophrenia?
Making Education Easy
This publication is a summary of a presentation by Dr Stephan Heres, Senior Psychiatrist at the Department of Psychiatry and Psychotherapy at the Centre for Disease Management at the Psychiatric Department, Technical University Munich, Germany. He spoke throughout New  Zealand in July/August 2012 on the attitudes of psychiatrists and patients towards depot (long-acting injectable) antipsychotic treatment of schizophrenia, the current efficacy evidence for depot antipsychotic use and the current outcomes of the OASE depot clinic in Munich. He acknowledges that the title of his presentation is a little provocative, but believes that the discussion of depot antipsychotic treatment as first-line therapy for schizophrenia is an important one. The compliance challenge
Dr Stephan Heres M.D.
It would appear that compliance with oral medications is not just an issue in psychiatry, with studies in Dr Stephan Heres is a Senior Psychiatrist at the a variety of therapeutic areas demonstrating low compliance rates. An example of the impact of non- Department of Psychiatry and Psychotherapy compliance was demonstrated in a review by Wiegratz et al who analysed contraceptive use in Germany.1 at the Centre for Disease Management at the They found that ideal' use (no missed pills) of oral ovulation inhibitors was associated with 0.3 pregnancies Psychiatric Department, Technical University per 100 women per year, while their typical' use (50% of women missed at least one pill and 25% at least Munich, Germany. He is also head of the two pills per cycle) was associated with eight pregnancies per 100 women per year. Dr Heres pointed out specialised schizophrenia outpatient depot clinic that remaining compliant with daily oral drug dosing is a challenge for everyone and that depot antipsychotic (OASE) at the university and head of the clinical treatment makes non-compliance more transparent to treating physicians. trial team.
Dr Heres' research interests include antipsychotic Relapse rates under depot treatment
depot treatment, psychopharmacology, and A recent meta-analysis of 10 randomised controlled trials (RCTs) comparing depot antipsychotic treatment clinical study design, with a special focus on bias with oral antipsychotic treatment revealed 1-year relapse rates with oral treatment of 35% and with depot of in drug trials. He has been involved as primary 25%.2 This 10% difference in relapse rate equates to a favourable number needed to treat (NNT) of 10. This investigator, sub-investigator, protocol author means that if 10 patients were treated with a depot antipsychotic rather than an oral antipsychotic, then one or study coordinator in more than 40 phase II, patient would be saved from a relapse. III and IV clinical trials or investigator-initiated A recent study using naturalistic data of all people in Finland aged 16-65 years who had their first trials, most recently for therapeutics under hospitalisation and a diagnosis of schizophrenia between 2000-2007, and who had not collected any investigation for the treatment of schizophrenia.
antipsychotic medication within the 6 months prior to admission, investigated non-compliance in first-episode patients.3 Of 2588 patients hospitalised with a first episode of schizophrenia, 58.2% collected a prescription for an antipsychotic within the first 30 days after hospital discharge, whereas 41.8% did not. In this nationwide cohort, only ≈8% of patients received depot injections as their first antipsychotic medication, About Research
but those patients had a 64% lower relapse risk compared with those receiving oral antipsychotic treatment.
Attitudes towards depot antipsychotic treatment
Research Review is an independent medical publishing organisation producing electronic publications in a wide variety of specialist Dr Heres and colleagues recently undertook a study to answer the question: How much more effective (with respect to relapse prevention) do depot antipsychotics have to be compared to oral antipsychotics before they are prescribed?4 They asked 106 psychiatrists to consider a hypothetical patient with schizophrenia requiring A Research Review Speaker Series is a an antipsychotic and asked them to choose which of two formulations (oral or depot injection) of a single summary of a speaking engagement by a antipsychotic agent they would use given the following scenarios regarding annual relapse rates for oral vs major local or international expert and allows depot injection: 35% vs 35%, 35% vs 30%, 35% vs 25%, 35% vs 20%, respectively. The psychiatrists were it to be made available to a wider audience informed that the two formulations of the agent had identical efficacy and side-effect profiles. Under the through the Research Review membership or scenario of equal annual relapse rates (35% each), the majority of psychiatrists (81%) chose to prescribe the oral formulation of the agent. This percentage decreased to 62% under the 35% vs 30% scenario, to 36% Research Review publications are intended under the 35% vs 25% scenario and to 11% under the 35% vs 20% scenario (see Figure 1). The findings
for New Zealand medical professionals. showed that a hypothetical 10% improvement in annual relapse rate with depot over oral antipsychotic was necessary to engender a majority switch from oral to depot use. However, in clinical practice we still see the majority of patients being treated with oral antipsychotic formulations despite their being a demonstrated 10% improvement in relapse rate with depot formulations compared with oral formulations.2 Subscribing to
A clear gap exists between knowing and doing' with regard to prescribing depot antipsychotics. A recent study in New Zealand by Miles and colleagues looking at psychiatrists' attitudes to, and knowledge about, depot risperidone found that outdated views regarding depot antipsychotics contribute to the gap between To subscribe to Research Review publications go to actual practice and what is thought to be desirable.5 Over the past two decades, the prescribing rate of depot antipsychotics has decreased worldwide. The prescribing of first-generation depot antipsychotics declined when oral second-generation antipsychotics a RESEARCH REVIEW publication
Research Review Speaker Series
Is antipsychotic depot treatment an underutilised gold standard in the long-term treatment of schizophrenia?
entered the market in the 1990s. Psychiatrists at the time hoped that the side-effect profile of these new available regarding the use of depots in such agents would mean a decrease in compliance issues and no need for depot antipsychotics. In the early 2000s, depot second-generation antipsychotics became available. Interestingly, in China since the late 1990s Results from a 2-year trial in South Africa by Emsley prescribing rates of depot antipsychotics in Beijing and Shanghai have differed significantly despite these and colleagues investigating the use of depot regions falling under the same national treatment guidelines and the same reimbursement criteria. Dr Heres risperidone 25-50 mg every 2 weeks for 2 years explained that the 4-fold difference seen in prescribing rates is simply due to local attitude (in particular in 50 patients with first-episode schizophrenia hospital attitude) towards the prescribing of these agents. revealed that >70% of patients stayed on the study drug until study completion and that <10% of patients experienced a relapse.8Emsley et al subsequently compared their depot risperidone findings with those from a study of 47 first-episode patients randomised to receive either oral risperidone or oral haloperidol.9 They found a 4-fold higher relapse rate in recipients of oral antipsychotics compared with those who had received depot risperidone. Dr Heres pointed out that one must be careful when extrapolating data such as this from different agents, and that while it might not be fair to say that there is a 4-fold difference in relapse rate, it would be fair to say that the rate of relapse was certainly higher under oral treatment.
Remission, as defined by the Remission in Schizo-phrenia Working Group, is a favourable outcome associated with a lower relapse rate, better quality of life and a better level of functioning.10 In Emsley et al's study of depot risperidone, 64% of patients reached remission.8 Of significance, 97% Figure 1. Difference in psychiatrists' choice of antipsychotic formulation when they are presented with
of those achieving remission on depot risperidone hypothetical differences in relapse rates.4 maintained this status until the end of the study compared with only approximately one-third of Dr Heres and colleagues surveyed 300 patients in nine psychiatric hospitals in Germany about their those receiving oral antipsychotics.8,9 preference in the mode of administration of antipsychotic treatment.6 Almost half of the patients were depot At the end of their 2-year depot risperidone trial, antipsychotic-naïve (n = 145), while 60 patients were currently receiving depot formulations, and 95 had Emsley and colleagues asked the 34 remaining previously received such agents. The survey found that overall, >40% of participants would accept depot responders if they would like to discontinue depot antipsychotics as a first or second treatment choice. Acceptance rates were 75% in those currently receiving treatment and 33 patients said yes (one patient depot antipsychotics, 45% in those with previous depot experience and 23% in depot-naïve participants, had been lost to follow-up).8 It is possible that all indicating that the subjective perception of any benefits from depot treatment rises with depot experience of those patients hoped to be in the small group (previous or ongoing). The low rate of acceptance in naïve patients, who are unable to see potential benefits of patients who suffer from only one episode of depot antipsychotic in their particular case, stresses the importance of peer-to-peer' education aimed of schizophrenia in their life-time. Follow-up of at providing patients with first-hand knowledge from patients experienced with such therapy. Interestingly, the 33 patients revealed relapse rates of 79% the rates identified in the survey exceed the current depot prescription rate in Germany of ≈17%. Also of at 12 months, 94% at 24 months and 97% interest, 95% of patients in the survey currently treated with depot antipsychotics had a >3-year history of at 36 months.11 Symptom severity returned to schizophrenia. This finding lead to the hypothesis that depot treatment was initiated later on in the course of levels close to those of the first episode and the treatment in those patients.
onset of recurrence symptoms was fairly abrupt. Dr Heres pointed out that most guidelines What are the main reasons for not prescribing depot antipsychotics?
recommend first-episode patients receive Dr Heres and colleagues surveyed 350 German psychiatrists as to their reasons for not prescribing depot antipsychotics for 1-3 years, but this is based on antipsychotics (first- or second-generation).7 They found that most reasons applied equally to first- and fairly scant research. Intermittent therapy is not second-generation agents, except for direct drug costs (second-generation agents) and risk of extrapyramidal side effects (first-generation agents). The main reason given for not prescribing depot antipsychotics was good compliance with oral antipsychotic treatment'. Dr Heres pointed out that this attitude is problematic as White matter changes in first-
numerous publications, including the one discussed above regarding oral contraceptive use, have shown that episode patients on antipsychotics
patients struggle daily to remain compliant with oral medications. He stressed that good compliance with oral Individuals with schizophrenia appear to have a antipsychotic treatment is not a good reason for not prescribing depot antipsychotics. dysregulated trajectory of frontal lobe myelination. The survey also found that only 35.5% of all patients suffering from schizophrenia have ever been offered Bartzokis et al have recently shown that first- depot antipsychotic treatment.7 Furthermore, first-episode schizophrenia patients are rarely considered episode schizophrenia patients exhibit a shift for depot antipsychotic treatment. This was a robust outcome, with subsequent surveys by Dr Heres and from white to grey matter in the frontal lobe of colleagues showing the same findings. the brain.12 This shift can be halted by treating First-episode schizophrenia patients
patients with oral atypical antipsychotics, but after approximately 12 months the shift from white to The question arises as to why psychiatrists are so hesitant to prescribe depot antipsychotics to patients grey recurs. Bartzokis et al speculated that this experiencing a first episode of schizophrenia. One explanation may be that in the 1990s first-episode phenomenon may be due to medication non- patients were treated with oral second-generation antipsychotics and there was no new evidence available compliance, and so investigated if these changes regarding depot use in first-episode patients. In the past few years, increasing evidence has become occur with depot antipsychotics. After 12 months a RESEARCH REVIEW publication
Research Review Speaker Series
Is antipsychotic depot treatment an underutilised gold standard in the long-term treatment of schizophrenia?
of treatment with oral risperidone, patients were randomised to either partaking in the compliance support programmes. Points can then be exchanged for continue oral therapy (n = 13) or to receive depot risperidone (n = 11), vouchers for the purchase of goods at various stores. and were compared with 14 healthy controls. Inversion recovery MRI at First results from the OASE project
6 months revealed that white matter volume remained stable in depot risperidone recipients, but decreased significantly in oral risperidone Depot risperidone recipients
recipients, resulting in a significant differential treatment effect. Depot risperidone became available in Germany in 2003. Eighteen-month Furthermore, tests of frontal lobe function revealed that white matter completer analysis of mild-to-moderately ill patients (n = 120; mean age 41 years; increase was associated with faster reaction times. Reaction times 61.9% female; 58.2% in remission) in the OASE project receiving depot risperidone for those receiving depot risperidone did not differ significantly from for schizophrenia or schizoaffective disorder revealed dropout rates of 34.2% at those of healthy volunteers, while those receiving oral risperidone had 12 months and 41.7% at 18 months (unpublished). A study recently undertaken in significantly slower reaction times.
New Zealand by Carswell and colleagues revealed a depot risperidone discontinuation rate of 42% at 12 months.13 These findings help highlight the benefit of the OASE project The OASE project
with regard to treatment compliance. Reasons given for dropout from the OASE project Dr Heres explained that Oase is the German word for Oasis, but also were: patient's decision 58%; treating psychiatrist changed 16%; side effects 8%; stands for Optimised Ambulatory outpatient treatment of Schizophrenia. participation in the programme deemed too elaborate 2%; patient moved 2%; lost to All patients attending the OASE clinic in Munich receive depot follow-up 2%; no reason stated 12%.
antipsychotics and approximately two-thirds are co-treated with oral Analysis of the primary end-point, inpatient days, in patients receiving depot antidepressants or mood stabilisers. The OASE project was initiated risperidone, revealed a 90% decrease in the number of days in hospital after entry into because, as with oral antipsychotics, patients on depot treatment have the OASE project; mean 72.1 days in hospital per patient per year and 73.5 days per a tendency to discontinue their treatment over time. The idea was to patient per 18 months prior to entry into the OASE project, compared with 8.1 inpatient start patients on depot antipsychotics and use the OASE clinic to keep days per patient per year and 7.5 inpatient days per patient per 18 months after entry them on track. To this end, the clinic was designed to appeal to patients into the project (see Figure 2). Quality of life, health status and medication adherence
with spacious rooms, pleasant décor, free Internet access and free also remained stable in these patients at 12 months. Dr Heres pointed out that a lot refreshments. Previous surveys have shown that these are the sorts of of effort has been invested in the OASE project and it is not possible to maintain this things that patients desire from such clinics.
for patients long-term. He commented that it maybe more realistic to expect a 40% decrease in the number of inpatient days for patients partaking in such a programme. At the OASE clinic, patients have access to stable contact persons and there are extra rooms for injection nurses. Dr Heres stressed that in a depot clinic, injection nurses are extremely important and that patients at the OASE clinic have a very good therapeutic alliance with the nurses. He also explained that unlike New Zealand, Germany does not have Compulsory Treatment Orders. Figure 2: Inpatient days in patients receiving depot risperidone prior to and during
Quarterly assessment of non-compliance risk
participation in the OASE project. As patients have to show up at the depot clinic in order to receive treatment, it is important to identify those at highest risk of not turning Depot olanzapine recipients
up. Furthermore, approximately two-thirds of patients attending the Depot olanzapine has only been used in Germany for approximately 3 years and while clinic are co-treated with oral agents and identifying patients at the numbers of users is growing each month, there were only 17 patients on the agent risk of becoming non-compliant with those agents is important. To included in the 18-month OASE completer analysis. Most of the patients received an this end, patients involved in the OASE project undergo quarterly oral equivalent olanzapine dose of 15-20 mg/day. At baseline, 70.6% were in remission. routine assessment of non-compliance risk, assessed using a 70-item The dropout rate was 23.5% at 12 months and 35.3% at 18 months (unpublished Compliance support programme
Analysis of inpatient days during the 12 months before and after entry into the Several support groups are available to patients attending the OASE clinic OASE project revealed a decrease of 89% (74.5 vs 8.1 days in hospital per patient); and include music therapy, a nicer-living' group and cultural activities. eighteen-month values were 103.6 vs 23.8 days per patient, a 77% decrease All patients undergo psychoeducation, receiving booster sessions every (see Figure 3). The Clinical Global Impression – Severity of Illness Scale score did
6 months. Patient's families are also strongly encouraged to partake in not differ significantly between baseline and after 12 or 18 months (ranging between psychoeducation as this has a very good compliance-enhancing effect. 3.2 and 3.5). This finding was consistent with that of McDonnell et al who looked at Metacognitive training is utilised, as is motivational interviewing. Each the long-term safety and efficacy of depot olanzapine for schizophrenia.14 Quality of patient is assigned an individual case-manager. A voucher incentive life, health status and medication adherence also remained stable among the 17 depot system has also been implemented, where patients earn points for olanzapine recipients at 12 months.
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Is antipsychotic depot treatment an underutilised gold standard in the long-term treatment of schizophrenia?
Engaging patients for antipsychotic depot
treatment - experience from the OASE
project
Dr Heres outlined the following key ways in which the OASE project has
engaged patients with depot antipsychotic treatment:
• All patients with schizophrenia or schizoaffective disorder must be
offered depot treatment routinely (100% approach); explicitly including all first-episode patients • Hand-over of detailed, balanced information on benefits and disadvantages of depot compared to oral drug treatment (manuscript-based). Also, cases of individual patients taking either an oral or depot antipsychotic and how they reached their treatment decision. • Shared decision-making in order to engender greater compliance• Peer-to-peer approach (a depot-experienced patient talks about her/his experience with this formulation). This is highly appreciated by patients and is a key intervention for handing over information regarding depot use and how this might be beneficial to an individual patient • Early introduction of the depot idea during the hospital stay Figure 3: Inpatient days in patients receiving depot olanzapine prior to and during
• Early contact to the OASE team and the OASE facilities participation in the OASE project. Do we currently exploit the full potential
of depot antipsychotics?
Dr Heres concluded his presentation with the following remarks
regarding the current status of depot antipsychotic treatment and
reminded the audience that drugs only work in patients who take them!
Subscribing to
• Depot antipsychotic therapy is still an exceptional approach rather than a routine treatment strategy – despite considerable advantages! • Psychiatrists anticipate a negative attitude of patients toward depot To subscribe or download treatment – such patient attitude is not verified in surveys! previous editions of Research Review • First-episode patients are rarely treated with depot antipsychotics publications go to – despite growing excellent evidence for their use! – why do we have to wait until the first relapse? • Depot antipsychotic initiation is a first step' – additional supportive programs help further optimise treatment outcomes and keep patients in the boat' References
1. Wiegratz I and Thaler CJ. Hormonal contraception--what kind, when, and for whom?
9. Emsley R et al. Oral versus injectable antipsychotic treatment in early psychosis: post hoc Dtsch Arztebl Int. 2011;108(28-29):495-505 comparison of two studies. Clin Ther. 2008;30(12):2378-86 2. Leucht C et al. Oral versus depot antipsychotic drugs for schizophrenia--a critical systematic 10. Andreasen NC et al. Remission in schizophrenia: proposed criteria and rationale for consensus. review and meta-analysis of randomised long-term trials. Schizophr Res. 2011;127(1-3):83-92 Am J Psychiatry 2005;162(3):441-9 3. Tiihonen J et al. A nationwide cohort study of oral and depot antipsychotics after first 11. Emsley R et al. Symptom recurrence following intermittent treatment in first-episode hospitalization for schizophrenia. Am J Psychiatry. 2011;168(6):603-9 schizophrenia successfully treated for 2 years: a 3-year open-label clinical study. J Clin 4. Hamann J et al. How much more effective do depot antipsychotics have to be compared to oral antipsychotics before they are prescribed? Eur Neuropsychopharmacol. 2010;20(4):276-9 12. Bartzokis G et al. Long acting injection versus oral risperidone in first-episode schizophrenia: 5. Miles SW et al. Determining what practising clinicians believe about long-acting injectable differential impact on white matter myelination trajectory. Schizophr Res. 2011;132(1):35-41 antipsychotic medication. Int J Psychiatry Clin Pract. 2011;15(2):135-44 13. Carswell C et al. Comparative effectiveness of long-acting risperidone in New Zealand: a report 6. Heres S et al. The attitude of patients towards antipsychotic depot treatment. of resource utilization and costs in a 12-month mirror-image analysis. Clin Drug Investig. Int Clin Psychopharmacol. 2007;22(5):275-82 7. Heres S et al. Attitudes of psychiatrists toward antipsychotic depot medication. J Clin Psychiatry 14. McDonnell D et al. Long-term safety and tolerability of open-label olanzapine long-acting injection in the treatment of schizophrenia: 190-week interim results. Clinical Medicine Insights: 8. Emsley R et al. Remission in patients with first-episode schizophrenia receiving assured Psychiatry. 2011;3:37-47 antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. Publication of this article was paid for by Eli Lilly. Dr Stephan Heres accepted financial support from Eli Lilly to present at this meeting. The content or opinions expressed in this publication may not reflect the views of Eli Lilly. Treatment decisions based on these data are the full responsibility of the prescribing physician. Before prescribing any of the medicines mentioned in this publication please review the data sheets available at .
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