Can the use of long-acting injectable antipsychotic preparations be increased in routine clinical practice and the benefits realised?

BACKGROUND: The use of continuing antipsychotic medication is an established evidence-based strategy for preventing relapse in people with schizophrenia, but medication adherence is known to be suboptimal. Covert non-adherence can be eliminated by the use of long-acting injectable (LAI) formulations. We sought to (1) raise awareness among clinicians of the potential benefits of LAI antipsychotic formulations, (2) increase use of these formulations for the treatment of schizophrenia in routine clinical practice and thereby (3) reduce the number of relapses requiring hospitalisation in patients with schizophrenia under our care. METHOD: Educational initiatives, promotion of reflective practice and patient-specific reminders were used to prompt increased use of LAI antipsychotic medication for patients with schizophrenia. Data relating to the use of these medications and the number of acute admissions for schizophrenia spectrum disorders (F20-29, ICD-10) over time were extracted from existing clinical information systems. RESULTS: Over the 3-year time frame of our local initiative, the use of LAI antipsychotic preparations increased by 11%, the number of acute admissions for schizophrenia/schizoaffective disorder (F20 and F25) decreased by 26% and the number of acute bed days occupied by patients with these diagnoses decreased by 8%. The number of admissions for other psychosis diagnoses (F21-24 and F28-29) did not show the same pattern of improvement. CONCLUSION: In our health care organisation, raising clinicians' awareness of the evidence base relating to the potentially favourable benefit-risk balance for LAI antipsychotic medication compared with oral formulations resulted in more use of the former. There were accompanying reductions in acute admissions and occupied bed days for patients with schizophrenia.

Attitudes of European physicians towards the use of long-acting injectable antipsychotics.

BACKGROUND: Prescription rates for long-acting injectable (LAI) antipsychotic formulations remain relatively low in Europe despite improved adherence over alternative oral antipsychotic treatments. This apparent under-prescription of LAI antipsychotics may have multiple contributing factors, including negative mental health practitioner attitudes towards the use of LAIs. METHODS: The Antipsychotic Long acTing injection in schizOphrenia (ALTO) non-interventional study (NIS), conducted across several European countries, utilised a questionnaire that was specifically designed to address physicians' attitudes and beliefs towards the treatment of schizophrenia with LAI antipsychotics. Exploratory principal component analysis (PCA) of feedback from the questionnaire aimed to identify and characterize the factors that best explained the physicians' attitudes towards prescription of LAIs. RESULTS: Overall, 136/234 solicited physicians returned fully completed questionnaires. Physicians' mean age was 48.5 years, with mean psychiatric experience of 20.0 years; 69.9% were male, 84.6% held a consultant position, and 91.9% had a clinical specialty in general adult care. Most physicians considered themselves to have a high level of clinical experience with LAI antipsychotics (77.2%), with an increased rate of LAI antipsychotics prescription over the last 5 years (59.6%). Although the majority of physicians (69.9%) declared feeling no difference in stress levels when offering LAI compared to oral antipsychotics, feelings of 'no/more stress' versus 'less stress' was found to influence prescription patterns. PCA identified six factors which collectively explained 66.1% of the variance in physician feedback. Multivariate analysis identified a positive correlation between physicians willing to accept usage of LAI antipsychotics and the positive attitude of colleagues (co-efficient 3.67; p = 0.016). CONCLUSIONS: The physician questionnaire in the ALTO study is the first to evaluate the attitudes around LAI antipsychotics across several European countries, on a larger scale. Findings from this study offer an important insight into how physician attitudes can influence the acceptance and usage of LAI antipsychotics to treat patients with schizophrenia.

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.

Dose-Response Meta-Analysis of Antipsychotic Drugs for Acute Schizophrenia.

OBJECTIVE: The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses. METHODS: A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses. RESULTS: Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice. CONCLUSIONS: In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Joint BAP NAPICU evidence-based consensus guidelines for the clinical management of acute disturbance: De-escalation and rapid tranquillisation.

The British Association for Psychopharmacology and the National Association of Psychiatric Intensive Care and Low Secure Units developed this joint evidence-based consensus guideline for the clinical management of acute disturbance. It includes recommendations for clinical practice and an algorithm to guide treatment by healthcare professionals with various options outlined according to their route of administration and category of evidence. Fundamental overarching principles are included and highlight the importance of treating the underlying disorder. There is a focus on three key interventions: de-escalation, pharmacological interventions pre-rapid tranquillisation and rapid tranquillisation (intramuscular and intravenous). Most of the evidence reviewed relates to emergency psychiatric care or acute psychiatric adult inpatient care, although we also sought evidence relevant to other common clinical settings including the general acute hospital and forensic psychiatry. We conclude that the variety of options available for the management of acute disturbance goes beyond the standard choices of lorazepam, haloperidol and promethazine and includes oral-inhaled loxapine, buccal midazolam, as well as a number of oral antipsychotics in addition to parenteral options of intramuscular aripiprazole, intramuscular droperidol and intramuscular olanzapine. Intravenous options, for settings where resuscitation equipment and trained staff are available to manage medical emergencies, are also included.

Baseline results from the European non-interventional Antipsychotic Long acTing injection in schizOphrenia (ALTO) study.

BACKGROUND: The Antipsychotic Long-acTing injection in schizOphrenia (ALTO) study was a non-interventional study across several European countries examining prescription of long-acting injectable (LAI) antipsychotics to identify sociodemographic and clinical characteristics of patients receiving and physicians prescribing LAIs. ALTO was also the first large-scale study in Europe to report on the use of both first- or second-generation antipsychotic (FGA- or SGA-) LAIs. METHODS: Patients with schizophrenia receiving a FGA- or SGA-LAI were enrolled between June 2013 and July 2014 and categorized as incident or prevalent users. Assessments included measures of disease severity, functioning, insight, well-being, attitudes towards antipsychotics, and quality of life. RESULTS: For the 572 patients, disease severity was generally mild-to-moderate and the majority were unemployed and/or socially withdrawn. 331/572 were prevalent LAI antipsychotic users; of whom 209 were prescribed FGA-LAI. Paliperidone was the most commonly prescribed SGA-LAI (56% of incident users, 21% of prevalent users). 337/572 (58.9%) were considered at risk of non-adherence. Prevalent LAI users had a tendency towards better insight levels (PANSS G12 item). Incident FGA-LAI users had more severe disease, poorer global functioning, lower quality of life, higher rates of non-adherence, and were more likely to have physician-reported lack of insight. CONCLUSIONS: These results indicate a lower pattern of FGA-LAI usage, reserved by prescribers for seemingly more difficult-to-treat patients and those least likely to adhere to oral medication.

Antipsychotic therapeutic drug monitoring: psychiatrists' attitudes and factors predicting likely future use.

BACKGROUND: This study aimed to explore predictive factors for future use of therapeutic drug monitoring (TDM) and to further examine psychiatrists' current prescribing practices and perspectives regarding antipsychotic TDM using plasma concentrations. METHOD: A cross-sectional study for consultant psychiatrists using a postal questionnaire was conducted in north-west England. Data were combined with those of a previous London-based study and principal axis factor analysis was conducted to identify predictors of future use of TDM. RESULTS: Most of the 181 participants (82.9%, 95% confidence interval 76.7-87.7%) agreed that 'if TDM for antipsychotics were readily available, I would use it'. Factor analysis identified five factors from the original 35 items regarding TDM. Four of the factors significantly predicted likely future use of antipsychotic TDM and together explained 40% of the variance in a multivariate linear regression model. Likely future use increased with positive attitudes and expectations, and decreased with potential barriers, negative attitudes and negative expectations. Scientific perspectives of TDM and psychiatrist characteristics were not significant predictors. CONCLUSION: Most senior psychiatrists indicated that they would use antipsychotic TDM if available. However, psychiatrists' attitudes and expectations and the potential barriers need to be addressed, in addition to the scientific evidence, before widespread use of antipsychotic TDM is likely in clinical practice.

Olanzapine and risperidone plasma concentration therapeutic drug monitoring: A feasibility study.

BACKGROUND: This study aimed to develop a clinically acceptable method of therapeutic drug monitoring (TDM) for olanzapine and risperidone and to evaluate the feasibility of its implementation. METHOD: A non-randomised study of inpatients from five Mental Health Trusts was conducted, with a clinical interview at the time of TDM and a subsequent 6-week follow-up review of clinical notes. The TDM intervention comprised: (a) a venous blood sample taken 12 hours post-dose, 7-10 days after drug initiation, and (b) rapid results feedback, with interpretation algorithm guidance. RESULTS: Thirty-two participants provided samples (19 prescribed olanzapine, 13 risperidone). Twenty-six participants remained on the target drug at study end, with seven experiencing a dose change, for whom only four of the TDM results were confirmed as having been checked. Mean dose increased for olanzapine (0.9 mg/day, range 0-10) and decreased for risperidone (-0.3 mg/day, range -4-3). CONCLUSION: TDM can be implemented as part of routine clinical practice for both drugs. However, the lack of robust supporting evidence for or against antipsychotic TDM has probably led to a lack of enthusiasm for and interest in the results. Nevertheless, the advent of less invasive measures and the targeting of patients who might be more likely to benefit may facilitate uptake.

The use of psychotropic medication in patients with emotionally unstable personality disorder under the care of UK mental health services.

BACKGROUND: Guideline recommendations for the pharmacologic treatment of personality disorder lack consensus, particularly for emotionally unstable personality disorder (EUPD), and there is limited information on current prescribing practice in the United Kingdom. OBJECTIVE: To characterize the nature and quality of current prescribing practice for personality disorder across the United Kingdom, as part of a quality improvement program. METHOD: A cross-sectional survey of self-selected psychiatric services providing care for adults with personality disorder (ICD-10 criteria) was conducted. Data were collected during May 2012. RESULTS: Of 2,600 patients with a diagnosis of personality disorder, more than two-thirds (68%) had a diagnosis of EUPD. Almost all (92%) patients in the EUPD subgroup were prescribed psychotropic medication, most commonly an antidepressant or antipsychotic, principally for symptoms and behaviors that characterize EUPD, particularly affective dysregulation. Prescribing patterns were similar between those who had a diagnosed comorbid mental illness and those who had EUPD alone, but the latter group was less likely to have had their medication reviewed over the previous year, particularly with respect to tolerability (53% vs 43%). CONCLUSIONS: The use of psychotropic medication in EUPD in the United Kingdom is largely outside the licensed indications. Whether the treatment target is identified as intrinsic symptoms of EUPD or comorbid mental illness may depend on the diagnostic threshold of individual clinicians. Compared with prescribing for EUPD where there is judged to be a comorbid mental illness, the use of off-label medication for EUPD alone is less systematically reviewed and monitored, so opportunities for learning may be lost. Treatment may be continued long term by default.

Dose Equivalents for Second-Generation Antipsychotic Drugs: The Classical Mean Dose Method.

BACKGROUND: The concept of dose equivalence is important for many purposes. The classical approach published by Davis in 1974 subsequently dominated textbooks for several decades. It was based on the assumption that the mean doses found in flexible-dose trials reflect the average optimum dose which can be used for the calculation of dose equivalence. We are the first to apply the method to second-generation antipsychotics. METHODS: We searched for randomized, double-blind, flexible-dose trials in acutely ill patients with schizophrenia that examined 13 oral second-generation antipsychotics, haloperidol, and chlorpromazine (last search June 2014). We calculated the mean doses of each drug weighted by sample size and divided them by the weighted mean olanzapine dose to obtain olanzapine equivalents. RESULTS: We included 75 studies with 16 555 participants. The doses equivalent to 1 mg/d olanzapine were: amisulpride 38.3 mg/d, aripiprazole 1.4 mg/d, asenapine 0.9 mg/d, chlorpromazine 38.9 mg/d, clozapine 30.6 mg/d, haloperidol 0.7 mg/d, quetiapine 32.3mg/d, risperidone 0.4 mg/d, sertindole 1.1 mg/d, ziprasidone 7.9 mg/d, zotepine 13.2 mg/d. For iloperidone, lurasidone, and paliperidone no data were available. CONCLUSIONS: The classical mean dose method is not reliant on the limited availability of fixed-dose data at the lower end of the effective dose range, which is the major limitation of "minimum effective dose methods" and "dose-response curve methods." In contrast, the mean doses found by the current approach may have in part depended on the dose ranges chosen for the original trials. Ultimate conclusions on dose equivalence of antipsychotics will need to be based on a review of various methods.

Re-examining the role of benzodiazepines in the treatment of schizophrenia: a systematic review.

BACKGROUND: Benzodiazepine prescribing for schizophrenia occurs in clinical practice and antipsychotic trials. This review examined the clinical outcomes for benzodiazepines in schizophrenia. METHOD: A systematic search identified randomised controlled trials that evaluated benzodiazepines in comparison with placebo or antipsychotics, and also as adjuncts to antipsychotics. Relevant clinical outcome data was extracted. RESULTS: Twenty six studies were included with some reporting multiple comparisons. Seven short-term studies compared benzodiazepines with placebo: benzodiazepine superiority was found in two out of five studies for global improvements and two out of four studies for psychiatric/behavioural outcomes. Eleven studies compared benzodiazepines with first-generation antipsychotics (FGAs): four out of nine studies (including two long-term studies) reported greater global improvements for antipsychotics; four out of five studies showed no treatment differences for psychiatric/behavioural outcomes. Fourteen studies compared benzodiazepines (as adjunct to antipsychotics) vs antipsychotics alone (mostly FGAs); benzodiazepine superiority was found for global improvement in one out of eight studies and inferiority in two out of eight short-term studies whereas superiority was found for psychiatric/behavioural outcomes in three out of 12 short-term studies and inferiority in three out of 12 studies. CONCLUSION: Benzodiazepine superiority over placebo was found for global, psychiatric and behavioural outcomes, but inferiority to antipsychotics on longer-term global outcomes. Conflicting evidence exists regarding the addition of benzodiazepines to antipsychotics; thus the use of benzodiazepines in clinical practice and antipsychotic trials should be limited.

Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study.

BACKGROUND: In the UK and other high-income countries, life expectancy in people with schizophrenia is 20% lower than in the general population. AIMS: To examine the quality of assessment and treatment of physical health problems in people with schizophrenia. Method Retrospective audit of records of people with schizophrenia or schizoaffective disorder aged ⩾18. We collected data on nine key aspects of physical health for 5091 patients and combined these with a cross-sectional patient survey. RESULTS: Body mass index was recorded in 2599 (51.1%) patients during the previous 12 months and 1102 (21.6%) had evidence of assessment of all nine key measures. Among those with high blood sugar, there was recorded evidence of 53.5% receiving an appropriate intervention. Among those with dyslipidaemia, this was 19.9%. Despite this, most patients reported that they were satisfied with the physical healthcare they received. CONCLUSIONS: Assessment and treatment of common physical health problems in people with schizophrenia falls well below acceptable standards. Cooperation and communication between primary and secondary care services needs to improve if premature mortality in this group is to be reduced.

Dose equivalents for second-generation antipsychotics: the minimum effective dose method.

BACKGROUND: Clinicians need to know the right antipsychotic dose for optimized treatment, and the concept of dose equivalence is important for many clinical and scientific purposes. METHODS: We refined a method presented in 2003, which was based on the minimum effective doses found in fixed-dose studies. We operationalized the selection process, updated the original findings, and expanded them by systematically searching more recent literature and by including 13 second-generation antipsychotics. To qualify for the minimum effective dose, a dose had to be significantly more efficacious than placebo in the primary outcome of at least one randomized, double-blind, fixed-dose trial. In a sensitivity analysis, 2 positive trials were required. The minimum effective doses identified were subsequently used to derive olanzapine, risperidone, haloperidol, and chlorpromazine equivalents. RESULTS: We reviewed 73 included studies. The minimum effective daily doses/olanzapine equivalents based on our primary approach were: aripiprazole 10 mg/1.33, asenapine 10 mg/1.33, clozapine 300 mg/40, haloperidol 4 mg/0.53, iloperidone 8 mg/1.07, lurasidone 40 mg/5.33, olanzapine 7.5 mg/1, paliperidone 3 mg/0.4, quetiapine 150 mg/20, risperidone 2 mg/0.27, sertindole 12 mg/1.60, and ziprasidone 40 mg/5.33. For amisulpride and zotepine, reliable estimates could not be derived. CONCLUSIONS: This method for determining antipsychotic dose equivalence entails an operationalized and evidence-based approach that can be applied to the various antipsychotic drugs. As a limitation, the results are not applicable to specific populations such as first-episode or refractory patients. We recommend that alternative methods also be updated in order to minimize further differences between the methods and risk of subsequent bias.

Quality of prescribing for schizophrenia: evidence from a national audit in England and Wales.

The National Audit of Schizophrenia (NAS) examined the quality of care received in England and Wales. Part of the audit set out to determine whether six prescribing standards, set by the national clinical guidelines for schizophrenia, were being implemented and to prompt improvements in care. Mental Health Trusts and Health Boards provided data obtained from case-notes for adult patients living in the community with schizophrenia or schizoaffective disorder. An audit of practice tool was developed for data collection. Most of the 5055 patients reviewed were receiving pharmacological treatment according to national guidelines. However, 15.9% of the total sample (95%CI: 14.9-16.9) were prescribed two or more antipsychotics concurrently and 10.1% of patients (95%CI: 9.3-10.9) were prescribed medication in excess of recommended limits. Overall 23.7% (95%CI: 22.5-24.8) of patients were receiving clozapine. However, there were many with treatment resistance who had no clear reason documented as to why they had not had a trial of clozapine (430/1073, 40.1%). In conclusion, whilst most people were prescribed medication in accordance with nationally agreed standards, there was considerable variation between service providers. Antipsychotic polypharmacy, high dose prescribing and clozapine underutilisation in treatment resistance were all key concerns which need to be further addressed.

Psychiatrists' perspectives on antipsychotic dose and the role of plasma concentration therapeutic drug monitoring.

BACKGROUND: Why psychiatrists choose a particular dose of antipsychotic for an individual patient with schizophrenia is unknown. This study aimed to investigate consultant psychiatrists' perspectives on the dose titration and their attitudes towards therapeutic drug monitoring (TDM) for antipsychotics. METHOD: A cross-sectional quantitative questionnaire study of consultant psychiatrists based in London was conducted. A new questionnaire was developed, in part, based on the findings from focus groups. Themes included dose choice, titration, switching, and the pros and cons of TDM use. RESULTS: For 105 consultant psychiatrists, choice of antipsychotic was most influenced by perceived side-effects/tolerance (63.8%). When choosing an optimum dose, most based this on their past clinical experience of patients presenting in a similar way (80.0%), perspectives on the equivalent doses of 2 antipsychotics (69.5%), or the individual patient's stated dose preference (61.9%). Factors thought to warrant a lower dose (eg, first episode psychosis) were consistent with a former study, and 59.0% of the clinicians believed it acceptable to switch antipsychotics ≥4 per year. The majority of clinicians currently routinely use TDM for clozapine (82.9%), and previous use of TDM for clozapine was found to predict likely future use of TDM with antipsychotics (χ = 5.51, P = 0.019). Furthermore, clinicians agreed that TDM could assist in minimizing the risk of dose-related side effects (77.1%). However, 32.4% did not agree that TDM would improve clinical outcomes. Overall, there was a positive attitude towards TDM for antipsychotics, and almost all clinicians (84.8%, 95% confidence interval, 77.9-91.7) would use it if widely available. CONCLUSIONS: Current prescribing decisions regarding antipsychotic dose are mainly influenced by clinician intuition, previous experience, and patient preference. Although some expressed concerns regarding the evidence base, most clinicians reported that they would use TDM for antipsychotics if readily available.

Plasma quetiapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2000-2011.

OBJECTIVE: Suggested predose plasma quetiapine target ranges for effective therapy in schizophrenia lie between 50 and 500 µg/l. We aimed to examine data from a quetiapine therapeutic drug monitoring (TDM) service to assess the plasma quetiapine concentrations attained at specified doses in clinical practice. METHOD: We studied TDM data from patients given immediate-release quetiapine in the period 2000-2011. RESULTS: There were 946 samples from 487 patients (257 males, age at time of first sample, median [range] 34 [14-87] years, and 230 females, age at time of first sample, median [range] 38 [10-92] years). The plasma quetiapine concentration was <50 and <100 µg/l in 30% and 50% of samples, respectively (no quetiapine detected in 9% of samples). The relationship between dose and plasma quetiapine was poor. The mean (95% confidence interval [CI]) quetiapine dose was higher (t = 3.6, df = 446, p <0.01) in males versus females (641 [600-1240] and 548 [600-943] mg/day, respectively), although there was no difference in median dose (600 mg/day) or in the mean (95% CI) plasma quetiapine concentrations attained. Smoking habit had no discernible effect on plasma quetiapine concentration. CONCLUSIONS: There was a poor relationship between dose and plasma quetiapine concentration in this study, as found by others. This is probably because of the short plasma half-life of the drug, at least in part. Nevertheless, quetiapine TDM can help assess adherence and measurement of quetiapine metabolites, notably N-desalkylquetiapine, as well as quetiapine itself may enhance the value of quetiapine TDM in future.

How to compare doses of different antipsychotics: a systematic review of methods.

BACKGROUND: The ability to calculate equivalent dosage is important when comparing or switching between doses of different antipsychotics in the treatment of schizophrenia. It is also necessary when designing antipsychotic comparator trials which control for dosage. METHOD: A systematic review to identify and critically evaluate the methods available for the estimation of antipsychotic dose equivalence was conducted. Electronic searches were carried out using Medline and PubMed and additional information was requested from pharmaceutical companies. The identified methods were evaluated against specific criteria regarding scientific rigour, quality of source data underpinning the method, clinical applicability and utility. RESULTS: Eleven articles were identified that described methodologies for antipsychotic dose equivalence. Seven of these referred to calculated methods, including chlorpromazine equivalence, maximum dose and daily-defined dose, and relied on an evidence base from both fixed and flexible dosing data. The remaining four described consensus methods which were based on the knowledge and experience of experts. Chlorpromazine was used as the standard comparator drug in the majority of the calculated equivalence studies, whereas risperidone was used for most consensus methods. CONCLUSIONS: Comparison of methods for calculating antipsychotic dose equivalence suggests that different methods yield different equivalencies and the evidence is not sufficiently robust for any of these to be considered as a gold standard method. Thus, choice of method may introduce bias, either an over or underestimate of equivalent dosage, when designing head-to-head, antipsychotic, fixed-dose trials. Consequently, clinical trial reports should routinely include justification of the choice of method for calculating dose equivalence.

Naturalistic outcomes of community treatment orders: antipsychotic long-acting injections versus oral medication.

BACKGROUND: Community treatment orders (CTOs) are initiated to compel the patient in the community to take part in a management plan, of which medication is often a part. CTOs were introduced in 2008, in England and Wales. We evaluated naturalistic outcomes of CTOs, according to the antipsychotic formulation prescribed at CTO initiation. METHODS: A cohort study with prospective consecutive sampling and 1-year follow-up was conducted in a large mental health trust in South London. Measures included: demographics, psychotropics and CTO outcomes. Comparison groups were long-acting injection (LAI) versus oral formulations only, for the primary outcomes of time to CTO cessation in days and time to first hospital admission in days, whilst the CTO remained active. RESULTS: For the 188 included patients, the CTO ceased within 1 year, either due to revocation (22.3%), discharge (28.1%) or lapse (19.7%). The CTO was renewed at 6 months for 92 (48.9%) patients, and then 56 (29.8%) were renewed again at 12 months. The antipsychotic formulation at CTO initiation was more likely to be LAI (60.6%) than oral (39.4%). Time to CTO cessation was longer for LAI than oral (median 251 versus 182 days, p = 0.030). A total of 54 patients experienced at least one admission; there was no difference between groups by drug formulation (oral 28.4% versus LAI 28.9%, p = 0.933). The mean time to first admission was 147.1 days and did not differ by formulation. CONCLUSIONS: CTO duration was longer for those prescribed an antipsychotic LAI at CTO initiation, although the time to first admission and number of admissions did not differ between groups. CTOs not only compel treatment, but bind services to the patient, resulting in more intensive follow up. Whether enhanced treatment, via oral or LAI and enabled by the CTO, translates into improved clinical outcomes is yet to be determined.

Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response.

OBJECTIVE: To conduct a systematic review examining the relationships between olanzapine dose, clinical outcome, dopamine occupancy, and plasma concentration; and to evaluate the potential for therapeutic drug monitoring. METHODS: A search using Embase, Medline, and Pubmed was conducted; and the literature was systematically reviewed. Studies meeting inclusion criteria were examined. The relationships between olanzapine dose, response, dopamine occupancy, and concentration were analyzed using statistical regression. RESULTS: Ten studies were included in the analysis for dose-response. The effect size-dose relationship showed a typical dose-response curve with minimal rise in slope for doses higher than 10 mg/d. For the dose-occupancy relationship, 6 studies were included. Doses more than approximately 12 mg/d were sufficient to block 65% of striatal D2 receptors. Doses higher than 20 mg led to minimally higher receptor occupancies. Fifteen studies were included in the meta-regression of olanzapine mean concentrations. A linear relationship between mean plasma concentration and mean dose was observed. CONCLUSIONS: Our review suggests that the likelihood of a favorable response with olanzapine is maximized at doses of 10 to 15 mg/d (perhaps lower in nonsmoking females). Higher doses may be considered if 15 mg is ineffective and if plasma level is less than 20 ng/mL on that dose. There is a direct linear relationship between olanzapine dose and plasma concentration. Therapeutic drug monitoring may be useful in patients who are suspected of nonadherence, where there is potential for a drug interaction, and in patients taking 15 mg/d or more and who have not reached clinical response.