Maxine X. Patel

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.

A systematic review of aripiprazole--dose, plasma concentration, receptor occupancy, and response: implications for therapeutic drug monitoring.

OBJECTIVE To evaluate relationships between aripiprazole dose, plasma level, pharmacologic activity, and clinical outcome in order to evaluate the potential for therapeutic drug monitoring. DATA SOURCES In August 2008, we searched Embase, MEDLINE, and PubMed databases using the keywords aripiprazole, plasma levels, plasma concentration, and therapeutic drug monitoring. STUDY SELECTION Twenty-one reports were retrieved. Eight studies investigating the relationship between blood concentrations of aripiprazole and dose, dopamine D(2)/D(3) occupancy, and/or outcome and adverse effects were then selected. DATA EXTRACTION All data concerning plasma or serum concentrations of aripiprazole were included if concentrations were reported in relation to a dose, dopamine occupancy, or clinical outcome. Those reports solely investigating drug interactions were not included. DATA SYNTHESIS A strong correlation exists between aripiprazole dose and plasma concentration. Positron emission tomography analyses suggest that there are significant relationships between dopamine receptor occupancy and both aripiprazole dose and blood concentration. Dopamine receptor occupancy appears to reach a plateau at doses above 10 mg, supporting the observation found in dose-response studies that 10 mg/d is the optimal dose for aripiprazole. CONCLUSIONS The dose range for aripiprazole is well defined, and it reliably predicts plasma level, dopamine receptor occupancy, and clinical response. Plasma level variation appears to have minimal impact on clinical response, but it may predict some adverse effects. A putative target plasma level range of between 150 and 210 ng/mL is suggested. Therapeutic drug monitoring has limited value in the clinical use of aripiprazole, but it may be useful in assuring adherence and optimizing response in individuals.

Psychiatrists’ use, knowledge and attitudes to first- and second-generation antipsychotic long-acting injections: comparisons over 5 years

Psychiatrists’ attitudes and knowledge about antipsychotic long-acting injections (LAIs) are important given the increasing emphasis on patient choice in treatment and the availability of second-generation antipsychotic (SGA) LAIs. A cross-sectional study of consultant psychiatrists’ attitudes and knowledge in North West England was carried out. A pre-existing questionnaire on clinicians’ attitudes and knowledge regarding LAIs was updated. Of 102 participants, 50% reported a decrease in their use of LAIs. LAI prescribing was evenly split between first-generation antipsychotic (FGA) and SGA-LAIs. Most regarded LAIs as associated with better adherence (89%) than tablets. A substantial proportion believed that LAIs could not be used in first-episode psychosis (38%) and that patients always preferred tablets (33%). Compared with a previous sample, the current participants scored more favourably on a patient-centred attitude subscale (60.4% vs 63.5%, P = 0.034) and significantly fewer regarded LAIs as being stigmatising and old-fashioned. Reported LAI prescribing rates have decreased in the last 5 years despite an SGA-LAI becoming available and most clinicians regarding LAIs as effective. Most attitudes and knowledge have remained stable although concerns about stigma with LAI use have decreased. Concerns about patient acceptance continue as do negative views about some aspects of LAI use; these may compromise medication choices offered to patients.

Physical illness and lifestyle risk factors in people with their first presentation of psychosis

BackgroundThere is an increased prevalence of physical illness and poor lifestyle in patients with chronic schizophrenia. It is unclear whether these are present at the onset of psychosis or develop over the course of illness. We aimed to establish whether patients experiencing their first episode of psychosis have worse physical health and lifestyle than community controls without psychosis.MethodEighty-nine patients with new onset illness were compared to age and sex matched controls for self-reported physical illness and cardiovascular and respiratory risk factors.ResultsPatients reported more physical health complaints, mainly respiratory, compared with age and gender matched controls (odds ratio 2.85, 95% confidence interval 1.2–6.7). Patients were more likely to be cigarette smokers (1.82, 95% CI 1.0–3.3) and eat a fast food diet (1.04, 95% CI 1.0–1.1), but these differences were accounted for by patients’ unemployment status.ConclusionsSome risk factors for physical health problems are present at the onset of psychosis, but these may be explained by unemployment.

Depot and oral antipsychotics: patient preferences and attitudes are not the same thing.

Abstract Some clinicians believe that antipsychotic depot injections are unacceptable to patients. This cross-sectional study investigated patients’ attitudes regarding antipsychotics, and included within-participant comparisons. Two hundred and twenty-two out-patients with schizophrenia/schizoaffective disorder completed the Drug Attitude Inventory (DAI-10), scales on insight, side effects and treatment preferences. Formulation preference was associated with current medication formulation: depots were preferred by 43% (33/76) on depot vs 6% (8/146) on orals (P < 0.001). Attitudes (DAI scores) regarding current formulation were influenced by illness duration, extrapyramidal symptoms and insight but not by formulation (depot vs oral). For those with experience of both formulations, participants currently on tablets scored depots less favourably than oral (4.27 vs 6.89, P < 0.001); those on depot did not differentiate. When voluntary patients on maintenance antipsychotics are asked about their attitudes to their current medication, those on depot respond similarly to those on oral. However, when asked to state a preference for formulation (depot vs oral), patients tend to favour their current formulation. Whatever leads some to switch from depot to oral, leaves a lasting negative impression of the depot and this may limit uptake of newer depots.

Chronic fatigue syndrome in children: a cross sectional survey

Background: Chronic fatigue syndrome (CFS) in children is a controversial diagnosis with unclear aetiology, ill defined but likely increasing incidence, and debatable clinical management options. However these children experience real and considerable suffering. Appropriate research in this clinical population is sparse and usually occurs in tertiary referral units. Methods: Cross sectional survey of 36 children attending a GP specialist interest clinic in southeast England. Results: Patient sociodemographics and clinical morbidity were largely comparable to the literature from tertiary referral research centres. Some prognostic indicators for adults did not readily transfer to this younger age group, although several children had a positive family psychiatric history. Receiving treatment was associated with increased school attendance, but one third of subjects obtained no qualifications. Return to normal health or significant overall improvement was reported by 29/36 subjects. Conclusions: The outcomes in this setting are favourable and comparable to those seen in a controlled setting; this study supports the concept that the prognosis for CFS in children and adolescents is generally good. However, the impact of the illness is significant and this is perhaps most evident in terms of education. Current methods of reporting educational outcomes in the literature are varied and merit development of standardised tools.

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.

Prospective 6-month follow-up of patients prescribed risperidone long-acting injection: factors predicting favourable outcome

Risperidone long-acting injection (RLAI) is the first depot preparation of the so-called atypical antipsychotics. Efficacy is well established but effectiveness and factors predicting favourable outcome have only tentatively been evaluated. Our aim was to evaluate naturalistic outcome in patients given RLAI in normal clinical practice and to uncover factors predicting favourable outcome. Prescribers provided details of all patients prescribed RLAI on starting treatment and fortnightly thereafter. Patients were followed up for 6 months or until RLAI was discontinued. Main outcome measures were continuation with RLAI at 6 months and improvement in Clinical Global Impression (CGI) score. These outcomes were compared with clinical and patient data. Of 250 patients starting RLAI, 118 (47.2%) were still receiving it at 6 months. Patients were more likely to continue treatment with RLAI to 6 months if older than 55 yr [odds ratio (OR) 3.13, 95% CI 1.32-7.40, p=0.006] and if receiving a dose of >25 mg/2 wk RLAI (OR 2.37, 95% CI 1.40-3.99, p<0.001). An improvement of one point on the CGI scale (first vs. last assessment) was more likely in those prescribed RLAI because of poor prior adherence (OR 2.28, 95% CI 1.35-3.86, p=0.002) and less likely in those who had previously been prescribed clozapine (OR 0.29, 95% CI 0.14-0.61, p=0.001). Overall outcome of RLAI treatment is moderately good but better still when prescribed because of prior poor adherence and for more elderly patients. RLAI is less suitable for those who have previously received clozapine.

Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999-2009.

Olanzapine therapeutic drug monitoring (TDM) is the measurement of plasma olanzapine to assess adherence and guide dosage. We have audited data from an olanzapine TDM service, 1999-2009. Multiple linear regression analysis was conducted to investigate the contribution of dose, age, sex, body weight, and smoking status to the plasma olanzapine concentration. There were 5856 samples from 3207 patients. The prescribed olanzapine dosage was 2.5 to 95 mg/d. No olanzapine was detected in 6% of samples. For olanzapine dosages of 2.5 to 20 mg/d, only 35% of results were within a suggested target range of 20 to 39 ng/mL. At doses above 20 mg/d, 30% to 59% of results were 60 ng/mL or greater depending on dose band. In patients aged 17 years or younger (92 samples), median plasma olanzapine was higher than that in adult patients at almost all olanzapine doses. Multiple linear regression analysis of results from 627 adults from whom complete data were available showed that dose, smoking status, sex, age, and body weight together explained 24% the variance in plasma olanzapine. Degree of adherence, timing of sample postdose, drug-drug interactions, and pharmacogenetic factors also may have contributed to the observed variance. However, it is clear that female nonsmokers had higher plasma olanzapine concentrations for a given dose than male smokers. Olanzapine TDM is useful in assessing adherence and may have a role in limiting olanzapine dosage to minimize the risk of long-term toxicity.

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.