Anna Sparshatt

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.

Risperidone long-acting injection: a 6-year mirror-image study of healthcare resource use

Objective:  To evaluate naturalistic use of risperidone long‐acting injection (RLAI) and its effect on healthcare resource use.

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

ObjectiveTo 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. MethodsA 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. ResultsTen 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. ConclusionsOur 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.

Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review.

OBJECTIVE To assess the relationships among quetiapine blood concentration, daily dose, dopamine receptor occupancy, and clinical outcome in order, if possible, to define a target plasma level range in which therapeutic response is enhanced and adverse events are minimized. DATA SOURCES A search of the database Embase from 1974 to March 2009 and the databases MEDLINE and PubMed from 1966 to March 2009 was conducted. The drug name quetiapine was searched with each of the terms plasma levels, plasma concentration, therapeutic drug monitoring, and dopamine occupancy. STUDY SELECTION The search uncovered 42 relevant articles. All published reports of quetiapine plasma or serum concentration were considered for inclusion if reported in relation to a dose, clinical outcome, or dopamine occupancy. After application of exclusion criteria, 20 articles remained. DATA EXTRACTION Trials designed primarily to investigate an interaction between quetiapine and another medication were excluded, as were those designed to compare methods of blood sample analysis. DATA SYNTHESIS There was a weak correlation between quetiapine dose and measured plasma concentration (from trough samples). Quetiapine dose was correlated with central dopamine D(2) occupancy, although the relationship between plasma level and D(2) occupancy is less clear. CONCLUSIONS The dose-response relationship for (immediate-release) quetiapine is established. Data on plasma concentration-response relationships are not sufficiently robust to allow determination of a therapeutic plasma level range for quetiapine. Therapeutic drug monitoring procedures are thus probably not routinely useful in optimizing quetiapine dose. Further examination of the relationship between peak quetiapine plasma concentration and clinical response is necessary.

Antipsychotic prescribing in Black and White hospitalised patients

Ethnicity may affect the prescribing of antipsychotic treatment. Previous UK studies conducted in south London have found few differences in antipsychotic prescribing quality for Black and White patients. This larger multicentre study examined the effect of ethnicity on antipsychotic prescribing quality in areas serving the largest proportions of Black patients in the UK. A cross-sectional survey with collection of multiple confounding factors potentially affecting outcomes in eight secondary care units in England over a three month period. Participants were Black or White inpatients prescribed regular antipsychotics on the day of the survey. Antipsychotic dose (expressed as a percentage of licensed maximum), high dose (being prescribed antipsychotic medication above maximum dose), polypharmacy (more than one antipsychotic prescribed), type (typical or atypical antipsychotic) and costs were the main outcome measures. Data were collected for 938 patients. There were no significant differences in any outcome by ethnicity: dose (adjusted percentage difference 0.97 [95% confidence interval (CI) −4.28, 6.22], p = 0.72); high dose (adjusted odds ratio (AOR) 0.98 [CI 0.63, 1.51], p = 0.92); polypharmacy prescribed (AOR 1.15 [CI 0.87, 1.51], p = 0.33); polypharmacy administered (AOR 1.08 [CI 0.78, 1.49], p = 0.66); use of typical antipsychotics (AOR 1.25 [CI 0.87, 1.79], p = 0.22); and cost (adjusted effect size 1.75 [CI −9.81, 13.31], p = 0.77). Antipsychotic prescribing practice did not differ between Black and White patients.

A prospective 6‐month analysis of the naturalistic use of aripiprazole – factors predicting favourable outcome

Objective:  To evaluate the effectiveness of aripiprazole in clinical practice.

A naturalistic evaluation and audit database of agomelatine: clinical outcome at 12 weeks

To determine the effectiveness of agomelatine in routine clinical practice and explore factors associated with response and continuation.

Aripiprazole long-acting injection – a mirror image study of its effects on hospitalisation at one year:

Second generation antipsychotic long-acting injections have a greater cost than older depots. Their cost-effectiveness has yet to be established. We conducted a non-interventional, observational, follow-up of patients prescribed aripiprazole long-acting injection in two centres using a mirror image method. Data were available for 160 patients consecutively prescribed aripiprazole long-acting injection, of whom 30 were not included in the analysis (21 forensic patients, five incomplete data and four lost to follow-up). Of the 130 patients, 66 (51%) remained on aripiprazole long-acting injection at one year. The mean number of bed days in the year following aripiprazole long-acting injection initiation reduced to 22.82/patient (standard deviation [SD]=55.07) from 30.09/patient/year (SD=30.40) over the three years before initiation (p<0.001). The mean number of admissions fell from 0.71/patient/year (SD=0.55) to 0.45/patient/year (SD=0.93) over the same period (p<0.001). The median number of bed days in the three years before aripiprazole long-acting injection was 21.67/year; in the year following it was zero. Outcomes were not statistically better in those who remained on aripiprazole long-acting injection at one year compared with those who discontinued. The prescribing of aripiprazole long-acting injection reduces average bed days and admissions compared with prior treatments. The reduction in bed days is of a magnitude that renders aripiprazole long-acting injection broadly cost-neutral.