MAP Bayesian modelling combining striatal dopamine receptor occupancy and plasma concentrations to optimize antipsychotic dose regimens in individual patients.

AIMS: Develop a robust and user-friendly software tool for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone, in order to facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. METHODS: Previously developed population pharmacokinetic models for olanzapine and risperidone were combined with a pharmacodynamic model for D2 RO and implemented in the R programming language. Maximum a posteriori Bayesian estimation was used to provide predictions of plasma concentration and RO based on sparse concentration sampling. These predictions were then compared to observed plasma concentration and RO. RESULTS: The average (standard deviation) response times of the tools, defined as the time required for the application to predict parameter values and display the output, were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (95% confidence interval) of predicted vs. observed concentrations were 3.73 ng/mL (-2.42-9.87) and 10.816 ng/mL (6.71-14.93) for olanzapine, and 0.46 ng/mL (-4.56-5.47) and 6.68 ng/mL (3.57-9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and root mean squared error of RO were -1.47% (-4.65-1.69) and 5.80% (3.89-7.72) for olanzapine and -0.91% (-7.68-5.85) and 8.87% (4.56-13.17) for risperidone. CONCLUSION: Our monitoring software predicts concentration-time profiles and the corresponding D2 RO from sparsely sampled concentration measurements in an accessible and accurate form.

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia.

OBJECTIVE: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3 R) blockade by antipsychotics. METHODS: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate. RESULTS: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: ß = -.38, t = -2.48, P = .01; left: ß = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (ß = -.43, t = -0.26, P = .03). CONCLUSION: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit.

Cognition and Dopamine D2 Receptor Availability in the Striatum in Older Patients with Schizophrenia.

OBJECTIVES: To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D2 receptor availability in the whole striatum, and identify their relationship in patients with schizophrenia aged 50 years or older. DESIGN: Open-label prospective PET [11C]-raclopride study. SETTING: A tertiary care center outpatient setting. PARTICIPANTS: Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months. INTERVENTION: Gradual reduction in their olanzapine or risperidone daily dose of up to 40%. MEASUREMENTS: Clinical and cognitive assessments, and [11C]-raclopride PET to determine D2 receptor availability at baseline and after the dose reduction. Main outcome measures were overall cognition and D2 receptor availability in whole striatum. RESULTS: Reducing the antipsychotic dose resulted in an increase in D2 receptor availability in the whole striatum and an association between D2 receptor availability and overall cognition despite lack of change in the latter. There was also an association between change in D2 receptor availability and change in overall cognition. CONCLUSIONS: Our findings suggest that optimizing D2 receptor availability by reducing antipsychotic dose allows this system to contribute more significantly to cognitive function in patients with schizophrenia. This uncovered association could be harnessed by cognitive-enhancing interventions.

Estimating the effect of endogenous dopamine on baseline [(11) C]-(+)-PHNO binding in the human brain.

Endogenous dopamine (DA) levels at dopamine D2/3 receptors (D2/3 R) have been quantified in the living human brain using the agonist radiotracer [(11) C]-(+)-PHNO. As an agonist radiotracer, [(11) C]-(+)-PHNO is more sensitive to endogenous DA levels than antagonist radiotracers. We sought to determine the proportion of the variance in baseline [(11) C]-(+)-PHNO binding to D2/3 Rs which can be accounted for by variation in endogenous DA levels. This was done by computing the Pearson's coefficient for the correlation between baseline binding potential (BPND ) and the change in BPND after acute DA depletion, using previously published data. All correlations were inverse, and the proportion of the variance in baseline [(11) C]-(+)-PHNO BPND that can be accounted for by variation in endogenous DA levels across the striatal subregions ranged from 42-59%. These results indicate that lower baseline values of [(11) C]-(+)-PHNO BPND reflect greater stimulation by endogenous DA. To further validate this interpretation, we sought to examine whether these data could be used to estimate the dissociation constant (Kd) of DA at D2/3 R. In line with previous in vitro work, we estimated the in vivo Kd of DA to be around 20 nM. In summary, the agonist radiotracer [(11) C]-(+)-PHNO can detect the impact of endogenous DA levels at D2/3 R in the living human brain from a single baseline scan, and may be more sensitive to this impact than other commonly employed radiotracers.

Illness denial in schizophrenia spectrum disorders: a function of left hemisphere dominance.

Impaired illness awareness or anosognosia is a common, but poorly understood feature of schizophrenia that contributes to medication nonadherence and poor treatment outcomes. Here we present a functional imaging study to measure brain activity at the moment of illness denial. To accomplish this, participants with schizophrenia (n = 18) with varying degrees of illness awareness were confronted with their illness beliefs while undergoing functional MRI. To link structure with function, we explored the relationships among impaired illness awareness and brain activity during the illness denial task with cortical thickness. Impaired illness awareness was associated with increased brain activity in the left temporoparieto-occipital junction (TPO) and left medial prefrontal cortex (mPFC) at the moment of illness denial. Brain activity in the left mPFC appeared to be a function of participants' degree of self-reflectiveness, while the activity in the left TPO was associated with cortical thinning in this region and more specific to illness denial. Participants with impaired illness awareness had slower response times to illness related stimuli than those with good illness awareness. Increased left hemisphere brain activity in association with illness denial is consistent with the literature in other neuropsychiatric conditions attributing anosognosia or impaired illness awareness to left hemisphere dominance. The TPO and mPFC may represent putative targets for noninvasive treatment interventions, such as transcranial magnetic or direct current stimulation.

Therapeutic window for striatal dopamine D(2/3) receptor occupancy in older patients with schizophrenia: a pilot PET study.

OBJECTIVE: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D(2/3) receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D(2/3) relative receptor occupancy (RRO) on clinical outcomes in this population. DESIGN: Open-label intervention. SETTING: Centre for Addiction and Mental Health, Toronto. PARTICIPANTS: Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for D(2/3) RRO in dorsal putamen was assessed, using the region of interest analysis of [¹¹C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. RESULTS: Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D(2/3) RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D(2/3) RRO. CONCLUSION: EPS diminished less than 70% D(2/3) RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

Frontotemporoparietal asymmetry and lack of illness awareness in schizophrenia.

INTRODUCTION: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. METHODS: Both voxel-based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation-based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. RESULTS: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation-based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01). CONCLUSION: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume-based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations.

Estimated dopamine D2 receptor occupancy and remission in schizophrenia: analysis of the CATIE data.

In treating schizophrenia, 65% to 80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D2 receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D2 prediction model. Estimated mean ± SD peak and trough D2 receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D2 occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D2 receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D2 receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.

Mental health attitudes in Malta: a cross-sectional survey exploring the knowledge and perceptions of general practitioner trainees.

AIMS AND METHOD: This study aimed to assess current levels of knowledge, opinions and attitudes regarding mental health among the local cohort of general practitioner trainees (n = 45) working in Malta. A questionnaire adapted from the Mental Health Literacy Scale was used. Data were analysed using one-way analysis of variance and Pearson correlation tests. RESULTS: All participants had scores equal to or more than the mean score in their knowledge and confidence assessments; 51% of the participants achieved the maximum score for a very positive attitude towards mental health, with such scores found particularly among female trainees. Increased levels of knowledge are associated with a more positive attitude, which can in turn lead to greater acceptance and reduce stigma. CLINICAL IMPLICATIONS: Knowledge is a powerful tool for reducing stigma and improving the doctor-patient relationship, indicating that regular training initiatives are necessary to equip budding general practitioner specialists with the necessary skills and confidence.

Therapeutic Window for Striatal Dopamine D2/3 Receptor Occupancy in Older Patients With Schizophrenia: A Pilot PET Study.

OBJECTIVE:: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. DESIGN:: Open-label intervention. SETTING:: Centre for Addiction and Mental Health, Toronto. PARTICIPANTS:: Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. INTERVENTION:: A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. MEASUREMENTS:: Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. RESULTS:: Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D2/3 RRO. CONCLUSION:: EPS diminished less than 70% D2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia.

BACKGROUND: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting. DESIGN: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates. SETTING: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007. PARTICIPANTS: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril). MEASUREMENTS: A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder. RESULTS: A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years. CONCLUSIONS: Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.

Predicting plasma concentration of risperidone associated with dosage change: a population pharmacokinetic study.

BACKGROUND: Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change. METHODS: Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study. RESULTS: The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively). CONCLUSIONS: Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.

Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation.

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.

Cognitive-Behavioral Social Skills Training for patients with late-life schizophrenia and the moderating effect of executive dysfunction.

The objectives of this study are to test the efficacy of Cognitive-Behavioral Social Skills Training (CBSST) in enhancing social function in a sample of older patients with schizophrenia, and to assess whether baseline cognition moderates response to CBSST. To address these objectives, we conducted a randomized controlled trial of 63 participants, randomized 1:1 into CBSST or Treatment-As-Usual (TAU). The setting was a community-based geriatric mental health outpatient clinic in Toronto, Ontario, Canada. Data were collected at baseline, and week 18, 36 and 52, between June 2008 and May 2014. Participants were outpatients, aged 60 or older, with a diagnosis of schizophrenia or schizoaffective disorder and no evidence of dementia or other conditions associated with cognitive or functional impairment. The intervention was a weekly group CBSST for 36 weeks. Cognition, including executive function, was assessed at baseline. Modified total score on the Independent Living Skills Survey (ILSS) at 18, 36, and 52 weeks was the primary outcome measure. In a linear mixed model analysis, the ILSS trajectory was better in the CBSST group than the TAU group, with significantly better function at 36 (Cohen's d = 0.75) and 52 weeks (Cohen's d = 0.92). Baseline executive dysfunction moderated CBSST response, whereby participants with more severe executive dysfunction experienced the most improvement in ILSS. CBSST was efficacious in patients with late-life schizophrenia and prevented decline in social function over a one-year period. CBSST was most beneficial for patients with more severe executive dysfunction, i.e., those who needed skills training the most.

Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia.

BACKGROUND: Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia. AIMS: To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia. METHOD: Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of metaregression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment. RESULTS: Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0­76%).The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression ­ Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356). CONCLUSIONS: Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early.More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

Predicting dopamine D2 receptor occupancy from plasma levels of antipsychotic drugs: a systematic review and pooled analysis.

Measuring dopamine D2 receptor occupancy levels using positron emission tomography (PET) is still widely unavailable. The objective of this study was to evaluate the accuracy of predicting D2 occupancy from the antipsychotic plasma level in patients with schizophrenia. Positron emission tomographic studies that measured plasma levels of antipsychotics and their corresponding D2 occupancy levels were identified, using MEDLINE and EMBASE (last search: March 2010). Antipsychotics that were investigated in a total of 20 subjects or more were included. All data points for each antipsychotic were fit to a one-site binding model to estimate the total plasma concentration of each antipsychotic associated with a 50% occupancy (ED50) of brain D2 receptors. The mean prediction error and the root mean squared prediction error were used to measure the predictive performance of individual D2 receptor occupancies from plasma drug levels derived from a one-site occupancy model using an ED50 value calculated for each data point. A total of 34 treatment arms from 23 studies involving 281 subjects were included. The mean (95% confidence interval) prediction errors and root squared prediction errors were as low as 0.0 (-1.8 to 1.8) and 8.9 (7.6-10.2) for risperidone (n = 98); 0.0 (-3.5 to 3.5) and 15.1 (12.9-17.3) for clozapine (n = 75); -0.1 (-1.2 to 1.2), 0.0 (-1.9 to 1.9), and 4.6 (3.5-5.8) for olanzapine (n = 42); 0.1 (-3.4 to 3.5) and 9.9 (7.3-12.5) for haloperidol (n = 35); and -0.1 (-3.3 to 3.1) and 12.3 (8.8-15.7) for ziprasidone (n = 31), respectively. These findings suggest that D2 occupancy of antipsychotics could be estimated with a high degree of accuracy using widely available plasma levels.

Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis.

Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative) / Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window.

Neurobiology of delusions in Alzheimer's disease.

Alzheimer's disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities. Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.

Effects of aging on 5-HT(2A) R binding: a HRRT PET study with and without partial volume corrections.

OBJECTIVE: We explored whether prior findings of reduction in serotonin 2A receptor (5-HT(2A) R) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. METHODS: We derived 5-HT(2A) R nondisplaceable binding potentials (BP(ND) ) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. RESULTS: The 5-HT(2A) R BP(ND) s decreased with age, a relationship best described by an exponential-decay regression. The BP(ND) s were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. CONCLUSIONS: These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects.

Impact of feedback from pharmacists in reducing antipsychotic polypharmacy in schizophrenia.

The objective was to examine effects of active interventions on physician's prescribing of antipsychotic polypharmacy. Prescriptions for patients with schizophrenia at the Centre for Addiction and Mental Health, Canada were collected in 2006 (n = 648) and 2008 (n = 778). During the intervening period, a pharmacist monitored prescriptions with antipsychotic polypharmacy and contacted corresponding prescribers to provide education on risks of polypharmacy. Moreover, educational sessions on polypharmacy were presented to inpatient and outpatient teams. A three-fold decrease in the prevalence of antipsychotic polypharmacy was observed between 2006 (18.3%) and 2008 (6.6%). Thus, active monitoring of prescriptions with educational interventions could reduce antipsychotic polypharmacy.