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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. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The relationship between age and prescribed antipsychotic dose in patients with schizophrenia has been examined by assuming only a linear correlation in two age subgroups at most. The age of illness onset has also not been under adequate consideration in past prescription surveys. The objective of this study was to better evaluate these age effects on antipsychotic dose prescribed in these patients across a broad age range. METHODS: Review of prescriptions for antipsychotic medications in patients with schizophrenia spectrum disorders was conducted across 30 sites in Tokyo. A total of 1,418 patients (655 inpatients, 763 males, age range: 16.6-90.2 years) were studied. RESULTS: Age had significant effects on prescribed antipsychotic dose; the dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The age of illness onset also had significant effects on the dose; late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychoses (VLOS) patients received lower doses than early onset schizophrenia (EOS) patients. LOS and VLOS patients who did not experience any hospitalization for the previous year were treated with (1/2) and (1/3), respectively, of the dose for EOS of comparable current age. CONCLUSION: Our results suggested biphasic effects of age on antipsychotic dose prescribed in patients with schizophrenia spectrum disorders. The natural history of schizophrenia and physiological aging may contribute to this inverted U-shaped relationship. In addition, our results may add another evidence of distinction among EOS, LOS, and VLOS from a clinical psychopharmacological perspective. [ABSTRACT FROM AUTHOR]

Objectives: Antipsychotic medications improve psychosis but often induce a state of dysphoria in patients. Blockade of the dopamine D(2) receptors, which is thought to mediate their efficacy, has also been implicated in producing this adverse subjective experience. The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D(2) receptor binding potential and occupancy values and adverse subjective experience. Method: Patients with recent-onset psychosis (N=12) were randomly assigned to low or high doses of olanzapine or risperidone. Subjective experiences, motor side effects, and striatal and extrastriatal dopamine D(2) receptors (determined with [(11)C]raclopride and [(11)C]FLB 457 PET scans, respectively) were evaluated after 2 weeks of continuous antipsychotic treatment. Results: Higher dopamine D(2) receptor occupancy and binding potentials in the striatal (dorsal and ventral), temporal, and insular regions were associated with subjective experience. The finding was confirmed with two convergent methods of analysis (region-of-interest and voxel-based statistics), and the same relationship was observed using two different dopamine receptor measures (observed binding potential values and age- and sex-corrected occupancy values). Conclusions: Higher D(2) receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D(2)) mechanisms may be critical in improving the treatment of psychosis. [ABSTRACT FROM AUTHOR]

Background: While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D(2) receptor density over 6-24 months, no study has examined the long-term stability of D(2) receptor measures in medicated patients.Methods: Four schizophrenia patients receiving a stable dose of risperidone underwent [(11)C]raclopride positron emission tomography scans on two occasions 5-14 months apart.Results: Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D(2) binding potential and D(2) occupancy were good.Conclusions: The finding supports the validity of quantification of D(2) receptor binding in longitudinal PET studies of medicated patients with schizophrenia. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Impaired illness awareness (Imp-IA) in schizophrenia is associated with interhemispheric imbalance, resulting in left hemisphere dominance, primarily within the posterior parietal area (PPA). This may represent an interhemispheric "disconnection syndrome" between PPAs. To test this hypothesis, we aimed to determine if diffusion-based measures of white matter integrity were disrupted in the corpus callosal tracts linking PPAs (i.e., splenium) in patients with Imp-IA in schizophrenia. T1-weighted and diffusion-weighted scans were acquired on a 1.5T GE scanner for 100 participants with a DSM-IV-TR diagnosis of schizophrenia and 134 healthy controls aged 18 to 79 years. The corpus callosal white matter tracts were compared among patients with Imp-IA (n = 40), intact illness awareness (n = 60), and healthy controls. White matter disruption was measured with fractional anisotropy (FA) and mean diffusivity (MD). Group differences in FA were found in the splenium, with patients with Imp-IA having the lowest FA, which remained significant after controlling for sex, age, global cognition, and premorbid intelligence. No group differences in MD were observed. Splenial white matter tracts of the corpus callosum appear compromised in patients with Imp-IA. Transcallosal interhemispheric PPA white matter disruption may represent a "disconnection syndrome", manifesting as Imp-IA in schizophrenia. Future studies are required to investigate the effects of noninvasive brain stimulation interventions, such as transcranial direct current or magnetic stimulation, on Imp-IA in association with white matter changes in patients with schizophrenia.

Impaired insight into illness (IMP-INS) is common among individuals with schizophrenia spectrum disorders (SSD), contributing to medication nonadherence and poor clinical outcomes. Caloric vestibular simulation (CVS) is typically used to assess peripheral vestibular system function. Left cold CVS is also a transiently effective treatment for IMP-INS and hemineglect secondary to right brain hemisphere stroke, and possibly for IMP-INS and mood stabilization in patients with SSD. Participants with SSD and moderate-to-severe IMP-INS participated in an exploratory double blind, crossover, randomized controlled study of the effects of CVS on IMP-INS. Participants sequentially received all experimental conditions-left cold (4°C), right cold, and body temperature/sham CVS-in a random order. Repeated measures ANOVA were performed to compare changes in IMP-INS, mood and positive symptom severity pre and 30min post CVS. A significant interaction was found between CVS condition, time, and body temperature nystagmus peak slow phase velocity (PSPV) for IMP-INS, indicating that single session left cold CVS transiently improved IMP-INS while right cold CVS may have worsened IMP-INS, particularly in participants with greater vestibular reactivity (i.e. higher PSPV) to body temperature CVS. The procedure's effectiveness is attributed to stimulation of underactive right hemisphere circuits via vestibular nuclei projections to the contralateral hemisphere., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objective: Impaired insight into illness in schizophrenia is associated with illness severity and deficits in premorbid intellectual function, executive function, and memory. A previous study of patients aged 60 years and older found that illness severity and premorbid intellectual function accounted for variance in insight impairment. As such, we aimed to test whether similar relationships would be observed in earlier life., Methods: A retrospective analysis was performed on 1 large sample of participants (n = 171) with a DSM-IV-TR diagnosis of schizophrenia aged 19 to 79 years acquired from 2 studies: (1) a psychosocial intervention trial for older persons with schizophrenia (June 2008 to May 2014) and (2) a diffusion tensor imaging and genetics study of psychosis across the life span (February 2007 to December 2013). We assessed insight into illness using the Positive and Negative Syndrome Scale (PANSS) item G12 and explored its relationship to illness severity (PANSS total modified), premorbid intellectual function (Wechsler Test of Adult Reading [WTAR]), and cognition., Results: Insight impairment was more severe in later life (≥ 60 years) than in earlier years (t = -3.75, P < .001). Across the whole sample, the variance of impaired insight was explained by PANSS total modified (Exp[B] = 1.070, P < .001) and WTAR scores (Exp[B] = 0.970, P = .028). Although age and cognition were correlated with impaired insight, they did not independently contribute to its variance. However, the relationships between impaired insight and illness severity and between impaired insight and cognition, particularly working memory, were stronger in later life than in earlier life., Conclusions: These results suggest an opportunity for intervention may exist with cognitive-enhancing neurostimulation or medications to improve insight into illness in schizophrenia across the life span., Trial Registration: Original study registered on ClinicalTrials.gov (identifier: NCT00832845)., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Objectives: To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D 2 receptor availability in the whole striatum, and identify their relationship in patients with schizophrenia aged 50 years or older., Design: Open-label prospective PET [ 11 C]-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 [ 11 C]-raclopride PET to determine D 2 receptor availability at baseline and after the dose reduction. Main outcome measures were overall cognition and D 2 receptor availability in whole striatum., Results: Reducing the antipsychotic dose resulted in an increase in D 2 receptor availability in the whole striatum and an association between D 2 receptor availability and overall cognition despite lack of change in the latter. There was also an association between change in D 2 receptor availability and change in overall cognition., Conclusions: Our findings suggest that optimizing D 2 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., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Although hyperprolactinemia carries a long-term risk of morbidity, the threshold of dopamine D2/3 receptor (D2/3R) occupancy for hyperprolactinemia has not been investigated in older patients with schizophrenia. Data were taken from a positron emission tomography (PET) study conducted between August 2007 and August 2015. The present post hoc study included 42 clinically stable outpatients with schizophrenia (DSM-IV) (mean ± SD age = 60.2 ± 6.7 years) taking olanzapine or risperidone. Subjects underwent [¹¹C]-raclopride PET scans to measure D2/3R occupancy before and after reducing their dose of antipsychotic by up to 40%. Blood samples were collected before each PET scan to measure prolactin levels., Methods: The relationship between prolactin levels and D2/3R occupancy was examined using stepwise linear regression analyses. The D2/3R occupancy thresholds for hyperprolactinemia were explored using Fisher exact tests., Results: Prolactin levels decreased following dose reduction (mean ± SD = 24.1 ± 30.2 ng/mL to 17.2 ± 15.1 ng/mL; P < .001). Prolactin levels were associated with female gender (β = .32, P = .006, vs male), antipsychotics (β = .23, P = .02, risperidone vs olanzapine), and D2/3R occupancy (β = .23, P = .04). Those with D2/3R occupancy of 66% or higher were more likely to have hyperprolactinemia than those with D2/3R occupancy lower than 66% (P = .03). Sensitivity, specificity, positive predictive value, and negative predictive value of this threshold were 0.44, 0.81, 0.78, and 0.48, respectively. We identified a D2/3R occupancy threshold for hyperprolactinemia of 66% in older patients with schizophrenia, which is lower than that reported in younger patients (73%) by other researchers., Conclusions: Our results suggest a higher sensitivity to antipsychotics in older patients. Prolactin levels could assist in the determination of appropriate antipsychotic dosing to minimize adverse effects., Trial Registration: ClinicalTrials.gov identifier: NCT00716755., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

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., (© 2016 Wiley Periodicals, Inc.)

Rationale: Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial., Objective: The objective of this study was to examine the relationship between antipsychotic-related dopamine D 2/3 receptor occupancy and negative symptoms in patients with schizophrenia., Methods: Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [ 11 C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose., Results: No significant relationship was found between antipsychotic-related dopamine D 2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship., Conclusions: Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

Background: Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested., Methods: Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1 ± 7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [(11)C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value., Results: The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P = .001 for olanzapine; r = 0.67, P = .02 for risperidone)., Conclusions: D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Antipsychotic polypharmacy (APP) is employed routinely, although it remains controversial because robust evidence supporting its efficacy is lacking. In addition, it is associated with increased costs, higher antipsychotic dosing, and greater risk of side effects. Surprisingly, no prospective, randomized, double-blind studies have addressed this issue; the present investigation set out to fill this gap in knowledge., Method: A 12-week, double-blind, randomized, placebo-controlled, single-site study was carried out in individuals with schizophrenia or schizoaffective disorder (DSM-IV) receiving a designated primary antipsychotic plus a secondary antipsychotic, with doses stabilized for each. Individuals were randomly assigned to APP (N = 17), reflecting current treatment, or antipsychotic monotherapy (APM) (N = 18), in which the secondary antipsychotic was discontinued. Assessments occurred weekly during month 1 and every 2 weeks during months 2 and 3; the primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Other measures included the Clinical Global Impressions (CGI) scale, Simpson-Angus Scale, and Barnes Akathisia Scale. The study was carried out between August 2006 and March 2011., Results: Withdrawal due to clinical deterioration occurred in 1 individual receiving APP (5.8%) and in 4 individuals in the APM group (22.2%). Overall, however, there was no indication of clinical worsening with APM, as measured using BPRS and CGI scale., Conclusions: Almost 80% (n = 14) of individuals with schizophrenia or schizoaffective disorder currently receiving APP could be safely transitioned to APM with no clinical deterioration. For those who do deteriorate, risk appears greatest in the first several months. From another perspective, results also indicate that a minority of individuals benefit from APP, and research focusing on identifying this group may represent the best strategy to curb excessive use of APP., Trial Registration: ClinicalTrials.gov identifier: NCT00493233., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Introduction: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge., Methods: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM(®), using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information., Results: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001)., Discussion: Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty., (© Georg Thieme Verlag KG Stuttgart · New York.)

Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [(11)C]-(+)-PHNO (n=72, mean±s.d. age=40±15, range=18 to 73) and the antagonist [(11)C]-Raclopride (n=70, mean±s.d. age =40±14, range=18 to 73) (both, n=33). The contribution of D3R to the [(11)C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [(11)C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate (r(70)=-0.32, P=0.005). No correlations were observed in the other regions. With [(11)C]-Raclopride, negative correlations were observed between age and BPND in the caudate (r(68)=-0.50, P<0.001), putamen (r(68)=-0.41, P<0.001), and ventral striatum (r(68)=-0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age.

Importance: Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS., Objective: To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS., Design, Setting, and Participants: An open-label, single-arm prospective study with a 3- to 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged ≥ 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015., Interventions: Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction., Main Outcomes and Measures: Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels)., Results: Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stability was 50%. Extrapyramidal symptoms (EPSs) were more likely to occur with D2/3R occupancies higher than 60%: 90.5% (19 of 21) of the participants with baseline EPSs and 76.9% (10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancies were lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58% [15%] vs 72% [10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased., Conclusions and Relevance: Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

Background: No study has examined dopamine D₂/₃ receptor (D₂/₃R) availability in antipsychotic-free older patients with schizophrenia., Methods: We included patients with schizophrenia 50 years or older who were antipsychotic-free for at least 3 months. We compared non-displaceable binding potential (BPND) of [(11)C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls., Results: Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=.42, p=.52)., Conclusion: The preliminary results suggest no differences in D₂/₃R availability between antipsychotic-free older patients with schizophrenia and controls., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (© 2014 Wiley Periodicals, Inc.)

The aim of this study was to develop self-report and clinician-rated versions of an insight scale that would be easy to administer, sensitive to small changes, and inclusive of the core dimensions of clinical insight into psychosis. Ten-item self-report (VAGUS-SR) and five-item clinician-rated (VAGUS-CR) scales were designed to measure the dimensions of insight into psychosis and evaluated in 215 and 140 participants, respectively (www.vagusonline.com). Tests of reliability and validity were performed. Both the VAGUS-SR and VAGUS-CR showed good internal consistency and reliability. They demonstrated good convergent and discriminant validity. Both versions were strongly correlated with one another and with the Schedule for the Assessment of Insight and Birchwood Insight Scale. Exploratory factor analyses identified three possible latent components of insight. The VAGUS-CR and VAGUS-SR are valid, reliable and easy to administer. They are build on previous insight scales with separate clinician-rated and self-report versions. The VAGUS-SR exhibited a multidimensional factor structure. Using a 10-point Likert scale for each item, the VAGUS has the capacity to detect small, temporally sensitive changes in insight, which is essential for intervention studies with neurostimulation or rapidly acting medications., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions., Methods: Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight-Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses., Results: As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC)., Conclusion: Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this analysis was to evaluate both cross-sectional and longitudinal relationships between estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in patients with schizophrenia., Method: The data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used in this analysis. The cross-sectional data included 371 patients receiving risperidone, olanzapine, or ziprasidone, who had completed the Drug Attitude Inventory (DAI-10) at six months and provided plasma antipsychotic concentrations. Samples were analyzed to examine the relationship between DAI-10 total scores and estimated D2 occupancy using Spearman's rank correlations, followed by multiple regression analysis. In addition, to elucidate the relationship between changes in DAI-10 scores and estimated D2 occupancy, the longitudinal data from 45 patients who experienced an increase in antipsychotic dosage between six and 12months were analyzed. Mean peak and trough D2 occupancy levels were estimated from plasma antipsychotic concentrations using a population pharmacokinetic approach., Results: A positive association was found between estimated D2 occupancy and DAI-10 total scores in patients receiving ziprasidone in the cross-sectional dataset (rs=0.395, P=0.001). In contrast, a negative association was found in changes in estimated D2 occupancy and DAI-10 scores among patients receiving olanzapine in the longitudinal dataset (rs=-0.534, P=0.010). No significant associations were found in patients receiving risperidone, or in the whole sample regarding both cross-sectional and longitudinal datasets., Conclusion: Dopamine D2 receptor occupancy may mediate subjective experience/drug attitude in patients with schizophrenia. The directionality may however differ between antipsychotics, which warrants further investigation., (© 2013.)

Impaired insight into illness is a common but poorly understood phenomenon in schizophrenia. Several studies in midlife adults with schizophrenia have reported an association between impaired insight and illness severity, executive dysfunction, premorbid intellectual function, and to a lesser degree attention. Aging is associated with a decline in attention and executive function. Thus, the relationship between cognition and insight is expected to differ between younger and older adults with schizophrenia. This study assessed this relationship among 50 patients with schizophrenia 60 years and older. Insight was explained by illness severity (16.2% of the variance) and premorbid intellectual function (23.9% of the variance), but not by attention or executive function. Our findings suggest that the predictors of insight in schizophrenia differ early and later in life. In particular, insight's association with attention and executive function observed in younger patients is attenuated by age-related changes in cognition. In contrast, premorbid intellectual function continues to be a strong predictor of insight in late life, which highlights the need to better understand and enhance cognitive function early in the course of schizophrenia., (© 2013.)

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.

Background: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics., Methods: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated., Results: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.)., Conclusion: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial., Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions., Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%., Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.

Objective: To determine predictors of hospital length of stay (LOS) for adult and geriatric patients with mood disorders admitted to inpatient psychiatric beds., Method: Admission and discharge data from a large urban mental health centre, from 2005 to 2010 inclusive, were retrospectively analyzed. Using the Resident Assessment Instrument-Mental Health, an assessment that is used to collect demographic and clinical information within 72 hours of hospital admission, 199 geriatric mood disorder admissions were compared with 570 adult mood disorder admissions. Predictors of hospital LOS were determined using a series of general linear models., Results: Living alone, number of recent psychiatric admissions, involuntary admission, and close or constant observation level predict longer hospital LOS in geriatric, but not in adult mood disorder, patients. Conversely, pain on admission predicts shorter hospital LOS in geriatric, but not among adult, mood disorder patients. Predictors of longer hospital LOS, irrespective of admission group (adult, compared with geriatric), include incapacity, negative symptoms, and increased dependence for instrumental activities of daily living., Conclusions: Addressing these predictive factors early on during admission and in the community may result in shorter hospital LOS and more optimal use of resources.

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.

Background: Cognitive deficits are core features in schizophrenia. Disruption in cholinergic neurotransmission has been associated with executive dysfunction in animals and humans. The objective of this study was to evaluate the impact of compromised cholinergic pathways on executive versus non-executive cognitive functions of patients with schizophrenia., Methods: 62 patients with schizophrenia and 62 age- and sex-matched non-psychiatric control subjects ("controls") were assessed and compared using: clinical measures, cognitive measures of global cognition, executive function, and memory; and an MRI-based visual rating scale that assesses damage strategically localized within the cholinergic pathways., Results: 11 of the 62 patients with schizophrenia (17.7%) and 6 of the 62 controls (9.7%) had compromised cholinergic pathways. These proportions were not statistically significant. Patients and controls with compromised cholinergic pathways were more impaired on measures related to executive function than patients or controls without compromised pathways., Conclusions: Patients with schizophrenia have worse executive function than controls. Compromised cholinergic pathways appear to worsen the executive dysfunction observed in schizophrenia. If these preliminary findings are replicated, they could lead to the identification of a subgroup of patients with schizophrenia who could specifically benefit from interventions enhancing cholinergic neurotransmission., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean±SD age, 48.8±13.8years; male [N=14]; Asians [N=23], Caucasians [N=12]; risperidone [N=20] at 3.2±2.3mg/day, and olanzapine [N=15] at 9.2±4.9mg/day) between September and December 2010. 48.6% (N=17) did not achieve a continuous blockade of ≥65%. Moreover, 11.4% (N=4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥65%. The results suggest that sustained D2 receptor occupancy levels of ≥65% may not always be necessary for the maintenance treatment of schizophrenia., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

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.

Background: There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response., Method: A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response., Results: Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000 mg/day for ≥ 6 weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters., Conclusion: Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (© 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.)

Although patients with schizophrenia are reported to have excess mortality compared with the general population, many affected patients will nonetheless survive and continue to have the disorder in later life. Consequently, geriatric schizophrenia will be a significant public health concern in the years to come, and evidence-based treatment of schizophrenia in older patients is becoming an urgent issue. However, there has been a paucity of comparative data to guide selection of antipsychotics for schizophrenia in late life. The primary aim of this review was to synthesize the available evidence on management of late-life schizophrenia with antipsychotic medications; a secondary aim was to evaluate treatment resistance in this population. Accordingly, PubMed and EMBASE were searched using the keywords 'antipsychotics', 'age' and 'schizophrenia' to identify psychopharmacological studies of antipsychotics in late-life schizophrenia (last search 30 April 2011). The literature search identified 23 prospective studies of use of antipsychotics for schizophrenia in older patients (generally age ≥65 years), including eight double-blind trials. The sample size was smaller than 40 patients for 52% of the studies. Two of the double-blind studies were post hoc analyses and one was a placebo-controlled trial. In the largest double-blind study, olanzapine (n = 88, median dose 10 mg/day) and risperidone (n = 87, median dose 2 mg/day) were compared in patients not resistant to these therapies, with similar effects. There have also been several open-label trials of these two agents that have shown efficacy and tolerability in non-resistant patients. Evidence on other antipsychotics has been scarce and less robust. The gold standard for treatment-resistant schizophrenia is clozapine. However, almost all of the studies of clozapine to date have effectively excluded older patients with schizophrenia. Only one small study has evaluated clozapine (n = 24, mean dose 300 mg/day) in comparison with chlorpromazine (n = 18, mean dose 600 mg/day) in a difficult-to-treat older population; the investigators reported that both treatments were similarly efficacious. Furthermore, there has been little compelling evidence in favour of or against augmentation of antipsychotics with other psychotropic medications in the older age group. Treatment of non-resistant, late-life schizophrenia with olanzapine and risperidone appears to be supported by the available evidence. However, data on geriatric patients with schizophrenia are generally scarce, particularly for treatment-resistant subpopulations, underscoring the need for more research in this important area.

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 (0–76%).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.

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.

Background: It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention., Aim: To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia., Data Source: Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009)., Data Extraction: Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis., Data Synthesis: Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose., Conclusions: Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.

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.

Objective: Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite-N-desmethylclozapine (NDMC)-could explain these discrepancies., Methods: Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC., Results: Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model., Conclusions: After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition.

Objective: To compare antipsychotic prescribing patterns in younger (aged 59 years or younger) and older (aged 60 years or older) patients with psychotic or mood disorders., Method: Pharmacy records of all patients discharged from the Centre for Addiction and Mental Health over a 21-month period were reviewed. A total of 1357 patients who were prescribed an antipsychotic at the time of their discharge were included in the analysis (956 with a primary psychotic disorder and 401 with a primary mood disorder). World Health Organization-defined daily doses were used as the standardized dosing unit., Results: Both in patients with a primary psychotic disorder and in patients with a primary mood disorder, the prescribing patterns were similar in older and younger patients, with no statistical difference in the proportions receiving first-generation antipsychotics, second-generation antipsychotics (SGAs), multiple antipsychotics, or long-acting (depot) antipsychotics. Overall, the mean daily antipsychotic doses were lower only in the older group of patients with a primary mood disorder. However, the mean dose of SGAs was about 30% lower in older patients in both diagnostic groups. Regardless of age, patients with a mood disorder were prescribed lower doses of antipsychotics than those with a psychotic disorder., Conclusions: Our data suggest that older patients are prescribed lower antipsychotic dosages primarily when using SGAs. This finding emphasizes the need for dose-finding studies assessing both the efficacy and the safety of antipsychotics in older patients with a psychotic or mood disorder.

Antipsychotic medications are widely used to manage psychotic and behavioral disorders in older adults, including primary psychotic disorders such as schizophrenia, and psychosis and behavioral disturbances associated with dementia. These two broad diagnostic indications are associated with contrasting recommended treatment durations, with the former requiring indefinite treatment across the life span. Antipsychotic drug dosing for schizophrenia is based primarily on studies of younger patients and thus may not apply to older adults. It is critically important to address the effects of aging on antipsychotic dosing given the recent emergence of data that suggest a critical role for age-related sensitivity to these drugs. Antipsychotic drugs are not only associated with somatic and neurological adverse effects but also increased all-cause mortality and sudden cardiac death in this vulnerable population. This review focuses on the sensitivity of older adults to adverse effects from antipsychotic medications and the current pharmacokinetic and pharmacodynamic explanatory models of susceptibility. Implications of recent research findings for individualized pharmacotherapy are discussed.

The negative impact of antipsychotic drugs on attention is expected to be greater in late-life schizophrenia because of the age-related changes in the dopamine receptor reserve. The objective of this study was to examine the relationship between dopamine D2 receptor blockade by risperidone and the cognitive function in late-life schizophrenia. Subjects with schizophrenia or schizoaffective disorder aged 50 or older who were receiving risperidone completed a [C]raclopride positron emission tomography scan to measure D2-binding potential in the striatum. The D2 receptor blockade by risperidone was calculated using age-corrected measures from healthy individuals and region of interest analysis of dynamic positron emission tomography data coregistered to the subjects' magnetic resonance imaging scans. Cognitive function was assessed using a battery of neuropsychological tests that included the Dementia Rating Scale-2 (DRS). Eleven subjects (mean +/- SD age, 64 +/- 8 years) participated in this study. The mean +/- SD D2 receptor blockade was 69% +/- 14% (range, 34%-80%). The age-corrected score on the attention subscale in the DRS was negatively correlated with the D2 receptor blockade. The DRS attention subscale score was lower in the subjects who experienced 74.9% or higher D2 blockade (median value, corresponding to a daily risperidone dose of >3.0 mg) than in those who did not. Although a causal attribution cannot be made in light of the cross-sectional nature of this study, the results suggest the critical importance of identifying the lowest effective dose of antipsychotic drugs in older patients with schizophrenia.

Antipsychotic medications are the standard of care for both acute and maintenance treatment of schizophrenia, the latter requiring an indefinite treatment across a patient's life span. However, dosing and tolerability of antipsychotics have been studied primarily in younger patients, and very limited data are available for age- and phase-specific dosing. This leaves the clinician with no guidance on dose adjustment as patients grow older-an issue of critical importance, especially in light of recent concerns about increased morbidity and mortality associated with antipsychotics.

Age effects on dosing of antipsychotics in schizophrenia and mechanisms underlying those effects have not been well understood. The objective of this article is to review the literature regarding effects of age on antipsychotic dosing in schizophrenia and potential mechanisms underlying the age-related antipsychotic sensitivity. According to prescription surveys, age appears to have biphasic effects on prescribed antipsychotic dose. The dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The first half of this inverted U-shaped relationship may be attributable to a deterioration process in the early phase of schizophrenia and the contribution of 'tachyphylaxis' of antipsychotics on the dopaminergic system. The following age-related decline in prescribed dose is likely associated with physiological aging. Recent data suggest that this increased antipsychotic sensitivity with age comes from age-related functional decline in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. Although the evidence on potential mechanisms underlying age effects on antipsychotic dosing is still limited, alterations in the dopaminergic system due to aging and chronic exposure to this drug may contribute to the inverted U-shaped relationship between dose and age. This age-related antipsychotic sensitivity highlights the importance of finding the lowest possible effective dose of antipsychotic drugs as patients age to enhance therapeutic effects as well as minimize their side effects.

Background: Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old., Methods: Six healthy subjects (age range = 65-78 years) completed two [18F]-setoperone PET scans on two separate occasions 5-16 weeks apart., Results: The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions., Conclusion: We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples.