Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment.

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment-resistant and ultratreatment-resistant schizophrenia.

AIM: Validating the vulnerabilities and pathologies underlying treatment-resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS. METHODS: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first-line antipsychotics (FL-Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ-Resp) and 22 FL- and clozapine-resistant patients (patients with ultratreatment-resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis. RESULTS: Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [gH ] = 0.75; P = 0.013, gH  = 0.96) and FL-Resp (P = 0.007, gH  = 1.00; P = 0.002, gH  = 1.31) in the left medial parietal cortex (Lt-MPC). In addition, both CLZ-Resp and URS had lower SA in the Lt-MPC than FL-Resp (P < 0.001, gH  = 1.22; P < 0.001, gH  = 1.75). LGI and SA were positively correlated in non-TRS (FL-Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ-Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non-TRS versus TRS with LGI and SA in the Lt-MPC were 0.79 and 0.85, respectively. SA in the Lt-MPC was inversely correlated with negative symptoms (ρ = -0.40, P = 0.018) and clozapine plasma levels (ρ = -0.35, P = 0.042) in TRS. CONCLUSION: LGI and SA in the Lt-MPC, a functional hub in the default-mode network, were abnormally reduced in TRS compared with non-TRS. Thus, altered LGI and SA in the Lt-MPC might be structural features associated with genetic vulnerability to TRS.

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.

A Measure of Illness Awareness in Individuals With Nicotine Dependence-Nicotine Use Awareness and Insight Scale.

INTRODUCTION: Impaired illness awareness or the inability to recognize that one has a dependence on nicotine may be a major barrier to seeking cessation treatment. To better understand the role of impaired illness awareness on treatment-seeking behavior and clinical outcomes, we developed and examined the psychometric properties of a novel scale measuring illness awareness in individuals with dependence on nicotine. AIMS AND METHODS: We developed the Nicotine Use Awareness and Insight Scale (NAS), a 7-item self-report measure to assess the theoretical construct of illness awareness in individuals with dependence on nicotine (www.illnessawarenessscales.com). Data from participants 18 years of age or older were collected via a web-based survey company, Dynata. Participants with moderate dependence on nicotine were included, defined by a score of four or more on the Fagerström Test for Cigarette Dependence (FTCD) or the FTCD adapted for electronic cigarettes (eFTCD). RESULTS: A total of 100 participants (mean [SD] age = 49.1 [16.1] years, 52% women) that met the inclusion criteria for either FTCD (n = 50) or eFTCD (n = 50) were included. The NAS demonstrated good convergent (r = .74, p < .001) and discriminant validity (r = .03, p = .786). It also demonstrated good internal consistency (Cronbach's alpha = 0.78) and one-month test-retest reliability (intra-class correlation = 0.86). An exploratory factor analysis yielded the retention of two components. CONCLUSIONS: The NAS is a novel scale to asses illness awareness in individuals with dependence on nicotine. This study provides initial support for the psychometric validity and reliability of NAS. IMPLICATIONS: The NAS may be used in research and clinical practice to evaluate the impact of impaired illness awareness on treatment-seeking behavior and clinical outcomes.

Impaired insight into illness is unrelated to subjective happiness, success, and life satisfaction in schizophrenia.

BACKGROUND: Impaired insight into illness is a common feature of schizophrenia. Improved insight is associated with better treatment adherence and clinical outcomes. At the same time, improving insight has been suggested to increase depressive symptoms and diminish quality of life. The aim of this study was to examine the associations between impaired insight and degree of subjective happiness, perceived level of success, and life satisfaction in patients with schizophrenia spectrum disorders. METHODS: A total of 108 participants with schizophrenia or schizoaffective disorder were included. Data for this study were obtained from our group's previous investigation that examined the relationship between impaired insight and visuospatial attention. Insight into illness was measured by the VAGUS scale, which assesses general illness awareness, accurate symptom attribution, awareness of the need for treatment, and awareness of the negative consequences attributable to the illness. RESULTS: Our results revealed no association among the VAGUS average and subscale scores and degree of subjective happiness, perceived level of success, and life satisfaction. CONCLUSIONS: Our study suggests that insight into illness is not related to subjective happiness, life satisfaction, or perceived level of success in patients with schizophrenia, which is in contrast to previous reports that demonstrate an association between insight into illness and depression.

A Measure to Assess Illness Awareness in Problem Gambling: Gambling Awareness and Insight Scale (GAS).

Impaired subjective awareness of problem gambling may act as a barrier to help-seeking and treatment adherence. However, the impact of impaired problem gambling awareness on clinical and social outcomes has received little empirical study. The aim of this study was to develop and investigate the psychometric properties of a novel scale that measures impaired illness awareness in individuals with problem gambling. We developed the Gambling Awareness and Insight Scale (GAS), a self-report measure that assesses the core theoretical constructs of illness awareness in problem gambling, namely General Disorder or Problem Awareness, Accurate Symptom Attribution, Awareness of Need for Treatment and the Negative Consequences attributable to problem gambling ( www.illnessawarenessscales.com ). Data were acquired from an online survey platform, Dynata, to evaluate the psychometric properties of the GAS. A total of 100 participants aged 18 years or older with problem gambling defined by a score of 4 or more on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Pathological Gambling Diagnostic Form were included. The GAS demonstrated good convergent (r = 0.57, p < 0.001) and discriminant validity (r = - 0.18, p = 0.080). It also demonstrated good internal consistency (Cronbach's α = 0.80) and one-month test-retest reliability (intra-class correlation = 0.86). An exploratory factor analysis suggested retention of two components. The GAS is a novel psychometric tool designed to evaluate impaired subjective illness awareness in problem gambling. Initial evidence suggests that the GAS can be used in research and clinical settings to evaluate the impact of impaired problem gambling awareness on adherence to treatment programs, clinical and psychosocial outcomes. Replication in applied settings is needed.

Anti-vaccination attitudes are associated with less analytical and more intuitive reasoning.

Online anti-vaccination rhetoric has produced far reaching negative health consequences. Persons who endorse anti-vaccination attitudes may employ less analytical reasoning when problem solving. Considering limitations in previous research, we used an online web-based survey (n = 760; mean age = 47.69; 388 males, 372 females) to address this question. Analytical reasoning was negatively correlated with anti-vaccination attitudes (r = -.18, p < .0001). This relationship remained significant after statistically controlling for potential confounders, including age, sex, education, and religiosity (r = -.16, p < .0001). We hope that elucidating the cognitive, non-information-based aspects of anti-vaccination attitudes will help to guide effective educational interventions aimed at improving public health in the future.

Measuring amphetamine-induced dopamine release in humans: A comparative meta-analysis of [11 C]-raclopride and [11 C]-(+)-PHNO studies.

The radiotracers [11 C]-raclopride and [11 C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [11 C]-(+)-PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [11 C]raclopride. To date, only one study has been published comparing the sensitivity of these two radiotracers to amphetamine-induced dopamine release in healthy persons. Unfortunately, conflicting findings in the literature suggests that the dose of amphetamine they employed (0.3 mg/kg, p.o.) may not reliably reduce [11 C]-raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [11 C]-(+)-PHNO is more sensitive to displacement by amphetamine in humans than [11 C]-raclopride. In order to clarify these issues, we conducted a comparative meta-analysis summarizing the effects of amphetamine on [11 C]-raclopride and [11 C]-(+)-PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [11 C]-raclopride binding in the caudate. Second, the greater sensitivity of [11 C]-(+)-PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [11 C]-(+)-PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [11 C]-raclopride in healthy persons. We recommend that future displacement studies with these radiotracers employ 0.5 mg/kg, p.o. of amphetamine with a dose, post-scan interval of at least 3 hr. Using this dose of amphetamine, [11 C]-raclopride studies should employ at least n = 34 participants per group, while [11 C]-(+)-PHNO studies should employ at least n = 6 participants per group, in order to be sufficiently powered (80%) to detect changes in radiotracer binding within the caudate.

Structural Brain Differences Between Cognitively Impaired Patients With and Without Apathy.

OBJECTIVE: Since apathy increases in prevalence with severity of dementia pathology, we sought to distinguish concomitant neurodegenerative processes from brain differences associated with apathy in persons with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). We examined relative structural brain differences between case-control matched cognitively impaired patients with and without apathy. DESIGN: Cross-sectional case-control study. SETTING: Fifty-eight clinical sites in phase 2 of the AD Neuroimaging Initiative across the United States and Canada. PARTICIPANTS: The ≥ 55 years of age with MCI or AD dementia and no major neurological disorders aside from suspected incipient AD dementia. Participants with apathy (n=69) were age-, sex-, apolipoprotein E ε4 allele carrier status-, Mini-Mental State Exam score-, and MCI or AD dementia diagnosis-matched to participants without apathy (n=149). INTERVENTIONS: The 3-tesla T1-weighted MRI scan and neurocognitive assessments. Using the Neuropsychiatric Inventory apathy domain scores, participants were dichotomized into a with-apathy group (score ≥ 1) and a without-apathy group (score = 0). MEASUREMENTS: Cortical thicknesses from 24 a priori regions of interest involved in frontostriatal circuits and frontotemporal association areas. RESULTS: False-discovery rate adjusted within-group comparisons between participants with apathy and participants without apathy showed thinner right medial orbitofrontal (mOFC; meandifference(MD)±standarderrorofMD(SE)=-0.0879±0.0257mm; standardizedMD(d)=-0.4456) and left rostral anterior cingulate (rACC; MD±SE=-0.0905±0.0325mm; d=-0.3574) cortices and thicker left middle temporal cortices (MTC; MD±SE=0.0688±0.0239mm; d=0.3311) in those with apathy. CONCLUSION: Atrophy of the right mOFC and left rACC and sparing of atrophy in the left MTC are associated with apathy in cognitively impaired persons.

Further in vivo characterization of [11 C]-(+)-PHNO uptake into a retina-like region of interest in humans.

The neurotransmitter dopamine is present in the retina and is involved in several modulatory functions. Unlike in rodents, dopamine D3 receptors are expressed in the retina of humans. Recently, uptake of the D3 receptor-preferring radiotracer [11 C]-(+)-PHNO has been observed in a retina-like region of interest (ROI) in humans. Here, we attempted to quantify [11 C]-(+)-PHNO uptake into this ROI using an independent sample, employing an extended scan acquisition time (120 min) and arterial kinetic modeling. Data from 14 healthy controls were analyzed (Mean Age: 38.41 ± 9.55, 3 female), 8 of which provided arterial line input function data (Mean Age: 41.07 ± 7.82, 3 female). Using Ichise's multilinear analysis (MA1) method, it was possible to quantify the volume of distribution (VT ) of [11 C]-(+)-PHNO in this retina-like region (Mean VT  = 13.56 ± 3.52; Mean χ2  = 2.08 ± 2.20). Notably, the shape of the time activity curve resembled closely that of the globus pallidus. Moreover, the VT values in the retina correlated well with binding potential (BPND ) values calculated using the simplified reference tissue model (Mean BPND  = 2.11 ± .94; Mean χ2  = 5.76 ± 2.56), employing the cerebellum as the reference region (r = .76, r2  = .58). In summary, we provide evidence that the in vivo uptake of [11 C]-(+)-PHNO into a retina-like ROI in humans can be quantified using both arterial blood sampling (VT ) and simplified reference tissue methods (BPND ).

Expression of dopamine D2 and D3 receptors in the human retina revealed by positron emission tomography and targeted mass spectrometry.

Dopamine D2 receptors (D2R) are expressed in the human retina and play an important role in the modulation of neural responses to light-adaptation. However, it is unknown whether dopamine D3 receptors (D3R) are expressed in the human retina. Using positron emission tomography (PET), we have observed significant uptake of the D3R-preferring agonist radiotracer [11C]-(+)-PHNO into the retina of humans in vivo. This led us to examine whether [11C]-(+)-PHNO binding in the retina was quantifiable using reference tissue methods and if D3R are expressed in human post-mortem retinal tissue. [11C]-(+)-PHNO data from 49 healthy controls (mean age: 39.96 ± 14.36; 16 female) and 12 antipsychotic-naïve patients with schizophrenia (mean age: 25.75 ± 6.25; 4 female) were analyzed. We observed no differences in [11C]-(+)-PHNO binding in the retina between first-episode, drug-naïve patients with schizophrenia and healthy controls. Post-mortem retinal tissues from four healthy persons (mean age: 59.75 ± 9.11; 2 female) and four patients with schizophrenia (mean age: 54 ± 17.11; 2 female) were analyzed using a targeted mass spectrometry technique: parallel reaction monitoring (PRM) analysis. Using targeted mass spectrometry, we confirmed that D3R are expressed in human retinal tissue ex vivo. Notably, there was far greater expression of D2R relative to D3R in the healthy human retina (∼12:1). Moreover, PRM analysis revealed reduced D2R, but not D3R, expression in the retinas of non-first episode patients with schizophrenia compared to healthy controls. We confirm that D3R are expressed in the human retina. Future studies are needed to determine what proportion of the [11C]-(+)-PHNO signal in the human retina in vivo is due to binding to D3R versus D2R. Knowledge that both D2R and D3R are expressed in the human retina, and potentially quantifiable in vivo using [11C]-(+)-PHNO, poses new research avenues for better understanding the role of retinal dopamine in human vision. This work may have important implications for elucidating pathophysiological and antipsychotic induced visual deficits in schizophrenia.

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.

Trait impulsiveness is related to smaller post-commissural putamen volumes in males but not females.

Impulsivity is considered a vulnerability trait for addiction. Recently, we found trait non-planning impulsiveness measured with the Karolinska Scales of Personality was negatively correlated with dopamine D2/3 receptor availability in the ventral striatum of healthy humans. While also observed in rodents, human studies have failed to find this association with other measures of trait impulsivity. We explored whether another rodent finding, reduced ventral striatum volume with greater impulsivity, could also be observed in humans using this scale. Non-planning impulsiveness was measured in 52 healthy subjects (21 female; mean age: 33.06 ± 9.69) using the Karolinska Scales of Personality. Striatal subregion volumes, including the globus pallidus, were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Although failing to support our a priori hypothesis, there was a significant sex interaction in the post-commissural putamen with impulsiveness. Exploratory analyses revealed impulsiveness was negatively correlated with post-commissural putamen volumes in males, but positively correlated in females. We replicated this finding in males in an increased sample (including all 52 previous subjects) who provided impulsiveness measured by the Temperament and Character Inventory (n = 73; 32 female; mean age: 33.48 ± 9.75). These correlations by sex were statistically different from one another, the main finding with the Kasolinksa Scales of Personality surviving correction for multiple comparisons. While impulsivity may be related to reduced ventral striatal D2/3 receptors across sexes, males but not females may show significant reductions in post-commissural putamen volume. These findings have important implications for understanding biological markers underlying sex differences in drug addiction vulnerability.

The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11 C]-raclopride and [11 C]-(+)-PHNO PET.

BACKGROUND: Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D2/3 receptors (D2/3 R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D2/3 R availability measured with an antagonist radiotracer ([11 C]-raclopride) versus an agonist radiotracer ([11 C]-(+)-PHNO) were examined. METHODS: Data from 62 subjects scanned with [11 C]-raclopride (mean age = 38.98 ± 14.45; 23 female) and 68 subjects scanned with [11 C]-(+)-PHNO (mean age = 38.54 ± 14.59; 25 female) were used. Subcortical volumes were extracted from T1-weighted images using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Partial correlations were used controlling for age, gender, and total brain volume. RESULTS: For [11 C]-(+)-PHNO, ventral caudate volumes were positively correlated with BPND in the dorsal caudate and globus pallidus (GP). Ventral striatum (VS) volumes were positively correlated with BPND in the VS. With [11 C]-raclopride, BPND in the VS was negatively correlated with subiculum volume of the hippocampus. Moreover, BPND in the GP was negatively correlated with the volume of the lateral posterior nucleus of the thalamus. CONCLUSION: Findings are purely exploratory and presented corrected and uncorrected for multiple comparisons. We hope they will help inform the interpretation of future PET studies where concurrent changes in D2/3 R and brain morphology are observed. Hum Brain Mapp 38:5519-5534, 2017. © 2017 Wiley Periodicals, Inc.

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.

Exploring the Relationship Between Body Mass Index and Positive Symptom Severity in Persons at Clinical High Risk for Psychosis.

Metabolic health and positive symptom severity has been investigated in schizophrenia, but not in clinical high risk (CHR) patients. We hypothesized that greater body mass index (BMI) in CHR patients would be related to less positive symptoms. We examined this relationship in CHR patients being treated with 1) no psychotropic medications (n = 58), 2) an antipsychotic (n = 14), or 3) an antidepressant without an antipsychotic (n = 10). We found no relationship between BMI and positive symptoms in unmedicated CHR patients, the majority of whom had a narrow BMI range between 20 and 30. However, in the smaller sample of CHR patients taking an antidepressant or antipsychotic, BMI was negatively correlated with positive symptoms. Although potentially underpowered, these preliminary findings provide initial steps in elucidating the relationships between metabolic health, neurochemistry, and symptom severity in CHR patients.

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.

Β-Amyloid Burden is Not Associated with Cognitive Impairment in Schizophrenia: A Systematic Review.

Current literature suggests that the pathology of schizophrenia (SCZ) has developmental origins. However, the neurodevelopmental theory of SCZ cannot solely explain progressive neurodegenerative processes in the illness. There is evidence of accelerated cognitive decline and increased risk of dementia in elderly patients with SCZ. Investigating ß-amyloid (Aß), we conducted a systematic review focusing on Aß in patients with SCZ. An OVID literature search using PsychINFO, Medline, and Embase databases was conducted, looking for studies that compared Aß levels between patients with SCZ and either elderly control subjects, patients with Alzheimer disease (AD), or patients with other psychiatric illnesses. Among 14 identified studies, 11 compared Aß between SCZ and elderly control subjects, 7 between SCZ and AD, and 3 between SCZ and other psychiatric illnesses. As a result, no evidence was found suggesting that Aß levels differ in patients with SCZ from elderly control subjects or patients with other psychiatric illnesses. All seven studies reported lower cortical Aß in patients with SCZ than patients with AD. Furthermore, three of the four studies, which investigated the relationship between Aß and cognitive impairment in SCZ, observed no association between two factors. The limitations of the included studies are small sample sizes, the inclusion of cerebrospinal fluid Aß or postmortem plaques rather than cortical Aß assessment in vivo, and the investigation of different brain regions. In conclusion, Aß deposition is not associated with cognitive decline in late-life SCZ. Future studies should investigate other neurodegenerative indicators in SCZ to better understand the pathophysiologic mechanisms underlying this illness.

Benzodiazepine Use Attenuates Cortical ß-Amyloid and is Not Associated with Progressive Cognitive Decline in Nondemented Elderly Adults: A Pilot Study Using F18-Florbetapir Positron Emission Tomography.

OBJECTIVE: It is inconclusive as to whether benzodiazepines (BZDs) are related to cognitive deterioration in the elderly populations. Animal studies suggest that γ-aminobutyric acid A receptor agonists, such as BZDs, may prevent Aß-neurotoxicity and reduce ß-amyloid (Aß). However, no studies have investigated the effects of BZD use on Aß in humans. METHODS: This cross-sectional, prospective study using Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada on nondemented elderly adults between 55 and 90 years of age assessed cortical Aß levels by positron emission tomography radiotracer F18-Florbetapir. Changes in global cognitive function and verbal memory performance over 2 years were assessed using scores on Montreal Cognitive Assessment and five domains of Rey Auditory Verbal Learning Test, respectively. RESULTS: Previous BZD users (N = 15) had lower cortical Aß levels in frontal (F(1, 26) = 8.82, p = 0.006), cingulate (F(1, 26) = 8.58, p = 0.007), parietal (F(1, 26) = 7.31, p = 0.012), and temporal (F(1, 26) = 7.67, p = 0.010) regions compared with matched BZD nonusers (N = 15), after controlling for history of psychiatric disorders and antidepressant use. Also, no differences were found in global cognitive function and changes in cortical Aß over 2 years between continuous BZD users (N = 15) andthe matched nonuser group (N = 15). CONCLUSION: Previous BZD use was associated with lower cortical Aß levels in nondemented elderly control subjects. Future studies with larger samples are required to replicate our findings.

Cortical Amyloid ß Deposition and Current Depressive Symptoms in Alzheimer Disease and Mild Cognitive Impairment.

Depressive symptoms are frequently seen in patients with dementia and mild cognitive impairment (MCI). Evidence suggests that there may be a link between current depressive symptoms and Alzheimer disease (AD)-associated pathological changes, such as an increase in cortical amyloid-ß (Aß). However, limited in vivo studies have explored the relationship between current depressive symptoms and cortical Aß in patients with MCI and AD. Our study, using a large sample of 455 patients with MCI and 153 patients with AD from the Alzheimer's disease Neuroimaging Initiatives, investigated whether current depressive symptoms are related to cortical Aß deposition. Depressive symptoms were assessed using the Geriatric Depression Scale and Neuropsychiatric Inventory-depression/dysphoria. Cortical Aß was quantified using positron emission tomography with the Aß probe(18)F-florbetapir (AV-45).(18)F-florbetapir standardized uptake value ratio (AV-45 SUVR) from the frontal, cingulate, parietal, and temporal regions was estimated. A global AV-45 SUVR, defined as the average of frontal, cingulate, precuneus, and parietal cortex, was also used. We observed that current depressive symptoms were not related to cortical Aß, after controlling for potential confounds, including history of major depression. We also observed that there was no difference in cortical Aß between matched participants with high and low depressive symptoms, as well as no difference between matched participants with the presence and absence of depressive symptoms. The association between depression and cortical Aß deposition does not exist, but the relationship is highly influenced by stressful events in the past, such as previous depressive episodes, and complex interactions of different pathways underlying both depression and dementia.