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CONDES-LARA, M., A. GRAFF-GUERRERO AND L. VEGA-RIVEROLL. Effects of cypermethrin on the electroencephalographic activity of the rat: A model of chemically induced seizures. NEUROTOXICOL TERATOL 21 (3) 293–298, 1999.—Cypermethrin is a potent representative member of the type II pyrethroid insecticides. This pyrethroid is used worldwide and has become a part of our environment. Until the present study, little information about its toxic effects in the central nervous system (CNS) was available. The aim of this study was, then, to determine the effects of repeated exposure to cypermethrin by means of assessing the electroencephalographic (EEG) activity in the rat. Cypermethrin was administered daily in a 300 mg/kg IP dose, below the LD 50 value. After daily administration, the EEG activity was recorded and evaluated for 30 min. Paroxysmal epileptic activity appeared after the first and second days of cypermethrin administration. Frequency and numbers of bursts of epileptic activity also increased throughout the days of exposure to cypermethrin. Some of the paroxysmal events were present with behavioral anomalies, such as generalized tonic–clonic seizures. These effects are important because they could be related to the incidence of epileptic activity in humans chronically exposed to cypermethrin.

Mounting evidence associates a lifetime history of major depression (LMD) with an increased risk for Alzheimer’s disease (AD). Studies have shown that major depression (MD) is strongly linked to pathophysiological markers of AD, such as cortical amyloid-f3 (Af3) burden. However, no imaging studies have shown in vivo whether an LMD is linked to increased Af3 accumulation in patients with mild cognitive impairment (MCI) in four cortical regions that have been highly associated with increased Af3 deposition in previous literature: frontal, cingulate, parietal, and temporal. Drawing from the ADNI database, we found that patients with amnestic MCI (aMCI) and an LMD (n = 39) had significantly higher (18)F-Florbetapir standardized uptake value ratios, a surrogate measure of Af3 deposition, mainly in the bilateral frontal cortex, compared to patients with aMCI without an LMD (n = 39) (p = 0.02). This difference was not explained by current depressive symptoms, vascular risk factors, or the use of different PET scanners. The results were reliable employing two independent methods for analysis: region-of-interest and voxel-based analyses. Increased Af3 in the bilateral frontal lobes may be a biomarker of depressive symptomology in aMCI patients. Further studies should test whether higher Af3 predicts future conversion into AD in this population.

Gaudiebility is defined as a set of modulators that regulates enjoyable experiences. Depressed patients are unable to enjoy life experiences. The aim of this pilot study was to test the efficacy of a group therapy approach based on gaudiebility principles in patients with unipolar depression. The experimental group included 7 patients who were diagnosed with unipolar depression and who scored less than 50 points on the gaudiebility scale. The control group consisted of 10 patients with similar characteristics. The experimental group was treated with both a standard treatment and gaudiebility therapy. The control group was treated only with the standard treatment. Our results showed improvement in the experimental group as indicated by the clinical scales evaluated: the Beck depression scale (24.57 to 13.14, p= 0.02), the gaudiebility scale (32.71 to 49.57, p= 0.04), the quality of life scale (87.14 to 104.43, p= 0.02), and the psychological well-being scale (61.86 to 82.14, p= 0.02). This improvement was maintained after both 3 months and 2 years. The control group showed statistically significant differences only in the quality of life scale (87.1 to 97.6, p= 0.014). Our study suggests that gaudiebility therapy intervention is effective as an additional treatment in patients with unipolar depression. Further exploration of this finding is required, including testing with other disorders and the use of a randomized placebo control study design.

Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.

Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including schizoaffective disorder). Meta-analyses were conducted to examine the effects of NPIs on blood BDNF levels by using the standardized mean differences (SMDs) between the intervention groups and controls. In total, six randomized controlled trials with 289 participants were included. Of them, five studies used exercise, physical training or diet products. One study used cognitive training. Overall, the BDNF levels in the NPI group increased significantly compared with the control groups (SMD = 0.95, 95% confidence interval (CI) = 0.07 to 1.83, p = 0.03). Subgroup analyses indicated beneficial effects of a non-exercise intervention on peripheral BDNF levels (SMD = 0.41, 95% CI = 0.08 to 0.74, p = 0.01). Meta-regression analyses showed that the completion rate influenced the variation in SMD (p = 0.01). Despite insufficient evidence to draw a conclusion, our results suggest that use of NPIs as adjunctive treatments, specifically non-exercise interventions, may affect positively serum or plasma BDNF in patients with schizophrenia.

Increased glutamate levels in the associative-striatum have been described in subjects at ultra-high risk for psychosis (UHR); nevertheless, it is unclear whether this abnormality predicts the conversion to psychosis. Nineteen subjects at UHR and 26 controls were studied using proton magnetic resonance spectroscopy. Subjects at UHR were clinically followed for 2 yr. Seven UHR subjects (37%) transitioned to a psychotic disorder and the remaining 12 did not exhibit psychotic symptoms at the most recent follow-up. The psychosis transition group had higher glutamate levels compared to both non-transition and control groups (p = 0.02 and p < 0.01, respectively; effect size 1.39). These pilot findings suggest that the conversion to psychosis is associated with increased glutamate levels in the associative-striatum.

Objective: To study the effect of memantine on apathy, a common symptom of behavioral variant frontotemporal dementia (bvFTD). Design: The patient underwent an off-label trial of memantine with behavioral inventories and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans performed at baseline, 7 weeks and 6 months. Subject: The patient was a 66-year-old male whose main manifestation of bvFTD was affective, behavioral and cognitive apathy. Intervention: The patient began memantine at an oral dose of 5 mg per morning and titrated up by 5 mg per week to the maintenance dose of 10 mg PO bid. Results: Informants reported reduction of the apathy. The insula and cerebellum, both involved in the salience network, showed improved metabolism. Conclusion: Further study to correlate the effects of memantine on apathy and the salience network in bvFTD are warranted.

Reply to ‘Letter in reference to de la Fuente-Sandoval, C. et al. Neuropsychopharmacology 36, 1781–1791, 2011’

Background: Referential delusions are the most common symptom of schizophrenia and offer an opportunity to examine the neural correlates of delusions because they occur in discrete episodes that can be studied in the scanner. The cortical midline structures (CMS) and subcortical regions, including the amygdala and striatum, are linked with self-reference in healthy adults. Less is known about the neural substrates of altered self-reference in schizophrenia. Methods: In this study, patients with schizophrenia experiencing prominent referential delusions (n = 18) and healthy control subjects (n = 17) were presented with ambiguous sentences while in the magnetic resonance imaging scanner and asked to rate whether they felt the sentences had been written specifically about them. The sentences were either generic (nonpersonalized) or individually tailored personalized sentences, designed to induce referential ideation. We hypothesized that both groups would show activity in the CMS, limbic, and striatal regions and that induced referential ideation would be associated with greater activity in striatal areas in patients with schizophrenia. Results: A robust main effect of endorsement (endorsed vs. nonendorsed) was observed in the CMS, as well as subcortical regions, including the nucleus accumbens/ventral striatum, amygdala, insula, and midbrain dopamine regions. A group-by-endorsement interaction was seen in the medial prefrontal cortex, insula and nucleus accumbens/ventral striatum. Activity in insula and ventral striatum also correlated with the strength of the delusions of reference. Conclusions: Referential ideation in persons with delusions is associated with heightened CMS, limbic and striatal activity and reduced differentiation between self- and non-self-relevant information. © 2011 Society of Biological Psychiatry.

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.

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 (

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.

The glutamatergic and dopaminergic systems are thought to be involved in the pathophysiology of schizophrenia. Their interaction has been widely documented and may have a role in the neurobiological basis of the disease. The aim of this study was to compare, using proton magnetic resonance spectroscopy (1H-MRS), glutamate levels in the precommissural dorsal-caudate (a dopamine-rich region) and the cerebellar cortex (negligible for dopamine) in the following: (1) 18 antipsychotic-naïve subjects with prodromal symptoms and considered to be at ultra high-risk for schizophrenia (UHR), (2) 18 antipsychotic-naïve first- episode psychosis patients (FEP), and (3) 40 age- and sex- matched healthy controls. All subjects underwent a 1H-MRS study using a 3Tesla scanner. Glutamate levels were quantified and corrected for the proportion of cerebrospinal fluid and percentage of gray matter in the voxel. The UHR and FEP groups showed higher levels of glutamate than controls, without differences between UHR and FEP. In the cerebellum, no differences were seen between the three groups. The higher glutamate level in the precommissural dorsal-caudate and not in the cerebellum of UHR and FEP suggests that a high glutamate level (a) precedes the onset of schizophrenia, and (b) is present in a dopamine-rich region previously implicated in the pathophysiology of schizophrenia., peer-reviewed

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 meta-regression 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., peer-reviewed

Introduction: Intriguing evidence suggests that antipsychotic medication exposure may potentially play a protective role in the process leading to amyloid deposition. In this study we examined brain amyloid imaging in persons with schizophrenia in late life using brain imaging with Pittsburg Compound-B (C-PIB). Methods: Subjects were recruited from the University of Iowa Carver College of Medicine Psychiatry outpatient clinic and inpatient neuropsychiatric unit. Inclusion criteria included patients from 55 to 75 years of age, at least 20 years of antipsychotic medication exposure, ability to undergo PET scan, and DSM-IV diagnosis of schizophrenia spectrum disorders: schizophrenia, schizoaffective disorder, delusional disorder. Exclusion criteria included unstable cardiovascular, cerebrovascular, neoplastic, serious systemic illness, Parkinson’s disease, epilepsy, head injury, or multiple sclerosis. Patients underwent PET imaging using C-PIB and neuropsychological testing using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The relationship between amyloid burden (C-PIB measured as standardized uptake ratio) and antipsychotic exposure, as well as cognitive performance were assessed. The standardized uptake value ratio (SUVR) of C-PIB uptake was calculated from predetermined regions of interest (ROI) (frontal, parietal, and temporal cortical regions) divided by the cerebellums C-PIB uptake. Results: There were 5 subjects, mean age 59, with 12-16 years of education, who completed the study. All had significant cognitive impairment on RBANS testing. No subjects had a SUVR (reflecting amyloid deposition) above a threshold that would be considered positive, only one subject had an SUVR that was in a questionably positive range. The relationship between amyloid deposition and cognition was non-significant. There also did not appear to be a relationship between amyloid deposition and years of antipsychotic medication use, except in respect to the patient with the greatest amount of antipsychotic use. This subject had the greatest amount of amyloid burden, although this was greatest in the occipital lobe. Conclusions: This is the first study to our knowledge, to study amyloid (C-PIB) imaging in schizophrenia. Our findings are consistent with previous Alzheimer’s literature demonstrating no clear association between amyloid deposition and cognitive testing, which was the case in our study. The oldest subject (66 years of age) in this study had the greatest amount of antipsychotic exposure (50 years) and highest SUVR, but when his data was combined with the remaining subjects there did not appear to be a relationship between antipsychotic exposure and amyloid burden. These findings suggest that amyloid deposition in persons with schizophrenia does have variance that may be attributable to antipsychotic medication exposure, but a larger sample of subjects will be needed to fully characterize the role of the exposure to medications.

Anosognosia or lack of illness awareness is a clinical manifestation of both schizophrenia and right hemispheric lesions associated with stroke, neurodegeneration, or traumatic brain injury. It is thought to result from right hemispheric dysfunction or interhemispheric disequilibrium, which provides a neuroanatomical model for illness unawareness in schizophrenia. Lack of insight contributes to medication nonadherence and poor treatment outcomes and is often refractory to pharmacological and psychological interventions. We present the first report of transient illness awareness (

In a recent human [(11)C]-(+)-PHNO positron emission tomography study, olanzapine, clozapine, and risperidone occupied D2 receptors in striatum (STR), but, despite their similar in vitro D2 and D3 affinities, failed to occupy D3 receptors in globus pallidus. This study had two aims: (1) to characterize the regional D2/D3 pharmacology of in vitro and ex vivo [(3)H]-(+)-PHNO binding sites in rat brain and (2) to compare, using [(3)H]-(+)-PHNO autoradiography, the ex vivo and in vitro pharmacology of olanzapine, clozapine, risperidone, and haloperidol. Using the D3-selective drug SB277011, we found that ex vivo and in vitro [(3)H]-(+)-PHNO binding in STR is exclusively due to D2, whereas that in cerebellar lobes 9 and 10 is exclusively due to D3. Surprisingly, the D3 contribution to [(3)H]-(+)-PHNO binding in the islands of Calleja, ventral pallidum, substantia nigra, and nucleus accumbens was greater ex vivo than in vitro. Ex vivo, systemically administered olanzapine, risperidone, and haloperidol, at doses occupying approximately 80% D2, did not occupy D3 receptors. Clozapine, which also occupied approximately 80% of D2 receptors ex vivo, occupied a smaller percentage of D3 receptors than predicted by its in vitro pharmacology. Across brain regions, ex vivo occupancy by antipsychotics was inversely related to the D3 contribution to [(3)H]-(+)-PHNO binding. In contrast, in vitro occupancy was similar across brain regions, independent of the regional D3 contribution. These data indicate that at clinically relevant doses, olanzapine, clozapine, risperidone, and haloperidol are D2-selective ex vivo. This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade.

Objective We explored whether prior findings of reduction in serotonin 2A receptor (5-HT2AR) 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-HT2AR nondisplaceable binding potentials (BPND) 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-HT2AR BPNDs decreased with age, a relationship best described by an exponential-decay regression. The BPNDs 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. Copyright © 2011 John Wiley & Sons, Ltd.

Social behavior and desire for social relationships have been independently linked to the serotonergic system, the prefrontal cortex, especially the orbitofrontal cortex (OFC), and the anterior cingulate cortex (ACC). The goal of this study was to explore the role of serotonin 5HT2A receptors in these brain regions in forming and maintaining close interpersonal relationships. Twenty-four healthy subjects completed the Temperament and Character Inventory (TCI) prior to undergoing [18F]setoperone brain positron emission tomography (PET) to measure serotonin 5HT2A receptor availability within the OFC (BA 11 and 47) and ACC (BA 32). We explored the relationship between desire for social relationships, as measured by the TCI reward dependence (RD) scale, and 5HT2A receptor non-displaceable binding potential (BPnd) in these regions. Scores of RD were negatively correlated with 5HT2A BPnd in the ACC (BA 32, r = –.528, p = .012) and OFC (BA 11, r = –.489, p = .021; BA 47, r = –.501, p = .017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships., peer-reviewed

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.

Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.

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., peer-reviewed

To compare glutamate levels (Glu) found in the dorsal-caudate nucleus (a dopamine rich region) and in the cerebellum (a low dopamine region) among: 1) schizophrenia patients undergoing an acute psychotic episode, 2) after receiving antidopaminergic treatment (Risperidone), and 3) healthy controls.Fourteen drug-free patients with schizophrenia and fourteen healthy controls were included. Patients underwent two proton magnetic resonance spectroscopy (1H-MRS) studies, one prior to treatment and the second after 6-weeks of daily Risperidone treatment. Controls underwent one 1H-MRS study. Glutamate levels were normalized according to the relative concentration of Creatine (Cr).The dorsal-caudate nucleus among schizophrenia patients showed higher levels of Glu/Cr during the drug-free condition (t = -2.16, p = 0.03) and after antipsychotic treatment (t = 2.12, p = 0.04) compared with controls. No difference was observed in the cerebellum between the drug-free, post-treatment and controls conditions.Our results suggest that the Glu increase observed in the dorsal-caudate in schizophrenia is illness-mediated and does not change after 6-weeks of antipsychotic treatment. Moreover, the lack of change detected in the cerebellum suggests that the Glu increase in schizophrenia is not ubiquitous within the brain and that may be associated with dopamine target regions.

Clinical evidence suggests that there is decreased pain sensitivity in schizophrenia; however, the neurobiological mechanism of this decrease remains unknown. Using functional magnetic resonance imaging, we examined the blood oxygen level-dependent (BOLD) changes induced by experimental pain-tolerance (endure) hot stimuli vs. non-painful stimuli during an acute psychotic episode in 12 drug-free patients with schizophrenia and in 13 gender- and age-matched healthy controls. The analyses revealed that patients showed a greater BOLD response at S1 compared with controls but a reduced BOLD response in the posterior cingulate cortex (PCC), insula, and brainstem during pain-tolerance stimuli. Pain-tolerance temperature was higher in patients than in healthy controls. BOLD response in the insula positively correlated with unpleasantness and temperature in controls, but this effect was not observed in patients. S1 BOLD response positively correlated with unpleasantness in patients but not in controls. These initial results confirm that unmedicated patients with schizophrenia have a higher pain tolerance than controls, decreased activation in pain affective–cognitive processing regions (insula, PCC, brainstem), and an over-activation of the primary sensory-discriminative pain processing region (S1). These pilot results are the first to explore the mechanism driving altered pain sensitivity in schizophrenia.

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.

OBJECTIVE: Aripiprazole has a unique pharmacological profile that includes partial agonism at D(2) receptors, antagonism at 5-HT(2) receptors, and partial agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder. METHOD: Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635. RESULTS: Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%. CONCLUSIONS: Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Creativity is important for social survival and individual wellbeing; science, art, philosophy and technology have been enriched and expanded by this trait. To our knowledge this is the first study probing differences in brain cerebral blood flow (CBF) between highly creative individuals (scientists and/or artists socially recognized for their contributions to their fields with creativity indexes corresponding to the 99% percentile) and average control subjects while performing a verbal task from the Torrance Tests of Creative Thinking. Additionally, we correlated CBF with creativity dimensions such as fluency, originality and flexibility. Subjects with a high creative performance showed greater CBF activity in right precentral gyrus, right culmen, left and right middle frontal gyrus, right frontal rectal gyrus, left frontal orbital gyrus, and left inferior gyrus (BA 6, 10, 11, 47, 20), and cerebellum; confirming bilateral cerebral contribution. These structures have been involved in cognition, emotion, working memory, and novelty response. The score on the three creativity dimensions--fluency, originality, and flexibility--correlated with CBF activation in right middle frontal gyrus and right rectal gyrus (Brodmann Area 6, 11). Moreover, fluency and flexibility strongly correlated with CBF in left inferior frontal gyrus and originality correlated with CBF in left superior temporal gyrus and cerebellar tonsil. These findings suggest an integration of perceptual, volitional, cognitive and emotional processes in creativity. The higher CBF found in particular brain regions of highly creative individuals during the performance of a creative task provides evidence of a specific neural network related to the creative process.

Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.

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.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.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).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.

Las pruebas psicométricas ayudan a la medición de características psicológicas que incluyen personalidad, motivación, habilidades intelectuales y rasgos psicopatológicos. El diagnóstico psicopatológico se puede respaldar en pruebas psicométricas que idealmente deben ser sencillas y de rápida aplicación. Dos de las pruebas más recurridas son el Listado de Síntomas 90 (SCL 90, por sus siglas en inglés) y el Inventario de Temperamento y Carácter (ITC). El SCL 90 evalúa el grado de “distrés” psicológico a través de 90 reactivos de tipo Likert, agrupados en nueve dimensiones y el ITC consiste en una escala autoaplicable que describe la personalidad con base en el modelo psicobiológico de Cloninger. En México, Cruz-Fuentes y cols., Lara y cols. y Sánchez de Carmona y cols. consideran al SCL 90 y al ITC como instrumentos útiles para la evaluación psicométrica en investigación clínica. Recientemente, instituciones de diversos países han elaborado de forma exitosa versiones computarizadas del SCL 90 y del ITC, lo cual agiliza la calificación y permite un almacenamiento permanente de los datos. El presente trabajo analiza la validez de aplicar una versión computarizada del SCL 90 y del ITC en México diseñada por el Instituto de Neurobiología de la UNAM. Tal versión cuenta con un programa en lenguaje Java, de fácil acceso para el usuario y compatible con cualquier ambiente computacional. El formato de las pruebas en su versión computarizada es similar a la versión lápizpapel, y sigue los lineamientos de calificación de reactivos presentados en los manuales de aplicación de ambas pruebas. Método Las versiones computarizadas del SCL 90 y del ITC se aplicaron en dos sesiones diferentes, a dos muestras de 30 participantes cada una (15 hombres-15 mujeres, media=30, D.E.=8 años de edad). Las versiones lápiz-papel de ambas escalas se aplicaron a dos muestras de iguales características. Las muestras fueron constituidas por trabajadores y estudiantes de la Universidad Nacional Autónoma de México, Campus Juriquilla y de la Universidad Autónoma de Querétaro. Se utilizó la prueba t de Student para analizar las diferencias entre los datos obtenidos en las versiones computarizadas y los datos de las versiones lápiz-papel. Asimismo se compararon gráficamente los resultados obtenidos en las versiones computarizadas con dos muestras de referencia constituidas por datos publicados sobre la validez y la confiabilidad del SCL 90 y del ITC en México. Resultados El tiempo invertido para responder el SCL 90 y el ITC es similar en las versiones computarizadas y de lápiz-papel. En ninguna de las dimensiones evaluadas en el SCL 90 y el ITC se encontraron diferencias significativas entre las respuestas de ambas versiones. La distribución gráfica de los resultados en cada dimensión del SCL 90, así como las medidas de tendencia central del ITC, fueron equivalentes en las versiones computarizadas y las versiones lápiz-papel de las muestras de referencia. Discusión Los resultados suponen que la aplicación por computadora de ambas escalas cumplen con los objetivos de evaluación para los cuales fueron diseñadas. La automaticidad para calificar los reactivos en la versión computarizada reduce los errores humanos en el conteo y permite la creación de extensas bases de datos para estudios comparativos epidemiológicos y longitudinales. Con base en los resultados las versiones computarizadas del SCL 90 y del ITC son consideradas como herramientas válidas y útiles para la evaluación psicométrica.

Background: Dysregulations of the major inhibitory and excitatory amino neurotransmitter systems of γ-aminobutyric acid and glutamate, respectively, have been described in patients with schizophrenia. However, it is unclear whether these abnormalities are present in subjects at ultra-high risk for psychosis. Methods: Twenty-three antipsychotic naive subjects at ultra-high risk and 24 healthy control subjects, matched for age, sex, handedness, cigarette smoking, and parental education, underwent proton magnetic resonance spectroscopy scans in the dorsal caudate bilaterally and the medial prefrontal cortex at 3T. Levels of γ-aminobutyric acid and of the combined resonance of glutamate and glutamine (Glx) were obtained using the standard J-editing technique and expressed as peak area ratios relative to the synchronously acquired unsuppressed voxel water signal. Results: Higher levels of γ-aminobutyric acid ( P

The kinetic modeling of [11C]-(+)-PHNO binding to the dopamine D2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [11C]-(+)-PHNO is the first agonist radioligand for the D2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time—activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k3/ k4 ratios. Coupling K1/ k2 between brain regions (Method C) or fixing K1/ k2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k3/ k4 as compared with an unconstrained 2CM. The k3/ k4 obtained with Method D ranged from 0.12 ± 0.03 in cerebellum to 3.93 ± 0.77 in GP and were similar to those obtained when coupling K1/ k2. Binding potentials (BPs) obtained using the simplified reference tissue model ( BPSRTM) ranged from 2.08 ± 0.34 in caudate to 3.55 ± 0.78 in GP and were highly correlated with k3/ k4 estimates obtained with Method D ( r = 0.98). However, BPSRTM were 11% ± 5% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BPSRTM. This study demonstrates that [11C]-(+)-PHNO can be used for the quantitative measurement of D2/3 densities and should enable further studies of potential D2/3 dysregulation in several important psychiatric and neurologic illnesses.

Background The prediction error (PE) hypothesized by the temporal difference model has been shown to correlate with the phasic activity of dopamine neurons during reward learning and the blood-oxygen level dependent (BOLD) response during reward and aversive conditioning tasks. We hypothesized that dopamine would modulate the PE related signal in aversive conditioning and that haloperidol would reduce PE related activity, while an acute dose of amphetamine would increase PE related activity in the ventral striatum. Methods Healthy participants took an acute dose of amphetamine, haloperidol, or placebo. We used functional magnetic resonance imaging (fMRI) to measure the BOLD signal while they carried out an aversive conditioning task, using cutaneous electrical stimulation as the unconditioned stimulus (US) and yellow and blue circles as conditioned stimulus (CS+ and CS−, respectively). Results Prediction error related BOLD activity was seen only in the ventral striatum in the placebo subjects. The subjects given amphetamine showed a wider network of PE related BOLD activity, including the ventral striatum, globus pallidus, putamen, insula, anterior cingulate, and substantia nigra/ventral tegmental area. Haloperidol subjects did not show PE related activity in any of these regions. Conclusions Our results provide the first demonstration that the modulation of dopamine transmission affects both the physiological correlates and PE related BOLD activity during aversive learning.

Dorsolateral prefrontal cortex (DLPFCx) has been implicated in pain perception and in a pain modulation pathway. However, the precise participation of this region is not completely understood. The aim of this study was to evaluate whether 1 Hz rTMS of DLPFCx modifies threshold and tolerance in experimental pain. The effect of 1 Hz rTMS during 15 min at 100% motor threshold was tested in one hundred and eighty right-handed healthy volunteers, using a parallel-group stimulation design. The stimulation sites were right or left DLPFCx, right or left motor cortex, vertex or sham. rTMS was applied in two experimental contexts: (1) To evaluate its transitory effect (interference or facilitation) during cold pressor threshold (CPTh) and tolerance (CPTt) and (2) to evaluate its long-term effect by stimulating before CPTh, CPTt, pain heat thermal threshold, pain pressure threshold and tolerance. During rTMS of right DLPFCx, an increase in left hand CPTt (mean +/- SD; 17.63 s +/- 5.58 to 30.94 s +/- 14.84, P < 0.001) and in right hand CPTt (18.65 s +/- 6.47 to 26.74 s +/- 11.85, P < 0.001) were shown. No other stimulation site modified any of the pain measures during or after rTMS. These results show that 1 Hz rTMS of right DLPFCx has a selective effect by increasing pain tolerance and also sustains a right hemisphere preference in pain processing.

Importance Increased glutamate levels in the right associative striatum have been described in patients during a first episode of psychosis. Whether this increase would persist after effective antipsychotic treatment is unknown. Objectives To compare the glutamate levels in antipsychotic-naive patients with first-episode psychosis in the right associative striatum and right cerebellar cortex using proton magnetic resonance spectroscopy before and 4 weeks after antipsychotic treatment and to compare these results with normative data from sex-matched healthy control subjects. Design, Setting, and Participants Before-after trial in an inpatient psychiatric research unit among 24 antipsychotic-naive patients with first-episode psychosis and 18 healthy controls matched for age, sex, handedness, and cigarette smoking. Interventions Participants underwent 2 proton magnetic resonance spectroscopy studies: patients were imaged at baseline and after 4 weeks of antipsychotic treatment, while controls were imaged at baseline and at 4 weeks after the baseline measurement. Patients were treated with oral risperidone (open label) for 4 weeks with dosages that were titrated on the basis of clinical judgment. Main Outcomes and Measures Glutamate levels were estimated using LCModel (version 6.2-1T) and were corrected for the cerebrospinal fluid proportion within the voxel. Results Patients with first-episode psychosis had higher levels of glutamate in the associative striatum and the cerebellum during the antipsychotic-naive condition compared with controls. After clinically effective antipsychotic treatment, glutamate levels significantly decreased in the associative striatum, with no significant change in the cerebellum. No differences in glutamate levels were observed between groups at 4 weeks. Conclusions and Relevance Increased glutamate levels observed at baseline in patients with first-episode psychosis normalized after 4 weeks of clinically effective antipsychotic treatment. These results provide support for the hypothesis that improvement in clinical symptoms might be related to a decrease in glutamate levels.

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 more than 6 months. Intervention A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. Measurements Dopamine D 2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [ 11 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 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.