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Adenosine A2A receptors are highly enriched in the basal ganglia system, a region that is functionally implicated in schizophrenia. Preclinical evidence suggests a cross-regulation between adenosine A2A and dopamine D2 receptors in this region and that it is linked to the sensitization of the dopamine system. However, the relationship between A2A receptor availability and schizophrenia has not been directly examined in vivo in patients with this disorder. To investigate, using positron emission tomography (PET), the availability of A2A receptors in patients diagnosed with schizophrenia in comparison to matched healthy controls. A2A receptor availability was measured using the PET tracer [11C]SCH442416. Twelve male patients with chronic schizophrenia were compared to 13 matched healthy subjects. All patients were medicated with antipsychotics and none presented with any motor or extrapyramidal symptoms. Binding potential (BPND), a ratio measure between specific and non-specific tracer uptake, were compared between the groups for the caudate, putamen, accumbens and globus pallidum. There was no differences between A2A receptor binding potential (BPND) of schizophrenia patients in the caudate (p = 0.16), putamen (p = 0.86), accumbens (p = 0.44) and globus pallidum (p = 0.09) to that of matched healthy subjects. There was also no significant correlation between [11C]SCH442416 binding and severity of psychotic symptoms (p = 0.2 to 0.82) or antipsychotic dosage (p = 0.13 to 0.34). By showing that A2A receptor availability in medicated patients with chronic male schizophrenia is not different than in healthy controls, this study does not support the primary role of this receptor in the pathogenesis of schizophrenia.

Nearly two decades ago, Berridge and Robinson conceptualized a role for dopamine in motivational salience, and in 2003 it was invoked as an explanation for psychosis in schizophrenia. In the years since, research developing and testing the “aberrant salience hypothesis” has grown steadily. However even basic questions remain: How is salience calculated and attributed in the brain, and how can we measure it? How does it involve dopamine signaling and how does it go wrong? How does it change with the course of psychosis and with treatment? Does abnormal salience attribution underlie all psychoses? This chapter reviews fifteen years of research into aberrant salience processing in psychosis. It compares the different operationalizations of salience processing in online and offline tasks in controls and in various patient groups. It provides an up-to-date picture of the state of the art, and suggest directions for future research.

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

Background Response to antidepressants in major depressive disorder is variable and determinants are not well understood or used to design clinical trials. We aimed to understand these determinants. Methods Supported by Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from industry sponsored randomized placebo-controlled trials of antidepressant drugs in adults with MDD. We examined patient and trial-design-related determinants of outcome as measured by change on Hamilton Depression Scale or Montgomery–Asberg Depression Rating Scale in 34 placebo-controlled trials (drug, n = 8260; placebo, n = 3957). Results While it is conventional for trials to be 6–8 weeks long, drug-placebo differences were nearly the same at week 4 as at week 6 and with lower dropout rates. At the multivariate level, having any of these attributes was significantly associated with greater drug vs. placebo differences on symptom improvement: female, increasing proportion of patients on placebo, centers located outside of North America, centers with low placebo response (regardless of active treatment response) and using randomized withdrawal designs. Limitations Data on compounds that failed were not available to us. Findings may not be relevant for new mechanisms of action. Conclusions Proof of concept trials can be shorter and efficiency improved by selecting enriched populations based on clinical and demographic variables, ensuring adequate balance of placebo patients, and carefully selecting and monitoring centers. In addition to improving drug discovery, patient exposure to placebo and experimental treatments can be reduced.

BACKGROUND: No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown.METHODS: This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual.FINDINGS: Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported.INTERPRETATION: For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation.FUNDING: European Commission Seventh Framework Program.

Introduction: There is an ongoing debate about whether negative affect are consequences or triggers of paranoid thinking. It has also been suggested that aberrant salience is central to the development of delusions. This study modelled the moment-to-moment relationships between negative affect, aberrant salience, and paranoia in acute inpatients with psychosis.Methods: Participants with active paranoid delusions were assessed using clinical rating scales and experience sampling method (ESM) over 14 days. ESM data were analysed using time-lagged multilevel regression modelling.Results: Both negative affect and aberrant salience predicted an increase in paranoia at the next time point. Conversely, the level of paranoia did not predict subsequent changes in negative affect or aberrant salience. Negative affect predicted an increase in aberrant salience at the next time point, and vice versa.Conclusions: Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom. Our results suggest both direct and indirect (via aberrant salience) pathways from negative affect to paranoia.

Adenosine A

Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [(11)C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [(11)C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [(11)C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [(11)C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [(11)C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.

Proton magnetic resonance spectroscopy ((1)H MRS) studies in schizophrenia patients generally report decreased levels of N-acetyl-aspartate (NAA), glutamate and glutathione, particularly in frontal cortex. However, these data are inconsistent in part due to confounds associated with clinical samples. The lack of validated diagnostic biomarkers also hampers analysis of the neurodevelopmental trajectory of neurochemical abnormalities. Rodent models are powerful tools to address these issues, particularly when combined with (1)H MRS (clinically comparable technology). We investigated the trajectory of metabolic changes in the prefrontal cortex during brain maturation from adolescence to adulthood in vivo using (1)H MRS in rats exposed prenatally to polyinosinic-polycytidylic acid (POL), a rodent model of maternal immune activation (MIA), an epidemiological risk factor for several psychiatric disorders with a neurodevelopmental origin. Longitudinal in vivo (1)H MRS revealed a significant decrease in PFC levels of GSH and taurine in adult, but not adolescent rats. Significant age×MIA interactions for PFC levels of NAA were also observed. These data replicate some deficits observed in the PFC of patients with schizophrenia. There were no significant changes in the levels of glutamate or any other metabolite. These data suggest prenatal exposure to POL leads to subtle metabolic perturbations of the normal maturing PFC, which may be related to subsequent behavioural abnormalities. Further work is however required to examine any potential confound of shipping stress on the presumed imbalances in PFC metabolites in POL-exposed offspring. Testing the interactions between MIA with stress or genetic risk variants will also be an important advance.

Neuroinflammation is increasingly implicated in the pathogenesis of Schizophrenia (SCZ). In addition, there is increasing evidence for a relationship between the dose and duration of antipsychotic drug (APD) treatment and reductions in grey matter volume. The potential contribution of microglia to these phenomena is however not yet defined. Adult rats were treated with a common vehicle, haloperidol (HAL, 2 mg/kg/day) or olanzapine (OLZ, 10 mg/kg/day) for 8 weeks via an osmotic mini-pump implanted subcutaneously. Microglial cells, identified by their Iba-1 immunoreactivity, were quantified in four regions of interest chosen based on previous neuroimaging data: the hippocampus, anterior cingulate cortex, corpus striatum, and secondary somatosensory cortex. Those cells were also analysed according to their morphology, providing an index of their activation state. Chronic APD treatment resulted in increased density of total microglia in the hippocampus, striatum, and somatosensory cortex, but not in the ACC. Importantly, in all brain regions studied, both APD tested led to a dramatic shift towards an amoeboid, reactive, microglial morphology after chronic treatment compared to vehicle-treated controls. These data provide the first in vivo evidence that chronic APD treatment at clinically relevant doses leads to microglial proliferation and morphological changes indicative of activated microglia in the naïve rat brain. Although caution needs to be exerted when extrapolating results from animals to patients, these data suggest a potential contribution of antipsychotic medication to markers of brain inflammation. Further investigation of the links between antipsychotic treatment and the immune system are warranted.

This Article was originally published under Nature Research’s License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

This Article was originally published under Nature Research’s License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Current antipsychotic medications have been the mainstay in the treatment of schizophrenia since chlorpromazine was introduced in 1952. However, all antipsychotics share the same mechanism of action, which involves a blockade of the dopamine D2-receptor. This chapter covers recent attempts to develop new treatments for psychotic disorders. These include new approaches to the delivery of existing antipsychotic medications and the most recent and promising mechanisms of action that are distinct from existing antipsychotics. Some of the new mechanisms of action include drugs targeting the glutamatergic system, the alpha7 nicotinic acetylcholine receptor, the phosphodiesterase 10A enzyme, or the muscarinic and serotoninergic system. Finally, we have reviewed a number of alternative nonpharmacological pathways, such as avatar therapy, repetitive transcranial magnetic stimulation, or cognitive remediation. The chapter ends by discussing some of the major challenges facing the development of new treatments for psychotic disorders.

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

Cognitive impairment associated with schizophrenia is a key predictor of functional outcomes. The FDA-accepted MATRICS Consensus Cognitive Battery (MCCB) is held to be the gold standard measure but there are concerns about its ease of administration, reliance on language causing problems with translation and possible practice effects. The CogState Schizophrenia Battery (SB) is suggested as a non-language-based alternative but there is no substantial, independent comparison. The objective of this study was to assess the reliability and validity of these two assessment batteries. One hundred forty-three participants with DSM-IV schizophrenia and schizoaffective disorder were recruited into three similar studies. Each study administered MCCB and SB tests on consecutive days (baseline 1 and 2) and follow-up 3–4 weeks later. Batteries’ test-retest reliability was similar: SB composites correlated r = 0.66–0.78 between baselines, MCCB domains r = 0.69–0.90. Baseline 2 and follow-up SB composites correlated r = 0.65–0.80 and MCCB domains r = 0.62–0.87. MCCB tasks’ practice effects (Glass’ ∆ = 0.02–0.46) exceeded SB’s (Glass’ ∆ = 0.02–0.34). While the batteries’ total scores correlated strongly (r = 0.79–0.82), apparently equivalent cognitive domains on each battery (e.g. psychomotor-attention) correlated r = 0.22–0.60, indicating substantial differences between some supposed counterparts. Clinical trials using either battery would benefit from initial practice sessions to ameliorate practice effects but the SB may be more suitable to measure change in the absence of repeated baselines. The MCCB domains’ better correlations with social skills performance suggest that it may have an advantage for measuring cognition in relation to functional outcome.

Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered in non-responders. We therefore aimed to test this in a prospective cohort, with a nested case-control comparison. 40 volunteers (26 patients with first-episode psychosis and 14 controls) received an 18F-DOPA Positron Emission Tomography scan to measure DSC (Kicer) prior to antipsychotic treatment. Clinical assessments (Positive and Negative Syndrome Scale, PANSS, and Global Assessment of Functioning, GAF) occurred at baseline and following antipsychotic treatment for a minimum of 4 weeks. Response was defined using improvement in PANSS Total score of >50%. Patients were followed up for at least 6 months, and remission criteria applied. There was a significant effect of group on Kicer in associative striatum (F(2, 37) = 7.9, p = 0.001). Kicer was significantly higher in responders compared with non-responders (Cohen’s d = 1.55, p = 0.01) and controls (Cohen’s d = 1.31, p = 0.02). Kicer showed significant positive correlations with improvements in PANSS-positive (r = 0.64, p

Perinatal brain injuries, including hippocampal lesions, cause lasting changes in dopamine function in rodents, but it is not known if this occurs in humans. We compared adults who were born very preterm with perinatal brain injury to those born very preterm without perinatal brain injury, and age-matched controls born at full term using [18F]-DOPA PET and structural MRI. Dopamine synthesis capacity was reduced in the perinatal brain injury group relative to those without brain injury (Cohen’s d = 1.36, p=0.02) and the control group (Cohen’s d = 1.07, p=0.01). Hippocampal volume was reduced in the perinatal brain injury group relative to controls (Cohen’s d = 1.17, p=0.01) and was positively correlated with striatal dopamine synthesis capacity (r = 0.344, p=0.03). This is the first evidence in humans linking neonatal hippocampal injury to adult dopamine dysfunction, and provides a potential mechanism linking early life risk factors to adult mental illness., eLife digest Thirteen million infants are born too early every year. Improved care allows many to survive, but these “preterm infants” still face an increased risk of death and many other complications. Infants born very early, before 32 weeks, are at risk of brain injury because the brain is normally still developing in the later stages of pregnancy. They also have an increased risk of developing mental health problems later in life. Early-life brain injuries in rats cause changes in the production of a chemical called dopamine. Dopamine is a chemical messenger in the brain that reinforces rewarding behaviour. People with schizophrenia and attention deficit hyperactivity disorder (ADHD) have abnormal levels of dopamine. Changes in brain dopamine levels may explain why early-life brain injury is linked to later mental illness. But first scientists must study whether similar changes occur in humans with an early-life brain injury. Now, Froudist-Walsh et al. use brain imaging to show that people born very early who suffered a brain injury have lower dopamine levels than other adults. Imaging techniques were used to scan the brains of 13 adults who were born before 32 weeks and who had a brain injury around birth, 13 adults born before 32 weeks without a brain injury, and 13 adults born at “full term” (around 39 to 40 weeks). Individuals with low dopamine levels reported difficulty concentrating and a lack of motivation and enjoyment in their lives. Both can be warning signs of mental health problems. People born prematurely without a brain injury had normal dopamine levels and did not report such symptoms. More studies may help scientists understand how early brain injuries may cause brain chemical differences later in life, and how these brain changes affect individual’s mental health. They may also help scientists develop treatments to prevent or treat mental illness in people who experienced a brain injury after a very early birth.

Despite five decades of search for clinically meaningful 'biomarkers' in schizophrenia there are still no common tests to inform diagnosis or treatment. Our aim was to understand why it has been so difficult to convert biological findings into clinical tests. We categorized all PubMed-indexed articles investigating psychosis-related biomarkers to date (over 3200). Studies showed an evident publication bias, a confusing array of terminology, and few systematic efforts at longitudinal evaluation or external validation. Fewer than 200 studies investigated biomarkers, longitudinally, for prediction of illness course and treatment response. These biomarkers were then evaluated in terms of their statistical reliability and clinical effect size. Only one passed our a priori threshold for clinical applicability. This is a modest record. In order to promote real progress, the field needs: (a) consistent use of terminology so that studies can be compared; (b) a system of standardized universal reporting to overcome the existing publication bias; and (c) practical criteria [a prototype is suggested here] for assessing the clinical applicability of the findings.

BackgroundPatients with schizophrenia have substantially reduced subjective well-being (SW) compared to healthy individuals. It has been suggested that diminished SW may be related to deficits in the neural processing of reward but this has not been shown directly. We hypothesized that, in schizophrenia, lower SW would be associated with attenuated reward-related activation in the reward network.MethodTwenty patients with schizophrenia with a range of SW underwent a functional magnetic resonance imaging (fMRI) reward task. The brain activity underlying reward anticipation and outcome in schizophrenia was examined and compared to that of 12 healthy participants using a full factorial analysis. Region of interest (ROI) analyses of areas within the reward network and whole-brain analyses were conducted to reveal neural correlates of SW.ResultsReward-related neural activity in schizophrenia was not significantly different from that of healthy participants; however, the patients with schizophrenia showed significantly diminished SW. Both ROI and whole-brain analyses confirmed that SW scores in the patients correlated significantly with activity, specifically in the dorsal anterior cingulate cortex (dACC), during both reward anticipation and reward outcome. This association was not seen in the healthy participants.ConclusionsIn patients with schizophrenia, reduced activation of the dACC during multiple aspects of reward processing is associated with lower SW. As the dACC has been widely linked to coupling of reward and action, and the link to SW is apparent over anticipation and outcome, these findings suggest that SW deficits in schizophrenia may be attributable to reduced integration of environmental rewarding cues, motivated behaviour and reward outcome.

BackgroundThe hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential.AimsTo bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia.MethodElectronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions.ResultsThe meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d =–0.32 (95% CI −0.68 to 0.03) for the thalamus, d =–0.23 (95% CI −0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI −0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus.ConclusionsThere is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis.

Background Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear. Methods With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, we undertook a focused postmortem investigation with stereology. Results We identified decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC. In contrast, an increase in the density of these cells was observed. Conclusions This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil. Although caution needs to be exerted when extrapolating results from animals to patients, this study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins.

Background: Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function. Methods: We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant Kicer) was measured with positron emission tomography and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F]-DOPA). Results: Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t36 = 2.54, p = .016) and its associative (effect size: .85; t36 = 2.54, p = .015) and limbic subdivisions (effect size: .74; t36 = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabis abuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = −.77, p < .001) and positively associated with age of onset of cannabis use (r = .51, p = .027) but was not associated with cannabis-induced psychotic-like symptoms (r = .32, p = .19). Conclusions: These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.

Outcomes in RCT's of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCT's. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p≤.05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question.

Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to (cumulatively) >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. These approaches complement the other main aim of GWAS studies on risk prediction approaches for improving detection, differential diagnosis, and clinical trial design. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC3 findings into new therapeutics.

IMPORTANCE: Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia. OBJECTIVE: To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used. INTERVENTIONS: Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses. MAIN OUTCOMES AND MEASURES: Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase. RESULTS: Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = –1.04; z = –0.59; P = .57), PANSS-positive (weighted β = –0.62; z = –0.93; P = .35), or PANSS-negative (weighted β = –0.12; z = –0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified. CONCLUSIONS AND RELEVANCE: Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02164981

Background Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus. Objectives We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms. Method Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome. Results Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from “typical” trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6 weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics. Conclusions Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow.

Large placebo response presents a major challenge for psychopharmacologic drug development and contributes to the increasing failure of psychiatric trials. The objective of this meta-regression analysis was to identify potential contributors to placebo response in randomized controlled trials of antipsychotic treatment in schizophrenia.The authors extracted trial design and clinical variables from eligible randomized controlled trials (N=50) identified through searches of MEDLINE (1960-2010) and other sources. Standardized mean change (SMC) was used as the effect size measure for placebo response, based on change scores on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale from baseline to endpoint (2 to 12 weeks).The results suggest significant heterogeneities (Q=387.83, df=49) in the magnitude of placebo response (mean SMC, -0.33, range -1.4 to 0.9) and in study quality. Both placebo SMC and study quality increased over time. Younger age, shorter duration of illness, greater baseline symptom severity, and shorter trial duration were significantly associated with greater placebo response, while country (United States compared with other countries) was not. More study sites, fewer university or Veterans Affairs treatment settings, and a lower percentage of patients assigned to receive placebo were associated with a greater placebo response, but these were not independent of publication year. Study quality affected the variability but not mean levels of placebo response.This study identified important patient characteristics and trial design factors affecting the level of placebo response and hence the likelihood of detecting efficacy signals in randomized controlled trials. Future studies should test whether controlling these factors improves the detection of an antipsychotic effect.

The Innovative Medicines Initiative (IMI) is Europe’s largest public-private initiative aiming to speed up the development of better and safer medicines for patients—and nowhere is the need more urgent than in the area of CNS medications (2015a). IMI is a joint undertaking between the European Union and the pharmaceutical industry association, European Federation of Pharmaceutical Industries and Associations (EFPIA), and supports collaborative research projects between the academia and industry. NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) which generated the articles in this supplement is one of the earliest IMI (2015b). In this Commentary, we introduce the Innovative Medicine Initiative and what makes it unique; we provide perspective on some of the achievements of NEWMEDS and some lessons learned in the process of this partnership over 5 years. The way the IMI consortia are brought together is unique. Before the Call is launched, a consortium of EFPIA companies and, in some cases, other large companies or organizations active in health research agree on the need to work together and with other stakeholders on a specific issue. The topic text is drafted and, following consultation with various groups, the details of the Call text is sent to the IMI Governing Board for approval. Stage 1 Once the Governing Board has given its green light, the Call is published and all interested parties from academia, smalland medium-sized enterprises (SMEs), patient organizations, regulatory agencies, etc. are invited to form consortia and to submit a proposal in response to the Call. The proposals are screened for eligibility and reviewed by independent experts. The experts rank the applications, and the consortium that submitted the top-ranked application is invited to proceed to Stage 2.

In this issue several articles1–4 are included describing the scientific background of the Framework Program 7 (FP7) EU-funded study, Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE). This 6-year study is designed to develop a treatment algorithm in (first-episode) schizophrenia and the tools to predict treatment outcome and improve compliance.

The aim of this study was to determine what variables predict a 'combined treatment outcome' (COMBOUT) in patients with chronic schizophrenia.This analysis (n=522) was based on a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients diagnosed with schizophrenia or a related disorder. COMBOUT was assessed using the PANSS for symptoms, CGI-S for overall clinical status, MADRS for depressive symptoms, QLS for functioning/QOL, and SWN-K for subjective well-being. Possible predictors included demographics as well as baseline scores (Model I), and early change (week 2) scores (Model II).Model I: significantly better outcome (higher COMBOUT score) was observed in patients with lower MADRS (T= - 6.36; p0.001) or higher QLS (T=5.05; p0.001) scores at baseline. Model II: significantly better COMBOUT was observed in patients with early improvement of QLS (T=4.93; p0.001), SWN-K (T=3.88; p0.001), PANSS (T= - 2.32; p=0.021) and CGI-S scores (T= - 2.22; p=0.027). Changes in EPS were not predictors of COMBOUT in the models tested.COMBOUT at endpoint was predicted by lower depressive symptom score and higher QOL at baseline and by early improvement in psychopathology, quality of life and subjective well-being.

BackgroundClozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians.AimsTo determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment.MethodClinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010.ResultsComplete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, PConclusionsSubstantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.

Elevated presynaptic striatal dopaminergic function is a robust feature of schizophrenia. However, the relationship between this dopamine abnormality and the response to dopamine-blocking antipsychotic treatments is unclear. The authors tested the hypothesis that in patients with schizophrenia the response to antipsychotic treatment would be related to the severity of presynaptic dopamine dysfunction, as indexed using [(18)F]-DOPA uptake positron emission tomography (PET).Twelve patients with treatment-resistant schizophrenia, twelve patients with schizophrenia who had responded to antipsychotics, and twelve healthy volunteers matched for gender, age, ethnicity, weight, and cigarette smoking underwent [(18)F]-DOPA PET scanning. [(18)F]-DOPA influx rate constants (K(i)(cer) values) were measured in the striatum and its functional subdivisions.Patients who had responded to antipsychotic treatment showed significantly higher K(i)(cer) striatal values than did patients with treatment-resistant illness (effect size=1.11) and healthy volunteers (effect size=1.12). The elevated [(18)F]-DOPA uptake was most marked in the associative (effect size=1.31) and the limbic (effect size=1.04) striatal subdivisions. There were no significant differences between patients with treatment-resistant illness and healthy volunteers in the whole striatum or any of its subdivisions.In some patients with schizophrenia, antipsychotic treatment may be ineffective because they do not exhibit the elevation in dopamine synthesis capacity that is classically associated with the disorder; this may reflect a different underlying pathophysiology or a differential effect of antipsychotic treatment.

Connectomic approaches using diffusion tensor imaging have contributed to our understanding of brain changes in psychosis, and could provide further insights into the neural mechanisms underlying response to antipsychotic treatment. We here studied the brain network organization in patients at their first episode of psychosis, evaluating whether connectome-based descriptions of brain networks predict response to treatment, and whether they change after treatment. Seventy-six patients with a first episode of psychosis and 74 healthy controls were included. Thirty-three patients were classified as responders after 12 weeks of antipsychotic treatment. Baseline brain structural networks were built using whole-brain diffusion tensor imaging tractography, and analysed using graph analysis and network-based statistics to explore baseline characteristics of patients who subsequently responded to treatment. A subgroup of 43 patients was rescanned at the 12-week follow-up, to study connectomic changes over time in relation to treatment response. At baseline, those subjects who subsequently responded to treatment, compared to those that did not, showed higher global efficiency in their structural connectomes, a network configuration that theoretically facilitates the flow of information. We did not find specific connectomic changes related to treatment response after 12 weeks of treatment. Our data suggest that patients who have an efficiently-wired connectome at first onset of psychosis show a better subsequent response to antipsychotics. However, response is not accompanied by specific structural changes over time detectable with this method.

Summary Background Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, offer an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment. Methods SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1:1:1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks' treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]). Findings Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean difference in score −1·37, 95% CI −2·27 to −0·47; p=0·0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: −3·77, 95% CI −4·40 to −3·14; p=0·3142. Results from the other two studies also did not differ from placebo (TwiLyte 0·58, 95% CI −0·34 to 1·50, p=0·22 for 10 mg and 0·43, −0·49 to 1·36, p=0·36 for 20 mg; MoonLyte 0·06, 95% CI −0·79 to 0·92, p=0·88 for 5 mg and 0·44, −0·41 to 1·28, p=0·31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation. Interpretation Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might offer only modest benefit to suboptimal responders to antipsychotics, if any. Funding F Hoffmann-La Roche.

Phosphodiesterase 10A (PDE10A) is an enzyme present in striatal medium spiny neurons that degrades the intracellular second messengers triggered by dopamine signaling. The pharmaceutical industry has considerable interest in PDE10A inhibitors because they have been shown to have an antipsychotic-like effect in animal models. However, the status of PDE10A in schizophrenia is unknown. Using a newly developed and validated radioligand, [(11)C]IMA107, the authors report the first in vivo assessment of PDE10A brain expression in patients with schizophrenia.The authors compared PDE10A availability in the brains of 12 patients with chronic schizophrenia and 12 matched healthy comparison subjects using [(11)C]IMA107 positron emission tomography (PET). Regional estimates of the binding potential (BPND) of [(11)C]IMA107 were generated from dynamic PET scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding.There was no significant difference in [(11)C]IMA107 BPND between schizophrenia patients and comparison subjects in any of the brain regions studied (thalamus, caudate, putamen, nucleus accumbens, globus pallidus, and substantia nigra). There was also no significant correlation between [(11)C]IMA107 BPND and the severity of psychotic symptoms or antipsychotic dosage.Patients with schizophrenia have normal availability of PDE10A in brain regions thought to be involved in the pathophysiology of this disorder. The findings do not support the proposal of an altered PDE10A availability in schizophrenia. The implication of this finding for future drug development is discussed.

A recent single-site study (Fisher et al., 2009. Am J Psychiatry. 166 (7) 805-11) showed that repeated training with the Brain Fitness Program (BFP) improved performance on a battery of neuropsychological tasks. If replicated these data suggest an important non-pharmacological method for ameliorating cognitive impairment in schizophrenia. Our study evaluated the BFP training effects in an open-label, multi-site, multinational clinical trial. Fifty-five stable adult patients with schizophrenia on regular antipsychotic medication completed ≥ 32 BFP training sessions over 8-10 weeks. Training effects on cognitive performance and functional capacity outcome measures were measured using CogState® schizophrenia battery, UCSD Performance based Skills Assessment (UPSA-2) and Cognitive Assessment Interview (CAI). BFP training showed a large and significant treatment effect on a training exercise task (auditory processing speed), however this effect did not generalize to improved performance on independent CogState® assessment. There were no significant effects on UPSA-2 or CAI scores. Our study demonstrated the feasibility of implementing BFP training in a multi-site study. However, BFP training did not show significant treatment effects on cognitive performance or functional capacity outcome measures despite showing large and significant effects on a training exercise.

Background Various schizophrenic symptoms are suggested to be linked to a dysfunction of the brain reward system. Several studies have found alterations in the reward processing in patients with schizophrenia; however, most previous findings might be confounded by medication effects. Methods Thirty-one antipsychotic-naive schizophrenia patients and 31 age- and gender-matched healthy control subjects were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. The task variant made it possible to separate overall salience (defined as arousing events) into behavioral salience (events where a predicted reward requires performance) and valence anticipation (the anticipation of a monetarily significant outcome) . Furthermore, the evaluation of monetary gain and loss was assessed. Results During reward anticipation, patients had a significant attenuation of the activation in ventral tegmentum, ventral striatum, and anterior cingulate cortex during presentation of salient cues. This signal attenuation in ventral striatum was correlated with the degree of positive symptoms. Signal attenuation was most pronounced for behavioral salience and nonsignificant for value anticipation. Furthermore, patients showed a changed activation pattern during outcome evaluation in right prefrontal cortex. Conclusion Our results suggest that changes during reward anticipation in schizophrenia are present from the beginning of the disease. This supports a possible involvement of reward disturbances in the pathophysiology of schizophrenia. The most pronounced changes were seen in relation to overall salience. In ventral striatum these changes were associated with the degree of positive symptoms.

Antipsychotic drugs act on the dopaminergic system (first-generation antipsychotics, FGA), but some also directly affect serotonergic function (second-generation antipsychotics, SGA) in the brain. Short and long-term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single-dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo-controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single-dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic-induced rCBF changes and brain alterations in schizophrenia. Hum Brain Mapp, 2013. (C) 2012 Wiley Periodicals, Inc.