A neuroimaging study of emotion-cognition interaction in schizophrenia: the effect of ziprasidone treatment.

Functional and structural brain changes associated with the cognitive processing of emotional visual stimuli were assessed in schizophrenic patients after 16 weeks of antipsychotic treatment with ziprasidone. Forty-five adults aged 18 to 40 were recruited: 15 schizophrenia patients (DSM-IV criteria) treated with ziprasidone (mean daily dose = 120 mg), 15 patients treated with other antipsychotics, and 15 healthy controls who did not receive any medication. Functional and structural neuroimaging data were acquired at baseline and 16 weeks after treatment initiation. In each session, participants selected stimuli, taken from standardized sets, based on their emotional valence. After ziprasidone treatment, several prefrontal regions, typically involved in cognitive control (anterior cingulate and ventrolateral prefrontal cortices), were significantly activated in patients in response to positive versus negative stimuli. This effect was greater whenever they had to select negative compared to positive stimuli, indicating an asymmetric effect of cognitive treatment of emotionally laden information. No such changes were observed for patients under other antipsychotics. In addition, there was an increase in the brain volume commonly recruited by healthy controls and patients under ziprasidone, in response to cognitive processing of emotional information. The structural analysis showed no significant changes in the density of gray and white matter in ziprasidone-treated patients compared to patients receiving other antipsychotic treatments. Our results suggest that functional changes in brain activity after ziprasidone medication precede structural and clinical manifestations, as markers that the treatment is efficient in restoring the functionality of prefrontal circuits involved in processing emotionally laden information in schizophrenia.

Plasma Endocannabinoid Alterations in Individuals with Substance Use Disorder are Dependent on the "Mirror Effect" of Schizophrenia.

Schizophrenia is a complex psychiatric disorder strongly associated with substance use disorders. Theoretically, schizophrenia and SUD may share endocannabinoid alterations in the brain reward system. The main endocannabinoids, anandamide, and 2-arachidonoylglycerol, are lipids which bind cannabinoid receptors. Oleoylethanolamide (OEA), a fatty-acid ethanolamide, binds peroxisome proliferator-activated receptors. The endocannabinoid system has been shown to be impaired in schizophrenia, and recently, our group has shown that schizophrenia patients with SUD have elevated peripheral levels of anandamide and OEA that do not normalize after 3-month treatment with quetiapine. Objective For comparative purposes, we aimed to measure endocannabinoids in non-psychosis substance abusers and non-abusing schizophrenia patients. Methods Using liquid chromatography and mass spectrometry, we measured plasma levels of anandamide and OEA in non-psychosis SUD patients, non-abusing schizophrenia patients, and healthy controls. In an open-label manner, all patients received 12-week treatment with quetiapine. Results Anandamide and OEA were reduced in substance abusers without schizophrenia, relative to healthy controls (p < 0.05). Both endocannabinoids were unchanged in non-abusing schizophrenia patients. After quetiapine, anandamide, and OEA levels remained significantly reduced the SUD group (p < 0.05). Discussion Taken together with results of our previous study performed in dual-diagnosis patients, our results suggest that peripheral anandamide and OEA levels are impaired in patients with SUD in opposite ways according to the presence or absence of schizophrenia. Endocannabinoid alterations did not change with treatment, suggesting that they are trait markers. Further studies are necessary to understand the role of endocannabinoids in substance abusers with and without schizophrenia and to examine therapeutic implications.

Evolution of Substance use, Neurological and Psychiatric Symptoms in Schizophrenia and Substance use Disorder Patients: A 12-Week, Pilot, Case-Control Trial with Quetiapine.

Neurological and psychiatric symptoms are consequences of substance abuse in schizophrenia and non-schizophrenia patients. The present case-control study examined changes in substance abuse/dependence, and neurological and psychiatric symptoms in substance abusers with [dual diagnosis (DD) group, n = 26] and without schizophrenia [substance use disorder (SUD) group, n = 24] and in non-abusing schizophrenia patients (SCZ group, n = 23) undergoing 12-week treatment with the atypical antipsychotic, quetiapine. Neurological and psychiatric symptoms were evaluated with the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Extrapyramidal Symptoms Rating Scale, and the Barnes Akathisia Rating Scale. At endpoint, DD and SCZ patients were receiving significantly higher doses of quetiapine (mean = 554 and 478 mg/day, respectively), relative to SUD patients (mean = 150 mg/day). We found that SUD patients showed greater improvement in weekly dollars spent on alcohol and drugs and SUD severity, compared to DD patients. At endpoint, there was no significant difference in dollars spent, but DD patients still had a higher mean SUD severity. Interestingly, DD patients had significantly higher parkinsonism and depression than SCZ patients at baseline and endpoint. On the other hand, we found that SUD patients had significantly more akathisia at baseline, improved more than SCZ patients, and this was related to cannabis abuse/dependence. Finally, SUD patients improved more in Positive and Negative Syndrome Scale positive scores than DD and SCZ patients. Taken together, our results provide evidence for increased vulnerability to the adverse effects of alcohol and drugs in schizophrenia patients. They also suggest that substance abuse/withdrawal may mimic some symptoms of schizophrenia. Future studies will need to determine the role quetiapine played in these improvements.

Relationships between Brain Structure and Metabolic Changes in Schizophrenia Patients Treated with Olanzapine: A Voxel-Based Morphometric Study.

Introduction. Second-generation antipsychotics treatment is associated with weight gain and metabolic disturbances. Although much research has been done on the topic, the precise mechanisms underlying such side effects are still not well understood. Method. We followed over 16 weeks a group of 17 schizophrenia patients who were treated with olanzapine and monitored biometric, clinical, and metabolic data, including ghrelin and leptin levels. All patients had a structural cerebral magnetic resonance imaging examination during the first week of their followup and at the end of the study. Results. We found positive and negative significant correlations between grey matter volumes of several brain regions and variations of body weight as well as of ghrelin and leptin levels. The right frontal operculum, bilateral precuneus, and bilateral hippocampal regions were found to be significantly associated with those changes. Conclusion. Our results suggest associations between brain structure and metabolic variations in schizophrenia patients taking olanzapine.

Extrapyramidal symptoms in substance abusers with and without schizophrenia and in nonabusing patients with schizophrenia.

Extrapyramidal symptoms (EPS) such as parkinsonism, dystonia, dyskinesia, and akathisia are conditions of impaired motor function, which are associated with chronic antipsychotic treatment in schizophrenia. In addition, EPS is often exacerbated by psychoactive substance (PAS) abuse, which is frequently observed in this population. Few studies, however, have investigated the contribution of PAS abuse on EPS in PAS-abusers without comorbid psychosis. This study compared the occurrence of EPS in outpatient schizophrenia patients with (DD group; n= 36) and without PAS abuse (SCZ group; n = 41) as well as in nonschizophrenia PAS abusers undergoing detoxification [substance use disorder (SUD) group; n = 38]. Psychiatric symptoms were measured using the Positive and Negative Syndrome Scale and the Calgary Depression Scale for schizophrenia. Extrapyramidal symptoms were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale. SUD diagnoses were complemented with urine drug screenings. We found that DD patients exhibited significantly more parkinsonism than SCZ patients. Our subanalyses revealed that cocaine and alcohol abuse/dependence was responsible for the increase in parkinsonism in DD patients. Additionally, we found that SUD individuals exhibited significantly more akathisia than SCZ patients. In these latter individuals, subanalyses revealed that alcohol and cannabis abuse/dependence was responsible for the increase in akathisia. Our results suggest that PAS abuse is a contributor to EPS in individuals with and without schizophrenia.

Pain perception in schizophrenia: no changes in diffuse noxious inhibitory controls (DNIC) but a lack of pain sensitization.

BACKGROUND: Pain is a dynamic phenomenon resulting from the activity of both excitatory (e.g. sensitization) and inhibitory endogenous modulation systems. Preliminary experimental studies have shown diminished pain sensitivity in schizophrenia patients. The objective of the study was to investigate the role of excitatory and inhibitory systems on pain perception in schizophrenia. METHODS: Participants were 23 patients with a schizophrenia-spectrum disorder (DSM-IV criteria) and 29 healthy volunteers, who did not differ in age, sex or ethnicity. Excitatory and inhibitory systems were elicited using a temporal summation test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory control (DNIC) by means of a cold-pressor test. RESULTS: Time was a significant predictor of pain scores in controls, but not in patients. That is, pain ratings increased during the tonic thermal stimulation among controls but not in schizophrenia patients. When correlation coefficients (between time and pain ratings) for patients and controls were compared, the correlation coefficient emerged as significantly weaker in the schizophrenia group (Z=12.04; p=0.0001), suggesting a lack of sensitization in schizophrenia. DNIC was similar in magnitude in both patients and controls. CONCLUSIONS: Diminished pain sensitivity in schizophrenia may be related to abnormal excitatory mechanisms, but not to DNIC. More studies are needed to better characterize the neurophysiological and neurochemical mechanisms involved in the lack of sensitization in schizophrenia.

Are cholinergic enhancers beneficial for memory in schizophrenia? An event-related potentials (ERPs) study of rivastigmine add-on therapy in a crossover trial.

Studies have reported beneficial effects of cholinergic enhancers, e.g., rivastigmine, on memory in schizophrenia but others have not. Possibly, these discrepancies are related to the lack of specificity of the tests used. This study investigated the effect of rivastigmine on memory in schizophrenia using event-related potentials (ERPs). Eighteen patients treated with atypical antipsychotic received rivastigmine adjuvant therapy in a randomized, crossover design. They were assessed at baseline (T1) and on two subsequent occasions (T2 and T3), where one half of the subjects were taken rivastigmine and the other half not. ERPs were recorded during a recognition memory task on each session. Behavioral and ERP data were analyzed using mixed ANOVA models first at T1 to detect potential group differences and for the trial (T1-T2) to determine the influence of rivastigmine, i.e., sessionxgroup interactions. The results showed no group difference at T1 except a trend for one group to be less efficient than the other on RT measures. When controlling for this difference the results on the trial data showed a trend for a benefit of rivastigmine on the RT memory effect. ERP analysis revealed that rivastigmine affects the amplitudes of two components elicited within 150-300 ms over posterior (reduced N2b) and frontal sites (enhanced P2a). It also enhances the magnitude of the memory (old/new) effect on two later components over posterior (N400) and frontal sites (F-N400). These results suggest that rivastigmine improves selective attention by enhancing interference inhibition processes (P2a) and lowering the reactivity to incoming stimulus (N2b). It also improves the integration of information with knowledge (N400) and with its context (F-N400). Generally, this study showed that the beneficial effect of rivastigmine on memory is not unitary but rather comes from its action at different time points within information processing cascade.

Neural correlates of sad feelings in schizophrenia with and without blunted affect.

OBJECTIVE: There have been reports that patients with schizophrenia have decreased activity in the prefrontal cortex during emotion processing. However, findings have been confounded by sample nonspecificity and explicit cognitive task interference with emotion processing. We aimed to further investigate this by examining the ventrolateral prefrontal cortex (VLPFC) activation in response to the passive viewing of sad film excerpts. METHODS: We presented film excerpts depicting sad and neutral social situations to 25 schizophrenia patients (14 with blunted affect [BA+] and 11 without blunted affect [BA-]) in an implicit perception task to evoke prefronto-limbic activity illustrated by blood oxygenation level-dependent functional magnetic resonance imaging. RESULTS: A random-effects analysis (2-sample t test) using statistical parametric mapping indicated that BA+ patients differed from BA- patients at a 0.05 level (P corrected for multiple comparisons). Consistent with our a priori hypothesis, BA- patients (relative to BA+ patients) showed significant activation in the right VLPFC. An exploratory analysis revealed the following loci of activation: caudate nucleus, VLPFC, middle prefrontal cortex, medial prefrontal cortex, anterior cingulate cortex, and anterior temporal pole in the BA- group; and hippocampus, cerebellum, anterior temporal pole, and midbrain in the BA+ group. CONCLUSIONS: We observed not only hypofrontality in the BA+ group but also dysfunctional circuitry distributed throughout the brain. The temporal and midbrain activation seen in the BA+ group may indicate that these brain regions were working harder to compensate for inactivation in other regions. These distributed dysfunctional circuits may form the neural basis of blunted affect through impairment of emotion processing in the brain that prevents it from processing input efficiently and producing output effectively, thereby leading to symptoms such as blunted affect.

Restoration of frontal activation during a treatment with quetiapine: an fMRI study of blunted affect in schizophrenia.

This study investigated changes in cerebral activation related to emotion processing in schizophrenia patients with blunted or flat affect (FA+) during treatment with quetiapine. Using functional magnetic resonance imaging (fMRI), brain activation in 12 FA+ schizophrenia patients during passive viewing of sad film excerpts was studied before and after a median of 5.5-months treatment with quetiapine. Random-effects 'paired sample t-test' analyses of brain activation before quetiapine (contrast=sad-neutral, before-after) revealed significant activation in the brainstem (pons, medulla). After quetiapine, the same contrast showed significant prefrontal activation (BA 9, 10 and 11). Activation of key prefrontal areas involved in emotion processing and significant symptoms improvement as measured by the subjective rating scale and PANSS suggests the potential effect of quetiapine in improving blunted affect related symptoms (i.e., passive withdrawal, emotional withdrawal, social avoidance) in schizophrenia.

Cerebral activity associated with auditory verbal hallucinations: a functional magnetic resonance imaging case study.

Among the many theories that have been advanced to explain the mechanism by which auditory verbal hallucinations (AVH) arise, 2 that have received a degree of empirical support are: the hypothesis that AVHs arise from misinterpreted inner speech and the proposal that they arise from aberrant activation of the primary auditory cortex. To test these hypotheses, we were fortunate to be able to study the interesting and rare case of a woman with schizophrenia who experienced continuous AVH which disappeared when she listened to loud external speech. Functional magnetic resonance imaging (fMRI) was used to measure the patient's brain activity in the temporal and inferior frontal regions during the AVHs and while the she was listening to external speech. The brain activity of a matched control subject was also recorded under the same experimental conditions. AVHs were associated with increased metabolic activity in the left primary auditory cortex and the right middle temporal gyrus. Our results suggest a possible interaction between these areas during AVHs and also that the hypotheses of defective internal monitoring and aberrant activation are not mutually exclusive. Potential limitations to the generalization of our results are discussed.