LETTERS TO THE EDITORS
Anandamide Is Involved in Appetite-Related Amygdala Hyperactivations in Schizophrenia Patients Treated With Olanzapine A Functional Magnetic Resonance Imaging Study To the Editors: n schizophrenia, the prevalence of metabolic syndrome, obesity, and type 2 diabetes is 2 to 3 times more elevated than it is in the general population.1 The reasons for this elevated prevalence of metabolic disorders in schizophrenia include poor dietary habits, physical inactivity, genetic factors, and antipsychotics.1 Endogenous cannabinoids (ECBs) have been overlooked as potential mediators of the comorbidity between schizophrenia and metabolic disorders. The main ECBs, anandamide (AEA) and 2-arachydonoylglycerol, bind 2 main cannabinoid receptors: CB1 and CB2.2 CB1 receptors are found in the brain in the cortex, limbic system, basal ganglia, brain stem, and cerebellum, and are also found in the peripheral metabolic system.2 CB2 receptors are mostly located in the peripheral immune cells.2 Palmithylethanolamide and oleylethanolamide (OEA) are 2 noncannabinoid bioactive fattyacid ethanolamides, which do not bind cannabinoid receptors, but bind with high-affinity peroxisome proliferatorYactivated receptor > (PPAR->).3 Importantly, mounting evidence suggests that the ECBs and fattyacid ethanolamides play a crucial role in the pathophysiology of both schizophrenia and metabolic disorders.3,4 Preliminary evidence suggests that the ECB system is impaired in schizophrenia. Recently, a positron emission tomography study has shown an elevation of CB1 receptor binding in schizophrenia patients across many brain regions.5 Moreover, cerebrospinal AEA levels have been shown to be increased in schizophrenia patients compared to healthy controls.4 Peripheral AEA and OEA levels have also been shown to be altered in schizophrenia, albeit inconsistently.4Y6 Endogenous cannabinoids contribute to weight gain via central and peripheral mechanisms. In animals, ECBs have been shown to be involved in the motivational aspects of food intake at the level of the hypothalamus, the nucleus accumbens,
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and possibly, the limbic forebrain.3,7 Peripheral mechanisms of ECB-induced weight gain have also been highlighted, including increased hepatic triglyceride biosynthesis, impaired pancreatic insulin sensitivity, and decreased glucose uptake in skeletal muscles.3 As for OEA, it has been shown to inhibit food intake by binding PPAR->.3 In humans, controlled trials of the CB1 inverse agonist rimonabant for the treatment of obesity have shown considerable reductions in body weight and the prevalence of the metabolic syndrome.8 Recently, our group has studied the neural correlates of appetite alterations in schizophrenia patients scanned before and after 16-week treatment with olanzapine, using functional magnetic resonance imaging (fMRI).9 One of the antipsychotics producing the most weight gain, olanzapine was chosen because it simulates appetite in schizophrenia.9 We found that olanzapine increased loci of activations in limbic regions in schizophrenia. The objective of the current analysis was to explore the associations between plasma AEA and OEA levels and the central mechanisms involved in appetite dysregulation in schizophrenia, during olanzapine treatment. Twenty-four schizophrenia patients (5 women) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were recruited (age, 30.0 T 9.4 years). None of them had a substance use disorder. Patients switched from other antipsychotics (except 3 who were drugfree) to olanzapine. Of these patients, 15 participated in both prescanning and postscanning sessions. All subjects signed an informed detailed consent form approved by the local ethics committee.9 Participants underwent whole-brain fMRI at high field (3 T) while they were in a satiated state (3 hours after the last meal), before and after treatment. In each fMRI session, subjects participated in a passive picture viewing task during Appetizing and Neutral conditions. Psychiatric symptoms, appetite, eating behavior, and body weight were measured before and after treatment, as well as blood levels of fasting glucose, insulin, and lipids.9 We collected blood samples (heparinized tubes), after an overnight fast, and measured AEA and OEA levels using mass spectrometry.10 We used the average blood oxygenation levelYdependent (BOLD) signal in the limbic brain regions which became more active to appetizing than neutral stimuli after olanzapine treatment. These
regions were located in the left amygdala and right insula (2 activation loci).9 In these regions, the effect of treatment was a ‘‘hyperactivity’’ in the BOLD signal in patients in response to appetizing images, significantly above levels seen in healthy controls.9 We evaluated the relationship between ECB levels and the BOLD signal change in these regions. Stepwise multiple regression analysis was used to assess the contribution of ECB levels on the variance observed in brain activity above and beyond the contribution from metabolic markers, since we previously found that changes in appetite-related amygdala activity were associated with changes in glucose and insulin levels over time.9 During treatment, patients gained weight, had fewer positive symptoms, and had increases in triglycerides and insulin levels.9 In contrast, plasma AEA and OEA levels did not vary significantly over time (AEAVbefore: 1.62 T 0.68; after: 1.44 T 0.52; Z = j1.42, P = 0.15/ OEAVbefore: 3.16 T 3.45; after: 1.98 T 1.47; Z = j1.70, P = 0.08). The moderation analysis indicated that the relationship between the AEA levels and the brain activity in amygdala in response to foodrelated as compared to neutral visual stimuli was significantly affected by the olanzapine treatment (F1,26 = 8.76, P G 0.01). Specifically, the interaction between AEA levels and treatment explained 21.9% more of variance in amygdala activation than each of these 2 variables alone. Furthermore, after controlling for the influence of glucose and insulin, the addition of AEA levels into the hierarchical regression model in the last step explained a significant proportion of the variability in amygdala activity above and beyond the variability already explained by the metabolites (24.3% when accounting for glucose; 27.9% for insulin; 40%, without metabolites; Ps G 0.05). We found no relationship between plasma OEA levels and the limbic brain regions found to be activated in schizophrenia as a result of olanzapine treatment. In a small sample of schizophrenia patients treated with olanzapine, we found that plasma AEA levels were positively associated with amygdala hyper-activations in response to appetizing food stimuli. This finding is consistent with the growing preclinical literature showing that ECBs, including AEA, are involved in the motivational aspect of food intake.3 In rodents, it has been shown that the amygdala is
Journal of Clinical Psychopharmacology
&
Volume 35, Number 1, February 2015
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology
&
Volume 35, Number 1, February 2015
critically involved in food motivation, and that CB1 receptors are found in moderateto-high concentrations in this region, raising the possibility that ECBs increase food motivation via the limbic forebrain.7 Plasma AEA and OEA levels did not change during treatment, a result that may be explained by the lack of affinity of olanzapine for CB1 receptors11 (note: its affinity for PPAR-> is unknown). Previously, De Marchi et al6 observed a decrease in blood AEA levels during olanzapine treatment in schizophrenia. However, patients in that study were in an acute phase at baseline, whereas our patients were clinically stable. Our results suggest that AEA may be a peripheral biomarker of the sensitized amygdala responses to food cues induced by olanzapine in schizophrenia. Such results echo the association that has been reported between the CNR1 gene and antipsychotic-related weight gain in schizophrenia.12 As for the lack of relationship between plasma OEA levels and brain activations, it may be due to the fact that OEA influences food intake mainly via peripheral mechanisms.3 Because our results are based on regression analyses, no causal relationship can be inferred from them. Also, the finding of a relationship between peripheral AEA levels and amygdala hyperactivations does not imply that AEA directly recruited the amygdala. However, the relationship between AEA and hyperactivity in response to appetizing stimuli after treatment was found only in the amygdala, despite the fact that similar patterns of changes in BOLD signal were observed in other regions. Moreover, the AEA-amygdala relationship remained significant even when considering the influence of metabolic markers. Finally, the study lacked a control group, so we cannot determine if the AEA-amygdala association reported here is schizophrenia-specific or not. To our knowledge, this is the first fMRI study to show a relationship between plasma AEA levels and the impaired limbic processing of food cues resulting from olanzapine treatment in schizophrenia. Our exploratory results will need to be replicated in larger samples, as they may have implications for the understanding of antipsychoticrelated weight gain in schizophrenia and for its treatment. AUTHOR DISCLOSURE INFORMATION This study was conducted as part of ES’s investigator-initiated trials (No: clinical trial: NCT00290121) funded by Eli Lilly Canada. Endocannabinoid assessments were funded by a grant from the Canadian Institutes of Health Research to
SP (CSU105837). SP is holder of the Eli Lilly Chair of Schizophrenia from the University of Montreal. Dr Potvin reports grants from FRQS, CIHR, FRQNT, FRQSC, Pfizer, Eli Lilly, Instituts Servier, and BMS, outside the submitted work. Dr Lungu has nothing to disclose. Dr Stip reports grants from Eli Lilly, during the conduct of the study; grants from Hoffman-Laroche, FRQS, CIHR, and Janssen-Ortho, outside the submitted work. Ste´phane Potvin, PhD Department of Psychiatry Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche du Centre Hospitalier de l’Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche de l’Institut Universitaire en Sante´ Mentale de Montre´al Montre´al, Que´bec Canada [email protected]
Ovidiu V. Lungu, PhD Department of Psychiatry Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche de l’Institut Universitaire de Ge´riatrie de Montre´al Montre´al, Que´bec Canada Center for Research in Aging Donald Berman Maimonides Geriatric Center Montreal, Que´bec Canada
Emmanuel Stip, MD, MSc Department of Psychiatry Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche de l’Institut Universitaire en Sante´ Mentale de Montre´al Montre´al, Que´bec Canada
Letters to the Editors 5. Ceccarini J, De Hert M, Van Winkel R, et al. Increased striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia. Neuroimage. 2013;79:304Y312. 6. De Marchi N, De Petrocellis L, Orlando P, et al. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003;2:5. 7. Kirkham TC, Williams CM, Fezza F, et al. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550Y557. 8. Christopoulou FD, Kiortsis DN. An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther. 2011;36:10Y18. 9. Stip E, Lungu OV, Anselmo K, et al. Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment. Transl Psychiatry. 2012;2:e128. 10. Desfosses J, Stip E, Bentaleb LA, et al. Plasma endocannabinoid alterations in individuals with substance use disorder are dependent on the ‘‘mirror effect’’ of schizophrenia. Front Psychiatry. 2012;3:85. 11. Theisen FM, Haberhausen M, Firnges MA, et al. No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J. 2007;7:275Y281. 12. Tiwari AK, Zai CC, Likhodi O, et al. A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacology. 2010;35:1315Y1324.
The Effects of Sodium Nitroprusside Treatment on Cognitive Deficits in Schizophrenia A Pilot Study
REFERENCES 1. Llorente M, Urrutia V. Diabetes, psychiatric disorders, and the metabolic effects of antipsychotic medications. Clin Diabetes. 2006;24:18Y24. 2. Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 2005;168:1Y51. 3. Maccarrone M, Gasperi V, Catani MV, et al. The endocannabinoid system and its relevance for nutrition. Annu Rev Nutr. 2010;30:423Y440. 4. Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology. 2004;29: 2108Y2114.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
To the Editors: y modulating the ‘‘glutamate-NO (nitric oxide)-cGMP’’ pathway,’’ a new paradigm for the treatment of schizophrenia seems to arise. Indeed, our group has recently published a double-blind placebo (PLB) controlled trial showing that an infusion of sodium nitroprusside (SNP), a nitric oxide donor, improved positive, negative, anxiety, and depressive symptoms of schizophrenic patients in a matter of hours.1 During this study, it seemed of interest to test the idea that SNP might also be effective in treating cognitive symptoms found in schizophrenia. For this purpose, it was performed, in
B
www.psychopharmacology.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
83
Anandamide Is Involved in Appetite-Related Amygdala Hyperactivations in Schizophrenia Patients Treated With Olanzapine A Functional Magnetic Resonance Imaging Study To the Editors: n schizophrenia, the prevalence of metabolic syndrome, obesity, and type 2 diabetes is 2 to 3 times more elevated than it is in the general population.1 The reasons for this elevated prevalence of metabolic disorders in schizophrenia include poor dietary habits, physical inactivity, genetic factors, and antipsychotics.1 Endogenous cannabinoids (ECBs) have been overlooked as potential mediators of the comorbidity between schizophrenia and metabolic disorders. The main ECBs, anandamide (AEA) and 2-arachydonoylglycerol, bind 2 main cannabinoid receptors: CB1 and CB2.2 CB1 receptors are found in the brain in the cortex, limbic system, basal ganglia, brain stem, and cerebellum, and are also found in the peripheral metabolic system.2 CB2 receptors are mostly located in the peripheral immune cells.2 Palmithylethanolamide and oleylethanolamide (OEA) are 2 noncannabinoid bioactive fattyacid ethanolamides, which do not bind cannabinoid receptors, but bind with high-affinity peroxisome proliferatorYactivated receptor > (PPAR->).3 Importantly, mounting evidence suggests that the ECBs and fattyacid ethanolamides play a crucial role in the pathophysiology of both schizophrenia and metabolic disorders.3,4 Preliminary evidence suggests that the ECB system is impaired in schizophrenia. Recently, a positron emission tomography study has shown an elevation of CB1 receptor binding in schizophrenia patients across many brain regions.5 Moreover, cerebrospinal AEA levels have been shown to be increased in schizophrenia patients compared to healthy controls.4 Peripheral AEA and OEA levels have also been shown to be altered in schizophrenia, albeit inconsistently.4Y6 Endogenous cannabinoids contribute to weight gain via central and peripheral mechanisms. In animals, ECBs have been shown to be involved in the motivational aspects of food intake at the level of the hypothalamus, the nucleus accumbens,
I
82
www.psychopharmacology.com
and possibly, the limbic forebrain.3,7 Peripheral mechanisms of ECB-induced weight gain have also been highlighted, including increased hepatic triglyceride biosynthesis, impaired pancreatic insulin sensitivity, and decreased glucose uptake in skeletal muscles.3 As for OEA, it has been shown to inhibit food intake by binding PPAR->.3 In humans, controlled trials of the CB1 inverse agonist rimonabant for the treatment of obesity have shown considerable reductions in body weight and the prevalence of the metabolic syndrome.8 Recently, our group has studied the neural correlates of appetite alterations in schizophrenia patients scanned before and after 16-week treatment with olanzapine, using functional magnetic resonance imaging (fMRI).9 One of the antipsychotics producing the most weight gain, olanzapine was chosen because it simulates appetite in schizophrenia.9 We found that olanzapine increased loci of activations in limbic regions in schizophrenia. The objective of the current analysis was to explore the associations between plasma AEA and OEA levels and the central mechanisms involved in appetite dysregulation in schizophrenia, during olanzapine treatment. Twenty-four schizophrenia patients (5 women) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were recruited (age, 30.0 T 9.4 years). None of them had a substance use disorder. Patients switched from other antipsychotics (except 3 who were drugfree) to olanzapine. Of these patients, 15 participated in both prescanning and postscanning sessions. All subjects signed an informed detailed consent form approved by the local ethics committee.9 Participants underwent whole-brain fMRI at high field (3 T) while they were in a satiated state (3 hours after the last meal), before and after treatment. In each fMRI session, subjects participated in a passive picture viewing task during Appetizing and Neutral conditions. Psychiatric symptoms, appetite, eating behavior, and body weight were measured before and after treatment, as well as blood levels of fasting glucose, insulin, and lipids.9 We collected blood samples (heparinized tubes), after an overnight fast, and measured AEA and OEA levels using mass spectrometry.10 We used the average blood oxygenation levelYdependent (BOLD) signal in the limbic brain regions which became more active to appetizing than neutral stimuli after olanzapine treatment. These
regions were located in the left amygdala and right insula (2 activation loci).9 In these regions, the effect of treatment was a ‘‘hyperactivity’’ in the BOLD signal in patients in response to appetizing images, significantly above levels seen in healthy controls.9 We evaluated the relationship between ECB levels and the BOLD signal change in these regions. Stepwise multiple regression analysis was used to assess the contribution of ECB levels on the variance observed in brain activity above and beyond the contribution from metabolic markers, since we previously found that changes in appetite-related amygdala activity were associated with changes in glucose and insulin levels over time.9 During treatment, patients gained weight, had fewer positive symptoms, and had increases in triglycerides and insulin levels.9 In contrast, plasma AEA and OEA levels did not vary significantly over time (AEAVbefore: 1.62 T 0.68; after: 1.44 T 0.52; Z = j1.42, P = 0.15/ OEAVbefore: 3.16 T 3.45; after: 1.98 T 1.47; Z = j1.70, P = 0.08). The moderation analysis indicated that the relationship between the AEA levels and the brain activity in amygdala in response to foodrelated as compared to neutral visual stimuli was significantly affected by the olanzapine treatment (F1,26 = 8.76, P G 0.01). Specifically, the interaction between AEA levels and treatment explained 21.9% more of variance in amygdala activation than each of these 2 variables alone. Furthermore, after controlling for the influence of glucose and insulin, the addition of AEA levels into the hierarchical regression model in the last step explained a significant proportion of the variability in amygdala activity above and beyond the variability already explained by the metabolites (24.3% when accounting for glucose; 27.9% for insulin; 40%, without metabolites; Ps G 0.05). We found no relationship between plasma OEA levels and the limbic brain regions found to be activated in schizophrenia as a result of olanzapine treatment. In a small sample of schizophrenia patients treated with olanzapine, we found that plasma AEA levels were positively associated with amygdala hyper-activations in response to appetizing food stimuli. This finding is consistent with the growing preclinical literature showing that ECBs, including AEA, are involved in the motivational aspect of food intake.3 In rodents, it has been shown that the amygdala is
Journal of Clinical Psychopharmacology
&
Volume 35, Number 1, February 2015
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology
&
Volume 35, Number 1, February 2015
critically involved in food motivation, and that CB1 receptors are found in moderateto-high concentrations in this region, raising the possibility that ECBs increase food motivation via the limbic forebrain.7 Plasma AEA and OEA levels did not change during treatment, a result that may be explained by the lack of affinity of olanzapine for CB1 receptors11 (note: its affinity for PPAR-> is unknown). Previously, De Marchi et al6 observed a decrease in blood AEA levels during olanzapine treatment in schizophrenia. However, patients in that study were in an acute phase at baseline, whereas our patients were clinically stable. Our results suggest that AEA may be a peripheral biomarker of the sensitized amygdala responses to food cues induced by olanzapine in schizophrenia. Such results echo the association that has been reported between the CNR1 gene and antipsychotic-related weight gain in schizophrenia.12 As for the lack of relationship between plasma OEA levels and brain activations, it may be due to the fact that OEA influences food intake mainly via peripheral mechanisms.3 Because our results are based on regression analyses, no causal relationship can be inferred from them. Also, the finding of a relationship between peripheral AEA levels and amygdala hyperactivations does not imply that AEA directly recruited the amygdala. However, the relationship between AEA and hyperactivity in response to appetizing stimuli after treatment was found only in the amygdala, despite the fact that similar patterns of changes in BOLD signal were observed in other regions. Moreover, the AEA-amygdala relationship remained significant even when considering the influence of metabolic markers. Finally, the study lacked a control group, so we cannot determine if the AEA-amygdala association reported here is schizophrenia-specific or not. To our knowledge, this is the first fMRI study to show a relationship between plasma AEA levels and the impaired limbic processing of food cues resulting from olanzapine treatment in schizophrenia. Our exploratory results will need to be replicated in larger samples, as they may have implications for the understanding of antipsychoticrelated weight gain in schizophrenia and for its treatment. AUTHOR DISCLOSURE INFORMATION This study was conducted as part of ES’s investigator-initiated trials (No: clinical trial: NCT00290121) funded by Eli Lilly Canada. Endocannabinoid assessments were funded by a grant from the Canadian Institutes of Health Research to
SP (CSU105837). SP is holder of the Eli Lilly Chair of Schizophrenia from the University of Montreal. Dr Potvin reports grants from FRQS, CIHR, FRQNT, FRQSC, Pfizer, Eli Lilly, Instituts Servier, and BMS, outside the submitted work. Dr Lungu has nothing to disclose. Dr Stip reports grants from Eli Lilly, during the conduct of the study; grants from Hoffman-Laroche, FRQS, CIHR, and Janssen-Ortho, outside the submitted work. Ste´phane Potvin, PhD Department of Psychiatry Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche du Centre Hospitalier de l’Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche de l’Institut Universitaire en Sante´ Mentale de Montre´al Montre´al, Que´bec Canada [email protected]
Ovidiu V. Lungu, PhD Department of Psychiatry Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche de l’Institut Universitaire de Ge´riatrie de Montre´al Montre´al, Que´bec Canada Center for Research in Aging Donald Berman Maimonides Geriatric Center Montreal, Que´bec Canada
Emmanuel Stip, MD, MSc Department of Psychiatry Universite´ de Montre´al Montre´al, Que´bec Canada Centre de Recherche de l’Institut Universitaire en Sante´ Mentale de Montre´al Montre´al, Que´bec Canada
Letters to the Editors 5. Ceccarini J, De Hert M, Van Winkel R, et al. Increased striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia. Neuroimage. 2013;79:304Y312. 6. De Marchi N, De Petrocellis L, Orlando P, et al. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003;2:5. 7. Kirkham TC, Williams CM, Fezza F, et al. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550Y557. 8. Christopoulou FD, Kiortsis DN. An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther. 2011;36:10Y18. 9. Stip E, Lungu OV, Anselmo K, et al. Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment. Transl Psychiatry. 2012;2:e128. 10. Desfosses J, Stip E, Bentaleb LA, et al. Plasma endocannabinoid alterations in individuals with substance use disorder are dependent on the ‘‘mirror effect’’ of schizophrenia. Front Psychiatry. 2012;3:85. 11. Theisen FM, Haberhausen M, Firnges MA, et al. No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J. 2007;7:275Y281. 12. Tiwari AK, Zai CC, Likhodi O, et al. A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacology. 2010;35:1315Y1324.
The Effects of Sodium Nitroprusside Treatment on Cognitive Deficits in Schizophrenia A Pilot Study
REFERENCES 1. Llorente M, Urrutia V. Diabetes, psychiatric disorders, and the metabolic effects of antipsychotic medications. Clin Diabetes. 2006;24:18Y24. 2. Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 2005;168:1Y51. 3. Maccarrone M, Gasperi V, Catani MV, et al. The endocannabinoid system and its relevance for nutrition. Annu Rev Nutr. 2010;30:423Y440. 4. Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology. 2004;29: 2108Y2114.
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
To the Editors: y modulating the ‘‘glutamate-NO (nitric oxide)-cGMP’’ pathway,’’ a new paradigm for the treatment of schizophrenia seems to arise. Indeed, our group has recently published a double-blind placebo (PLB) controlled trial showing that an infusion of sodium nitroprusside (SNP), a nitric oxide donor, improved positive, negative, anxiety, and depressive symptoms of schizophrenic patients in a matter of hours.1 During this study, it seemed of interest to test the idea that SNP might also be effective in treating cognitive symptoms found in schizophrenia. For this purpose, it was performed, in
B
www.psychopharmacology.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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