Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study

Conventional antidepressants have several important limitations, including a lack of direct effects on negative self-schema, which is at the core of Beck’s cognitive theory of depression. Based on previous studies showing a positive effect of ketamine on negative cognition, we compared reductions in negative self-schema between responders and non-responders to a single infusion of ketamine. In an open-label study, 26 participants with treatment-resistant depression received 0.5 mg/kg ketamine via infusion. Depression symptoms were assessed at baseline, 24 h, and 7 days after treatment with Montgomery-Åsberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI-II). Nine of the 26 participants fulfilled response criteria after 24 h. Of these, eight still fulfilled response criteria after 7 days. Response was defined as a reduction in MADRS total score of 50% or more. Responders improved significantly more than non-responders both 24 h and 7 days after ketamine treatment on the following BDI-II items: item 1 (“Sadness”), item 7 (“Self-Dislike”), and item 8 (“Self- Criticalness”). These results suggest an important therapeutic effect of ketamine on negative self-schema, which is a fundamental cognitive aspect of depression. This effect is unique and might be associated with ketamine’s profound effects on neuroplasticity. Small sample size and lack of a placebo control group are the major limitations of this study

Behavioral Response to Catecholamine Depletion in Individuals With Schizophrenia and Healthy Volunteers.

BACKGROUND AND HYPOTHESIS Dysfunction of the dopamine system is the leading neurobiological hypothesis of schizophrenia. In this study, we tested this hypothesis in the context of aberrance salience theory of delusions using catecholamine depletion. We hypothesized that acute dopamine depletion improves both positive symptoms and salience attribution in individuals with schizophrenia. STUDY DESIGN Catecholamine depletion was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 15 individuals with schizophrenia and 15 healthy volunteers. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were the Scale for the Assessment of Positive Symptoms and the Salience Attribution Test. STUDY RESULTS Catecholamine depletion transiently reduced specific psychotic symptoms in symptomatic individuals with schizophrenia, namely delusions and positive formal thought disorder (interaction treatment-by-timepoint, P = .013 and P = .010, respectively). We also found trends for catecholamine depletion to increase relevant bias and adaptive salience in participants with schizophrenia while decreasing them in healthy controls (interaction group-by-treatment, P = .060 and P = .089, respectively). Exploratory analyses revealed that in participants with schizophrenia, higher relevant bias at 3 hours after the end of AMPT treatment corresponded to lower delusional symptoms (Spearman's rho = -0.761, P = .001). CONCLUSIONS This study suggests that the relationship between dopamine hyperactivity and delusional symptoms in schizophrenia is mediated by impaired attribution of salience to reward-predicting stimuli

Child eating behavior predicts body mass index after 1 year: results from the Swiss Preschooler’s Health Study (SPLASHY)

Child obesity is a growing global issue. Preventing early development of overweight and obesity requires identifying reliable risk factors for high body mass index (BMI) in children. Child eating behavior might be an important and malleable risk factor that can be reliably assessed with the parent-report Child Eating Behavior Questionnaire (CEBQ). Using a hierarchical dataset (children nested within child care centers) from a representative cohort of Swiss preschool children, we tested whether eating behavior, assessed with a 7-factor solution of the CEBQ, and BMI at baseline predicted the outcome BMI after 1 year, controlling for socioeconomic status (n = 555; 47% female; mean age = 3.9 years, range: 2.2–6.6; mean BMI = 16 kg/m2, range: 11.2–23; mean age- and sex-corrected z-transformed BMI, zBMI = 0.4, range −4 to +4.7). The statistical model explained 65.2% of zBMI at follow-up. Baseline zBMI was a strong positive predictor, uniquely explaining 48.8% of outcome variance. A linear combination of all CEBQ scales, taken together, explained 10.7% of outcome variance. Due to their intercorrelations, uniquely explained variance by any individual scale was of negligible clinical relevance. Only food responsiveness was a significant predictor, when accounting for all other predictors and covariates in the model, and uniquely explained only 0.4% of outcome variance. Altogether, our results confirm, extend, and refine previous research on eating behavior and zBMI in preschool children, by adjusting for covariates, accounting for intercorrelations between predictors, partitioning explained outcome variance, and providing standardized beta estimates. Our findings show the importance of carefully examining the contribution of predictors in multiple regression models for clinically relevant outcomes

Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window

Abstract Background: Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic. Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats. Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders

Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window

Background: Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to nd out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic. Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats. Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1 mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical signi cance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders

Metabotropic Glutamate Receptor Subtype 5 in Males With Autism Spectrum Disorder: Preliminary Findings of a [11C]ABP688 Positron Emission Tomography Study

Background: Preclinical investigations suggesting a therapeutic potential for metabotropic glutamate receptor subtype 5 (mGluR5) antagonists in fragile X syndrome raised interest in mGluR5 in neurodevelopment disorders in general, including autism spectrum disorder (ASD) (Davenport et al, 2016; Gogliotti and Conn, 2016; Scharf et al, 2015). To investigate the role of mGluR5 in ASD in vivo we carried out a positron emission tomography (PET) study with the mGluR5-selective radiotracer [11C]ABP688 in subjects with ASD and healthy controls. Methods: Seventeen male subjects with ASD and 22 healthy male age-matched controls participated in this study. As our previous work showed that smoking profoundly and enduringly alters mGluR5 (Akkus et al, 2013), we matched both samples for smoking. As a result, the ASD sample included 11 non-smokers, 2 ex-smokers and four current smokers, and the control group 15 non-smokers, 2 exsmokers and five current smokers. We assessed psychopathology in both study groups with the Structured Clinical Interview for DSM-IV Axis I (SCID-I), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). In addition, we evaluated subjects with ASD using the Autism Diagnostic Observation Schedule (ADOS), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Obsessive Compulsive Inventory-Revised (OCI-R), Autism Quotient (AQ), and Empathy Quotient questionnaires (EQ). We acquired PET data with a bolus/infusion protocol, as previously reported (Burger et al, 2010). In brief, [11C]ABP688 was administered in a 50- mL volume with an infusion pump. Our previous work shows that 40 min after the start of radioligand infusion equilibrium between [11C]ABP688 in tissue and blood is achieved. To calculate the relative distribution volume (DVR), we normalized the average of PET images acquired at 45-60 min after scan onset to the radioactivity concentration in the cerebellum. We used PMOD (PNEUROTool) and R for data analysis. We compared mGluR5 DVR in both groups in 33 brain regions using two-tailed Welch’s t-tests, without correction for multiple comparisons. Results: Age did not differ significantly between subjects with ASD and controls when comparing the entire samples or their subgroups (all p-values>0.05, two-tailed). Overall, subjects with ASD scored higher in BAI and BDI (p<0.05, two-tailed). We found no significant differences in mGluR5 DVR in any of the brain regions when comparing the entire samples comprising smokers, ex-smokers, and non-smokers (all p-values > 0.05, two-tailed). As expected, in both samples, smokers displayed globally decreased mGluR5 DVR (p0.05, two-tailed). Exploratory correlation analyses involving BAI, BDI, AQ, EQ, and mGluR5 DVR in the straight gyrus, posterior superior temporal gyrus, and postcentral gyrus in nonsmokers with ASD yielded only one significant relationship: higher, i.e., more aberrant, mGluR5 DVR in the postcentral gyrus corresponded to lower, i.e., more aberrant, EQ score (Spearman’s rho = -0.64, p<0.05, two-tailed, uncorrected for multiple comparisons). Conclusions: To our knowledge, this is the first in vivo investigation of mGluR5 in persons with ASD. Our findings suggest increased mGluR5 DVR in the straight gyrus, the posterior superior temporal gyrus, and the postcentral gyrus in male non-smokers with ASD. Due to the small sample size and the exploratory nature of the statistical analyses, these results remain preliminary. Nevertheless, our findings provide a preliminary support for the involvement of mGluR5 in ASD, encourage the study of mGluR5 in larger samples, and suggest a therapeutic potential for agents targeting the mGluR5 in autism (Mehta et al, 2011; Silverman et al, 2010). Keywords: mGluR5 Receptors, Autism Spectrum Disorder, PET Imaging Disclosure: Nothing to Disclose

Neural response to catecholamine depletion in remitted bulimia nervosa: Relation to depression and relapse.

Bulimia nervosa has been associated with a dysregulated catecholamine system. Nevertheless, the influence of this dysregulation on bulimic symptoms, on neural activity, and on the course of the illness is not clear yet. An instructive paradigm for directly investigating the relationship between catecholaminergic functioning and bulimia nervosa has involved the behavioral and neural responses to experimental catecholamine depletion. The purpose of this study was to examine the neural substrate of catecholaminergic dysfunction in bulimia nervosa and its relationship to relapse. In a randomized, double-blind and crossover study design, catecholamine depletion was achieved by using the oral administration of alpha-methyl-paratyrosine (AMPT) over 24 h in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. In a follow-up telephone interview, bulimic relapse was assessed. Following AMPT, rBN participants revealed an increased vigor reduction and CBF decreases in the pallidum and posterior midcingulate cortex (pMCC) relative to HC participants showing no CBF changes in these regions. These results indicated that the pallidum and the pMCC are the functional neural correlates of the dysregulated catecholamine system in bulimia nervosa. Bulimic relapse was associated with increased depressive symptoms and CBF reduction in the hippocampus/parahippocampal gyrus following catecholamine depletion. AMPT-induced increased CBF in this region predicted staying in remission. These findings demonstrated the importance of depressive symptoms and the stress system in the course of bulimia nervosa

Predicting relapse in bulimia nervosa: Neural and behavioral response to catecholamine depletion

Background: Bulimia nervosa (BN) is a severe psychiatric disorder characterized by recurrent binge eating episodes followed by inappropriate compensatory behavior such as purging or excessive exercise. Frank proposed in his model of eating disorders that BN is associated with a desensitized dopamine system (Frank, 2016). However, direct investigations on the causal effect of a hypofunction of the dopamine system on neural activity, bulimic and depressive symptoms, and on the course of the illness are still missing. Catecholamine depletion induced by alpha-methyl-paratyrosine (AMPT) is an instructive paradigm to investigate directly the relationship between dopaminergic neurotransmission and the symptoms and course of BN. In our previous behavioral study, experimental catecholamine depletion provoked mild eating disorder symptoms in fully remitted BN (Grob et al, 2015). The purpose of this study was to examine the effect of catecholamine depletion on neural activity in BN. Furthermore, we were interested in the relationship between this effect and the risk for relapse. Methods: In a randomized, double-blind, crossover design, catecholamine depletion was achieved using the oral administration of AMPT over 24 hours in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. AMPT-induced mood and eating disorder symptoms were examined using the Montgomery-Åsberg Depression Scale (MADRS) (Schmidtke et al, 1988), the Eating Disorder Examination-Questionnaire (EDE-Q) (Hilbert and Tuschen-Caffier, 2006), and the vigor subscale of the Profile of Mood States (POMS) (McNair et al, 1981). Bulimic relapse was assessed in a follow-up telephone interview (latency varied between 18 and 42 months) after study participation. Results: RBN participants revealed no increases of eating disorder symptoms following AMPT administration. However, AMPT reduced POMS vigor in both groups, and this effect was stronger in rBN participants. Furthermore, in rBN participants, AMPT decreased CBF in the pallidum and posterior midcingulate cortex (pMCC), whereas in HC participants, we did not find AMPT-induced alterations in CBF in these brain regions. AMPT-induced depressive symptoms and reductions in CBF in the hippocampus/ parahippocampal gyrus predicted relapse in rBN participants. In contrast, AMPT-induced CBF increase in the hippocampus/ parahippocampal gyrus predicted remission. Conclusions: We demonstrated that AMPT decreased CBF in the pallidum and pMCC in rBN participants. In the context of the Frank model (Frank, 2016), these regions can be considered as neural correlates of the desensitized dopamine system in BN. In contrast to our previous study (Grob et al, 2015), we did not observe an AMPT-induced increase of eating disorder symptoms. However, our earlier investigation was carried out in a controlled environment, without food cues and with regular, standardized meals (Grob et al, 2015). The uncontrolled environment in which this study was conducted might have overridden the effect of AMPT on eating disorder symptoms. In rBN participants, AMPT reduced vigor more strongly than in healthy individuals. This vigor reduction might trigger eating disorder symptoms to counteract dopamine deficiency and the related depression-like mental state. AMPT-induced depressive symptoms and CBF reduction in the hippocampus predicted bulimic relapse. Binge eating was reported to have an anti-depressive and dopamine elevating effect (Jahng et al, 2012). Therefore, dopamine deficiency and a dysfunctional hippocampus activity might trigger inappropriate behavior, such as binge eating to reduce negative emotions and anhedonia. Our findings expand Frank’s model of eating disorders (Frank, 2016), and emphasize the importance of depressive symptoms and the stress system in the course of bulimia nervosa. Keywords: Bulimia Nervosa, Catecholamine Depletion, Relapse, Cerebral Blood Flow, Neuroimaging. Disclosure: Nothing to disclose