scholarly journals Clinical Efficacy and Target Engagement of Glutamatergic Drugs: Placebo-Controlled RCTs of Pomaglumetad and TS-134 for Reversal of Ketamine-Induced Psychotic Symptoms and PharmacoBOLD in Healthy Volunteers

2020 ◽  
Author(s):  
Joshua T. Kantrowitz ◽  
Jack Grinband ◽  
Donald C. Goff ◽  
Adrienne C. Lahti ◽  
Stephen R. Marder ◽  
...  
Keyword(s):  
Effect Size ◽  
Metabotropic Glutamate Receptor ◽  
Rating Scale ◽  
Clinical Symptoms ◽  
Anterior Cingulate ◽  
Psychotic Symptoms ◽  
High Dose ◽  
Size Estimation ◽  
Target Engagement ◽  
Dorsal Anterior Cingulate Cortex

AbstractWe tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs – pomaglumetad (POMA) and TS-134 – including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials – in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology.The POMA study was a double-blind, NIMH-sponsored, 10-day study of 80 or 320 mg/d POMA or placebo (1:1:1 ratio), designed to detect d>0.8 sd between-group effect-size differences. The TS-134 study was a single-blind, industry-sponsored, 6-day study of 20 or 60 mg/d TS-134 or placebo (5:5:2 ratio), designed to permit effect-size estimation for future studies. Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and Brief Psychiatric Rating Scale (BPRS).95 healthy controls were randomized to POMA and 63 to TS-134. High-dose POMA had significant within and between-group reduction in ketamine-induced BPRS total symptoms (p<0.01, d=-0.41; p=0.04, d=-0.44, respectively) but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 had significant/trend level, moderate to large within and between group effects on BPRS positive symptoms (p=0.02, d=-0.36; p=0.008, d=-0.82, respectively) and dACC pharmacoBOLD (p=0.004, d=-0.56; p=0.079, d=-0.50, respectively) using pooled across-study placebo data.High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed. TS-134 20 mg showed evidence of symptom reduction and target engagement, indicating a curvilinear dose-response curve. These results warrant further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

scholarly journals Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

2020 ◽  
Vol 45 (11) ◽  
pp. 1842-1850 ◽  
Author(s):  
Joshua T. Kantrowitz ◽  
Jack Grinband ◽  
Donald C. Goff ◽  
Adrienne C. Lahti ◽  
Stephen R. Marder ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Low Dose ◽  
Metabotropic Glutamate Receptor ◽  
Rating Scale ◽  
Controlled Trial ◽  
Anterior Cingulate ◽  
Psychotic Symptoms ◽  
High Dose ◽  
Target Engagement ◽  
Proof Of Mechanism

Abstract Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

scholarly journals Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

2019 ◽  
Author(s):  
Eleanor J. Cole ◽  
Katy H. Stimpson ◽  
Brandon S. Bentzley ◽  
Merve Gulser ◽  
Kirsten Cherian ◽  
...  
Keyword(s):  
Side Effects ◽  
Rating Scale ◽  
Neuropsychological Testing ◽  
Anterior Cingulate ◽  
High Dose ◽  
Delayed Response ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resting Motor Threshold ◽  
Resistant Depression

AbstractBackgroundCurrent treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment that is FDA-approved for treatment-resistant depression (TRD). Recent methodological advancements suggest iTBS could be improved through 1) treating with multiple sessions per day at optimally-spaced intervals, 2) applying a higher overall pulse-dose of stimulation and 3) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. We examined the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose, resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for TRD termed ‘Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)’.MethodsTwenty-one participants with TRD received open-label SAINT. FcMRI was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.ResultsNineteen of 21 participants (90.48%) met criteria for remission (≤10 on the Montgomery-Åsberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events.DiscussionOur accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatment-resistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study.Trial registrationClinicalTrials.gov NCT03240692

scholarly journals Deactivation of the dorsal anterior cingulate cortex indicated low postoperative sports levels in presurgical patients with chronic ankle instability

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiao’ao Xue ◽  
Shengkun Li ◽  
Hongyun Li ◽  
Qianru Li ◽  
Yinghui Hua
Keyword(s):  
Anterior Cingulate Cortex ◽  
Clinical Outcomes ◽  
Rating Scale ◽  
Ankle Instability ◽  
Cingulate Cortex ◽  
Chronic Ankle Instability ◽  
Anterior Cingulate ◽  
Healthy Controls ◽  
Dorsal Anterior Cingulate Cortex ◽  
Appraisal Processes

Abstract Background Injury-related fear contributed to disability in chronic ankle instability (CAI), while there still lacked exploration on the appraisal processes of the injury-related stimuli. This study aimed to compare the neural activities of the appraisal processes of sprain-related stimuli between presurgical chronic ankle instability patients and healthy controls through functional magnetic resonance imaging (fMRI) and evaluate its relationships with the clinical outcomes of orthopedic surgeries. Methods Eighteen presurgical CAI patients and fourteen healthy controls were recruited and underwent an fMRI session with visual stimulation of movies that showing typical ankle sprains accidents or control videos and the corresponding fear ratings. The clinical outcomes were collected at baseline and a minimum of 2 years after surgery; these included the American Orthopaedic Foot and Ankle Society (AOFAS) scores, the Numeric Rating Scale (NRS) scores, and the Tegner Activity Rating Scale scores. The two-sample t-test would be applied to identify which brain regions were influenced by CAI, and the correlation analysis would be applied to measure the relationship between the activation and clinical outcomes. Results Dorsal anterior cingulate cortex (dACC) was deactivated in CAI patients when compared with healthy controls, and the dACC deactivation strength revealed a moderate correlation with the values of fear ratings for all participants. The deactivation strength was negatively correlated with AOFAS at baseline, with Tegner at follow-up and its improvement. Conclusions Presurgical CAI patients presented deactivated dACC as a different neural activity of appraisal processes of sprain-related stimuli when compared with healthy controls, which was associated with lower postoperative sports levels. More comprehensive patients care including psychological interventions were needed in the clinical management of chronic ankle instability.

Effects of nicotine abstinence on clinical symptoms. Study at 3 and 6-months follow-up of outpatients with schizophrenia

2016 ◽  
Vol 33 (S1) ◽  
pp. s261-s262
Author(s):  
P.A. Sáiz Martinez ◽  
S. Al-Halabí ◽  
S. Fernández-Artamendi ◽  
L. García-Álvarez ◽  
E. Díaz-Mesa ◽  
...  
Keyword(s):  
Heart Rate ◽  
Tobacco Use ◽  
Rating Scale ◽  
Clinical Symptoms ◽  
Psychotic Symptoms ◽  
Control Group ◽  
Open Label ◽  
Anthropometric Measures ◽  
Nicotine Abstinence

IntroductionTobacco use has been associated with more excitement and agitation symptoms, greater severity of global psychopathology as measured by the Clinical General Impression (CGI) Scale, and psychotic symptoms in patients with schizophrenia.AimTo assess the effects of nicotine abstinence versus nicotine maintenance on the clinical symptoms of a sample of outpatients smokers diagnosed with schizophrenia.MethodsSample: 81 outpatients with schizophrenia [72.8% males; mean age (SD) = 43.35 (8.82)] currently smoking tobacco [no. of cigarettes (SD) = 27.96 (12.29)]. Desing: non-randomized, open-label, 6-month follow-up and multi-center study conducted at 3 sites in Spain (Oviedo, Santiago de Compostela and Orense). Instruments: Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression for Schizophrenia (CGI-SCH), Hamilton Depression Rating Scale (HDRS). Antropometric measures: Body mass index (BMI) and waist circumference. Vital sings: heart rate. Procedure: Patients were assigned to 2 conditions:– control group = patients continuing their tobacco use;– experimental group = patients participated in vareniclina or nicotine patches treatment for smoking cessation.Patients were evaluated at baseline (all patients smoking) and after 3 and 6 months.ResultsNo significant differences (P>.05) were found between groups at baseline evaluation. Likewise, there were no significant differences between smokers and non-smokers after treatment (3 and 6 months follow-up) in their clinical symptomatology (according to PANSS, HDRS and CGI-SCH), anthropometric measures and heart rate.ConclusionsNo significant differences were found in the clinical symptoms after a period of nicotine abstinence. Therefore, clinicians should motivate and help their patients to quit smoking (CIBERSAM - FIS PI11/01891).Disclosure of interestThe authors have not supplied their declaration of competing interest.

Structural brain network differences in bipolar disorder using with similarity-based approach

2020 ◽  
pp. 1-26
Author(s):  
Miho Ota ◽  
Takamasa Noda ◽  
Noriko Sato ◽  
Shinsuke Hidese ◽  
Toshiya Teraishi ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Gray Matter ◽  
Healthy Subjects ◽  
Rating Scale ◽  
Clinical Symptoms ◽  
Structural Connectivity ◽  
Clustering Coefficient ◽  
Anterior Cingulate ◽  
Biological Information ◽  
Network Metrics

ABSTRACT Objective: Previous studies have shown differences in the regional brain structure and function between patients with bipolar disorder (BD) and healthy subjects, but little is known about the structural connectivity between BD patients and healthy subjects. In this study, we evaluated the disease-related changes in regional structural connectivity derived from gray matter MRI scans. Methods: The subjects were 73 patients with BD and 80 healthy volunteers who underwent 3-Tesla MRI. Network metrics, such as the small world properties were computed. We also performed rendering of the network metric images such as the degree, betweenness centrality, and clustering coefficient, on individual brain image. Then, we estimated the differences between them, and evaluate the relationships between the clinical symptoms and the network metrics in the patients with BD. Results: BD patients showed a lower clustering coefficient in the right parietal region and left occipital region, compared with healthy subjects. A weak negative correlation between Young mania rating scale and clustering coefficient was found in left anterior cingulate cortex. Conclusions: We found differences in gray matter structural connectivity between BD patients and healthy subjects by a similarity-based approach. These points may provide objective biological information as an adjunct to the clinical diagnosis of BD.

scholarly journals Therapeutic Use of Cerebellar Intermittent Theta Burst Stimulation (iTBS) in a Sardinian Family Affected by Spinocerebellar Ataxia 38 (SCA 38)

2021 ◽  
Author(s):  
Angela Sanna ◽  
Paolo Follesa ◽  
Paolo Tacconi ◽  
Mariangela Serra ◽  
Maria Giuseppina Pisu ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Rating Scale ◽  
Clinical Symptoms ◽  
Therapeutic Use ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Motor Cortex Excitability ◽  
Before And After ◽  
Theta Burst ◽  
Serum Bdnf

AbstractSpinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38.

scholarly journals Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents

2021 ◽  
Vol 7 (15) ◽  
pp. eabf6780
Author(s):  
Corinde E. Wiers ◽  
Leandro F. Vendruscolo ◽  
Jan-Willem van der Veen ◽  
Peter Manza ◽  
Ehsan Shokri-Kojori ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Alcohol Withdrawal ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Anterior Cingulate ◽  
Dorsal Anterior Cingulate Cortex ◽  
Beneficial Effects ◽  
Alcohol Cues ◽  
History Of ◽  
To Receive

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower “wanting” and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

scholarly journals Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator

2021 ◽  
Author(s):  
Elisavet Kaltsouni ◽  
Patrick M. Fisher ◽  
Manon Dubol ◽  
Steinar Hustad ◽  
Rupert Lanzenberger ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Negative Relationship ◽  
Premenstrual Dysphoric Disorder ◽  
Aggressive Response ◽  
Anterior Cingulate ◽  
Reproductive Age ◽  
Gonadal Hormone ◽  
Dorsal Anterior Cingulate Cortex ◽  
Response Condition ◽  
Receptor Modulator

AbstractPremenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.

scholarly journals Anhedonia in Semantic Dementia—Exploring Right Hemispheric Contributions to the Loss of Pleasure

2021 ◽  
Vol 11 (8) ◽  
pp. 998
Author(s):  
Siobhán R. Shaw ◽  
Hashim El-Omar ◽  
Siddharth Ramanan ◽  
Olivier Piguet ◽  
Rebekah M. Ahmed ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Rating Scale ◽  
Right Hemisphere ◽  
Semantic Knowledge ◽  
Semantic Dementia ◽  
Anterior Cingulate ◽  
Functional Impairments ◽  
Lobe Atrophy

Semantic dementia (SD) is a younger-onset neurodegenerative disease characterised by progressive deterioration of the semantic knowledge base in the context of predominantly left-lateralised anterior temporal lobe (ATL) atrophy. Mounting evidence indicates the emergence of florid socioemotional changes in SD as atrophy encroaches into right temporal regions. How lateralisation of temporal lobe pathology impacts the hedonic experience in SD remains largely unknown yet has important implications for understanding socioemotional and functional impairments in this syndrome. Here, we explored how lateralisation of temporal lobe atrophy impacts anhedonia severity on the Snaith–Hamilton Pleasure Scale in 28 SD patients presenting with variable right- (SD-R) and left-predominant (SD-L) profiles of temporal lobe atrophy compared to that of 30 participants with Alzheimer’s disease and 30 healthy older Control participants. Relative to Controls, SD-R but not SD-L or Alzheimer’s patients showed clinically significant anhedonia, representing a clear departure from premorbid levels. Overall, anhedonia was more strongly associated with functional impairment on the Frontotemporal Dementia Functional Rating Scale and motivational changes on the Cambridge Behavioural Inventory in SD than in Alzheimer’s disease patients. Voxel-based morphometry analyses revealed that anhedonia severity correlated with reduced grey matter intensity in a restricted set of regions centred on right orbitofrontal and temporopolar cortices, bilateral posterior temporal cortices, as well as the anterior cingulate gyrus and parahippocampal gyrus, bilaterally. Finally, regression and mediation analysis indicated a unique role for right temporal lobe structures in modulating anhedonia in SD. Our findings suggest that degeneration of predominantly right-hemisphere structures deleteriously impacts the capacity to experience pleasure in SD. These findings offer important insights into hemispheric lateralisation of motivational disturbances in dementia and suggest that anhedonia may emerge at different timescales in the SD disease trajectory depending on the integrity of the right hemisphere.

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