Effects of a nicotinic agonist on the Brief Psychiatric Rating Scale five-factor subscale model in schizophrenia.
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ABSTRACT:
SUBMITTER: Lewis AS
PROVIDER: S-EPMC6476180 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
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Effects of a nicotinic agonist on the Brief Psychiatric Rating Scale five-factor subscale model in schizophrenia.
Lewis Alan S AS Olincy Ann A Buchanan Robert W RW Kem William R WR Picciotto Marina R MR Freedman Robert R
Schizophrenia research 20171016
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Project description: Not available
| S-EPMC10634518 | biostudies-literature
Project description:Bipolar disorder (BD) is a chronic and clinically complex disease, characterized by pathological disturbances in mood and energy. Cytokines can access the brain and their signaling pathways affect brain functions, such as neurotransmitter metabolism, neuroendocrine function, neural/synaptic plasticity, and mood neural circuitry. JAK 1 is the most common phosphorylation protein combined with the tyrosine kinase cytokine receptors; therefore, we investigated the association between the Janus family kinase 1 (JAK1) gene polymorphisms (rs2780895, rs4244165, and rs17127024) and susceptibility to BD. The case study population included 93 patients diagnosed with BD and 112 healthy controls, selected from the central coastal region of Tunisia. Polymerase chain reaction-restriction fragment length polymorphism was used to investigate these 3 JAK1 polymorphisms. We compared the sociodemographic and clinical parameters of 3 genotypes of this single nucleotide polymorphisms rs2780895, rs4244165, and rs17127024 of the JAK1 gene. The frequencies of the 3 genotypes were similar in the patient and control groups. One-way analysis of variance revealed a significant variation in rs4244165. After hospitalization, the average of the brief psychiatric rating scale score was significantly higher for the wild-type GG genotype than that for the double-mutation TT genotype (31.23% vs 22.85%, P = .043). The least significant difference post hoc test also showed a significant difference between the GG and TT genotypes at both hospital admission (P = .001) and after hospitalization (P = .012), with the GG genotype being associated with a higher brief psychiatric rating scale score. Haplotypic analysis revealed that the wild-type haplotype with the highest frequency (46.62%) was CTG. Our results showed no association between the 3 studied positions and bipolar disorder. However, the G-allele of rs4244165 in JAK1 is associated with the highest level of the brief psychiatric rating scale in patients with bipolar disorder. The JAK/signal transducer and activator of transcription pathway is an interesting therapeutic route that requires further investigations. Studying their regulatory regions can provide a clearer picture of all the interactions involved in the regulation of genetic expression in response to treatment.
| S-EPMC10508567 | biostudies-literature
Project description:ObjectiveNicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.MethodThirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.ResultsThere were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.ConclusionDMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.
| S-EPMC3746983 | biostudies-literature
Project description:Alpha7 nicotinic acetylcholine receptor (?7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor's sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of ?7 nAChR agonist/PAMs is warranted in larger studies that will have greater power.
| S-EPMC3732552 | biostudies-literature
Project description:In schizophrenia, none of the standard anxiety measures exhibit strong psychometric properties, and all performed poorly against quality assessment criteria. Developed for the schizophrenia population, this study examined the validity and reliability of the Staden Schizophrenia Anxiety Rating Scale (S-SARS) that measures both specified and undifferentiated anxiety. Among 353 schizophrenia patients, strong correlations with anxiety parameters supported the S-SARS's convergent validity. Criterion-related validity testing yielded accuracy, sensitivity, and specificity rates of around 95%. Its discriminant validity was observed for measures of depression, psychosis, akathisia, fatigue, vigour, procrastination, behavioural inhibition and activation, and personal growth and initiative. Structural validity was found in a single-factor unidimensional model with a 0.953 factor score. Excellent results were found for internal consistency (Cronbach's alpha = 0.931; Spearman-Brown coefficient = 0.937; Guttman split-half coefficient = 0.928) and inter-rater reliability (Krippendorff's alpha = 0.852). It incurred no more than a small error of measurement whereby the observed scores were within 1.54 to 3.58 of a true score on a zero to 50 scale. These strong psychometric properties suggest that the S-SARS is a valid and reliable instrument for measuring specified and undifferentiated anxiety in schizophrenia, providing the means for the accurate measurement of anxiolytic treatment effects.
| S-EPMC9028449 | biostudies-literature
Project description:ObjectiveTo determine if a single baseline adherence assessment (Brief Adherence Rating Scale [BARS]) could identify patients who are likely to respond to long-acting injectable (LAI) antipsychotic treatment.MethodThe current secondary analysis included a sub-sample of adult outpatients (N = 176) with schizophrenia or schizoaffective disorder who participated in the "A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS)" trial and had a baseline BARS assessment and a baseline and month 3 Positive and Negative Syndrome Scale (PANSS) rating. The main outcome was LAI treatment response, defined as a ≥ 20% decrease (baseline to month 3) on the PANSS total score. Receiver Operating Characteristic (ROC) and Area Under the Curve (AUC) analysis was conducted to determine the optimal cutpoint of baseline BARS adherence in discriminating LAI treatment response at month 3. A logistic mixed model estimated the odds of response to LAI treatment at month 3 from the optimal baseline BARS cutpoint.ResultsThe ROC analysis determined that the single baseline BARS rating (cutoff ≤66%), indicating low adherence, best discriminated patients likely to respond to LAI treatment (AUC = 0.603, SE = 0.046, 95% binomial exact CI = 0.527 to 0.676, p = 0.025), with 38% sensitivity and 85% specificity. The logistic mixed model analysis revealed that patients with ≤66% BARS adherence had 3.464 times the predicted odds (95% CI = 1.604 to 7.480, p = 0.001) of responding to LAI treatment than those who were >66% BARS adherent.ConclusionA single baseline BARS assessment discriminated response to LAI treatment suggesting it is a reasonable tool to identify candidates for LAI antipsychotic treatment.
| S-EPMC7306424 | biostudies-literature
Project description:3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is found during many tasks, including smooth pursuit eye movements, and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. After the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye movements, but the 75-mg dose was ineffective. The effect at the 150-mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of alpha7-nicotinic receptors on inhibitory interneurons in the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia.
| S-EPMC2834253 | biostudies-literature
Project description:Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test-retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r=-0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P<.001). These data suggest that the SCoRS has potential as a clinically relevant measure in clinical trials aiming to improve cognition in schizophrenia, and may be useful for clinical practice. The weaknesses of the SCoRS include its reliance on informant information, which is not available for some patients, and reduced validity when patient's self-report is the sole information source.
| S-EPMC4277931 | biostudies-literature
Project description:3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at ?7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia.Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the ?7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia.Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype.The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the ?7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents.
| S-EPMC3005969 | biostudies-literature
Project description:AimsThe purpose was to compare the frequency of needs of patients with schizophrenia in forensic services across five European countries as assessed by both the patients and their care staff.MethodsPatients with schizophrenia and a history of significant interpersonal violence were recruited from forensic psychiatric services in Austria, Germany, Italy, Poland and England. Participants' needs were assessed using the Camberwell Assessment of Needs-Forensic Version (CANFOR). Multiple linear regression analyses were used to identify predictors of numbers of needs.ResultsIn this sample, (n = 221) the most commonly reported need according to patients (71.0%) and staff (82.8%) was the management of psychotic symptoms. A need for information was mentioned by about 45% of staff and patients. Staff members reported a significantly higher number of total needs than patients (mean 6.9 vs. 6.2). In contrast, staff members reported a significantly lower number of unmet needs than patients (mean 2.0 vs. 2.5). Numbers of total needs and met needs differed between countries. Unmet needs as reported by patients showed positive associations with the absence of comorbid personality disorder, with higher positive symptom scores and lifetime suicide or self-harm history. Significant predictors of unmet needs according to staff were absence of comorbid personality disorder and higher positive as well as negative symptom scores according to PANSS.ConclusionsStaff rated a significantly higher number of total needs than patients, while patients rated more unmet needs. This indicates that patients' self-assessments of needs yield important information for providing sufficient help and support.
| S-EPMC9284498 | biostudies-literature