ResearchPad - academicsubjects-sci01870 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Prescribing Patterns of Psychotropic Drugs and Risk of Violent Behavior: A Prospective, Multicenter Study in Italy]]> https://www.researchpad.co/article/elastic_article_16181 This prospective cohort study aimed at evaluating patterns of polypharmacy and aggressive and violent behavior during a 1-year follow-up in patients with severe mental disorders.MethodsA total of 340 patients (125 inpatients from residential facilities and 215 outpatients) were evaluated at baseline with the Structured Clinical Interview for DSM-IV Axis I and II, Brief Psychiatric Rating Scale, Specific Levels of Functioning scale, Brown-Goodwin Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Barratt Impulsiveness Scale, and State-Trait Anger Expression Inventory-2. Aggressive behavior was rated every 15 days with the Modified Overt Aggression Scale and treatment compliance with the Medication Adherence Rating Scale.ResultsThe whole sample was prescribed mainly antipsychotics with high levels of polypharmacy. Clozapine prescription and higher compliance were associated with lower levels of aggressive and violent behavior. Patients with a history of violence who took clozapine were prescribed the highest number of drugs. The patterns of cumulative Modified Overt Aggression Scale mean scores of patients taking clozapine (n = 46), other antipsychotics (n = 257), and no antipsychotics (n = 37) were significantly different (P = .001). Patients taking clozapine showed a time trend at 1-year follow-up (24 evaluations) indicating a significantly lower level of aggressive behavior. Patient higher compliance was also associated with lower Modified Overt Aggression Scale ratings during the 1-year follow-up.ConclusionBoth inpatients and outpatients showed high levels of polypharmacy. Clozapine prescription was associated with lower Modified Overt Aggression Scale ratings compared with any other antipsychotics or other psychotropic drugs. Higher compliance was associated with lower levels of aggressive and violent behavior. ]]> <![CDATA[Making Sense of Computational Psychiatry]]> https://www.researchpad.co/article/elastic_article_16180 In psychiatry we often speak of constructing “models.” Here we try to make sense of what such a claim might mean, starting with the most fundamental question: “What is (and isn’t) a model?” We then discuss, in a concrete measurable sense, what it means for a model to be useful. In so doing, we first identify the added value that a computational model can provide in the context of accuracy and power. We then present limitations of standard statistical methods and provide suggestions for how we can expand the explanatory power of our analyses by reconceptualizing statistical models as dynamical systems. Finally, we address the problem of model building—suggesting ways in which computational psychiatry can escape the potential for cognitive biases imposed by classical hypothesis-driven research, exploiting deep systems-level information contained within neuroimaging data to advance our understanding of psychiatric neuroscience.

]]>
<![CDATA[A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity]]> https://www.researchpad.co/article/elastic_article_16179 Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans.MethodsUsing a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons.ResultsNominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562–treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate.ConclusionsPF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period.ClinicalTrials.gov IdentifierNCT02306876 ]]> <![CDATA[Monoamine Oxidase A Hypomethylation in Obsessive-Compulsive Disorder: Reversibility By Successful Psychotherapy?]]> https://www.researchpad.co/article/elastic_article_16178 Epigenetic markers such as DNA methylation of the monoamine oxidase A (MAOA) gene have previously been shown to be altered in anxiety- and stress-related disorders and to constitute a potential mechanism of action of psychotherapeutic interventions such as cognitive behavioral therapy in these disorders. The present study for the first time, to our knowledge, investigated MAOA methylation in patients with obsessive-compulsive disorder applying a longitudinal psychotherapy-epigenetic approach.MethodsThe present sample comprised 14 unmedicated female patients with primary obsessive-compulsive disorder and 14 age- and sex-matched healthy controls. MAOA promoter methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from whole blood before and after an 8- to 10-week semi-standardized, obsessive-compulsive disorder–specific cognitive behavioral therapy. Clinical response was assessed by means of the Yale-Brown Obsessive Compulsive Scale.ResultsSignificantly lower MAOA promoter methylation was discerned in obsessive-compulsive disorder patients relative to healthy controls. Data were available for 12 patients with obsessive-compulsive disorder and 14 controls. Furthermore, following cognitive behavioral therapy, clinical improvement, i.e., decreases in obsessive-compulsive disorder symptoms as indicated by lower scores on the Yale-Brown Obsessive Compulsive Scale was found to be significantly correlated with increases in MAOA methylation levels in patients (data available for n = 7).ConclusionsThe present pilot data suggest MAOA hypomethylation as a potential risk marker of obsessive-compulsive disorder and an increase in MAOA methylation levels as a possible mechanistic correlate of response to cognitive behavioral therapy in obsessive-compulsive disorder. ]]> <![CDATA[Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents]]> https://www.researchpad.co/article/Nf5adc2d8-17bf-4e10-be19-77ca00119502

Abstract

Background

Faster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates.

Methods

Phosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice.

Results

Compared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar.

Conclusions

Differential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The “balanced activation” of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.

]]>
<![CDATA[Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report]]> https://www.researchpad.co/article/Nf948cf8b-d7de-40c1-b4be-735106db4a59

Abstract

Introduction

Antidepressant drugs are effective therapies for major depressive disorder; however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effects. The aim of this study was to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment and their downstream effects on target gene expression.

Methods

A total 160 patients with major depressive disorder from the CAN-BIND-1 cohort were included. Side effects were assessed with the Toronto Side Effect Scale after 2 weeks of treatment with escitalopram. We assessed the relationship between side effects and changes in peripheral expression of miRNAs between baseline and week 2. For miRNA whose expression changed, we used target prediction algorithms to identify putative messenger RNA (mRNA) targets and assessed their expression.

Results

Nausea was experienced by 42.5% of patients. We identified 45 miRNAs whose expression changed on initiation of escitalopram treatment, of which 10 displayed a negative association with intensity of nausea (miR15b-5p, miR17-5p, miR20a-5p, miR20b-5p, miR103a-3p, miR103b, miR106a-5p, miR182-5p, miR185-5p, and miR660-5p). Additionally, we found negative associations between 4 microRNAs (miR20a-5p, miR106a-5p, miR185-5p, miR660-5p) and mRNA targets. The expression of the miR185-5p target, CAMK2δ was significantly decreased [log 2 mean = −0.048 (0.233)] between weeks 0 and 2 (P = .01)].

Conclusions

We identified an overexpression of miR185-5p during escitalopram treatment of major depressive disorder, which was negatively associated with intensity of nausea, and identified a potential mRNA target that may mediate this effect.

]]>
<![CDATA[Cardiovascular Adverse Reactions During Antipsychotic Treatment: Results of AMSP, A Drug Surveillance Program Between 1993 and 2013]]> https://www.researchpad.co/article/Ncd733c45-6823-4387-b381-5791aa5f7d62

Abstract

Background

Cardiovascular diseases are still the leading cause of global mortality. Some antipsychotic agents can show severe cardiovascular side effects and are also associated with metabolic syndrome.

Methods

This observational study was based on data of AMSP (Arzneimittelsicherheit in der Psychiatrie), a multicenter drug surveillance program in Austria, Germany and Switzerland, that recorded severe drug reactions in psychiatric inpatients.

Results

A total of 404 009 inpatients were monitored between 1993 and 2013, whereas 291 510 were treated with antipsychotics either in combination or alone. There were 376 cases of severe cardiovascular adverse reactions reported in the given timespan, yielding a relative frequency of 0.13%. The study revealed that incidence rates of cardiovascular adverse reactions were highest during treatment with ziprasidone (0.35%), prothipendyl (0.32%), and clozapine (0.23%). The lowest rate of cardiovascular symptoms occurred during treatment with promethazine (0.03%) as well as with aripiprazole (0.06%). The most common clinical symptoms were orthostatic collapse and severe hypotonia, sinustachycardia, QTc prolongation, myocarditis, and different forms of arrhythmia. The dosage at the timepoint when severe cardiovascular events occurred was not higher in any of the given antipsychotics than in everyday clinical practice and was in average therapeutic ranges. In terms of subclasses of antipsychotics, no significant statistical difference was seen in the overall frequencies of adverse reactions cases, when first-generation high potency, first-generation low potency, and second-generation antipsychotics were compared. Thirty percent of adverse events among second-generation antipsychotics were induced by clozapine.

Conclusions

Our findings on cardiovascular adverse reactions contribute to a better understanding of cardiovascular risk profiles of antipsychotic agents in inpatients.

]]>
<![CDATA[Antipsychotic Polypharmacy: A Dirty Little Secret or a Fashion?]]> https://www.researchpad.co/article/Nd4ac3fb2-589d-44cd-a555-a55bf614458a

Abstract

The term polypharmacy was originally coined to refer to problems related to multiple drug consumption and excessive drug use during the treatment of a disease or disorder. In the treatment of schizophrenia, polypharmacy usually refers to the simultaneous use of 2 or more antipsychotic medications or combined (adjunct) medications such as mood stabilizers, antidepressants, anxiolytics, or hypnotics in addition to single or multiple antipsychotics. Two decades ago, antipsychotic polypharmacy was criticized as being more expensive, having unproven efficacy, and causing more side effects. However, in recent years, antipsychotic polypharmacy has become more or less acceptable in the views of clinical practitioners and academic researchers. Results from recent reviews have suggested that the common practice of antipsychotic polypharmacy lacks double-blind or high-quality evidence of efficacy, except for negative symptom reduction with aripiprazole augmentation. We reviewed some representative studies that enrolled large numbers of patients and compared antipsychotic polypharmacy and monotherapy during the past decade. The results revealed that a certain proportion of select patients can benefit from antipsychotic polypharmacy without further negative consequences. Because most of the current treatment guidelines from different countries and organizations prefer monotherapy and discourage all antipsychotic polypharmacy, guidelines regarding the use of antipsychotic polypharmacy in clinical practice should be revised. On the basis of the findings of 2 large-scale studies from Asia and Europe, we also suggest ideal rates of various maintenance treatments of schizophrenia, which are as follows: antipsychotic polypharmacy, 30%; combined mood stabilizer, 15%; combined antidepressant, 10%; combined anxiolytics, 30%; and combined hypnotic, 10%.

]]>
<![CDATA[Obituary: Bruce McEwen]]> https://www.researchpad.co/article/Nf7497eed-c9ec-4399-95aa-087bbdfcc70a ]]> <![CDATA[Inhibitory Control of Basolateral Amygdalar Transmission to the Prefrontal Cortex by Local Corticotrophin Type 2 Receptor]]> https://www.researchpad.co/article/N5a8351ec-a154-4bc6-9937-8bb3e8137bd8

Abstract

Background

Basolateral amygdalar projections to the prefrontal cortex play a key role in modulating behavioral responses to stress stimuli. Among the different neuromodulators known to impact basolateral amygdalar-prefrontal cortex transmission, the corticotrophin releasing factor (CRF) is of particular interest because of its role in modulating anxiety and stress-associated behaviors. While CRF type 1 receptor (CRFR1) has been involved in prefrontal cortex functioning, the participation of CRF type 2 receptor (CRFR2) in basolateral amygdalar-prefrontal cortex synaptic transmission remains unclear.

Methods

Immunofluorescence anatomical studies using rat prefrontal cortex synaptosomes devoid of postsynaptic elements were performed in rats with intra basolateral amygdalar injection of biotinylated dextran amine. In vivo microdialysis and local field potential recordings were used to measure glutamate extracellular levels and changes in long-term potentiation in prefrontal cortex induced by basolateral amygdalar stimulation in the absence or presence of CRF receptor antagonists.

Results

We found evidence for the presynaptic expression of CRFR2 protein and mRNA in prefrontal cortex synaptic terminals originated from basolateral amygdalar. By means of microdialysis and electrophysiological recordings in combination with an intra-prefrontal cortex infusion of the CRFR2 antagonist antisauvagine-30, we were able to determine that CRFR2 is functionally positioned to limit the strength of basolateral amygdalar transmission to the prefrontal cortex through presynaptic inhibition of glutamate release.

Conclusions

Our study shows for the first time to our knowledge that CRFR2 is expressed in basolateral amygdalar afferents projecting to the prefrontal cortex and exerts an inhibitory control of prefrontal cortex responses to basolateral amygdalar inputs. Thus, changes in CRFR2 signaling are likely to disrupt the functional connectivity of the basolateral amygdalar-prefrontal cortex pathway and associated behavioral responses.

]]>
<![CDATA[Analysis of Time-Course, Dose-Effect, and Influencing Factors of Antidepressants in the Treatment of Acute Adult Patients With Major Depression]]> https://www.researchpad.co/article/Nc8acec65-c217-47ee-b483-ff09e5438354

Abstract

Objective

Model-based meta-analysis was used to describe the time-course and dose-effect relationships of antidepressants and also simultaneously investigate the impact of various factors on drug efficacy.

Methods

This study is a reanalysis of a published network meta-analysis. Only placebo-controlled trials were included in this study. The change rate in depression rating scale scores from baseline was used as an efficacy indicator because a continuous variable is more likely to reflect subtle differences in efficacy between drugs.

Results

A total 230 studies containing 64 346 patients were included in the analysis. The results showed that the number of study sites (single or multi-center) and the type of setting (inpatient or noninpatient) are important factors affecting the efficacy of antidepressants. After deducting the placebo effect, the maximum pure drug efficacy value of inpatients was 18.4% higher than that of noninpatients, and maximum pure drug efficacy value of single-center trials was 10.2% higher than that of multi-central trials. Amitriptyline showed the highest drug efficacy. The remaining 18 antidepressants were comparable or had little difference. Within the approved dose range, no significant dose-response relationship was observed. However, the time-course relationship is obvious for all antidepressants. In terms of safety, with the exception of amitriptyline, the dropout rate due to adverse events of other drugs was not more than 10% higher than that of the placebo group.

Conclusion

The number of study sites and the type of setting are significant impact factors for the efficacy of antidepressants. Except for amitriptyline, the other 18 antidepressants have little difference in efficacy and safety.

]]>
<![CDATA[Regulation of CRF mRNA in the Rat Extended Amygdala Following Chronic Cocaine: Sex Differences and Effect of Delta Opioid Receptor Agonism]]> https://www.researchpad.co/article/Nc69a6e42-e997-41b9-bdcc-885df6a7d5ea

Abstract

Background

Cocaine withdrawal activates stress systems. Females are more vulnerable to relapse to cocaine use and more sensitive to withdrawal-induced negative affect. Delta opioid receptors modulate anxiety-like behavior during cocaine withdrawal in rats. This study measured the time course of gene regulation of one of the main stress peptides, corticotropin-releasing factor (CRF), and its type 1 receptor in male and female rats as well as the ability of the delta opioid receptor agonist SNC80 to normalize cocaine withdrawal-induced changes in CRF mRNA.

Methods

Rats were injected with cocaine or saline 3 times daily for 14 days. Brains were collected 30 minutes, 24 hours, 48 hours, 7 days, and 14 days following the last injection. The paraventricular nucleus of the hypothalamus, central amygdala, and bed nucleus of the stria terminalis were processed for quantitative reverse transcriptase PCR measurement of CRF and CRFR1 mRNA. Additional rats received SNC80 during early cocaine withdrawal, and CRF mRNA was measured in the central amygdala.

Results

CRF mRNA was elevated in the central amygdala at 24 hours and the paraventricular nucleus at 48 hours of cocaine withdrawal in males and females. Significant sex differences in cocaine-induced CRF upregulation were found in the bed nucleus of the stria terminalis at 30 minutes and 24 hours. SNC80 administration attenuated the increase in CRF mRNA in the central amygdala of female rats only.

Conclusions

CRF mRNA regulation during cocaine withdrawal is sex, time, and brain region dependent. Administration of a delta opioid receptor agonist during early withdrawal may ameliorate stress-related negative affect in females by abrogating the induction of CRF mRNA.

]]>