Journal of Psychopharmacology最新文献

Introduction: Previous studies have examined the correlation between paroxetine concentrations and therapeutic efficacy in patients diagnosed with major depressive disorder (MDD), but findings have been contradictory.

Aims: This study aimed to investigate the relationships among plasma concentrations, severity of symptoms, and adverse drug reactions (ADRs) to optimize individual dosing.

Methods: Eighty-seven MDD patients, after completing treatment with paroxetine, were divided into low-concentration (LC, n = 38), medium-concentration (MC, n = 27), and high-concentration (HC, n = 22) groups, based on cutoff value concentrations with the 50% response rate and the laboratory alert level from the 2017 consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology. The severity of depression and anxiety was evaluated using a 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), respectively. Dosage, plasma concentrations, scale scores, and ADRs were recorded across the three groups at different treatment stages to define the therapeutic reference range.

Results: The 4-week plasma concentration of paroxetine (65.00 ng/mL) could predict the clinical response in MDD patients at 8 weeks. Symptom relief in patients with 4-week paroxetine concentrations ranging from 65.00 to 120.00 ng/mL at 8 weeks was greater than in those with concentrations below 65.00 ng/mL, with no significant difference observed above this range. In addition, more cases of liver injury and weight gain were observed in patients with high paroxetine concentrations.

Conclusion: Our results support that early paroxetine concentration may predict clinical efficacy and the incidence of ADRs, thus improving individual dosing regimens for MDD patients.

Background: Research on the pharmacogenetic influence of hepatic CYP450 enzyme 2D6 (CYP2D6) on metabolism of drugs for psychosis and associated outcome has been inconclusive. Some results suggest increased risk of adverse reactions in poor and intermediate metabolizers, while others find no relationship. However, retrospective designs may fail to account for the long-term pharmacological treatment of patients. Previous studies found that clinicians adapted risperidone dose successfully without knowledge of patient CYP2D6 phenotype.

Aim: Here, we aimed to replicate the results of those studies in a Dutch cohort of patients with psychosis (N = 418) on pharmacological treatment.

Method: We compared chlorpromazine-equivalent dose between CYP2D6 metabolizer phenotypes and investigated which factors were associated with dosage. This was repeated in two smaller subsets; patients prescribed pharmacogenetics-actionable drugs according to published guidelines, and risperidone-only as done previously.

Results: We found no relationship between chlorpromazine-equivalent dose and phenotype in any sample (complete sample: p = 0.3, actionable-subset: p = 0.82, risperidone-only: p = 0.34). Only clozapine dose was weakly associated with CYP2D6 phenotype (p = 0.03).

Conclusion: Clinicians were thus not intuitively adapting dose to CYP2D6 activity in this sample, nor was CYP2D6 activity associated with prescribed dose. Although the previous studies could not be replicated, this study may provide support for existing and future pharmacogenetic research.

Background: The effects of panic disorder (PD) and pharmacotherapy on brain functional hubs in drug-free patients, and the utility of their degree centrality (DC) in diagnosing and predicting treatment response (TR) for PD, remained unclear.

Aims: This study aimed to assess the effects of PD and paroxetine on brain functional hubs in drug-free patients and to identify neuroimaging biomarkers for diagnosing and predicting TR in patients with PD.

Methods: Imaging data from 54 medication-free PD patients and 54 matched healthy controls (HCs) underwent DC and functional connectivity (FC) analyses before and after a 4-week paroxetine treatment. Diagnosis and prediction of TR models for PD were constructed using support vector machine (SVM) and support vector regression (SVR), with DC as features.

Results: Patients with PD showed aberrant DC and FC in the anterior cingulum, temporal, and occipital areas compared with HCs at baseline. After treatment, DC of the patients increased in the calcarine cortex, lingual gyrus, and cerebellum IV/V, along with improved clinical symptoms. Utilizing voxel-wise DC values at baseline, the SVM effectively distinguished patients with PD from HCs with an accuracy of 83.33%. In SVR, the predicted TR significantly correlated with the observed TR (correlation coefficient (r) = 0.893, Mean Squared Error = 0.009).

Conclusion: Patients with PD exhibited abnormal DC and FC, notably in the limbic network, temporal, and occipital regions. Paroxetine ameliorated patients' symptoms while altering their brain FC. SVM and SVR models, utilizing baseline DC, effectively distinguished the patients from HCs and accurately predicted TR.

Background: As classic psychedelics' therapeutic potential is studied and their popularity continues to rise, it is important to establish their relative risks and benefits. Previous surveys have tended to use convenience sampling on social media, select participants who have had either extremely positive or negative effects, and have not compared the risk/benefit profile of psychedelics to other substances.

Aims: To address these limitations, we gathered samples from an opt-in panel service using quota-based sampling to approximate demographics representing US Census data, did not pre-specify positive or negative experiences, and compared experiences with psychedelics to those with cannabis.

Methods: We conducted two studies, one using a between-subjects design (n = 743) and one using a within-subjects design (n = 514), in which participants recruited from an opt-in panel service reflected on prior experience with psychedelics or cannabis and indicated self-reported risks and benefits associated with their experience.

Results: Results indicated that first or most memorable psychedelic experiences were associated with greater acute challenging effects and persisting negative effects than first or most memorable cannabis experiences, but psychedelic experiences were also associated with greater positive acute and persisting effects. Common predictors of negative and positive acute and persisting effects with psychedelics included various experience qualities (e.g., dose level, presence of others) and individual differences (e.g., religiosity, personality), though only to a small degree.

Conclusions: These findings on psychedelic experiences provide a more nuanced characterization of risks and benefits and their predictors.

Background: Ayahuasca is an Amazonian brew with 5-HT_2A-dependent psychedelic effects taken by religious groups globally. Recently, psychedelics have been shown to impair the formation of recollections (hippocampal-dependent episodic memory for specific details) and potentially distort memory while remembering. However, psychedelics spare or enhance the formation of familiarity-based memory (cortical-dependent feeling of knowing that a stimulus has been processed).

Aims: Given the growing literature on the plasticity-promoting effects of psychedelics, we investigated the acute impact of ayahuasca on recollection, familiarity, and false memory in an observational study of 24 Santo Daime members with >500 lifetime ayahuasca uses on average.

Methods: Participants completed a false memory task at baseline and after they consumed a self-selected dose of ayahuasca prepared by their church (average dose contained 3.36 and 170.64 mg of N,N-dimethyltryptamine and β-carbolines, respectively).

Results: Surprisingly, pre-encoding administration of ayahuasca enhanced hit rates, memory accuracy, and recollection but had no impact on familiarity or false memory. Although practice effects cannot be discounted, these memory enhancements were large and selective, as multiple measures of false memory and metamemory did not improve across testing sessions. β-carboline activity potentially accounted for this recollection enhancement that diverges from past psychedelic research. Although ayahuasca did not impact familiarity, these estimates were generally elevated across conditions compared to past work, alluding to a consequence of frequently driving cortical plasticity.

Conclusions: When encoding and retrieval took place under acute ayahuasca effects in experienced ayahuasca users, susceptibility to memory distortions did not increase, potentially owing to enhancements in memory accuracy.

Background: Electroconvulsive therapy (ECT) is a highly effective treatment for severe depression. However, its utilization is limited to the most severely ill patients due to stigma, healthcare provider unfamiliarity, and concerns regarding cognitive side effects. Erythropoietin (EPO) is a promising add-on treatment during ECT due to its potential to increase neuroplasticity and cognition.

Aims: To explore the effects of EPO administration on cortical thickness and hippocampal volumes.

Methods: In a randomized, double-blinded, placebo-controlled trial, we previously investigated the impact of EPO (40,000 IU) versus placebo (saline) infusions on cognitive side effects of unipolar or bipolar depression patients undergoing eight ECT sessions over 2.5 weeks. This cross-sectional magnetic resonance imaging study explores the effect of EPO on cortical thickness and hippocampal volumes 3 days post-ECT in 37 of the EPO trial patients (EPO n = 21; placebo n = 16).

Results: Compared to the placebo group, EPO-treated patients displayed thicker cortex in distributed regions of the right hemisphere, predominantly in the parietal and occipital areas. There were no significant group differences in the hippocampal volumes or prefrontal cortex thickness.

Conclusions: EPO treatment may produce a selective increase in the right-side occipito-parietal cortical thickness. In contrast, the thickness of other cognition-relevant structures was not significantly affected. This aligns with our previously reported finding that EPO has a selective effect on autobiographical memory and associated right-side parietal activity in the absence of changes in global cognition. It remains to be investigated whether longer EPO treatment and follow-up assessment may be necessary for overt structural changes in cognition-relevant brain networks.

Background: Methotrexate (MTX) is a cytotoxic drug that can trigger neurotoxicity via enhancing oxidative stress, apoptosis, and inflammation. On the other hand, erythropoietin (EPO) functions as an antioxidant, anti-apoptotic, and anti-inflammatory agent, in addition to its hematopoietic effects.

Aim: The present study was developed to examine the neuroprotective impact of EPO against MTX-provoked neurotoxicity in rats.

Methods: Chemo fog was elicited in Wistar rats via injection of one dosage of MTX (20 mg/kg, i.p) on the sixth day of the study. EPO was injected at 500 IU/kg/day, i.p for 10 successive days.

Results: MTX triggered memory and learning impairment as evidenced by Morris water maze, passive avoidance, and Y-maze cognitive tests. In addition, MTX induced oxidative stress as evident from the decline in hippocampal Nrf2 and HO-1 levels. MTX brought about apoptosis, as demonstrated by the elevation in p53, caspase-3, and Bax levels, as well as the decrease in Bcl2 levels. MTX also decreased Beclin-1, an autophagy-related marker, and increased P62 expression. In addition, MTX downregulated Sirt-1/AKT/FoxO3a pathway and increased miRNA-34a gene expression. Moreover, MTX increased acetylcholinesterase activity and reduced neurogenesis. EPO administration remarkably counteracted MTX-induced molecular and behavioral disorders in rat hippocampi.

Conclusion: Our findings impart preclinical indication for repurposing of EPO as a promising neuroprotective agent through modulating miRNA-34a, autophagy, and the Sirt-1/FoxO3a signaling pathway.

There is an increasing awareness of the link between chronic alcohol consumption and the development of cognitive, behavioural and functional deficits. Currently, preventative strategies are limited and require engagement in dedicated long-term rehabilitation and sobriety services, the availability of which is low. The acute alcohol withdrawal syndrome is an episode of neurochemical imbalance leading to autonomic dysregulation, increased seizure risk and cognitive disorientation. In addition to harm from symptoms of alcohol withdrawal (e.g. seizures), the underpinning neurochemical changes may also lead to cytotoxicity through various cellular mechanisms, which long-term, may translate to some of the cognitive impairments observed in Alcohol-Related Brain Damage (ARBD). Here we review some of the pharmacological and neurochemical mechanisms underpinning alcohol withdrawal. We discuss the cellular and pharmacological basis of various potential neuroprotective strategies that warrant further exploration in clinical populations with a view to preventing the development of ARBD. Such strategies, when integrated into the clinical management of acute alcohol withdrawal, may impact large populations of individuals, who currently face limited dedicated service delivery and healthcare resource.

Background: Whether responses to treatment of major depressive episodes differ between women and men or with bipolar (BD) and major depressive disorders (MDD) remains unresolved.

Aims: To test for diagnostic and sex differences in responses to treatment of depression.

Methods: We compared changes in the 21-item Hamilton Depression Rating Scale (HDRS₂₁) ratings of depression (n = 3243) between women (64.7%) and men, and between DSM-5-TR BD ([n = 253] and subtypes I [BD1] vs II [BD2]) and MDD (n = 2990), using bivariate comparisons and multivariate modeling.

Results: Treatments included clinically individualized use of antidepressants (by 92.4%, in doses averaging 90.0 mg/day imipramine-equivalent), sometimes with mood-stabilizing agents (32.1%), second-generation antipsychotics (18.8%), or psychotherapy (38.6%). Depression ratings decreased by 60.6% to a final mean HDRS score of 7.44; response rate (⩾50% reduction in HDRS) averaged 63.7%. Outcomes were very similar in women and men as well as with BD versus MDD, and between BD subtypes. Moreover, age, duration of illness, initial HDRS score, dose of antidepressant, and weeks of treatment, as well as sex and diagnosis were not associated with improvement of HDRS with treatment. Only 6/42 comparisons involving 21 individual HDRS items differed significantly in improvement between sexes or diagnoses. Results were very similar to the Montgomery-Åsberg Depression Rating Scale depression ratings. Only 2.0% of the subjects experienced mood-switching into clinical (hypo)mania and the final Young Mania Rating Scale ratings averaged 0.63.

Conclusions: Responses to clinical treatment (as % reduction of HDRS score, response rate, or final HDRS score) of depressed women versus men, and BD (including BD1 vs BD2) versus MDD were substantial and very similar.

Background: Alcohol-related cues are known to influence craving levels, a hallmark of alcohol misuse. Binge drinking (BD), a pattern of heavy alcohol use, has been associated with cognitive and neurofunctional alterations, including alcohol attentional bias, memory impairments, as well as disrupted activity in prefrontal- and reward-related regions. However, literature is yet to explore how memories associated with alcohol-related cues are processed by BDs, and how the recall of this information may influence their reward processing.

Aims: The present functional magnetic resonance imaging (fMRI) study aimed to investigate the neurofunctional signatures of BD during an associative memory task.

Method: In all, 36 university students, 20 BDs and 16 alcohol abstainers, were asked to memorize neutral objects paired with either alcohol or non-alcohol-related contexts. Subsequently, neutral stimuli were presented, and participants were asked to classify them as being previously paired with alcohol- or non-alcohol-related contexts.

Results: While behavioral performance was similar in both groups, during the recall of alcohol-related cues, BDs showed increased brain activation in two clusters including the thalamus, globus pallidus and dorsal striatum, and cerebellum and occipital fusiform gyrus, respectively.

Conclusion: These findings suggest that BDs display augmented brain activity in areas responsible for mental imagery and reward processing when trying to recall alcohol-related cues, which might ultimately contribute to alcohol craving, even without being directly exposed to an alcohol-related context. These results highlight the importance of considering how alcohol-related contexts may influence alcohol-seeking behavior and, consequently, the maintenance or increase in alcohol use.