Chronic exposure to cannabinoids during adolescence causes long-lasting behavioral deficits in adult mice

Regular use of marijuana during adolescence enhances the risk of long-lasting neurobiological changes in adulthood. The present study was aimed at assessing the effect of long-term administration of the synthetic cannabinoid WIN55212.2 during adolescence in young adult mice. Adolescent mice aged 5 weeks were subjected daily to the pharmacological action of WIN55212.2 for 3 weeks and were then left undisturbed in their home cage for a 5-week period and finally evaluated by behavioral testing. Mice that received the drug during adolescence showed memory impairment in the Morris water maze, as well as a dose-dependent memory impairment in fear conditioning. In addition, the administration of 3 mg/kg WIN55212.2 in adolescence increased adult hippocampal AEA levels and promoted DNA hypermethylation at the intragenic region of the intracellular signaling modulator Rgs7, which was accompanied by a lower rate of mRNA transcription of this gene, suggesting a potential causal relation. Although the concrete mechanisms underlying the behavioral observations remain to be elucidated, we demonstrate that long-term administration of 3 mg/kg of WIN during adolescence leads to increased endocannabinoid levels and altered Rgs7 expression in adulthood and establish a potential link to epigenetic changes.Beca Ramón y Caja

Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

Introduction The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. Objectives We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. Methods Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. Results High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml. Conclusion VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN’s dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations

The cross-sectional GRAS sample: A comprehensive phenotypical data collection of schizophrenic patients

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia.</p> <p>Methods</p> <p>For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected.</p> <p>Results</p> <p>The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail.</p> <p>Conclusions</p> <p>The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.</p

Therapeutic drug monitoring of drugs for treatment of substance-related disorders

IntroductionThe effect of pharmacotherapy of substance-related disorders is moderate at best.ObjectivesTherapeutic drug monitoring (TDM) could be an instrument to improve the outcomes. TDM is for most of these drugs not established yet.AimsThe authors built a literature based rating scale to evaluate the necessity of TDM for these pharmacological agents.MethodsA literature research was performed for TDM related properties of acamprosate, bupropion, buprenorphine, clomethiazole, disulfiram, methadone, naltrexone, and varenicline. A rating scale was established for evaluation. It included 28 items related to five categories (efficacy, toxicity, pharmacokinetics, patient characteristics and cost effectiveness). For comparison, three reference substances with established TDM were similarly assessed: clozapine, lithium and nortriptyline.ResultsThe three reference substances, lithium, clozapine and nortriptyline, achieved scores of 15, 18, and 14 points, respectively. Rating of methadone (19 points), bupropion (14 points), buprenorphine (14 points), disulfiram (13) and naltrexone (12 points in the indication opioid-dependency and 10 points in the indication alcohol dependency) achieved more than 30% of the reachable points, whereas acamprosate (9 points), clomethiazole (9 points), and varenicline (5 points) had fewer points especially in the main characteristics in favor of TDM.ConclusionsThese results suggest this rating scale is sensitive to detect the appropriateness of TDM for drug treatment. Literature based rating and clinical experience give evidence that TDM has the potential to optimize the pharmacotherapy of substance related-disorders with different rank orders of the single substances.</jats:sec

A new rating scale to evaluate the potential benefit of therapeutic drug monitoring

Aims: Therapeutic Drug Monitoring (TDM) is an established tool to optimize thepharmacotherapy with immunosupressants, antibiotics, antiretroviral agents, anticonvulsantsand psychotropic drugs. The TDM expert group of the Association ofNeuropsychopharmacolgy and Pharmacopsychiatry recommended clinical guidelinesfor TDM of psychotropic drugs in 2004 and in 2011. They allocate 4 levelsof recommendation based on studies reporting plasma concentrations and clinicaloutcomes. To evaluate the additional benefit for drugs without direct evidence forTDM and to verify the recommendation levels of the expert group the authorsbuilt a new rating scale. Methods: This rating scale included 28 items and wasdivided in 5 categories: Efficacy, toxicity, pharmacokinetics, patient characteristicsand cost effectiveness. A literature search was performed for 10 antidepressants,10 antipsychotics, 8 drugs used in the treatment of substance related disordersand lithium, thereafter, a comparison with the assessment of the TDMexpert group was carried out. Results: The antidepressants as well as the antipsychoticsshowed a high and significant correlation with the recommendations inthe consensus guidelines. However, meanderings could be detected for the drugsused in the therapy of substance related disorders, for which TDM is mostly notestablished yet. The result of the antidepressants and antipsychotics permits aclassification of the reachable points; upper 13 - TDM strongly recommended10 to 13 - TDM recommended, 8 to 10 - TDM useful and below 8 - TDMpotentially useful. Conclusion: These results suggest this rating scale is sensitiveto detect the appropriateness of TDM for drug treatment. For those drugs TDM isnot established a more objective estimation is possible, thus the scoring helps tofocus on the most likely drugs to require TDM

Molecular signatures of psychosocial stress and cognition are modulated by chronic lithium treatment

Chronic psychosocial stress is an important environmental risk factor of psychiatric diseases such as schizophrenia. Social defeat in rodents has been shown to be associated with maladaptive cellular and behavioral consequences including cognitive impairments. Although gene expression changes upon psychosocial stress have been described, a comprehensive transcriptome profiling study at the global level in precisely defined hippocampal subregions which are associated with learning has been lacking. In this study, we exposed adult C57Bl/6N mice for 3 weeks to “resident-intruder” paradigm and combined laser capture microdissection with microarray analyses to identify transcriptomic signatures of chronic psychosocial stress in dentate gyrus and CA3 subregion of the dorsal hippocampus. At the individual transcript level, we detected subregion specific stress responses whereas gene set enrichment analyses (GSEA) identified several common pathways upregulated upon chronic psychosocial stress related to proteasomal function and energy supply. Behavioral profiling revealed stress-associated impairments most prominent in fear memory formation which was prevented by chronic lithium treatment. Thus, we again microdissected the CA3 region and performed global transcriptome analysis to search for molecular signatures altered by lithium treatment in stressed animals. By combining GSEA with unsupervised clustering, we detected pathways that are regulated by stress and lithium in the CA3 region of the hippocampus including proteasomal components, oxidative phosphorylation, and anti-oxidative mechanisms. Our study thus provides insight into hidden molecular phenotypes of chronic psychosocial stress and lithium treatment and proves a beneficial role for lithium treatment as an agent attenuating negative effects of psychosocial stress on cognition