Sleep Regulates Incubation of Cocaine Craving

After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine selfadministration, rats exhibited persistent reductionin nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats duringtheir active (dark) phase ofthe day, which selectively decreasedthe fragmentation of REM sleep duringtheir inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depictingthe progressiveintensification of cocaine seeking after withdrawal. In contrast, experimentallyincreasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substratethat can be engaged by sleepto regulate cocaine craving and relapse, anddemonstrate sleep-basedtherapeutic opportunitiesfor cocaine addiction.

Leia o artigo na íntegra:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588606/pdf/zns13300.pdf

Conteúdo de aulas do prof. Thiago Coronato Nunes.

What do the genetic association data say about the high risk of suicide in people with depression?

BACKGROUND: Available sources indicate that the risk of suicide in people with major depression is higher than other psychiatric disorders. Although it seems that these two conditions may have a shared cause in some cases, no studies have been conducted to identify a common basis for them.

METHODS: In this study, following an extensive review of literature, we found almost all the genes that are involved in major depression and suicidal behavior, and we isolated genes shared between the two conditions. Then, we found all physical or functional interactions within three mentioned gene sets and reconstructed three genetic interactive networks. All networks were analyzed topologically and enriched functionally. Finally, using a drug repurposing approach, we found the main available drugs that interacted with the most central genes shared between suicidal behavior and depression.

RESULTS: The results demonstrated that BDNF, SLC6A4, CREB1, and TNF are the most fundamental shared genes; and generally, disordered dopaminergic, serotonergic, and immunologic pathways in neuronal projections are the main shared deficient pathways. In addition, we found two genes, SLC6A4 and SLC6A2, to be the main therapeutic targets, and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) and Tricyclic Antidepressants (TCA) to be the most effective drugs for individuals with depression at risk for suicide.

CONCLUSIONS: Our results, in addition to shedding light on the integrated molecular basis of depression-suicide, offer new therapeutic targets for individuals with depression at high risk for suicide and could pave the way for future preclinical and clinical studies. However, integrative systems biology-based studies highly depend on existing data and related databases, as well as the arrival of new experimental data sources in the future, possibly affecting the current results.

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https://drive.google.com/file/d/1oUvPJkmDUjbcKlG0kD7z4n3wsDFtGAND/view?usp=sharing

Association of DNA methylation in BDNF with escitalopram treatment response in depressed Chinese Han patients

Purpose: The neurotrophin brain-derived neurotrophic factor (BDNF) has been found to be associated with both the pathophysiology of depression and antidepressants response. Gene expression differences were partly mediated by SNP, which might be identified as a predictor of antidepressant response. In the present study, we attempt to identify whether DNA methylation, another factor known to affect gene transcription, might also predict antidepressant response.

mETHODS: A total of 85 depressed Chinese Han patients were followed-up 8 weeks after initiating escitalopram treatment. Treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The bisulfate sequencing was used to assess DNA methylation. Four single nucleotide polymorphisms (SNPs) in the BDNF gene were genotyped using PCR-RFLP or PCR sequencing.

RESULTS: We identified a DNA methylation predictor (P = 0.006-0.036) and a DNA methylation by LES interaction predictor (OR = 1.442 [1.057-1.968], P = 0.021) of general antidepressant treatment response. Lower mean BDNF DNA methylation was associated with impaired antidepressant response. Furthermore, the present data indicated that age, life stress, and SNPs genotype might be likely related to DNA methylation status. Average DNA methylation of BDNF at baseline was significantly lower than that at endpoint after 8 weeks of escitalopram treatment, which was based only on a subset of cases (n = 44).

CONCLUSIONS: Our results suggest that BDNF DNA hypomethylation and its interaction with lower LES score might result in impaired antidepressant treatment response. The pharmacoepigenetic study could eventually help in finding epigenetic biomarkers of antidepressant response.

Leia o artigo na íntegra: 

https://drive.google.com/file/d/1V3CDpJSHDjyb8e_cewaiKyUGHlw3nHFk/view?usp=sharing

Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review

Background: Selective serotonin reuptake inhibitors (SSRI) are widely used in medical practice. They have been associated with a broad range of symptoms, whose clinical meaning has not been fully appreciated. 

Methods: The PRISMA guidelines were followed to conduct a systematic review of the literature. Titles, abstracts, and topics were searched using the following terms: ‘withdrawal symptoms’ OR ‘withdrawal syndrome’ OR ‘discontinuation syndrome’ OR ‘discontinuation symptoms’, AND ‘SSRI’ OR ‘serotonin’ OR ‘antidepressant’ OR ‘paroxetine’ OR ‘fluoxetine’ OR ‘sertraline’ OR ‘fluvoxamine’ OR ‘citalopram’ OR ‘escitalopram’. The electronic research literature databases included CINAHL, the Cochrane Library, PubMed and Web-of-Science from inception of each database to July 2014. 

Results: There were 15 randomized controlled studies, 4 open trials, 4 retrospective investigations, and 38 case reports. The prevalence of the syndrome was variable, and its estimation was hindered by a lack of case identification in many studies. Symptoms typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering. However, many variations are possible, including late onset and/or longer persistence of disturbances. Symptoms may be easily misidentified as signs of impending relapse. 

Conclusions: Clinicians need to add SSRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs. The term ‘discontinuation syndrome’ that is currently used minimizes the potential vulnerabilities induced by SSRI and should be replaced by ‘withdrawal syndrome’. 

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https://drive.google.com/file/d/1lKJhkZ0w4tX9FDFIDFWn-dRdp_H4sUTg/view?usp=sharing

Cognitive Effects of Benzodiazepines in Psychogeriatric Patients

Introduction: Previous studies have shown cognitive impairment in long-term benzodiazepine users compared to non-users. However, little is known about such eff ects in a population of geriatric psychiatry patients. The aim of this study was to identify differences between benzodiazepine users and non-users on standardized tests of the cognitive fi elds of learning and memory, executive functions and vigilance, at admittance to a department of geriatric psychiatry.

Materials and Methods: Hopkins verbal learning test, Stroop test and digit vigilance test were performed in all patients. Test performances were compared between benzodiazepine users (n = 168) and non-users (n = 73). A multiple linear regression model was used, adjusting for different baseline characteristics (years of education, dementia and depression).

Results: No significant differences in test results were found between benzodiazepine users and non-users on 11 out of 12 cognitive tests results. On one of the 12 test results (time used on the digit vigilance test), benzodiazepine users showed better performance compared to non-users (β = − 0.20, p = 0.032). This finding was not statistically significant after Bonferroni correction for multiple testing.

Conclusion: This study of geriatric psychiatry benzodiazepine users did not reveal cognitive impairment compared to non-users on the cognitive areas tested. Other possible negative consequences of benzodiazepine use should, however, also be considered when prescribing drugs to older patients.

Leia o artigo na íntegra:

https://drive.google.com/open?id=0B5pZ7PZOg6M_UV9uY3BabEJyLXc

O uso do metilfenidato em pacientes com fadiga relacionada à neoplasia maligna

A fadiga relacionada à neoplasia maligna impacta na qualidade de vida do paciente de forma

severa, diminuindo sua capacidade funcional diária. Desta forma, deve-se abordar de forma

ampla as orientações gerais sobre a fadiga a fim de beneficiar o paciente com medidas

farmacológicas e não farmacológicas a serem adotadas, seja a fadiga moderada ou severa,

adotando aos pacientes com fadiga leve e que não interfira na qualidade de vida o tratamento

não farmacológico como única medida terapêutica. No entanto, observa-se que o tratamento

não farmacológico se mostra promissor com o uso de terapias cognitivas-comportamentais,

exercícios físicos e terapias do sono. Enquanto o tratamento farmacológico, tem apresentados

resultados favoráveis incluindo o uso de psicoestimulantes como metilfenidato (em pacientes

com fadiga severa). Através de uma abordagem multidisciplinar o tratamento pode ser

oferecido, onde individualize-se as opções terapêuticas dentro de um contexto que promova o

diagnóstico acurado da fadiga relacionada ao câncer, além de um tratamento específico e

adequado para cada paciente que apresente este sintoma de extrema relevância e que gera um

grande impacto na qualidade de vida de pacientes com câncer.

Acesse o trabalho completo:

https://drive.google.com/file/d/1IMm2pWfHOK2fpgVCLPq9KKCqbU6d2SoO/view?usp=sharing