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Efavirenz (EFV) is used for antiretroviral treatment of HIV infection, and successfully inhibits viral replication and mother-to-child transmission of HIV during pregnancy and childbirth. Unfortunately, the drug induces neuropsychiatric symptoms such as anxiety and depressed mood and potentially affects cognitive performance. EFV acts on, among others, the serotonin transporter and serotonin receptors that are expressed in the developing brain. Yet, how perinatal EFV exposure affects brain cytoarchitecture remains unclear. Here, we exposed pregnant and lactating rats to EFV, and examined in the medial prefrontal cortex (mPFC) of their adult offspring the effects of the maternal EFV exposure on cortical architecture. We observed a significant decrease in the number of cells, mainly mature neurons, in the infra/prelimbic and cingulate cortices of adult offspring. Next, we found an altered cortical cytoarchitecture characterized by a significant reduction in deep- and superficial-layer cells. This was accompanied by a sharp increase in programmed cell death, as we identified a significantly higher number of cleaved Caspase-3-positive cells. Finally, the serotonergic and dopaminergic innervation of the mPFC subdomains was increased. Thus, the perinatal exposure to EFV provoked in the mPFC of adult offspring cell death, significant changes in cytoarchitecture, and disturbances in serotonergic and dopaminergic innervation. Our results are important in the light of EFV treatment of HIV-positive pregnant women, and its effect on brain development and cognitive behavior., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The gamma-hydroxybutyric acid (GHB) withdrawal syndrome often has a fulminant course, with a rapid onset and swift progression of severe complications. In clinical practice, two pharmacological regimens are commonly used to counteract withdrawal symptoms during GHB detoxification: tapering with benzodiazepines (BZDs) or tapering with pharmaceutical GHB. In Belgium, standard treatment is tapering with BZDs, while in the Netherlands, pharmaceutical GHB is the preferred treatment method. Though BZDs are cheaper and readily available, case studies suggest GHB tapering results in less severe withdrawal and fewer complications., Objectives: This study aimed to compare two treatments-as-usual in tapering methods on withdrawal, craving and adverse events during detoxification in GHB-dependent patients., Methods: In this multicentre non-randomised indirect comparison of two treatments-as-usual, patients with GHB dependence received BZD tapering (Belgian sample: n = 42) or GHB tapering (Dutch sample: n = 42, matched historical sample). Withdrawal was assessed using the Subjective and Objective Withdrawal Scales, craving was assessed with a Visual Analogue Scale and adverse events were systematically recorded. Differences in withdrawal and craving were analysed using a linear mixed-model analysis, with 'days in admission' and 'detoxification method' as fixed factors. Differences in adverse events were analysed using a Chi-square analysis., Results: Withdrawal decreased over time in both groups. Withdrawal severity was higher in patients receiving BZD tapering (subjective mean = 36.50, standard deviation = 21.08; objective mean = 8.05, standard deviation = 4.68) than in patients receiving pharmaceutical GHB tapering (subjective mean = 15.90; standard deviation = 13.83; objective mean = 3.72; standard deviation = 2.56). No differences in craving were found. Adverse events were more common in the BZD than the GHB group, especially delirium (20 vs 2.5%, respectively)., Conclusions: These results support earlier work that BZD tapering might not always sufficiently dampen withdrawal in GHB-dependent patients. However, it needs to be taken into account that both treatments were assessed in separate countries. Based on the current findings, tapering with pharmaceutical GHB could be considered for patients with GHB dependence during detoxification, as it has potentially less severe withdrawal and fewer complications than BZD tapering.

Unprotected sexual contact continues to be a main cause of HIV transmission and poses certain key populations at increased risk for HIV infection. One of the populations at high risk are men who have sex with men. A subset of MSM engages in chemsex, whereby consumption of illicit drugs is used to facilitate or enhance sexual activity. This practice can have several negative consequences, such as sexually transmitted infections (including HIV) and mental health problems (including compulsive sexual behavior, addiction, and mood disorders). In this article, we provide our perspective on the current situation that medical professionals dealing with MSM living with HIV often feel empty-handed in how to deal with these behavioral and psychological issues. Close collaboration between somatic and mental health professionals is key to address treatment needs of people living with HIV, regarding the negative consequences of chemsex and their overall quality of life. In this article, we discuss possibilities for psychological treatment, including behavioral skills training to improve impulse control and reduce compulsive sexual behaviors among MSM living with HIV who persistently engage in sexual transmission risk behavior, based on our experience with implementing such an intervention. Important barriers and facilitators for further implementation of behavioral interventions will be discussed. Reduction of HIV transmission risk behavior is needed to achieve the WHO aim to end HIV as a public health threat by 2030. We propose that close collaboration between somatic and mental health professionals and implementation of behavioral interventions for risk populations are key to achieve this goal., (Copyright © 2020 Arends, van den Heuvel, Foeken-Verwoert, Grintjes, Keizer, Schene, van der Ven and Schellekens.)

Impaired brain processing of alcohol-related rewards has been suggested to play a central role in alcohol use disorder. Yet, evidence remains inconsistent and mainly originates from studies in which participants passively observe alcohol cues or taste alcohol. Here, we designed a protocol in which beer consumption was predicted by incentive cues and contingent on instrumental action closer to real life situations. We predicted that anticipating and receiving beer (compared with water) would elicit activity in the brain reward network and that this activity would correlate with drinking level across participants. The sample consisted of 150 beer-drinking males, aged 18 to 25 years. Three groups were defined based on alcohol use disorders identification test (AUDIT) scores: light drinkers (n = 39), at-risk drinkers (n = 64), and dependent drinkers (n = 47). fMRI measures were obtained while participants engaged in the beer incentive delay task involving beer- and water-predicting cues followed by real sips of beer or water. During anticipation, outcome notification and delivery of beer compared with water, higher activity was found in a reward-related brain network including the dorsal medial prefrontal cortex, orbitofrontal cortex, and amygdala. Yet, no activity was observed in the striatum, and no differences were found between the groups. Our results reveal that anticipating, obtaining, and tasting beer activates parts of the brain reward network, but that these brain responses do not differentiate between different drinking levels., (© 2019 The Authors Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Alcohol Use Disorder (AUD) and depressive disorder often co-exist and have a shared heritability. This study aimed to investigate Brain-Derived Neurotrophic Factor (BDNF) and three Cell Adhesion Molecules (CAMs) as transdiagnostic biomarkers in AUD and depression co-morbidity., Methods: In a cross-sectional study, patients with AUD (n=22), AUD and depression (n=19), and healthy controls (n=20) were examined. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale. Anhedonia, alcohol use and dependence, craving, and social adaptation were assessed through self-report questionnaires. BDNF and CAM concentrations in peripheral serum were measured after overnight fasting using a Luminex assay. After controlling for age and gender, biomarker levels were compared across groups. The association between biomarker concentrations and symptom severity scales were explored using correlation and multiple regression analyses., Results: BDNF and Neuronal CAM were lower in patients with AUD with and without depression compared to healthy controls. No differences were observed for Vascular CAM-1 and Interstitial CAM-1. BDNF correlated negatively with anhedonia levels. BDNF, age and gender together explained 21% of variability in anhedonia levels., Conclusion: This pilot study suggests that peripheral levels of BDNF and NCAM might be reduced in AUD with and without comorbid mood disorder. Since low BDNF levels were associated with self- reported anhedonia across these conditions, BDNF and anhedonia might reflect transdiagnostic aspects involved in AUD and depression., (Copyright © 2020 Levchuk, Meeder, Roschina, Loonen, Boiko, Michalitskaya, Epimakhova, Losenkov, Simutkin, Bokhan, Schellekens and Ivanova.)

Background: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) often co-occur. Both disorders are characterized by impulsive choice. However, little is known about the effects of substance misuse (SM) and family history of SUD (FH) on impulsive choice in ADHD-SUD comorbidity. Impulsive choice is also linked to callous-unemotional (CU) traits, which are suggested to play a role in ADHD-SUD comorbidity. Our aim was to examine the effects of (1) FH and (2) SM on impulsive choice, while exploring the role of CU traits., Methods: Impulsive choice was assessed with the delay discounting (DD) task. We compared task performance across (1) ADHD patients and controls with or without FH of SUD (ADHD FH+: n = 86; ADHD FH-: n = 63; control FH+: n = 49; control FH-: n = 72; mean age of the whole sample [n = 270]: 16.39, SD: 3.43) and (2) family history-matched ADHD groups with and without SM and controls (ADHD + SM: n = 62; ADHD-only: n = 62; controls: n = 62; mean age of the whole sample [n = 186]: 18.01, SD: 2.71). Effects of CU traits were explored by adding this as a covariate in all analyses., Results: (1) There was no main effect of FH on DD. (2) We found increased DD in ADHD + SM compared to ADHD-only and no difference between ADHD-only and controls. Finally, increased DD was associated with increased callous traits only in ADHD FH+ and control FH+., Conclusions: In adolescents and young adults with ADHD, high impulsive choice might only be present in those with comorbid SM and in an FH+ subgroup with high callous traits. This suggests that impulsive choice in ADHD might result from (1) effects of SM and (2) a combined effect of SUD vulnerability and high callousness. Future studies should investigate efficacy of early interventions, targeting CU traits., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Background: Childhood adversity is known to influence personality development. Studies suggest that distinct types of childhood adversities have differential effects on personality dimensions. However, different types of adversity often co-occur, and personality dimensions are strongly interconnected., Objective: The aim of this study was to use a network approach to analyze the interrelationships between different types of childhood adversity and diverse personality dimensions integratively., Participants and Setting: We used previously collected data on 142 alcohol dependent patients and 102 healthy controls., Methods: The participants completed the Interview for Traumatic Events in Childhood, the Parental Acceptance and Rejection Questionnaire and the Temperament and Character Inventory. Outcomes on the subscales of these instruments were included in the network analysis., Results: The resulting network showed strong connections between different types of childhood adversity, and between the different temperaments and characters of personality. Childhood adversity, mainly physical abuse and maternal rejection, was connected to most personality dimensions, except for reward dependence. Physical abuse showed the highest centrality measures, indicating a central, important role in the network., Conclusions: These findings confirm that different types of childhood adverse experiences often co-occur, and suggest that specifically physical and emotional abuse, and maternal rejection might play a prominent role in shaping personality., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Catatonia is a syndrome that can present in different forms and can occur in multiple psychiatric and somatic conditions. This case report describes lethal catatonia caused by delayed toxic leukoencephalopathy after excessive use of cocaine and methadone. The characteristic radiographic imaging and biphasic course are discussed., Case Report: A 54-year-old woman was presented unconsciously at the emergency department after intoxication with methadone and cocaine. After initial recovery, her condition deteriorated unexpectedly, resulting in lethal catatonia. Magnetic resonance imaging (MRI) showed hyperintense white matter abnormalities and diffusion restriction, evident for leukoencephalopathy., Discussion: Catatonia can develop in multiple psychiatric and somatic diseases, including toxic leukoencephalopathy. A biphasic course and specific MRI findings are characteristics for delayed toxic leukoencephalopathy, due to intoxication with drugs.

Background: Efavirenz is commonly prescribed for children with HIV infection, yet little is known about risks of neuropsychiatric side-effects. We aimed to compare competence (social involvement, activities, and school performance) and psychopathology (internalising and externalising problems), cognitive performance (intelligence and working memory), and adherence in Tanzanian children on an efavirenz-based versus a non-efavirenz-based regimen., Methods: In this multicentre, cross-sectional, observational study, we included consecutive children (aged 6-12 years) with HIV infection, on combination antiretroviral therapy (cART) for at least 6 months, and with viral loads of less than 1000 copies per mL from HIV care clinics of three primary health facilities and three referral hospitals in Moshi, Kilimanjaro, Tanzania. Children with acute illnesses, medication switch in the 6 months before the study visit, and any history of brain injury or developmental delay before cART initiation were excluded. All interviews and assessments were done by trained local research nurses under the supervision of a medical doctor. The primary outcomes, competence and psychopathology, were measured with the Child Behavior Checklist. We used ANCOVA to assess differences between groups. This study is registered with ClinicalTrials.gov, number NCT03227653., Findings: Between June 19, 2017, and Dec 14, 2017, 141 children were analysed, of whom 72 (51%) used efavirenz-based cART and 69 (49%) used non-efavirenz-based cART. After controlling for age, sex, and clinical and demographic confounders, we observed lower competence (adjusted mean difference -2·43 [95% CI -4·19 to -0·67], p=0·0071), largely driven by lower school performance scores (adjusted mean difference -0·91 [-1·42 to -0·40], p=0·00055), in the efavirenz group than in the non-efavirenz group. More total (adjusted mean difference 5·96 [95% CI -1·12 to 13·04], p=0·098) and internalising (adjusted mean difference 2·00 [-0·29 to 4·29], p=0·086) behavioural problems were seen in the efavirenz group than in the non-efavirenz group, although these findings were non-significant. No differences were found in externalising problems (adjusted mean difference 0·78 [95% CI -1·55 to 3·11], p=0·51)., Interpretation: Our results suggest that treatment with efavirenz in children is associated with a mild increase in neuropsychiatric symptoms, especially in children who receive doses higher than or equal to the WHO recommended doses for efavirenz. Clinical awareness and adequate follow-up of neuropsychiatric symptoms in efavirenz in children remain warranted., Funding: Aidsfonds, Radboud University Medical Center., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

HIV, hepatitis B and C, and syphilis share common transmission routes of which primarily unsafe sexual contact and injecting drug use are important. Impulsivity is a major factor contributing to this transmission risk behavior; however comprehensive studies within female, prison, and Asian populations are scarce. This cross-sectional study aims to delineate the contributions of different aspects of impulsivity to risk behavior, among female inmates living in a prison in Jakarta (N = 214). The relationships between various aspects of impulsivity, risk behaviors and seropositivity were tested using analyses of variance and logistic regression analyses. Motor impulsivity was related to alcohol use, reward-related impulsivity to drug use, and cognitive/goal-directed impulsivity to sexual risk behavior. Finally, goal-directed impulsivity was also directly associated with seropositivity. Specific aspects of impulsivity are associated with different types of risk behavior in Indonesian female prisoners, which can be relevant for future studies on infection prevention strategies for such a population., Competing Interests: The authors have declared that no competing interests exist.

Efavirenz is recommended as a preferred first-line drug for women of childbearing potential living with human immunodeficiency virus. Efavirenz is known for its central nervous system side effects, which are partly mediated by serotonergic actions. The neurotransmitter serotonin exerts neurotrophic effects during neurodevelopment and antenatal exposure to serotonergic agents has been linked to developmental delay. Although the teratogenic risks of efavirenz appear to be minimal, data on long-term developmental effects remain scarce. Here, we aimed to investigate the short- and long-term behavioral and neurodevelopmental effects of perinatal efavirenz exposure. We treated pregnant rats from gestation day 1 until postnatal day 7 with efavirenz (100 mg/kg) or vehicle. We measured behavioral outcomes in male offspring during the first 3 postnatal weeks, adolescence and adulthood, and conducted brain immunohistochemistry analyses after sacrifice. Perinatal efavirenz exposure resulted in reduced body weight and delayed reflex and motor development. During adulthood, we observed a decrease in the total number of cells and mature neurons in the motor cortex, as well as an increase in the number of Caspase-3-positive cells and serotonergic fibers. Together, our data show a developmental delay and persistent changes in the brain motor cortex of rats exposed to efavirenz perinatally. Because over 1 million children born annually are exposed to antiretroviral therapy, our findings underline the need for clinical studies on long-term neurodevelopmental outcomes of perinatal exposure to efavirenz.

Short Summary: : In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption.

Background: Gamma-hydroxybutyrate (GHB) dependence is associated with a severe, potentially lethal, withdrawal syndrome and relapse rates as high as 60% within 3 months of detoxification. Baclofen has been shown to decrease self-administration of GHB in mice and reduce relapse in a case series of GHB-dependent patients. Controlled studies on the effectiveness of baclofen to prevent relapse in GHB-dependent patients are lacking., Aim: The aim of this study was to assess effectiveness of baclofen in preventing relapse in GHB-dependent patients., Methods: This was an out-patient, multicentre, open-label, non-randomized, controlled trial in GHB-dependent patients (n = 107) in the Netherlands. Treatment as usual (TAU, n = 70) was compared with TAU plus baclofen 45-60 mg/day for 3 months (n = 37). Outcome measures were rates of lapse (any use) and relapse (using GHB on average once a week or more), based on self-report. Side effects were monitored with a baclofen side-effects questionnaire. Treatment groups were compared using Chi square analyses, with both per-protocol (PP) and intention-to-treat (ITT) analyses., Results: GHB-dependent patients treated with baclofen after detoxification showed no reduced lapse rates, but reduced relapse and dropout rates, compared with patients receiving TAU only (24 vs 50%). While both ITT and PP analyses revealed similar results, the effectiveness of baclofen prescribed PP was slightly higher than in ITT analysis. Patients reported overall limited side effects, with the most frequently reported being feeling tired (28%), sleepiness (14%) and feeling depressed (14%). No serious adverse events were reported., Conclusions: This study showed potential effectiveness of baclofen in preventing relapse in patients with GHB dependence after detoxification. Though promising, future studies with longer follow-up and a randomized double-blind design should confirm these findings before recommendations for clinical practice can be made., Clinical Trial Registration: Netherlands Trial Register with number NTR4528.

The habenula (Hb) is an evolutionary well-conserved structure located in the epithalamus. The Hb receives inputs from the septum, basal ganglia, hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the inhibitory rostromedial tegmental nucleus (RMTg) and the excitatory interpeduncular nucleus (IPN), which regulate the activity of midbrain monoaminergic nuclei. The Hb is postulated to play a key role in reward and aversion processing across species, including humans, and to be implicated in the different stages of transition from recreational drug intake to addiction and co-morbid mood disorders. The Hb is divided into two anatomically and functionally distinct nuclei, the lateral (LHb) and the medial (MHb), which are primarily involved in reward-seeking (LHb) and misery-fleeing (MHb) behavior by controlling the RMTg and IPN, respectively. This review provides a neuroanatomical description of the Hb, discusses preclinical and human findings regarding its role in the development of addiction and co-morbid mood disorders, and addresses future directions in this area., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The non-nucleoside reverse transcriptase inhibitor efavirenz is part of the WHO guidelines for preferred first-line treatment of HIV-1-infected adults, pregnant and lactating women, and children. Efavirenz is well known to cause CNS toxicity. Although good data for CNS toxicity are available for adults, the opposite is true for children. Paediatric studies on this topic frequently suffer from small sample sizes or absence of thorough neuropsychiatric assessments. In this Personal View, we focus on two knowledge gaps of CNS toxicity of efavirenz in children. First, plasma concentrations of efavirenz are difficult to predict in children because of immaturity of and genetic variation in metabolic enzymes. Second, efavirenz exerts a lysergide (LSD)-like effect on brain serotonergic pathways and affects CNS metabolic pathways, including mitochondrial function. Whether these effects interfere with normal brain development is unknown. These uncertainties underline the imminent need for better monitoring of mental health and neurocognitive development in children given and exposed to efavirenz., (Copyright © 2016 Elsevier Ltd. All rights reserved.)