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Fulltext Self-management with alcohol over lifespan: psychological mechanisms, neurobiological underpinnings, and risk assessment

Müller CP, Schumann G, Rehm J, Kornhuber J, Lenz B

Mol Psychiatry, 2023 Jul;28(7):2683-2696.
PMID: 37117460 DOI: 10.1038/s41380-023-02074-3

Self-management includes all behavioural measures and cognitive activities aimed at coping with challenges arising throughout the lifespan. While virtually all of these challenges can be met without pharmacological means, alcohol consumption has long been instrumentalized as a supporting tool to help coping with problems arising selectively at adolescence, adulthood, and ageing. Here, we present, to our knowledge, the first systematic review of alcohol instrumentalization throughout lifespan. We searched MEDLINE, Google Scholar, PsycINFO and CINAHL (from Jan, 1990, to Dec, 2022) and analysed consumption patterns, goals and potential neurobiological mechanisms. Evidence shows a regular non-addictive use of alcohol to self-manage developmental issues during adolescence, adulthood, and ageing. Alcohol is selectively used to overcome problems arising from dysfunctional personality traits, which manifest in adolescence. A large range of psychiatric disorders gives rise to alcohol use for the self-management of distinct symptoms starting mainly in adulthood. We identify those neuropharmacological effects of alcohol that selectively serve self-management under specific conditions. Finally, we discuss the adverse effects and associated risks that arise from the use of alcohol for self-management. Even well-controlled alcohol use adversely impacts health. Based on these findings, we suggest the implementation of an entirely new view. Health policy action may actively embrace both sides of the phenomenon through a personalized informed use that allows for harm-controlled self-management with alcohol.
Sex-specific effects of different types of prenatal stress on foetal testosterone levels and NMDA expression in mice

Kalinichenko LS, Smaga I, Filip M, Lenz B, Kornhuber J, Müller CP

Behav Brain Res, 2023 Feb 15;439:114225.
PMID: 36435218 DOI: 10.1016/j.bbr.2022.114225

Prenatal stress is a critical life event often resulting in mental illnesses in the offspring. The critical developmental processes, which might trigger a cascade of molecular events resulting in mental disorders in adulthood, are still to be elucidated. Here we proposed that sex hormones, particularly testosterone, might determine the "developmental programming" of long-term consequences of prenatal stress in foetuses of both sexes. We observed that severe prenatal stress in the model of repeated corticosterone injections enhanced brain levels of corticosterone and testosterone in male foetuses. The expression of GluN1 and GluN2A, but not GluN2B NMDA receptor subunits were significantly reduced in the brain of stressed male foetuses. However, female foetuses were protected against stress effects on the brain corticosterone and testosterone levels. More moderate types of stress, such as repeated restraint stress and chronic unpredictable stress, did not induce an increase in brain corticosterone in dams and testosterone concentrations in foetuses of both sexes. Moreover, chronic unpredictable stress reduced brain testosterone concentration in male foetuses. Altogether, changes in brain testosterone level might be one of the crucial mechanisms determining the development of long-term consequences of severe prenatal stress in male, but not in female foetuses. Targeting this mechanism might allow to develop principally new prediction and therapeutic approaches for prenatal stress-associated psychiatric disorders.
Fulltext INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance

F Smit E, Dooms C, Raskin J, Nadal E, Tho LM, Le X, et al.

Future Oncol, 2022 Mar;18(9):1039-1054.
PMID: 34918545 DOI: 10.2217/fon-2021-1406

MET amplification (METamp), a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors, occurs in up to 30% of patients with non-small-cell lung cancer (NSCLC) progressing on first-line osimertinib. Combining osimertinib with a MET inhibitor, such as tepotinib, an oral, highly selective, potent MET tyrosine kinase inhibitor, may overcome METamp-driven resistance. INSIGHT 2 (NCT03940703), an international, open-label, multicenter phase II trial, assesses tepotinib plus osimertinib in patients with advanced/metastatic EGFR-mutant NSCLC and acquired resistance to first-line osimertinib and METamp, determined centrally by fluorescence in situ hybridization (gene copy number ≥5 and/or MET/CEP7 ≥2) at time of progression. Patients will receive tepotinib 500 mg (450 mg active moiety) plus osimertinib 80 mg once-a-day. The primary end point is objective response, and secondary end points include duration of response, progression-free survival, overall survival and safety. Trial registration number: NCT03940703 (clinicaltrials.gov).
Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males

Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, et al.

Cereb Cortex, 2023 Jan 05;33(3):844-864.
PMID: 35296883 DOI: 10.1093/cercor/bhac106

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
Fulltext Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, et al.

Mol Psychiatry, 2021 Dec;26(12):7403-7416.
PMID: 34584229 DOI: 10.1038/s41380-021-01304-w

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.
Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study

Hoffmann S, Gerhardt S, Mühle C, Reinhard I, Reichert D, Bach P, et al.

Am J Psychiatry, 2024 May 01;181(5):445-456.
PMID: 38196336 DOI: 10.1176/appi.ajp.20230027

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD.
METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling.
RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively.
CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.