Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder.

BACKGROUND: In Canada, low awareness of evidence-based interventions for the clinical management of alcohol use disorder exists among health care providers and people who could benefit from care. To address this gap, the Canadian Research Initiative in Substance Misuse convened a national committee to develop a guideline for the clinical management of high-risk drinking and alcohol use disorder. METHODS: Development of this guideline followed the ADAPTE process, building upon the 2019 British Columbia provincial guideline for alcohol use disorder. A national guideline committee (consisting of 36 members with diverse expertise, including academics, clinicians, people with lived and living experiences of alcohol use, and people who self-identified as Indigenous or Métis) selected priority topics, reviewed evidence and reached consensus on the recommendations. We used the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) and the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts to ensure the guideline met international standards for transparency, high quality and methodological rigour. We rated the final recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool; the recommendations underwent external review by 13 national and international experts and stakeholders. RECOMMENDATIONS: The guideline includes 15 recommendations that cover screening, diagnosis, withdrawal management and ongoing treatment, including psychosocial treatment interventions, pharmacotherapies and community-based programs. The guideline committee identified a need to emphasize both underused interventions that may be beneficial and common prescribing and other practice patterns that are not evidence based and that may potentially worsen alcohol use outcomes. INTERPRETATION: The guideline is intended to be a resource for physicians, policymakers and other clinical and nonclinical personnel, as well as individuals, families and communities affected by alcohol use. The recommendations seek to provide a framework for addressing a large burden of unmet treatment and care needs for alcohol use disorder within Canada in an evidence-based manner.

Ligne directrice canadienne pour la prise en charge clinique de la consommation d'alcool à risque élevé et du trouble d'utilisation de l'alcool.

CONTEXTE: Au Canada, on note que les équipes soignantes et les personnes qui bénéficieraient de soins ciblés connaissent peu les interventions fondées sur des données probantes pour la prise en charge clinique du trouble d'utilisation de l'alcool. Pour combler cette lacune, l'Initiative canadienne de recherche sur l'abus de substances a créé un comité national dans le but d'élaborer une ligne directrice pour la prise en charge clinique de la consommation d'alcool à risque élevé et du trouble lié à la consommation d'alcool. MÉTHODES: L'élaboration de cette ligne directrice s'est faite selon le processus ADAPTE, et est inspirée par une ligne directrice britanno-colombienne de 2019 pour le trouble lié à la consommation d'alcool. Un comité national de rédaction de la ligne directrice (composé de 36 membres de divers horizons, notamment des universitaires, des médecins, des personnes ayant ou ayant eu des expériences de consommation d'alcool et des personnes s'identifiant comme Autochtones ou Métis) a choisi les thèmes prioritaires, a passé en revue les données probantes et atteint un consensus relatif aux recommandations. Nous avons utilisé l'outil AGREE II (Appraisal of Guidelines for Research and Evaluation Instrument II) et les principes de divulgation des intérêts et de gestion des conflits lors du processus de rédaction des lignes directrices (Principles for Disclosure of Interests and Management of Conflicts in Guidelines) publiés en anglais par le Réseau international des lignes directrices (Guidelines International Network) pour nous assurer que la ligne directrice répondait aux normes internationales de transparence, de qualité élevée et de rigueur méthodologique. Nous avons évalué les recommandations finales à l'aide de l'approche GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Les recommandations ont fait l'objet d'une revue externe par 13 spécialistes et parties prenantes d'ici et de l'étranger. RECOMMANDATIONS: La ligne directrice comprend 15 recommandations qui concernent le dépistage, le diagnostic, la prise en charge du sevrage et le traitement continu, y compris les interventions psychosociales, les pharmacothérapies et les programmes communautaires. Le comité de rédaction de la ligne directrice a reconnu la nécessité d'insister sur la sous-utilisation des interventions qui pourraient être bénéfiques et sur les modes de prescription et autres pratiques d'usage courant qui ne reposent pas sur des données probantes et pourraient aggraver les effets de la consommation d'alcool. INTERPRÉTATION: La ligne directrice se veut une ressource à l'intention des médecins, des responsables des orientations politiques et des membres des équipes cliniques et autres, de même que des personnes, des familles et des communautés affectées par la consommation d'alcool. Ces recommandations proposent un cadre fondé sur des données probantes pour alléger le lourd fardeau du trouble d'utilisation de l'alcool au Canada et combler les besoins en matière de traitements et de soins.

Expanding access to addictions care: Implementation of a 24-hour healthcare provider support line in British Columbia, Canada.

BACKGROUND: Morbidity and mortality related to substance use have risen to catastrophic levels in North America, and treatment services are often difficult to access. In response, the province of British Columbia (BC), Canada, launched a province-wide addiction medicine support phone line that offers clinicians immediate access to phone consultation with an addictions medicine expert. The service operates 24/7 is accessible to any clinician in the province seeking assistance with an addiction-related question. We describe an evaluation of the reach and perceived impact of the service over its first two years. METHODS: The 24/7 Addiction Medicine Clinician Support Line was evaluated prospectively from June 2020 to April 2022. All provider-to-provider encounters were included. Data was collected from two primary sources: health provider demographic information collected at the time of consultation, and optional clinician surveys conducted after the consultation was complete. Descriptive data are presented as numerical values and percentages. RESULTS: Over the 22-month evaluation period, 1,279 consultations were requested by 631 distinct care providers across British Columbia. The service averaged 15 calls per week across the province, and 51.5% of calls were made outside of business hours. Physicians made the majority of calls to the service (n = 865, 67.6%), followed by nurse practitioners (n = 162, 12.7%). Among those who completed a follow-up survey (n = 258 calls, 20.2% total calls), 81.8% (n = 211) were "very" or "extremely" satisfied with the consultation. Of these respondents, 65.5% (n = 169) reported that the consultation led to the provision of better care for their patient, with 58.1% (n = 150) initiating a new prescription and 22.1% (n = 57) reporting expedited treatment for their patient. The consultation area of focus was most commonly opioid use (n = 417; 59.6%), followed by polysubstance use (n = 98; 14.0%). CONCLUSIONS: The impact of the 24/7 Addiction Clinician Support Line was widespread, and the service increased accessibility to evidence-based addictions treatment across a range of care settings. Clinicians expressed a high degree of satisfaction with the service. To our knowledge, this province-wide program is the first of its kind in North America, offering a scalable and adaptable model to support access to evidence-based addictions care in under-resourced settings.

Cellular and serotonergic correlates of habituated neuroendocrine responses in male and female rats.

Male and females appear equally capable of showing habituated hypothalamic-pituitary-adrenal (HPA) axis output responses to repeated exposures of the same challenge. Whether this reflects, within males and females, common mechanisms of decreased neuronal activity within stress responding, afferents to the paraventricular hypothalamic nucleus (PVH), the final common pathway to the HPA axis, has not been examined. Here we compared in adult male and female rats the extent to which declines in HPA axis responses to repeated restraint are met by habituated cellular (Fos) responses, in addition to changes in serotonin (5-hydroxytryptamine; 5-HT) expression and signaling, which normally stimulates the HPA axis. Thus, alterations in this component of HPA axis drive could provide an underlying basis for sex differences in adaptive responses. Males and females showed reliable declines in ACTH and corticosterone responses after 10 daily episodes of repeated restraint, recapitulated, in largest part, by similar regional patterns of Fos habituation, including within the PVH, several stress sensitive cell groups of the limbic forebrain, as well as within the raphe nucleus. Serotonin staining in the dorsal raphe and terminal profiles in the forebrain continued to reflect a higher pre-synaptic capacity for the 5-HT system in females. The sexual dimorphism encountered within the lateral septum and medial preoptic area of control animals was less distinguished in the repeat condition, however, whereas 5-HT varicosities in the PVH increased after repeated restraint only in females. Relative to their singly restrained counterparts, males displayed an increase in 5-HT 1 A receptor expression in the raphe nucleus after repeated restraint, whereas females showed a decrease in 5-HT 1 A mRNA levels in the hippocampus and in the zona incerta, representing the most proximal of cell groups expressing the 5-HT 1 A receptor in the vicinity of the PVH. In conclusion, similar regional profiles of cellular habituation in males and females suggest common CNS substrates of neuroendocrine adaptation. However, this process may be met by underlying sex differences in serotonergic control, given the respective roles for pre- and postsynaptic 5-HT 1 A receptors in mediating serotonin availability and signal transfer.

Organizational and activational effects of testosterone on masculinization of female physiological and behavioral stress responses.

The prevalence of affective disorders is two times greater in women than in men. The onset of anxiety and depression occurs at different ages that may correspond to key developmental periods when the brain is more vulnerable to hormonal and exogenous influences. Because stressful life events can precipitate disease onset, the development of greater stress sensitivity in females may contribute to their increased vulnerability. Gonadal hormone exposure in males during early development and again from puberty onward plays a prominent role in sexually dimorphic brain formation, possibly contributing to sex differences in stress responsivity. Therefore, organizational effects of testosterone propionate (TP) administered postnatally and activational effects of TP administered beginning at puberty on adult female physiological and behavioral stress responses were examined in mice. Although the activational effects of TP in females ameliorated the sex difference in the hypothalamic-pituitary-adrenal axis stress response, there was no effect of postnatal TP. Similarly, higher immobile time in intact females in the tail suspension test was blunted by activational TP in the absence of postnatal TP. However, in the marble-burying test of anxiety-like behaviors, organizational and activational TP independently resulted in increased burying behaviors. These results show that TP administration has distinct effects on reducing physiological and behavioral stress responsivity in rodent models and suggest that sex differences in these responses may partially result from the absence of testosterone in females.

Identifying early behavioral and molecular markers of future stress sensitivity.

Puberty is a plastic period of neurological development when critical maturation of stress pathways occurs. Abnormal maturation may be predictive of future stress sensitivity and affective disorder risk. To identify potential early markers of stress-related disease predisposition, we examined physiological and behavioral stress responses in male pubertal mice compared with adults, using a genetic model of elevated stress sensitivity, CRF receptor-2 (CRFR2)-deficient mice. Juvenile mice of both genotypes exhibited greater basal and stress-induced corticosterone levels than adult mice, indicating that overall hypothalamic-pituitary-adrenal axis sensitivity diminishes in adulthood. However, juvenile CRFR2-deficient mice displayed a delayed stress recovery typical of adults of this genotype, suggesting an early marker of stress sensitivity. The adult phenotype of reduced hippocampal glucocorticoid receptor expression in these sensitive mice was also detected during puberty. This reduction may account for an impaired hypothalamic-pituitary-adrenal axis negative feedback and as such be an early indicator of a stress-sensitive phenotype. Examination of behavioral responses to stress revealed that CRFR2-deficient mice show exaggerated postpubertal maturation. Although wild-type mice did not alter their burying response to stress-provoking marbles after puberty, CRFR2-deficient mice showed a dramatic increase in burying behavior. We conclude that identification of abnormal pubertal stress pathway maturation may be predictive of adult heightened stress sensitivity and future susceptibility to stress-related affective disorders.

Sex differences in serotonin (5-HT) 1A receptor regulation of HPA axis and dorsal raphe responses to acute restraint.

The serotonin (5-HT) 1A receptor subtype has been implicated as an important mediator for the stimulatory influence of serotonin on stress hypothalamic-pituitary-adrenal (HPA) activity, at least in males. Females show greater HPA axis responses to stress compared to males. To determine the nature by which the 5-HT 1A receptor contributes to the sex difference in stress, we examined neuroendocrine and cellular (Fos) responses in male and female rats receiving systemic injections of the 5-HT 1A receptor antagonist, WAY 100635, prior to acute restraint exposure. WAY decreased the corticosterone response in males, but not in females. In the paraventricular nucleus of the hypothalamus (PVH), WAY produced similar decrements in the restraint-induced activation (Fos) of neuroendocrine neurons in males and females. In contrast to the PVH, WAY administration increased total Fos activation in the dorsal raphe nucleus, but only in males. WAY also provoked higher Fos responses within subsets of dorsal raphe cells identified as serotonergic (tryptophan hydroxylase-, TPH-ir) in both males and females. These data provide evidence to suggest a differential influence of presynaptic 5-HT 1A receptors to regulate the stress-induced recruitment of non-serotonergic dorsal raphe neurons in males and females. At present, we cannot rule out a possible role for estrogen in females to alter 5-HT outflow to the HPA axis. There was a negative correlation between estrogen and Fos responses within TPH-positive cells in the dorsal raphe of WAY-administered females, whereas a positive correlation was found between estrogen and 5-HT 1A mRNA expression localized to the region of the zona incerta in close proximity to the PVH. As the raphe complex and 5-HT system impinge on several central autonomic, behavioral and neuroendocrine control systems, the current findings provide an important framework for future studies directed at sex differences in adaptive homeostatic responses.

Sex differences in the HPA axis.

The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.

Androgenic influence on serotonergic activation of the HPA stress axis.

The higher incidence of stress-mediated affective disorders in women may be a function of gonadal hormone influence on complex interactions between serotonin and neural circuits that mediate the hypothalamic-pituitary-adrenal (HPA) stress axis. The paraventricular nucleus of the hypothalamus (PVN) receives serotonergic innervation, and selective serotonin reuptake inhibitors such as citalopram activate the HPA axis independent of stress. We have previously demonstrated that the magnitude of this serotonergic activation was greater in females and was attenuated by testosterone administration; however, the potential central sites of action where androgens reduce these serotonergic effects have not been determined. Therefore, we examined a time course of corticosterone production and used central c-Fos protein levels to assay neuronal activation in stress-related brain regions in female, male, and gonadectomized male mice after an acute citalopram injection (15 mg/kg). In the hippocampus, c-Fos-immunoreactivity was greater in males than in females or gonadectomized males. This same pattern emerged in the lateral septum after vehicle and gonadectomy reversed the effect of citalopram. These regions are important for inhibitory influences on the PVN, and accordingly, hippocampal c-Fos levels were negatively correlated with corticosterone production. No sex differences in c-Fos were detected in the PVN, cingulate cortex, or paraventricular thalamus in response to vehicle or citalopram. These data support brain region-specific regulation of the HPA axis where sex differences may be mediated partly through androgen enhancement of signaling in inhibitory regions.

Sex differences in the serotonergic influence on the hypothalamic-pituitary-adrenal stress axis.

Appropriate interactions between serotonin (5-HT) and stress pathways are critical for maintaining homeostasis. Dysregulation of hypothalamic-pituitary-adrenal (HPA) stress axis is a common feature in affective disorders in which an involvement of 5-HT neurocircuitry has been implicated in disease vulnerability and treatment responsiveness. Because there is a greater prevalence of affective disorders in women, sex differences in the 5-HTergic influence on stress pathways may contribute to disease disparity. Therefore, our studies compared stress or citalopram-induced corticosterone levels in male and female mice. To determine whether sex-dependent HPA axis responsiveness was mediated by the difference in testosterone levels, testosterone-treated females were also examined. Gene expression patterns in 5-HTergic and stress neurocircuitry were analyzed to determine sites of potential sex differences and mechanisms of testosterone action. As expected, restraint stress corticosterone levels were higher in intact females and were masculinized by testosterone. Interestingly, citalopram administration independent of stress resulted in a greater corticosterone response in females, which was also masculinized by testosterone. Analyses along the 5-HT-HPA axis revealed sex differences including greater pituitary 5-HT receptors and adrenal weights in females. Moreover, in stress-regulatory regions, we found sex differences in glucocorticoid receptor and glutamic acid decarboxylase expression supportive of greater inhibitory modulation and feedback potential in males. Taken together, these data suggest that multiple sites related to 5-HTergic stimulation, corticosterone production, and negative feedback of HPA neurocircuitry combine to produce higher female stress responsiveness. These studies support a potential for sex-specific involvement of 5-HT and stress pathways in the etiology of affective disorders.

Androgen regulation of corticotropin-releasing hormone receptor 2 (CRHR2) mRNA expression and receptor binding in the rat brain.

Stress-induced affective disorders, such as depression and anxiety, are more prevalent in females than in males. The reduced vulnerability to these disorders in males may be due to the presence of androgens, which are known to dampen the stress response and reduce anxiety-like behaviors. However, a neurobiological mechanism for this sex difference has yet to be elucidated. Corticotropin-releasing hormone receptor 2 (CRHR2) has been implicated in regulating anxiety-type behaviors and is expressed in stress-responsive brain regions that also contain androgen receptors (AR). We hypothesized that androgen may exert its effects through actions on CRHR2 and we therefore examined the regulation of CRHR2 mRNA and receptor binding in the male rat forebrain following androgen administration. Young adult male Sprague/Dawley rats were gonadectomized (GDX) and treated with the non-aromatizable androgen, dihydrotestosterone propionate (DHTP) using hormone filled Silastic capsules. Control animals received empty capsules. Using quantitative real-time RT-PCR, CRHR2 mRNA levels were determined in block-dissected brain regions. DHTP treatment significantly increased CRHR2 mRNA expression in the hippocampus, hypothalamus, and lateral septum (p<0.01) when compared to vehicle-treated controls. A similar trend was observed in amygdala (p= 0.05). Furthermore, in vitro autoradiography revealed significantly higher CRHR2 binding in the lateral septum in androgen-treated males, with the highest difference observed in the ventral lateral region. Regulation of CRHR2 mRNA by AR was also examined using an in vitro approach. Hippocampal neurons, which contain high levels of AR, were harvested from E17-18 rat fetuses, and maintained in primary culture for 14 days. Neurons were then treated with dihydrotestosterone (DHT; 1 nM), DHT plus flutamide (an androgen receptor antagonist), or vehicle for 48 h. CRHR2 mRNA levels were measured using quantitative real-time RT-PCR. Consistent with in vivo studies, DHT significantly increased CRHR2 mRNA expression in hippocampal neurons (p<.02) compared to vehicle-treated controls. Flutamide treatment prevented the effect of DHT on CRHR2 mRNA indicating that DHT's effect on CRHR2 expression is AR-mediated. Thus, the CRHR2 gene appears to be a target for regulation by AR and these data suggest a potential mechanism by which androgen may alter mood and anxiety-related behaviors.