IMPORTANCE Methadone access may be uniquely vulnerable to disruption during COVID-19, and even short delays in access are associated with decreased medication initiation and increased illicit opioid use and overdose death. Relative to Canada, US methadone provision is more restricted and limited to specialized opioid treatment programs. OBJECTIVE To compare timely access to methadone initiation in the US and Canada during COVID-19. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was conducted from May to June 2020. Participating clinics provided methadone for opioid use disorder in 14 US states and territories and 3 Canadian provinces with the highest opioid overdose death rates. Statistical analysis was performed from July 2020 to January 2021. EXPOSURES Nation and type of health insurance (US Medicaid and US self-pay vs Canadian provincial). MAIN OUTCOMES AND MEASURES Proportion of clinics accepting new patients and days to first appointment. RESULTS Among 268 of 298 US clinics contacted as a patient with Medicaid (90%), 271 of 301 US clinics contacted as a self-pay patient (90%), and 237 of 288 Canadian clinics contacted as a patient with provincial insurance (82%), new patients were accepted for methadone at 231 clinics (86%) during US Medicaid contacts, 230 clinics (85%) during US self-pay contacts, and at 210 clinics (89%)during Canadian contacts. Among clinics not accepting new patients, at least 44% of 27 clinics reported that the COVID-19 pandemic was the reason. The mean wait for first appointment was greater among US Medicaid contacts (3.5 days [95% CI, 2.9-4.2 days]) and US self-pay contacts (4.1 days [95% CI, 3.4-4.8 days]) than Canadian contacts (1.9 days [95% CI, 1.7-2.1 days]) (P < .001).Open-access model (walk-in hours for new patients without an appointment) utilization was reported by 57 Medicaid (30%), 57 self-pay (30%), and 115 Canadian (59%) contacts offering an appointment. CONCLUSIONS AND RELEVANCEIn this cross-sectional study of 2 nations, more than 1 in 10 methadone clinics were not accepting new patients. Canadian clinics offered more timely methadone access than US opioid treatment programs. These results suggest that the methadone access shortage was exacerbated by COVID-19 and that changes to the US opioid treatment program model are needed to improve the timeliness of access. Increased open-access model adoption may increase timely access.

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Depression is more prevalent in women than in men, and women are at a heightened risk for depression during the postpartum and perimenopause. There is also evidence to suggest that the ovarian hormone milieu may dictate antidepressant efficacy. Thus, it is important to investigate the role of ovarian hormones in the pathogenesis of depression and in the mechanisms that may underlie antidepressant efficacy. In the present study, we used 10-month-old female Sprague-Dawley rats to examine the effects of long-term ovarian hormone deprivation on the development of depressive-like endophenotypes after chronic stress, and on antidepressant efficacy. Four months following ovariectomy (OVX) or sham surgery, all rats were subjected to 6 weeks of chronic unpredictable stress (CUS). During the last 3 weeks of CUS, rats received daily injections of fluoxetine (5 mg/kg) or vehicle. All rats were assessed on measures of anxiety- and depressive-like behavior, hypothalamic-pituitary-adrenal (HPA) negative feedback inhibition, and on markers of neurogenesis and microglia in the dentate gyrus. Our findings demonstrate that long-term ovarian hormone deprivation increased anxiety and depressive-like behavior, as seen by increased immobility in the forced swim test and latency to feed in the novelty suppressed feeding test, and decreased sucrose preference. Further, long-term OVX resulted in impaired HPA negative feedback inhibition, as seen in the dexamethasone suppression test. Fluoxetine treatment showed limited behavioral and neuroendocrine efficacy, however it reduced microglial (Iba-1) expression, and increased cell proliferation, neurogenesis (via cell survival), and the expression of the polysialylated neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus, although these effects varied by region (dorsal, ventral) and ovarian status. Taken together, our findings demonstrate that ovarian hormones may impart resilience against the behavioral and neuroendocrine consequences of chronic unpredictable stress, and may modulate the effects of fluoxetine on cell proliferation, neurogenesis, and PSA-NCAM in the middle-aged female.

1The maternal brain displays considerable plasticity, and motherhood is associated with changes in 2 affective and cognitive function. Motherhood can alter the trajectory of brain ageing, including 3 modifications to neuroplasticity and cognition. Here, we investigated the short-and long-term effects of 4 motherhood on hippocampal neurogenesis, microglial density and morphology, and circulating 5 cytokines, domains known to be altered with age and implicated in cognition and mood. Female rats 6 were bred then euthanized during gestation or at various postpartum timepoints, culminating in middle 7 age, and nulliparous rats served as age-matched controls. Hippocampal neurogenesis was significantly 8 suppressed during gestation and the postpartum period. Interestingly, neurogenesis declined significantly 9 in middle-aged nulliparous rats, but increased in primiparous rats across the same period. Transient 10 postpartum adaptations to the neuroimmune environment of the hippocampus were evidenced, as Iba-1-11 immunoreactive microglia assumed a de-ramified morphology followed by increased density. 12 Intriguingly, ageing-related changes in circulating cytokines were dependent on parity. These 13 adaptations in neurogenic and immune processes may have ramifications for maternal mood and 14 cognition across the peripartum period and beyond. 15