Impact of the mental health reform in Israel on health care and mortality among people with severe mental illness.

OBJECTIVE: Reports show disparities in the health care of people with severe mental illness (SMI). Yet, the moderating effect of mental health reforms on the health care disparities remain unexplored. The current study aimed to investigate the outcomes of the mental health reform in Israel on the use of health services among people with SMI. METHOD: A case-control epidemiological study comparing the use of health services 3.5 years before and after the mental health reform for service users diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder. Data on health services included: blood cholesterol test (LDL), hemogalobin-A1C test, and visits to general practitioners (GPs) and specialists. Mortality was recorded. RESULTS: Following the reform the number of visits to GPs was decreased among service users of the three SMI groups, as well as visits to specialists among service users with a schizoaffective or bipolar disorder. Following the reform service users of the three SMI groups showed no-change in the performance of LDL test. Complex findings were noted with regard to the performance of Hemoglobin-A1C test. Mortality rates were higher among service users with SMI and the relative risk were similar before and after the reform. CONCLUSIONS: Users of the three SMI groups showed no benefits of the mental health reform in terms of use of health services. Improved health care can be attained by a closer collaboration between the primary physicians and community mental health services.

Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia.

Importance: Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested. Objective: To examine the association between adult ADHD and the risk of dementia. Design, Setting, and Participants: This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023. Exposure: Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision); otherwise, absent. Main Outcome and Measures: Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented. Results: At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly (P < .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P < .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild. Conclusions and Relevance: In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.

The Effect of Short-Term Acute Residential Treatment on Psychiatric Rehospitalization.

ABSTRACT: Short-Term Acute Residential Treatment (START) homes, located in the community and operating in noninstitutional atmospheres, seek to reduce rehospitalization. This report investigates whether these homes reduced rates and duration of subsequent inpatient stays in psychiatric hospitals. For 107 patients treated in START homes after psychiatric hospitalization, we compared the number and duration of psychiatric hospitalizations before and after their START stay. We found that, compared with the year before the START stay, in the year after the START stay, patients had fewer episodes of rehospitalization (1.60 [SD = 1.23] vs. 0.63 [SD = 1.05], t[106] = 7.097, p < 0.001) and a briefer accumulative duration of inpatient stays (41.60 days [SD = 49.4] vs. 26.60 days [SD = 53.25], t[106] = -2.32, p < 0.03). This suggests that START homes can reduce rehospitalization rates and should be considered a valid alternative to psychiatric hospitalization.

Rates of Spontaneous Abortion in Israel Before and During the COVID-19 Pandemic.

This cross-sectional study uses electronic health record data to compare monthly incidence rates of spontaneous abortion in Israel before and during the COVID-19 pandemic.

Somatic comorbidities of mental disorders in pregnancy.

BACKGROUND: Mental and physical health conditions are frequently comorbid. Despite the widespread physiological and behavioral changes during pregnancy, the pattern of comorbidities among women in pregnancy is not well studied. This study aimed to systematically examine the associations between mental and somatic disorders before and during pregnancy. METHOD: The study used data from mothers of a nationally representative birth cohort of children born in Israel (1997-2008). We compared the risk of all major somatic disorders (International Classification of Diseases, Ninth Revision) in pregnant women with and without a mental disorder. All analyses were adjusted for maternal age, child's birth year, family socioeconomic status, and the total number of maternal encounters with health services around pregnancy period. RESULTS: The analytical sample included 77,030 mother-child dyads, with 30,083 unique mothers. The mean age at child's birth was 29.8 years. Prevalence of diagnosis of mental disorder around pregnancy in our sample was 4.4%. Comorbidity between mental and somatic disorders was two times higher than the comorbidity between pairs of different somatic disorders. Of the 17 somatic disorder categories, seven were positively associated with mental health disorders. The highly prevalent comorbidities associated with mental disorders in pregnancy included e.g. musculoskeletal (OR = 1.30; 95% CI = 1.20-1.42) and digestive system diseases (OR = 1.23; 95% CI = 1.13-1.34). CONCLUSIONS: We observed that associations between maternal diagnoses and mental health stand out from the general pattern of comorbidity between nonmental health diseases. The study results confirm the need for screening for mental disorders during pregnancy and for potential comorbid conditions associated with mental disorders.

Opioid Exposure and the Risk of Dementia: A National Cohort Study.

OBJECTIVES: To examine the association between prescription opioid use and the risk of dementia in old-age, since existing studies of the association are few, and the evidence is inconsistent. DESIGN: Prospective national cohort study (N = 91,307, aged 60 years and over), without a dementia diagnosis for ten years, followed-up for incident dementia from January 2013 to October 2017. MEASUREMENTS: Opioid exposure was based on opioid purchases classified from Anatomical Therapeutic Chemical Classification system codes (N02A), and classified as exposed if the purchase period covered at least 60 days within a 120-day interval; otherwise, unexposed. SETTING: Healthcare maintenance organization in Israel. RESULTS: During follow-up, 2,849 (3.1%) persons were opioid exposed (mean age 73.94 ± 6.71 years), and 5,298 (5.8 %) persons developed dementia (mean age 78.07 ± 6.54 years). Cox regression models were fitted to quantify the risk of incident dementia with Hazard Ratios (HR) and their associated 95% Confidence Intervals (CI). The opioid exposed group aged 75+ to 80 years were at an increased risk of incident dementia (Adjusted HR = 1.39, 95% CI = 1.01, 1.92, Z-statistic = 2.02, p <0.05) compared to the unexposed. The point-precision estimates were generally similar to the primary analysis across fourteen sensitivity analyses. CONCLUSION: Policymakers, caregivers, patients, and clinicians may wish to consider that opioid exposure aged 75-80 is linked with an increased dementia risk to balance the potential benefits and adverse side effects of opioid use in old age.

Increased incident rates of antidepressant use during the COVID-19 pandemic: interrupted time-series analysis of a nationally representative sample.

BACKGROUND: The COVID-19 pandemic has been associated with increased levels of depression and anxiety with implications for the use of antidepressant medications. METHODS: The incident rate of antidepressant fills before and during the COVID-19 pandemic were compared using interrupted time-series analysis followed by comprehensive sensitivity analyses on data derived from electronic medical records from a large health management organization providing nationwide services to 14% of the Israeli population. The dataset covered the period from 1 January 2013 to 1 February 2021, with 1 March 2020 onwards defined as the period of the COVID-19 pandemic. Forecasting analysis was implemented to test the effect of the vaccine roll-out and easing of social restrictions on antidepressant use. RESULTS: The sample consisted of 852 233 persons with a total antidepressant incident fill count of 139 535.4 (total cumulative rate per 100 000 = 16 372.91, 95% CI 16 287.19-16 459.01). We calculated the proportion of antidepressant prescription fills for the COVID-19 period, and the counterfactual proportion for the same period, assuming COVID-19 had not occurred. The difference in these proportions was significant [Cohen's h = 10-3 (0.16), 95% CI 10-3 ( - 0.71 to 1.03)]. The pandemic was associated with a significant increase in the slope of the incident rate of antidepressant fills (slope change = 0.01, 95% CI 0.00-0.03; p = 0.04) and a monthly increase of 2% compared to the counterfactual (the estimated rate assuming no pandemic occurred). The increased rate was more pronounced in women, and was not modified by lockdown on/off periods, socioeconomic or SARS-CoV-2 status. The rate of observed antidepressant fills was similar to that forecasted under the assumption of ongoing COVID-19 distress. CONCLUSION: These findings underscore the toll of the pandemic on mental health and inform mental health policy and service delivery during and after implementing COVID-19 attenuation strategies.

Attempted suicide rates before and during the COVID-19 pandemic: interrupted time series analysis of a nationally representative sample.

BACKGROUND: To characterize the association between the protracted biopsychosocial coronavirus disease 2019 (COVID-19) pandemic exposures and incident suicide attempt rates. METHODS: Data were from a nationally representative cohort based on electronic health records from January 2013 to February 2021 (N = 852 233), with an interrupted time series study design. For the primary analysis, the effect of COVID-19 pandemic on incident suicide attempts warranting in-patient hospital treatment was quantified by fitting a Poisson regression and modeling the relative risk (RR) and the corresponding 95% confidence intervals (CIs). Scenarios were forecast to predict attempted suicide rates at 10 months after social mitigation strategies. Fourteen sensitivity analyses were performed to test the robustness of the results. RESULTS: Despite the increasing trend in the unexposed interval, the interval exposed to the COVID-19 pandemic was statistically significant (p < 0.001) associated with a reduced RR of incident attempted suicide (RR = 0.63, 95% CI 0.52-0.78). Consistent with the primary analysis, sensitivity analysis of sociodemographic groups and methodological factors were statistically significant (p < 0.05). No effect modification was identified for COVID-19 lockdown intervals or COVID-19 illness status. All three forecast scenarios at 10 months projected a suicide attempt rate increase from 12.49 (7.42-21.01) to 21.38 (12.71-35.99). CONCLUSIONS: The interval exposed to the protracted mass social trauma of the COVID-19 pandemic was associated with a lower suicide attempt rate compared to the unexposed interval. However, this trend is likely to reverse 10 months after lifting social mitigation policies, underscoring the need for enhanced implementation of public health policy for suicide prevention.

Serum folate deficiency and the risks of dementia and all-cause mortality: a national study of old age.

BACKGROUND: The association between serum folate deficiency and the risk of dementia in old age is unclear, perhaps owing to small sample sizes, the competing risk of mortality or reverse causation. OBJECTIVE: To examine the associations between serum folate deficiency and the risks of incident dementia and all-cause mortality in a large national sample of older adults. METHODS: A prospective cohort aged 60-75 years (n=27 188) without pre-existing dementia for at least 10 years, was tested for serum concentrations of folate and followed up for dementia or all-cause mortality. Serum folate deficiency was classified as present (<4.4 ng/mL), otherwise absent. HRs and 95% CIs from competing risks Cox models were fitted to quantify the associations between serum folate deficiency and the risks of dementia and all-cause mortality. To examine reverse causation, the analysis was stratified by duration of follow-up. FINDINGS: The presence compared with the absence of serum folate deficiency was associated with higher risks of dementia (HR=1.68; 95% CI 1.32 to 2.13; p<0.001) and all-cause mortality (HR=2.98; 95% CI 2.52 to 3.52; p<0.001). Evidence for reverse causation were moderate for dementia and mild for all-cause mortality. CONCLUSIONS: Serum concentrations of folate may function as a biomarker used to identify those at risk of dementia and mortality; however, reverse causation is likely. Further research is needed to examine the role of serum folate deficiency in dementia aetiology. CLINICAL IMPLICATIONS: Serum folate deficiency in older adults requires monitoring and treatment for preventative measures and/or as part of implemented therapeutic strategies.

Biopsychosocial exposure to the COVID-19 pandemic and the relative risk of schizophrenia: Interrupted time-series analysis of a nationally representative sample.

BACKGROUND: Studies of COVID-19 pandemic biopsychosocial exposure and schizophrenia risk showed contradictory results, were undertaken early in the pandemic, and did not consider lockdowns or COVID-19 infection. Hence, we examined the association between COVID-19 biopsychosocial exposure and incident schizophrenia. METHODS: An interrupted time-series study design was implemented based on Israeli electronic health records from 2013 to 2021 with national coverage. The period coinciding with the COVID-19 pandemic biopsychosocial exposures from March 2020 to February 2021 was classified as exposed, otherwise unexposed. The effect of the COVID-19 pandemic on incident schizophrenia was quantified by fitting a Poisson regression and modeling the relative risk (RR) and corresponding 95% confidence intervals (CI). Three scenarios were projected from the third lockdown to 10 months to forecast incident schizophrenia rates and their associated 95% prediction intervals (PI). RESULTS: The total population (N = 736,356) yielded 4,310 cases of incident schizophrenia over time. The primary analysis showed that the period exposed to the COVID-19 pandemic was associated with a reduced RR (RR = 0.81, 95% CI = 0.73, 0.91, p < 0.001). This conclusion was supported in 12 sensitivity analyses, including scrutinizing lockdowns and COVID-19 infection status. Two of three forecast scenarios projected an incident increase (6.74, 95% PI = 5.80, 7.84; 7.40, 95% PI = 6.36, 8.60). CONCLUSIONS: The reduced risk of schizophrenia during the pandemic suggests no immediate triggering of new onsets either by the virus or the pandemic-induced psychosocial adversities. Once restrictions are lifted, the increased projected presentations have implications for clinicians and healthcare policy.

Optimal interpregnancy interval in autism spectrum disorder: A multi-national study of a modifiable risk factor.

It is biologically plausible that risk of autism spectrum disorder (ASD) is elevated by both short and long interpregnancy intervals (IPI). We conducted a retrospective cohort study of singleton, non-nulliparous live births, 1998-2007 in Denmark, Finland, and Sweden (N = 925,523 births). Optimal IPI was defined as the IPI at which minimum risk was observed. Generalized additive models were used to estimate relative risks (RR) of ASD and 95% Confidence Intervals (CI). Population impact fractions (PIF) for ASD were estimated under scenarios for shifts in the IPI distribution. We observed that the association between ASD (N = 9302) and IPI was U-shaped for all countries. ASD risk was lowest (optimal IPI) at 35 months for all countries combined, and at 30, 33, and 39 months in Denmark, Finland, and Sweden, respectively. Fully adjusted RRs at IPIs of 6, 12, and 60 months were 1.41 (95% CI: 1.08, 1.85), 1.26 (95% CI: 1.02, 1.56), and 1.24 (95% CI: 0.98, 1.58) compared to an IPI of 35 months. Under the most conservative scenario PIFs ranged from 5% (95% CI: 1%-8%) in Denmark to 9% (95% CI: 6%-12%) in Sweden. The minimum ASD risk followed IPIs of 30-39 months across three countries. These results reflect both direct IPI effects and other, closely related social and biological pathways. If our results reflect biologically causal effects, increasing optimal IPIs and reducing their indications, such as unintended pregnancy and delayed age at first pregnancy has the potential to prevent a salient proportion of ASD cases. LAY SUMMARY: Waiting 35 months to conceive again after giving birth resulted in the least risk of autism. Shorter and longer intervals resulted in risks that were up to 50% and 85% higher, respectively. About 5% to 9% of autism cases might be avoided by optimizing birth spacing.

Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study.

BACKGROUND: Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring. METHODS: This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period). RESULTS: The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11]. CONCLUSIONS: Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Risk of dementia and death in very-late-onset schizophrenia-like psychosis: A national cohort study.

Knowledge is limited regarding the risks of death and dementia in very-late onset schizophrenia-like psychosis (VLOS). This study aims to scrutinize the associations between VLOS with the risks of death and dementia. Based on a prospective Israeli cohort study with national coverage, 94,120 persons without dementia or schizophrenia diagnoses aged 60 to 90 in 2012 were followed-up for the risks of dementia or death from 2013 to 2017. VLOS was classified as present from the age of the first ICD-9 diagnosis during follow-up, otherwise as absent. Hazard ratios (HR) with confidence intervals (95% CI) were computed with survival models to quantify the associations between VLOS and the risks of death and dementia, without and with adjustment for confounding. Nine sensitivity analyses were computed to examine the robustness of the results. The group with VLOS, compared to the group without, had higher death (n = 61, 18.5% vs. n = 7028, 7.5%, respectively) and dementia (n = 64, 19.5% vs. n = 5962, 6.4%, respectively) rates. In the primary analysis, the group with VLOS compared to the group without had increased risks of death (unadjusted HR = 3.10, 95% CI = 2.36, 4.06, P < .001; adjusted HR = 2.89, 95% CI = 2.15, 3.89; P < .001) and dementia (unadjusted HR = 3.81, 95% CI = 2.90, 4.99, P < .001; adjusted HR = 2.67, 95% CI = 1.82, 3.91; P < .001). The results remained statistically significant (P < .05) in all sensitivity analyses, including among persons without antipsychotic medication. The results may support notions of increased dementia risk and accelerated aging in VLOS, or that VLOS is a prodromal state of dementia.

Identification of newborns at risk for autism using electronic medical records and machine learning.

BACKGROUND: Current approaches for early identification of individuals at high risk for autism spectrum disorder (ASD) in the general population are limited, and most ASD patients are not identified until after the age of 4. This is despite substantial evidence suggesting that early diagnosis and intervention improves developmental course and outcome. The aim of the current study was to test the ability of machine learning (ML) models applied to electronic medical records (EMRs) to predict ASD early in life, in a general population sample. METHODS: We used EMR data from a single Israeli Health Maintenance Organization, including EMR information for parents of 1,397 ASD children (ICD-9/10) and 94,741 non-ASD children born between January 1st, 1997 and December 31st, 2008. Routinely available parental sociodemographic information, parental medical histories, and prescribed medications data were used to generate features to train various ML algorithms, including multivariate logistic regression, artificial neural networks, and random forest. Prediction performance was evaluated with 10-fold cross-validation by computing the area under the receiver operating characteristic curve (AUC; C-statistic), sensitivity, specificity, accuracy, false positive rate, and precision (positive predictive value [PPV]). RESULTS: All ML models tested had similar performance. The average performance across all models had C-statistic of 0.709, sensitivity of 29.93%, specificity of 98.18%, accuracy of 95.62%, false positive rate of 1.81%, and PPV of 43.35% for predicting ASD in this dataset. CONCLUSIONS: We conclude that ML algorithms combined with EMR capture early life ASD risk as well as reveal previously unknown features to be associated with ASD-risk. Such approaches may be able to enhance the ability for accurate and efficient early detection of ASD in large populations of children.

Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort.

Importance: The origins and development of autism spectrum disorder (ASD) remain unresolved. No individual-level study has provided estimates of additive genetic, maternal, and environmental effects in ASD across several countries. Objective: To estimate the additive genetic, maternal, and environmental effects in ASD. Design, Setting, and Participants: Population-based, multinational cohort study including full birth cohorts of children from Denmark, Finland, Sweden, Israel, and Western Australia born between January 1, 1998, and December 31, 2011, and followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018. Main Outcomes and Measures: Across 5 countries, models were fitted to estimate variance components describing the total variance in risk for ASD occurrence owing to additive genetics, maternal, and shared and nonshared environmental effects. Results: The analytic sample included 2 001 631 individuals, of whom 1 027 546 (51.3%) were male. Among the entire sample, 22 156 were diagnosed with ASD. The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel). For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%). Maternal effect was estimated to range from 0.4% to 1.6%. Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD. Conclusions and Relevance: Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects. The results suggest possible modest differences in the sources of ASD risk between countries.

[LONG-ACTING INJECTABLE ANTIPSYCHOTICS IN SCHIZOPHRENIA].

INTRODUCTION: Long-acting injectable antipsychotics (LAI AP) were mainly developed with the intention to improve adherence to treatment in schizophrenia patients and to reduce the high rates of relapses and re-hospitalizations due to treatment discontinuation. Several studies comparing LAI AP with oral antipsychotics in schizophrenia have been performed, in which RCTs (considered to be the 'gold standard' for clinical trial design) generally show no benefit for LAI AP over oral drugs, whereas observational studies do. The more pragmatic the study design, the more likely it is to show a benefit for LAI AP versus oral therapy. Seeing that the percentage of patients who are currently being treated with LAI AP is far from the percentage of non-adherent patients, it can be argued that LAI AP are significantly underused. LAI AP formulations of antipsychotics have traditionally been used for those patients with schizophrenia with the most severe symptoms, poorest compliance, most hospitalizations, and poorest outcomes, namely at the latter stages of their illness. However, an increasing number of authors suggest that early-phase patients may have the most to gain from LAI AP, at a time when their disorder is most treatable and when avoidance of recurrences and re-hospitalizations may lead to the greatest benefits. To prove the advantage of LAI AP versus oral antipsychotics, there has been an evolution to a new type of clinical trial design that combines some of the best features of both naturalistic "real life" studies and RCTs, namely pragmatic RCT. Currently, there is an ongoing trial in Israel and European countries (the EULAST study) that is an example of this kind of "new" clinical trial design. EULAST is a pragmatic randomized open label cohort study that includes a naturalistic type of follow-up among schizophrenic patients who are early in the disease course. Hopefully, it will dispel doubts concerning the advantages of LAI AP versus oral antipsychotics and will help clinicians to optimize patient's outcomes.

Exposure to Antidepressant Medication and the Risk of Incident Dementia.

OBJECTIVE: To test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia. METHODS: A prospective national matched cohort study from Israel (N = 71,515) without dementia (2002-2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes. RESULTS: In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47. CONCLUSION: In this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.