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Annual Rates of Depression in the Adult General Managed Care Enrollee Population, 1999-2005, by Gender (N=400,111)
Source publication
In 2003, the U.S. Food and Drug Administration (FDA) issued a public health advisory about the risk of suicidality in pediatric patients taking selective serotonin reuptake inhibitors (SSRIs) for depression, and in 2005, the agency mandated a black box warning and medication guide indicating that pediatric and adult patients may be at risk. The aut...
Context in source publication
Similar publications
To quantify the frequency and type of new safety information arising from studies performed under the auspices of the Pediatric Exclusivity Program, to describe the dissemination of these findings in the peer-reviewed literature and compare this with the US Food and Drug Administration (FDA) review, and to describe their effect on pediatric labelin...
Citations
... Depressive disorder is a highly prevalent illness recognized as a significant public health issue worldwide [1][2][3][4]. It often results in serious social losses [5] and is closely associated with the risk of death, comorbidity, and disability [6][7][8][9]. ...
Background
Prior studies have reported a potential relationship between depressive disorder (DD), immune function, and inflammatory response. Some studies have also confirmed the correlation between immune and inflammatory responses and Bell’s palsy. Considering that the pathophysiology of these two diseases has several similarities, this study investigates if DD raises the risk of developing Bell’s palsy.
Methods
This nationwide propensity score-weighting cohort study utilized Taiwan National Health Insurance data. 44,198 patients with DD were identified as the DD cohort and 1,433,650 adult subjects without DD were identified as the comparison cohort. The inverse probability of treatment weighting (IPTW) strategy was used to balance the differences of covariates between two groups. The 5-year incidence of Bell’s palsy was evaluated using the Cox proportional-hazard model, presenting results in terms of hazard ratios (HRs) and 95% confidence intervals (CIs).
Results
The average age of DD patients was 48.3 ± 17.3 years, and 61.86% were female. After propensity score-weighting strategy, no significant demographic differences emerged between the DD and comparison cohort. The Cox proportional hazards model revealed a statistically significant adjusted IPTW-HR of 1.315 (95% CI: 1.168–1.481) for Bell’s palsy in DD patients compared to comparison subjects. Further independent factors for Bell’s palsy in this model were age (IPTW-HR: 1.012, 95% CI: 1.010–1.013, p < 0.0001), sex (IPTW-HR: 0.909, 95% CI: 0.869–0.952, p < 0.0001), hypertension (IPTW-HR: 1.268, 95% CI: 1.186–1.355, p < 0.0001), hyperlipidemia (IPTW-HR: 1.084, 95% CI: 1.001–1.173, p = 0.047), and diabetes (IPTW-HR: 1.513, 95% CI: 1.398–1.637, p < 0.0001)
Conclusion
This Study confirmed that individuals with DD face an elevated risk of developing Bell’s palsy. These findings hold significant implications for both clinicians and researchers, shedding light on the potential interplay between mental health and the risk of certain physical health outcomes.
... Although the warning was meant to increase safety, several studies have suggested unintended consequences (55,56), including decreased diagnosis of depression (57) and reduced antidepressant usage (58). At the same time, suicide rates have continued to climb. ...
Suicide is a leading cause of death that is often preventable. This article reviews the role of medications in treating suicidal behavior and in preventing suicide. For an acute suicidal crisis, ketamine, and perhaps esketamine, are emerging as important tools. For patients with chronic suicidality, clozapine remains the only U.S. Food and Drug Administration (FDA) approved antisuicidal medication, and its use is predominantly for patients with schizophrenia and schizoaffective disorder. An abundance of literature supports the use of lithium among patients with mood disorders, including those with major depressive disorder. Despite the black box warning regarding antidepressants and suicide risk among children, adolescents, and young adults, antidepressants are widely used and remain helpful in reducing suicidal thoughts and behaviors, primarily among patients with mood disorders. Treatment guidelines focus on the importance of optimizing treatment of the psychiatric conditions known to be associated with suicide risk. For patients with these conditions, the authors recommend focusing on suicide as an independent treatment target and using an enhanced medication management strategy that includes maintaining a supportive, nonjudgmental therapeutic relationship; flexibility; collaboration; measurement-based care; consideration of combining medications with nonpharmacologic, evidence-based strategies; and ongoing safety planning.
... The impact on prescription and suicide rates observed in this investigation exhibited both similarities and differences to those reported in previous studies in other countries. Similar additional warnings on labelling suppressed the increasing trend in prescription rates in targeted and non-targeted populations in some studies [7,8,10,14]. In contrast, in Canada, SSRI prescription increased in the young population from 2005 to 2009, after the addition of the FDA warning. ...
... The present study demonstrated a slight decrease in the suicide rates of young populations in 2009, which is when the global economic crisis occurred. However, the level of AD use decreased in the US, and the increase in the rates of suicide attempts occurred simultaneously with the decreased use of ADs in the young population after the addition of the warning by the FDA [7,14]. In the present study, on the other hand, even the prescription rate rose after the labelling change. ...
... The household income, extent of job insecurity and poverty, level of education, and living conditions of enrolees in the JMDC database may differ from individuals covered by other social health insurance schemes. Fourthly, the JMDC database contained potential measurement biases such as coding inaccuracies and underreporting, which claims databases have by their nature [14]. Therefore, the diagnosis of depression could be more than the actual number given, because patients who did not need medication would not include the codes for depression if it was not required for reimbursement. ...
Background
In October 2007, the Japanese Health Authority directed that precautions be added to antidepressants (ADs) labelling regarding suicide risk among young people.
This study evaluates the impact of the labelling change on AD prescriptions and Japanese adolescent suicide rates.
Methods
We compared AD prescription rates per 100,000 population as a primary outcome. The intervention group comprised adolescents (10–24 years), while the control group comprised adults (25–64 years). We defined the pre-intervention period as January 2005 to October 2007 and post-intervention as November 2007 to February 2013. Monthly prescription rate data from a commercial claims database were triangulated with annual suicide rates in Japan. We performed segmented regression analysis for the prescription rates, using a quasi-Poisson model, and tested for level and trend changes.
Results
The commercial claims database included 152,686 adolescents and 195,251 adults during the pre-intervention period and 846,367 adolescents and 1,352,453 adults during post-intervention. Post-intervention, the overall AD prescription rates decreased only in adult males (-95.8 prescription per 100,000) but increased in all other groups. The mean annual suicide rate increased in adolescent males (+1.5 suicides per 100,000) but decreased in all other groups. Overall, the upward trend became moderate or inverse in all groups post-intervention but with a large difference between males and females. The suicide rates rose slightly in adolescents but began declining in adults a year post-intervention. In females, changes in level, trend, and suicide rates were very small in both adolescents and adults.
Conclusions
Contrary to expectations, the mean prescription rates only decreased in adult males, but not in adolescents, regardless of gender. Downward level and trend change were clearly observed in adult males but not in adolescents, the original target of the updated warning. There were no clear temporal associations between suicide rates and the labelling change in either group.
... Public health advisories impact incident, but not prevalent use [9,10]. Boxed warnings are associated with utilization reductions, but substitution between classes occurs [11][12][13][14][15][16][17]. Empirical evidence shows that boxed warnings have mixed results in leading to lower drug utilization. ...
Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003–2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010–2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.
... For example, reminding patients of the cost savings from a copayment intervention voucher may encourage them to use those savings on other medications. More broadly, although we observed a positive indirect consequence in this analysis of ARTEMIS, indirect consequences can be positive or negative [13][14][15][16] and may affect the overall effectiveness of a health services intervention, reinforcing the need for rigorous testing of these interventions before widespread implementation. 17 There was no interaction observed between whether a patient had ever filled a non-P2Y 12 inhibitor secondary prevention medication at the same time as a P2Y 12 inhibitor and the observed association with persistence (A) or adherence (B) in taking other cardiovascular medications. ...
Importance
The Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS) cluster-randomized trial found that copayment reduction for P2Y12 inhibitors improved 1-year patient persistence in taking that medication.
Objective
To assess whether providing copayment reduction for P2Y12 inhibitors increases patient persistence in taking other secondary prevention cardiovascular medications.
Design, Setting, and Participants
This post hoc analysis of the ARTEMIS trial includes data from 287 hospitals that enrolled patients between June 2015 and September 2016. Patients hospitalized with acute myocardial infarction were included. Data analysis occurred from May 2018 through August 2019.
Interventions
Hospitals randomized to the intervention provided patients vouchers that waived copayments for P2Y12 inhibitors fills for 1 year. Hospitals randomized to usual care did not provide study vouchers.
Main Outcomes and Measures
Persistence in taking β-blocker, statin, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker medications at 1 year, defined as the absence of a gap in medication supply of 30 or more days by pharmacy fill data in the intervention-arm (intent-to-treat) population.
Results
A total of 131 hospitals (with 5109 patients) were randomized to the intervention, and 156 hospitals (with 3264 patients) randomized to the control group. Patients discharged from intervention hospitals had higher persistence in taking statins (2247 [46.1%] vs 1300 [41.9%]; adjusted odds ratio, 1.11 [95% CI, 1.00-1.24]), and β-blockers (2235 [47.6%] vs 1277 [42.5%]; odds ratio, 1.23 [95% CI, 1.10-1.38]), although the association was smaller than that seen for P2Y12 inhibitors (odds ratio, 1.47 [95% CI, 1.29-1.66]). Persistence in taking angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers were also numerically higher among patients in the intervention arm than in the usual-care arm, but this was not significant after risk adjustment (1520 [43.9%] vs 847 [40.5%]; adjusted odds ratio, 1.10 [95% CI, 0.97-1.24]). Patients in the intervention arm reported greater financial burden associated with medication cost than the patients in the usual-care arm at baseline, but these differences were no longer significant at 1 year.
Conclusions and Relevance
Reducing patient copayments for 1 medication class increased persistence not only to that therapy class but may also have modestly increased persistence to other post–myocardial infarction secondary prevention medications. These findings have important implications for the clinical utility and cost-effectiveness of medication cost-assistance programs.
Trial Registration
ClinicalTrials.gov Identifier: NCT02406677
... A large US study showed that there were significant reductions of antidepressant utilization rates within two years after the FDA warning and that these continously remained lower than the rates of 2004 (30). The drop could, however, also illustrate a 'spilover effect' because studies showed that the antidepressant regulatory warnings actually led to a reduction in the numbers of youths (31)(32)(33) and adults (33,34) diagnosed with depression and treated for the disorder. Still, this does not explain the trend of an increasing use in Sweden, where the licensed indications for antidepressants are similar to those of Denmark and Norway. ...
Objective:
To compare antidepressant utilization in individuals aged 5-19 years from the Scandinavian countries.
Methods:
A population-based drug utilization study using publicly available data of antidepressant use from Denmark, Norway, and Sweden.
Results:
In the study period from 2007 to 2017, the proportion of antidepressant users increased markedly in Sweden (9.3-18.0/1000) compared to Norway (5.1-7.6/1,000) and Denmark (9.3-7.5/1,000). In 2017, the cumulated defined daily doses (DDD) of selective serotonin reuptake inhibitors was 5,611/1,000 inhabitants in Sweden, 2,709/1,000 in Denmark, and 1,848/1,000 in Norway. The use of 'other antidepressants' (ATC code N06AX) also increased in Sweden with a higher DDD in 2017 (497/1,000) compared to Denmark (225/1,000) and Norway (170/1,000). The use of tricyclic antidepressants was generally low in 2017 with DDDs ranging between 30-42 per 1,000. The proportion of antidepressant users was highest among 15-19 year-old individuals. Girls were more likely to receive treatment than boys, and the treated female/male ratios per 1,000 were similar in Sweden (2.39), Denmark (2.44), and Norway (2.63).
Conclusion:
Even in highly comparable health-care systems like the Scandinavian countries', variation in antidepressant use is considerable. Swedish children and adolescents have a markedly higher and still increasing use of antidepressants compared to Danish and Norwegian peers.
... In 2003, the FDA warned of an association between SSRI prescription and suicidality in paediatric patients (<18); subsequently, prescription of SSRIs in newly diagnosed adult patients decreased, without compensation by alternative medicines or treatment, leaving a potentially serious condition untreated. 5,6 The warning issued by the UK Committee on Safety Medicines in 1995, that oral contraceptive pills containing gestodene or desogestrel were associated with a higher risk of venous thromboembolism, has had a negative impact on public health. A significant number of women either switched brands or ceased contraception altogether following the announcement. ...
... Some describe a reduction of SSRIs use only (Nemeroff et al. 2007;Olfson, Marcus, & Druss, 2008). Others show that, as mentioned above, depression diagnoses declined and alternative therapies such as psychotherapy or the prescription of an antipsychotic or anxiolytic did not increase (Kurian et al. 2007;Libby et al. 2007;Valuck et al. 2007). Finally, other more disturbing studies, note an increase in suicide rates after the publication of the warnings (Gibbons et al. 2007;Katz et al. 2008). ...
Les troubles des conduites alimentaires (TCA) et les troubles des conduites suicidaires (TCS) sont des pathologies mentales graves. Ces deux troubles représentent un problème de santé publique majeur. En effet, il s’agit de pathologies pour lesquelles les pronostics sont médiocres, ayant un impact lourd sur la vie des patients et de leur entourage et représentant un coût élevé pour la société. Il n’existe actuellement aucun biomarqueur validé dans l’une ou l’autre de ces pathologies. L’objectif de ce travail est de réussir à identifier de potentiels biomarqueurs dans ces deux troubles. L’identification de biomarqueurs potentiels pourrait être utile dans divers domaines : faciliter le diagnostic des patients, améliorer la prise en charge des patients et enfin servir de cibles thérapeutiques dans le but d’élaborer de nouveaux traitements plus efficaces. Nous présenterons dans ce travail l’intérêt et l’utilisation des biomarqueurs en psychiatrie puis deux axes d’exploration des TCA ainsi qu’un axe d’exploration des TCS: l’approche neuropsychologique ainsi que l’approche biologique pour les TCA et l’approche génétique pour les TCS. Concernant les TCA, nos résultats suggèrent un intérêt potentiel des oestro-progestatifs dans l’amélioration des fonctions cognitives des patientes. Au sujet des TCS, il semblerait que deux des polymorphismes génétiques que nous avons étudiés (l’un du gène MOR et l’autre du gène SKA2) soient associés avec le risque d’émergence d’idées suicidaires au cours de l’initiation d’un traitement antidépresseur. Si ces études étaient répliquées, ces divers éléments pourraient s’avérer être des outils diagnostics et thérapeutiques.
... Given the widespread media coverage, we considered the combination of FDA warnings and media reports as the policy exposure. Previous studies have found reductions in antidepressant treatment in all age groups following the warnings and no increases in use of treatment alternatives (eg, psychotherapy, atypical antipsychotics), 24,27,28,[38][39][40] suggesting an overall reduction in treatment of mood disorders. Because depression is an independent risk factor for suicidality and appropriate treatment with antidepressants is effective in reducing depressive symptoms, 41-43 the falling rates of treatment of mood disorder following the policy and lack of increased outpatient monitoring of youth with mood disorder 44 had the potential to increase suicide attempts and completed suicides at the population level-the 2 measures of unintended (indirect, latent) impacts of the policy considered in this study. ...
... To avoid introducing selection bias, we did not limit our cohorts to individuals with a coded depression diagnosis. This is because previousstudies showed that rates of depression diagnosis changed after the warnings, 24,38,40 including rates in populations that are part of our study sample. 46 Further, outpatient claims are frequently incomplete for mental health conditions like depression. ...
Background:
New health policies may have intended and unintended consequences. Active surveillance of population-level data may provide initial signals of policy effects for further rigorous evaluation soon after policy implementation.
Objective:
This study evaluated the utility of sequential analysis for prospectively assessing signals of health policy impacts. As a policy example, we studied the consequences of the widely publicized Food and Drug Administration's warnings cautioning that antidepressant use could increase suicidal risk in youth.
Method:
This was a retrospective, longitudinal study, modeling prospective surveillance, using the maximized sequential probability ratio test. We used historical data (2000-2010) from 11 health systems in the US Mental Health Research Network. The study cohort included adolescents (ages 10-17 y) and young adults (ages 18-29 y), who were targeted by the warnings, and adults (ages 30-64 y) as a comparison group. Outcome measures were observed and expected events of 2 possible unintended policy outcomes: psychotropic drug poisonings (as a proxy for suicide attempts) and completed suicides.
Results:
We detected statistically significant (P<0.05) signals of excess risk for suicidal behavior in adolescents and young adults within 5-7 quarters of the warnings. The excess risk in psychotropic drug poisonings was consistent with results from a previous, more rigorous interrupted time series analysis but use of the maximized sequential probability ratio test method allows timely detection. While we also detected signals of increased risk of completed suicide in these younger age groups, on its own it should not be taken as conclusive evidence that the policy caused the signal. A statistical signal indicates the need for further scrutiny using rigorous quasi-experimental studies to investigate the possibility of a cause-and-effect relationship.
Conclusions:
This was a proof-of-concept study. Prospective, periodic evaluation of administrative health care data using sequential analysis can provide timely population-based signals of effects of health policies. This method may be useful to use as new policies are introduced.
... However, this decrease in use seemed to be associated with an unintended increase in suicide rates in children and adolescents due to untreated patients [27]. In the same context, time-series analyses of antidepressant prescribing in adults showed statistically and clinically significant spill-over effects associated with the 2003 Food and Drug Administration public health advisory on antidepressant use in paediatric patients [44]. In addition, the impact of pharmacovigilance on health outcomes is often more difficult to measure due to a lack of adequate data sources and the difficulty of proving a causal association between the observed changes and the regulatory intervention, particularly at product level. ...
Aim:
Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.
Methods:
We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted.
Results:
From 1,246 screened articles, 229 were eligible for full-text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%). 55% of studies measured changes in drug utilisation patterns, 27% evaluated health outcomes and 18% targeted knowledge, behaviour, or changes in clinical practice. Unintended consequences like switching therapies or spill-over effects were rarely evaluated. Two thirds used before-after time series and 15.7% before-after cross-sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%).
Conclusion:
Whilst impact evaluation of pharmacovigilance and product-specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs.
