BACKGROUND:Opioid-induced respiratory depression remains a critical public safety concern. Previous clinical findings demonstrated decreased hypercapnic ventilation after 5 days when paroxetine, a selective serotonin reuptake inhibitor (SSRI), was administered alone or with oxycodone. However, uncertainty remained whether chronic use of SSRIs could cause similar respiratory effects. This study investigated whether chronic use of paroxetine and another SSRI, escitalopram, led to a similar decrease in ventilatory response to hypercapnia. METHODS:In this randomized, double-blind, three-period crossover trial, healthy participants were administered one of the following: 40 mg paroxetine from days 1 to 6 and 60 mg from days 7 to 21, 20 mg escitalopram from days 1 to 6 and 30 mg from days 7 to 21, and placebo from days 1 to 21. A dose of 10 mg oxycodone was coadministered on days 6, 12, and 21. Hyperoxic-hypercapnic ventilation was measured using Duffin's rebreathing. RESULTS:Of the 27 participants, 22 (81%) completed the trial. Paroxetine and escitalopram both significantly decreased hyperoxic-hypercapnic ventilation when coadministered with oxycodone compared to oxycodone alone on day 21 (paroxetine mean difference, -6.5 l/min; one-sided 97.5% CI, -∞ to -3.1; P < 0.001; escitalopram mean difference, -5.5 l/min; one-sided 97.5% CI, -∞ to -2.1; P = 0.001) and when administered alone compared to placebo on day 20 (paroxetine mean difference, -6.5 l/min; one-sided 97.5% CI, -∞ to -2.1; P = 0.003; escitalopram mean difference, -6.9 l/min; one-sided 97.5% CI, -∞ to -2.5; P = 0.002). CONCLUSIONS:Both paroxetine and escitalopram, alone and coadministered with oxycodone, decrease hypercapnic ventilation after 21 days, suggesting that SSRIs may have a class effect on hypercapnic ventilation that persists with chronic use.

BACKGROUND:Benzodiazepines can exacerbate opioid-induced respiratory depression by furthering the decrease in central respiratory drive and causing loss of upper airway patency potentially leading to airway obstruction. This study aimed to determine if co-administration of benzodiazepines and opioids significantly decreases hypercapnic ventilation compared with opioids alone. METHODS:We conducted a randomised, double-blind, four-period crossover trial in 20 healthy participants to assess whether i.v. midazolam (0.0375 mg kg-1 in the first five participants; 0.075 mg kg-1 in 15 participants) plus oral oxycodone (10 mg), compared with oxycodone alone, decreases minute ventilation at an end-tidal carbon dioxide (Pco2) of 7.3 kPa using modified Read rebreathing methodology. RESULTS:Midazolam administered with oxycodone, compared with oxycodone alone, did not significantly decrease minute ventilation at an end-tidal Pco2 of 7.3 kPa (23.5 vs 25.2 L min-1; mean difference -1.7 L min-1, one-sided 95% confidence interval -∞ to 1.6; P=0.21). However, midazolam plus oxycodone increased resting end-tidal Pco2 compared with oxycodone alone (5.8 vs 5.6 kPa; mean difference 0.2 kPa, 95% confidence interval 0.0-0.4). Nine of 15 (60%) participants fell asleep or snored on midazolam plus oxycodone, compared with 0 of 15 (0%) on oxycodone alone. CONCLUSIONS:Midazolam co-administered with oxycodone did not decrease hypercapnic ventilation, compared with oxycodone alone, but did affect tidal volume, ventilatory frequency, and resting end-tidal Pco2. These findings support the hypothesis that benzodiazepines influence ventilation by inducing relaxation of the respiratory muscles and highlight the need for additional investigations to elucidate the potential for upper airway obstruction when benzodiazepines and opioids are co-administered. CLINICAL TRIAL REGISTRATION:NCT04310579.

Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies. To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease. Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019. Oral antipsychotics. Adjusted odds ratios (aOR) and 95

PurposeObservational studies assessing effects of medical products on suicidal behavior often rely on health record data to account for pre-existing risk. We assess whether high-dimensional models predicting suicide risk using data derived from insurance claims and electronic health records (EHRs) are superior to models using data from insurance claims alone.MethodsData were from seven large health systems identified outpatient mental health visits by patients aged 11 or older between 1/1/2009 and 9/30/2017. Data for the 5 years prior to each visit identified potential predictors of suicidal behavior typically available from insurance claims (e.g., mental health diagnoses, procedure codes, medication dispensings) and additional potential predictors available from EHRs (self-reported race and ethnicity, responses to Patient Health Questionnaire or PHQ-9 depression questionnaires). Nonfatal self-harm events following each visit were identified from insurance claims data and fatal self-harm events were identified by linkage to state mortality records. Random forest models predicting nonfatal or fatal self-harm over 90 days following each visit were developed in a 70% random sample of visits and validated in a held-out sample of 30%. Performance of models using linked claims and EHR data was compared to models using claims data only.ResultsAmong 15 845 047 encounters by 1 574 612 patients, 99 098 (0.6%) were followed by a self-harm event within 90 days. Overall classification performance did not differ between the best-fitting model using all data (area under the receiver operating curve or AUC = 0.846, 95% CI 0.839-0.854) and the best-fitting model limited to data available from insurance claims (AUC = 0.846, 95% CI 0.838-0.853). Competing models showed similar classification performance across a range of cut-points and similar calibration performance across a range of risk strata. Results were similar when the sample was limited to health systems and time periods where PHQ-9 depression questionnaires were recorded more frequently.ConclusionInvestigators using health record data to account for pre-existing risk in observational studies of suicidal behavior need not limit that research to databases including linked EHR data.

Purpose/Background Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. Methods/Procedures We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. Findings/Results We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. Implications/Conclusions As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

SESSION TITLE: COPD Assessment Tools and ComorbiditiesSESSION TYPE: Rapid Fire Original InvPRESENTED ON: 10/17/2022 12:15 pm - 1:15 pmPURPOSE: Background: Case reports and observational studies describe severe respiratory events associated with antipsychotic use.Purpose: To determine whether antipsychotic use is associated with an increased risk of acute respiratory failure (ARF) requiring invasive mechanical ventilation in patients with chronic obstructive pulmonary disease (COPD).METHODS: We conducted a case-crossover study among US Medicare Fee-for-Service beneficiaries with COPD diagnosed with ARF requiring invasive mechanical ventilation between January 2007 and December 2019. We excluded beneficiaries with prior ARF, active cancer treatment, select conditions that may cause ARF, use of antipsychotics as anti-emetics or by a non-oral route, and those hospitalized or residing in a skilled nursing facility (Part A) during the case and/or control periods. We ascertained antipsychotic exposure in the case and control windows, defined as -1 to -14 and -75 to -88 days prior to admission, respectively. We used conditional logistic regression adjusted for use of select CNS depressants, oral corticosteroids, COPD medications, presence of delirium, and ARF background rate to calculate adjusted odd ratios (aORs) of ARF with use of antipsychotics in the case period compared to the control period. To assess effect modification, we performed analyses in subgroups defined by age, sex, race, dementia, heart failure, home oxygen use, frailty score, reason for entering Medicare, and nursing home residence.RESULTS: We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the risk window and 1,728 only during the control window. The aOR of antipsychotic use within 14 days before ARF was 1.13 (1.06, 1.20). Risk was not increased in patients below age 75 years (aOR 18-49 years: 1.01 [0.85, 1.20]; 50-64 years: 1.03 [0.93, 1.15]; 65-74 years: 1.12 [0.98, 1.28]), but was increased in patients ages 75-84 years (aOR: 1.37 [1.17, 1.60]) and 85+ years (aOR: 1.50 [1.20, 1.89]). The risk of ARF with antipsychotic use was also increased in patients residing in nursing homes and with high frailty scores.CONCLUSIONS: Recent antipsychotic use by older Medicare beneficiaries with COPD was associated with increased risk of ARF. Ongoing efforts include evaluating the interaction of age with other relevant covariates, as well in certain subgroups, and addressing potential concerns of violation of intermittent use and exposure time-trend assumptions and persistent user bias. This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.CLINICAL IMPLICATIONS: Recent antipsychotic use may increase the risk of acute respiratory failure requiring intubation and mechanical ventilation in older patients with COPD.DISCLOSURES: No relevant relationships Added 04/01/2022 by Armen Avagyan, value=SalaryRemoved 04/01/2022 by Armen AvagyanSpouse has direct stock ownership relationship with Abbvie Please note: 1980-present Added 04/13/2022 by Amy Brehm, value=DividendsSpouse has direct ownership of stock relationship with Bristol Myers Please note: 1980-present Added 04/13/2022 by Amy Brehm, value=DividendsSpouse has direct ownership of stock relationship with Johnson & Johnson Please note: 2013-present Added 04/12/2022 by Amy Brehm, value=DividendsNo relevant relationships by David GrahamNo relevant relationships by Jeff KelmanNo relevant relationships by Hyeseung LeeNo relevant relationships by Kira LeishearNo relevant relationships by anchi loNo relevant relationships by Thomas MaCurdyNo relevant relationships by Andrew MosholderNo relevant relationships by Silvia Perez-VilarNo relevant relationships Added 03/30/2022 by Elizabeth Smith, value=SalaryRemoved 03/30/2022 by Elizabeth SmithNo relevant relationships by Marc StoneNo relevant relationships by Michael WerneckeNo relevant relationships by yueqin zhao SESSION TITLE: COPD Assessment Tools and Comorbidities SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: Background: Case reports and observational studies describe severe respiratory events associated with antipsychotic use. Purpose: To determine whether antipsychotic use is associated with an increased risk of acute respiratory failure (ARF) requiring invasive mechanical ventilation in patients with chronic obstructive pulmonary disease (COPD). METHODS: We conducted a case-crossover study among US Medicare Fee-for-Service beneficiaries with COPD diagnosed with ARF requiring invasive mechanical ventilation between January 2007 and December 2019. We excluded beneficiaries with prior ARF, active cancer treatment, select conditions that may cause ARF, use of antipsychotics as anti-emetics or by a non-oral route, and those hospitalized or residing in a skilled nursing facility (Part A) during the case and/or control periods. We ascertained antipsychotic exposure in the case and control windows, defined as -1 to -14 and -75 to -88 days prior to admission, respectively. We used conditional logistic regression adjusted for use of select CNS depressants, oral corticosteroids, COPD medications, presence of delirium, and ARF background rate to calculate adjusted odd ratios (aORs) of ARF with use of antipsychotics in the case period compared to the control period. To assess effect modification, we performed analyses in subgroups defined by age, sex, race, dementia, heart failure, home oxygen use, frailty score, reason for entering Medicare, and nursing home residence. RESULTS: We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the risk window and 1,728 only during the control window. The aOR of antipsychotic use within 14 days before ARF was 1.13 (1.06, 1.20). Risk was not increased in patients below age 75 years (aOR 18-49 years: 1.01 [0.85, 1.20]; 50-64 years: 1.03 [0.93, 1.15]; 65-74 years: 1.12 [0.98, 1.28]), but was increased in patients ages 75-84 years (aOR: 1.37 [1.17, 1.60]) and 85+ years (aOR: 1.50 [1.20, 1.89]). The risk of ARF with antipsychotic use was also increased in patients residing in nursing homes and with high frailty scores. CONCLUSIONS: Recent antipsychotic use by older Medicare beneficiaries with COPD was associated with increased risk of ARF. Ongoing efforts include evaluating the interaction of age with other relevant covariates, as well in certain subgroups, and addressing potential concerns of violation of intermittent use and exposure time-trend assumptions and persistent user bias. This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies. CLINICAL IMPLICATIONS: Recent antipsychotic use may increase the risk of acute respiratory failure requiring intubation and mechanical ventilation in older patients with COPD. DISCLOSURES: No relevant relationships Added 04/01/2022 by Armen Avagyan, value=Salary Removed 04/01/2022 by Armen Avagyan Spouse has direct stock ownership relationship with Abbvie Please note: 1980-present Added 04/13/2022 by Amy Brehm, value=Dividends Spouse has direct ownership of stock relationship with Bristol Myers Please note: 1980-present Added 04/13/2022 by Amy Brehm, value=Dividends Spouse has direct ownership of stock relationship with Johnson & Johnson Please note: 2013-present Added 04/12/2022 by Amy Brehm, value=Dividends No relevant relationships by David Graham No relevant relationships by Jeff Kelman No relevant relationships by Hyeseung Lee No relevant relationships by Kira Leishear No relevant relationships by anchi lo No relevant relationships by Thomas MaCurdy No relevant relationships by Andrew Mosholder No relevant relationships by Silvia Perez-Vilar No relevant relationships Added 03/30/2022 by Elizabeth Smith, value=Salary Removed 03/30/2022 by Elizabeth Smith No relevant relationships by Marc Stone No relevant relationships by Michael Wernecke No relevant relationships by yueqin zhao

Objectives To characterize individual participant level response distributions to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration from 1979 to 2016. Design Individual participant data analysis. Population 232 randomized, double blind, placebo controlled trials of drug monotherapy for major depressive disorder submitted by drug developers to the FDA between 1979 and 2016, comprising 73 388 adult and child participants meeting the inclusion criteria for efficacy studies on antidepressants. Main outcome measures Responses were converted to Hamilton Rating Scale for Depression (HAMD17) equivalent scores where other measures were used to assess efficacy. Multivariable analyses examined the effects of age, sex, baseline severity, and year of the study on improvements in depressive symptoms in the antidepressant and placebo groups. Response distributions were analyzed with finite mixture models. Results The random effects mean difference between drug and placebo favored drug (1.75 points, 95% confidence interval 1.63 to 1.86). Differences between drug and placebo increased significantly (P<0.001) with greater baseline severity. After controlling for participant characteristics at baseline, no trends in treatment effect or placebo response over time were found. The best fitting model of response distributions was three normal distributions, with mean improvements from baseline to end of treatment of 16.0, 8.9, and 1.7 points. These distributions were designated Large, Non-specific, and Minimal responses, respectively. Participants who were treated with a drug were more likely to have a Large response (24.5% v 9.6%) and less likely to have a Minimal response (12.2.% v 21.5%). Conclusions The trimodal response distributions suggests that about 15% of participants have a substantial antidepressant effect beyond a placebo effect in clinical trials, highlighting the need for predictors of meaningful responses specific to drug treatment.

Importance Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration ClinicalTrials.gov Identifier: NCT04310579.

OBJECTIVEAssess the accuracy of ICD-10-CM coding of self-harm injuries and poisonings to identify self-harm events.MATERIALS AND METHODSIn 7 integrated health systems, records data identified patients reporting frequent suicidal ideation. Records then identified subsequent ICD-10-CM injury and poisoning codes indicating self-harm as well as selected codes in 3 categories where uncoded self-harm events might be found: injuries and poisonings coded as undetermined intent, those coded accidental, and injuries with no coding of intent. For injury and poisoning encounters with diagnoses in those 4 groups, relevant clinical text was extracted from records and assessed by a blinded panel regarding documentation of self-harm intent.RESULTSDiagnostic codes selected for review include all codes for self-harm, 43 codes for undetermined intent, 26 codes for accidental intent, and 46 codes for injuries without coding of intent. Clinical text was available for review for 285 events originally coded as self-harm, 85 coded as undetermined intent, 302 coded as accidents, and 438 injury events with no coding of intent. Blinded review of full-text clinical records found documentation of self-harm intent in 254 (89.1%) of those originally coded as self-harm, 24 (28.2%) of those coded as undetermined, 24 (7.9%) of those coded as accidental, and 48 (11.0%) of those without coding of intent.CONCLUSIONSAmong patients at high risk, nearly 90% of injuries and poisonings with ICD-10-CM coding of self-harm have documentation of self-harm intent. Reliance on ICD-10-CM coding of intent to identify self-harm would fail to include a small proportion of true self-harm events.

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO(2)). The current study used that model to assess the impact on respiration of non-benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO(2) above the oxycodone effect. Analyses indicated that most pCO(2) interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO(2) recorded with oxycodone-paroxetine co-administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug-drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co-administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

Timely adverse event pattern detection and resolution, related to drugs, vaccines, and medical devices, can save lives and further quality of life. However, determining conclusions from the data can prove too time consuming for manual analysis, and can produce qualitative results at best. This paper applies a combination of exploratory and predictive text analytic techniques against FAERS data to signal primary textual cues from narratives associated with serious adverse drug events. Specifically, we will run models to generate Boolean combinations of terms and phrases for serious versus non-serious events, including the absence of terms. Additionally, we will assess two characteristic scores tied to drug associations with adverse events via association and market basket analysis. This project provides global observations about the relationship between drugs and adverse events, depicts trends and characterizes the details of serious events, and highlight events misclassified as non-serious for re-investigation. This project serves as proof of concept that modeling and text analysis is useful in adverse event review.

It is highly desirable to be able to evaluate the effect of policy interventions. Such evaluations should have expected outcomes based upon sound theory and be carefully planned, objectively evaluated and prospectively executed. In many cases, however, assessments originate with investigators' poorly substantiated beliefs about the effects of a policy. Instead of designing studies that test falsifiable hypotheses, these investigators adopt methods and data sources that serve as little more than descriptions of these beliefs in the guise of analysis. Interrupted time series analysis is one of the most popular forms of analysis used to present these beliefs. It is intuitively appealing but, in most cases, it is based upon false analogies, fallacious assumptions and analytical errors.

Response to the response of Kuldorff and Lu et al.

This study was conducted in order to assess the prevalence of use of selective serotonin reuptake inhibitors (SSRIs) among pregnant women delivering a liveborn infant in the USA. A retrospective study was conducted using the automated databases of 15 health-care systems participating in the Mini-Sentinel program. Diagnosis and procedure codes were used to identify women ages 10 to 54 years delivering a liveborn infant between April 2001 and December 2013. A comparison group of age- and date-matched women without live births was identified. The frequency of use of SSRIs was identified from outpatient dispensing data. Among the 1,895,519 liveborn deliveries, 113,689 women (6.0 %) were exposed to an SSRI during pregnancy during the period 2001–2013; 5.4 % were exposed to an SSRI during 2013. During the corresponding time period, 10.5 % of the age- and date-matched cohort of women without live births was exposed to an SSRI, with 10.1 % exposed to an SSRI during 2013. The most common agents dispensed during pregnancy were sertraline (n = 48,678), fluoxetine (n = 28,983), and citalopram (n = 20,591). Among those women exposed to an SSRI during pregnancy, 53.8 % had a diagnosis of depression and 37.3 % had a diagnosis of an anxiety disorder during pregnancy or within 180 days prior to pregnancy. Our finding that 6 % of women with live births were prescribed SSRIs during pregnancy highlights the importance of understanding the differential effects of these medications and other therapeutic options on the developing fetus and on the pregnant women.

Sharma and colleagues essentially duplicate, with more limited data, many of the analyses presented in our 2009 paper but seem not to have read our paper very carefully.1 2 They write, “The FDA did not consider the limitations of the trials that we identified and introduced some of their own—for example, by …

Therecently published observational study by Zivin et al. (1) examined the risk of cardiac arrhythmias andmortality among patients taking high-dosage (.40mg/day), medium-dosage (21–40 mg/day), and low-dosage (#20 mg/day) citalopram. The authors concluded that high-dosage citalopram was not associated with increased rates of cardiac arrhythmias or overall mortality compared with lowdosage citalopram. Indeed, higher dosages were associated with fewer adverse outcomes; the unadjusted mortality rate for patients taking high dosages was about half that observed with low dosages. On the basis of their findings, they questioned the FDA’s warning to avoid dosages exceeding 40 mg/day. The approach the authors took, however, was unlikely to detect differences in potentially life-threatening arrhythmias, and for reasons explained below, we believe the 60 mg/day citalopram dosage should be avoided. A randomized, placeboand activecontrolled,double-blind,dose-escalation, crossover study (a “thoroughQTstudy”) has unequivocally demonstrated dosedependent QT prolongation with citalopram. The 60 mg/day dosage caused greater prolongation (18.5 ms) than lower dosages (20 mg/day, 8.5 ms; 40 mg/day, 12.6 ms) and the standard active control drug known to prolong the QT interval (moxifloxacin, 13.4 ms) (2). Although the magnitude of QT effect leading to concern is a matter of judgment, QT prolongation above 15 ms can increase the risk of potentially fatal torsade de pointes-type ventricular tachycardia (3). Under real-world conditions, drug interactions can magnify the effect, as has been demonstrated with citalopram and pimozide (4). Most important, even if the increase in mortality risk from the 60 mg/day dosage is small, use of that dosage cannot be justified, as it was not more effective than 40 mg/day in phase 3 trials (5). Therefore, the FDA updated the labeling for citalopram and, in 2011 and 2012, issued drug safety communications advising avoidance of citalopram dosages above 40 mg/day (2). Observational studies using large administrative databases have not been successful for identifying drug-induced torsade de pointes (6). None of eight observational cohort studies conducted to evaluate the cardiac safety of cisapride or terfenadine, which have been removed from the U.S. market because they clearly cause torsade de pointes, showed an increased risk with either drug (6–8). Torsade de pointes is rare, even with drugs that unequivocally cause it; the incidence rate is estimated to be in the range of 1 per 12,000 to 120,000 patients (6). Moreover, a person who develops fatal ventricular tachycardia or ventricular fibrillation

Since the 2004 FDA decision to require a boxed warning on antidepressants regarding the risk of suicidality in children and adolescents, people who feared adverse consequences of that decision have found support for their view in various seriously flawed studies.

ED FROM Stone M, Laughren T, Jones ML, et al. Risk f suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009;339:b2880. Correspondence to: Marc Stone, Department of Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993–0002, USA; marc.stone@fda.hhs.gov Source of funding: This research received no specifi c grant from any funding agency in the public, commercial, or not-for-profi t sectors. ▶ Additional notes are published online only at http://ebmh/bmj.com/content/vol13/ issue2 Review: antidepressants associated with increased risk of suicidality in adults aged less than 25 years