An artificial intelligence algorithm for co-clustering to help in pharmacovigilance before and during the COVID-19 pandemic.

AIMS: Monitoring drug safety in real-world settings is the primary aim of pharmacovigilance. Frequent adverse drug reactions (ADRs) are usually identified during drug development. Rare ones are mostly characterized through post-marketing scrutiny, increasingly with the use of data mining and disproportionality approaches, which lead to new drug safety signals. Nonetheless, waves of excessive numbers of reports, often stirred up by social media, may overwhelm and distort this process, as observed recently with levothyroxine or COVID-19 vaccines. As human resources become rarer in the field of pharmacovigilance, we aimed to evaluate the performance of an unsupervised co-clustering method to help the monitoring of drug safety. METHODS: A dynamic latent block model (dLBM), based on a time-dependent co-clustering generative method, was used to summarize all regional ADR reports (n = 45 269) issued between 1 January 2012 and 28 February 2022. After analysis of their intra and extra interrelationships, all reports were grouped into different cluster types (time, drug, ADR). RESULTS: Our model clustered all reports in 10 time, 10 ADR and 9 drug collections. Based on such clustering, three prominent societal problems were detected, subsequent to public health concerns about drug safety, including a prominent media hype about the perceived safety of COVID-19 vaccines. The dLBM also highlighted some specific drug-ADR relationships, such as the association between antiplatelets, anticoagulants and bleeding. CONCLUSIONS: Co-clustering and dLBM appear as promising tools to explore large pharmacovigilance databases. They allow, 'unsupervisedly', the detection, exploration and strengthening of safety signals, facilitating the analysis of massive upsurges of reports.

A systematic analysis and data mining of opioid-related adverse events submitted to the FAERS database.

The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the risks presented by opioid exposure, as well as the individual risk profiles of specific opioid drugs and the potential relationships among the opioids. In this study, 92 opioids were identified from the list of all Food and Drug Administration (FDA)-approved drugs, annotated by RxNorm and were classified into 13 opioid groups: buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol. A total of 14,970,399 AE reports were retrieved and downloaded from the FDA Adverse Events Reporting System (FAERS) from 2004, Quarter 1 to 2020, Quarter 3. After data processing, Empirical Bayes Geometric Mean (EBGM) was then applied which identified 3317 pairs of potential risk signals within the 13 opioid groups. Based on these potential safety signals, a comparative analysis was pursued to provide a global overview of opioid-related AEs for all 13 groups of FDA-approved prescription opioids. The top 10 most reported AEs for each opioid class were then presented. Both network analysis and hierarchical clustering analysis were conducted to further explore the relationship between opioids. Results from the network analysis revealed a close association among fentanyl, oxycodone, hydrocodone, and hydromorphone, which shared more than 22 AEs. In addition, much less commonly reported AEs were shared among dihydrocodeine, meperidine, oxymorphone, and tapentadol. On the contrary, the hierarchical clustering analysis further categorized the 13 opioid classes into two groups by comparing the full profiles of presence/absence of AEs. The results of network analysis and hierarchical clustering analysis were not only consistent and cross-validated each other but also provided a better and deeper understanding of the associations and relationships between the 13 opioid groups with respect to their adverse effect profiles.

High risks adverse events associated with trastuzumab emtansine and trastuzumab deruxtecan for the treatment of HER2-positive/mutated malignancies: a pharmacovigilance study based on the FAERS database.

BACKGROUND: T-DM1 and T-DXd are two promising antibody-drug conjugates for treating advanced HER2-positive breast cancer and HER2-mutated lung cancer. Understanding the differences in the adverse events (AEs) profile of both drugs may help clinicians make an appropriate treatment decision. RESEARCH DESIGN AND METHODS: All data obtained from the FDA Adverse Event Reporting System (FAERS) database from Q1 2004 to Q3 2022 underwent disproportionality analysis and Bayesian analysis to detect and assess the AE signals of T-DM1 and T-DXd for comparison. RESULTS: A total of 2,113 and 1,269 AE reports associated with T-DM1 and T-Dxd, respectively, were retrieved from FAERS database, in which, respondents were mostly elderly women. Their statistical differences (p < 0.001), poses high incidence of thrombocytopenia, including cardiotoxicity (p < 0.05) for T-DM1, while myelosuppression, interstitial lung disease (ILD), and pneumonitis for T-DXd. Splenomegaly, nodular regenerative hyperplasia, hepatic cirrhosis, portal hypertension, neuropathy peripheral, and spider nevus, are particular to T-DM1. Similarly, febrile neutropenia, pneumocystis jirovecii pneumonia, neutrophil count decreased, and KL-6 increased, are unique to T-DXd. CONCLUSIONS: T-DXd is more likely to induce ILD/pneumonia and myelosuppression than T-DM1, whereas T-DM1 has higher risk of hepatotoxicity, cardiotoxicity, and thrombocytopenia than T-DXd. T-DM1-related hepatotoxicity may need redefinition. Clinicians may need to balance the benefits and risks of antibody-drug conjugates treatment for certain patients.

Ocular adverse events associated with anti-VEGF therapy: A pharmacovigilance study of the FDA adverse event reporting system (FAERS).

Background: The purpose of this study is to identify and characterize ocular adverse events (AEs) that are significantly associated with anti-VEGF drugs for treatment of neovascular age-related macular degeneration and compare the differences between each drug, and provide clinical reference. Methods: Ocular AEs submitted to the US Food and Drug Administration were analyzed to map the safety profile of anti-VEGF drugs. The Pharmacovigilance tools used for the quantitative detection of signals were reporting odds ratio and bayesian confidence propagation neural network. Results: A total of 10,608,503 AE reports were retrieved from FAERS, with 20,836 for ranibizumab, 19,107 for aflibercept, and 2,442 for brolucizumab between the reporting period of Q1, 2004 and Q3, 2021. We found and analyzed the different AEs with the strongest signal in each drug-ranibizumab-macular ischaemia (ROR = 205.27, IC-2SD = 3.70), retinal pigment epithelial tear (ROR = 836.54, IC-2SD = 7.19); aflibercept-intraocular pressure increased (ROR = 31.09, IC-2SD = 4.61), endophthalmitis (ROR = 178.27, IC-2SD = 6.70); brolucizumab-retinal vasculitis (ROR = 2930.41, IC-2SD = 7.47) and/or retinal artery occlusion (ROR = 391.11, IC-2SD = 6.10), dry eye (ROR = 12.48, IC-2SD = 2.88). Conclusion: The presence of AEs should bring clinical attention. The use of anti-VEGF drugs should be based on the patient's underlying or present medical condition to reduce any adverse event associated with the treatment.

Potential safety signals for antibacterial agents from the Brazilian national pharmacovigilance database (Vigimed/VigiFlow).

Antibacterial drugs are a widely used drug class due to the frequency of infectious diseases globally. Risks knowledge should ground these medicines' selection. Data mining in large databases is essential to identify early safety signals and to support pharmacovigilance systems. We conducted a cross-sectional study to assess adverse drug events related to antibiotics reporting between December 2018 and December 2021 in the Brazilian database (Vigimed/VigiFlow). We used the Reporting Odds Ratio (ROR) disproportionality analysis method to identify disproportionate reporting signals (SDR), referring to statistical combinations between drugs and adverse events. Vancomycin was the most reported antibiotic (n = 1,733), followed by ceftriaxone (n = 1,277) and piperacillin and tazobactam (n = 1,024). We detected 294 safety signals related to antibacterials. We identified azithromycin leading in the number of safety signals (n = 49), followed by polymyxin B (n = 25). Of these, 95 were not provided for in the drug label and had little or no reports in the medical literature. Three serious events are associated with ceftazidime and avibactam, a new drug in the Brazilian market. We also found suicide attempts as a sign associated with amoxicillin/clavulanate. Gait disturbance, a worrying event, especially in the elderly, was associated with azithromycin. Our findings may help guide further pharmacoepidemiologic studies and monitoring safety signals in pharmacovigilance.

Signals from the Dutch national spontaneous reporting system: Characteristics and regulatory actions.

PURPOSE: The aim of the study is to characterise safety signals based on the Dutch spontaneous reporting system (SRS) and to investigate the association between signal characteristics and Product Information (PI) update stratified by approval type: centrally authorised products (CAPs) versus nationally and decentralised authorised products (NAPs). METHODS: This study evaluates the full cohort of signals disseminated from the Dutch SRS in the period from 2008 to 2017. Each retrieved signal was characterised on a number of aspects. The signal management process from signal generation to a potential PI update was analysed in four steps: (1) signal characterisation; (2) proposed actions by the Dutch national competent authority (NCA) for the signals; (3) presence of PI update (yes/no) and association with signal characteristics; (4) timing from the moment the signal was issued to PI update. For step 1-3 we stratified products in CAPs and NAPs. RESULTS: Of all signals, 88.7% led to a proposed regulatory action by the NCA. Signals from the Dutch SRS for CAPs versus NAPs more often concerned biologicals, important medical events, class effects and shorter periods since marketing authorization. We detected PI updates for 26.2% of CAP signals and 61.3% of NAP signals. CONCLUSIONS: The Dutch SRSs remains an important source of signals. There are some notable differences in the characteristics of signals for CAPs versus NAPs. Signals for NAPs more frequently led to PI updates.

Serious Adverse Drug Reactions and Safety Signals in Children: A Nationwide Database Study.

Children are more exposed to inappropriate medicine use and its consequent harms. Spontaneous reporting of suspected Serious Adverse Drug Reactions (SADR) increases knowledge and prevention of pharmacotherapy risk. Disproportionality measures are useful to quantify unexpected safety issues associated with a given drug-event pair (signals of disproportionality). This cross-sectional study aimed to assess SADR reporting and safety signals for Brazilian children from 0-12 years old, notified between January 2008 and December 2013 from the Brazilian Surveillance Agency (Notivisa). Information from serious reports (gender and age of the patient, event description, suspected drug) was included. Disproportionality analysis based on Reporting Odds Ratios with a confidence interval of 95% was conducted to identify possible signals of disproportionate reporting (SDR). Almost 30% of 1,977 suspected SADR was related to babies (0-1-year-old). 69% of reports happened with intravenous dosage forms, and 35% of suspected SADR involved off label use according to age. Laronidase, miglustat, imipenem/cilastatin, and clofarabine were involved in six or more suspected deaths among 75 deaths reported. There were 107 SDRs, of which 16 events (15%) were not described in the product labels. There was a relatively higher number of SADRs in Brazilian children compared with studies from other countries. SDRs found, (especially drug-event pairs 'imipenen/cilastatin-pneumonia' and 'laronidase-respiratory insufficiency') should be investigated more. The reports of SADR with IV dosage forms and OL drug use suggest the need for drug research and the use of better dosage forms for children in Brazil.

Evaluation of Serious Postmarket Safety Signals Within 2 Years of FDA Approval for New Cancer Drugs.

BACKGROUND: We examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here. METHODS: We identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns. RESULTS: Fifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval. CONCLUSION: Based on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug. IMPLICATIONS FOR PRACTICE: The majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.

Deconstructing the Pharmacovigilance Hype Cycle.

Data science is making increasing contributions to pharmacovigilance. Although the technical innovation of these works are indisputable, efficient progress in real-world pharmacovigilance signal detection may be hampered by corresponding technology life cycle effects, with a resulting tendency to conclude that, with large enough datasets and intricate algorithms, "the numbers speak for themselves," discounting the importance of clinical and scientific judgment. A practical consequence is overzealous declarations regarding the safety or lack of safety of drugs. We describe these concerns through a critical discussion of key results and conclusions from case studies selected to illustrate these points.

New safety signals assessed by the Pharmacovigilance Risk Assessment Committee at EU level in 2014-2017.

BACKGROUND: Safety monitoring of all drugs throughout their entire life cycle is mandatory in order to protect the public health. Our objective was to describe all new safety signals assessed at EU level by the Pharmacovigilance Risk Assessment Committee (PRAC). METHODS: Publicly available data on signals assessment from PRAC meeting minutes for the period January 2014-November 2017 were analyzed and classified. RESULTS: A total of 239 new signals for 194 drugs/drug combinations/therapeutic classes were evaluated by PRAC. A total of 154 signals were triggered by spontaneous reporting, 31 by literature case reports, and 26 by observational studies. In 188 signals, the drugs involved were authorized for more than 5 years. The drug classes for which most signals were detected were antineoplastic/immunomodulators (n = 75), anti-infectives (n = 34), and drugs acting on the nervous system (n = 27). Signals were triggered for drug interactions (n = 15), in utero exposure (n = 7), medication errors (n = 6), and for different disorders, among which the skin/subcutaneous tissue disorders were more common. PRAC recommendations consisted in label updates (n = 86), in Direct Healthcare Professional Communications (n = 17), and in eight recommendations for a more complex evaluation through referral procedures. CONCLUSIONS: Most new signals assessed were triggered by spontaneous reporting and led to routine risk minimization measures, such as updating the product information.

The effects of the non-contingent presentation of safety signals on the elimination of safety behaviors: An experimental comparison between individuals with low and high obsessive-compulsive profiles.

BACKGROUND AND OBJECTIVES: Safety behaviors, defined as engagement in avoidance within safe environments, are a key symptom of obsessive-compulsive and related disorders. They may interfere with daily functioning and as such their emission should be reduced. The purpose of the current study is to investigate the effects of the non-contingent presentation of safety signals (cues produced by safety behaviors) on reducing safety behaviors in participants self-reporting low and high OCD profiles. METHODS: In total, 32 participants were asked to play a game to gain points and avoid their loss. After having developed avoidance behavior, evidenced by maintaining all of their earned points, they were exposed to safe environments where no point loss was programmed. In Test 1, safety cues (blue bar) were produced contingent on performing safety behaviors. In Test 2, safety cues were presented continuously without any response requirement. RESULTS: Findings demonstrated that high OCD group displayed higher rates of safety behaviors than low OCD group. However, exposure to the non-contingent presentation of safety signals eliminated their emission in both groups. LIMITATIONS: Future studies need to evaluate the effects of different non-contingent schedules on the suppression of safety behaviors. CONCLUSIONS: These findings contribute to the literature by demonstrating that non-contingent introduction of safety signals eliminated safety behaviors completely, even in high OCD participants, who performed safety behavior at higher rates. Such a treatment protocol may ameliorate exposure therapy in which response prevention constitutes a key element and is generally associated with increased drop-out rates.

Generalisation of fear in PTSD related to prolonged childhood maltreatment: an experimental study.

BACKGROUND: Fear responses are particularly intense and persistent in post-traumatic stress disorder (PTSD), and can be evoked by unspecific cues that resemble the original traumatic event. Overgeneralisation of fear might be one of the underlying mechanisms. We investigated the generalisation and discrimination of fear in individuals with and without PTSD related to prolonged childhood maltreatment. METHODS: Sixty trauma-exposed women with (N = 30) and without (N = 30) PTSD and 30 healthy control participants (HC) underwent a fear conditioning and generalisation paradigm. In a contingency learning procedure, one of two circles of different sizes was associated with an electrical shock (danger cue), while the other circle represented a safety cue. During generalisation testing, online risk ratings, reaction times and fear-potentiated startle were measured in response to safety and danger cues as well as to eight generalisation stimuli, i.e. circles of parametrically varying size creating a continuum of similarity between the danger and safety cue. RESULTS: The increase in reaction times from the safety cue across the different generalisation classes to the danger cue was less pronounced in PTSD compared with HC. Moreover, PTSD participants expected higher risk of an aversive event independent of stimulus types and task. CONCLUSIONS: Alterations in generalisation constitute one part of fear memory alterations in PTSD. Neither the accuracy of a risk judgement nor the strength of the induced fear was affected. Instead, processing times as an index of uncertainty during risk judgements suggested a reduced differentiation between safety and threat in PTSD.

The role of safety signals in fear extinction: An analogue study.

BACKGROUND AND OBJECTIVES: Safety signals are conditioned inhibitory stimuli that indicate the absence of unconditioned stimuli. It is not clear whether the presence of safety signals is detrimental or beneficial in extinction-based interventions. The purpose of this study was to evaluate the effect of safety signals on autonomic and expectancy fear-related responses. METHODS: Following the conditional discrimination paradigm (AX +, BX-), undergraduate students (N = 48) underwent an aversive conditioning procedure, while safety signals were experimentally created. Participants were randomly assigned to one of two conditions during extinction: presence or absence of safety signals. RESULTS: Significant reductions of fear-related responses were found in both groups. Expectancy measures showed that the presence of safety signals did not interfere with reduction of fear related responses at follow-up. LIMITATIONS: The analogue nature of the study affects its ecological validity. There are some methodological issues. CONCLUSIONS: Safety signals did not interfere with extinction learning. Attention may be a mechanism associated with the maintenance of fear responses.

Neural basis of impaired safety signaling in Obsessive Compulsive Disorder.

The ability to assign safety to stimuli in the environment is integral to everyday functioning. A key brain region for this evaluation is the ventromedial prefrontal cortex (vmPFC). To investigate the importance of vmPFC safety signaling, we used neuroimaging of Pavlovian fear reversal, a paradigm that involves flexible updating when the contingencies for a threatening (CS+) and safe (CS-) stimulus reverse, in a prototypical disorder of inflexible behavior influenced by anxiety, Obsessive Compulsive Disorder (OCD). Skin conductance responses in OCD patients (n = 43) failed to differentiate during reversal compared with healthy controls (n = 35), although significant differentiation did occur during early conditioning and amygdala BOLD signaling was unaffected in these patients. Increased vmPFC activation (for CS+ > CS-) during early conditioning predicted the degree of generalization in OCD patients during reversal, whereas vmPFC safety signals were absent throughout learning in these patients. Regions of the salience network (dorsal anterior cingulate, insula, and thalamus) showed early learning task-related hyperconnectivity with the vmPFC in OCD, consistent with biased processing of the CS+. Our findings reveal an absence of vmPFC safety signaling in OCD, undermining flexible threat updating and explicit contingency knowledge. Although differential threat learning can occur to some extent in the absence of vmPFC safety signals, effective CS- signaling becomes crucial during conflicting threat and safety cues. These results promote further investigation of vmPFC safety signaling in other anxiety disorders, with potential implications for the development of exposure-based therapies, in which safety signaling is likely to play a key role.

Emotion regulation during threat: Parsing the time course and consequences of safety signal processing.

Improved understanding of fear inhibition processes can inform the etiology and treatment of anxiety disorders. Safety signals can reduce fear to threat, but precise mechanisms remain unclear. Safety signals may acquire attentional salience and affective properties (e.g., relief) independent of the threat; alternatively, safety signals may only hold affective value in the presence of simultaneous threat. To clarify such mechanisms, an experimental paradigm assessed independent processing of threat and safety cues. Participants viewed a series of red and green words from two semantic categories. Shocks were administered following red words (cue+). No shocks followed green words (cue-). Words from one category were defined as safety signals (SS); no shocks were administered on cue+ trials. Words from the other (control) category did not provide information regarding shock administration. Threat (cue+ vs. cue-) and safety (SS+ vs. SS-) were fully crossed. Startle response and ERPs were recorded. Startle response was increased during cue+ versus cue-. Safety signals reduced startle response during cue+, but had no effect on startle response during cue-. ERP analyses (PD130 and P3) suggested that participants parsed threat and safety signal information in parallel. Motivated attention was not associated with safety signals in the absence of threat. Overall, these results confirm that fear can be reduced by safety signals. Furthermore, safety signals do not appear to hold inherent hedonic salience independent of their effect during threat. Instead, safety signals appear to enable participants to engage in effective top-down emotion regulatory processes.

Cognitive flexibility mediates the relation between intolerance of uncertainty and safety signal responding in those with panic disorder.

There is a growing literature associating anxiety disorders with an inability to inhibit defensive responding during safety conditions of threatening tasks. However, investigations on the relation between panic disorder (PD) and defensive responding to safety have yielded mixed results. A recent study from our laboratory revealed that intolerance of uncertainty (IU) moderates this association, such that only individuals with PD and a high IU exhibit heightened startle potentiation during safety. The mechanism underlying this relationship is unknown. Given that safety conditions typically alternate with periods of threat, cognitive flexibility (i.e., the ability to adjust one's habitual responding to a situation, given the input of new information) may be involved in the ongoing reappraisal of danger and adjustment of defensive responding. Thus, the present study sought to investigate whether deficits in cognitive flexibility mediate the association between IU and defensive responding to safety among a sample of 71 adults diagnosed with PD. As hypothesised, cognitive flexibility mediated the relationship between IU and heightened startle potentiation during safety conditions. This finding suggests that within this subgroup, a failure to inhibit defensive responding during safety conditions may be due to deficits in cognitive flexibility.

Best Practices for Improving the Quality of Individual Case Safety Reports in Pharmacovigilance.

BACKGROUND: The quality of individual case safety reports (ICSRs) plays a vital role in identifying new safety signals in pharmacovigilance. This article focuses on establishing a method for ensuring the quality data. OBJECTIVE: To develop an in-house method for assessing the documentation grading and completeness score of ICSRs. METHODS: In the proposed method, 16 parameters, from report title to case narrative, are adopted to assess the quality of ICSRs. The in-house method ensures the completeness of the data and enhances the quality of ICSRs. RESULTS: The in-house method was found effective in calculating the completeness score of ICSR ranges from 0.05 to 1. Indian ICSR completeness scores significantly improved after the implementation of the proposed method in the third quarter of 2013. In 2014 and until the third quarter of 2015, the score was found to be 0.91 and 0.93 out of 1, respectively. CONCLUSION: The higher quality ICSRs aids in more effective identification of new drug safety alerts and provides evidence-based information for regulating the drug safety.

Maintenance of safety behaviors via response-produced stimuli.

Animal studies suggest that safety behaviors may be maintained by internally or externally produced safety signals, which function as positive reinforcers. We designed two experiments to test this phenomenon with humans. Participants played a computerized game in which they could earn or lose treasures by clicking on a map. In baseline, losses could be postponed by pressing a pedal that also produced a blue bar at the bottom of the screen. During test conditions, no losses were programmed, and pedal presses turned the bar from yellow to blue (Test 1) or blue to yellow (Test 2). In Experiment 2, new participants were exposed to the same conditions but were given information about the safety of the test environment. In both experiments, participants engaged in high rates of pedal pressing when presses were followed by blue bars, suggesting the bar functioned as a safety signal. We discuss how these findings may relate to safety behaviors commonly observed in certain mental health disorders.

Adversity in early and mid-adolescence is associated with elevated startle responses to safety cues in late adolescence.

Elevated responding to safety cues in the context of threat is associated with anxiety disorder onset, but pathways underlying such responding remain unclear. This study examined whether childhood/adolescent adversity was associated with larger startle reflexes during safe phases of a fear potentiation startle paradigm (following delivery of an aversive stimulus) that predict anxiety disorders. Participants (N = 104) came from the Youth Emotion Project, a longitudinal study of risk factors for emotional disorders. Participants with no baseline psychopathology underwent a startle modulation protocol and were assessed for childhood and adolescent adversities using a validated interview. Adolescent adversity was associated with larger startle reflexes during the safe phases following an aversive stimulus. Neither child nor adolescent adversities were associated with responding during any other phase of the protocol. These findings suggest a pathway between adolescent adversity and a risk factor for anxiety disorders wherein adolescent adversity contributes to impaired responding to safety cues.