Quantifying heterogeneity in mood-alcohol relationships with idiographic causal models.

BACKGROUND: Ecological momentary assessment (EMA) studies have provided conflicting evidence for the mood regulation tenet that people drink in response to positive and negative moods. The current study examined mood-to-alcohol relationships idiographically to quantify the prevalence and intensity of relationships between positive and negative moods and drinking across individuals. METHOD: We used two EMA samples: 96 heavy drinking college students (sample 1) and 19 young adults completing an ecological momentary intervention (EMI) for drinking to cope (sample 2). Mood and alcohol use were measured multiple times per day for 4-6 weeks. Mood-alcohol relationships were examined using three different analytic approaches: standard multilevel modeling, group causal modeling, and idiographic causal modeling. RESULTS: Both multilevel modeling and group causal modeling showed that participants in both samples drank in response to positive moods only. However, idiographic causal analyses revealed that only 63% and 21% of subjects (in samples 1 and 2, respectively) drank following any positive mood. Many subjects (24% and 58%) did not drink in response to either positive or negative mood in their daily lives, and very few (5% and 16%) drank in response to negative moods throughout the EMA protocol, despite sample 2 being selected specifically because they endorse drinking to cope with negative mood. CONCLUSION: Traditional group-level analyses and corresponding population-wide theories assume relative homogeneity within populations in mood-alcohol relationships, but this nomothetic approach failed to characterize accurately the relationship between mood and alcohol use in approximately half of the subjects in two samples that were demographically and clinically homogeneous. Given inconsistent findings in the mood-alcohol relationships to date, we conclude that idiographic causal analyses can provide a foundation for more accurate theories of mood and alcohol use. In addition, idiographic causal models may also help improve psychosocial treatments through direct use in clinical settings.

Causal Network Modeling of the Determinants of Drinking Behavior in Comorbid Alcohol Use and Anxiety Disorder.

BACKGROUND: Anxiety and depression disorders (internalizing psychopathology) occur in approximately 50% of patients with alcohol use disorder (AUD) and mark a 2-fold increase in the rate of relapse in the months following treatment. In a previous study using network modeling, we found that perceived stress and drinking to cope (DTC) with negative affect were central to maintaining network associations between internalizing psychopathology INTP and drinking in comorbid individuals. Here, we extend this approach to a causal framework. METHODS: Measures of INTP, drinking urges/behavior, abstinence self-efficacy, and DTC were obtained from 362 adult AUD treatment patients who had a co-occurring anxiety disorder. Data were analyzed using a machine-learning algorithm ("Greedy Fast Causal Inference"[ GFCI]) that infers paths of causal influence while identifying potential influences associated with unmeasured ("latent") variables. RESULTS: DTC with negative affect served as a central hub for 2 distinct causal paths leading to drinking behavior, (i) a direct syndromic pathway originating with social anxiety and (ii) an indirect stress pathway originating with perceived stress. CONCLUSIONS: Findings expand the field's knowledge of the paths of influence that lead from internalizing disorder to drinking in AUD as shown by the first application in psychopathology of a powerful network analysis algorithm (GFCI) to model these causal relationships.

Extinction and beyond: an expanded framework for exposure and response prevention for obsessive-compulsive disorder.

Exposure therapy is a first-line, empirically validated treatment for anxiety, obsessive-compulsive, and trauma-related disorders. Extinction learning is the predominant theoretical framework for exposure therapy, whereby repeated disconfirmation of a feared outcome yields fear reduction over time. Although this framework has strong empirical support and substantial translational utility, extinction learning is unlikely to be the sole process underlying the therapeutic effects of exposure therapy. In our clinic, we commonly treat obsessive-compulsive disorder (OCD) patients successfully with exposure therapy even when some or all of their feared outcomes are not amenable to disconfirmation and, by extension, to extinction learning. Herein, we present a generic clinical vignette illustrating a commonly encountered feared outcome in OCD that cannot be disconfirmed through exposure (damnation resulting from blasphemous thoughts). We describe two specific non-extinction-based strategies we commonly employ in such cases, and we associate these strategies with known change mechanisms that might account for their effectiveness: (1) non-associative habituation to aversive stimuli, and (2) fear-memory elicitation and subsequent reconsolidation. We discuss the limitations inherent in the reverse-translational approach taken and its opportunities for expanding the framework of exposure therapy.

World Health Organization (WHO) risk level reductions in inpatients with alcohol use disorder and comorbid anxiety disorders.

OBJECTIVE: Studies have demonstrated that reduced drinking without total abstinence is associated with improved outcomes in outpatients with alcohol use disorder (AUD). We sought to examine this question in AUD inpatients who have comorbid anxiety disorders, a common presentation in AUD. METHOD: This is a secondary analysis of data from a randomized controlled trial for N = 241 inpatients with AUD and comorbid anxiety disorders. Change from baseline drinking level was measured at 1-, 4-, and 12-months postdischarge, and psychological and functional outcomes were measured at 4- and 12-months postdischarge. Three groups were compared: abstinent, reduced (reduced drinking by 1-3 World Health Organization drinking risk levels without abstinence), or nonreduced (maintained or increased drinking risk level). RESULTS: At 1-, 4-, and 12-months posttreatment, most patients reported abstinence (83, 63, and 60%), and 11, 25, and 26% reported drinking at a reduced level. Drinking reductions achieved at 1-month posttreatment were maintained at 12-month posttreatment by 74% of participants. Overall, the abstinent group reported the best psychological and functional outcomes at follow-ups, followed by the reduced group. Few differences were observed between reducers and nonreducers, but reducers reported significantly better alcohol dependence severity and alcohol-related problems than nonreducers. CONCLUSIONS: Though abstinence was associated with the best outcomes in this abstinence-based treatment sample, we conclude that reduced drinking is also associated with significant improvements in alcohol-related outcomes in inpatients with AUD and comorbid anxiety disorders.At 1-, 4-, and 12-months posttreatment, most patients reported abstinence (83, 63, and 60%), and 11, 25, and 26% reported drinking at a reduced level. Drinking reductions achieved at 1-month posttreatment were maintained at 12-month posttreatment by 74% of participants. Overall, the abstinent group reported the best psychological and functional outcomes at follow-ups, followed by the reduced group. Few differences were observed between reducers and nonreducers, but reducers reported significantly (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Evidence for an alcohol-related "harm paradox" in individuals with internalizing disorders: Test and replication in two independent community samples.

BACKGROUND: Internalizing (anxiety and mood) disorders (INTD) commonly co-occur (are "comorbid") with alcohol use disorder (AUD). The literature suggests that excessive alcohol use aimed at coping with INTD symptoms is, at best, a partial explanation for the high comorbidity rates observed. We hypothesized that individuals with INTD experience greater susceptibility to developing AUD symptoms due to the partially shared neurobiological dysfunctions underlying both conditions. We probe this hypothesis by testing the prediction that, after accounting for the volume of alcohol intake, individuals with INTD experience higher levels of alcohol-related symptoms. METHODS: Data from the National Epidemiological Survey on Alcohol-Related Conditions (NESARC) Wave 3 were used for the primary analyses, and NESARC Wave 1 data were used for independent replication analyses. Individuals who reported any alcohol use in the prior year were categorized as: (1) never having had an INTD diagnosis ("INTD-Never"); (2) having a remitted INTD diagnosis only ("INTD-Remitted"); or (3) having current INTD diagnosis ("INTD-Current"). Between-group contrasts of alcohol-related symptoms controlled for total alcohol intake (past year), drinking pattern (e.g., binging) and variables previously shown to mark exaggerated AUD symptoms relative to drinking amount (e.g., SES, gender, and family history). RESULTS: With all covariates in the model, individuals in the INTD-Current group and the INTD-Remitted group reported significantly greater alcohol-related symptoms than those in the INTD-Never group but did not themselves differ in level of alcohol-related symptoms. These results were replicated in the NESARC 1 dataset. CONCLUSIONS: Individuals with INTD experience more alcohol-related symptoms than those who drink at the same level. While considering other explanations, we argue that this "harm paradox" is best explained by the view that INTD confers a neurobiologically mediated susceptibility to the development of AUD symptoms.

Alcohol dependence is related to overall internalizing psychopathology load rather than to particular internalizing disorders: evidence from a national sample.

BACKGROUND: Alcohol dependence is more prevalent among those with any one of several anxiety or depressive ("internalizing") disorders than among those in the general population. However, because internalizing disorders are highly intercorrelated, it is ambiguous whether alcohol dependence is related to internalizing psychopathology components that are: (i) unique to a particular internalizing disorder ("specific"); versus (ii) shared across a number of internalizing disorders ("general"). To clarify this ambiguity, we employed structural equation and logistic models to decompose the specific versus general components of internalizing psychopathology and then related these components separately to alcohol dependence. METHODS: The data were based on face-to-face interviews of U.S. community residents collected in the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 43,093). RESULTS: Both analytic approaches demonstrated that increases in the general internalizing psychopathology load are accompanied by increases in the prevalence of alcohol dependence. Once the general internalizing psychopathology load is accounted for, knowing whether a particular internalizing disorder is present or absent provides little additional information regarding the prevalence of alcohol dependence. CONCLUSIONS: The components of internalizing psychopathology that are associated with alcohol dependence are shared and cumulative among common anxiety and depressive disorders. These findings have the potential to influence clinical and scientific conceptualizations of the association between alcohol dependence and internalizing psychopathology.

Risk Pathways Contributing to the Alcohol Harm Paradox: Socioeconomic Deprivation Confers Susceptibility to Alcohol Dependence via Greater Exposure to Aversive Experience, Internalizing Symptoms and Drinking to Cope.

Socioeconomic deprivation is associated with greater alcohol problems despite lower alcohol consumption, but the mechanisms underpinning this alcohol harm paradox remain obscure. Fragmented published evidence collectively supports a multistage causal risk pathway wherein socioeconomic deprivation increases the probability of exposure to aversive experience, which promotes internalizing symptoms (depression and anxiety), which promotes drinking alcohol to cope with negative affect, which in turn accelerates the transition from alcohol use to dependence. To evaluate this proposed risk pathway, 219 hazardous drinkers from an undergraduate population completed questionnaires assessing these constructs in a single, cross sectional, online survey. Partial correlation coefficients revealed that each variable showed the strongest unique association with the next variable in the proposed multistage model, when adjusting for the other variables. Bootstrapped serial mediation analysis revealed that the indirect pathway linking all the variables in the proposed serial order was significant, while all other permutations were non-significant. Network centrality analysis corroborated the serial order of this indirect path. Finally, risk ratios estimated by categorizing the variables suggested that socioeconomic deprivation increased the risk of aversive experience by 32%, which increased the risk of internalizing symptoms by 180%, which increased the risk of drinking to cope by 64%, which increased susceptibility to alcohol dependence by 59%. These preliminary findings need to be corroborated by future research, nevertheless, they call for prevention strategies founded on social justice and the minimization of aversive experience in socially deprived individuals to mitigate mental health problems, maladaptive coping and addiction.

The direct effect of drinking to cope on alcohol problems is not mediated by alcohol consumption: Invariance across gender and countries.

Background: Drinking to cope with negative affect confers a direct risk of alcohol problems independently of greater alcohol consumption (i.e., confers susceptibility to the alcohol harm paradox). However, it remains unclear whether this risk is common across gender and countries. Methods: The current study applied path analysis to two cross-sectional samples of 18-25-year-old undergraduate hazardous drinking students recruited from the UK (Study 1; N = 873) and internationally (Study 2; N = 4064 recruited in Argentina, Canada, South Africa, Spain, Uruguay, USA, and England). The Drinking Motives Questionnaire (DMQ) measured drinking to cope with negative affect and drinking to enhance positive affect (i.e., enhancement motives). The Alcohol Use Disorders Identification Test (AUDIT) measured alcohol consumption and problems. Results: In both studies, drinking to cope with negative affect had a direct effect on alcohol problems (S1: ß = 0.259, SE = 0.031, p <.001; S2: ß = 0.255, SE = 0.017, p <.001), and only a negligible proportion of this effect was mediated by alcohol consumption (S1: 2.58 %, p =.550; S2: 0.79 %, p=.538). By contrast, drinking to enhance positive affect had a smaller direct effect on alcohol problems (S1: ß = 0.000, SE = 0.033, p =.989; S2: ß = 0.044, SE = 0.017, p =.009), and a substantial proportion of this effect was mediated by greater alcohol consumption (S1: 99.76 %, p <.001; S2: 60.36 %, p <.001). Crucially, in both studies, the direct effect of drinking to cope on alcohol problems was invariant across gender and countries. Conclusions: These findings suggest that individuals who endorse drinking to cope with negative affect are uniquely susceptible to the alcohol harm paradox, that is, greater alcohol problems which cannot be explained by greater alcohol consumption, and this susceptibility is common across gender and countries.

The Proposal Preparation Program: A Group Mentoring, Faculty Development Model to Facilitate the Submission and Funding of NIH Grant Applications.

This article describes the University of Minnesota Medical School Proposal Preparation Program (P3). P3 is designed to develop grant-writing skills for assistant professors preparing their first K- or R-series application to the National Institutes of Health (NIH). Three 4-month P3 cycles are conducted annually. For each cycle, a cohort of around 10 assistant professor participants and 5 regular faculty mentors meet for ten ~2-hour group sessions. Participants receive iterative oral and written feedback on their proposals in development within a small, interdisciplinary, group mentoring setting providing structure, accountability, guidance, and support. Between sessions, 1 peer and 1 mentor are assigned (on a rotating basis) to critique each participant's developing application. The sessions include a brief mentor-led presentation on a particular grant section followed by discussion of each participant's application conducted by the assigned reviewers. The cycle concludes with a mock NIH review session, in which each participant is matched with a University of Minnesota faculty content expert who critiques their completed application using NIH guidelines. In a survey sent to all past P3 participants as of 2018 (n = 194), 88% of respondents reported having submitted their P3-developed NIH grant, and 35% of these submitters reported funding success. A separate analysis of institutional data for all past P3 participants as of 2016 (n = 165) showed that 73% submitted at least 1 NIH proposal since completing P3 and that 43% of these had acquired NIH funding, for a combined total of $193 million in funding awarded. The estimated rate at which participants obtained funding for their P3-developed grant application (~35%) exceeds the national annual NIH grant funding rates (~20%) by approximately 50%. This article provides the practical information needed for other institutions to implement a P3-like program and presents a cost-benefit analysis showing the advantages of doing so.

Meta-analysis of supplemental treatment for depressive and anxiety disorders in patients being treated for alcohol dependence.

Approximately half of those receiving treatment for an alcohol use disorder (AUD) also suffer with an anxiety or depressive (internalizing) disorder. Because all internalizing disorders mark a poor alcohol treatment outcome, it seems reasonable to supplement AUD treatment with a psychiatric intervention when these disorders co-occur with AUD. However, this conclusion may be faulty given that the various possible interrelationships between AUD and internalizing disorders do not uniformly imply a high therapeutic yield from this approach. Unfortunately, the studies conducted to date have been too few and too small to resolve this important clinical issue with confidence. Therefore, we used a meta-analytic method to synthesize the effects from published randomized controlled trials examining the impact of supplementing AUD treatment with a psychiatric treatment for co-occurring internalizing disorder (N = 15). We found a pooled effect size (d) of .32 for internalizing outcomes and .22 for a composite of alcohol outcomes; however, the alcohol outcomes effect sizes were greater than this for some specific outcome domains. Subgroups that differed in terms of internalizing outcomes included treatment type (medication vs. cognitive behavioral therapy) and treatment focus (anxiety vs. depression). There was also a trend for the studies with better internalizing disorder outcomes to have better alcohol outcomes. These results indicate that clinical outcomes (both psychiatric and alcohol-related) could be somewhat improved by supplementing AUD treatment with psychiatric treatment for co-occurring internalizing disorder.

Co-Occurring Alcohol Use Disorder and Anxiety: Bridging Psychiatric, Psychological, and Neurobiological Perspectives.

A substantial number of people who have problems with alcohol also experience strong anxiety and mood problems. This article provides an overview of the evolving perspectives of this association in the context of three related disciplines-psychiatry, psychology, and neuroscience. Psychiatric and epidemiological studies show that having either an anxiety- or alcohol-related diagnosis elevates the prospective risk for developing the other disorder. From the psychological perspective, behavioral research demonstrates that drinking to cope with negative affect is a potent marker for current and future problems with alcohol. Neuroscientific research implicates overlapping neurobiological systems and psychological processes in promoting the rise of negative affect and alcohol misuse. The psychiatric perspective that alcohol misuse and co-occurring anxiety represent neurobiologically distinct diagnostic conditions has dominated the field for many decades. However, recent research provides increasing support for the neuroscientific perspective that these conditions share underlying, mutually exacerbating, neurobiological processes.

Assessing the collective utility of multiple analyses on clinical alcohol use disorder data.

OBJECTIVE: The objective of this study was to assess the potential of combining graph learning methods with latent variable estimation methods for mining clinically useful information from observational clinical data sets. MATERIALS AND METHODS: The data set contained self-reported measures of psychopathology symptoms from a clinical sample receiving treatment for alcohol use disorder. We used the traditional graph learning methods: Graphical Least Absolute Shrinkage and Selection Operator, and Friedman's hill climbing algorithm; traditional latent variable estimation method factor analysis; recently developed graph learning method Greedy Fast Causal Inference; and recently developed latent variable estimation method Find One Factor Clusters. Methods were assessed qualitatively by the content of their findings. RESULTS: Recently developed graphical methods identified potential latent variables (ie, not represented in the model) influencing particular scores. Recently developed latent effect estimation methods identified plausible cross-score loadings that were not found with factor analysis. A graphical analysis of individual items identified a mistake in wording on 1 questionnaire and provided further evidence that certain scores are not reflective of indirectly measured common causes. DISCUSSION AND CONCLUSION: Our findings suggest that a combination of Greedy Fast Causal Inference and Find One Factor Clusters can enhance the evidence-based information yield from psychopathological constructs and questionnaires. Traditional methods provided some of the same information but missed other important findings. These conclusions point the way toward more informative interrogations of existing and future data sets than are commonly employed at present.

Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis.

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

Methodological Advances in the Study of Hidden Variables: A Demonstration on Clinical Alcohol Use Disorder Data.

Research in the domain of psychopathology has been hindered by hidden variables-variables that are important to understanding and treating psychopathological illnesses but are unmeasured. Recent methodological advances in machine learning have culminated in the ability to discover and identify the influence of hidden variables that confound the observed relationships among measured variables. We apply a combination of traditional methods and more recent advances to a data set of alcohol use disorder patients with comorbid internalizing disorders, and find that the increasingly advanced methods produce increasingly informative and reliable results. These results include novel findings evaluated positively by our psychopathologists, as well as findings validated with knowledge from existing literature. We also find that advanced graph discovery methods can guide the use of latent variable modeling procedures, which can in turn explain the output of the graph discovery methods, resulting in a synergistic relationship between two seemingly distinct classes of methods.

D-cycloserine augmented exposure therapy for obsessive-compulsive disorder.

BACKGROUND: D-cycloserine (DCS), a glutamatergic partial N-methyl-d-aspartate (NMDA) agonist, can facilitate extinction learning related to cued fear in animals and humans. We predicted that DCS would accelerate obsession-related distress reduction in patients with obsessive-compulsive disorder (OCD) undergoing extinction-based exposure therapy. METHODS: We administered DCS (125 mg) or placebo in a double-blind fashion to individuals with OCD approximately 2 hours before each exposure session. RESULTS: D-cycloserine decreased both the number of exposure sessions required to achieve clinical milestones and the rate of therapy dropout. After four exposure sessions, patients in the DCS group reported significantly greater decreases in obsession-related distress compared with the placebo group; however, after additional sessions, the placebo group tended to catch up. CONCLUSIONS: D-cycloserine augmentation has the potential to increase the efficiency, palatability, and overall effectiveness of standard exposure therapy for OCD.

Urge to gamble in problem gamblers exposed to a casino environment.

Cue-reactivity has received increased attention in addiction research, though not for gambling in particular. We examined cue reactivity in 18 problem gamblers by accompanying them to a gaming casino and measuring their subjective urge to gamble over a 1-h period. Half of the sample was additionally exposed to a gambling-specific negative mood induction (NMI) manipulation via guided imagery. Overall, about two-thirds of the sample reported moderate to high-gambling urges during the casino exposure. Additionally, the NMI reduced cue-reactivity. Finally, gambling urges in both groups decreased over the course of the exposure sessions. These findings suggest that a majority of problem gamblers experience the urge to gamble when exposed to gambling cues and that the intensity of these urges decrease with time, especially in the presence of a gambling-relevant NMI. Cue exposure should be studied further as a potential tool in the treatment of problem gambling.

The use of cognitive-behavioral therapy in the University of Minnesota's outpatient psychiatry clinic.

Cognitive-behavioral therapy (CBT) refers to a group of therapeutic techniques that can be categorized broadly as psychoeducation, cognitive restructuring, and behavioral exposure. Unlike other psychotherapeutic approaches, CBT is derived from learning laboratory experimentation rather than conjecture and theorizing. This article provides background information concerning the origins and practice of cognitive and behavioral therapies and summarizes findings from a recently completed research project at the University of Minnesota that integrates new neuroscientific findings and CBT.

A network approach to modeling comorbid internalizing and alcohol use disorders.

Internalizing disorders co-occur with alcohol use disorder (AUD) at a rate that exceeds chance and compromise conventional AUD treatment. The "vicious cycle" model of comorbidity specifies drinking to cope (DTC) as a link between these disorders that, when not directly addressed, undermines the effectiveness of conventional treatments. Interventions based on this model have proven successful but there is no direct evidence for how and to what extent DTC contributes to the maintenance of comorbidity. In the present study, we used network analysis to depict associations between syndrome-specific groupings of internalizing symptoms, alcohol craving, and drinking behavior, as well as DTC and other extradiagnostic variables specified in the vicious cycle model (e.g., perceived stress and coping self-efficacy). Network analyses of 362 individuals with comorbid anxiety and AUD assessed at the beginning of residential AUD treatment indicated that while internalizing conditions and drinking elements had only weak direct associations, they were strongly connected with DTC and perceived stress. Consistent with this, centrality indices showed that DTC ranked as the most central/important element in the network in terms of its "connectedness" to all other network elements. A series of model simulations-in which individual elements were statistically controlled for-demonstrated that DTC accounted for all the relationships between the drinking-related elements and internalizing elements in the network; no other variable had this effect. Taken together, our findings suggest that DTC may serve as a "keystone" process in maintaining comorbidity between internalizing disorders and AUD. (PsycINFO Database Record

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data.

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Suffocation and respiratory responses to carbon dioxide and breath holding challenges in individuals with panic disorder.

OBJECTIVE: Findings showing that individuals with panic disorder (PD) are prone to experience panic attacks when inhaling CO2-enriched air have given rise to the hypothesis that physiological systems underlying the experience of suffocation may be important in the etiology of PD. In this study, we tested several predictions stemming from this view. METHODS: Forty individuals with PD and 32 controls underwent both a breath-holding challenge and a CO2 rebreathing challenge. A wide array of physiological and psychological responses, including continuous measurements of subjective suffocation, was recorded. RESULTS: Individuals with PD experienced elevated physiological reactivity to both challenges and greater levels of suffocation sensations during the rebreathing challenge. Furthermore, PD individuals who experienced a panic attack in response to the rebreathing challenge exhibited faster but shallower breathing during the challenge than did other PD individuals. CONCLUSION: Findings are consistent with theories linking PD to hypersensitive brain systems underlying the experience of suffocation. The possibility that subjective suffocation was in part mediated by peripheral interoceptive disturbances (vs. brainstem dysregulation) is discussed.