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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/)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© 2018 by the Research Society on Alcoholism.)

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.

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, ((c) 2017 APA, all rights reserved).)

Background: Epidemiological studies and theory implicate drinking to cope (DTC) with anxiety as a potent moderator of the association between anxiety disorder (AnxD) and problematic alcohol use. However, the relevance of DTC to the treatment of alcohol use disorder (AUD) in those with a co-occurring AnxD has not been well studied. To address this, we examined whether DTC moderates the impact of two therapies: (1) a cognitive behavioral therapy (CBT) designed to reduce DTC and anxiety symptoms; (2) a progressive muscle relaxation training (PMRT) program designed to reduce anxiety symptoms only., Methods: Patients undergoing a standard AUD residential treatment with a co-occurring AnxD (N=218) were randomly assigned to also receive either the CBT or PMRT. DTC in the 30 days prior to treatment was measured using the Unpleasant Emotions subscale of the Inventory of Drinking Situations., Results: Confirming the predicted moderator model, the results indicated a significant interaction between treatment group and level of pre-treatment DTC behavior. Probing this interaction revealed that for those reporting more pre-treatment DTC behavior, 4-month alcohol outcomes were superior in the CBT group relative to the PMRT group. For those reporting less pre-treatment DTC behavior, however, 4-month alcohol outcomes were similar and relatively good in both treatment groups., Conclusions: These findings establish a meaningful clinical distinction among those with co-occurring AUD-AnxD based on the degree to which the symptoms of the two disorders are functionally linked through DTC. Those whose co-occurring AUD-AnxD is more versus less strongly linked via DTC are especially likely to benefit from standard AUD treatment that is augmented by a brief CBT designed to disrupt this functional link., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Recent studies using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) have found that some personality disorders (PDs) increase the persistence of several Axis I disorders. However, these effects are potentially confounded with the data collection wave in which PDs were assessed. Our aim was to extend published analyses to the case of anxiety disorders and to determine the robustness of the associations to analyses examining time-of-measurement effects. Persistence of anxiety disorders was defined either as follow-up diagnosis among participants diagnosed at baseline ("prediction") or baseline diagnosis among participants diagnosed at follow-up ("post-diction"). Results revealed a robust pattern of higher odds ratios for post-diction among PDs assessed at baseline, and lower odds ratios for post-diction among PDs assessed at follow-up, suggesting a time of measurement artifact. Although only 4% of associations were robust to both predictive and post-dictive analyses, these were consistent with previous research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Clinical trials are typically designed to test the effect of a specific treatment on a single diagnostic entity. However, because common internalizing disorders are highly correlated ('co-morbid'), we sought to establish a practical and parsimonious method to characterize and quantify changes in a broad spectrum of internalizing psychopathology targeted for treatment in a clinical trial contrasting two transdiagnostic psychosocial interventions., Method: Alcohol dependence treatment patients who had any of several common internalizing disorders were randomized to a six-session cognitive-behavioral therapy (CBT) experimental treatment condition or a progressive muscle relaxation training (PMRT) comparison treatment condition. Internalizing psychopathology was characterized at baseline and 4 months following treatment in terms of the latent structure of six distinct internalizing symptom domain surveys., Results: Exploratory structural equation modeling (ESEM) identified a two-factor solution at both baseline and the 4-month follow-up: Distress (measures of depression, trait anxiety and worry) and Fear (measures of panic anxiety, social anxiety and agoraphobia). Although confirmatory factor analysis (CFA) demonstrated measurement invariance between the time-points, structural models showed that the latent means of Fear and Distress decreased substantially from baseline to follow-up for both groups, with a small but statistically significant advantage for the CBT group in terms of Distress (but not Fear) reduction., Conclusions: The approach demonstrated in this study provides a practical solution to modeling co-morbidity in a clinical trial and is consistent with converging evidence pointing to the dimensional structure of internalizing psychopathology.

Objective: Treatment for alcohol use disorder (AUD) is far less effective for those with a co-occurring anxiety disorder. Surprisingly, adding an independent anxiety treatment to AUD treatment does not substantially improve the poor alcohol outcomes of these patients. This may reflect the lack of attention from independent treatments to the dynamic interaction of anxiety symptoms with alcohol use and drinking motivation. On the basis of this view, we assembled a cognitive behavioral therapy (CBT) program designed to both reduce anxiety symptoms and weaken the links between the experience of anxiety and the motivation to drink., Method: 344 patients undergoing residential AUD treatment with current social phobia, generalized anxiety disorder, or panic disorder were randomly assigned to receive either the CBT or an active comparison treatment, progressive muscle relaxation training (PMRT). Assessments took place immediately following treatment and 4 months later (n = 247)., Results: As predicted, the CBT group demonstrated significantly better alcohol outcomes 4 months following treatment than did the PMRT group. Although both groups experienced a substantial degree of anxiety reduction following treatment, there were no significant group differences immediately after treatment and only a slight advantage for the CBT group 4 months after treatment., Conclusions: These findings suggest that specific interventions aimed at weakening the association between the experience of anxiety and drinking motivation play an important role in improving the alcohol outcomes of these difficult-to-treat patients beyond that of anxiety reduction alone.

Objective: Recent work shows that the time from the initial use of nicotine, cannabis, and alcohol to the onset of dependence on these substances is shorter ("telescoped") in anxiety-disordered individuals. Previously, we hypothesized that telescoping may result from a shared neurobiology underlying both anxiety disorders and dependence. This hypothesis implies that telescoping occurs because individuals with an anxiety disorder transition to dependence with less overall drug exposure ("dependence susceptibility"). To investigate this further, we examined an estimate of the amount smoked (rather than the time transpired) from smoking initiation milestones to the onset of nicotine dependence in those with and without an anxiety disorder., Method: We used the subset of respondents in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Wave 1 who reported having smoked at least 100 cigarettes (N = 18,013). All data were based on face-to-face interviews., Results: Individuals with any anxiety disorder transitioned to nicotine dependence after smoking fewer total cigarettes than did individuals with no anxiety disorder. Furthermore, those with more than one anxiety disorder transitioned to nicotine dependence after smoking fewer cigarettes than did those with one anxiety disorder only. Several potentially confounding covariates were controlled for in these analyses., Conclusions: Dependence susceptibility is a novel concept with the potential to inform theoretical accounts of and prevention strategies for substance dependence among those with an anxiety disorder. In addition to nicotine, our theory and past data suggest that dependence susceptibility for other addictive substances (e.g., alcohol) also would be found among those with an anxiety disorder.

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., (Copyright © 2011 by the Research Society on Alcoholism.)

Objective: The frequent co-occurrence of alcohol dependence and anxiety disorder is a long-standing clinical conundrum. An underdeveloped perspective on this issue concerns the impact of a co-occurring anxiety disorder on the sequence and developmental course of alcohol-related milestones. Extrapolating from the body of basic science indicating overlap in the neurobiological processes associated with both anxiety disorder and alcohol dependence-particularly those involving the hypothalamic-pituitary-adrenal axis and elements of the amygdala- we hypothesized that anxiety-disordered individuals are vulnerable to the rapid development of alcohol dependence. Specifically, we predicted that the time from pre-dependence alcohol milestones (e.g., age at which regular drinking began) to post-dependence alcohol milestones would be briefer ("telescoped") among those with an anxiety disorder., Method: Seventy-eight individuals with alcohol dependence who had recently begun a chemical dependency treatment program underwent a diagnostic interview to determine the presence of current anxiety disorders and to establish the age at which several alcohol use and dependence milestones were first achieved., Results: We found that, compared with others in the sample, anxiety-disordered individuals transitioned significantly more quickly from the time they first began drinking regularly and first began getting drunk regularly to the onset of alcohol dependence, as well as from most pre-dependence alcohol milestones to the point at which their alcohol dependence was most severe., Conclusions: Individuals with anxiety disorders transition from regular drinking to alcohol dependence more rapidly than do individuals without anxiety disorders. These findings contribute to an improved understanding of the etiology of comorbidity and suggest novel directions for future research.

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., (© American Academy of Addiction Psychiatry.)

Alcohol dependence (AD) is more likely to occur among individuals with rather than without an anxiety disorder. Self-medication theory (SMT) holds that drinking behavior is negatively reinforced when alcohol temporarily reduces anxiety and that the resulting escalation of drinking increases the risk for AD. We set out to empirically scrutinize SMT using the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) dataset. We found that only a minority (about 20%) of anxiety disordered individuals endorsed drinking to control anxiety symptoms. This minority drank more alcohol, had a higher cross-sectional rate of AD, and was at higher risk for developing new AD over four years compared to anxiety disordered non-self-medicators and individuals with no anxiety disorder. Consistent with SMT, increased prospective risk for AD among self-medicators is partially mediated by an increased level of alcohol use. Understanding the processes that promote and inhibit self-medication should be a priority for anxiety disorder researchers., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Anxiety disorders are present in a high percentage of alcoholism treatment patients. We tested the prediction that having a comorbid anxiety disorder increases the prospective risk for relapse to drinking after alcoholism treatment. We also explored the prospective associations of specific anxiety syndromes (and depression) with drinking and anxiety outcomes., Methods: We assessed the diagnostic status and daily drinking patterns of 82 individuals approximately one week after they entered alcoholism treatment (baseline) and again approximately 120 days later (follow-up) (n=53)., Results: Consistent with study predictions, those with a baseline anxiety disorder (approximately 55%) were significantly more likely than others to meet various definitions of drinking relapse over the course of the follow-up. Regression models showed that baseline social phobia was the single best predictor of a return to any drinking after treatment, whereas panic disorder was the single best predictor of a relapse to alcohol dependence after treatment. Having multiple anxiety disorders (versus any specific anxiety disorder) at the baseline was the strongest predictor of having at least one active ("persistent") anxiety disorder at the follow-up. Cross-sectional analysis at the follow-up showed that anxiety disorder persisted in the absence of a relapse to alcohol dependence far more often than relapse to alcohol dependence occurred in the absence of a persistent anxiety disorder., Conclusions: Screening for comorbid anxiety disorder in alcoholism treatment patients is warranted and, where found, should be considered a marker of high relapse risk relative to that of noncomorbid patients. The capacity of specific anxiety treatment to mitigate relapse risk among comorbid patients remains an open question.

Background: Depression and anxiety are common disorders and have substantially overlapping symptom complexes. Not surprisingly, treatment approaches are similar for both conditions with the selective serotonin reuptake inhibitors (SSRIs) as the initial therapy of choice. However, after first line treatments have been deployed, residual symptoms are often problematic. Augmentation strategies to address these difficulties are an area of active investigation. This study assessed aripiprazole as adjunctive therapy to SSRIs for patients with persistent anxiety symptoms complicating a depression or anxiety disorder., Methods: Ten patients who had been receiving SSRIs for at least 6 weeks, but still had clinically significant anxiety symptoms, were enrolled in an open label, flexibly-dosed study of adjunctive aripiprazole. Clinical status was assessed with the Hamilton Anxiety Rating Scale (HAM-A), Montgomery Asberg Rating Scale (MADRS), and Sheehan Disability Scale (SDS)., Results: Eighty percent of the subjects had a greater than 50% reduction of symptoms on these outcome measures by week 2 of therapy, and continued with further decrements in symptoms throughout the course of the study., Conclusions: The results of this trial provide preliminary evidence that aripiprazole may be an effective adjunctive treatment in individuals on SSRIs with residual symptoms of anxiety or depression. More rigorous double-blind studies are warranted to confirm and elucidate the potential role of aripiprazole in these conditions.

Alcohol, administered acutely, is known to cause CO(2) hyposensitivity. CO(2) hypersensitivity associated with anxiogenic hyperventilation (HV) could reasonably be expected to emerge as an opponent process upon withdrawal from chronic alcohol use. To test this hypothesis, we applied two well-known methods to quantify CO(2) sensitivity in recently detoxified alcohol-dependent individuals and never alcohol-disordered individuals who are social drinkers. We found that the alcoholic group exhibited significantly greater CO(2) sensitivity than did controls in response to both challenges. Indirect evidence of chronic HV was also obtained. These findings implicate the effect of chronic alcohol use on CNS-based CO(2) sensitivity in heightening the vulnerability to disturbing anxiety symptoms and syndromes exhibited by alcoholic individuals. Future work must verify that pathological drinking actually causes the dysregulated respiratory responding observed in this study as is inferred in our conclusions.

Objective: To identify predictors of treatment response to 8 weeks of cognitive-behavioral therapy (CBT) among anxious-depressed adolescents with school refusal, half of whom received imipramine plus CBT and half of whom received placebo plus CBT., Method: A hierarchical multiple regression analysis was used to evaluate the following variables as potential predictors of treatment response as measured by school attendance at the end of treatment: baseline severity (school attendance at baseline), drug group (imipramine versus placebo), presence of separation anxiety disorder (SAD), and presence of avoidant disorder (AD)., Results: Baseline attendance, CBT plus imipramine, SAD, and AD were significant predictors of treatment response and accounted for 51% of the variance in outcome. Specifically, a higher rate of attendance at baseline and receiving imipramine predicted a better response to treatment whereas the presence of SAD and AD predicted a poorer response to treatment. The relationship between sociodemographic variables and treatment outcome was also evaluated. Age and socioeconomic status were unrelated to school attendance after treatment. Males had significantly higher rates of attendance after treatment than females., Conclusions: Adolescents with school refusal are a heterogeneous population and require individualized treatment planning. Variables such as diagnosis and severity at the start of treatment should be taken into consideration when planning treatment.

Anxiety sensitivity (AS) is a cognitive, individual difference variable characterized by a fear of arousal-related bodily sensations due to beliefs that such sensations are signs of impending catastrophic physical, psychological, or social outcomes. AS has been linked to increased risk for the development and maintenance of panic attacks and anxiety disorders, and more recently has been related to risk for other psychopathological conditions including those related to substance misuse. This article introduces a special issue of Addictive Behaviors focusing on cutting edge findings on the relations of AS to substance use and abuse. We set the stage for the following series of eight novel empirical papers by providing a review of background on the ways in which AS has been hypothetically linked to increased risk for the development of substance abuse and addiction. We also consider whether AS might be differentially related to risk for abuse of specific classes of drugs with different pharmacological effects (e.g., depressants vs. stimulants). Finally, we consider how AS might be related to substance use disorder maintenance or relapse risk through its putative effects in increasing drug withdrawal severity and in lowering tolerance for withdrawal symptoms. Our overriding goal in writing this Introduction was to provide an organizational template for integrating the featured studies and to recommend promising directions for future work into the association of AS and substance use-related problems.

Anxiety sensitivity (AS), the tendency to interpret feelings of anxiety as dangerous, is a core dispositional trait in a well articulated and extensively studied cognitive model of proneness to anxiety disorder. In recent years, there has been an increasing body of findings that also links AS to the tendency to use alcohol in general and the tendency to use alcohol as a means of coping with negative affect in particular. We expand on this empirical base by proposing and testing a theoretical model in which anxiety symptoms mediate the association between AS and alcohol use. That is, we propose that AS promotes anxiety symptoms, which, in turn, promote alcohol use aimed at coping with anxiety and other negative affect states. Over a 1-year data collection period, we assessed 82 alcohol-dependent individuals shortly after they began an intensive alcoholism treatment program. Self-reported anxiety symptoms associated with distinct anxiety syndromes were obtained with reference to the month period preceding their entry into the treatment program. Other information, including the presence of withdrawal symptoms, was obtained via interview. We found that syndrome-related anxiety symptoms and Trait Anxiety, but not State Anxiety or withdrawal symptoms, mediated the significant association between AS and the self-reported tendency to use alcohol as a means of controlling anxiety symptoms. Demonstrating a similar pattern of findings, but much less robustly so, were tests of these mediator models using alcohol use aimed at coping with negative affect (vs. coping with anxiety per se) as an outcome. In discussing these findings, we attempt to further develop a coherent model that incorporates AS, anxiety symptoms, and drinking motives. Our findings suggest that these relationships may differ for negative affect not specifically related to anxiety. We also discuss the possible associations of AS to withdrawal symptoms implied by our findings.

It is generally agreed that problems related to alcohol use and anxiety tend to occur within the same individual ("comorbidity"); however, the cause of this association remains controversial. Three prominent perspectives are that anxiety disorder promotes pathological alcohol use, that pathological alcohol use promotes anxiety disorder and that a third factor promotes both conditions. We review laboratory, clinical, family, and prospective studies bearing on the validity of these explanatory models. Findings converge on the conclusion that anxiety disorder and alcohol disorder can both serve to initiate the other, especially in cases of alcohol dependence versus alcohol abuse alone. Further, evidence from clinical studies suggests that anxiety disorder can contribute to the maintenance of and relapse to pathological alcohol use. Relying heavily on pharmacological and behavioral laboratory findings, we tentatively propose that short-term anxiety reduction from alcohol use, in concert with longer-term anxiety induction from chronic drinking and withdrawal, can initiate a vicious feed-forward cycle of increasing anxiety symptoms and alcohol use that results in comorbidity.

Objective: Cross-sectional studies show a robust association between anxiety disorders and alcohol use disorders (comorbidity); however, this methodology does not allow for the testing of causal models. The authors attempted to overcome this limitation by examining comorbid relationships prospectively., Method: Male and female college students were assessed as freshmen (year 1), and then again at years 4 and 7, for selected 12-month anxiety disorders (generalized anxiety disorder, agoraphobia, and social phobia or panic) diagnosed according to the National Institute of Mental Health Diagnostic Interview Schedule (DIS) and DSM-III and for 12-month DIS/DSM-III alcohol use disorders (alcohol dependence alone and alcohol abuse or dependence)., Results: Cross-sectionally, the odds of having either an anxiety disorder or an alcohol use disorder were two- to fivefold greater when the other condition was present. Prospectively, the odds of developing a new alcohol dependence diagnosis at year 7 increased from 3.5 to five times for those diagnosed with an anxiety disorder at years 1 or 4. Conversely, the odds of developing a new anxiety disorder at year 7 increased by about four times for those diagnosed with alcohol dependence at years 1 or 4. When alcohol abuse and dependence were combined, the pattern of findings was similar, albeit weaker. Multivariate path models provide similar results and highlight the reciprocal influence of alcohol use disorders and anxiety disorders., Conclusions: Alcohol use disorders (especially alcohol dependence) and anxiety disorders demonstrate a reciprocal causal relationship over time, with anxiety disorders leading to alcohol dependence and vice versa.

Background: This study tested whether alcohol consumption reduces anxiety and panic associated with a panic-challenge procedure., Methods: Subjects with panic disorder were randomly assigned to consume either a moderate dose of alcohol or a nonalcoholic placebo. All subjects were told that they were drinking alcohol to control beverage expectancies. Following the beverage administration, subjects underwent a panic challenge (35% carbon dioxide) and a series of anxiety symptom assessments., Results: Subjects who consumed alcohol reported significantly less state anxiety both before and after the challenge. In response to the challenge, subjects who consumed alcohol experienced significantly fewer panic attacks when applying liberal panic criteria; however, this effect only approached significance when applying conservative panic criteria., Conclusions: These findings suggest that alcohol acts acutely to reduce both panic and the anxiety surrounding panic, and they lend support to the view that drinking behavior among those with panic disorder is reinforced by this effect. We suggest that this process may contribute to the high rate at which alcohol-use disorders co-occur with panic disorder.

As more pharmacologic treatment and research on child and adolescent psychiatric patients are conducted, the common problem of blood-drawing fears will need to be addressed. Avoidance of blood-drawing could jeopardize an individual's physical and mental health, and inhibit the collection of data aimed at furthering the study of psychiatric disorders in youth. This report describes the naturalistic application of specific techniques for managing severe blood-drawing fears in adolescent subjects undergoing a clinical trial. The adolescents (ages 12-18) were 44 consecutive school refusers with comorbid anxiety and major depressive disorders. Of the school-refusing adolescents, 27% (12 of 44) were observed to have a severe fear of blood-drawing. A management strategy comprised of providing information, distraction, supportive reassurance, and exposure appeared successful in managing the fears of blood-drawing in all of the adolescents, except two. These 2 adolescents refused to enter the treatment study due to a marked fear of blood-drawing. All 10 subjects who exhibited a fear of blood-drawing and were able to complete the initial blood test, using the interventions noted, were able to obtain subsequent venipunctures with minimal or no avoidance behavior. These preliminary findings suggest that blood-drawing fears can be effectively managed in most cases, though controlled studies of these interventions are needed.

We evaluated the effects of gender and family history for alcoholism on the co-occurrence of anxiety disorders and alcohol disorders ("comorbidity") in a large university student sample (N = 489). A structured diagnostic interview was used to elicit life-time histories of anxiety disorder (29%) and alcohol disorder (26%). The proportion of subjects receiving an alcohol diagnosis was significantly greater among those with an anxiety diagnosis (39% vs. 21%). Male subjects, as well as those with a parental history of alcoholism, had a significantly greater base-rate of alcohol disorder than did other subjects. However, these factors did not affect the relative increase in risk for an alcohol disorder associated with the presence of an anxiety disorder; that is, these factors did not interact with (i.e., moderate) comorbidity risk. In discussing these results, we emphasize issues relevant to identifying and distinguishing between interaction effects and base-rate effects in comorbidity studies.

Cardiology patients with normal coronary angiography demonstrate continuing and substantial social, health, and work disability. We hypothesized that the diagnosis of panic disorder would mark those for whom continuing disability is most likely. We interviewed 72 such patients at the time of their normal angiogram, and then again an average of 38 months later. Those with panic disorder (n = 36) demonstrated significantly more disability at follow-up than did the other study patients. We conclude that those patients with normal angiograms who have panic disorder are more disabled than those who do not have panic disorder. Panic disorder in psychiatric samples has been shown to be highly treatable. Therefore, early identification and treatment of panic disorder in this group is likely to minimize the suffering associated with this condition.

Objective: Nonfearful panic disorder meets the DSM-III-R criteria for panic disorder but is not associated with subjective fear and anxiety. The authors determined its prevalence in a group of neurology patients and assessed its diagnostic validity as a panic disorder subtype by evaluating the response of the patients with nonfearful panic disorder to sodium lactate and antipanic pharmacotherapy., Method: The subjects were all neurology patients referred over 1 year to a university hospital's psychiatric consultation service because of negative medical workups for their symptoms (N = 48). Patients who met the DSM-III-R criteria for panic disorder but did not report subjective anxiety or fear during panic episodes were diagnosed as having nonfearful panic disorder. Afterward, each of those patients received a sodium lactate infusion and, 5 hours later, a sodium chloride infusion. They were then treated with antipanic medication and followed for at least 6 months., Results: Of the 48 neurology patients referred for psychiatric evaluation, 11 (23%) met the criteria for panic disorder, and all 11 met the criteria for nonfearful panic disorder. All 11 responded positively to lactate but not to placebo, and they each experienced an at least 75% reduction in symptoms during the 6-month follow-up period. Detailed case reports of three of these patients are presented., Conclusions: These findings support the construct and predictive diagnostic validity of nonfearful panic disorder as a subtype of panic disorder and suggest that a lack of attention to this group leads to both the underestimation of the prevalence of panic disorder and to the withholding of potentially successful treatments for this group.

The idea that people suffering from anxiety have a proclivity to consume alcohol to relieve their symptoms is supported by reports showing high comorbidity rates of alcohol and anxiety problems. The authors reviewed relevant epidemiologic surveys, family studies, and field studies and conclude that the relationship between alcohol problems and anxiety appears to be variable among the anxiety disorders. In agoraphobia and social phobia, alcohol problems appear more likely to follow from attempts at self-medication of anxiety symptoms, but panic disorder and generalized anxiety disorder may be more likely to follow from pathological alcohol consumption. Simple phobia does not appear to be related to alcohol problems in any meaningful way.

'Non-fearful panic disorder' (NFPD) is a condition that meets DSM III-R criteria for panic disorder but lacks a report of subjective fear or anxiety. Presenting the first comprehensive overview of this issue, the authors describe studies investigating a wide range of apparently overlapping phenomena including NFPD, 'somatically expressed panic', 'non-cognitive panic', 'alexithymic panic', 'non-clinical panic', and 'masked anxiety'. The review shows that such conditions account for from 20 to 40% of the panic disorder found in various medical populations, and that this group resembles conventional panic disorder in cross-sectional comparisons. We emphasize that a 'triple-response' model of anxiety is consistent with our conclusion that NFPD should be conceptualized as a panic disorder subtype. Finally, we discuss unresolved issues regarding the construct and predictive diagnostic validity of NFPD.

Recent data indicate that a substantial number of cardiology patients with chest pain and no clinical evidence of coronary artery disease suffer from panic disorder. Discriminant function analysis reveals that a self-report anxiety measure alone, or in conjunction with minimal demographic information, can predict whether such patients have panic disorder. Predictive accuracy ranges from 69 to 76% correct classification, significantly improving upon chance predictions alone. A 'split-half' design was used in order to cross-validate predictive equations, and the total sample was also analyzed so as to provide the most stable equation. Clinical and future research implications of these findings are discussed.