Resting Hypoconnectivity of Theoretically Defined Addiction Networks during Early Abstinence Predicts Subsequent Relapse in Alcohol Use Disorder.

Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.

Drinking to cope with negative emotions moderates alcohol use disorder treatment response in patients with co-occurring anxiety disorder.

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.

Modeling and treating internalizing psychopathology in a clinical trial: a latent variable structural equation modeling approach.

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.

The pharmacologic and expectancy effects of alcohol on social anxiety in individuals with social phobia.

Individuals with social phobia are at an increased risk for alcohol problems. Individuals with social phobia could increase their risk for pathological alcohol use if they drink as a means of coping with anxiety-provoking social situations. Providing a circumscribed test of this view, we evaluate the effect of alcohol on the intensity of social phobia anxiety responses. Sixty-one individuals with social phobia gave two speech challenges in front of a group ('social anxiety challenge'), one occurring before and one after they consumed either: (a) an alcoholic drink they were told contained alcohol ('alcohol group'), (b) a non-alcoholic drink they were told contained alcohol ('placebo group'), or, (c) a non-alcoholic drink they were told contained no alcohol ('control group'). Both the alcohol group and the placebo group showed greater reduction in performance anxiety from the first to the second speech challenge than did the control group. Further, there was a strong trend in the data for the alcohol group to show greater reduction in performance anxiety from the first to the second speech challenge than did the placebo group. We concluded from these findings that the pharmacologic effects of alcohol and the belief that one consumed alcohol decrease social performance anxiety in an additive fashion. These results provide direct support for the negatively reinforcing properties of alcohol and are consistent with the view that symptom reduction may motivate alcohol use among socially phobic individuals.

Introduction to the Special Issue on "Anxiety Sensitivity and Addictive Behaviors".

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 mediates the association between anxiety sensitivity and coping-related drinking motives in alcoholism treatment patients.

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.

Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder.

A previous report [Blouin et al., 1998: Nat Genet 20:70-73] suggesting linkage to chromosomes 13q32 and 8p21 in families with schizophrenia led us to investigate these regions in a large set of 301 multiplex families with schizophrenia. Multipoint analyses failed to reveal evidence for linkage to any portion of chromosome 13, while only a weakly positive score was present on 8p using the identical marker reported in the earlier report. Failure to confirm the Blouin et al claims in a substantially larger cohort adds emphasis to the inconsistency of the findings concerning linkage in schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:235-239, 2000.

Individual differences predictive of drinking to manage anxiety among non-problem drinkers with panic disorder.

BACKGROUND: Alcohol problems co-occur with anxiety disorders at a rate that far exceeds chance ("comorbidity"). One view suggests that risk for developing a comorbid alcohol use disorder is increased when alcohol is used routinely to cope with anxiety symptoms ("self-medication"). Indicating that this view is overly broad, however, the literature suggests that only a subgroup of anxiety-disordered individuals tend to drink to manage their symptoms. Therefore, we set out to identify psychological characteristics that might mark those for whom drinking to cope with anxiety is most likely. Our survey of the literature identified several possibilities, including anxiety-related personality traits (anxiety sensitivity, self-consciousness and Trait Anxiety); higher-order personality dimensions (Harm Avoidance, Reward Dependence, and Novelty Seeking); and, finally, alcohol outcome expectancies (specifically, those related to tension-reducing effects from alcohol). METHODS: In a sample of nonproblem drinkers with panic disorder, we regressed predictor variables on several alcohol use measures, including drinking aimed at the control of anxiety symptoms ("self-medication"). RESULTS: Although each variable related positively to a self-medicating style of drinking, expectancies for tension reduction from alcohol use accounted for about twice as much variance as did the other predictors. With simultaneous entry in a step-wise regression analysis, only tension-reduction alcohol outcome expectancies and the Harm Avoidance personality dimension were retained as significant predictors. CONCLUSIONS: Findings suggest that development of a self-medicating style of drinking among individuals with panic disorder is predicated, in part, on specific psychological characteristics of the individual. Alcohol outcome expectancies emerged as the single most important predictor of drinking behavior in this anxiety-disordered sample.

Expectancies for alcohol to affect tension and anxiety as a function of time.

Alcohol outcome expectancies have been linked to drinking behavior on both empirical and theoretical grounds. Although typically measured as a static construct, we hypothesized that expectancies may be time-specific. Subjects rated their expectancies for a moderate amount of alcohol to increase, decrease, or not change their level of tension and anxiety. Ratings were repeated for when the intoxicating effects of the drinking would be: (1) "at their peak;" (2) "nearly worn off;" and (3) "completely worn off" (Time Epochs 1-3, respectively). As predicted, most subjects (72%) expected alcohol to reduce tension and anxiety at Time Epoch 1; however, significantly fewer subjects expected this effect at Time Epochs 2 and 3 (25% and 2%, respectively). Conversely, few subjects expected alcohol to worsen tension and anxiety at Time Epoch 1 (3.5%); however, significantly more subjects expected this effect at Time Epochs 2 and 3 (31% and 34%, respectively). Expectancies for Time Epoch 1 related most strongly to several measures of alcohol use, including drinking for the purpose of reducing tension (whole sample) and drinking frequency (men but not women). These findings show that tension-reduction expectancies are not stable over the course of a drinking episode and suggest the possibility of a treatment approach aimed at amplifying attention to expectancies for alcohol's more negative longer-term effects.

Imipramine plus cognitive-behavioral therapy in the treatment of school refusal.

OBJECTIVE: To investigate the efficacy of 8 weeks of imipramine versus placebo in combination with cognitive-behavioral therapy (CBT) for the treatment of school-refusing adolescents with comorbid anxiety and major depressive disorders. METHOD: This was a randomized, double-blind trial with 63 subjects entering the study and 47 completing. Outcome measures were weekly school attendance rates based on percentage of hours attended and anxiety and depression rating scales. RESULTS: Over the course of treatment, school attendance improved significantly for the imipramine group (z = 4.36, p < .001) but not for the placebo group (z = 1.26, not significant). School attendance of the imipramine group improved at a significantly faster rate than did that of the placebo group (z = 2.39, p = .017). Over the 8 weeks of treatment, there was a significant difference between groups on attendance after controlling for baseline attendance; mean attendance rate in the final week was 70.1% +/- 30.6% for the imipramine group and 27.6% +/- 36.1% for the placebo group (p < .001). Defining remission as 75% school attendance, 54.2% of the imipramine group met this criterion after treatment compared with only 16.7% from the placebo group (p = .007). Anxiety and depression rating scales decreased significantly across treatment for both groups, with depression on the Children's Depression Rating Scale-Revised decreasing at a significantly faster rate in the imipramine group compared with the placebo group (z = 2.08, p = .037). CONCLUSIONS: Imipramine plus CBT is significantly more efficacious than placebo plus CBT in improving school attendance and decreasing symptoms of depression in school-refusing adolescents with comorbid anxiety and depression.

The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and 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.

Psychological and physiological predictors of response to carbon dioxide challenge in individuals with panic disorder.

Past studies in nonclinical samples have found that suffocation fear, but not a behavioral index of carbon dioxide (CO2) sensitivity (i.e., breath-holding duration), predicts anxious response to CO2 challenge. These associations were examined in individuals with panic disorder while adding more sensitive indices of CO2 sensitivity. Consistent with the earlier studies, the authors found that suffocation fear predicted anxious responding to CO2 challenge but breath-holding duration did not. However, highly precise measures of CO2 sensitivity, not included in earlier studies, did predict anxious challenge responding. These findings support the predictive value and possible etiological relevance of both specific psychological variables and physiological CO2 sensitivity in panic vulnerability. Further work is still needed to determine whether the findings are specific to panic disorder.

The effects of restraint stress on voluntary ethanol consumption in rats.

Sixty Wistar rats (Rattus norvegicus) were assigned to 4 groups of 15 rats each: ethanol stress (ES), ethanol no-stress (EN), isocaloric stress (IS) and isocaloric no-stress (IN). The effect of restraint stress on daily intake of ethanol and a 0.72% solution of glucose was examined in an ABA design (stress-no stress-stress). During the stress phases, 2 groups were subjected to daily 15-min restraint stress, whereas 2 groups were placed in different cages for 15 min as a control. All 4 groups were then given 6-hr access to their assigned liquid alone for 4 days followed by a choice between their assigned liquid and water on the 5th day. The ES group significantly increased their ethanol intake (g/kg) compared to the EN group on choice days but not on forced days. Percentage preference for ethanol was significantly greater and increased at a faster rate over the 75-day testing period compared with the EN group. However, total ethanol consumption (g/kg) and percentage preference did not vary as a function of phase. It is notable that the effects of restraint stress on ethanol self-administration persisted even after the stress schedule was removed.

Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia.

OBJECTIVE: The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. METHOD: Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. RESULTS: Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. CONCLUSIONS: Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.

Prospective analysis of the relation between DSM-III anxiety disorders and alcohol use disorders.

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.

Reduction of the parahippocampal gyrus and the hippocampus in patients with chronic schizophrenia.

BACKGROUND: There have been many studies reporting reduced volume of the hippocampus or other limbic structures in patients with schizophrenia, but the literature is inconsistent. AIMS: To compare patients with either first-episode or chronic schizophrenia with controls using high-resolution volumetric magnetic resonance imaging (MRI) scans. METHOD: Thirteen patients with first-episode schizophrenia, 27 with chronic schizophrenia and 31 controls had 1.5 mm coronal slices taken through the whole brain using a spoiled-grass MRI acquisition protocol. RESULTS: The parahippocampal gyrus was reduced significantly on the left side in patients with chronic schizophrenia compared with controls for both male and female patients, whereas the hippocampus was reduced significantly on both sides only in female patients. There were no significant reductions in any structure between patients with first-episode schizophrenia and controls. CONCLUSIONS: Volumetric reduction seen in patients with chronic schizophrenia may be due to an active degenerative process occurring after the onset of illness.

Association of brain structural change with the heterogeneous course of schizophrenia from early childhood through five years subsequent to a first hospitalization.

Fifty first-episode patients with schizophrenia were followed for 5 years subsequent to their first hospitalization. The course of illness was charted prospectively and premorbid childhood histories were obtained retrospectively at the initial evaluation, and MRI scans were obtained initially and at each follow-up. Fifteen different life-time patterns of illness course emerged, although none were specifically associated with structural brain change. A deterioration in premorbid scores was positively correlated with larger ventricular volume at the first hospitalization, and the larger the ventricles, the less the subsequent change in ventricular size thereafter. An analysis to see whether initial hemispheric and ventricular size could predict different course types only revealed that patients with an acute onset and complete recovery had significantly smaller ventricles than all others. No differences emerged for initial hemispheric size. Thirty-four percent of patients individually showed some association of brain ventricular size and 28% hemisphere volume reductions with fluctuation in psychotic symptoms. Paradoxically, most showed larger ventricles and smaller hemispheres to be associated with clinical improvement, rather than the predicted reverse. These latter data question the notion that the structural brain changes seen over time in some patients are related to poor outcome, although small ventricular size in those patients with acute onset may be predictive of recovery. Thus, brain structural change is occurring early in the course of illness and may be a consequence of the process leading to resolution.

Phenomenological and pharmacological study of provoked obsessive/anxiety symptoms in obsessive-compulsive disorder: a preliminary study.

BACKGROUND: Inclusion of obsessive-compulsive disorder (OCD) as an anxiety disorder in DSM-i.v. assumes that anxiety is the primary symptom of OCD; however, persuasive empirical evidence in support of this view has not been presented yet. In the present study we hypothesized that provoked anxiety symptoms respond better to intravenous diazepam than would provoked obsessions. We, therefore, reasoned that anxiety symptoms are secondary symptoms of OCD. METHODS: To test the hypothesis we designed a double-blind, randomized, placebo-controlled crossover study. Patients underwent four experimental conditions in which the sequence of symptom provocation and i.v. injection of (placebo or diazepam) were alternated. Baseline and i.v. injection-induced symptom changes were assessed using visual analogs. RESULTS: Obsessions and anxiety correlated strongly for all four experimental conditions in which the sequence of the symptom provocation and diazepam i.v. injections was alternated. i.v. diazepam injection before and after symptom provocation failed to preferentially modulate anxiety symptoms over obsessions. Unexpectedly, in the group in which i.v. diazepam injection preceded the symptom provocation, reduction of mean obsessions was even more pronounced. CONCLUSIONS: Strong correlations between anxiety and obsessions at baseline, during symptom provocation, and after i.v. diazepam infusion suggest that anxiety and obsessions are tightly coupled phenomena in OCD.