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We prospectively examined the relation of relative telomere lengths (RTLs), a marker of biological aging, to phobic anxiety in later-life. RTLs in peripheral blood leukocytes were measured among 3,194 women in the Nurses’ Health Study who provided blood samples in 1989/90. The Crown-Crisp Phobic Index (CCI, range=0-16) was assessed in 1988 and 2004. Only participants with CCI≤3 (consistent with no meaningful anxiety symptoms) in 1988 were included. We related baseline RTLs to odds ratios (ORs) of incident high phobic anxiety symptoms (CCI≥6). To enhance clinical relevance, we used finite mixture modeling (FMM) to relate baseline RTLs to latent classes of CCI in 2004. Overall, RTLs were not significantly associated with high phobic anxiety symptoms after 16 years of follow-up. However, FMM identified 3 groups of phobic symptoms in later-life: severe, minimal/intermediate, non-anxious. The severe group had non-significantly shorter multivariable-adjusted mean RTLs than the minimal/intermediate and non-anxious groups. Women with shorter telomeres vs. longest telomeres had non-significantly higher likelihood of being in the severe vs. non-anxious group. Overall, there was no significant linear association between RTLs and incident phobic anxiety symptoms. Further work is required to explore potential connections of telomere length and emergence of severe phobic anxiety symptoms during later-life.

This paper discusses each of several potential consequences of bereavement. First, we describe ordinary grief, followed by a discussion of grief gone awry, or complicated grief (CG). Then, we cover other potential adverse outcomes of bereavement, each of which may contribute to, but are not identical with, CG: general medical comorbidity, mood disorders, post-traumatic stress disorder, anxiety, and substance use.

Complicated grief (CG) is a bereavement specific syndrome chiefly characterized by symptoms of persistent separation distress. Physiological reactivity to reminders of the loss and repeated acute pangs or waves of severe anxiety and psychological pain are prominent features of CG. Fear of this grief-related physiological arousal may contribute to CG by increasing the distress associated with grief reactions and increasing the likelihood of maladaptive coping strategies and grief-related avoidance. Here, we examined anxiety sensitivity (i.e., the fear of anxiety-related sensations; AS) in two studies of bereaved adults with and without CG. In both studies, bereaved adults with CG exhibited elevated AS relative to those without CG. In Study 2, AS was positively associated with CG symptom severity among those with CG. These findings are consistent with the possibility that AS contributes to the development or maintenance of CG symptoms.

1. Social anxiety disorder is a common illness with significant associated disability. Serotonin selective reuptake inhibitors (SSRIs) have become first-line treatment given their improved tolerability; however, there are few reports on the use of citalopram. 2. Nine consecutive patients with a primary diagnosis of DSM-IV generalized social phobia were prospectively treated with citalopram. 3. Citalopram was generally well-tolerated, and seven patients achieved responder status. 4. This series of patients improved significantly on all measures. Results suggest that citalopram may be a safe and effective treatment for social anxiety disorder.

Social anxiety disorder (SAD) is among the most common anxiety disorders (Kessler et al., 2005). Epidemiological surveys further show that SAD, and particularly the generalized subtype, is associated with significant personal and societal costs (Schneier et al., 1994; Schneier, Johnson, Hornig, Liebowitz, & Weissman, 1992), underscoring the need for effective interventions. Cognitive-behavioral therapy (CBT) has been established as an efficacious intervention for SAD (Hofmann & Smits, 2008). CBT emphasizes repeated or prolonged confrontation to feared cues often in combination with cognitive restructuring (Hofmann & Otto, 2008), with the goal of assisting patients in reacquiring a sense of safety in social interaction and performance situations (Otto, Smits, & Reese, 2004). CBT, delivered in individual or group format, has been shown to outperform both pill and psychological placebo treatment (Davidson et al., 2004; Heimberg et al., 1998) and yields medium to large reductions in symptom severity (Clark et al., 2003). Although efficacious, CBT results in suboptimal outcomes for many. Indeed, treatment non-response rates in large clinical trials have been 50% or higher (Davidson et al., 2004), and most individuals do not achieve remission (Blanco et al., 2010; Davidson et al., 2004). The observation of suboptimal outcomes of CBT for SAD has prompted research on augmentation strategies. One exciting development in this area has been the application of dcycloserine (DCS), a partial agonist at the N-methyl-D-aspartate (NMDA) receptor (Anderson & Insel, 2006; Davis, Ressler, Rothbaum, & Richardson, 2006; Hofmann, Smits, Asnaani, Gutner, & Otto, 2011). Following preclinical research demonstrating that DCS can facilitate extinction learning in rodents by enhancing NMDA receptor function (Davis et al., 2006), initial studies of DCS for augmenting exposure therapy for the anxiety disorders have yielded promising results (Bontempo, Panza, & Bloch, 2012). With respect to SAD, Hofmann and colleagues (Hofmann, Meuret, et al., 2006) initially showed that patients receiving DCS 1 hour prior to the last 4 sessions of a 5-session CBT protocol evidenced significantly greater rates of improvement than patients who received pill placebo. This finding was later replicated by an independent group (Guastella, 2008). Given these positive findings, DCS as an augmentation strategy was subsequently applied to a standard 12-session course of group CBT for SAD, examining the degree to which it extends treatment gains in a full rather than an abbreviated protocol (Hofmann et al., in press) As has been the case for CBT as a single modality treatment, response to DCS-augmented CBT has been variable across individuals with SAD (Hofmann, Pollack, & Otto, 2006; Hofmann et al., in press). The aim of the present study is to identify individual characteristics that differentiate response to DCS augmentation in a large-scale clinical trial comparing DCS-augmented group CBT to placebo-augmented group CBT in medication-free adults with generalized SAD (Hofmann et al., in press). In the context of this study, individual characteristics associated with differences in outcome between the experimental and the control condition are considered moderators (Kraemer, Wilson, Fairburn, & Agras, 2002) or prescriptive variables (Fournier et al., 2009), whereas individual characteristics associated with outcome regardless of study condition are considered predictor or prognostic variables (Fournier et al., 2009). Accordingly, in addition to identifying individual characteristics that differentiate responding to DCS, this analysis has the potential to identify individual characteristics that are prognostic of responding to CBT for SAD regardless of DCS augmentation. We hope that the findings of this study will stimulate research aiming to refine the understanding of the mechanisms by which CBT (with or without DCS) reduces anxiety pathology, and thereby aid in achieving the goal of personalized therapy (Anderson & Insel, 2006). Constrained by the limitations of the assessment protocol for the parent trial, we evaluated the patient characteristics available in our database that are also routinely assessed in clinical practice (e.g., demographic characteristics, clinical characteristics, and personality traits). Research relating the efficacy of DCS augmentation to these patient characteristics is limited to some preliminary work in PTSD. De Kleine and colleagues (de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012) recently reported that differences between DCS-augmented CBT and placebo-augmented CBT with respect to symptom reduction were greater among patients who presented with more severe symptoms than patients who presented with less severe symptoms at baseline. However, because this post-hoc moderator analysis did not include any covariates, it is impossible to rule out possible third-variable explanations for the clinical severity-DCS efficacy relation observed in this study (e.g., comorbid diagnoses, sex, neuroticism, etc.). Extant research on the relation between patient characteristics and CBT outcome for SAD has frequently pointed to depression severity as an important predictor (i.e., prognostic factor), although the findings have been mixed. Specifically, baseline depression severity has been associated with greater symptom severity at the end of CBT for SAD (Collimore & Rector, 2012; Erwin, Heimberg, Juster, & Mindlin, 2002; Ledley et al., 2005; Turner, Beidel, Wolff, Spaulding, & Jacob, 1996) and with less symptom improvement during CBT (Chambless, Tran, & Glass, 1997; Ledley et al., 2005). Several studies have, however, failed to observe the relation between depression and rate of change during CBT for SAD (Erwin et al., 2002; Joormann, Kosfelder, & Schulte, 2005; Turner et al., 1996), suggesting that baseline depression severity may simply be associated with greater symptom severity before and after treatment, but not necessarily the efficacy of CBT for SAD. Interestingly, McEvoy and colleagues (McEvoy, Nathan, Rapee, & Campbell, 2012) did not identify comorbid depression as a predictor of CBT for SAD outcome in an analysis that also included a number of other individual characteristic variables (e.g., age, gender, social anxiety symptom severity, number of comorbid diagnosis, degree of life interference). Instead, social anxiety symptom severity and number of comorbid diagnosis emerged as prognostic factors in this analysis. Together, these findings highlight the importance of evaluating multiple prospective prognostic or prescriptive variables simultaneously rather than in isolation. Although it has been proposed that personality traits have implications for the outcome of psychotherapy for anxiety disorders (Zinbarg, Uliaszek, & Adler, 2008), there has been no research to our knowledge evaluating the prognostic (or prescriptive) value of personality traits (e.g., agreeableness, conscientiousness, extraversion, neuroticism, and openness) with respect to the outcome of CBT for SAD (or DCS augmentation). Given findings in the literature linking conscientiousness to health behaviors and greater treatment adherence (Axelsson, Brink, Lundgren, & Lotvall, 2011; Hill & Roberts, 2011), it is plausible that those low in conscientiousness are less able to comply with or utilize treatment. Because it is notable that the advantages for DCS augmentation are much greater in very brief treatments (Guastella, 2008; Hofmann, Meuret, et al., 2006) than in the current 12-session protocol (Hofmann et al., in press), it is possible that patients low in conscientiousness, who may not receive the full dose of CBT, may benefit more from enhancement with DCS. Should it be the case that the DCS augmentation effects are indeed stronger for individuals for whom a standard course of CBT leaves ample room for improvement (see de Kleine et al., 2012), high agreeableness may also emerge as a prognostic and prescriptive variable in our analysis, as it has been associated with suboptimal responding to exposure-based intervention for panic disorder (Harcourt, Kirkby, Daniels, & Montgomery, 1998). Because extant research on predictors of the efficacy of CBT for SAD and DCS augmentation of CBT, respectively, is limited in scope and has yielded inconsistent findings, we employed an exploratory, hypothesis-generating, rather than hypothesis-driven framework in the present study. Here, we specifically aimed to determine the unique prescriptive and/or prognostic value of each patient characteristic, by evaluating its predictive value while controlling for the influence of other patient characteristics. Acknowledging that multiple tests increase the risk of Type 1 error, we adopted an approach to handling this concern that was developed by Fournier and colleagues (Fournier et al., 2009) and later used by Amir and colleagues (Amir, Taylor, & Donohue, 2011). Specifically, we selected the patient characteristics assessed at the baseline visit and categorized these in meaningful domains (e.g., demographic characteristics, clinical characteristics, and personality traits). The first step involved a step-wise procedure to identify significant prognostic and prescriptive variables within each domain. The second step involved the simultaneous entry of these prescriptive and prognostic variables identified for each domain in one final model.

Only a minority of patients with social anxiety disorder (SAD) has a robust therapeutic response to evidence-based serotonin reuptake inhibitor (SSRI) treatment. To help improve the personalized medicine approach to psychiatric care, we evaluated several candidate genetic predictors of SSRI response in SAD. At the start of a randomized controlled trial (NCT00282828), 346 patients with SAD at three sites received protocol-driven, open-label treatment with sertraline, up to 200. mg/d over 10 weeks. Efficacy was determined using a continuous measure of outcome (Liebowitz Social Anxiety Scale (LSAS)) and dichotomous indicators of response (LSAS ≤ 50) and remission (LSAS ≤ 30). Predictors of efficacy were examined in multivariate regression models that included eight polymorphic variants in four candidate genes (four in RGS2, two in HTR2A, one in SLC6A2, and one in SLC6A4). Adjusting for genetic ancestral cluster and non-genetic predictors of response, all four single-nucleotide polymorphisms (SNPs) in RGS2 predicted change in LSAS over time, at study-wise significance (p=0.00833), with the minor allele associated with less improvement over time. After adjusting for genetic ancestral cluster and non-genetic predictors of remission, two of the four RGS2 SNPs predicted likelihood of remission at or just below study-wise significance (p=0.025): rs4606 (AOR=0.49 (95% CI=0.27-0.90), p=0.022) and rs1819741 (AOR=0.50 (95% CI=0.28-0.92), p=0.027). Variation in RGS2, a gene previously shown to be associated with social anxiety phenotypes and serotonergic neurotransmission, may be a biomarker of the likelihood of substantially benefiting from sertraline among patients with SAD.

The neuropeptide oxytocin is implicated in social processing, and recent research has begun to explore how gender relates to the reported effects. This study examined the effects of oxytocin on social affective perception and learning.Forty-seven male and female participants made judgments of faces during two different tasks, after being randomized to either double-blinded intranasal oxytocin or placebo. In the first task, "unseen" affective stimuli were presented in a continuous flash suppression paradigm, and participants evaluated faces paired with these stimuli on dimensions of competence, trustworthiness, and warmth. In the second task, participants learned affective associations between neutral faces and affective acts through a gossip learning procedure and later made affective ratings of the faces.In both tasks, we found that gender moderated the effect of oxytocin, such that male participants in the oxytocin condition rated faces more negatively, compared with placebo. The opposite pattern of findings emerged for female participants: they rated faces more positively in the oxytocin condition, compared with placebo.These findings contribute to a small but growing body of research demonstrating differential effects of oxytocin in men and women.

The authors examined whether D-cycloserine, a partial agonist at the glutamatergic N-methyl-d-aspartate receptor, augments and accelerates a full course of comprehensive cognitive-behavioral therapy (CBT) in adults with generalized social anxiety disorder.This was a multisite randomized placebo-controlled efficacy study with 169 medication-free adults with generalized social anxiety disorder, of whom 144 completed the 12-week treatment and 131 completed the three follow-up assessments. Patients were randomly assigned to receive 50 mg of D-cycloserine or placebo 1 hour before each of five exposure sessions that were part of a 12-session cognitive-behavioral group treatment. Response and remission status was determined at baseline, throughout treatment, at end of treatment, and at 1-, 3-, and 6-month follow-up assessments by assessors who were blind to treatment condition.D-Cycloserine-augmented and placebo-augmented CBT were associated with similar completion rates (87% and 82%), response rates (79.3% and 73.3%), and remission rates (34.5% and 24.4%) at the posttreatment assessment; response and remission rates were largely maintained at the follow-up assessments. Although D-cycloserine was associated with a 24%-33% faster rate of improvement in symptom severity and remission rates relative to placebo during the treatment phase, the groups did not differ in response and remission rates.D-Cycloserine did not augment a full course of comprehensive CBT for social anxiety disorder.

Generalized anxiety disorder (GAD) is a condition characterized by worry and physiological arousal symptoms that causes significant disabilities in patients’ lives. In order to improve psychotherapeutic interventions, a careful characterization of the deficiencies of this population as well as factors that ameliorate disability is crucial. Variables that have not traditionally been the focus of research should be considered, such as trait mindfulness and self-compassion. We investigated whether GAD patients would report lower mindfulness and self-compassion levels than healthy stressed individuals. Eighty-seven GAD patients and 49 healthy controls completed the Five Facet Mindfulness Questionnaire, the Self-Compassion Scale, and measures of anxiety. Patients with GAD also completed the Sheehan Disability Scale. Results showed that GAD patients had lower mindfulness and self-compassion than healthy stressed controls, and both were negatively correlated with levels of anxiety, worry, and anxiety sensitivity. In patients, mindfulness was a better predictor of disability than actual anxiety symptom scores. These findings highlight that in the presence of anxiety symptoms, mindfulness can be a factor that helps protect against feeling disabled by the disorder. The findings thereby add an important variable to the characterization of this disorder and should be taken into consideration for future treatment development.

Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p=.083); among women, the LKM practitioners had significantly longer RTL than controls, (p=.007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity.

We aimed to examine whether pretreatment with escitalopram would be associated with reduced fear acquisition and enhanced extinction learning in a fear conditioning paradigm, compared with placebo.Healthy volunteers were randomized in double-blind fashion, to 14 days of escitalopram 10 mg/day (n = 18) or placebo (n = 20) prior to a classical fear conditioning paradigm.Although escitalopram was associated with a smaller skin conductance (SC) orienting response during habituation, no medication effects on fear acquisition were found. Escitalopram was associated with faster extinction of SC responses, compared with placebo, as revealed by a significant drug × conditioned stimulus × trial interaction for early extinction (F(3, 30) = 3.26, p = 0.035) and late extinction (F(3, 30) = 3.27, p = 0.035) trials. After adjustment for age, orienting response, and acquisition, results from linear contrast remained significant for early extinction (F(1, 29) = 5.43, p = 0.027).Escitalopram administered for 14 days prior to a fear conditioning paradigm did not influence acquisition of a conditioned fear response but did facilitate extinction learning. Impairments in extinction learning have been identified as a key component of posttraumatic stress disorder; our preliminary findings suggest that additional experimental and clinical studies assessing the efficacy of selective serotonin reuptake inhibitors for posttraumatic stress disorder prevention are warranted.

Importance To our knowledge, this is the first placebo-controlled randomized clinical trial to evaluate the efficacy of antidepressant pharmacotherapy, with and without complicated grief psychotherapy, in the treatment of complicated grief. Objective To confirm the efficacy of a targeted complicated grief treatment (CGT), determine whether citalopram (CIT) enhances CGT outcome, and examine CIT efficacy without CGT. Design, Setting, and Participants Included in the study were 395 bereaved adults who met criteria for CG recruited from March 2010 to September 2014 from academic medical centers in Boston, Massachusetts; New York, New York; Pittsburgh, Pennsylvania; and San Diego, California. Co-occurring substance abuse, psychosis, mania, and cognitive impairment were exclusionary. Study participants were randomized using site-specific permuted blocks stratified by major depression into groups prescribed CIT (n = 101), placebo (PLA; n = 99), CGT with CIT (n = 99), and CGT with PLA (n = 96). Independent evaluators conducted monthly assessments for 20 weeks. Response rates were compared under the intention-to-treat principle, including all randomized participants in a logistic regression with inverse probability weighting. Interventions All participants received protocolized pharmacotherapy optimized by flexible dosing, psychoeducation, grief monitoring, and encouragement to engage in activities. Half were also randomized to receive manualized CGT in 16 concurrent weekly sessions. Main Outcomes and Measures Complicated grief–anchored Clinical Global Impression scale measurments every 4 weeks. Response was measured as a rating of “much improved” or “very much improved.” Results Of the 395 study participants, 308 (78.0%) were female and 325 (82.3%) were white. Participants’ response to CGT with PLA vs PLA (82.5% vs 54.8%; relative risk [RR], 1.51; 95% CI, 1.16-1.95; P = .002; number needed to treat [NNT], 3.6) suggested the efficacy of CGT, and the addition of CIT did not significantly improve CGT outcome (CGT with CIT vs CGT with PLA: 83.7% vs 82.5%; RR, 1.01; 95% CI, 0.88-1.17; P = .84; NNT, 84). However, depressive symptoms decreased significantly more when CIT was added to treatment (CGT with CIT vs CGT with PLA: model-based adjusted mean [standard error] difference, −2.06 [1.00]; 95% CI, −4.02 to −0.11; P = .04). By contrast, adding CGT improved CIT outcome (CIT vs CGT with CIT: 69.3% vs 83.7%; RR, 1.21; 95% CI, 1.00-1.46; P = .05; NNT, 6.9). Last, participant response to CIT was not significantly different from PLA at week 12 (45.9% vs 37.9%; RR, 1.21; 95% CI, 0.82-1.81; P = .35; NNT, 12.4) or at week 20 (69.3% vs 54.8%; RR, 1.26; 95% CI, 0.95-1.68; P = .11; NNT, 6.9). Rates of suicidal ideation diminished to a substantially greater extent among participants receiving CGT than among those who did not. Conclusions and Relevance Complicated grief treatment is the treatment of choice for CG, and the addition of CIT optimizes the treatment of co-occurring depressive symptoms. Trial Registration clinicaltrials.gov Identifier:NCT01179568

Mindfulness meditation has met increasing interest as a therapeutic strategy for anxiety disorders, but prior studies have been limited by methodological concerns, including a lack of an active comparison group. This is the first randomized, controlled trial comparing the manualized Mindfulness-Based Stress Reduction (MBSR) program with an active control for generalized anxiety disorder (GAD), a disorder characterized by chronic worry and physiologic hyperarousal symptoms.Ninety-three individuals with DSM-IV-diagnosed GAD were randomly assigned to an 8-week group intervention with MBSR or to an attention control, Stress Management Education (SME), between 2009 and 2011. Anxiety symptoms were measured with the Hamilton Anxiety Rating Scale (HAMA; primary outcome measure), the Clinical Global Impressions-Severity of Illness and -Improvement scales (CGI-S and CGI-I), and the Beck Anxiety Inventory (BAI). Stress reactivity was assessed by comparing anxiety and distress during pretreatment and posttreatment administration of the Trier Social Stress Test (TSST).A modified intent-to-treat analysis including participants who completed at least 1 session of MBSR (n = 48) or SME (n = 41) showed that both interventions led to significant (P.0001) reductions in HAMA scores at endpoint, but did not significantly differ. MBSR, however, was associated with a significantly greater reduction in anxiety as measured by the CGI-S, the CGI-I, and the BAI (all P values.05). MBSR was also associated with greater reductions than SME in anxiety and distress ratings in response to the TSST stress challenge (P.05) and a greater increase in positive self-statements (P = .004).These results suggest that MBSR may have a beneficial effect on anxiety symptoms in GAD and may also improve stress reactivity and coping as measured in a laboratory stress challenge.ClinicalTrials.gov identifier: NCT01033851.

The Social Phobia Inventory (SPIN) is a widely used measure in mental health settings and a 3-item version (mini-SPIN) has been developed as a screening instrument for social anxiety disorder. In the present study, we examined the psychometric properties of the SPIN and developed a brief version (mini-SPIN-R) designed to assess social anxiety severity using item response theory. Our sample included 569 individuals with social anxiety disorder who participated in 2 clinical trials and filled out a battery of self-report measures. Using a nonparametric kernel smoothing method we identified the most sensitive items of the SPIN. These 3 items comprised the mini-SPIN-R, which was found to have greater internal consistency, and to capture a greater range of symptoms compared to the mini-SPIN. The mini-SPIN-R evidenced superior convergent validity compared to the mini-SPIN and both measures had similar divergent validity. Thus, the mini-SPIN-R is a promising brief measure of social anxiety severity.

Generalized Social Anxiety Disorder (GSAD) is characterized by excessive fear and avoidance of several types of social and performance situations. The pathophysiology is not well understood, but research in animals and humans has provided evidence that oxytocin helps regulate normal social affiliative behavior. Previous work in healthy male subjects demonstrated a rise in plasma oxytocin after receiving a high trust signal. To examine the oxytocin system in GSAD, we measured plasma oxytocin in GSAD patients and controls, before and after the social "Trust Game," a neuroeconomic test examining trust behavior and reaction to trust using real monetary incentives.Thirty-nine subjects with GSAD and 28 healthy controls provided three blood samples for oxytocin measurement before the Trust Game, and one sample after the game. Plasma estradiol was also measured at baseline. The Trust Game protocol version prioritized the sending of a signal of high cooperation and trust to all participants. All analyses controlled for gender and estradiol levels.Mean oxytocin levels post-Trust Game (P = .025), and overall (area under the curve, P = .011) were lower in GSADpatients compared to controls, after controlling for sex and estradiol. There was no significant change in oxytocin levels after the game in either group.We report low plasma oxytocin levels in patients with GSAD during a prosocial laboratory task paradigm. Additional research will be important to further examine the relationship between oxytocin and social behavior in GSAD.

The current proposal aims to directly compare the psychotherapy and medication treatments for PTSD considered to have the most evidence for effectiveness. While both SSRI and PE have demonstrated efficacy, there are significant individual differences in clinical responses to both treatments. To achieve best clinical outcomes and to utilize available treatment most effectively, it is critical to examine how PTSD and related psychopathology and functional impairment change with these treatments alone and in combination. Further, in order to inform clinical practice, we plan to examine psychological and neurobiological predictors of response to treatment and mechanisms of change during treatment (pre to post treatment change) based on previously identified predictors, including emotion regulation and processing with fMRI in response to emotional challenge tasks, DNA and mRNA (pre and post treatment), and cortisol response to awakening. The primary activity and focus this year has been on recruitment and retention. We obtained funding to expand to 2 new CBOCs that are under the coverage of current IRBs. We were also approved for a 1-year no cost extension. Completion of study research and treatment protocol is our primary focus for the coming year. As of 12/21/15, we have recruited and randomized 203 Veterans and 92 Veterans have completed the Week 52 final study assessment visit.

Background: Few data are available on the effects of a psychiatric label on medical residents’ attitudes towards an individual. Aims: To investigate the effect of a psychiatric label on the attitudes of medical residents towards an individual. Methods: Medical residents were randomly assigned to one of two vignettes describing the same apparently healthy person, differing only in the presence of a psychiatric label for one of them. Participants ( N = 322) reported their attitudes towards the described individual and their willingness to treat this person. Results: Residents allocated to the psychiatric-diagnostic label group reported being less at ease with becoming the individual’s nextdoor neighbour, working in the same place, sharing a house, having him look after their children, having a member of their family date him, having their finances run by the individual, less willing to become friends with the described individual and more uneasy having to examine him the next time he visits the emergency room. Conclusion: Implementing effective programmes to combat stigma in the curriculum of medical residents appears to be needed.

The present study examined negative mood regulation expectancies, anxiety symptom severity, and quality of life in a sample of 167 patients with social anxiety disorder (SAD) and 165 healthy controls with no DSM-IV Axis I disorders. Participants completed the Generalized Expectancies for Negative Mood Regulation Scale (NMR), the Beck Anxiety Inventory, and the Quality of Life Enjoyment and Satisfaction Questionnaire. SAD symptom severity was assessed using the Liebowitz Social Anxiety Scale. Individuals with SAD scored significantly lower than controls on the NMR. Among SAD participants, NMR scores were negatively correlated with anxiety symptoms and SAD severity, and positively correlated with quality of life. NMR expectancies positively predicted quality of life even after controlling for demographic variables, comorbid diagnoses, anxiety symptoms, and SAD severity. Individuals with SAD may be less likely to engage in emotion regulating strategies due to negative beliefs regarding their effectiveness, thereby contributing to poorer quality of life.

This is the first trial examining duloxetine for generalized social anxiety disorder (GSAD) and the effect of increased dose for those without early remission.Individuals (n=39) with GSAD received 6 weeks of open-label duloxetine 60 mg/day; those with a Liebowitz Social Anxiety Disorder Scale (LSAS) score30 at week 6 were randomized in double-blind fashion to an additional 18 weeks of continued duloxetine 60 mg/day or to duloxetine 120 mg/day.Duloxetine was associated with a significant LSAS reduction at week 6 (91.3 [17.7] to 69.8 [28.5], paired t [df]=5.2 [38], P.0001), and randomized participants overall continued to improve at week 24 (74.6 [23.9] to 60.3 [29.7]; paired t [df]=3.3 [27], P=.0026). Though the increased dose strategy was associated with a moderate effect size (Cohen's d=.57), there was no significant difference at week 24 endpoint in LSAS reduction (20.5 [26.0] versus 7.3 [17.2], t [df]=1.6 [26], P=.13) nor remission (33% versus 8%) for duloxetine with dose increased to 120 mg/day compared to duloxetine continued at 60 mg/day. Overall, 44% (17/39) discontinued prior to week 24.Though with limited power, these data provide preliminary support for the efficacy of duloxetine for GSAD, and suggest continued improvement but limited remission overall at 24 weeks for individuals remaining symptomatic at week 6. These observations warrant further controlled study.

Despite its acute efficacy for the treatment of panic disorder, benzodiazepines (BZs) are associated with a withdrawal syndrome that closely mimics anxiety sensations, leading to difficulty with treatment discontinuation and often disorder relapse. An exposure-based cognitive-behavioral treatment for BZ discontinuation, Panic Control Treatment for BZ Discontinuation (PCT-BD) targets the fear of these sensations and has demonstrated efficacy in preventing disorder relapse and facilitating successful BZ discontinuation among patients with panic disorder. In this randomized controlled trial, PCT-BD was compared to taper-alone and a taper plus a relaxation condition to control for the effect of therapist contact and support among 47 patients with panic disorder seeking taper from BZs. Based on the primary outcome of successful discontinuation of BZ use, results indicate that adjunctive CBT provided additive benefits above both taper alone and taper plus relaxation, with consistently medium and large effect sizes over time that reached significance at the six month follow-up evaluation. The efficacy of CBT relative to either of the other taper conditions reflected very large and significant effect sizes at that time. These findings suggest that PCT-BD provides specific efficacy for the successful discontinuation from BZs, even when controlling for therapist contact and relaxation training.

Background: There is a paucity of data examining the prevalence and impact of childhood maltreatment in patients presenting with a primary diagnosis of social anxiety disorder (SAD). We thus examined the presence of a broad spectrum of childhood maltreatment, including physical, sexual, and emotional abuse and neglect, in treatment-seeking individuals with the generalized subtype of SAD (GSAD). We hypothesized that a history of childhood maltreatment would be associated with greater SAD symptom severity and poorer associated function. Methods: One hundred and three participants with a primary diagnosis of GSAD (mean age 37±14; 70% male) completed the well-validated, self-rated Childhood Trauma Questionnaire (CTQ), as well as measures of SAD symptom severity and quality of life. Results: Fully 70% (n=72) of the GSAD sample met severity criteria for at least one type of childhood abuse or neglect as measured by the CTQ subscales using previously established thresholds. CTQ total score adjusted for age and gender was associated with greater SAD severity, and poorer quality of life, function, and resilience. Further, the number of types of maltreatment present had an additive effect, with specific associations for emotional abuse and neglect with SAD severity. Conclusions: Despite the use of validated assessments, our findings are limited by the retrospective and subjective nature of self-report measures used to assess childhood maltreatment. Nonetheless, these data suggest a high rate of childhood maltreatment in individuals seeking treatment for GSAD, and the association of maltreatment with greater disorder severity suggests that screening is clinically prudent. Depression and Anxiety 26:1027–1032, 2009. © 2009 Wiley-Liss, Inc.

Objective The development of novel strategies for the treatment of posttraumatic stress disorder (PTSD) represents a critical public health need. We present the first prospective, randomized, double-blind, placebo-controlled trial of a non-benzodiazepine hypnotic agent for the treatment of PTSD and associated insomnia. Method Twenty-four patients with PTSD by DSM-IV criteria and sleep disturbance were treated in a randomized, double-blind, placebo-controlled crossover study of 3 weeks of eszopiclone 3 mg at bedtime compared to placebo. The primary outcome measures were changes in scores on the Short PTSD Rating Interview (SPRINT) and the Pittsburgh Sleep Quality Index (PSQI). The data were collected from April 2006 to June 2008. Results Three weeks of eszopiclone pharmacotherapy was associated with significantly greater improvement than placebo on PTSD symptom measures including the SPRINT (P = .032) and the Clinician-Administered PTSD Scale (P = .003), as well as on measures of sleep including the PSQI (P = .011) and sleep latency (P = .044). Greater improvement with eszopiclone on PTSD measures was present even when specific sleep-related items were excluded. Adverse events were consistent with the known profile of the drug. Conclusions This study provides initial evidence that pharmacotherapy with eszopiclone may be associated with short-term improvement in overall PTSD severity as well as associated sleep disturbance. Longer, more definitive study of eszopiclone in PTSD is warranted. Trial registration clinicaltrials.gov Identifier: NCT00120250.

Generalized anxiety disorder (GAD) has a high rate of comorbidity with other psychiatric disorders, including major depressive disorder (MDD), bipolar disorder, other anxiety disorders, and substance use disorders. The similarities between GAD and MDD have led some to suggest that GAD should be reclassified as a mood disorder. The concurrence of GAD with another disorder heightens a patient's risk for impairment, disability, and suicidality. Clinical trials for GAD and disorders that are most likely to occur with GAD have generally not taken comorbidity into account, and there is a paucity of data guiding how comorbidity should inform treatment selection. Research into the biology and psychopathology underlying the high rate of comorbidity of GAD and into efficacious interventions for GAD with comorbidity is needed.

Background: Proinflammatory cytokines have been reported to be elevated in individuals experiencing chronic stress as well as in those with major depressive disorder. Much less is known about cytokines in anxiety disorders such as posttraumatic stress disorder (PTSD) and panic disorder (PD). We hypothesized that PD and PTSD would be associated with a generalized proinflammatory cytokine signature. Method: We utilized Luminex technology to examine 20 cytokines and chemokines in serum from 48 well-characterized individuals with a primary DSM-IV PD or PTSD diagnosis, and 48 age- and gender-matched healthy controls. We conservatively employed a Bonferroni correction for multiple testing (α=.05/20=.0025). Results: Individuals with primary PTSD or PD had significantly elevated median peripheral cytokine levels for 18 of 20 different cytokines compared to age- and gender-matched healthy controls (all P

Panic disorder with or without agoraphobia is a common, often chronic and refractory anxiety disorder. Although a number of pharmacotherapies are now indicated for panic disorder, many patients do not respond to available interventions. We hypothesized that duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI) that has greater initial noradrenergic effects than venlafaxine, would have broad efficacy for individuals with panic disorder. Fifteen individuals with panic disorder with or without agoraphobia received 8 weeks of open label duloxetine flexibly dosed from 60 to 120 mg per day. Duloxetine treatment resulted in significant anxiolysis as measured by the primary outcome measure, the Panic Disorder Severity Scale (PDSS) (paired t(df) = 4.02(14), P= 0.0013), as well as measures of generalized anxiety, depression and quality of life (all P < 0.05). Although definitive conclusions are limited due to its small open-label nature, this first prospective study provides preliminary support for the efficacy of duloxetine for panic disorder and suggests larger randomized controlled study is warranted.

Anxiety is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association (Diagnostic and Statistical Manual of Mental Disorders, 2000)) as an “apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria or somatic symptoms of tension” (American Psychiatric Association (Diagnostic and Statistical Manual of Mental Disorders, 2000 p. 820)). The anxiety disorders in the DSM-IV include panic disorder with and without agoraphobia, generalized anxiety disorder, social phobia, specific phobia, posttraumatic stress disorder, and obsessive compulsive disorder. Measures for evaluating anxiety disorders can be useful in clinical practice and research as a tool for measuring change due to treatment, comparing disorder severity and symptom presentation across groups, motivating patients by systematically discussing the extent of their symptoms and impairment, and informing the clinician of symptom presentation and areas of impairment in each individual patient. This chapter is designed to aid clinicians and researchers in choosing empirically driven measures to guide their clinical and research endeavors for each of the aforementioned anxiety disorders. Whenever appropriate, measures are reprinted to facilitate this process.

Purpose A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients. General methods We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls. Findings There were no significant differences in GABA, glutamate or glutamine between patients and controls. Conclusions Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder.

Oxytocin is a neuropeptide recently associated with social behavior in animals and humans, but the study of its function in populations with social deficits such as autism, schizophrenia, and social anxiety disorder has only recently begun. We measured plasma oxytocin in 24 patients with Generalized Social Anxiety Disorder (GSAD) and 22 healthy controls using an enzyme‐linked immunosorbent assay. There were no significant differences in oxytocin level (pg/mL) between patients (M = 163.0, SD = 109.4) and controls (M = 145.0, SD = 52.9, z = 0.21, P= 0.8). Within the GSAD sample, however, higher social anxiety symptom severity adjusted for age and gender was associated with higher oxytocin level (R(2)= 0.21, β= 0.014, SE = 0.006, t = 2.18, P= 0.04). In addition, dissatisfaction with social relationships was associated with higher oxytocin levels (R(2)= 0.18, β=–0.20, SE = 0.10, t =–2.01, P= 0.05). Our data provide preliminary support for a link between social anxiety severity and plasma oxytocin. These findings may suggest a possible role for oxytocin as a facilitator of social behavior, an effect which may not be fully utilized in individuals with severe social anxiety.

Introduction:Individuals with anxiety disorders often remain symptomatic despite treatment with a first-line pharmacologic agent. More research examining pharmacotherapy augmentation strategies to improve outcomes is needed.Methods:In an 8-week, open-label, prospective augmentation study, we examined the efficacy and tolerability of the novel antipsychotic agent aripiprazole for adult outpatients with generalized anxiety disorder (n=13) or panic disorder (n=10) who remained symptomatic despite treatment for at least 8 weeks with an adequate (or maximally tolerated) dose of typical pharmacotherapy.Results:Aripiprazole augmentation was associated with a significant reduction in Clinical Global Impressions-Severity scores (paired t=4.41, df=22, PConclusion:These data provide preliminary evidence that aripiprazole may be a useful augmentation strategy for individuals with generalized anxiety disorder or panic disorder who show a limited response to initial pharmacotherapy.

Corticolimbic circuitry has been implicated in generalized social anxiety disorder (gSAD) by several neuroimaging symptom provocation studies. However, there are limited data regarding resting state or treatment effects on regional cerebral metabolic rate of glucose uptake (rCMRglu). Given evidence for anxiolytic effects conferred by tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor, the present [(18)F] fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) study sought to (1) compare resting rCMRglu between healthy control (HC) and pretreatment gSAD cohorts, (2) examine pre- to post-tiagabine treatment rCMRglu changes in gSAD, and (3) determine rCMRglu predictors of tiagabine treatment response. Fifteen unmedicated individuals with gSAD and ten HCs underwent a baseline (pretreatment) resting-state (18)FDG-PET scan. Twelve of the gSAD individuals completed an open, 6-week, flexible dose trial of tiagabine, and underwent a second (posttreatment) resting-state (18)FDG-PET scan. Compared to the HC subjects, individuals with gSAD demonstrated less pretreatment rCMRglu within the anterior cingulate cortex and ventral medial prefrontal cortex (vmPFC) at baseline. Following tiagabine treatment, vmPFC rCMRglu increased significantly in the gSAD group. Further, the magnitude of treatment response was inversely correlated with pretreatment rCMRglu within vmPFC. Taken together the present findings converge with neuroimaging findings from studies of social cognition in healthy individuals and symptom provocation in gSAD to support a role for the vmPFC in the pathophysiology of gSAD. Given the pharmacological profile of tiagabine, these findings suggest that its therapeutic effects in gSAD may be mediated by GABAergic modulation within the vmPFC.

OBJECTIVE Little is known about the efficacy of "next step" strategies for patients with post-traumatic stress disorder (PTSD) who remain symptomatic despite treatment. This study prospectively examines the relative efficacy of augmentation of continued prolonged exposure therapy (PE) with paroxetine CR versus placebo for individuals remaining symptomatic despite a course of PE. METHOD Adult outpatients meeting DSM-IV criteria for PTSD were recruited from February 2003 to September 2005 at 4 academic centers. Phase I consisted of 8 sessions of individual PE over a 4- to 6-week period. Participants who remained symptomatic, defined as a score of >or= 6 on the Short PTSD Rating Interview (SPRINT) and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score >or= 3, were randomly assigned to the addition of paroxetine CR or matched placebo to an additional 5 sessions of PE (Phase II). RESULTS Consistent with prior studies, the 44 Phase I completers improved significantly with initial PE (SPRINT: paired t = 7.6, df = 41, p < .0001; CGI-S: paired t = 6.37, df = 41, p < .0001). Counter to our hypothesis, however, we found no additive benefit of augmentation of continued PE with paroxetine CR compared to pill placebo for the 23 randomly assigned patients, with relatively minimal further gains overall in Phase II. CONCLUSION Although replication with larger samples is needed before definitive conclusions can be drawn, our data do not support the addition of paroxetine CR compared with placebo to continued PE for individuals with PTSD who remain symptomatic after initial PE, suggesting that the development of novel treatment approaches for PTSD refractory to PE is needed. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier NCT00215163.

To examine the relationship of sleep disturbance with complicated grief (CG) in patients with bipolar disorder (BD).Adults with DSM-IV BD were asked if they ever experienced significant loss and, if so, completed the Inventory of Complicated Grief. Subjective sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). The association of CG with sleep disturbance was assessed in univariate t-tests, and in multivariate analyses controlling for the presence of anxiety disorder comorbidity and current bipolar recovery status.Individuals with CG had significantly higher mean PSQI scores (10.9 versus 7.9, p = 0.003) than those without CG. Further, within the group of BD participants who had experienced a significant loss, those with CG had significantly poorer sleep (p = 0.01). CG remained significantly associated with greater sleep impairment after adjustment for comorbid anxiety disorder and bipolar mood state. This additive impairment in sleep with CG comorbidity was evident for four of the PSQI component scales: sleep quality, sleep duration, sleep efficiency and sleep disturbance.Our data indicate a significant association of CG with poor sleep in individuals with BD. Disturbed sleep may be a mechanism by which CG increases the burden of illness in BD.

The Anxiety Disorders Association of America convened a conference of experts to address treatment-resistant anxiety disorders and review promising novel approaches to the treatment of refractory anxiety disorders. Workgroup leaders and other participants reviewed the literature and considered the presentations and discussions from the conference. Authors placed the emerging literature on new therapeutic approaches into clinical perspective and identified unmet needs and priority areas for future research. There is a relative paucity of efforts addressing inadequate response to anxiety disorder treatment. Systematic efforts to exhaust all therapeutic options and overcome barriers to effective treatment delivery are needed before patients can be considered treatment refractory. Cognitive behavioral therapy, especially in combination with pharmacotherapy, must be tailored to accommodate the effects of clinical context on treatment response. The literature on pharmacologic treatment of refractory anxiety disorders is small but growing and includes studies of augmentation strategies and non-traditional anxiolytics. Research efforts to discover new pharmacologic targets are focusing on neuronal systems that mediate responses to stress and fear. A number of clinical and basic science studies were proposed that would advance the research agenda and improve treatment of patients with anxiety disorders. Significant advances have been made in the development of psychotherapeutic and pharmacologic treatments for anxiety disorders. Unfortunately, many patients remain symptomatic and functionally impaired. Progress in the development of new treatments has great promise, but will only succeed through a concerted research effort that systematically evaluates potential areas of importance and properly uses scarce resources.

Pharmacotherapy is an effective treatment for generalized anxiety disorder (GAD), but few studies have examined the nature of decline of anxiety and depression during pharmacotherapy for GAD and even fewer studies have examined predictors of symptom decline. This study examined the decline in symptoms of anxiety and depression in patients with GAD during a 6-week open trial of fluoxetine. Growth curve analyses indicated that pharmacotherapy with fluoxetine led to significant declines in symptoms of anxiety and depression over the 6 weeks of treatment. However, the decay slope observed for anxiety symptoms was significantly greater than that for depressive symptoms. Further analyses revealed that the decline in anxiety remained significant after accounting for the changes in symptoms of depression. However, the effect of treatment on depression was no longer significant after controlling for the reduction in anxiety symptoms. Overall anxiety sensitivity (AS) did not moderate the level of reduction in symptoms of anxiety or depression during pharmacotherapy. However, AS specific to physical concerns demonstated a marginal negative association with decline in anxiety and depression. AS specific to social concerns also demonstrated a marginal negative association with decline in anxiety symptoms. These findings suggest that the decline in anxiety symptoms is independent of the decline in symptoms of depression during pharmacotherapy for GAD and specific AS dimensions may predict symptom change in GAD.

The loss of a lovedone is inevitable yet remains one of themost intenseandpainfulstressorsapersonwillexperience.Nonetheless,most people navigate through the pain and intensity of acute grief without clinical intervention. As individuals adapt to loss, the level of distress generally diminishes over time with a return to an altered but meaningful lifewithout thedeceased.Aminority,approximately7%,1 will continue to have amore severe and persistent form of grief, referred to as complicated grief. Recently, complicated grief was included in the Diagnostic and Statistical Manual of Mental Disorders (FifthEdition)2asapersistentcomplexbereavementdisorder requiring additional research, but also within trauma and stressor-related disorders, consistent with the notion that complicated grief is a stressor-relatedcondition.3Althoughproposeddiagnosticcriteriasets havesomedifferences (eg, requiring6or 12monthssince thedeath), the core constructs are shared. Common symptoms include yearningor longing for thedeceased,difficultyacceptingoradaptingtothe loss, self-blame,avoidanceof remindersof thedeceased, andpreoccupationwith the circumstances of the death. Complicatedgrief ismore common inolder adults (variablydefined as older than 55 or 61 years), with prevalence estimates from 9% to 25%.1,4 Complicated grief is associated with functional impairment, medical morbidity, cognitive impairments, and suicidal ideation.3,4 It is thus a condition in need of identification and treatment by health care professionals, yet relatively limited research is available toguide the treatmentofcomplicatedgrief,5withdataspecific to older adults particularly lacking. In a recent article in JAMAPsychiatry, Shear andcolleagues6 reported a randomized clinical trial of a 16-week targeted psychoJAMAPSYCHIATRY

Little is known about cultural differences in the expression of distress in anxiety disorders. Previous cross-cultural studies of depression have found a greater somatic focus in Asian populations. We examined anxiety symptoms in patients with generalized anxiety disorder (GAD) in urban mental health settings in Nepal (N = 30) and in the United States (N = 23). Participants completed the Beck Anxiety Inventory (BAI). The overall BAI score and somatic and psychological subscales were compared. While there was no difference in total BAI scores, the Nepali group scored higher on the somatic subscale (i.e. "dizziness" and "indigestion," t[df] = -2.63[50], p < 0.05), while the American group scored higher on the psychological subscale (i.e. "scared" and "nervous," t[df] = 3.27[50], p < 0.01). Nepali patients with GAD had higher levels of somatic symptoms and lower levels of psychological symptoms than American patients with GAD. Possible explanations include differences in cultural traditions of describing distress and the mind-body dichotomy.

Women have a higher prevalence of generalized anxiety disorder (GAD) than do men, but few studies have assessed gender differences in response to pharmacotherapy. In this study we examined gender as a correlate of response to 6 weeks of open, prospective fluoxetine treatment in 23 men and 22 women with a primary diagnosis of GAD. There was no difference by gender in age or prevalence of mood and anxiety comorbidity; however, GAD onset occurred at a significantly younger age in women compared with men. Despite a lack of difference in baseline severity measures, women had a significantly poorer response to fluoxetine as measured by both the Hamilton Anxiety Rating Scale (HAM-A) and Clinician Global Impression-Severity Scale (CGI-S). In multivariate analyses, there was a significant interaction between age of onset and gender: men with younger age of onset and women with older age of onset exhibited poorer response on the HAM-A. These data, though limited in sample size and by the post hoc nature of our analyses, offer preliminary support that women with GAD, particularly those with a later age of onset, may have a poorer response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Larger placebo-controlled trials are needed to more definitively examine gender and treatment response in anxiety disorders.

Few randomized, placebo-controlled trials have evaluated the comparative efficacy and tolerability of more than one pharmacological agent for panic disorder. The primary objective of this study was to compare the efficacy and tolerability of venlafaxine extended release (ER) with placebo in treating panic disorder. Secondary objectives included comparing paroxetine with venlafaxine ER and placebo. Outpatients aged ≥18 years (placebo, n = 157; venlafaxine ER 75 mg, n = 156; venlafaxine ER 225 mg, n = 160; paroxetine, n = 151), with a primary diagnosis of panic disorder (±agoraphobia) based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for ≥3 months were randomly assigned to receive venlafaxine ER (titrated to 75 mg/day or 225 mg/day), paroxetine (titrated to 40 mg/day), or placebo for 12 weeks. The primary efficacy measure was the percentage of patients free of full-symptom panic attacks (≥ four symptoms) at endpoint. Key secondary outcomes included the Panic Disorder Severity Scale (PDSS) mean score change and response. At endpoint, all active treatment groups showed a significantly (P

To date, no large-scale, controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75 mg/day or 150 mg/day), or paroxetine 40 mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions--Severity (CGI-S) and--Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder.

BackgroundThe impact of anxiety disorders has not been well delineated in prospective studies of bipolar disorder.AimsTo examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning.MethodA thousand out-patients with bipolar disorder were followed prospectively for 1 year.ResultsA current comorbid anxiety disorder (present in 31.9% of participants) was associated with fewer days well, a lower likelihood of timely recovery from depression, risk of earlier relapse, lower quality of life and diminished role function over 1 year of prospective study. The negative impact was greater with multiple anxiety disorders.ConclusionsAnxiety disorders, including those present during relative euthymia, predicted a poorer bipolar course. The detrimental effects of anxiety were not simply a feature of mood state. Treatment studies targeting anxiety disorders will help to clarify the nature of the impact of anxiety on bipolar course.