Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results: Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

Brain connectomics predict response to treatment in social anxiety disorder.

We asked whether brain connectomics can predict response to treatment for a neuropsychiatric disorder better than conventional clinical measures. Pre-treatment resting-state brain functional connectivity and diffusion-weighted structural connectivity were measured in 38 patients with social anxiety disorder (SAD) to predict subsequent treatment response to cognitive behavioral therapy (CBT). We used a priori bilateral anatomical amygdala seed-driven resting connectivity and probabilistic tractography of the right inferior longitudinal fasciculus together with a data-driven multivoxel pattern analysis of whole-brain resting-state connectivity before treatment to predict improvement in social anxiety after CBT. Each connectomic measure improved the prediction of individuals' treatment outcomes significantly better than a clinical measure of initial severity, and combining the multimodal connectomics yielded a fivefold improvement in predicting treatment response. Generalization of the findings was supported by leave-one-out cross-validation. After dividing patients into better or worse responders, logistic regression of connectomic predictors and initial severity combined with leave-one-out cross-validation yielded a categorical prediction of clinical improvement with 81% accuracy, 84% sensitivity and 78% specificity. Connectomics of the human brain, measured by widely available imaging methods, may provide brain-based biomarkers (neuromarkers) supporting precision medicine that better guide patients with neuropsychiatric diseases to optimal available treatments, and thus translate basic neuroimaging into medical practice.

The role of anxiety sensitivity in sleep disturbance in panic disorder.

Previous research has demonstrated that individuals with panic disorder (PD) report significant sleep disturbances, although the mechanism of this disturbance is not clear. Patients with PD tend to report abnormally high levels of anxiety sensitivity (AS). Because higher AS involves increases in attention and fearfulness about anxiety and associated physical sensations, which in turn may cause excessive psychological and physiologic arousal, we hypothesized that amongst individuals with PD, higher AS would be associated with sleep disruption, particularly in the form of increased sleep latency. As expected, PD was associated with poorer sleep as measured by the Global Pittsburgh Sleep Quality Index (PSQI) compared to controls and AS was significantly associated with longer sleep latency. Our data suggest that sleep disturbance, and in particular sleep latency, in PD may be partly due to high levels of AS, which can be targeted with cognitive-behavioral therapeutic strategies.

Nightmares among Cambodian refugees: the breaching of concentric ontological security.

This article explores the nightmares of Cambodian refugees in a cultural context, and the role of nightmares in the trauma ontology of this population, including their role in generating post-traumatic stress disorder (PTSD). Among Cambodian refugees attending a psychiatric clinic, we found that having a nightmare was strongly associated with having PTSD (chi(2) = 61.7, P < 0.001, odds ratio = 126); that nightmares caused much distress upon awakening, including panic attacks, fear of bodily dysfunction, flashbacks and difficulty returning to sleep; that nightmare content was frequently related to traumatic events; that nightmares resulted in a decrease in the sense of "concentric ontology security" (i.e., in an increased sense of physical and spiritual vulnerability in a culture that conceives of the self in terms of concentric, protective layers), including fears of being attacked by ghosts; and that nightmares frequently led to the performance of specific practices and rituals aiming to extrude and repel attacking forces and to create "protective layers." Cases are presented to illustrate these findings. The Discussion considers some treatment implications of the study.

Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder.

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 (alpha=.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<.0025). To assess for the presence of a generalized proinflammatory state, we also examined the proportion of subjects with detectable levels of at least six of nine common proinflammatory cytokines and chemokines (IL-6, IL-1alpha, IL-1beta, IL-8, MCP-1, MIP-1alpha, Eotaxin, GM-CSF, and IFN-alpha). For men and women, 87% of anxiety patients had six or more detectable levels of these proinflammatory cytokines, compared with only 25% of controls (Fisher's Exact Test (FET) P=.000). Confirmatory analysis of the subset of individuals without current psychiatric medication use or comorbid depression was of comparable significance. CONCLUSIONS: These findings suggest that a generalized inflammatory state may be present in individuals with PD or PTSD.

A detailed examination of cytokine abnormalities in Major Depressive Disorder.

Recent technological advances offer an opportunity to further elucidate the complex cytokine network in Major Depressive Disorder (MDD). Twenty cytokines were simultaneously assessed in 49 individuals with MDD and 49 age and gender matched controls. Multiple pro-inflammatory and two anti-inflammatory cytokines were significantly elevated in the MDD sample, including an antidepressant naïve subset. These data support a generalized chronic inflammatory state in MDD, and implicate additional cytokines and chemokines previously linked to cardiovascular disease.

Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders.

BACKGROUND: The impact of anxiety disorders has not been well delineated in prospective studies of bipolar disorder. AIMS: To examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning. METHOD: A thousand thousand out-patients with bipolar disorder were followed prospectively for 1 year. RESULTS: A 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 I year of prospective study. The negative impact was greater with multiple anxiety disorders. CONCLUSIONS: Anxiety 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.

Assessment of posttraumatic stress disorder in Cambodian refugees using the Clinician-Administered PTSD Scale: psychometric properties and symptom severity.

Posttraumatic stress disorder (PTSD) symptoms were assessed by using the Clinician-Administered PTSD Scale (CAPS) in a consecutive sample of Cambodian refugees attending a psychiatric clinic in the United States. Psychometric properties of the translated CAPS and severity of PTSD-related symptoms were examined. The CAPS demonstrated adequate psychometric properties, including coefficient alpha (.92) and item-total correlations (.48-.85). Of the sample 56% (101/179) met Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for current PTSD. Those patients who met criteria for current PTSD had significantly higher CAPS total scores (M = 65.3, SD = 18.1) than those who did not meet the criteria (M = 13.9, SD = 16.7).

Olfactory-triggered panic attacks among Cambodian refugees attending a psychiatric clinic.

Olfactory panic attacks have not been systematically assessed in a psychiatric population by any previous studies. Among Cambodian refugees attending a psychiatric clinic, the present investigation determines the following: (a) 1-month current prevalence of olfactory-triggered panic attacks, (b) associated psychopathology (Hopkins Symptom Checklist and the Structured Clinical Interview for DSM-IV-diagnosed posttraumatic stress disorder [PTSD]), and (c) frequency in events of olfactory panic of catastrophic cognitions (Panic Attack Cognitions Scale [PACQ]) and flashbacks (Clinician-Administered PTSD flashback scale). Forty-five percent of 100 consecutive psychiatric patients were found to have suffered an olfactory-triggered panic attack in the previous month; having current olfactory panic attacks was highly correlated with psychopathology (e.g., to PTSD diagnosis: and chi(2)=50.0; df=1; p<.001); and during olfactory-triggered panic attacks, catastrophic cognitions and flashbacks were common. Possible mechanisms for generation of high rates of olfactory-triggered panic attacks in this population are discussed (the "traumatic memory/catastrophic cognitions/interoceptive conditioning/escalating arousal" or "TCIE" model of panic generation) as are treatment implications.

Ropinirole for antidepressant-induced sexual dysfunction.

Sexual dysfunction is a relatively common side-effect of antidepressants, occurring in approximately one-half of patients, and is associated with significant distress and treatment non-compliance. Dopaminergic agents have been reported to be helpful for the treatment of antidepressant-induced sexual dysfunction and, in this report, we examined the efficacy of the dopamine agonist ropinirole for this indication. Thirteen patients (three women, 10 men), aged 42.6 +/- 7.7 years, who reported sexual dysfunction on a stable dose of antidepressant, were treated openly with ropinirole initiated at 0.25 mg/day and titrated up to 2-4 mg/day over 4 weeks, as tolerated. Ten of the 13 took ropinirole for at least 4 weeks, one discontinued due to an adverse event and two because of lack of response. Sexual dysfunction, as assessed by the Arizona Sexual Experience Scale scores, was reduced from 18.8 +/- 3.6 to 13.8 +/- 4.3 after 4 weeks on ropinirole at a mean dose of 2.1 mg/day. Overall, seven of 13 patients (54%) were rated as responders on the Clinical Global Impression of Improvement Scale. The addition of ropinirole may represent a potentially useful treatment strategy for antidepressant-induced sexual dysfunction.

An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder.

OBJECTIVE: Serotonin selective reuptake inhibitors (SSRIs) are now considered the first-line pharmacotherapy for panic disorder. The preferential use and the presumption of greater tolerability of SSRIs relative to older agents, such as tricyclic antidepressants, occurred without direct comparisons between the two classes of medication. In this study the authors used an effect-size analysis to provide an initial comparison. METHOD: The authors conducted an effect-size analysis of 12 placebo-controlled, efficacy trials of SSRIs for panic disorder and compared these results to findings obtained in a recent meta-analysis of non-SSRI treatments for panic disorder. RESULTS: The mean effect size for acute treatment outcome for SSRIs relative to placebo was 0.55, not significantly different from that for antidepressants in general (0.55) and for imipramine in particular (0.48). More recent studies of SSRIs, and studies using larger samples, were associated with lower effect sizes. No significant differences were found in dropout rates between those taking SSRIs and those taking older agents during acute treatment. CONCLUSIONS: An effect-size analysis of controlled studies of treatments for panic disorder revealed no significant differences between SSRIs and older antidepressants in terms of efficacy or tolerability in short-term trials. An inverse relationship was evident between sample size and effect size for SSRIs. Early studies of small samples may have led to initial overestimations of the efficacy of SSRIs for panic disorder.

Childhood history of anxiety disorders among adults with social phobia: rates, correlates, and comparisons with patients with panic disorder.

We examined the rates and correlates of a childhood history of anxiety disorders in 100 adults with a primary diagnosis of social phobia (social anxiety disorder). Adulthood and childhood disorders were assessed by experienced clinicians with structured clinical interviews. Rates of childhood anxiety disorders were evaluated to diagnostic comorbidity and a comparison group of patients with panic disorder. Onset of social phobia occurred before age 18 in 80% of the sample. Over half of the sample (54%) met criteria for one or more childhood anxiety disorders other than social phobia: 47% for overanxious disorder, 25% for avoidant disorder, 13% for separation anxiety disorder, and 1% for childhood agoraphobia. A history of childhood anxiety was associated with an early age of onset of social phobia, greater severity of fear and avoidance of social situations, greater fears of negative evaluation, and greater anxiety and depression morbidity. Rates of childhood social phobia, overanxious disorder, and avoidant disorder were significantly higher in patients with social phobia relative to our panic-disordered comparison group. We found approximately equal rates of a childhood history of separation anxiety disorder in patients with social phobia and panic disorder, providing further evidence against a unique relationship between separation anxiety disorder and panic disorder.

The anxiety sensitivity index: item analysis and suggestions for refinement.

Anxiety sensitivity is the fear of anxiety-related sensations, and is measured by the 16-item Anxiety Sensitivity Index (ASI). Despite the popularity and utility of the ASI in research, a number of studies have provided evidence for the inadequacy of several items, and item-to-scale correlations for the ASI have not been published. In this study, a converging set of analyses to evaluate the item adequacy and factor structure of the ASI was used. The results of these multiple analyses converged nicely suggesting that Items 1, 5, 7, 8, and 13 should be considered for removal from the instrument. The impact of removing these problematic items from the scale was explored through the reanalysis of data from 3 previously published studies that compared the original ASI with the new 11-item version (the ASI minus the 5 problematic items). The results of these analyses suggest that the 2 scales function comparably in many respects but that the new version may be a more precise measure of anxiety sensitivity. The 11-item ASI appears to tap 2 primary aspects of anxiety sensitivity: fears of somatic sensations of anxiety and fears of loss of mental control. Suggestions for further development of the ASI are offered.

Optimizing pharmacotherapy of generalized anxiety disorder to achieve remission.

More than half of patients with generalized anxiety disorder (GAD) have chronic and persistent symptomatology that may warrant ongoing pharmacotherapy. Many of these patients also have significant comorbid mood and anxiety disorders. There is growing consensus among clinicians that the treatment goal for anxiety disorders should be remission, including the minimization of anxiety and depression and resolution of functional impairment. Clinical management strategies for optimizing pharmacotherapy aimed at achieving remission in GAD include attention to drug selection, dosing levels, and duration of treatment. To optimize treatment for GAD with the goal of achieving remission, it is reasonable to select an agent with demonstrated effectiveness for GAD and associated comorbidities as well as a favorable side effect profile. Dosing and duration of treatment should be adequate, and consideration of adjunctive strategies for refractory patients may be warranted. This article discusses the optimization of pharmacotherapy with the goal of promoting remission in patients with GAD.

Citalopram for social phobia: a clinical case series.

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. Nine consecutive patients with a primary diagnosis of DSM-IV generalized social phobia were prospectively treated with citalopram. Citalopram was generally well-tolerated, and seven patients achieved responder status. This series of patients improved significantly on all measures. Results suggest that citalopram may be a safe and effective treatment for social anxiety disorder.

Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH-A).

The Hamilton Anxiety Rating Scale, a widely used clinical interview assessment tool, lacks instructions for administration and clear anchor points for the assignment of severity ratings. We developed a Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and report on a study comparing this version to the traditional form of this scale. Experienced interviewers from three Anxiety Disorders research sites conducted videotaped interviews using both traditional and structured instruments in 89 participants. A subset of the tapes was co-rated by all raters. Participants completed self-report symptom questionnaires. We observed high inter-rater and test-retest reliability using both formats. The structured format produced similar but consistently higher (+ 4.2) scores. Correlation with a self-report measure of overall anxiety was also high and virtually identical for the two versions. We conclude that in settings where extensive training is not practical, the structured scale is an acceptable alternative to the traditional Hamilton Anxiety instrument.

Comorbidity, neurobiology, and pharmacotherapy of social anxiety disorder.

Social anxiety disorder is a common psychiatric illness that imposes persistent functional impairment and disability on persons who have the disorder. The disorder is characterized by a marked and persistent fear of social or performance situations in which embarrassment may occur. It is the most prevalent of any anxiety disorder and is the third most common psychiatric disorder after depression and alcohol abuse. Social anxiety disorder typically begins during childhood with a mean age at onset between 14 and 16 years and is sometimes preceded by a history of social inhibition or shyness. Persons who have social anxiety disorder either endure or avoid social situations altogether because the fear of embarrassment causes such intense anxiety; such avoidance may ultimately interfere with occupational and/or social functioning and lead to significant disability. The duration of social anxiety disorder is frequently lifelong, and there is a high degree of comorbidity with other psychiatric disorders. Social anxiety disorder is a serious illness that frequently runs a chronic course and is associated with significant morbidity. Patients should be treated aggressively using pharmacotherapeutic agents that can be tolerated over the long term. Cognitive-behavioral therapy should also be considered in treatment planning. Efforts to increase the recognition of social anxiety disorder as a common, distressing, and disabling condition are critical. This article discusses the comorbidity, neurobiology, and pharmacotherapy of social anxiety disorder.

Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial.

BACKGROUND: The objective of this randomized, double-blind, placebo-controlled study was to investigate the efficacy and safety of paroxetine in outpatients with generalized anxiety disorder (GAD). METHOD: Male and female outpatients 18 years and older who met DSM-IV criteria for GAD and had baseline scores of at least 20 on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with paroxetine (20-50 mg/day) or placebo for 8 weeks. The primary efficacy variable was the mean change from baseline in the total score of the HAM-A. Additional key efficacy variables were the change from baseline in the scores of the HAM-A items anxious mood and tension, the anxiety subscale of the Hospital Anxiety and Depression Scale, and the Sheehan Disability Scale (SDS). The proportions of patients fulfilling response and remission criteria at week 8 were also determined. RESULTS: The intent-to-treat population included 324 patients. At week 8, compared with the placebo group (N = 163), the paroxetine group (N = 161) had a significantly greater reduction of GAD symptoms on all of the above-mentioned efficacy variables. On the HAM-A anxious mood item, which encompasses the cardinal symptoms of GAD, significantly greater efficacy was observed from week 1 and on the SDS significantly greater improvement was documented in the domain "social life" as early as week 4 for paroxetine compared with placebo. In both the last-observation-carried-forward and completer data sets, significantly greater proportions of paroxetine-treated patients achieved response or remission by week 8. Treatment with paroxetine was well tolerated, and the number and type of adverse events recorded in the paroxetine group correspond to the known safety profile of this medication. CONCLUSION: Paroxetine in doses of 20 to 50 mg once daily is effective in the treatment of patients with GAD. Improvement of core symptoms of GAD occurs early and is associated with significant reduction in disability after only 8 weeks of treatment.

Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.

Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder.