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.

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.

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.

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.

Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial.

BACKGROUND: The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder. We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder. METHODS: One hundred seventy-six nondepressed outpatients with panic disorder, with or without agoraphobia, from 10 sites followed identical protocols that used a flexible-dose design. After 2 weeks of single-blind placebo, patients were randomly assigned to 10 weeks of double-blind, flexible-dose treatment with either sertraline hydrochloride (50-200 mg/d) or placebo. RESULTS: Sertraline-treated patients exhibited significantly greater improvement (P=.01) at end point than did patients treated with placebo for the primary outcome variable, panic attack frequency. Significant differences between groups were also evident for clinician and patient assessments of improvement as measured by the Clinical Global Impression Improvement (P=.01) and Severity (P=.009) Scales, Panic Disorder Severity Scale ratings (P=.03), high end-state function assessment (P=.03), Patient Global Evaluation rating (P=.01), and quality of life scores (P=.003). Adverse events, generally characterized as either mild or moderate, were not significantly different in overall incidence between the sertraline and placebo groups. CONCLUSION: Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder.

Sleep panic attacks: an association with childhood anxiety and adult psychopathology.

The authors examine whether the presence of sleep panic attacks identifies a subgroup of panic disorder patients. Subjects (n = 95) were consecutive patients with panic disorder participating in the MGH longitudinal study of panic disorder. Patients were evaluated with structured interviews to establish adult anxiety and affective disorders, and the presence of childhood anxiety disorders. Patients were queried whether they had ever experienced at least one panic attack during sleep. Patients with a history of sleep panic had significantly higher rates of comorbid generalized anxiety disorder (p < 0.01), social phobia (p < 0.03), and major depression (p < 0.005). The trend was toward longer length of illness (p < 0.09) and were more likely to have a history of an anxiety disorder during childhood (p < 0.005). The presence of sleep panic attacks may delineate a subgroup of panic disorder patients with early difficulties with anxiety, and comorbid mood and anxiety disorders as adults.

Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder.

OBJECTIVE: This study evaluated the efficacy and safety of fixed doses of once-daily extended-release (XR) venlafaxine in outpatients with generalized anxiety disorder without concomitant major depressive disorder. METHOD: Adult outpatients with generalized anxiety disorder but not major depressive disorder with total scores of 18 or higher on the Hamilton Rating Scale for Anxiety and scores of 2 or higher on its anxious mood and tension factors were eligible. Patients were randomly assigned to receive placebo or venlafaxine XR (75, 150, or 225 mg/day) for 8 weeks. Primary efficacy variables were final total and psychic anxiety factor scores on the Hamilton anxiety scale and final severity and global improvement item scores on the Clinical Global Impression (CGI) scale. RESULTS: Of the 377 patients entering the study, 370 were included in a safety analysis and 349 in an efficacy analysis. Adjusted mean scores at 8 weeks (last-observation-carried-forward analysis) were significantly lower for one or more of the venlafaxine XR groups in four of four primary and three of four secondary outcome measures than for the placebo group. These included a change of 1.7 (versus 1.3) from baseline on CGI severity item scores and a final score of 2.2 (versus 2.6) on the CGI global improvement item. All doses of venlafaxine XR were well tolerated. CONCLUSIONS: Venlafaxine XR is an effective and well-tolerated option for the short-term treatment of generalized anxiety disorder in outpatients without major depressive disorder.

Fluvoxamine treatment of social phobia (social anxiety disorder): a double-blind, placebo-controlled study.

OBJECTIVE: The purpose of this study was to determine the efficacy of fluvoxamine for the treatment of social phobia (social anxiety disorder). METHOD: In a 12-week multicenter, double-blind, randomized, placebo-controlled trial, 92 patients with social phobia were treated with the selective serotonin reuptake inhibitor fluvoxamine; 91.3% of the patients had the generalized subtype of the disorder. The primary criterion for response was a rating of "much improved" or "very much improved" on the Clinical Global Impression of Improvement scale. Secondary response criteria were changes on three specialized rating scales for social phobia symptoms: the Brief Social Phobia Scale, the Social Phobia Inventory, and the Liebowitz Social Anxiety Scale. Psychosocial impairment was assessed in three domains (disruption of work, social life, and home/family life) by using the Sheehan Disability Scale. RESULTS: The mean daily dose of fluvoxamine was 202 mg (SD = 86). At study end or with the last observation carried forward, within the evaluable subjects (N = 86) there was a significantly higher proportion of responders in the fluvoxamine group (42.9%, N = 18) than in the placebo group (22.7%, N = 10). Similarly, fluvoxamine was superior to placebo on all social phobia rating scales at week 8 and beyond. Fluvoxamine also resulted in significantly greater decreases in measures of psychosocial disability than did placebo. Overall, fluvoxamine was well tolerated and safe. CONCLUSIONS: These findings indicate that fluvoxamine is efficacious in the pharmacologic management of serious forms of social phobia.

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.

Prevalence of panic in patients referred for pulmonary function testing at a major medical center.

OBJECTIVE: The authors examined the prevalence and correlates of panic disorder in a group of patients who were referred for pulmonary function testing. METHOD: Patients (N = 115) were screened for the presence of panic attacks and panic disorder with a self-report questionnaire; a subgroup (N = 25) received structured diagnostic assessment. RESULTS: Of the 115 patients, 41% (N = 47) reported panic attacks and 17% (N = 20) met screening criteria for panic disorder. From the confirmed rate of panic disorder among the subgroup who received structured diagnostic assessment, the overall prevalence rate of panic disorder was estimated to be 11% and included six of the nine patients (67%) who had a diagnosis of chronic obstructive pulmonary disease. There were no significant differences between patients with and without panic in the severity of pulmonary function abnormalities or in the response to bronchodilators. However, patients with panic attacks were significantly more likely to report dyspnea at rest and irritable bowel symptoms and tended to report difficulty swallowing. CONCLUSIONS: This study suggests that panic disorder and subsyndromal panic are relatively common and may be unrecognized and inadequately treated in patients who present with respiratory symptoms.

Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder.

OBJECTIVE: The primary disadvantage of high-potency benzodiazepine treatment for panic disorder is the difficulty of discontinuing the treatment. During treatment discontinuation, new symptoms may emerge and anxiety may return, preventing many patients from successfully discontinuing their treatment. In this controlled, randomized trial the authors investigated the efficacy of a cognitive-behavioral program for patients with panic disorder who were attempting to discontinue treatment with high-potency benzodiazepines. METHOD: Outpatients treated for panic disorder with alprazolam or clonazepam for a minimum of 6 months and expressing a desire to stop taking the medication (N = 33) were randomly assigned to one of two taper conditions: a slow taper condition alone or a slow taper condition in conjunction with 10 weeks of group cognitive-behavioral therapy. RESULTS: The rate of successful discontinuation of benzodiazepine treatment was significantly higher for the patients receiving the cognitive-behavioral program (13 of 17; 76%) than for the patients receiving the slow taper program alone (four of 16; 25%). There was no difference in the likelihood of discontinuation success between the patients treated with alprazolam and those who received clonazepam. At the 3-month follow-up evaluation, 77% of the patients in the cognitive-behavioral program who successfully discontinued benzodiazepine treatment remained benzodiazepine free. CONCLUSIONS: These findings support the efficacy of cognitive-behavioral interventions in aiding benzodiazepine discontinuation for patients with panic disorder.

Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group.

OBJECTIVE: Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessments are unreliable, studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement. The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement. METHOD: Patients with a diagnosis of panic disorder (N = 243) were randomly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo. Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores. Other assessments included a panic attack inventory, clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale, a phobia rating scale, the Hamilton Anxiety Rating Scale, the 21-item Hamilton Depression Rating Scale, and the Sheehan Disability Scale. Correlations were determined between outcomes in individual symptom domains and overall clinical outcome. RESULTS: Fluoxetine, particularly the 20-mg/day dose, was associated with more improvement than was placebo in patients with panic disorder across multiple symptom measures, including global improvement, total panic attack frequency, phobic symptoms, and functional impairment. Global improvement was most highly correlated with reductions in overall anxiety and phobic symptoms and least correlated with reduction in panic attacks. Fluoxetine treatment for panic disorder was well tolerated, with a safety profile consistent with that observed for fluoxetine in other disorders. CONCLUSIONS: These data provide support for the efficacy and safety of fluoxetine treatment in reducing panic attacks, phobic symptoms, anxiety, and depressive symptoms in patients with panic disorder. Reductions in panic attack frequency in subjects given either fluoxetine or placebo were less closely related to overall clinical improvement than reductions in phobic avoidance, anxiety, depressive symptoms, and functional impairment, suggesting that outcome measures in this disorder should be more broadly based.

Relationship of childhood anxiety to adult panic disorder: correlates and influence on course.

OBJECTIVE: This study investigated the correlates of a childhood history of anxiety disorders in adult patients participating in a longitudinal study of panic disorder. The authors hypothesized that a history of anxiety during childhood would be associated with higher rates of comorbid anxiety and depressive disorders, greater likelihood of anxiety disorders in family members, and greater chronicity, as reflected by decreased time spent in remission. METHOD: The presence of a childhood history of anxiety disorders was assessed by structured interview, and its association with comorbid anxiety and depressive disorders, family history, and select anxiety severity variables was examined in a replication sample of 94 patients. The influence of childhood anxiety on the prospectively ascertained course of disorder was assessed in a full group of 194 patients. RESULTS: Over half (54%) of the patients experienced anxiety disorders during childhood. These patients experienced higher rates of comorbid anxiety and depression, family history of anxiety, and increased levels of agoraphobia, panic frequency, and global severity of illness at baseline evaluation. Childhood anxiety disorders were not independently associated with the number of months in remission or the severity of illness over time, although a modest effect for this variable was evident when degree of avoidance and anxiety sensitivity at baseline were statistically controlled. CONCLUSIONS: Adult panic patients with a history of anxiety disorders in childhood have elevated rates of comorbid anxiety and depressive disorders and a tendency toward increased avoidance, but there was not strong evidence that these patients respond differently to treatment over time.

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.

Clonazepam: a review of open clinical trials.

Data were collected on 50 patients with panic attacks who were treated with clonazepam to determine the drug's antipanic efficacy. At a mean duration of 54.3 weeks, 62% of the patients remained in treatment and 38% were lost to follow-up. Of those remaining in treatment, 90% had a good response to clonazepam and 10% a poor response. The author concludes that clonazepam demonstrated antipanic efficacy, that the development of tolerance or abuse was not a problem, and that most of the patients are being effectively maintained at 2-3 mg/day of clonazepam.

Social anxiety disorder: designing a pharmacologic treatment strategy.

Growing appreciation of the prevalence of and morbid sequelae associated with social anxiety disorder has focused increasing interest on the development of effective treatment strategies. A number of pharmacologic interventions, including the monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase A, beta-blockers, benzodiazepines, and selective serotonin reuptake inhibitors, have demonstrated efficacy for the treatment of social anxiety disorder. The choice of initial treatment depends on a variety of factors including comorbidity, prior treatment history, patient preference, and adverse effect profile. This article will examine the effectiveness of various pharmacologic agents for the treatment of social anxiety disorder, discuss considerations for long-term management, and review strategies for optimizing treatment in patients who are partially responsive or unresponsive to initial therapy.

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.

Long-term management of panic disorder.

The high-potency benzodiazepines have been effective in short-term treatment of panic disorder, but systematic investigation of their long-term efficacy and safety is necessary. In a 1-year follow-up study of patients continuing treatment with clonazepam, 90% maintained a positive response without developing significant tolerance. In a 2.5-year follow-up study of alprazolam therapy, little evidence of tolerance emerged and initial therapeutic gains were maintained, even among patients who decreased or discontinued medication. As with antidepressants, many patients remain on high-potency benzodiazepine medication after short-term treatment; the choice of maintenance agent should reflect side effects of treatment as well as the ease of discontinuation. The high-potency benzodiazepines are a reasonable alternative to antidepressants, which involve problems of morbidity, noncompliance, and risk for overdose. Discontinuation may be less difficult with the longer-acting high-potency benzodiazepines, which thus may be advantageous for long-term treatment. It is necessary to determine the contributions of all aspects of treatment, both behavioral and pharmacologic, to the longitudinal course of patients with panic disorders.

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.