Maintenance of Wellness in Patients With Obsessive-Compulsive Disorder Who Discontinue Medication After Exposure/Response Prevention Augmentation: A Randomized Clinical Trial.

IMPORTANCE: Serotonin reuptake inhibitors (SRIs) are the only medications approved for obsessive-compulsive disorder (OCD), yet most patients taking SRIs exhibit significant symptoms. Adding exposure/response prevention (EX/RP) therapy improves symptoms, but it is unknown whether patients maintain wellness after discontinuing SRIs. OBJECTIVE: To assess whether patients with OCD who are taking SRIs and have attained wellness after EX/RP augmentation can discontinue their SRI with noninferior outcomes compared with those who continue their SRI therapy. DESIGN, SETTING, AND PARTICIPANTS: A 24-week, double-blind, randomized clinical trial was performed from May 3, 2013, to June 25, 2018. The trial took place at US academic medical centers. Participants included 137 adults with a principal diagnosis of OCD (≥1 year) who were taking an SRI (≥12 weeks), had at least moderate symptoms (defined as Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] score ≥18 points), and received as many as 25 sessions of EX/RP therapy. Those who attained wellness (Y-BOCS score ≤14 points; 103 patients [75.2%]) were study eligible. Data were analyzed from June 29, 2019, to October 2, 2021. INTERVENTION: Participants were randomly assigned either to receive taper to placebo (taper group) or to continue their SRI (continuation group) and monitored for 24 weeks. MAIN OUTCOME AND MEASURES: The Y-BOCS score (range, 0-40 points) was the primary outcome; the Hamilton Depression Rating Scale (HDRS; range, 0-52 points) and the Quality-of-Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; range, 0%-100%) scores were secondary outcomes. Outcomes were assessed at 8 time points by independent evaluators who were blinded to randomization. The taper regimen was hypothesized to be noninferior to continuation at 24 weeks using a 1-sided α value of .05. RESULTS: A total of 101 patients (mean [SD] age, 31.0 [11.2] years; 55 women [54.5%]) participated in the trial: 51 patients (50.5%) in the taper group and 50 patients (49.5%) in the continuation group. At 24 weeks, patients in the taper group had noninferior results compared with patients in the continuation group (mean [SD] Y-BOCS score: taper group, 11.47 [6.56] points; continuation group: 11.51 [5.97] points; difference, -0.04 points; 1-sided 95% CI, -∞ to 2.09 points [below the noninferiority margin of 3.0 points]; mean [SD] HDRS score: taper group, 5.69 [3.84] points; continuation group, 4.61 [3.46] points; difference, 1.08 points; 1-sided 95% CI, -∞ to 2.28 points [below the noninferiority margin of 2.5 points]; mean [SD] Q-LES-Q-SF score: taper group, 68.01% [15.28%]; continuation group, 70.01% [15.59%]; difference, 2.00%; 1-sided 95% CI, -∞ to 6.83 [below the noninferiority margin of 7.75]). However, the taper group had higher rates of clinical worsening (23 of 51 [45%] vs 12 of 50 [24%]; P = .04). CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial show that patients with OCD who achieve wellness after EX/RP therapy could, on average, discontinue their SRI with noninferior outcomes compared with those who continued their SRI. Those who tapered the SRI had higher clinical worsening rates. Future research should evaluate if SRI half-life alters these rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01686087.

Maximizing remission from cognitive-behavioral therapy in medicated adults with obsessive-compulsive disorder.

Practice guidelines for adults with obsessive-compulsive disorder (OCD) recommend augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention (EX/RP). However, fewer than half of patients remit after a standard 17-session EX/RP course. We studied whether extending the course increased overall remission rates and which patient factors predicted remission. Participants were 137 adults with clinically significant OCD (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score ≥18) despite an adequate SRI trial (≥12 weeks). Continuing their SRI, patients received 17 sessions of twice-weekly EX/RP (standard course). Patients who did not remit (Y-BOCS ≤12) received up to 8 additional sessions (extended course). Of 137 entrants, 123 completed treatment: 49 (35.8%) remitted with the standard course and another 46 (33.6%) with the extended course. Poorer patient homework adherence, more Obsessive-Compulsive Personality Disorder (OCPD) traits, and the Brain-Derived Neurotrophic Factor (BDNF) Val66MET genotype were associated with lower odds of standard course remission. Only homework adherence differentiated non-remitters from extended course remitters. Extending the EX/RP course from 17 to 25 sessions enabled many (69.3%) OCD patients on SRIs to achieve remission. Although behavioral (patient homework adherence), psychological (OCPD traits), and biological (BDNF genotype) factors influenced odds of EX/RP remission, homework adherence was the most potent patient factor overall.

The Association between Insomnia and Anxiety Symptoms in a Naturalistic Anxiety Treatment Setting.

Objective/Background: Few studies have examined the relationship between insomnia and anxiety treatment outcomes in naturalistic settings. Furthermore, prior studies typically examine insomnia within a single anxiety diagnosis without accounting for the high overlap between disorders. Here we investigate the association between insomnia and multiple anxiety disorders over a course of cognitive behavioral treatment (CBT) in a naturalistic treatment setting. Participants: Insomnia was assessed in 326 patients seeking treatment at a clinic specializing in CBT for anxiety. Methods: Multilevel modeling was used to investigate whether insomnia moderated reductions in anxiety symptoms. A cross-lagged analysis tested for bidirectional effects between insomnia and anxiety. Multiple regression was used to investigate the relationship between insomnia and anxiety while controlling for the other anxiety disorders and depression. Results: While there was a significant reduction in insomnia during treatment in all anxiety disorders, the majority of the most severe patients remained in the clinical range at post-treatment. Baseline insomnia did not significantly moderate anxiety outcomes, suggesting that patients with high or low levels of insomnia will do equally well in CBT for anxiety. The bidirectional effect between insomnia and anxiety did not reach significance. Additionally, posttraumatic stress disorder, generalized anxiety disorder, and panic disorder were associated with the greatest endorsement of insomnia, after controlling for the overlap between disorders. Conclusions: Sleep problems may persist after anxiety treatment, suggesting that CBT for insomnia may be warranted during or after a course of CBT for anxiety. Importantly, baseline insomnia does not impede anxiety reduction during CBT.

Beyond the Constraints of an RCT: Naturalistic Treatment Outcomes for Anxiety-Related Disorders.

Despite considerable data from randomized controlled trials supporting use of behavioral therapies for anxiety disorders and anxiety-related disorders, there is a relative scarcity of data demonstrating that such findings are generalizable to patients in nonresearch settings, and a lack of standardized repeated outcome measurement in such settings. Using one of the largest examinations of naturalistic outcomes of behavioral therapies in treatment-seeking patients (N = 489), we examined the clinical characteristics and treatment outcomes of patients seeking treatment for anxiety and anxiety-related disorders in the past 3 years. Patients seeking treatment at a clinic specializing in cognitive-behavioral therapy (CBT) completed self-report questionnaires via an electronic data capture system and diagnostic interview at baseline, and were reassessed at mid- and posttreatment. Patients with anxiety and related disorders were assessed for changes in symptom severity and secondary outcomes (impairment/functioning, quality of life, and depression) over the course of therapy. Patients showed clinically significant and statistically reliable improvement in anxiety symptom severity scores over treatment (p < .001), after controlling for number of sessions received. Patients also showed significant improvement in depression, quality of life, and functioning (p values ≤ .001). We also found significant improvement in disorder-specific symptoms, including obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social anxiety disorder (p values ≤ .001). Importance of, and ways to facilitate, integration of more routine assessment of a broader range of symptoms via online assessment systems and methods to better determine the effectiveness of CBT in naturalistic clinics are discussed.

The Evolution of Color Pattern in Butterflyfishes (Chaetodontidae).

Coral reef fishes constitute one of the most diverse assemblages of vertebrates on the planet. Color patterns are known to serve a number of functions including intra- and inter-specific signaling, camouflage, mimicry, and defense. However, the relative importance of these and other factors in shaping color pattern evolution is poorly understood. Here we conduct a comparative phylogenetic analysis of color pattern evolution in the butterflyfishes (Chaetodontidae). Using recently developed tools for quantifying color pattern geometry as well as machine learning approaches, we investigate the tempo of evolution of color pattern elements and test whether ecological variables relating to defense, depth, and social behavior predict color pattern evolution. Butterflyfishes exhibit high diversity in measures of chromatic conspicuousness and the degrees of fine versus gross scale color patterning. Surprisingly, most diversity in color pattern was not predicted by any of the measures of ecology in our study, although we did find a significant but weak relationship between the level of fine scale patterning and some aspects of defensive morphology. We find that the tempo of color pattern diversification in butterflyfishes has increased toward the present and suggest that rapid evolution, presumably in response to evolutionary pressures surrounding speciation and lineage divergence, has effectively decoupled color pattern geometry from some aspects of ecology. Machine learning classification of color pattern appears to rely on a set of features that are weakly correlated with current color pattern geometry descriptors, but that may be better suited for the detection of discrete components of color pattern. A key challenge for future studies lies in determining whether rapid evolution has generally decoupled color patterns from ecology, or whether convergence in function produces convergence in color pattern at phylogenetic scales.

Benefits and Challenges of Delivering Tele-rehabilitation Services to Rural Veterans.

Veterans residing in underserved rural areas face many barriers to accessing high-quality rehabilitation services. This article describes the benefits and challenges of using technology for delivery of rehabilitation services to rural Veterans using TeleHOME, an innovative tele-rehabilitation program. TeleHOME enables rehabilitation providers to remotely assess the Veteran's functional abilities and needs in his or her own home where these tasks must be performed. This technology increases the ability of all team members to contribute to interdisciplinary care, but also requires greater levels of team integration. One month after the completion of the TeleHOME project, we met with clinicians to discuss their perceptions of whether and how use of the technology affected interdisciplinary care processes, and what approaches were used to meet team-based goals. TeleHOME can improve access to rehabilitation services for rural Veterans, but will also bring about novel integrative care processes that may improve the effectiveness of such services. Recommendations to overcome challenges to optimize the implementation and delivery of TeleHOME services as well as to better inform clinicians working with rural Veterans are discussed.

Heme axial methionine fluxionality in Hydrogenobacter thermophilus cytochrome c552.

The heme group in paramagnetic (S = 1/2) ferricytochromes c typically displays a markedly asymmetric distribution of unpaired electron spin density among the heme pyrrole beta substituents. This asymmetry is determined by the orientations of the heme axial ligands, histidine and methionine. One exception to this is ferricytochrome c(552) from Hydrogenobacter thermophilus, which has similar amounts of unpaired electron spin density at the beta substituents on all four heme pyrroles. Here, determination of the orientation of the magnetic axes and analysis of NMR line shapes for H. thermophilus ferricytochrome c(552) is performed. These data reveal that the unusual electronic structure for this protein is a result of fluxionality of the heme axial methionine. It is proposed that the ligand undergoes inversion at the pyramidal sulfur, and the rapid interconversion between two diastereomeric forms results in the unusual heme electronic structure. Thus a fluxional process for a metal-bound amino acid side chain has now been identified.

Characterization of Hydrogenobacter thermophilus cytochromes c(552 )expressed in the cytoplasm and periplasm of Escherichia coli.

Hydrogenobacter thermophilus cytochrome c(552) ( Ht cyt c(552)) is a small monoheme protein in the cytochrome c(551) family. Ht cyt c(552) is unique because it is hypothesized to undergo spontaneous cytoplasmic maturation (covalent heme attachment) when expressed in Escherichia coli. This is in contrast to the usual maturation route for bacterial cytochromes c that occurs in the cellular periplasm, where maturation factors direct heme attachment. Here, the expression of Ht cyts c(552) in the periplasm as well as the cytoplasm of E. coli is reported. The products are characterized by absorption, circular dichroism, and NMR spectroscopy as well as mass spectrometry, proteolysis, and denaturation studies. The periplasmic product's properties are found to be indistinguishable from those reported for protein isolated from Ht cells, while the major cytoplasmic product exhibits structural anomalies in the region of the N-terminal helix. These anomalies are shown to result from the retention of the N-terminal methionine in the cytoplasmic product, and not from heme attachment errors. The (1)H NMR chemical shifts of the heme methyls of the oxidized ( S=1/2) expression products display a unique pattern not previously reported for a cytochrome c with histidine-methionine axial ligation, although they are consistent with native-like heme ligation. These results support the hypothesis that proper heme attachment can occur spontaneously in the E. coli cytoplasm for Ht cyt c(552).