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.

Changes in coping behavior in a randomized controlled trial of concurrent treatment for PTSD and alcohol dependence.

OBJECTIVE: The current study examines changes in coping among 165 adults meeting DSM-IV criteria for co-morbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). METHOD: Participants were randomized to receive naltrexone or placebo, with or without prolonged exposure (PE). All participants received supportive counseling focused on alcohol use (BRENDA). Assessments of coping, PTSD, and AD were conducted at pre-treatment, mid-treatment, post-treatment, 3-month follow-up, and 6-month follow-up. RESULTS: Participants exhibited significant decreases in both avoidant coping and adaptive coping from pre-treatment to 6-month follow-up across all groups. Participants who received PE showed faster decreases in avoidant coping during this period than participants who did not receive PE. PTSD symptom reduction was associated with changes in both avoidant and adaptive coping across groups. Improvement in PTSD symptoms was related to a faster rate of reduction in avoidant coping in the PE groups compared to those receiving BRENDA alone. CONCLUSIONS: The current results suggest that concurrent treatment for co-morbid PTSD-AD decreases avoidant and adaptive coping, and participants who show greater reductions in PTSD symptoms also show greater changes in coping style. Consistent with theorized mechanisms of change in PE, the addition of PE to supportive counseling for AD was associated with a greater reduction of avoidant coping than supportive counseling alone.

Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.

BACKGROUND: Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias. METHODS: The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations. RESULTS: A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation. CONCLUSION: Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.

Predictors of unsuccessful magnetic resonance imaging scanning in older generalized anxiety disorder patients and controls.

A thorough understanding of the neurobiology of late life anxiety is likely to depend on the use of brain imaging techniques such as magnetic resonance imaging (MRI). Generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders in older adults, and is thus a focus for neurobiological studies using MRI. This study tested 1-3 weeks predictors of unsuccessful scan outcomes (i.e., scan trials in which the participant moved excessively or prematurely terminated the scan) in older adults with GAD (n = 39) and age- and sex-matched nonanxious controls (n = 21). It was hypothesized that successful completion of a prior MRI scan, clinical status (GAD versus control), and scores on the Anxiety Sensitivity Index (ASI; Peterson et al. 1986), a measure tapping psychological aspects of medical interventions, would predict scan outcome when current diagnoses of claustrophobia were controlled. In logistic regression analyses, unsuccessful scan outcome was predicted by prior MRI completion and ASI Mental Concerns subscale scores, but not clinical status. This model correctly classified 91% of successful and 71% of unsuccessful scans. An alternative model that included a single ASI item rather than Mental Concerns subscale scores showed similar performance, and a model including categorical anxiety sensitivity groups was also effective but slightly less accurate. Implications for improving the success rates of MRI with older adults are discussed.

Feasibility and acceptance of a nonpharmacological cognitive remediation intervention for patients with Parkinson disease.

Many patients with idiopathic Parkinson disease (PD) experience deficits in executive skills (ES; eg, attentional control, self-monitoring), which are associated with a range of impairing symptoms such as visual hallucinations, decreased motor control, and increased apathy. Pharmacological methods for improving ES in PD have shown to be somewhat unreliable. The goal of this study was to evaluate the feasibility and patient acceptance of a nonpharmacological cognitive remediation program that aimed to improve sustained, selective, alternating, and divided attentional abilities in a sample of 16 nondemented PD patients. Based on ratings of 4 feasibility dimensions (fatigue, effort, progress, enjoyment), patients with PD demonstrated a high degree of acceptance and successfully engaged in the program. As predicted, ratings of progress differed significantly across tasks according to difficulty level and were positively related to posttraining improvement in ES. Fatigue ratings showed negative associations with other indices across task types, suggesting that monitoring fatigue during cognitive remediation is essential. Patients' ratings of enjoyment did not correspond to task difficulty, indicating that tasks could be simultaneously challenging and rewarding. Males reported exerting greater effort during the training than females. It was concluded that the intervention is appropriate for testing in a randomized controlled trial.

A Novel Approach to Treating Anxiety and Enhancing Executive Skills in an Older Adult with Parkinson's Disease.

Scientific interest in the nonmotoric symptoms of Parkinson's disease (PD) has increased dramatically, and psychiatric symptoms (e.g., cognitive impairment, anxiety and mood disorders) are now considered prime targets for treatment optimization. Psychiatric complications in PD are quite common, affecting as many as 60 to 80% of patients. This study describes the case of a 74 year-old male with PD who presented with complaints of anxiety and trouble with memory and attention. A combined cognitive behavior therapy and cognitive enhancement intervention was delivered in ten 90-to-120 minute sessions. The patient showed a reduction in anxiety symptoms that was of sufficient magnitude to meet criteria for 'responder' status. His cognitive skills were mostly unchanged, despite the rigorous rehabilitation practice. Implications for treatment and strategies for enhancing therapeutic benefits are discussed.

The relation of worry to prefrontal cortex volume in older adults with and without generalized anxiety disorder.

Despite the widespread prevalence of generalized anxiety disorder (GAD) in later life, almost nothing is known about the neural aspects of worry in adults over the age of 60. Given the ongoing rapid increase in the older adult population, the relatively poor response rates to current interventions for late life GAD, and the effects of age-related changes to the brain, additional research on worry neurobiology is needed. The study group comprised 15 older GAD patients and 15 matched controls who were compared on clinical measures and brain volumes. It was expected that prefrontal cortex (PFC) volumes [medial orbital cortex (mOFC), dorsolateral cortex (DLPFC)] would show positive relations to worry scores, and weaker relations to more general measures of anxiety and depression. Negative relations were expected between amygdala volumes and worry scores. As expected, mOFC volumes were positively related to worry scores; however, DLPFC and amygdala volumes were not. The mOFC is involved in emotional decision-making under uncertain conditions and has the ability to suppress the amygdala, both of which are hypothesized functions of worry. Results are partly consistent with GAD theory and suggest that worry may involve neural areas that are also involved in the successful control of anxiety.