Alexander Bystritsky

Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial.

CONTEXT Improving the quality of mental health care requires moving clinical interventions from controlled research settings into real-world practice settings. Although such advances have been made for depression, little work has been performed for anxiety disorders. OBJECTIVE To determine whether a flexible treatment-delivery model for multiple primary care anxiety disorders (panic, generalized anxiety, social anxiety, and posttraumatic stress disorders) would be better than usual care (UC). DESIGN, SETTING, AND PATIENTS A randomized controlled effectiveness trial of Coordinated Anxiety Learning and Management (CALM) compared with UC in 17 primary care clinics in 4 US cities. Between June 2006 and April 2008, 1004 patients with anxiety disorders (with or without major depression), aged 18 to 75 years, English- or Spanish-speaking, were enrolled and subsequently received treatment for 3 to 12 months. Blinded follow-up assessments at 6, 12, and 18 months after baseline were completed in October 2009. INTERVENTION CALM allowed choice of cognitive behavioral therapy (CBT), medication, or both; included real-time Web-based outcomes monitoring to optimize treatment decisions; and a computer-assisted program to optimize delivery of CBT by nonexpert care managers who also assisted primary care clinicians in promoting adherence and optimizing medications. MAIN OUTCOME MEASURES Twelve-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptoms score. Secondary outcomes included proportion of responders (> or = 50% reduction from pretreatment BSI-12 score) and remitters (total BSI-12 score < 6). RESULTS A significantly greater improvement for CALM vs UC in global anxiety symptoms was found (BSI-12 group mean differences of -2.49 [95% confidence interval {CI}, -3.59 to -1.40], -2.63 [95% CI, -3.73 to -1.54], and -1.63 [95% CI, -2.73 to -0.53] at 6, 12, and 18 months, respectively). At 12 months, response and remission rates (CALM vs UC) were 63.66% (95% CI, 58.95%-68.37%) vs 44.68% (95% CI, 39.76%-49.59%), and 51.49% (95% CI, 46.60%-56.38%) vs 33.28% (95% CI, 28.62%-37.93%), with a number needed to treat of 5.27 (95% CI, 4.18-7.13) for response and 5.50 (95% CI, 4.32-7.55) for remission. CONCLUSION For patients with anxiety disorders treated in primary care clinics, CALM compared with UC resulted in greater improvement in anxiety symptoms, depression symptoms, functional disability, and quality of care during 18 months of follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00347269.

Estrogen Replacement and Response to Fluoxetine in a Multicenter Geriatric Depression Trial

The estrogen decrease of the postmenopausal state may be a factor in both the pathogenesis of late-life depression and in therapeutic response. Studies of nondepressed women over 60 given estrogen replacement therapy (ERT) suggest improvement in mood. The authors compared clinical response of elderly depressed women outpatients entering a 6-week, randomized, placebo-controlled, double-blind, multicenter trial of fluoxetine (20 mg/day); 72 patients received ERT, and 286 did not. There was a significant interaction between ERT status and treatment effect (P = 0.015). Patients on ERT who received fluoxetine had substantially greater mean Ham-D percentage improvement than patients on ERT who received placebo (40.1% vs. 17.0%, respectively); fluoxetine-treated patients not on ERT did not show benefit significantly greater than placebo-treated patients not on ERT. ERT use may augment fluoxetine response in elderly depressed outpatients and should be considered as a factor in clinical trials in elderly women.

Focused ultrasound modulates region-specific brain activity

We demonstrated the in vivo feasibility of using focused ultrasound (FUS) to transiently modulate (through either stimulation or suppression) the function of regional brain tissue in rabbits. FUS was delivered in a train of pulses at low acoustic energy, far below the cavitation threshold, to the animals somatomotor and visual areas, as guided by anatomical and functional information from magnetic resonance imaging (MRI). The temporary alterations in the brain function affected by the sonication were characterized by both electrophysiological recordings and functional brain mapping achieved through the use of functional MRI (fMRI). The modulatory effects were bimodal, whereby the brain activity could either be stimulated or selectively suppressed. Histological analysis of the excised brain tissue after the sonication demonstrated that the FUS did not elicit any tissue damages. Unlike transcranial magnetic stimulation, FUS can be applied to deep structures in the brain with greater spatial precision. Transient modulation of brain function using image-guided and anatomically-targeted FUS would enable the investigation of functional connectivity between brain regions and will eventually lead to a better understanding of localized brain functions. It is anticipated that the use of this technology will have an impact on brain research and may offer novel therapeutic interventions in various neurological conditions and psychiatric disorders.

Functional impact and health utility of anxiety disorders in primary care outpatients.

Objective:The objective of this study was to examine the relative impact of anxiety disorders and major depression on functional status and health-related quality of life of primary care outpatients. Method:Four hundred eighty adult outpatients at an index visit to their primary care provider were classified by structured diagnostic interview as having anxiety disorders (panic disorder with or without agoraphobia, social phobia, and posttraumatic stress disorder; generalized anxiety disorder was also assessed in a subset) with or without major depression. Functional status, sick days from work, and health-related quality of life (including a preference-based measure) were assessed using standardized measures adjusting for the impact of comorbid medical illnesses. Relative impact of the various anxiety disorders and major depression on these indices was evaluated. Results:In multivariate regression analyses simultaneously adjusting for age, sex, number of chronic medical conditions, education, and/or poverty status, each of major depression, panic disorder, posttraumatic stress disorder, and social phobia contributed independently and relatively equally to the prediction of disability and functional outcomes. Generalized anxiety disorder had relatively little impact on these indices when the effects of comorbid major depression were considered. Overall, anxiety disorders were associated with substantial decrements in preference-based health states. Conclusions:These observations demonstrate that the presence of each of 3 common anxiety disorders (ie, panic disorder, posttraumatic stress disorder, and social phobia)—over and above the impact of chronic physical illness, major depression, and other socioeconomic factors—contributes in an approximately additive fashion to the prediction of poor functioning, reduced health-related quality of life, and more sick days from work. Greater awareness of the deleterious impact of anxiety disorders in primary care is warranted.

Functional MRI changes during panic anticipation and imagery exposure.

While undergoing fMRI, six patients with DSM IV diagnosis of panic disorder and six normal controls performed directed imagery of neutral, moderate and high anxiety situations based on an individually determined behavioral hierarchy. Brain activity was compared during high vs neutral anxiety blocks for each group of subjects using SPM99b. Panic patients showed increased activity in inferior frontal cortex, hippocampus and throughout the cingulate both anterior and posterior, extending into the orbitofrontal cortex and encompassing both hemispheres. These areas may constitute the important circuit in the psychopathology of panic disorder. We propose that this pattern of activity may enhance the encoding and retrieval of strong emotional events, facilitating the recapitulation of traumatic experiences and leading to panic disorder in vulnerable individuals.

A review of low-intensity focused ultrasound pulsation

With the recent approval by the Food and Drug Administration (FDA) of Deep Brain Stimulation (DBS) for Parkinsons Disease, dystonia and obsessive compulsive disorder (OCD), vagus nerve stimulation (VNS) for epilepsy and depression, and repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression, neuromodulation has become increasingly relevant to clinical research. However, these techniques have significant drawbacks (eg, lack of special specificity and depth for the rTMS, and invasiveness and cumbersome maintenance for DBS). This article reviews the background, rationale, and pilot studies to date, using a new brain stimulation method-low-intensity focused ultrasound pulsation (LIFUP). The ability of ultrasound to be focused noninvasively through the skull anywhere within the brain, together with concurrent imaging (ie, functional magnetic resonance imaging [fMRI]) techniques, may create a role for research and clinical use of LIFUP. This technique is still in preclinical testing and needs to be assessed thoroughly before being advanced to clinical trials. In this study, we review over 50 years of research data on the use of focused ultrasound (FUS) in neuronal tissue and live brain, and propose novel applications of this noninvasive neuromodulation method.

Validation of a Brief Measure of Anxiety-Related Severity and Impairment: The Overall Anxiety Severity and Impairment Scale (OASIS)

BACKGROUND The Overall Anxiety Severity and Impairment Scale (OASIS) is a 5-item self-report measure that can be used to assess severity and impairment associated with any anxiety disorder or multiple anxiety disorders. A prior investigation with a nonclinical sample supported the reliability and validity of the OASIS; however, to date it has not been validated for use in clinical samples. METHODS The present study assessed the psychometric properties of the OASIS in a large sample (N=1036) of primary care patients whose physicians referred them to an anxiety disorders treatment study. Latent structure, internal consistency, convergent/discriminant validity, and cut-score analyses were conducted. RESULTS Exploratory and confirmatory factor analyses supported a unidimensional structure. The five OASIS items displayed strong loadings on the single factor and had a high degree of internal consistency. OASIS scores demonstrated robust correlations with global and disorder-specific measures of anxiety, and weak correlations with measures of unrelated constructs. A cut-score of 8 correctly classified 87% of this sample as having an anxiety diagnosis or not. LIMITATIONS Convergent validity measures consisted solely of other self-report measures of anxiety. Future studies should evaluate the convergence of OASIS scores with clinician-rated and behavioral measures of anxiety severity. CONCLUSIONS Overall, this investigation suggests that the OASIS is a valid instrument for measurement of anxiety severity and impairment in clinical samples. Its brevity and applicability to a wide range of anxiety disorders enhance its utility as a screening and assessment tool.

Predictors of Treatment Response in Obsessive-Compulsive Disorder: Multivariate Analyses From a Multicenter Trial of Clomipramine

There have been many attempts to find predictors of the therapeutic response to the clomipramine treatment of obsessive-compulsive disorder. The majority of studies have failed to identify such predictors. Possible reasons for this failure include the small sample size of most studies, samples homogeneous with respect to the study factors of interest, and the use of statistical procedures that are insensitive to individual differences or that inadequately control for confounding. We have reanalyzed data from Ciba-Geigys large, multicenter clinical trial of clomipramine for obsessive-compulsive disorder, using stratification and regression techniques to identify multiple prognostic factors and control for confounders. We assessed the relationship between therapeutic response and baseline measures such as severity of symptoms, type of symptoms (obsessions, compulsions, depression), length of illness, age of onset, and other demographic factors (age, race, and sex). We found age of onset to be a strong predictor of response to clomipramine: people who develop obsessive-compulsive disorder later in life have a better chance of responding than do those who become ill earlier, independent of length of illness. We also found that baseline depression is associated with response, but the association appears to be nonlinear.

Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity

BackgroundEpilepsy is a common neurological disorder, which is attributed to uncontrollable abnormal hyper-excitability of neurons. We investigated the feasibility of using low-intensity, pulsed radiation of focused ultrasound (FUS) to non-invasively suppress epileptic activity in an animal model (rat), which was induced by the intraperitonial injection of pentylenetetrazol (PTZ).ResultsAfter the onset of induced seizures, FUS was transcranially administered to the brain twice for three minutes each while undergoing electroencephalographic (EEG) monitoring. An air-backed, spherical segment ultrasound transducer (diameter: 6 cm; radius-of-curvature: 7 cm) operating at a fundamental frequency of 690 KHz was used to deliver a train of 0.5 msec-long pulses of sonication at a repetitive rate of 100 Hz to the thalamic areas of the brain. The acoustic intensity (130 mW/cm2) used in the experiment was sufficiently within the range of safety guidelines for the clinical ultrasound imaging. The occurrence of epileptic EEG bursts from epilepsy-induced rats significantly decreased after sonication when it was compared to the pre-sonication epileptic state. The PTZ-induced control group that did not receive any sonication showed a sustained number of epileptic EEG signal bursts. The animals that underwent sonication also showed less severe epileptic behavior, as assessed by the Racine score. Histological analysis confirmed that the sonication did not cause any damage to the brain tissue.ConclusionsThese results revealed that low-intensity, pulsed FUS sonication suppressed the number of epileptic signal bursts using acute epilepsy model in animal. Due to its non-invasiveness and spatial selectivity, FUS may offer new perspectives for a possible non-invasive treatment of epilepsy.

Specificity of attentional bias in panic disorder and social phobia

Anxious individuals have an attentional bias for threatening information. However, the specificity of this attentional bias among patients with different anxiety disorders remains unclear. The primary goal of this study was to compare Stroop response times to a range of emotionally positive and threatening words in patients with different anxiety disorders and nonanxious controls. Patients with panic disorder (n = 15), social phobia (n = 15), and control subjects (n = 15) participated in a computerized Stroop color-naming task of positive and threatening words related to panic, social concerns, general concerns, as well as neutral words. When compared to others, patients with panic disorder exhibited longer response times to all threatening word types, whereas patients with social phobia demonstrated longer response times to social-threat words only. These findings suggest that patients with panic disorder may possess a broader fear network and thus display more generalized attentional bias to threat than socially anxious patients.