Moderators and predictors of response to cognitive-behavioral therapy augmentation of pharmacotherapy in obsessive-compulsive disorder.

BACKGROUND: Cognitive-behavioral therapy (CBT) consisting of exposure and response prevention (EX/RP) is efficacious as a treatment for obsessive-compulsive disorder (OCD). However, about half of patients have a partial or poor response to EX/RP treatment. This study examined potential predictors and moderators of CBT augmentation of pharmacotherapy, to identify variables associated with a poorer response to OCD treatment. METHOD: Data were drawn from a large randomized controlled trial that compared the augmenting effects of EX/RP to stress management training (SMT; an active CBT control) among 108 participants receiving a therapeutic dose of a serotonin reuptake inhibitor (SRI). Stepwise regression was used to determine the model specification. RESULTS: Pretreatment OCD severity and gender were significant moderators of outcome: severity affected SMT (but not EX/RP) outcome; and gender affected EX/RP (but not SMT) outcome. Adjusting for treatment type and pretreatment severity, significant predictors included greater co-morbidity, number of past SRI trials, and lower quality of life (QoL). Significant moderators, including their main-effects, and predictors accounted for 37.2% of the total variance in outcome, comparable to the impact of treatment type alone (R2=30.5%). These findings were replicated in the subgroup analysis of EX/RP alone (R2=55.2%). CONCLUSIONS: This is the first randomized controlled study to examine moderators and predictors of CBT augmentation of SRI pharmacotherapy. Although effect sizes for individual predictors tended to be small, their combined effect was comparable to that of treatment. Thus, future research should examine whether monitoring for a combination of these risk factors and targeting them with multi-modular strategies can improve EX/RP outcome.

Comparison of the Association Between Goal-Directed Planning and Self-reported Compulsivity vs Obsessive-Compulsive Disorder Diagnosis.

Importance: Dimensional definitions of transdiagnostic mental health problems have been suggested as an alternative to categorical diagnoses, having the advantage of capturing heterogeneity within diagnostic categories and similarity across them and bridging more naturally psychological and neural substrates. Objective: To examine whether a self-reported compulsivity dimension has a stronger association with goal-directed and related higher-order cognitive deficits compared with a diagnosis of obsessive-compulsive disorder (OCD). Design, Setting, and Participants: In this cross-sectional study, patients with OCD and/or generalized anxiety disorder (GAD) from across the United States completed a telephone-based diagnostic interview by a trained rater, internet-based cognitive testing, and self-reported clinical assessments from October 8, 2015, to October 1, 2017. Follow-up data were collected to test for replicability. Main Outcomes and Measures: Performance was measured on a test of goal-directed planning and cognitive flexibility (Wisconsin Card Sorting Test [WCST]) and a test of abstract reasoning. Clinical variables included DSM-5 diagnosis of OCD and GAD and 3 psychiatric symptom dimensions (general distress, compulsivity, and obsessionality) derived from a factor analysis. Results: Of 285 individuals in the analysis (mean [SD] age, 32 [12] years; age range, 18-77 years; 219 [76.8%] female), 111 had OCD; 82, GAD; and 92, OCD and GAD. A diagnosis of OCD was not associated with goal-directed performance compared with GAD at baseline (ß [SE], -0.02 [0.02]; P = .18). In contrast, a compulsivity dimension was negatively associated with goal-directed performance (ß [SE], -0.05 [0.02]; P = .003). Results for abstract reasoning task and WCST mirrored this pattern; the compulsivity dimension was associated with abstract reasoning (ß [SE], 2.99 [0.63]; P < .001) and several indicators of WCST performance (eg, categories completed: ß [SE], -0.57 [0.09]; P < .001), whereas OCD diagnosis was not (abstract reasoning: ß [SE], 0.39 [0.66]; P = .56; categories completed: ß [SE], -0.09 [0.10]; P = .38). Other symptom dimensions relevant to OCD, obsessionality, and general distress had no reliable association with goal-directed performance, WCST, or abstract reasoning. Obsessionality had a positive association with requiring more trials to reach the first category on the WCST at baseline (ß [SE], 2.92 [1.39]; P = .04), and general distress was associated with impaired goal-directed performance at baseline (ß [SE],-0.04 [0.02]; P = .01). However, unlike the key results of this study, neither survived correction for multiple comparisons or was replicated at follow-up testing. Conclusions and Relevance: Deficits in goal-directed planning in OCD may be more strongly associated with a compulsivity dimension than with OCD diagnosis. This result may have implications for research assessing the association between brain mechanisms and clinical manifestations and for understanding the structure of mental illness.

The classification of Obsessive-Compulsive and Related Disorders in the ICD-11.

BACKGROUND: To present the rationale for the new Obsessive-Compulsive and Related Disorders (OCRD) grouping in the Mental and Behavioural Disorders chapter of the Eleventh Revision of the World Health Organization's International Classification of Diseases and Related Health Problems (ICD-11), including the conceptualization and essential features of disorders in this grouping. METHODS: Review of the recommendations of the ICD-11 Working Group on the Classification for OCRD. These sought to maximize clinical utility, global applicability, and scientific validity. RESULTS: The rationale for the grouping is based on common clinical features of included disorders including repetitive unwanted thoughts and associated behaviours, and is supported by emerging evidence from imaging, neurochemical, and genetic studies. The proposed grouping includes obsessive-compulsive disorder, body dysmorphic disorder, hypochondriasis, olfactory reference disorder, and hoarding disorder. Body-focused repetitive behaviour disorders, including trichotillomania and excoriation disorder are also included. Tourette disorder, a neurological disorder in ICD-11, and personality disorder with anankastic features, a personality disorder in ICD-11, are recommended for cross-referencing. LIMITATIONS: Alternative nosological conceptualizations have been described in the literature and have some merit and empirical basis. Further work is needed to determine whether the proposed ICD-11 OCRD grouping and diagnostic guidelines are mostly likely to achieve the goals of maximizing clinical utility and global applicability. CONCLUSION: It is anticipated that creation of an OCRD grouping will contribute to accurate identification and appropriate treatment of affected patients as well as research efforts aimed at improving our understanding of the prevalence, assessment, and management of its constituent disorders.

First-episode major depression. Few sex differences in course.

BACKGROUND: There is a sex difference in the prevalence of unipolar major depression. This study sought to determine whether there is a sex difference in its course. METHODS: The National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies provided data on 96 male and 101 female subjects who were diagnosed as having a first episode of unipolar major depressive disorder at intake and on whom prospective data were available. We looked for differences at intake in factors other than sex that might affect the course of illness: demographic factors, characteristic features of the first depressive episode, psychiatric history, and family history of depression. We then examined the course of depression of these subjects during the following 15 years. RESULTS: The subjects were similar at intake, enabling us to focus on sex when we looked for differences in the course. Most subjects recovered from their first episode of major depression, but the majority had at least 1 recurrence in the following 5 years. During the following 15 years, male and female subjects did not differ significantly in the time to recovery, the overall time to first recurrence, of the number or severity of recurrences of major depressive episodes. There was no evidence for a more chronic course of depression in women. CONCLUSION: There were few significant sex differences in the course of major depressive disorder in this study population.

Childhood trauma and dissociative symptoms in panic disorder.

OBJECTIVE: Childhood trauma has been associated with increased risk for both panic disorder and dissociative symptoms in adulthood. The authors hypothesized that among individuals with a primary diagnosis of panic disorder, those experiencing depersonalization/derealization during panic attacks would be more likely to have a history of childhood trauma. METHOD: Rates of traumatic events were compared between panic disorder patients with (N=34) and without (N=40) prominent depersonalization/derealization during panic attacks. Symptom severity in the two groups was also examined. RESULTS: Contrary to the authors' hypothesis, no evidence was found that depersonalization/derealization during panic attacks was associated with childhood trauma. Minimal differences in severity of illness were found between patients with dissociative symptoms and those without such symptoms. CONCLUSIONS: This finding is consistent with a multifactorial model of dissociation. Factors other than childhood trauma and general psychopathology may underlie vulnerability to dissociative symptoms in panic disorder.

Origin and identification of fibers in the cranial nerve IX-X complex of Xenopus laevis: Lucifer Yellow backfills in vitro.

The central projections of individual components of the IX-X nerve complex in the South African clawed frog, Xenopus laevis, were mapped by dye diffusion with Lucifer Yellow in an isolated brain preparation. The method reliably revealed fiber tracts, termination zones, and detailed cell morphology. In addition, motor neurons could be doubly labelled by retrograde transport of horseradish peroxidase from muscle targets followed by backfilling the appropriate nerves with Lucifer Yellow. The most anterior root associated with the nerve IX-X complex, root 1, is composed of lateral line afferents that terminate in the medial medulla. Root 2 contains sensory fibers that terminate in the nucleus tractus solitarii and axons of lateral line efferent neurons. Root 3 is composed of sensory and motor fibers, including a major somatosensory component that terminates in posterior medulla and anterior spinal cord, and axons from cranial nerve nucleus IX-X. The most posterior root of the IX-X nerve complex, root 4, contains axons of laryngeal motor neurons and of general visceral efferent neurons.

Cognitive-behavioral therapy as an adjunct to serotonin reuptake inhibitors in obsessive-compulsive disorder: an open trial.

BACKGROUND: We report the results of an open trial of cognitive-behavioral therapy (CBT) using exposure and ritual prevention as an adjunct to serotonin reuptake inhibitors (SRIs) in obsessive-compulsive disorder (OCD). We hypothesized that exposure and ritual prevention would significantly reduce OCD symptoms in patients who remained symptomatic despite an adequate trial of an SRI and enable patients to discontinue their medication. METHOD: OCD patients taking an adequate dose of an SRI > or = 12 weeks who remained symptomatic (i.e., a Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score > or = 16) were eligible. While taking a stable dose of an SRI, patients received 17 sessions of exposure and ritual prevention. For the intent-to-treat group, the paired t test was used to compare scores on the Y-BOCS, the National Institute of Mental Health (NIMH) Global OCD scale, the Clinical Global Impressions scale, and the Hamilton Rating Scale for Depression before and after exposure and ritual prevention. RESULTS: Six of 7 eligible patients entered the study, and 5 completed it. All 6 improved on all OCD measures. The mean +/- SD Y-BOCS score was 23.8 +/- 2.6 prior to exposure and ritual prevention and 12.2 +/- 4.3 after it (p < .001). The mean percentage decrease on the Y-BOCS was 49% (range, 26%-61%). Patients were rated by the therapist and rated themselves as much (N = 4) or very much (N = 2) improved. Blood drug levels did not change in most patients during exposure and ritual prevention; thus, the improvement was attributed to this type of therapy. No patients discontinued their medication. CONCLUSION: This open trial suggests that CBT using exposure and ritual prevention can lead to a significant reduction in OCD symptoms in patients who remain symptomatic despite an adequate trial of an SRI.

Symptom provocation alters behavioral ratings and brain electrical activity in obsessive-compulsive disorder: a preliminary study.

Regional brain activity was measured using quantitative electroencephalography (EEG) in six patients with obsessive-compulsive disorder (OCD) during live and imaginal exposure to feared contaminants. OCD symptoms increased significantly from baseline levels during live and imaginal exposures. However, live exposure provoked significantly more OCD symptoms than imaginal exposure. There was a significant change in the anterior-to-posterior scalp distribution of alpha power during live exposure. These preliminary results suggest that: (1) live exposure is more effective than imaginal exposure in altering behavioral and electrophysiological measures; and (2) live exposure is associated with regional EEG changes in OCD.

Obsessive-compulsive disorder: an overview.

In this article, which is the first in a three-part series, the authors provide an overview of the current state of our knowledge of the phenomenology, etiology, and diagnosis of OCD. The DSM-IV criteria for OCD are presented and explicated. Disorders that are commonly comorbid with OCD (e.g., major depressive disorder, other anxiety dis-orders, Tourette's disorder) are described. The authors also discuss disorders such as body dysmorphic disorder that may be related to OCD and are often termed OCD spectrum disorders. OCD is likely to have multiple causes and the authors discuss behavioral, neuroanatomical, and neurochemical theories of OCD. Two treatments have demonstrated efficacy in OCD, cognitive-behavioral therapy and pharmacotherapy with serotonergic reuptake inhibitors, and the authors discuss how these treatments may work in light of what is known about the etiology of the disorder. The different subtypes of OCD that have been proposed are described along with their implications for treatment. The article concludes with a discussion of diagnosis that provides specific guidance for the clinician on how to assess a patient for possible OCD. The next two articles in this series will cover cognitive-behavioral and medication treatment in detail.

Brain pathways for learned and unlearned vocalizations differ in zebra finches.

Male zebra finches sing, females do not. However, both sexes produce the "long call" when placed in visual isolation. This call is sexually dimorphic; it includes learned components in males but not in females. The 3 learned features of the male long call are a high fundamental frequency, a fast frequency modulation, and a short, stable duration. These features are learned by the male during development, as is song. Since similar features are also found in song syllables, we wanted to know whether long-call production depends on the same CNS pathway that controls song production. Three critical components of the song pathway are telencephalic nuclei HVC, RA, and the tracheosyringeal (ts) nerves innervating the syrinx. In male zebra finches, bilateral section of the ts nerves affected the fundamental frequency and fast frequency modulations of both the long call and song but left the temporal features intact. Ts nerve section had no effect on the female long call. Bilateral lesions of either HVC or RA in males affected the fundamental frequency, fast frequency modulations, and temporal structure of both the long call and song. Similar lesions had no effect on the female long call. These results demonstrate that HVC, RA, and the ts nerves make critical contributions to the acoustic features of the male long call and song, while the temporal pattern depends on HVC and RA but not the ts nerves. HVC and RA lesions remove all the learned features that distinguish the male call and reveal a simple unlearned vocalization shared by both sexes. We suggest that the learned features of oscine songbird vocalizations are controlled by a telencephalic pathway that acts in concert with other pathways responsible for simpler, unlearned vocalizations.

Early estrogen treatment alone causes female zebra finches to produce learned, male-like vocalizations.

The male zebra finch produces learned song and long calls while the female does not. This difference in behavior is believed to result from the action of sex steroids on brain areas responsible for vocal production and learning. In this study, the female zebra finch was used to explore further the specific role sex steroids play in vocal masculinization. We show that estradiol (E2) treatment at birth was sufficient to masculinize the vocal behavior of female zebra finches. Thirteen of 18 females treated with E2 as nestlings produced song-like vocalizations. Fifteen of 18 produced long calls with male-typical features. The degree of masculinization varied between individuals. Of the 15 early E2 females that produced at least one type of male-like vocalization, 7 showed evidence of vocal learning from their tutors. The ability of E2 to cause masculinization of vocal behavior was age dependent: treatment from birth was most effective, treatment at 20 days of age was partially effective, and treatment in adulthood was ineffective. The effect of subsequent testosterone exposure in adulthood differed depending on the quality of the vocalization produced after E2 treatment alone. These results suggest that E2 may play a more important role than previously thought in the development of sex differences in vocal behavior. Furthermore, this study demonstrates that exogenous E2 treatment alone can induce vocal learning.

Early estrogen treatment of female zebra finches masculinizes the brain pathway for learned vocalizations.

Telencephalic nucleus HVC and its two efferent targets, RA and X, play essential roles in the production of complex, learned vocalizations in the male zebra finch. Normal females do not produce these learned vocalizations; HVC, RA, and X are small in volume, and HVC and RA are not synaptically connected. We have shown that estrogen treatment during development causes females to learn and produce male-like vocalizations. This article describes the neural masculinization of these E2 females, replicating and extending the work of others. Female zebra finches were treated with 17 beta-estradiol (E2) at hatching, at 14-22 days of age, or as adults. In adulthood, the volumes of nucleus RA and area X were measured and the efferent projections of nucleus HVC examined using the anterograde tracer PHA-L. Early, sustained E2 treatment caused the greatest increase in the volume of RA and X, the innervation of RA and X by HVC axons, and the masculinization of auditory responses of cells in RA. Treatments that lasted for a shorter period or started later in development resulted in different patterns of partial brain masculinization. E2 treatment in adulthood had no effect on the volume of RA or X or their innervation by HVC. Bilateral lesions of the tracheosyringeal nerves or of HVC had the same effects on the male-typical vocalizations produced by E2 females as they do on the vocalizations produced by males. These results demonstrate that the neural masculinization of telencephalic nuclei induced by E2 treatment sets up a functional circuit in females similar to one in males that enables the learning and production of complex vocalizations.

Electrical stimulation in forebrain nuclei elicits learned vocal patterns in songbirds.

1. Microstimulation (trains of biphasic current pulses at 50-400 Hz lasting 2-4 s) was delivered unilaterally to known vocal control areas in the brains of zebra finches and canaries to elicit vocalizations. 2. Simple vocalizations were elicited from the midbrain, and the lowest thresholds were obtained from the dorsomedial nucleus of the intercollicular complex (DM). 3. Vocalizations elicited from forebrain vocal control nuclei higher vocal center (HVC) and robustus archistriatalis (RA) were complex, with features specific not only to the species, but to the individual bird's own learned song. 4. Complex acoustic features depended on innervation of the bird's vocal organ and were lost when the tracheosyringeal nerve was cut. 5. We suggest that stimulation of the forebrain vocal pathway activates a dedicated neural circuit that generates the temporal structure of song and whose specific pattern of activity is programmed during sensorimotor learning in each individual.

General principles in the pharmacotherapy of antidepressant-induced rapid cycling: a case series.

The treatment of depression in patients who rapidly cycle once they receive antidepressant medication is a difficult clinical problem. Hurowitz and Liebowitz presented six patients with antidepressant-induced rapid cycling and proposed guidelines for how to manage medications in these patients. In this article, we present six new cases of antidepressant-induced rapid cycling as well as follow-up from four of the previous cases. We conclude that DSM-IV criteria are not sufficiently sensitive to diagnose antidepressant-induced rapid cycling and that the treatment guidelines of Hurowitz and Liebowitz, although not foolproof, are useful. General recommendations for treating patients with antidepressant-induced rapid cycling are discussed.

The relationship between perception and production in songbird vocal imitation: what learned calls can teach us.

Songbirds produce calls as well as song. This paper summarizes four studies of the zebra finch long call, used by both sexes in similar behavioral contexts. Female long calls are acoustically simpler than male long calls, which include acoustic features learned during development. Production of these male-typical features requires an intact nucleus robustus archistriatalis, the sexually-dimorphic source of the telencephalic projection to brainstem vocal effectors. In experiments that quantified the long calls produced in response to long call playbacks, intact adult zebra finch males, but not females, show a categorical preference for the long calls of females over those of males. Experiments with synthetic stimuli showed that males classify long call stimuli that they hear by gender, using both spectral and temporal information, but that females use only temporal information. Juvenile males (<45 days) did not show the categorical preference, but it emerged during the same period when the robustus archistriatalis matures anatomically and the first male-typical vocalizations are produced. Adult males with robustus archistriatalis lesions lost the categorical preference for female long calls, suggesting that the robustus archistriatalis plays a role in long call discrimination. These results demonstrate that calls complement song as a potent tool for studying the neurobiology of vocal communication.

Hormonal influences on natal dispersal in free-living Belding's ground squirrels (Spermophilus beldingi).

Preliminary identification of the physiological causes of natal dispersal in two populations of free-living Belding's ground squirrels (Spermophilus beldingi) was attempted in the Sierra Nevada of California. Two competing hypotheses, each suggesting a different endocrinological cause for natal dispersal in this species were tested. Data collected by observation, trapping, and telemetry during three field seasons (1979-1981) contradict predictions of the hypothesis that concurrent, high levels of circulating gonadal steroids cause natal dispersal. Rather the data suggest that perinatal exposure to androgen subsequently results in dispersal of treated individuals. The hormone may promote dispersal behavior through its mediating effects on juveniles' exploratory and social behaviors, and on their responsiveness to frightening stimuli. Possible interactions of endocrine mechanisms with other proximal and ultimate causes of dispersal are discussed.

Imipramine in the treatment of social phobia.

We report the results of an 8-week open trial of imipramine in 15 patients with social phobia. Nine patients completed the trial; six dropped out early because of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was 15% and 18% for the intent-to-treat and completer groups, respectively; the overall response rate (based on the Clinical Global Impression Scale of 1 or 2, very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The results from this open trial do not support the efficacy of imipramine as a treatment for social phobia.