Anxiety Disorders: Fineberg N

Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ, Anonymous00037, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J. · Department of Psychiatry and Psychotherapy, University of Gottingen, Gottingen, Germany. · World J Biol Psychiatry. · Pubmed #18949648 No free full text.

Abstract: In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Stein DJ, Carey PD, Lochner C, Seedat S, Fineberg N, Andersen EW. · Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. · CNS Spectr. · Pubmed #18567973 links to  free full text

Abstract: INTRODUCTION: There is a substantial body of evidence that obsessive-compulsive disorder (OCD) symptoms can be grouped into a series of discrete dimensions, and some evidence that not all OCD symptom dimensions respond equally well to pharmacologic or psychotherapeutic intervention. The response of OCD symptom dimensions to 12 weeks of treatment with escitalopram or placebo was investigated. METHODS: Data from a randomized, double-blind, placebo-controlled study of escitalopram in 466 adults with OCD were analyzed. Exploratory factor analysis of individual items of the Yale-Brown Obsessive-Compulsive Scale checklist was performed and subscale scores based on the extracted factors were determined. Analyses of covariance were undertaken to determine whether inclusion of each subscale score in these models impacted on the efficacy of escitalopram versus placebo. RESULTS: Exploratory factor analysis of individual Yale-Brown Obsessive-Compulsive Scale items yielded 5 factors (contamination/cleaning, harm/checking, hoarding/symmetry, religious/sexual, and somatic/hypochondriacal). Analyses of covariance including all the subscales demonstrated that escitalopram was more effective than placebo. There was a significant interaction for the hoarding/symmetry factor, which was associated with a poor treatment response. CONCLUSION: Escitalopram shows good efficacy across the range of OCD symptom dimensions. Nevertheless, hoarding/symmetry was associated with a poorer treatment response. Hoarding/symmetry may be particularly characteristic of an early-onset group of OCD patients, with the involvement of neurotransmitters other than serotonin. Further work is needed to delineate fully the subtypes of OCD, and their correlates with underlying psychobiology and treatment responsivity.

Menzies L, Williams GB, Chamberlain SR, Ooi C, Fineberg N, Suckling J, Sahakian BJ, Robbins TW, Bullmore ET. · Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB22QQ, UK. · Am J Psychiatry. · Pubmed #18519525 No free full text.

Abstract: OBJECTIVE: Obsessive-compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysconnectivity of large-scale brain systems. The extent of white matter abnormalities in OCD is unknown, and the genetic basis of this disorder is poorly understood. The authors used diffusion tensor imaging, a magnetic resonance imaging technique, for examining white matter abnormalities in brain structure through quantification of water diffusion, to confirm whether white matter abnormalities exist in OCD. They also explored whether such abnormalities occur in healthy first-degree relatives of patients, indicating they may be endophenotypes representing increased genetic risk for OCD. METHOD: The authors used diffusion tensor imaging to measure fractional anisotropy of white matter in 30 patients with OCD, 30 unaffected first-degree relatives, and 30 matched healthy comparison subjects. Regions of significantly abnormal fractional anisotropy in patients in relation to healthy comparison subjects were identified by permutation tests. The authors assessed whether these abnormalities were also evident in the first-degree relatives. A secondary region-of-interest analysis was undertaken to assess the extent of replication between our data and previous relevant literature. RESULTS: Patients with OCD demonstrated significantly reduced fractional anisotropy in a large region of right inferior parietal white matter and significantly increased fractional anisotropy in a right medial frontal region. Relatives also exhibited significant abnormalities of fractional anisotropy in these regions. CONCLUSIONS: These findings indicate that OCD is associated with white matter abnormalities in parietal and frontal regions. Similar abnormalities in unaffected first-degree relatives suggest these may be white matter endophenotypes for OCD.

Menzies L, Achard S, Chamberlain SR, Fineberg N, Chen CH, del Campo N, Sahakian BJ, Robbins TW, Bullmore E. · Brain Mapping Unit, University of Cambridge, Cambridge, UK. · Brain. · Pubmed #17855376 links to  free full text

Abstract: Endophenotypes (intermediate phenotypes) are objective, heritable, quantitative traits hypothesized to represent genetic risk for polygenic disorders at more biologically tractable levels than distal behavioural and clinical phenotypes. It is theorized that endophenotype models of disease will help to clarify both diagnostic classification and aetiological understanding of complex brain disorders such as obsessive-compulsive disorder (OCD). To investigate endophenotypes in OCD, we measured brain structure using magnetic resonance imaging (MRI), and behavioural performance on a response inhibition task (Stop-Signal) in 31 OCD patients, 31 of their unaffected first-degree relatives, and 31 unrelated matched controls. Both patients and relatives had delayed response inhibition on the Stop-Signal task compared with healthy controls. We used a multivoxel analysis method (partial least squares) to identify large-scale brain systems in which anatomical variation was associated with variation in performance on the response inhibition task. Behavioural impairment on the Stop-Signal task, occurring predominantly in patients and relatives, was significantly associated with reduced grey matter in orbitofrontal and right inferior frontal regions and increased grey matter in cingulate, parietal and striatal regions. A novel permutation test indicated significant familial effects on variation of the MRI markers of inhibitory processing, supporting the candidacy of these brain structural systems as endophenotypes of OCD. In summary, structural variation in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCD, representing the first evidence for a neurocognitive endophenotype of OCD.

Simpson J, Cove J, Fineberg N, Msetfi RM, J Ball L. · Department of Clinical Psychology, Lancaster University, Lancaster, UK. · Br J Clin Psychol. · Pubmed #17651534 No free full text.

Abstract: OBJECTIVES: The aim of this study was to investigate the inductive and deductive reasoning abilities of people with obsessive-compulsive disorder (OCD). Following previous research, it was predicted that people with OCD would show different abilities on inductive reasoning tasks but similar abilities to controls on deductive reasoning tasks. DESIGN: A two-group comparison was used with both groups matched on a range of demographic variables. Where appropriate, unmatched variables were entered into the analyses as covariates. METHODS: Twenty-three people with OCD and 25 control participants were assessed on two tasks: an inductive reasoning task (the 20-questions task) and a deductive reasoning task (a syllogistic reasoning task with a content-neutral and content-emotional manipulation). RESULTS: While no group differences emerged on several of the parameters of the inductive reasoning task, the OCD group did differ on one, and arguably the most important, parameter by asking fewer correct direct-hypothesis questions. The syllogistic reasoning task results were analysed using both correct response and conclusion acceptance data. While no main effects of group were evident, significant interactions indicated important differences in the way the OCD group reasoned with content neutral and emotional syllogisms. CONCLUSIONS: It was argued that the OCD group's patterns of response on both tasks were characterized by the need for more information, states of uncertainty, and doubt and postponement of a final decision.

Stein DJ, Andersen EW, Tonnoir B, Fineberg N. · University of Cape Town, Republic of South Africa. · Curr Med Res Opin. · Pubmed #17407626 No free full text.

Abstract: OBJECTIVE: A randomized, placebo controlled fixed-dose trial was undertaken to determine the efficacy and tolerability of escitalopram in obsessive-compulsive disorder (OCD), using paroxetine as the active reference. RESEARCH DESIGN AND METHODS: A total of 466 adults with OCD from specialized clinical centres, psychiatric hospital departments, psychiatric practices, or general practice were randomized to one of four treatment groups: escitalopram 10 mg/day (n = 116), escitalopram 20 mg/day (n = 116), paroxetine 40 mg/day (n = 119), or placebo (n = 115) for 24 weeks. The primary efficacy endpoint was the mean change in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score from baseline to week 12. Secondary efficacy endpoints included remission (defined as Y-BOCS total score < or =10), NIMH-OCS, and CGI-S and CGI-I scores at weeks 12 and 24. Tolerability was based on the incidence of adverse events, and on changes in vital signs (blood pressure and pulse). Main outcome measures; Results: Escitalopram 20 mg/day was superior to placebo on the primary and all secondary outcome endpoints, including remission. Escitalopram 10 mg/day and paroxetine 40 mg/day were also effective on the primary scale as well as some other outcome measures. In the escitalopram 20 mg/day group, the improvement in Y-BOCS total score was significantly better than in the placebo group as early as week 6. The most common AEs in the active treatment groups were nausea (19-27%), headache (17-22%), and fatigue (12-19%). More paroxetine-treated patients withdrew due to adverse events than escitalopram- or placebo-treated patients. CONCLUSION: Given that escitalopram 20 mg/day was associated with an earlier onset, higher response and remission rates, improved functioning, and better tolerability than the reference drug, escitalopram deserves to be considered as one of the first-line agents in the pharmacotherapy of OCD for longer-term treatment periods.

Pooley EC, Fineberg N, Harrison PJ. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. · Mol Psychiatry. · Pubmed #17264842 No free full text.

Abstract: Existing data suggest a genetic association between the met(158) allele of catechol-O-methyltransferase (COMT) and obsessive-compulsive disorder (OCD). However, the results are inconclusive and complicated by possible gender differences. We sought to resolve the question in two ways. First, we carried out a new case-control study in 87 adults with OCD and 327 healthy comparison subjects. The study replicated reports of an increased met(158) allele frequency in men with OCD (odds ratio (OR)=1.91, 95% confidence interval (CI) 1.07-3.40, P=0.026), with no effect in women (OR=1.13, 95% CI 0.74-1.72, P=0.56). Second, we performed a meta-analysis of all published case-control data (n=1908 subjects). This revealed an association of COMT met(158) with OCD (OR=1.23, 95% CI 1.06-1.42, P=0.005) and an interaction with gender (z=4.27, P<0.0001). The association between COMT met(158) and OCD was present in men (OR=1.88, 95% CI 1.45-2.44, P<0.001) but not in women (OR=0.98, 95% CI 0.78-1.22, P=0.83). We conclude that COMT may play a role in the genetic aetiology of OCD in men. The biological plausibility of the association is increased by the functionality of the val(158)met polymorphism in terms of its effect on COMT enzyme activity, and by the role of COMT in cortical dopamine signalling and information processing. The finding also extends the evidence for sexual dimorphism in COMT and in OCD.

Denys D, Fineberg N, Carey PD, Stein DJ. · The Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands. · Biol Psychiatry. · Pubmed #17241831 No free full text.

Abstract: BACKGROUND: The purpose of this study was to assess the effect of type and dose of serotonin reuptake inhibitors (SRIs) on treatment outcome in quetiapine addition trials for obsessive-compulsive disorder. METHODS: Results from all available, double blind, placebo-controlled quetiapine addition trials were pooled. Treatment outcome was assessed in a sample of 102 patients by change from baseline to end point on the Yale-Brown obsessive-compulsive scale (Y-BOCS). RESULTS: Quetiapine addition was superior with a mean Y-BOCS decrease of 6.8 +/- 6.7 compared with placebo with a decrease of 3.9 +/- 6.5 points. Patients with the lowest SRI dose showed the largest decrease on the Y-BOCS (11.6 +/- 7.7) compared with patients with the median dose (6.1 +/- 6.1) and highest dose (5.9 +/- 6.4). CONCLUSIONS: We found a superior response in the quetiapine addition group compared with the placebo group. The best response was achieved with the combination of clomipramine, fluoxetine, and fluvoxamine and with the lowest SRI doses.