A Randomized Controlled Trial of Cognitive Behavioral Group Therapy for Bipolar Disorder

Background: This study evaluated the effectiveness of adjunctive cognitive behavioral group therapy (CBGT) to prevent recurrence of episodes in euthymic patients with bipolar disorder. Methods: A randomized controlled single-blind trial was conducted with 50 patients with bipolar disorder types I and II followed up for at least 12 months in an outpatient service and whose disease was in remission. An experimental CBGT manual was developed and added to treatment as usual (TAU), and results were compared with TAU alone. Results: Intention-to-treat analysis showed that there was no difference between groups in terms of time until any relapse (Wilcoxon = 0.667; p = 0.414). When considering type of relapse, there was still no difference in either depressive (Wilcoxon = 3.328; p = 0.068) or manic episodes (Wilcoxon = 1.498; p = 0.221). Although occurrence of episodes also did not differ between groups (chi(2) = 0.28; p = 0.59), median time to relapse was longer for patients treated with CBGT compared to TAU (Mann-Whitney = -2.554; p = 0.011). Conclusions:Time to recurrence and number of episodes were not different in the group of patients treated with CBGT. However, median time to relapse was shorter in the TAU group. Studies with larger samples may help to clarify whether our CBGT approach prevents new episodes of bipolar disorder. Our findings also indicated that CBGT is feasible in euthymic patients with bipolar disorder and should be investigated in future studies. To our knowledge, this is the first publication of a controlled trial of CBGT for euthymic patients with bipolar disorder. Copyright (C) 2011 S. Karger AG, Basel

A Randomized Clinical Trial to Examine Enhancing Cognitive-Behavioral Group Therapy for Obsessive-Compulsive Disorder with Motivational Interviewing and Thought Mapping

Background: Obsessive-compulsive disorder (OCD) is characterized by repeated and persistent attempts to control thoughts and actions with rituals. These rituals are used in order to prevent feared or personally distressing outcomes. Cognitive behavioral group therapy (CBGT) has been reported to be effective for treating OCD patients. However, about one-third (30%) of patients do not benefit from CBGT. Some of these patients do not show significant improvement and continue to use rituals following CBGT, partially because they fail to complete the exposure and ritual prevention (ERP) exercises. Consequently, it is important to motivate patients to fully engage in CBGT treatment and complete the ERP exercises. Aims: A randomized behavioral trial examined 12 weeks of manual directed CBGT, with the addition of individual sessions of Motivational Interviewing (MI) and Thought Mapping (TM), and compared treatment outcome to the effectiveness of CBGT group alone. Method: Subjects were randomized (n = 93) into a CBGT group or a CBGT group with MI+TM. Results: When the two groups were compared, both groups reduced OCD symptoms. However, symptom reduction and remission were significantly higher in the MI+TM CBGT group. Positive outcomes were also maintained, with additional symptom reduction at the 3-month follow-up for the MI TM CBGT group. Conclusions: Adding two individual sessions of MI and TM before CBGT successfully reduced OCD symptoms and was more effective than using CBGT group alone.

Assessment of Personality Dimensions in Children and Adolescents with Bipolar Disorder Using the Junior Temperament and Character Inventory

Objective: We compared temperament and character traits in children and adolescents with bipolar disorder (BP) and healthy control (HC) subjects. Method: Sixty nine subjects (38 BP and 31 HC), 8-17 years old, were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime. Temperament and character traits were measured with parent and child versions of the Junior Temperament and Character Inventory. Results: BP subjects scored higher on novelty seeking, harm avoidance, and fantasy subscales, and lower on reward dependence, persistence, self-directedness, and cooperativeness compared to HC(all p < 0.007), by child and parent reports. These findings were consistent in both children and adolescents. Higher parent-rated novelty seeking, lower self-directedness, and lower cooperativeness were associated with co-morbid attention-deficit/hyperactivity disorder (ADHD). Lower parent-rated reward dependence was associated with co-morbid conduct disorder, and higher child-rated persistence was associated with co-morbid anxiety. Conclusions: These findings support previous reports of differences in temperament in BP children and adolescents and may assist in a greater understating of BP children and adolescents beyond mood symptomatology.

Temporomandibular Disorder in Brazilian Patients: A Preliminary Study

The objective of the current study was to evaluate disease-related beliefs, adherence to treatment, quality of life, coping strategies and cognitive status in a group of Brazilian patients with Temporomandibular Disorder (TMD). Thirty patients were evaluated with a semi-directed interview, the Coping Strategies Inventory, and a Mini-Mental State Examination. Although half (50%) of the patients had known their diagnosis long term, 40% of the sample were not correctly following proposed treatment. All patients had a similar pattern of pain behavior related to TMD, while disease-related beliefs, quality of life and coping strategies were variable. Expectations about treatment also had significant association with treatment adherence. The findings of this study suggest that a more thorough understanding of individual differences in TMD is warranted.

Platelet GSK3B activity in patients with late-life depression: Marker of depressive episode severity and cognitive impairment?

Objective. Increased GSK3B activity has been reported as a state marker of major affective episodes in patients with depression and bipolar disorder. No study so far has addressed GSK3B activity in late-life depression. The aims of the present study were to determine GSK3B activity in platelets of elderly patients with major depression, and the association between GSK3B activity and the severity of depressive symptoms and cognitive impairment. Methods. Forty drug-free elderly patients with major depressive episode were compared to healthy older adults (n == 13). Severity of the depressive episode and current cognitive state were determined by the Hamilton Depression Scale (HAM-D) and the Cambridge Cognitive Test (CAMCOG), respectively. Total- and ser-9-phosphorylated GSK3B (tGSK3B and pGSK3B) were determined in platelets by enzyme immunometric assays (EIA). GSK3B activity was indirectly inferred by the GSK3B ratio (i.e. pGSK3B/tGSK3B). Results. Elderly depressed patients had significantly lower pGSK3B levels (P == 0.03) and GSK3B ratio (P == 0.03), indicating higher GSK3B activity. Higher GSK3B activity were observed in patients with severe depressive episode (HAM-D scores > 22, P == 0.03) and with cognitive impairment (CAMCOG scores < 86, P == 0.01). Conclusion. The present findings provide additional evidence of the involvement of GSK3B in the pathophysiology of late-life major depression. Higher GSK3B activity may be more relevant in those patients with more severe depressive symptoms and cognitive impairment.

Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report

Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naive patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.

Cognitive functioning in subjects with recent-onset psychosis from a low-middle-income environment: Multiple-domain deficits and longitudinal evaluation

Cognitive deficits are a key feature of recent-onset psychosis, but there is no consensus on whether such deficits are generalized or confined to specific domains. Besides, it is unclear whether cognitive deficits: a) are found in psychotic patients in samples from outside high-income countries; and b) whether they progress uniformly over time in schizophrenia and affective psychoses. We applied 12 tests organized into eight cognitive domains, comparing psychosis patients (n = 56, time from initial contact = 677.95+/-183.27 days) versus healthy controls (n = 70) recruited from the same area of Sao Paulo, Brazil. Longitudinal comparisons (digit span and verbal fluency) were conducted between a previous assessment of the subjects carried out at their psychosis onset, and the current follow-up evaluation. Psychosis patients differed significantly from controls on five domains, most prominently on verbal memory. Cognitive deficits remained detectable in separate comparisons of the schizophrenia subgroup and, to a lesser extent, the affective psychosis subjects against controls. Longitudinal comparisons indicated significant improvement in schizophrenia, affective psychoses, and control subjects, with no significant group-by-time interactions. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non-affective nature, which persist over time. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

(1)H magnetic resonance spectroscopy imaging of the hippocampus in patients with panic disorder

Recent theories of panic disorder propose an extensive involvement of limbic system structures, such as the hippocampus, in the pathophysiology of this condition. Despite this, no prior study has examined exclusively the hippocampal neurochemistry in this disorder. The current study used proton magnetic resonance spectroscopy imaging ((1)H-MRSI) to examine possible abnormalities in the hippocampus in panic disorder patients. Participants comprised 25 panic patients and 18 psychiatrically healthy controls. N-acetylaspartate (NAA, a putative marker of neuronal viability) and choline (Cho, involved in the synthesis and degradation of cell membranes) levels were quantified relative to creatine (Cr, which is thought to be relatively stable among individuals and in different metabolic condition) in both right and left hippocampi. Compared with controls, panic patients demonstrated significantly lower NAA/Cr in the left hippocampus. No other difference was detected. This result is consistent with previous neuroimaging findings of hippocampal alterations in panic and provides the first neurochemical evidence suggestive of involvement of this structure in the disorder. Moreover, lower left hippocampal NAA/Cr in panic disorder may possibly reflect neuronal loss and/or neuronal metabolic dysfunction, and could be related to a deficit in evaluating ambiguous cues. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Regional gray matter abnormalities in panic disorder: A voxel-based morphometry study

Although abnonnalities in brain structures involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of panic disorder (PD), relatively few studies have made use of voxel-based morphometry (VBM) magnetic resonance imaging (MRI) to determine structural brain abnormalities in PD. We have assessed gray matter volume in 19 PD patients and 20 healthy volunteers using VBM. Images were acquired using a 1.5 T MRI scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. A relative increase in gay matter volume was found in the left insula of PD patients compared with controls. Additional structures showing differential increases were the left superior temporal gyrus, the midbrain, and the pons. A relative gray matter deficit was found in the right anterior cingulate cortex. The insula and anterior cingulate abnormalities may be relevant to the pathophysiology of PD, since these structures participate in the evaluation process that ascribes negative emotional meaning to potentially distressing cognitive and interoceptive sensory information. The abnormal brain stem structures may be involved in the generation of panic attacks. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

A NEUROECONOMIC MODELING OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)

In this paper we present a new neuroeconomics model for decision-making applied to the Attention-Deficit/Hyperactivity Disorder (ADHD). The model is based on the hypothesis that decision-making is dependent on the evaluation of expected rewards and risks assessed simultaneously in two decision spaces: the personal (PDS) and the interpersonal emotional spaces (IDS). Motivation to act is triggered by necessities identified in PDS or IDS. The adequacy of an action in fulfilling a given necessity is assumed to be dependent on the expected reward and risk evaluated in the decision spaces. Conflict generated by expected reward and risk influences the easiness (cognitive effort) and the future perspective of the decision-making. Finally, the willingness (not) to act is proposed to be a function of the expected reward (or risk), adequacy, easiness and future perspective. The two most frequent clinical forms are ADHD hyperactive (AD/HDhyp) and ADHD inattentive (AD/HDdin). AD/HDhyp behavior is hypothesized to be a consequence of experiencing high rewarding expectancies for short periods of time, low risk evaluation, and short future perspective for decision-making. AD/HDin is hypothesized to be a consequence of experiencing high rewarding expectancies for long periods of time, low risk evaluation, and long future perspective for decision-making.

Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment

Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer`s disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2 +/- 210.5; 581.9 +/- 379.4; and 777.5 +/- 467.8 pg/l respectively; P < 0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8 +/- 463.0; stable MCI, 724.0 +/- 343.4; P = 0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR = 3.0 CI(95%) [1.2-7.8], P = 0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR = 4.4 CI(95%) [1.6-12.1], P = 0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.

Noninvasive Brain Stimulation With High-Frequency and Low-Intensity Repetitive Transcranial Magnetic Stimulation Treatment for Posttraumatic Stress Disorder

Objective: We aimed to investigate the efficacy of 20 Hz repetitive transcranial magnetic stimulation (rTMS) of either right or left dorsolateral prefrontal cortex (DLPFC) as compared to sham rTMS for the relief of posttraumatic stress disorder (PTSD)-associated symptoms. Method: In this double-blind, placebo-controlled phase II trial conducted between October 2005 and July 2008, 30 patients with DSM-IV-diagnosed PTSD were randomly assigned to receive 1 of the following treatments: active 20 Hz rTMS of the right DLPFC, active 20 Hz rTMS of the left DLPFC, or sham rTMS. Treatments were administered in 10 daily sessions over 2 weeks. A blinded rater assessed severity of core PTSD symptoms, depression, and anxiety before, during, and after completion of the treatment protocol. In addition, a battery of neuropsychological tests was measured before and after treatment. Results: Results show that both active conditions-20 Hz rTMS of left and right DLPFC induced a significant decrease in PTSD symptoms as indexed by the PTSD Checklist and Treatment Outcome PTSD Scale; however, right rTMS induced a larger effect as compared to left rTMS. In addition, there was a significant improvement of mood after left rTMS and a significant reduction of anxiety following right rTMS. Improvements in PTSD symptoms were long lasting; effects were still significant at the 3-month follow-up. Finally, neuropsychological evaluation showed that active 20 Hz rTMS is not associated with cognitive worsening and is safe for use in patients with PTSD. Conclusions: These results support the notion that modulation of prefrontal cortex can alleviate the core symptoms of PTSD and suggest that high-frequency rTMS of right DLPFC might be the optimal treatment strategy. J an Psychiatry 2010;71(8):992-999 (C) Copyright 2009 Physicians Postgraduate Press, Inc.

The impact of trauma and post-traumatic stress disorder on the treatment response of patients with obsessive-compulsive disorder

Few case series studies have addressed the issue of treatment response in patients with obsessive-compulsive disorder (OCD) and comorbid post-traumatic stress disorder (PTSD), and there are no prospective studies addressing response to conventional treatment in OCD patients with a history of trauma (HT). The present study aimed to investigate, prospectively, the impact of HT or PTSD on two systematic, first-line treatments for OCD. Two hundred and nineteen non-treatment-resistant OCD outpatients were treated with either group cognitive-behavioral therapy (GCBT n = 147) or monotherapy with a selective serotonin reuptake inhibitor (SSRI n = 72). Presence of HT and PTSD were assessed at intake, as part of a broader clinical and demographical baseline characterization of the sample. Severity and types of OCD symptoms were assessed with the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and the Dimensional YBOCS (DYBOCS), respectively. Depression and anxiety symptoms were measured with the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). Both treatments had 12-week duration. Treatment response was considered as a categorical [35% or greater reduction in baseline YBOCS scores plus a Clinical Global Impression-Improvement rating of better (2) or much better (1)] and continuous variable (absolute number reduction in baseline YBOCS scores). Treatment response was compared between the OCD + HT group versus the OCD without HT group and between the OCD + PTSD group versus the OCD without PTSD group. Parametric and non-parametric tests were used when indicated. Data on HT and PTSD were available for 215 subjects. Thirty-eight subjects (17.67% of the whole sample) had a positive HT (OCD + HT group) and 22 subjects (57.89% of the OCD + HT group and 10.23% of the whole sample) met full DSM-IV criteria for PTSD. The OCD + HT and OCD without HT groups presented similar response to GCBT (60% of responders in the first group and 63% of responders in the second group, p = 1.00). Regarding SSRI treatment, the difference between the response of the OCD + HT (47.4%) and OCD without HT (22.2%) groups was marginally significant (p = 0.07). In addition, the OCD + PTSD group presented a greater treatment response than the OCD without PTSD group when treatment response was considered as a continuous variable (p = 0.01). The age when the first trauma occurred had no impact on treatment response. In terms of specific OCD symptom dimensions, as measured by the DYBOCS, OCD treatment fostered greater reductions for the OCD + PTSD group than for the OCD without PTSD group in the scores of contamination obsessions and cleaning compulsions, collecting and hoarding and miscellaneous obsessions and related compulsions (including illness concerns and mental rituals, among others). The OCD + PTSD group also presented a greater reduction in anxiety scores than the OCD without PTSD group (p = 0.003). The presence of HT or PTSD was not related to a poorer treatment response in this sample of non-treatment-resistant OCD patients. Unexpectedly, OCD patients with PTSD presented a greater magnitude of response when compared with OCD without PTSD patients in specific OCD symptom dimensions. Future studies are needed to clarify if trauma and PTSD have a more significant impact on the onset and clinical expression of OCD than on the conventional treatment for this condition, and whether OCD stemming from trauma would constitute a subtype of OCD with a distinct response to conventional treatment.

Apolipoprotein E genotype and Cognition in Bipolar Disorder

Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimer`s Disease (AD). APOE allele *3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the *4 allele is a well-established risk factor for CD, while the *2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD-type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18-35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele *2 presented better cognitive performance. The presence of allele *4 was associated with worse performance in a few executive tasks. APOE *3*3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD-type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.

Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder

Emotional liability and mood dysregulation characterize bipolar disorder (BID), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18-56 years): 21 with a DSM-IV diagnosis of BID, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (I)CM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG-sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG-sgCG signaling in BD than HC. There was no between-group difference in sgCG-DLPFC effective connectivity. In BD, abnormally increased right PHG-sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.