Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis.

Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.

Gender differences in alpha-[(11)C]MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: a positron emission tomography study.

Women are at higher risk than men for developing major depressive disorder (MDD), but the mechanisms underlying this higher risk are unknown. Here, we report proportionally normalized alpha-[(11)C]methyl-L-tryptophan brain trapping constant (alpha-[(11)C]MTrp K*(N)), an index of serotonin synthesis, in 25 medication-free individuals with MDD and in 25 gender- and age-matched healthy subjects who were studied using positron emission tomography (PET). Comparisons of alpha-[(11)C]MTrp K*(N) values between the men and women were conducted at the voxel and cluster levels using Statistical Parametric Mapping 2 (SPM2) analysis. In addition, the alpha-[(11)C]MTrp K*(N) values on both sides of the brain were extracted and compared to identify the left to right differences, as well as the gender differences. Women with MDD displayed higher alpha-[(11)C]MTrp K*(N) than men in the inferior frontal gyrus, anterior cingulate cortex (ACC), parahippocampal gyrus, precuneus, superior parietal lobule, and occipital lingual gyrus. In a matched group of normal subjects the gender differences were opposite from those found in MDD patients. Significant hemispheric differences in fronto-limbic structures between men and women with MDD were also observed. The K*(N) extracted from the volumes identified in MDD patients and in male and female normal subjects suggested no significant differences between males and females. In conclusion, depressed women have higher serotonin synthesis in multiple regions of the prefrontal cortex and limbic system involved with mood regulation, as compared with depressed men. Gender differences in brain serotonin synthesis may be related to higher risk for MDD in women.

Alterations in brain serotonin synthesis in male alcoholics measured using positron emission tomography.

BACKGROUND: A consistent association between low endogenous 5HT function and high alcohol preference has been observed, and a number of serotonergic manipulations (uptake blockers, agonists) alter alcohol consumption in animals and humans. Studies have also shown an inverse relationship between alcohol use and cerebrospinal fluid levels of serotonin metabolites, suggesting that chronic alcohol consumption produces alterations in serotonin synthesis or release. METHODS: The objective of the study was to characterize regional brain serotonin synthesis in nondepressed chronic alcoholics at treatment entry in comparison to normal nonalcoholic controls using PET and the tracer alpha-[(11)C]-methyl-L-tryptophan. RESULTS: Comparisons of the alcoholics and controls by SPM found that there were significant differences in the rate of serotonin synthesis between groups. Serotonin synthesis was significantly lower among alcoholics in Brodmann Area (BA) 9, 10, and 32. However, serotonin synthesis among the alcoholics group was significantly higher than controls at BA19 in the occipital lobe and around the transverse temporal convolution in the left superior temporal gyrus (BA41). In addition, there were correlations between regional serotonin synthesis and a quantity-frequency measure of alcohol consumption. Regions showing a significant negative correlation with QF included the bilateral rectus gyri (BA11) in the orbitofrontal area, the bilateral medial frontal area (BA6), and the right amygdala. CONCLUSIONS: Current alcoholism is associated with serotonergic abnormalities in brain regions that are known to be involved in planning, judgment, self-control, and emotional regulation.

Cerebral glucose metabolism associated with a fear network in panic disorder.

The present study was performed to assess cerebral glucose metabolism in patients with panic disorder using positron emission tomography. F-fluorodeoxyglucose positron emission tomography with voxel-based analysis was used to compare regional brain glucose utilization in 12 nonmedicated panic disorder patients, without their experiencing panic attacks during positron emission tomography acquisition, with that in 22 healthy controls. Panic disorder patients showed appreciably high state anxiety before scanning, and exhibited significantly higher levels of glucose uptake in the bilateral amygdala, hippocampus, and thalamus, and in the midbrain, caudal pons, medulla, and cerebellum than controls. These results provided the first functional neuroimaging support in human patients for the neuroanatomical hypothesis of panic disorder focusing on the amygdala-based fear network.

Brain regional alpha-[11C]methyl-L-tryptophan trapping, used as an index of 5-HT synthesis, in healthy adults: absence of an age effect.

PURPOSE: Previous functional neuroimaging studies suggest that selective aspects of the brain serotonin (5-HT) system change during the aging process. Here, we assessed the effects of aging on the brain regional alpha-[(11)C]methyl-L: -tryptophan (alpha-[(11)C]MTrp) trapping rate constant (K*; microl.g(-1).min(-1)), which, with certain assumptions, could be taken as a proxy of 5-HT synthesis. METHODS: Thirty-six healthy right-handed subjects had positron emission tomography (PET) scans following injection with alpha-[(11)C]MTrp [18 males aged 46.6 +/- 22.2 years (range 20-80 years) and 18 females aged 33.0 +/- 15.5 years (range 20-80 years)]. The trapping rate constant, K*, was calculated with the graphical method for irreversible ligands using the sinus-venous input function. A priori selected volumes of interest (VOIs) were defined using an automatic algorithm. RESULTS: VOI analysis showed no correlation between age and brain regional K* values. As reported by others, significant age-related reductions of gray matter were observed in the thalamus and frontal and cingulate cortices; even with partial volume correction there was still no significant relationship between K* and age. Further exploratory SPM voxelwise correlation between age and alpha-[(11)C]MTrp trapping, using p = 0.05 (uncorrected), as well as voxel-based morphometry, was in agreement with the VOI analysis. CONCLUSION: The dissociation between age-related changes in brain anatomy and this index of serotonin synthesis suggests independent mechanisms underlying the normal aging process.

Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive-behavioral therapy.

Several neuroanatomical hypotheses of panic disorder have been proposed focusing on the significant role of the amygdala and PAG-related "panic neurocircuitry." Although cognitive-behavioral therapy is effective in patients with panic disorder, its therapeutic mechanism of action in the brain remains unclear. The present study was performed to investigate regional brain glucose metabolic changes associated with successful completion of cognitive-behavioral therapy in panic disorder patients. The regional glucose utilization in patients with panic disorder was compared before and after cognitive-behavioral therapy using positron emission tomography with (18)F-fluorodeoxyglucose. In 11 of 12 patients who showed improvement after cognitive-behavioral therapy, decreased glucose utilization was detected in the right hippocampus, left anterior cingulate, left cerebellum, and pons, whereas increased glucose utilization was seen in the bilateral medial prefrontal cortices. Significant correlations were found between the percent change relative to the pretreatment value of glucose utilization in the left medial prefrontal cortex and those of anxiety and agoraphobia-related subscale of the Panic Disorder Severity Scale, and between that of the midbrain and that of the number of panic attacks during the 4 weeks before each scan in all 12 patients. The completion of successful cognitive-behavioral therapy involved not only reduction of the baseline hyperactivity in several brain areas but also adaptive metabolic changes of the bilateral medial prefrontal cortices in panic disorder patients.