Brain serotonin 1A receptor binding in bulimia nervosa.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the first choice for the pharmacologic treatment of bulimia nervosa, but there are no published data on the putative altered serotonin (5-HT) receptor characteristics in patients with bulimia. Experimental studies suggest that the therapeutic antidepressant effect of SSRIs is mediated via 5-HT(1A) receptors. The aim of this study was to measure brain 5-HT(1A) receptor binding among nonmedicated patients with bulimia nervosa. METHODS: Positron emission tomography (PET) with a selective 5-HT(1A) ligand, [11C]WAY-100635, was performed on eight unmedicated patients with bulimia and 10 healthy comparison subjects. RESULTS: The binding potential values were greater in patients than in control subjects in all brain regions studied. The most robust differences were observed in the angular gyrus, the medial prefrontal cortex, and the posterior cingulate cortex. CONCLUSIONS: These results suggest that brain 5-HT(1A) receptor binding is increased in several cortical areas in patients with bulimia nervosa during their state of impulsive binge eating.     

Pharmacotherapy of social anxiety disorder.

Over the last few years, a number of medications have demonstrated their efficacy in the acute treatment of social anxiety disorder. At present, selective serotonin reuptake inhibitors probably constitute the first line treatment, based on their safety, tolerability, and efficacy in the treatment of social anxiety disorder and common comorbid conditions. Data from single trials suggest that clonazepam, bromazepam, and gabapentin may have efficacy similar to the serotonin reuptake inhibitors, but further studies are needed to confirm these findings. The monoamine oxidase inhibitor phenelzine appears to be at least as efficacious as these other agents, but should be reserved for cases that fail to respond to these safer medications. Among the reversible inhibitors of monoamine oxidase A, brofaromine may also be an effective drug, while moclobemide appears to be less potent.Future research directions should include delineating ways to achieve remission (as opposed to response); developing strategies for augmenting partial responders and treating nonresponders to first line approaches; studying the long-term response to medication and prevention of relapse when medication is discontinued; clarifying ways to integrate psychosocial and pharmacological treatment approaches; developing predictors of which patients do best with which treatments; and the treatment of social anxiety disorder in children and adolescents.     

Decreased 5-HT1A receptor binding in amygdala of schizophrenia.

BACKGROUND: On the basis of postmortem data and the pharmacological action of atypical antipsychotics, serotonin-1A receptors are of interest in the study of the pathophysiology of schizophrenia. To investigate serotonin-1A receptors in schizophrenia and their relation to symptoms, we measured the availability of serotonin-1A receptors in patients with schizophrenia using positron emission tomography with [carbonyl-(11)C]WAY-100635. METHODS: Serotonin-1A receptor binding of 11 patients with schizophrenia (8 drug-naive and 3 drug-free) was compared with that of 22 age-matched and gender-matched healthy control subjects. Symptoms were assessed using the Positive and Negative Syndrome Scale. Serotonin-1A receptor binding in selected regions of interest was quantified by binding potential obtained by the reference tissue method. RESULTS: The regional binding potential value was lower in the amygdala by about 19% in patients with schizophrenia than in normal controls. A significant negative correlation was observed between binding potential in the amygdala and the negative and depression/anxiety symptom scores on the five-symptom subscale of the Positive and Negative Syndrome Scale. CONCLUSIONS: Decreased serotonin-1A receptor binding in the amygdala may underlie the affective components included in the symptoms of negative and depression/anxiety in schizophrenia.     

Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety.

BACKGROUND: The anxious phenotype of the 5-HT1A receptor knockout mouse and the anxiolytic properties of 5-HT1A agonists suggest that the 5-HT1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT1A binding. METHODS: Positron emission tomography with [carbonyl-11C]WAY-100635 was used to estimate regional 5-HT1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT1A BP. RESULTS: Higher psychic (beta >or= .63) and lower somatic (beta 相似文献   

Quantification of 5-HT1A and 5-HT2A receptor Binding in Depressed Suicide Attempters and Non-Attempters

Objective: To determine serotonin system abnormalities related to major depression or previous suicidal behavior.

Methods: [¹¹C]WAY100635, [¹⁸F]altanserin and positron emission tomography were used to compare 5-HT_1A and 5-HT_2A binding in MDD patients divided into eight past suicide attempters (>4yrs prior to scanning) and eight lifetime non-attempters, and both groups were compared to eight healthy volunteers.

Results: The two receptor types differed in binding pattern across brain regions from each other, but there were no differences in binding between healthy volunteers and the two depressed groups or between depressed suicide attempters and non-attempters. No effects of depression severity or lifetime aggression were observed for either receptor.

Conclusion: Limitations of this study include small sample size and absence of high lethality suicide attempts in the depressed attempter group. No trait-like binding correlations with past suicide attempt or current depression were observed. Given the heterogeneity of nonfatal suicidal behavior, a larger sample study emphasizing higher lethality suicide attempts may find the serotonin biological phenotype seen in suicide decedents.     

The experience of disability and quality of life in social anxiety disorder

Although disability is a concept most often associated with role dysfunction, and quality of life is most often associated with life satisfaction, these terms are frequently used interchangeably in the literature. In contrast, this study proposes that disability and quality of life are independent but related constructs. Additionally, we propose that disability partially mediates the relationship between symptoms and quality of life. That is, greater symptoms are associated with more impairment, which is, in turn, associated with less satisfaction with one's life. Ninety-six individuals with social anxiety disorder were given measures of social anxiety symptoms, disability, and quality of life. The results of the study suggest that disability and quality of life are, in fact, distinct concepts, and the experience of disability partially mediates the relationship between a patient's experience of symptoms and his or her perceived life satisfaction.     

Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635.

BACKGROUND: Research from neuroendocrine challenge and other indirect studies has suggested increased central 5-HT function in chronic fatigue syndrome (CFS) and increased 5-HT1A receptor sensitivity. We assessed brain 5-HT1A receptor binding potential directly using the specific radioligand [11C]WAY-100635 and positron emission tomography (PET). METHODS: We selected 10 patients from a tertiary referral clinic who fulfilled the CDC consensus criteria for CFS. To assemble a homogenous group and avoid confounding effects, we enrolled only subjects who were completely medication-free and did not have current comorbid psychiatric illness. We also scanned 10 healthy control subjects. RESULTS: There was a widespread reduction in 5-HT1A receptor binding potential in CFS relative to control subjects. This was particularly marked in the hippocampus bilaterally, where a 23% reduction was observed. CONCLUSIONS: There is evidence of decreased 5-HT1A receptor number or affinity in CFS. This may be a primary feature of CFS, related to the underlying pathophysiology, or a finding secondary to other processes, such as previous depression, other biological changes or the behavioral consequences of CFS.     

Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography.

BACKGROUND: Serotonin 5-HT(2A) receptors play an important role in the regulation of many functions that are disturbed in patients with major depressive disorder. Postmortem and positron emission tomography studies have reported both increased and decreased 5-HT(2A) receptor binding in different limbic and paralimbic regions. METHODS: We conducted a quantitative 5-HT(2A) receptor binding study using positron emission tomography and [(18)F]altanserin of four regions hypothesized to have altered levels of 5-HT(2A) receptors in major depressive disorder. Using a four-compartment model, the 5-HT(2A) receptor distribution was estimated by calculating the regional [(18)F]altanserin k(3)/k(4) ratio in which k(3) is the rate of binding to the receptor and k(4) is the rate of dissociation from the receptor. Forty-six antidepressant-free patients with major depressive disorder and 29 healthy control subjects were enrolled. RESULTS: 5-HT(2A) receptor binding in the hippocampus was reduced by 29% in depressed subjects (p =.004). In other regions, 5-HT(2A) receptor binding was decreased (averaging 15%) but not significantly. Both groups had similar age-dependent decreases in 5-HT(2A) receptors throughout all brain regions. CONCLUSIONS: Altered serotoninergic function in the hippocampus is likely involved in the disturbances of mood regulation in major depressive disorder, although the specific role of the 5-HT(2A) receptor changes is still unclear.     

Mini-SPIN: A brief screening assessment for generalized social anxiety disorder.

The objectives of this study are to develop a brief self-rated screening instrument for generalized social anxiety disorder (GSAD) and to test the efficiency of the instrument. The Social Phobia Inventory (SPIN), a 17-item self-administered scale for GSAD, was given to 263 individuals with GSAD and controls. A subset of three items yielding high sensitivity and specificity for the diagnosis of GSAD was identified. This abbreviated version of the SPIN (Mini-SPIN) was administered to a group of managed care patients in conjunction with an epidemiological study of GSAD. Patients (n = 7,165) were sent a questionnaire comprising the Mini-SPIN and a brief depression screener. Respondents screening positive for GSAD on the Mini-SPIN (n = 344) were interviewed using the social phobia module of the Structured Clinical Interview for DSM-IV (SCID) to verify the diagnosis. A random sample of those who screened negative for GSAD on the Mini-SPIN were administered a similar interview to identify two control groups without GSAD for comparison (n = 673). With this information, the sensitivity, specificity, and positive and negative predictive values for the Mini-SPIN were determined (weighted for sampling). Using a cutoff score of 6 or greater, the Mini-SPIN demonstrated a sensitivity of 88.7%, specificity of 90.0%, positive predictive value of 52.5%, and negative predictive value of 98.5%. The scale possessed 90% accuracy (efficiency) in diagnosing the presence or absence of GSAD in a managed care population. The Mini-SPIN demonstrates good efficiency, supporting its utility as a screening tool for generalized social anxiety disorder.     

Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide.

BACKGROUND: In vivo studies find altered serotonin function associated with aggressive and suicidal behaviors. Postmortem studies also reveal serotonergic alterations in suicide subjects but have not reported on the relationship between aggression and the serotonin system. We measured 5-hydroxytryptamine 2A (5-HT(2A)) receptor binding in prefrontal cortex of suicide and nonsuicide subjects and explored the relationship between 5-HT(2A) receptor binding, lifetime aggression, and suicide. METHODS: The 5-HT(2A) receptor binding in coronal sections of prefrontal cortex was quantified by autoradiography with [(3)H] ketanserin in 37 suicide subjects and 73 nonsuicide subjects. The relationship between [(3)H] ketanserin binding and lifetime aggression, rated on the Brown-Goodwin Aggression History Scale, was assessed controlling for age and sex. RESULTS: In suicide subjects, lifetime aggression scores correlated positively with [(3)H] ketanserin binding in all prefrontal Brodmann areas examined, after adjusting for age and sex. This was not the case in nonsuicide subjects. We found no significant differences in aggression scores or [(3)H] ketanserin binding between the suicide subjects and nonsuicide subjects. CONCLUSIONS: The relationship between aggression and 5-HT(2A) receptor binding in suicide subjects, but not in nonsuicide subjects, may reflect differences in the regulation of the 5-HT(2A) receptor related to suicidal behavior and perhaps other proaggressive changes in brains of suicide subjects.     

Citalopram treatment of social anxiety disorder with comorbid major depression

Treatment of patients with both social anxiety disorder and major depression has been little studied although social anxiety disorder and depression frequently co-occur. Each disorder has been shown to respond to serotonin reuptake inhibitor treatment. Objectives of this study were to characterize a sample of these comorbid patients and to assess response to treatment with citalopram. Patients with primary DSM-IV generalized subtype of social anxiety disorder and comorbid major depression (N = 21) were assessed for symptoms of each disorder, including atypical depressive features, and functional impairment. Patients were treated with a flexible dose of open label citalopram for 12 weeks. Response rates for the intention-to-treat sample at week 12 were 14/21 (66.7%) for social anxiety disorder and 16/21 (76.2%) for depression. All continuous measures of social anxiety, depression, and functional impairment improved significantly with treatment, but depression symptoms responded more rapidly and more completely than social anxiety symptoms. Mean dose of citalopram at study endpoint was 37.6 mg/day. Only three patients (14.3%) fulfilled DSM-IV criteria for atypical features of depression, although 18 (85.7%) fulfilled the criterion for interpersonal rejection sensitivity. Citalopram treatment may benefit patients with primary social anxiety disorder and comorbid major depression, and it should be further studied in controlled trials. Improvement in social anxiety disorder symptoms lagged behind improvement in depression, and greater than 12 weeks of treatment may be required to assess full social anxiety response in patients with comorbid depression. The overlap of social anxiety disorder with atypical features of depression may primarily be due to the shared feature of rejection sensitivity.     

Subtyping social anxiety disorder in developed and developing countries

Background: Although social anxiety disorder (SAD) is classified in the fourth edition of The Diagnostic and Statistical Manual (DSM‐IV) into generalized and non‐generalized subtypes, community surveys in Western countries find no evidence of disjunctions in the dose–response relationship between number of social fears and outcomes to support this distinction. We aimed to determine whether this holds across a broader set of developed and developing countries, and whether subtyping according to number of performance versus interactional fears would be more useful. Methods: The World Health Organization's World Mental Health Survey Initiative undertook population epidemiological surveys in 11 developing and 9 developed countries, using the Composite International Diagnostic Interview to assess DSM‐IV disorders. Fourteen performance and interactional fears were assessed. Associations between number of social fears in SAD and numerous outcomes (age‐of‐onset, persistence, severity, comorbidity, treatment) were examined. Additional analyses examined associations with number of performance fears versus number of interactional fears. Results: Lifetime social fears are quite common in both developed (15.9%) and developing (14.3%) countries, but lifetime SAD is much more common in the former (6.1%) than latter (2.1%) countries. Among those with SAD, persistence, severity, comorbidity, and treatment have dose–response relationships with number of social fears, with no clear nonlinearity in relationships that would support a distinction between generalized and non‐generalized SAD. The distinction between performance fears and interactional fears is generally not important in predicting these same outcomes. Conclusion: No evidence is found to support subtyping SAD on the basis of either number of social fears or number of performance fears versus number of interactional fears. Depression and Anxiety, 2010. © 2009 Wiley‐Liss, Inc.     

A taxometric investigation of the latent structure of social anxiety disorder in outpatients with anxiety and mood disorders

The latent structure of social phobia was examined in a sample of 2,035 outpatients with anxiety and mood disorders to determine whether the disorder operates in a categorical or dimensional fashion. We performed three mathematically distinct taxometric procedures-MAMBAC, MAXEIG, and L-Mode-using five indicators constructed from clinical interview ratings and questionnaire measures of social anxiety symptoms. Results from screening analyses and simulated comparison data consistently indicated that the data were suitable for taxometric analysis. The collective results across procedures, consistency tests, and analysis of simulated comparison data produced converging evidence in support of the conclusion that the latent structure of social phobia is dimensional.     

Paroxetine in social anxiety disorder: a randomized placebo-controlled study.

OBJECTIVE: The aim of this study was to evaluate the utility of paroxetine treatment in social anxiety disorder. METHOD: Previously undiagnosed and untreated subjects with social anxiety disorder (generalized social phobia) were selected from among responders to a newspaper advertisement. They were randomized to double-blind treatment with paroxetine 20-50 mg daily or placebo for 3 months. Outcome measures were self-rated social anxiety and avoidance behaviour, and clinician-rated global assessment of improvement. RESULTS: Significant differences in efficacy between treatments (intent-to-treat analysis: 44 subjects on paroxetine and 48 subjects on placebo) were noted after 4-6 weeks, increasing through the treatment period in the paroxetine group. Nine subjects on paroxetine and 3 subjects on placebo discontinued the treatment due to adverse events. Sexual side-effects were noted by 18 subjects on paroxetine and 4 subjects on placebo. CONCLUSION: Paroxetine was effective in alleviating symptoms and avoidance behaviour in social anxiety disorder.     

Cognitive-behavioral therapy for social anxiety disorder: current status and future directions.

Cognitive-behavioral therapy (CBT) is the most thoroughly studied nonpharmacologic approach to the treatment of social anxiety disorder, and its efficacy has been demonstrated in a large number of investigations. This article summarizes the data on the efficacy of CBT for the treatment of the symptoms of social anxiety disorder and impaired quality of life. The relative efficacy of various CBT approaches, both in the short-term and over extended follow-up periods, is reviewed. Factors associated with more or less positive response to CBT among patients with social anxiety disorder are examined. Special attention is given to the comparison of CBT with pharmacologic approaches to the treatment of social anxiety disorder and the potential utility of combining these approaches. Future directions in the application of combinations of CBT and pharmacotherapy to the treatment of social anxiety disorder are discussed.     

Confirmation of fenfluramine effect on 5-HT(1B) receptor binding of [(11)C]AZ10419369 using an equilibrium approach

Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [(11)C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [(11)C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K(bol) values. The fenfluramine effect on [(11)C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [(11)C]AZ10419369 binding potential (BP(ND)) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP(ND) of the occipital cortex decreased by 39%, from 1.38±0.04 to 0.84±0.09. This study confirms that the new 5-HT(1B) receptor radioligand [(11)C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [(11)C]AZ10419369 and PET.     

Serotonin-lesion Myoclonic syndromes. I. Neurochemical profile and S-1 receptor binding

This paper and the following one describe the effects of L-5-hydroxytryptophan (5-HTP) (after 3 intracisternal injections of 5,7-dihydroxytryptamine (DHT], fenfluramine (FF), p-chloroamphetamine (PCA) and drug combinations on (i) brain regional amine concentration (HPLC with LEC) and serotonin S-1 receptor binding; and (ii) 'serotonergic' behaviors in the same adult rats. Serotonin (5-HT) neurotoxins produced significantly different regional profiles of 5-HT depletion. Multiple DHT injections caused a 90-100% depletion of 5-HT concurrently in neocortex, hippocampus, striatum, septum/accumbens, pons, cerebellum, and cervical cord. Only PCA significantly depleted midbrain. Drug combinations with DHT resembled DHT alone rather than additive depletions, except for PCA + DHT, which produced a hybrid pattern of depletion. The S-1 binding assay, using cold 5-HT to displace [3H]5-HT, was performed with and without ascorbate, EDTA, CaCl2, and pargyline. Without ascorbate, binding was specific, saturable, region-dependent, and non-linear with high (Kd 1-3 nM) and low affinity (10-20 nM) components but no cooperativity (0.8 less than nH less than 1.0). Bmax and Kd did not differ significantly between vehicle- and drug-treated animals in neocortex, hippocampus, striatum, thalamus, hypothalamus, midbrain, pons, medulla, cervical cord, cerebellum, or septum/accumbens two weeks after lesioning, while the assay did detect a 60% reduction in Bmax induced by ascorbic acid (1 mM). The effects of assay conditions exceeded the changes sometimes reported in S-1 receptor Bmax after 5-HT lesions.     

Brain activation during anticipatory anxiety in social anxiety disorder

Exaggerated anticipatory anxiety during expectation of performance-related situations is an important feature of the psychopathology of social anxiety disorder (SAD). The neural basis of anticipatory anxiety in SAD has not been investigated in controlled studies. The current study used functional magnetic resonance imaging (fMRI) to investigate the neural correlates during the anticipation of public and evaluated speaking vs a control condition in 17 SAD patients and 17 healthy control subjects. FMRI results show increased activation of the insula and decreased activation of the ventral striatum in SAD patients, compared to control subjects during anticipation of a speech vs the control condition. In addition, an activation of the amygdala in SAD patients during the first half of the anticipation phase in the speech condition was observed. Finally, the amount of anticipatory anxiety of SAD patients was negatively correlated to the activation of the ventral striatum. This suggests an association between incentive function, motivation and anticipatory anxiety when SAD patients expect a performance situation.