Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.

The free-viewing matrix task: A reliable measure of attention allocation in psychopathology.

Aberrant attention allocation has been implicated in the etiology and maintenance of a range of psychopathologies. However, three decades of research, relying primarily on manual response-time tasks, have been challenged on the grounds of poor reliability of its attention bias indices. Here, in a large, multisite, international study we provide reliability information for a new eye-tracking-based measure of attention allocation and its relation to psychopathology and age. Data from 1567 participants, across a wide range of psychiatric diagnoses and ages, were aggregated from nine sites around the world. Of these, 213 participants also provided retest data. Acceptable overall internal consistency and test-retest reliability were observed among adult participants (Cronbach's alpha = 0.86 and r(213) = 0.89, respectively), as well as across all examined psychopathologies. Youth demonstrated lower internal consistency scores (Cronbach's alpha = 0.65). Finally, the percent dwell time index derived from the task statistically differentiated between healthy participants and participants diagnosed with social anxiety disorder, major depression, and post-traumatic stress disorder. These results potentially address a long-standing reliability crisis in this research field. Aberrant attention allocation patterns in a variety of psychiatric disorders may be targeted with the hope of affecting symptoms. The attention allocation index derived from the matrix task offers reliable means to measure such cognitive target engagement in clinical contexts.

Pilot study of single-dose psilocybin for serotonin reuptake inhibitor-resistant body dysmorphic disorder.

OBJECTIVE: Body dysmorphic disorder (BDD) is an often-severe condition in which individuals are preoccupied by misperceptions of their appearance as defective or ugly. Only serotonin reuptake inhibitors and cognitive-behavioral therapy have been demonstrated efficacious in randomized controlled trials. Psilocybin is a psychedelic drug with growing evidence for safety and efficacy in treatment of depression. This study aimed to pilot test the feasibility, tolerability, safety, and efficacy of psilocybin treatment of adults with BDD. METHODS: In this open-label trial, 12 adults (8 women, 4 men) with moderate-to-severe non-delusional BDD that had been unresponsive to at least one serotonin reuptake inhibitor trial received a single oral dose of psilocybin 25 mg. There was no control group. Psychological support was provided before, during, and after the dosing session. The primary outcome measure for efficacy was the Yale-Brown Obsessive Compulsive Disorder Scale Modified for BDD (BDD-YBOCS) score during 12 weeks of assessments after dosing. RESULTS: All participants completed dosing and all follow-up assessments. BDD-YBOCS scores decreased significantly over 12 weeks of follow-up (p < .001) with a large effect size (partial eta squared = 0.54), and significant changes from baseline were present at week 1 and persisted through week 12. Secondary efficacy measures of BDD symptoms, conviction of belief, negative affect, and disability also improved significantly, and no serious adverse events occurred. At week 12, seven participants (58%) were rated responders, based on ≥30% decrease in BDD-YBOCS. CONCLUSION: This study provides promising preliminary support for psilocybin as a treatment of BDD, warranting future controlled studies.

Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Resting state connectivity predictors of symptom change during gaze-contingent music reward therapy of social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is common, first-line treatments are often only partially effective, and reliable predictors of treatment response are lacking. Here, we assessed resting state functional connectivity (rsFC) at pre-treatment and during early treatment as a potential predictor of response to a novel attention bias modification procedure, gaze-contingent music reward therapy (GC-MRT). METHODS: Thirty-two adults with SAD were treated with GC-MRT. rsFC was assessed with multi-voxel pattern analysis of fMRI at pre-treatment and after 2-3 weeks. For comparison, 20 healthy control (HC) participants without treatment were assessed twice for rsFC over the same time period. All SAD participants underwent clinical evaluation at pre-treatment, early-treatment (week 2-3), and post-treatment. RESULTS: SAD and depressive symptoms improved significantly from pre-treatment to post-treatment. After 2-3 weeks of treatment, decreased connectivity between the executive control network (ECN) and salience network (SN), and increased connectivity within the ECN predicted improvement in SAD and depressive symptoms at week 8. Increased connectivity between the ECN and default mode network (DMN) predicted greater improvement in SAD but not depressive symptoms at week 8. Connectivity within the DMN decreased significantly after 2-3 weeks of treatment in the SAD group, while no changes were found in HC over the same time interval. CONCLUSION: We identified early changes in rsFC during a course of GC-MRT for SAD that predicted symptom change. Connectivity changes within the ECN, ECN-DMN, and ECN-SN may be related to mechanisms underlying the clinical effects of GC-MRT and warrant further study in controlled trials.

Development and initial validation of the Visual Social Anxiety Scale (VSAS): Could a picture be worth a thousand words?

Accurate assessment is crucial for determining appropriate therapeutic interventions for social anxiety and conducting sound clinical research. While self-report measures of social anxiety are widely used in both research and clinical settings, they have several drawbacks inherent to their textual nature. Here, we describe the development and initial validation of the Visual Social Anxiety Scale (VSAS), a novel picture-based self-report measure of social anxiety, based on the well-established widely-used Liebowitz Social Anxiety Scale (LSAS). Specifically, the 24 items of the LSAS were used as the basis for social situations to be included in the VSAS. First, pictures to serve as VSAS items were selected using a rigorous two-phase process (four pilot studies; n = 225). Next, reliability (internal consistency, test-retest) and validity (convergent, discriminant) were explored with new participants (n = 304) who completed the VSAS and a battery of additional self-report questionnaires, delivered in a random order. The VSAS was completed again a month later (n = 260/304). The VSAS showed high internal consistency and test-retest reliability, and good convergent and discriminant validities. VSAS correlations with convergent measures were significantly greater than its correlations with discriminant measures. Thus, the VSAS shows initial promise as a novel picture-based self-report measure of social anxiety.

Fast evidence accumulation in social anxiety disorder enhances decision making in a probabilistic reward task.

Choices and response times in two-alternative decision-making tasks can be modeled by assuming that individuals steadily accrue evidence in favor of each alternative until a response boundary for one of them is crossed, at which point that alternative is chosen. Prior studies have reported that evidence accumulation during decision-making tasks takes longer in adults with psychopathology than in healthy controls, indicating that slow evidence accumulation may be transdiagnostic. However, few studies have examined perceptual decision making in anxiety disorders, where hypervigilance might enhance performance. Therefore, this study used the Hierarchical Drift Diffusion model to investigate evidence accumulation in adults with social anxiety disorder (SAD) and healthy controls as they performed a probabilistic reward task (PRT), in which social rewards were delivered for correct perceptual judgments. Adults with SAD completed the PRT before and after gaze-contingent music reward therapy (GCMRT), which trains attention allocation and has shown efficacy for SAD. Healthy controls also completed the PRT twice. Results revealed excellent performance in adults with SAD, especially after GCMRT: relative to controls, they showed faster evidence accumulation, better discriminability, and earned more rewards. These data highlight a positive effect of attention training on performance in anxious adults and show how a behavioral trait that is typically problematic-hypervigilance in SAD-can nevertheless confer advantages in certain contexts. The data also indicate that, in contrast to other forms of psychopathology, SAD is not characterized by slow evidence accumulation, at least in the context of the social PRT. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Neurophysiological predictors of gaze-contingent music reward therapy among adults with social anxiety disorder.

Social anxiety disorder (SAD) is associated with fear of negative evaluation and heightened performance monitoring. The best-established treatments help only a subset of patients, and there are no well-established predictors of treatment response. The current study investigated whether individual differences in processing errors might predict response to gaze-contingent music reward therapy (GC-MRT). At baseline, healthy control subjects (HC; n = 20) and adults with SAD (n = 29), ages 19-43 years, completed the Flanker Task while electroencephalography (EEG) data were recorded. SAD participants then received up to 12 sessions over 8 weeks of GC-MRT, designed to train participants' attention away from threatening and toward neutral faces. Clinical assessments were completed 9- (post-treatment) and 20-weeks (follow-up) after initiating the treatment. At baseline, compared to HC, SAD performed the task more accurately and exhibited increased error-related negativity (ERN) and delta power to error commission. After controlling for age and baseline symptoms, more negative ERN and increased frontal midline theta (FMT) predicted reduced self-reported social anxiety symptoms at post-treatment, and FMT also predicted clinician-rated and self-reported symptom reduction at the follow-up assessment. Hypervigilance to error is characteristic of SAD and warrants further research as a predictor of treatment response for GC-MRT.

Differential reinforcement learning responses to positive and negative information in unmedicated individuals with depression.

Major depressive disorder (MDD) is characterized by behavioral and neural abnormalities in processing both rewarding and aversive stimuli, which may impact motivational and affective symptoms. Learning paradigms have been used to assess reinforcement encoding abnormalities in MDD and their association with dysfunctional incentive-based behavior, but how the valence and context of information modulate this learning is not well understood. To address these gaps, we examined responses to positive and negative reinforcement across multiple temporal phases of information processing. While undergoing functional magnetic resonance imaging (fMRI), 47 participants (23 unmedicated, predominantly medication-naïve participants with MDD and 24 demographically-matched HC participants) completed a probabilistic, feedback-based reinforcement learning task that allowed us to separate neural activation during motor response (choice) from reinforcement feedback and monetary outcome across two independent conditions: pursuing gains and avoiding losses. In the gain condition, MDD participants showed overall blunted learning responses (prediction error) in the dorsal striatum when receiving monetary outcome, and reduced responses in ventral striatum for positive, but not negative, prediction error. The MDD group showed enhanced sensitivity to negative information, and symptom severity was associated with better behavioral performance in the loss condition. These findings suggest that striatal responses during learning are abnormal in individuals with MDD but vary with the valence of information.

Increased attention allocation to socially threatening faces in social anxiety disorder: A replication study.

BACKGROUND: Threat-related attention bias has been implicated in the etiology and maintenance of social anxiety disorder (SAD), with attentional research increasingly using eye-tracking methodology to overcome the poor psychometric properties of response-time-based tasks and measures. Yet, extant eye-tracking research in social anxiety has mostly failed to report on psychometrics and attempts to replicate past results are rare. Therefore, we attempted to replicate a previously published eye-tracking study of gaze patterns in socially anxious and nonanxious participants as they viewed social threatening and neutral faces, while also exploring the psychometric properties of the attentional measures used. METHODS: Gaze was monitored as participants freely viewed 60 different matrices comprised of eight socially-threatening and eight neutral faces, presented for 6000 ms each. Gaze patterns directed at threat and neutral areas of interest (AOIs) were compared by group. Internal consistency and test-retest reliability were also evaluated. RESULTS: Relative to healthy controls, socially anxious patients dwelled significantly longer on threat faces, replicating prior findings with the same task. Internal consistency of total dwell time on threat and neutral AOIs was high, and two-week test-retest reliability was acceptable. LIMITATIONS: Test-retest reliability was only examined for the control group, which had a small sample size. CONCLUSION: Increased dwell time on socially threatening stimuli is a reliable, stable, and generalizable measure of attentional bias in adults with social anxiety.

Heterogeneity in Fear Processing across and within Anxiety, Eating, and Compulsive Disorders.

BACKGROUND: To assess within and across diagnosis variability we examined fear processing in healthy controls (HC) and three diagnostic groups that share symptoms of pathological anxiety: obsessive compulsive disorder (OCD); social anxiety disorder (SAD), and anorexia nervosa (AN). METHODS: Unmedicated adults (N=166) participated in a paradigm assessing associative fear acquisition, extinction, extinction recall, and fear renewal. Data were analyzed from two perspectives: comparison of each disorder to HC and exploratory latent class analysis (LCA) of the combined data. RESULTS: The diagnosis-based analyses indicated significantly increased fear renewal in OCD and trends toward decreased extinction recall in OCD and increased renewal in SAD. The LCA indicated four Response Types, none of which were congruent with the diagnostic categories. Most participants had a normative response (50%) or a moderate extinction recall deficit (30%). The two remaining groups (8% each) had more extreme responses: one showed complete failure of extinction recall; the other persistent arousal in expectation of, but prior to, actual conditioning (threat sensitivity). LIMITATIONS: Due to small sample size (N=20) results for AN are regarded as preliminary. CONCLUSIONS: Our diagnosis-based findings are consistent with previous data suggesting an association between pathological anxiety and difficulties maintaining fear extinction. The LCA reveal substantial within-diagnosis heterogeneity in fear processing and support inclusion of empirically driven approaches as a complement to standard analyses. This heterogeneity may also have implications for treatment, particularly cognitive behavioral therapy, which relies on strengthening extinction recall and requires patients to tolerate anxious expectation in order to engage with feared situations.

Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression.

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

Anterior hippocampal volume predicts affect-focused psychotherapy outcome.

BACKGROUND: The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)]. METHODS: Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes. RESULTS: Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome. CONCLUSIONS: This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

Impaired generalization of reward but not loss in obsessive-compulsive disorder.

BACKGROUND: Generalizing from past experiences can be adaptive by allowing those experiences to guide behavior in new situations. Generalizing too much, however, can be maladaptive. For example, individuals with pathological anxiety are believed to overgeneralize emotional responses from past threats, broadening their scope of fears. Whether individuals with pathological anxiety overgeneralize in other situations remains unclear. METHODS: The present study (N = 57) used a monetary sensory preconditioning paradigm with rewards and losses to address this question in individuals with obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD), comparing them to healthy comparison subjects (HC). In all groups, we tested direct learning of associations between cues and reward vs. loss outcomes, as well as generalization of learning to novel choice options. RESULTS: We found no differences between the three groups in the direct learning of stimuli with their outcomes: all subjects demonstrated intact stimulus-response learning by choosing rewarding options and avoiding negative ones. However, OCD subjects were less likely to generalize from rewards than either the SAD or HC groups, and this impairment was not found for losses. Additionally, greater deficits in reward generalization were correlated with severity of threat estimation, as measured by a subscale of the Obsessive Beliefs Questionnaire, both within OCD and across all groups. CONCLUSIONS: These findings suggest that a compromised ability to generalize from rewarding events may impede adaptive behavior in OCD and in those susceptible to high estimation of threat.

Bias-contingent attention bias modification and attention control training in treatment of PTSD: a randomized control trial.

BACKGROUND: Randomized control trials (RCTs) comparing attention control training (ACT) and attention bias modification (ABM) in posttraumatic stress disorder (PTSD) have shown mixed results. The current RCT extends the extant literature by comparing the efficacy of ACT and a novel bias-contingent-ABM (BC-ABM), in which direction of training is contingent upon the direction of pre-treatment attention bias (AB), in a sample of civilian patients with PTSD. METHODS: Fifty treatment-seeking civilian patients with PTSD were randomly assigned to either ACT or BC-ABM. Clinician and self-report measures of PTSD and depression, as well as AB and attention bias variability (ABV), were acquired pre- and post-treatment. RESULTS: ACT yielded greater reductions in PTSD and depressive symptoms on both clinician-rated and self-reported measures compared with BC-ABM. The BC-ABM condition successfully shifted ABs in the intended training direction. In the ACT group, there was no significant change in ABV or AB from pre- to post-treatment. CONCLUSIONS: The current RCT extends previous results in being the first to apply ABM that is contingent upon AB at pre-treatment. This personalized BC-ABM approach is associated with significant reductions in symptoms. However, ACT produces even greater reductions, thereby emerging as a promising treatment for PTSD.

Does centrality in a cross-sectional network suggest intervention targets for social anxiety disorder?

OBJECTIVE: Network analysis allows us to identify the most interconnected (i.e., central) symptoms, and multiple authors have suggested that these symptoms might be important treatment targets. This is because change in central symptoms (relative to others) should have greater impact on change in all other symptoms. It has been argued that networks derived from cross-sectional data may help identify such important symptoms. We tested this hypothesis in social anxiety disorder. METHOD: We first estimated a state-of-the-art regularized partial correlation network based on participants with social anxiety disorder (n = 910) to determine which symptoms were more central. Next, we tested whether change in these central symptoms were indeed more related to overall symptom change in a separate dataset of participants with social anxiety disorder who underwent a variety of treatments (n = 244). We also tested whether relatively superficial item properties (infrequency of endorsement and variance of items) might account for any effects shown for central symptoms. RESULTS: Centrality indices successfully predicted how strongly changes in items correlated with change in the remainder of the items. Findings were limited to the measure used in the network and did not generalize to three other measures related to social anxiety severity. In contrast, infrequency of endorsement showed associations across all measures. CONCLUSIONS: The transfer of recently published results from cross-sectional network analyses to treatment data is unlikely to be straightforward. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Exposure-based therapy changes amygdala and hippocampus resting-state functional connectivity in patients with posttraumatic stress disorder.

BACKGROUND: Recent research suggests that posttraumatic stress disorder (PTSD) is associated with altered amygdala and hippocampal resting-state functional connectivity (rsFC). However, less research has examined whether Prolonged Exposure (PE), a first line exposure-based treatment for PTSD, has the potential to alter resting state neural networks. METHODS: A total of 24 patients with PTSD and 26 matched trauma-exposed healthy controls (TEHCs) underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. PTSD patients were scanned a second time after completing 10-session PE in which patients narrated a detailed trauma account (imaginal exposure) and confronted trauma reminders (in vivo exposure) to extinguish trauma-related fear responses. TEHC were scanned again following a 10-week waiting period. Seed regions of interest (ROIs) included centromedial amygdala (CMA), basolateral amygdala (BLA), and the hippocampus. RESULTS: Post- versus pretreatment comparisons indicated increased rsFC of the BLA and CMA with the orbitofrontal cortex (OFC), and hippocampus-medial prefrontal cortex (mPFC) among patients with PTSD, but not among TEHC participants. CONCLUSIONS: Enhanced amygdala and hippocampus rsFC with prefrontal cortical regions following PE could underlie improved capacity for inhibition and re-evaluation of threat, and heightened memory encoding and retrieval ability, respectively. These findings encourage further investigation of this circuitry as a therapeutic target in PTSD.

Dopamine Release in Antidepressant-Naive Major Depressive Disorder: A Multimodal [11C]-(+)-PHNO Positron Emission Tomography and Functional Magnetic Resonance Imaging Study.

BACKGROUND: Mesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D2/D3 receptor availability in MDD. METHODS: Twenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D3-preferring ligand [11C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks. RESULTS: MDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (ΔBPND) (-34% vs. -30%; p = .072, d = 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND were not significantly associated with blood oxygen level-dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response rate = 72.7%). CONCLUSIONS: [11C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D2/D3 availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.

Pharmacotherapy for social anxiety disorder: Interpersonal predictors of outcome and the mediating role of the working alliance.

Social anxiety disorder (SAD) is highly prevalent and associated with high levels of impairment and distress. Therapies for SAD leave many patients symptomatic at the end of treatment, and little is known about predictors or mechanisms of treatment outcome. Given the interpersonal dysfunction fundamental to SAD, this study investigated whether prominent interpersonal features of SAD (submissive behavior, childhood maltreatment, suppression of anger, and depression) predicted attrition and response to pharmacotherapy and whether the working alliance mediated these relationships. This is the first study to examine the role of the working alliance in pharmacotherapy for SAD. One hundred thirty-eight treatment-seeking individuals with a primary diagnosis of SAD received 12 weeks of open treatment with paroxetine. Higher levels of depression predicted greater severity of SAD at the end of treatment, and higher levels of submissive behavior and childhood emotional maltreatment predicted a greater probability of attrition from treatment. The psychiatrist-assessed working alliance mediated response to pharmacotherapy for individuals who reported a history of emotional maltreatment. These results identify variables that predict pharmacotherapy outcome and emphasize the importance of the working alliance as a mechanism of treatment response for those with a history of emotional maltreatment. Implications for person-specific treatment selection are discussed.