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Selective serotonin reuptake inhibitors (SSRIs), widely used for anxiety and depression, are often criticized for their perceived similarity in efficacy to placebo treatments and the unclear connection between brain serotonin levels, on one hand, and the symptomatology of these disorders, on the other. In this perspective paper we discuss the complex mechanisms behind SSRI and placebo treatments in managing social anxiety disorder (SAD), focusing on both pharmacological and expectancy effects. Through a series of neuroimaging studies using positron emission tomography (PET), we investigated the neural, neurochemical and behavioral changes associated with SSRI and placebo responses in SAD patients. Results from one study revealed that both SSRI and placebo responders showed equal reductions in amygdala activity, a region central to fear processing, as well as comparable improvements in social anxiety symptoms. These findings suggest shared neural pathways between SSRIs and placebos, possibly related to response expectancies. In another study, we manipulated patient expectations using a deception design, showing that overt SSRI treatment yielded greater symptom reduction than covert administration. PET results further underscored the influence of expectation on dopamine signaling. Furthermore, PET data on serotonin transporters indicated that serotonin reuptake inhibition alone does not fully account for SSRIs' clinical efficacy, as serotonin transporter occupancy was not correlated with symptom improvement. In yet another study, combining SSRIs with cognitive-behavioral therapy (CBT) led to more robust and longer-lasting outcomes than placebo combined with CBT, with distinct effects on brain monoamine transporters. Overall, these findings emphasize the intricate interplay between pharmacology, brain mechanisms, and psychological expectations in the treatment of SAD.

Objectives

Individuals with idiopathic hypersomnia (IH) report several subjective emotional and cognitive symptoms, as well as impairments in daily functioning. Coping strategies are frequently used, but their effectiveness is perceived to be minimal. The aim of the present study was to delve into the patient perspective on navigating life with IH, emphasizing patients’ personal narratives.

Method

Utilizing a purposeful sample method, twelve participants diagnosed with IH underwent telephone interviews guided by a semi-structured protocol. The interviews were subjected to thematic analysis to extract relevant themes.

Results

Analysis unveiled three primary themes along with subthemes: 1) Being confined, characterized by excessive daytime sleepiness, negative emotional processes and cognitive disturbances, 2) Missing out on life, involving loss of time and adverse social consequences, and 3) Trying to cope, encompassing strategies like napping, adapting, activating oneself and mentally fighting sleepiness, while also embracing acceptance and self-compassion.

Conclusions

The identified themes reflected numerous aspects previously reported to be associated with living with IH. Notably, the study brought novel subthemes to light, such as the existential dilemma of “sleeping one’s life away” and feelings of guilt and shame. Furthermore, the study underscored the significance of acceptance and self-compassion as coping strategies.

Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we built and validated supervised neuroanatomical machine learning models for individual-level inferences, using a case-control design and the largest known neuroimaging database on youth anxiety disorders: the ENIGMA-Anxiety Consortium (N = 3,343; age = 10-25 years; global sites = 32). Modest, yet robust, brain-based classifications were achieved for specific anxiety disorders (panic disorder), but also transdiagnostically for all anxiety disorders when patients were subgrouped according to their sex, medication status and symptom severity (area under the receiver operating characteristic curve, 0.59-0.63). Classifications were driven by neuroanatomical features (cortical thickness, cortical surface area and subcortical volumes) in fronto-striato-limbic and temporoparietal regions. This benchmark study within a large, heterogeneous and multisite sample of youth with anxiety disorders reveals that only modest classification performances can be realistically achieved with machine learning using neuroanatomical data.

Perinatal affective disorders are common, but standard screening measures reliant on subjective self-reports might not be sufficient to identify pregnant women at-risk for developing postpartum depression and anxiety. Lower heart rate variability (HRV) has been shown to be associated with affective disorders. The current exploratory study aimed to evaluate the predictive utility of late pregnancy HRV measurements of postpartum affective symptoms. A subset of participants from the BASIC study (Uppsala, Sweden) took part in a sub-study at pregnancy week 38 where HRV was measured before and after a mild stressor (n = 122). Outcome measures were 6-week postpartum depression and anxiety symptoms as quantified by the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Anxiety Inventory (BAI). In total, 112 women were included in a depression outcome analysis and 106 women were included in an anxiety outcome analysis. Group comparisons indicated that lower pregnancy HRV was associated with depressive or anxious symptomatology at 6 weeks postpartum. Elastic net logistic regression analyses indicated that HRV indices alone were not predictive of postpartum depression or anxiety outcomes, but HRV indices were selected as predictors in a combined model with background and pregnancy variables. ROC curves for the combined models gave an area under the curve (AUC) of 0.93 for the depression outcome and an AUC of 0.83 for the anxiety outcome. HRV indices predictive of postpartum depression generally differed from those predictive of postpartum anxiety. HRV indices did not significantly improve prediction models comprised of psychological measures only in women with pregnancy depression or anxiety.

Introduction

The diagnostic process for idiopathic hypersomnia (IH) is complex due to the diverse aetiologies of daytime somnolence, ambiguous pathophysiological understanding, and symptom variability. Current diagnostic instruments, such as the multiple sleep latency test (MSLT), are limited in their ability to fully represent IH's diverse nature. This study endeavours to delineate subgroups among IH patients via cluster analysis of polysomnographic data and to examine the temporal evolution of their symptomatology, aiming to enhance the granularity of understanding and individualized treatment approaches for IH.

Methods

This study included individuals referred to the Uppsala Centre for Sleep Disorders from 2010 to 2019, who were diagnosed with IH based on the International Classification of Sleep Disorders-3 (ICSD-3) criteria, following a thorough diagnostic evaluation. The final cohort, after excluding participants with incomplete data or significant comorbid sleep-related respiratory conditions, comprised 69 subjects, including 49 females and 20 males, with an average age of 40 years. Data were collected through polysomnography (PSG), MSLT, and standardized questionnaires. A two-step cluster analysis was employed to navigate the heterogeneity within IH, focusing on objective time allocation across different sleep stages and sleep efficiency derived from PSG. The study also aimed to track subgroup-specific changes in symptomatology over time, with follow-ups ranging from 21 to 179 months post-diagnosis.

Results

The two-step cluster analysis yielded two distinct groups with a satisfactory silhouette coefficient: Cluster 1 (n = 29; 42 %) and Cluster 2 (n = 40; 58 %). Cluster 1 exhibited increased deep sleep duration, reduced stage 2 sleep, and higher sleep maintenance efficiency compared to Cluster 2. Further analyses of non-clustering variables indicated shorter wake after sleep onset in Cluster 1, but no significant differences in other sleep parameters, MSLT outcomes, body mass index, age, or self-reported measures of sleep inertia or medication usage. Long-term follow-up assessments showed an overall improvement in excessive daytime sleepiness, with no significant inter-cluster differences.

Conclusion

This exploratory two-step cluster analysis of IH-diagnosed patients discerned two subgroups with distinct nocturnal sleep characteristics, aligning with prior findings and endorsing the notion that IH may encompass several phenotypes, each potentially requiring tailored therapeutic strategies. Further research is imperative to substantiate these findings.

Importance  Social anxiety disorder (SAD) can be adequately treated with cognitive behavioral therapy (CBT). However, there is a large gap in knowledge on factors associated with prognosis, and it is unclear whether symptom severity predicts response to CBT for SAD.

Objective  To examine baseline SAD symptom severity as a moderator of the association between CBT and symptom change in patients with SAD.

Data Sources  For this systematic review and individual patient data meta-analysis (IPDMA), PubMed, PsycInfo, Embase, and the Cochrane Library were searched from January 1, 1990, to January 13, 2023. Primary search topics were social anxiety disorder, cognitive behavior therapy, and randomized controlled trial.

Study Selection  Inclusion criteria were randomized clinical trials comparing CBT with being on a waiting list and using the Liebowitz Social Anxiety Scale (LSAS) in adults with a primary clinical diagnosis of SAD.

Data Extraction and Synthesis  Authors of included studies were approached to provide individual-level data. Data were extracted by pairs of authors following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and risk of bias was assessed using the Cochrane tool. An IPDMA was conducted using a 2-stage approach for the association of CBT with change in LSAS scores from baseline to posttreatment and for the interaction effect of baseline LSAS score by condition using random-effects models.

Main Outcomes and Measures  The main outcome was the baseline to posttreatment change in symptom severity measured by the LSAS.

Results  A total of 12 studies including 1246 patients with SAD (mean [SD] age, 35.3 [10.9] years; 738 [59.2%] female) were included in the meta-analysis. A waiting list–controlled association between CBT and pretreatment to posttreatment LSAS change was found (b = –20.3; 95% CI, −24.9 to −15.6; P < .001; Cohen d = –0.95; 95% CI, −1.16 to −0.73). Baseline LSAS scores moderated the differences between CBT and waiting list with respect to pretreatment to posttreatment symptom reductions (b = –0.22; 95% CI, −0.39 to −0.06; P = .009), indicating that individuals with severe symptoms had larger waiting list–controlled symptom reductions after CBT (Cohen d = –1.13 [95% CI, −1.39 to −0.88] for patients with very severe SAD; Cohen d = –0.54 [95% CI, −0.80 to −0.29] for patients with mild SAD).

Conclusions and Relevance  In this systematic review and IPDMA, higher baseline SAD symptom severity was associated with greater (absolute but not relative) symptom reductions after CBT in patients with SAD. The findings contribute to personalized care by suggesting that clinicians can confidently offer CBT to individuals with severe SAD symptoms.

Background: Social anxiety disorder (SAD) is associated with aberrant emotional information processing while little is known about non-emotional cognitive processing biases. The dorsal anterior cingulate cortex (dACC) has been implicated in SAD neuropathology and is activated both by emotional and non-affective cognitive challenges like the Multisource Interference Task (MSIT).

Methods: Here, we used fMRI to compare dACC activity and test performance during MSIT in 69 SAD patients and 38 healthy controls. In addition to patient-control comparisons, we examined whether neural activity in the dACC correlated with social anxiety, trait anxiety or depression levels.

Results: The MSIT activated the dACC as expected but with no differences in task performance or neural reactivity between SAD patients and controls. There were no significant correlations between dACC activity and social or trait anxiety symptom severity. In patients, there was a significant negative correlation between dACC activity and depressive symptoms.

Conclusions: In absence of affective challenge, we found no disorder-related cognitive profile in SAD patients since neither MSIT task performance nor dACC neural activity deviated in patients relative to controls.

Post-traumatic stress disorder (PTSD) and anxiety disorders are among the most prevalent psychiatric conditions worldwide sharing many clinical manifestations and, most likely, neural mechanisms as suggested by neuroimaging research. While the so-called fear circuitry and traditional limbic structures of the brain, particularly the amygdala, have been extensively studied in sufferers of these disorders, the cerebellum has been relatively underexplored. The aim of this paper was to present a mini-review of functional (task-activity or resting-state connectivity) and structural (gray matter volume) results on the cerebellum as reported in magnetic resonance imaging studies of patients with PTSD or anxiety disorders (49 selected studies in 1,494 patients). While mixed results were noted overall, e.g., regarding the direction of effects and anatomical localization, cerebellar structures like the vermis seem to be highly involved. Still, the neurofunctional and structural alterations reported for the cerebellum in excessive anxiety and trauma are complex, and in need of further evaluation.

Objective To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC). Methods In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9 to 11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point. Results SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. PBMC mtDNA-cn did not significantly correlate with plasma ccf-mtDNA in patients. Conclusion This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.