Antipsychotic agents in anxiety disorders: An umbrella review.

BACKGROUND: Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs. OBJECTIVE: The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436). METHODS: An initial search was undertaken to identify systematic reviews and meta-analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) scale. RESULTS: The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta-analyses were included in the analysis. Most of the systematic reviews and meta-analyses were deemed low-quality through AMSTAR-2 with only one review being deemed high-quality. In evaluating the monotherapies with antipsychotics compared with first-line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD). CONCLUSIONS: This umbrella review indicates a lack of high-quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long-term and larger-scale studies of antipsychotics in anxiety disorders are needed.

EEG Microstates in Mood and Anxiety Disorders: A Meta-analysis.

To reduce the psycho-social burden increasing attention has focused on brain abnormalities in the most prevalent and highly co-occurring neuropsychiatric disorders, such as mood and anxiety. However, high inter-study variability in these patients results in inconsistent and contradictory alterations in the fast temporal dynamics of large-scale networks as measured by EEG microstates. Thus, in this meta-analysis, we aim to investigate the consistency of these changes to better understand possible common neuro-dynamical mechanisms of these disorders.In the systematic search, twelve studies investigating EEG microstate changes in participants with mood and anxiety disorders and individuals with subclinical depression were included in this meta-analysis, adding up to 787 participants.The results suggest that EEG microstates consistently discriminate mood and anxiety impairments from the general population in patients and subclinical states. Specifically, we found a small significant effect size for B microstates in patients compared to healthy controls, with larger effect sizes for increased B presence in unmedicated patients with comorbidity. In a subgroup meta-analysis of ten mood disorder studies, microstate D showed a significant effect size for decreased presence. When investigating only the two anxiety disorder studies, we found a significantly small effect size for the increased microstate A and a medium effect size for decreased microstate E (one study). However, more studies are needed to elucidate whether these findings are diagnostic-specific markers.Results are discussed in relation to the functional meaning of microstates and possible contribution to an explanatory mechanism of overlapping symptomatology of mood and anxiety disorders.

Enhanced interhemispheric resting-state functional connectivity of the visual network is an early treatment response of paroxetine in patients with panic disorder.

This study aimed to detect alterations in interhemispheric interactions in patients with panic disorder (PD), determine whether such alterations could serve as biomarkers for the diagnosis and prediction of therapeutic outcomes, and map dynamic changes in interhemispheric interactions in patients with PD after treatment. Fifty-four patients with PD and 54 healthy controls (HCs) were enrolled in this study. All participants underwent clinical assessment and a resting-state functional magnetic resonance imaging scan at (i) baseline and (ii) after paroxetine treatment for 4 weeks. A voxel-mirrored homotopic connectivity (VMHC) indicator, support vector machine (SVM), and support vector regression (SVR) were used in this study. Patients with PD showed reduced VMHC in the fusiform, middle temporal/occipital, and postcentral/precentral gyri, relative to those of HCs. After treatment, the patients exhibited enhanced VMHC in the lingual gyrus, relative to the baseline data. The VMHC of the fusiform and postcentral/precentral gyri contributed most to the classification (accuracy = 87.04%). The predicted changes were accessed from the SVR using the aberrant VMHC as features. Positive correlations (p < 0.001) were indicated between the actual and predicted changes in the severity of anxiety. These findings suggest that impaired interhemispheric coordination in the cognitive-sensory network characterized PD and that VMHC can serve as biomarkers and predictors of the efficiency of PD treatment. Enhanced VMHC in the lingual gyrus of patients with PD after treatment implied that pharmacotherapy recruited the visual network in the early stages.

Effects of antidepressant on FKBP51 mRNA expression and neuroendocrine hormones in patients with panic disorder.

OBJECTIVE: The purpose of this study was to investigate the effects of escitalopram on the peripheral expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes (FKBP51, HSP90, NR3C1 and POMC) and HPA-axis hormones in patients with panic disorder (PD). METHODS: Seventy-seven patients with PD were treated with escitalopram for 12 weeks. All participants were assessed for the severity of panic symptoms using the Panic Disorder Severity Scale (PDSS). The expression of HPA-axis genes was measured using real-time quantitative fluorescent PCR, and ACTH and cortisol levels were measured using chemiluminescence at baseline and after 12 weeks of treatment. RESULTS: At baseline, patients with PD had elevated levels of ACTH and cortisol, and FKBP51 expression in comparison to healthy controls (all p < 0.01). Correlation analysis revealed that FKBP51 expression levels were significantly positively related to cortisol levels and the severity of PD (all p < 0.01). Furthermore, baseline ACTH and cortisol levels, and FKBP51 expression levels were significantly reduced after 12 weeks of treatment, and the change in the PDSS score from baseline to post-treatment was significantly and positively related to the change in cortisol (p < 0.01). CONCLUSIONS: The results suggest that PD may be associated with elevated levels of ACTH and cortisol, and FKBP51 expression, and that all three biomarkers are substantially decreased in patients who have received escitalopram treatment.

Anxiety, a significant risk factor for coronary artery disease: what is the best index.

BACKGROUND: Coronary artery disease (CAD) is known as the leading cause of disability and death globally. Anxiety disorders are also recognized as common types of mental disorders that substantially impact global health. Iran ranks among the countries with a high incidence of CAD and anxiety disorders. Therefore, the present study aims to determine the potential association and epidemiological aspects of anxiety and CAD within the population of Mashhad, the second most popoulos city in Iran. METHODS: The present study is based on extracted data from the Mashhad stroke and heart atherosclerotic disorder (MASHAD) study which is a 10-year prospective cohort study intended to assess the effects of various CAD risk factors among Mashhad city residents. Anxiety scores were assessed at the baseline using Beck Anxiety Inventory and individuals were classified based on the BAI 4-factor structure model which included autonomic, cognitive, panic, and neuromotor components. Accordingly, the association between baseline anxiety scores and the BAI four-factor model with the risk of CAD events was analyzed using SPSS software version 21. RESULTS: Based on the results, 60.4% of the sample were female, and 5.6% were classified as having severe forms of anxiety. Moreover, severe anxiety was more prevalent in females. Results showed a 1.7% risk of CAD (p-value < 0.001) over 10 years with one unit increase in anxiety score. Based on the 4-factor model structure, we found that only panic disorder could significantly increase the risk of CAD by 1.1% over the 10-year follow-up (p-value < 0.001). CONCLUSION: Anxiety symptoms, particularly panic disorder, are independently and significantly associated with an increased overall risk of developing CAD over a 10-year period. Therefore, further studies are warranted to investigate the mechanisms through which anxiety may cause CAD, as well as possible interventions to mitigate these processes.

A causal relationship between panic disorder and risk of alzheimer disease: a two-sample mendelian randomization analysis.

BACKGROUND: Observational studies have suggested a link between panic disorder (PD) and Alzheimer disease (AD). This study aimed to identify the underlying association of PD with the risk of AD using Mendelian randomization. METHODS: Genetic instrumental variables (IVs) were retrieved in the genome-wide association study between PD and AD. Then, five different models, namely inverse variance weighting (IVW), weighted median, weighted mode, MR-Egger and MR-robust adjusted profile scores (MR-RAPS), were used for MR Analysis. Finally, the heterogeneity and pleiotropy of identified IVs were verified by multiple sensitivity tests. RESULTS: The Cochran's Q test based on MR Egger and IVW showed that no evidence of heterogeneity was found in the effects of instrumental variables, so a fixed-effect model was used. IVW analysis (OR 1.000479, 95% CI [1.000147056, 1.000811539], p = 0.005) indicated that PD was associated with an increased risk of AD, and a causal association existed between them. Meanwhile, weighted median (OR 1.000513373, 95% CI [1.000052145, 1.000974814], p = 0.029) and MR-RAPS (OR 1.000510118, 95% CI [1.000148046, 1.00087232], p = 0.006) also showed the similar findings. In addition, extensive sensitivity analyses confirmed the robustness and accuracy of these results. CONCLUSION: This investigation provides evidence of a potential causal relationship between PD and the increased risk of AD. Based on our MR results, when diagnosing and treating patients with PD, clinicians should pay more attention to their AD-related symptoms to choose therapeutic measures or minimize comorbidities. Furthermore, the development of drugs that improve both PD and AD may better treat patients with these comorbidities.

Personalized virtual reality exposure for panic disorder and agoraphobia: A preliminary neurophysiological study.

BACKGROUND: Personalization is considered an important principle in virtual reality (VR) exposure therapy. We aimed to identify whether personalized VR exposure could provoke increased anxiety in patients with panic disorder and agoraphobia as it is considered the first step in successful treatment for anxiety. METHODS: We performed a double-arm, one-day preliminary study among 28 patients with panic disorder and agoraphobia. Three sessions of VR exposure, including a theater, train, and elevator scenario, were conducted in two groups. In the personalized group (n = 14), the brightness and crowd density were customized based on a pre-assessment. In the control group (n = 14), these conditions were fully randomized. Self-reported anxiety, heart rate, skin conductance, and electroencephalography were measured before, during, and after the VR sessions. RESULTS: In the later VR sessions, higher self-reported anxiety levels measured by the Visual Analogue Scale were observed in the personalized exposure group. Increased heart rates during and after the VR sessions were observed in the personalized group. The changes in skin conductance peaks were not significantly different between the groups, but the increase in skin conductance was associated with the participants' perception of presence. The electroencephalogram showed widespread increases in alpha waves in the frontal and temporal areas of the brain in the personalized group than in the control group. CONCLUSION: Personalized VR exposure elicits stronger anxiogenic effects in patients with panic disorder and agoraphobia as suggested by self-report and neurophysiological data. Personalization of VR exposure has the potential for effective behavioral therapy.

Discrimination between healthy participants and people with panic disorder based on polygenic scores for psychiatric disorders and for intermediate phenotypes using machine learning.

OBJECTIVE: Panic disorder is a modestly heritable condition. Currently, diagnosis is based only on clinical symptoms; identifying objective biomarkers and a more reliable diagnostic procedure is desirable. We investigated whether people with panic disorder can be reliably diagnosed utilizing combinations of multiple polygenic scores for psychiatric disorders and their intermediate phenotypes, compared with single polygenic score approaches, by applying specific machine learning techniques. METHODS: Polygenic scores for 48 psychiatric disorders and intermediate phenotypes based on large-scale genome-wide association studies (n = 7556-1,131,881) were calculated for people with panic disorder (n = 718) and healthy controls (n = 1717). Discrimination between people with panic disorder and healthy controls was based on the 48 polygenic scores using five methods for classification: logistic regression, neural networks, quadratic discriminant analysis, random forests and a support vector machine. Differences in discrimination accuracy (area under the curve) due to an increased number of polygenic score combinations and differences in the accuracy across five classifiers were investigated. RESULTS: All five classifiers performed relatively well for distinguishing people with panic disorder from healthy controls by increasing the number of polygenic scores. Of the 48 polygenic scores, the polygenic score for anxiety UK Biobank was the most useful for discrimination by the classifiers. In combinations of two or three polygenic scores, the polygenic score for anxiety UK Biobank was included as one of polygenic scores in all classifiers. When all 48 polygenic scores were used in combination, the greatest areas under the curve significantly differed among the five classifiers. Support vector machine and logistic regression had higher accuracy than quadratic discriminant analysis and random forests. For each classifier, the greatest area under the curve was 0.600 ± 0.030 for logistic regression (polygenic score combinations N = 14), 0.591 ± 0.039 for neural networks (N = 9), 0.603 ± 0.033 for quadratic discriminant analysis (N = 10), 0.572 ± 0.039 for random forests (N = 25) and 0.617 ± 0.041 for support vector machine (N = 11). The greatest areas under the curve at the best polygenic score combination significantly differed among the five classifiers. Random forests had the lowest accuracy among classifiers. Support vector machine had higher accuracy than neural networks. CONCLUSIONS: These findings suggest that increasing the number of polygenic score combinations up to approximately 10 effectively improved the discrimination accuracy and that support vector machine exhibited greater accuracy among classifiers. However, the discrimination accuracy for panic disorder, when based solely on polygenic score combinations, was found to be modest.

The Effectiveness of a Digital App for Reduction of Clinical Symptoms in Individuals With Panic Disorder: Randomized Controlled Trial.

BACKGROUND: Panic disorder is a common and important disease in clinical practice that decreases individual productivity and increases health care use. Treatments comprise medication and cognitive behavioral therapy. However, adverse medication effects and poor treatment compliance mean new therapeutic models are needed. OBJECTIVE: We hypothesized that digital therapy for panic disorder may improve panic disorder symptoms and that treatment response would be associated with brain activity changes assessed with functional near-infrared spectroscopy (fNIRS). METHODS: Individuals (n=50) with a history of panic attacks were recruited. Symptoms were assessed before and after the use of an app for panic disorder, which in this study was a smartphone-based app for treating the clinical symptoms of panic disorder, panic symptoms, depressive symptoms, and anxiety. The hemodynamics in the frontal cortex during the resting state were measured via fNIRS. The app had 4 parts: diary, education, quest, and serious games. The study trial was approved by the institutional review board of Chung-Ang University Hospital (1041078-202112-HR-349-01) and written informed consent was obtained from all participants. RESULTS: The number of participants with improved panic symptoms in the app use group (20/25, 80%) was greater than that in the control group (6/21, 29%; χ21=12.3; P=.005). During treatment, the improvement in the Panic Disorder Severity Scale (PDSS) score in the app use group was greater than that in the control group (F1,44=7.03; P=.01). In the app use group, the total PDSS score declined by 42.5% (mean score 14.3, SD 6.5 at baseline and mean score 7.2, SD 3.6 after the intervention), whereas the PDSS score declined by 14.6% in the control group (mean score 12.4, SD 5.2 at baseline and mean score 9.8, SD 7.9 after the intervention). There were no significant differences in accumulated oxygenated hemoglobin (accHbO2) at baseline between the app use and control groups. During treatment, the reduction in accHbO2 in the right ventrolateral prefrontal cortex (VLPFC; F1,44=8.22; P=.006) and the right orbitofrontal cortex (OFC; F1,44=8.88; P=.005) was greater in the app use than the control group. CONCLUSIONS: Apps for panic disorder should effectively reduce symptoms and VLPFC and OFC brain activity in patients with panic disorder. The improvement of panic disorder symptoms was positively correlated with decreased VLPFC and OFC brain activity in the resting state. TRIAL REGISTRATION: Clinical Research Information Service KCT0007280; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=21448.

Electrocardiographic frontal QRS-T angle is independently associated with panic disorder.

OBJECTIVE: Panic disorder (PD) may cause serious cardiac arrhythmias by causing electrical abnormalities. Abnormal P-wave axis (aPwa), presence of fragmented QRS (fQRS), wide frontal QRS-T angle (fQRSTa), QRS duration corrected (QRSdc) and log/ logQRS duration/RR interval (log/logQRS/RR) have been correlated with increased risk of serious supraventricular and ventricular cardiac arrhythmias in a general population. The purpose of this study was to compare these newly explored atrial and ventricular arrhythmia indicators in patients with PD and in healthy subjects. METHOD: A total of 169 newly diagnosed PD patients and 128 healthy subjects were included in the study. The Panic and Agoraphobia Scale (PAS) was administered, and 12-lead electrocardiography (ECG) measurements were obtained. Electrocardiographic parameters including aPwa, fQRSTa, presence of fQRS, QRS duration corrected (QRSdc), and log/logQRS duration/RR distance (log/logQRS/RR) were compared between the two groups. RESULTS: aPwa and fQRS, in addition to fQRSTa, QRSdc, and log/ logQRS/RR ratio values, were significantly increased in the PD group compared to healthy controls. Correlation analyses revealed that wider fQRSTa, number of fQRS derivation, number of total fQRS, wider QRSdc, and log/logQRS/RR ratio significantly correlated with PAS score. Logistic regression analysis demonstrated that fQRSTa and the number of total fQRS were independently associated with PD. CONCLUSION: PD is associated with wider fQRSTa, QRSdc, and log/logQRS/RR in addition to the increased abnormal aPwa and presence of fQRS. These findings suggest that untreated PD patients may be susceptible to supraventricular and ventricular arrhythmia, indicating that ECG should be routinely obtained in the management of PD patients.

Investigating the Interplay Between Mental Health Conditions and Social Connectedness on Suicide Risk: Findings from a Clinical Sample of Adolescents.

This study examined whether school and community connectedness buffer the relationships between mental health conditions and suicide risk in a clinical sample of adolescents with histories of substance use disorders. Data from 294 adolescents were examined, with approximately 58% reporting lifetime suicidal ideation and/or prior attempts. Multinomial logistic regression was used to examine main and interaction effects on a three-category measure of suicide risk. Depression severity and panic disorder were associated with elevated suicidal ideation risk, whereas disordered eating was associated with elevated risk of attempts. Higher school-based positive peer interactions, school safety, and neighborhood social connection levels were associated with reduced suicide attempt risk. Moderation analyses revealed that high neighborhood social connection levels may partially mitigate the elevated likelihood of attempting suicide associated with disordered eating. Findings suggest clinical populations of adolescents may benefit from approaches aiming to promote social connectedness, further supporting a comprehensive approach to suicide prevention.

Cognitive change before sudden gains in cognitive behavioural therapy for panic disorder.

BACKGROUND: Sudden gains occur in a range of disorders and treatments and are of clinical and theoretical significance if they can shed light on therapeutic change processes. This study investigated the relationship between sudden gains in panic symptoms and preceding cognitive change during cognitive behavioural therapy (CBT) for panic disorder. METHOD: Participants with panic disorder completed in session measures of panic symptoms and catastrophic cognitions. Independent samples t-tests were used to compare the post-treatment score of those who met criteria for one or more sudden gain during treatment with those who did not, and to compare within-session cognitive change between pre-sudden gain sessions and the previous (control) session. RESULTS: Twenty-two (42%) of 53 participants experienced a sudden gain during treatment. Participants demonstrating a sudden gain showed more improvement in panic symptoms from pre- to post-treatment than those without a sudden gain. The within-session cognitive change score in the pre-gain session was significantly greater than in the control session. CONCLUSIONS: Sudden gains occurred in individual CBT for panic disorder and within-session cognitive change was associated with sudden gains. This is consistent with the cognitive model of panic disorder and highlights how sudden gains can help to identify key change processes.

[Treatment resistance in anxiety disorders-Definition and treatment options]. / Therapieresistenz bei Angsterkrankungen ­ Definition und Behandlungsoptionen.

Treatment resistance in anxiety disorders represents a clinical challenge, contributes to the chronicity of the diseases as well as sequential comorbidities, and is associated with a significant individual and socioeconomic burden. This narrative review presents the operational definition of treatment resistance in anxiety disorders according to international consensus criteria (< 50% reduction in the Hamilton Anxiety Scale, HAM­A, score or < 50% reduction in the Beck Anxiety Inventory, BAI, score or a clinical global impression-improvement, CGI­I, score > 2). At least two unsuccessful guideline-based treatment attempts with pharmacological monotherapy or at least one unsuccessful treatment attempt with adequately delivered cognitive behavioral therapy are required. Pharmacotherapeutically, after excluding pseudo-resistance, switching the medication within one class or to another class and augmentation strategies with other antidepressants (mirtazapine, agomelatine), antipsychotics (quetiapine) or anticonvulsants (valproate) are recommended. Psychotherapeutically, third-wave therapies, psychodynamic therapy, systemic therapy and physical exercise can be considered for therapy resistance. In cases of no response to psychotherapy or pharmacotherapy, the respective other form of therapy or a combination of both should be offered. Compounds targeting the glutamatergic and endocannabinoid systems as well as neuropeptides are being tested as potential innovative pharmaceuticals for treatment-resistant anxiety disorders. There is an urgent need for further research to identify predictive markers and mechanisms as well as to develop innovative pharmacological and psychotherapeutic interventions for treatment-resistant anxiety disorders.

Effects of panic-specific cognitive behavioural and psychodynamic psychotherapies on work ability in a doubly randomised clinical trial.

Objective: The effects of panic-specific psychotherapy on occupational functioning remain under-researched. This study tests whether two brief psychotherapies for Panic Disorder with or without Agoraphobia (PD/A) may generate improvement in work ability. Methods: Adults (N = 221) with a primary diagnosis of PD/A were randomised to wait-list, panic-focused psychodynamic psychotherapy (PFPP), panic control treatment (PCT), or to the choice between the two treatments. Participants completed the Work Ability Inventory (WAI) at baseline, post-treatment, and during 24-month follow-ups. Change in WAI scores were assessed using segmented multilevel linear growth models, and mediation was explored through path analysis. Results: WAI scores changed from the moderate to good range between baseline and post-treatment (SMD = 0.45; 95% CI [0.33, 0.57]) and continued to increase throughout the follow-up (SMD = 0.16; 95% CI [0.03, 0.28]) with no differences between treatments or allocation forms. In PFPP (but not in PCT) pre- to post-treatment change in WAI was mediated by reduction in panic symptoms and WAI predicted employment status and absences. Conclusions: Two brief panic specific psychotherapies, one cognitive behavioural and one psychodynamic, produced short and long-term increases in work ability.

Moderators of short- and long-term outcomes in panic control treatment and panic-focused psychodynamic psychotherapy.

OBJECTIVE: The objective was to test the hypothesis that externalizing and internalizing helpfulness beliefs and learning styles at baseline moderate panic severity and overall mental illness as short-term and long-term outcomes of two panic-focused psychotherapies, Panic Control Treatment (PCT) and Panic-Focused Psychodynamic Psychotherapy (PFPP). METHOD: Participants were 108 adults with DSM-IV Panic Disorder with or without Agoraphobia (PD/A) who were randomized to treatment in a trial of PCT and PFPP. Piece-wise/segmented multilevel modeling was used to test three-way interactions (Treatments × Moderator × Time), with participants and therapists as random factors. Outcome variables were clinician-rated panic severity and self-rated mental illness post-treatment and during follow-up. RESULTS: Patients' externalizing (but not internalizing) helpfulness beliefs moderated mental illness outcomes during follow-up (but not during treatment); low levels of Externalization were facilitative for PFPP but not PCT. Internalizing and externalizing helpfulness beliefs and learning style did not moderate clinician-rated panic severity, whether short- or long-term. CONCLUSIONS: These results suggest that helpfulness beliefs and learning style have limited use in assignment to either PCT or PFPP for PD/A. Although further research is needed, low levels of helpfulness beliefs about externalizing coping may play a role in mental illness outcomes for PFPP.

Association between panic disorder and childhood adversities: a systematic review and meta-analysis.

BACKGROUND: Adverse childhood experiences (ACEs) increase the risk of mental health difficulties in general, but the link to panic disorder (PD) has received comparatively little attention. There are no data for the magnitudes between ACEs and PD. This systematic review and meta-analysis estimated the overall, as well as the subgroups, odds ratio of having PD in adults who report ACEs, compared to adults who do not. METHODS: The study was pre-registered on PROSPERO [CRD42018111506] and the database was searched in June 2021. In order to overcome the violation of independent assumptions due to multiple estimations from the same samples, we utilized a robust variance estimation model that supports meta-analysis for clustered estimations. Accordingly, an advanced method relaxing the distributional and asymptotic assumptions was used to assess publication bias and sensitivity. RESULTS: The literature search and screening returned 34 final studies, comprising 192,182 participants. Ninety-six estimations of 20 types of ACEs were extracted. Pooled ORs are: overall 2.2, CI (1.82-2.58), sexual abuse 1.92, CI (1.37-2.46), physical abuse 1.71, CI (1.37-2.05), emotional abuse 1.61, CI (0.868-2.35), emotional neglect 1.53, CI (0.756-2.31), parental alcoholism 1.83, CI (1.24-2.43), and parental separation/loss 1.82, CI (1.14-2.50). No between-group difference was identified by either sociolegal classification (abuse, neglect, household dysfunction) or threat-deprivation dimensions (high on threat, high on deprivation and mixed). CONCLUSIONS: There are links of mild to medium strength between overall ACEs and PD as well as individual ACEs. The homogeneous effect sizes across ACEs either suggest the effects of ACEs on PD are comparable, or raised the question whether the categorical or dimensional approaches to classifying ACEs are the definitive ways to conceptualize the impact of ACEs on later mental health.

CBT treatment delivery formats for panic disorder: a systematic review and network meta-analysis of randomised controlled trials.

Several in-person and remote delivery formats of cognitive-behavioural therapy (CBT) for panic disorder are available, but up-to-date and comprehensive evidence on their comparative efficacy and acceptability is lacking. Our aim was to evaluate the comparative efficacy and acceptability of all CBT delivery formats to treat panic disorder. To answer our question we performed a systematic review and network meta-analysis of randomised controlled trials. We searched MEDLINE, Embase, PsycINFO, and CENTRAL, from inception to 1st January 2022. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO. We found a total of 74 trials with 6699 participants. Evidence suggests that face-to-face group [standardised mean differences (s.m.d.) -0.47, 95% confidence interval (CI) -0.87 to -0.07; CINeMA = moderate], face-to-face individual (s.m.d. -0.43, 95% CI -0.70 to -0.15; CINeMA = Moderate), and guided self-help (SMD -0.42, 95% CI -0.77 to -0.07; CINeMA = low), are superior to treatment as usual in terms of efficacy, whilst unguided self-help is not (SMD -0.21, 95% CI -0.58 to -0.16; CINeMA = low). In terms of acceptability (i.e. all-cause discontinuation from the trial) CBT delivery formats did not differ significantly from each other. Our findings are clear in that there are no efficacy differences between CBT delivered as guided self-help, or in the face-to-face individual or group format in the treatment of panic disorder. No CBT delivery format provided high confidence in the evidence at the CINeMA evaluation.

Altered DNA Methylation of the Serotonin Transporter Gene Associated with Early Life Stress and White Matter Microalterations in Korean Patients with Panic Disorder.

INTRODUCTION: Changes in the DNA methylation of 5-HTTLPR are associated with the pathophysiology of panic disorder (PD). This study was conducted to investigate the association between stressful life events and the level of 5-HTTLPR methylation in patients with PD. We also examined whether these factors were associated with white matter alterations in psychological trauma-related regions. METHODS: The participants comprised 232 patients with PD and 93 healthy adults of Korean descent. DNA methylation levels of five cytosine-phosphate-guanine (CpG) sites in the 5-HTTLPR region were analyzed. Voxel-wise statistical analysis of diffusion tensor imaging data was performed within the trauma-related regions. RESULTS: PD patients showed significantly lower levels of the DNA methylation at 5-HTTLPR 5 CpG sites than healthy controls. In patients with PD, the DNA methylation levels at 5-HTTLPR 5 CpG sites showed significant negative association with the parental separation-related psychological distress, and positive correlations with the fractional anisotropy values of the superior longitudinal fasciculus (SLF) which might be related to trait anxiety. CONCLUSION: Early life stress was significantly associated with DNA methylation levels at 5-HTTLPR related to the decreased white matter integrity in the SLF region in PD. Decreased white matter connectivity in the SLF might be related to trait anxiety and is vital to the pathophysiology of PD.

Pharmacologic predictors of benzodiazepine response trajectory in anxiety disorders: a Bayesian hierarchical modeling meta-analysis.

BACKGROUND: Despite frequent benzodiazepine use in anxiety disorders, the trajectory and magnitude of benzodiazepine response and the effects of benzodiazepine potency, lipophilicity, and dose on improvement are unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel group, placebo-controlled trials of benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in anxiety was evaluated as a function of medication, disorder, time, potency, lipophilicity, and standardized dose and compared among benzodiazepines. RESULTS: Data from 65 trials (73 arms, 7 medications, 7110 patients) were included. In the logarithmic model of response, treatment effects emerged within 1 week of beginning treatment (standardized benzodiazepine-placebo difference = -0.235 ± 0.024, CrI: -0.283 to -0.186, P < .001) and placebo response plateaued at week 4. Doses <6 mg per day (lorazepam equivalents) produced faster and larger improvement than higher doses (P = .039 for low vs medium dose and P = .005 for high vs medium dose) and less lipophilic benzodiazepines (beta = 0.028 ± 0.013, P = .030) produced a greater response over time. Relative to the reference benzodiazepine (lorazepam), clonazepam (beta = -0.217 ± 0.95, P = .021) had a greater trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam). CONCLUSIONS: In adults with anxiety disorders, benzodiazepine-related improvement emerges early, and the trajectory and magnitude of improvement is related to dose and lipophilicity. Lower doses and less lipophilic benzodiazepines produce greater improvement.

Latency to selective serotonin reuptake inhibitor vs benzodiazepine treatment in patients with panic disorder: a naturalistic study.

BACKGROUND: Panic disorder (PD) is a prevalent and impairing anxiety disorder with previous reports suggesting that the longer the condition remains untreated, the greater the likelihood of nonresponse. However, patients with PD may wait for years before receiving a guideline-recommended pharmacological treatment. The widespread prescription of benzodiazepines (BDZ) for managing anxiety symptoms and disorders might delay the administration of pharmacotherapy according to guidelines (eg, selective serotonin reuptake inhibitors, SSRIs). The present study aimed to determine the mean duration of untreated illness (DUI) in a sample of PD patients, to quantify and compare DUI-SSRI to DUI-BDZ, and to compare findings with those from previous investigations. METHODS: Three hundred and fourteen patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of PD were recruited from an Italian outpatient psychotherapy unit, and epidemiological and clinical variables were retrieved from medical records. Descriptive statistical analyses were undertaken for sociodemographic and clinical variables, Wilcoxon matched-pair signed rank test was applied to compare the distribution of DUI-SSRI vs DUI-BDZ, and Welch's t test was performed to compare findings with those from previous studies. RESULTS: The mean DUI-SSRI of the total sample was 64.25 ± 112.74 months, while the mean DUI-BDZ was significantly shorter (35.09 ± 78.62 months; P < 0.0001). A significantly longer DUI-SSRI, compared to findings from previous studies, was also observed. CONCLUSIONS: The present results confirm a substantial delay in implementing adequate pharmacological treatments in patients with PD, and highlight the discrepancy between recommendations from international treatment guidelines and common clinical practice in relation to BDZ prescription.