Treatment-resistant Generalized Anxiety Disorder Research Articles

A pilot study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder

ObjectiveThis study intended to evaluate a possible therapeutic effect among patients with treatment-refractory generalized anxiety disorder (trGAD) by using transcranial focused ultrasound (tfUS) to modulate amygdalar activity. MethodsTwenty-five participants with severe trGAD as outlined in the DSM-V were recruited from Los Angeles neurology and psychiatry clinics. All participants completed eight weekly 10-min tfUS sessions targeting the right amygdala. Functional and structural neuroimaging were used to navigate individual targets. Outcome measures including the Hamilton Anxiety Inventory (HAM-A, primary outcome) and Beck Anxiety Inventory (BAI) were collected at baseline and protocol completion. Upon study completion, participants were asked to report perceived change in clinical status using the Patient Global Impression – Improvement (PGI-I) scale. Data was collected from May 2020 through January 2023. ResultsAll participants were able to tolerate treatment without notable side effects. No adverse events were reported. A Wilcoxon Signed-Rank Test was conducted to compare pre- and post-tfUS measures of anxiety. tfUS resulted in a significant decrease in anxiety as measured by the HAM-A (W = −3.69, p < 0.001, pre-post-Δ = −12.64 ± 12.51) and the BAI (W = −3.94, p < 0.001, pre-post-Δ = −12.88 ± 10.42). Sixteen (16) of twenty-five (25) total participants indicated clinically significant benefit on PGI-I scores at completion. ConclusionThis study provides preliminary evidence supporting the safety and efficacy of tfUS as a clinical intervention. These results warrant further investigation of tfUS as a therapeutic intervention for anxiety and other psychiatric and neurological disorders. ClinicalTrials.gov identifierNCT04250441.

2022 MHC Awards and Recognition.

The Mental Health Clinician (MHC) continues to be a valuable resource for psychiatric practitioners and researchers with nearly 1 million article views in 2022. MHC is now indexed in PubMed, Scopus, and DOAJ which reflects the quality of our authors, reviewers, and editorial board. The editorial board is very appreciative of everyone who submitted a manuscript or authored a peer review in 2022 and would like to acknowledge those whose contributions have been exceptionally significant.The MHC Editors' Choice Award for Outstanding Articles identifies those manuscripts that received a great deal of attention in 2022. The winners were chosen from articles published in the last 4 years (2019-2022) by the number of article views through PubMed. The editorial board commends these winners for such significant contributions to the psychopharmacology literature!Ansara E. Management of treatment-resistant generalized anxiety disorder. Ment Health Clin [Internet]. 2020;10(6):326-334. DOI: 10.9740/mhc.2020.11.326.Finegan A, Mabrouk U, Nelson, LA. Gabapentin-induced bilateral lower extremity edema in patient with pervasive developmental disorder and schizoaffective disorder. Ment Health Clin [Internet]. 2020;10(4):250-253. DOI: 10.9740/mhc.2020.07.250.Laskey C, Opitz B. Tinnitus associated with benzodiazepine withdrawal syndrome: A case report and literature review. Ment Health Clin [Internet]. 2020;10(3):100-3. DOI: 10.9740/mhc.2020.05.100.Each MHC manuscript undergoes review by at least 3 peers and the quality of MHC's articles is directly related to its base of excellent peer reviewers. Being a peer reviewer is an often-under-recognized service that requires significant uncompensated time and effort. For someone to be invited again and again as a peer reviewer, their reviews must consistently be timely and of high quality. We wish to recognize our most reliable peer reviewers with the designations of Outstanding Peer Reviewer and Trusted Peer Reviewer, for those having completed at least 20 and 10 reviews since January 1, 2015, respectively.A heartfelt thank you to all of our peer reviewers for The Mental Health Clinician in 2022 and congratulations to our Outstanding and Trusted Peer Reviewers!Last, but not least, we would like to thank the current MHC editorial board for their tireless efforts in ensuring that we publish quality content. The journal would not be possible without the combined experience and dedication of these editors, and we are indebted to their continued efforts.

A pilot study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder

A pilot study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder

A case study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder and major depressive disorder

A case study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder and major depressive disorder

A pilot study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder

A pilot study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder

Management of treatment-resistant generalized anxiety disorder.

Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry. Around half of the patients treated for GAD will fail to respond to initial treatment. Treatment-resistant (or refractory) GAD is defined as failure to respond to at least 1 trial of antidepressant therapy at adequate dose and duration. Review of the literature indicates several potential medication classes and individual agents that can be used as augmentation strategies to treat residual symptoms when recommended therapy per clinical practice guidelines fails. A thorough literature search revealed 2 medication classes with the largest amount of data to support their use in treatment-resistant GAD treatment: gamma-aminobutyric acid–related agents and atypical antipsychotics. This article focuses on evidence-based recommendations for the use of these agents as adjunctive therapies for patients with treatment-resistant GAD. Different pharmacologic approaches to use these agents are demonstrated through 2 patient cases in which patients have failed first-line treatment options.

Yogic Breathing Instruction in Patients with Treatment-Resistant Generalized Anxiety Disorder: Pilot Study.

Aim:This study aims to evaluate the feasibility and effects of instruction in yogic breathing techniques (Pranayama) in patients with treatment-resistant generalized anxiety disorder (GAD) in UK secondary mental health services settings.Materials and Methods:Participants were adult primary or secondary care patients with a primary diagnosis of GAD (with or without comorbidity) and persistent anxiety symptoms of at least moderate intensity, despite prior treatment with two or more medications of proven efficacy. Patients participated in group-delivered yogic breathing training and practice for 12 weeks. Structured assessments were performed at baseline, after 1, 2, and 6 weeks of instruction, and at end-point. Participants also completed the antisaccade (emotional variant) task and startle response task at baseline and end-point.Results:At baseline, participating patients (n = 9) had moderate-to-severe anxiety symptoms and mild-to-moderate depressive symptoms, they attended 84% of offered sessions and provided positive feedback on the content and delivery of treatment. Symptom severity reduced significantly from baseline to end-point. There were greater errors on negative trials compared to neutral trials in the antisaccade task at baseline, and a significant reduction in antisaccade errors for negative stimuli as compared to neutral stimuli between baseline and end-point: but there were no significant differences in either mean heart rate or startle response between baseline and end-point.Limitations:The absence of a control group and small sample size.Conclusion:Yogic breathing techniques proved simple to learn and may be beneficial in reducing anxiety and depressive symptoms in patients with treatment-resistant GAD. Yogic breathing had no effect on autonomic arousal, but the reduction in errors to negative stimuli in the antisaccade task suggests an improvement in attention control during the intervention accompanying the reduction in symptoms.

Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety.

BackgroundKetamine is swiftly effective in a range of neurotic disorders that are resistant to conventional antidepressant and anxiolytic drugs. The neural basis for its therapeutic action is unknown. Here we report the effects of ketamine on the EEG of patients with treatment-resistant generalized anxiety and social anxiety disorders.MethodsTwelve patients with refractory DSM-IV generalized anxiety disorder and/or social anxiety disorder provided EEG during 10 minutes of relaxation before and 2 hours after receiving double-blind drug administration. Three ascending ketamine dose levels (0.25, 0.5, and 1 mg/kg) and midazolam (0.01 mg/kg) were given at 1-week intervals to each patient, with the midazolam counterbalanced in dosing position across patients. Anxiety was assessed pre- and postdose with the Fear Questionnaire and HAM-A.ResultsKetamine dose-dependently improved Fear Questionnaire but not HAM-A scores, decreased EEG power most at low (delta) frequency, and increased it most at high (gamma) frequency. Only the decrease in medium-low (theta) frequency at right frontal sites predicted the effect of ketamine on the Fear Questionnaire. Ketamine produced no improvement in Higuchi’s fractal dimension at any dose or systematic changes in frontal alpha asymmetry.ConclusionsKetamine may achieve its effects on treatment-resistant generalized anxiety disorder and social anxiety disorder through related mechanisms to the common reduction by conventional anxiolytic drugs in right frontal theta. However, in the current study midazolam did not have such an effect, and it remains to be determined whether, unlike conventional anxiolytics, ketamine changes right frontal theta when it is effective in treatment-resistant depression.

The Treatment of Refractory Generalized Anxiety Disorder

Purpose Generalized anxiety disorder (GAD) is one of the most common anxiety disorders, afflicting approximately 6% of the general population in their lifetime. It has a chronic and episodic course, requiring a long-term treatment approach. A variety of pharmacological agents and psychological treatments have been shown to be efficacious as GAD treatments; however, remission effect sizes for first-line treatments are small. This review aims to examine the existing evidence for next-step pharmacological and psychological treatments for individuals who remain symptomatic after first-line treatment. Recent Findings Relatively few studies have examined next-step treatments for treatment-resistant GAD (TR-GAD). The bulk of the available treatment-resistant literature has investigated augmentation with atypical antipsychotics or pregabalin. Summary Unfortunately, there is little information to guide clinicians in this area. The strongest evidence supports augmentation with pregabalin, however, this is based primarily upon one study. Approaches to consider when treating patients with TR-GAD are discussed.

A multicomponent yoga-based, breath intervention program as an adjunctive treatment in patients suffering from generalized anxiety disorder with or without comorbidities

Objectives:The aim of this study is to evaluate the efficacy and tolerability of Sudarshan Kriya Yoga (SKY) course in generalized anxiety disorder (GAD) outpatients, who after eight weeks of an appropriate dose of traditional therapy had not yet achieved remission.Subjects:The adult participants (18-65 years) were outpatients with a primary diagnosis of GAD with or without comorbidities on the Mini-International Neuropsychiatric Interview (MINI). Participants had a minimum of eight weeks standard treatment with an appropriate dose of a standard prescription anxiolytic, a clinician global impression-severity (CGI-S) score of 5-7, a Hamilton anxiety scale (HAM-A) total score ≥20 including a score of >2 on the anxious mood and tension items.Materials and Methods:Forty-one patients were enrolled in an open-label trial of the SKY course as an adjunct to standard treatment of GAD at the START Clinic for Mood and Anxiety Disorders, a tertiary care mood and anxiety disorder clinic in Toronto. The SKY course was administered over five days (22 h total). Subjects were encouraged to practice the yoga breathing techniques at home for 20 min per day after the course and were offered group practice sessions for 2 h once a week led by certified yoga instructors. The primary outcome measure was the mean change from pre-treatment on the HAM-A scale. Psychological measures were obtained at baseline and four weeks after completing the intervention.Results:Thirty-one patients completed the program (mean age 42.6 ± 13.3 years). Among completers, significant reductions occurred in the pre- and post-intervention mean HAM-A total score (t=4.59; P<0.01) and psychic subscale (t=5.00; P≤0.01). The response rate was 73% and the remission rate 41% as measured on the HAM-A.Conclusion:The results of this small pilot trial suggest that the SKY course represents a potentially valuable adjunct to standard pharmacotherapy in patients with GAD or treatment-resistant GAD, and warrants further investigation. In particular, changes in worry and body symptoms showed significant improvements that may further our understanding of the mechanism of change in the tolerance of anxiety and worry.

Pharmacological treatment of generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic, relapsing, debilitating disorder, associated with markedly impaired social and occupational functioning. Pharmacological treatment is considered standard care and several drug classes are now FDA approved for the treatment of GAD. While there are clear data for the efficacy of short-term acute treatment, long-term treatment and treatment-resistant GAD remain challenging.Areas covered: This article describes current pharmacological treatment options for GAD, with focus on benzodiazepines, azapirones, antidepressants and anticonvulsant and antipsychotic drugs. Recent findings from placebo-controlled clinical trials are reviewed and evidence-based clinical implications are discussed. A PubMed search was completed using the terms: ‘generalized anxiety disorder AND treatment’ and ‘generalized anxiety disorder AND therapy’. Additional pivotal trials were included for a historical perspective (older landmark trials that established efficacy and safety for older drug classes in the treatment of GAD).Expert opinion: Efficacy for treatment of GAD has been established for several different drug classes. At present, based on clear efficacy and good tolerability, first-line treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated. If an initial, at least moderate, clinical response is achieved under antidepressant therapy, treatment should be at least continued for 12 months.

Adjunctive Use of Atypical Antipsychotics for Treatment‐Resistant Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is a common, chronic mental illness that has a significant burden on the patient's quality of life. Treatment for GAD routinely consists of monotherapy with a proven anxiolytic such as an antidepressant or benzodiazepine, but many patients do not respond fully to these drugs, and additional treatment may be needed. Therefore, we reviewed the safety and efficacy of atypical antipsychotics as adjunct therapy to standard GAD pharmacotherapy in patients deemed treatment resistant. We performed a literature search of the MEDLINE database for English-language articles published from January 1966-May 2009. Identified articles were evaluated, and only open-label trials and randomized controlled trials (RCTs) were included in the review. Relevant references from the articles were also evaluated. Only a few reports of large-scale RCTs that assessed an atypical antipsychotic for treatment-resistant GAD have been published. Articles were found for five of the eight currently available atypical antipsychotics, but not for asenapine, clozapine, and paliperidone. Several open-label trials and smaller RCTs support the need for further evaluation of aripiprazole and quetiapine for treatment-refractory GAD, although one quetiapine trial demonstrated negative results. There is disparate data for risperidone, with one open-label trial and one small RCT showing positive results and one large RCT showing negative results. One open-label trial of ziprasidone and one RCT of olanzapine both showed beneficial effects of the drugs. Adverse effects were specific to each agent, with weight gain being the most common, but many studies did not monitor systematically for lipid level, weight, or glucose level changes. Although data suggest efficacy regarding the use of atypical antipsychotics for augmentation of treatment-refractory GAD, more rigorous studies (large, double-blind, placebo-controlled trials) on the safety and efficacy of these agents are needed in order to recommend their use in patients with GAD.

Ziprasidone Treatment of Refractory Generalized Anxiety Disorder

This 8-week, randomized, double-blind, placebo-controlled, flexible-dose trial assessed the efficacy, safety, and tolerability of ziprasidone in adults with treatment-resistant generalized anxiety disorder (GAD). Seventy-three subjects with treatment-resistant GAD were recruited, and 62 were randomized to either ziprasidone or placebo treatment at a ratio of 2:1 using a flexible dosing strategy (20-80 mg daily). Randomization was stratified into 2 subtypes of patients, those in whom the study drug was used as augmentation and those who have stopped their ineffective medications before entering the present trial (nonaugmented group). The subjects' clinical status was monitored weekly throughout the course of the study and included the Hamilton Anxiety Scale (primary outcome measure), the Clinical Global Impression Improvement and Severity of Illness scales, the Hamilton Depression Scale, the Sheehan Disability Scale, the Hospital Anxiety and Depression Scale, and the Abnormal Involuntary Movements Scale. Sixty-two patients were randomized to ziprasidone (n = 41) or placebo (n = 21). The dropout rate was 24%, consisting of 2 placebo patients and 13 ziprasidone patients. There was no statistically significant difference in the Hamilton Anxiety Scale score reduction between the drug and placebo groups. However, statistical trends were observed for an augmentation-study medication interaction effect, with ziprasidone patients producing more improvement in the nonaugmented than in the augmented group. This study provides pilot data for an augmentation-study medication interaction effect with ziprasidone patients producing more improvement in the nonaugmented than in the augmented group. Based on the data obtained in this trial and the subsequent power analyses, a future double-blind placebo-controlled trial should include at least 150 treatment-resistant GAD nonaugmented patients randomized to ziprasidone and placebo in a 1:1 ratio.

Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: A flexible-dose, open-label pilot trial

Background Generalized anxiety disorder (GAD) is a chronic disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result in troublesome side effects. Methods This was a 12-week, open-label, flexible-dose study to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 40 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of ≤10 at week 12), Clinical Global Impressions-Severity of Illness (CGI-S), Clinical Global Impressions-Global Improvement (CGI-I), Pittsburgh Sleep Quality Index (PSQI) and Penn State Worry Questionnaire (PSWQ). Results Adjunctive quetiapine (mean dose 386 mg/day at week 12) significantly reduced the HAM-A total scores from pre-treatment (29.8 ± 9.0) to week 12 (9.0 ± 10.2) (−20.6; p < 0.001). The HAM-A remission rate was 72.1% at week 12. Adjunctive quetiapine resulted in a significant reduction in all efficacy measures by study end. Quetiapine was well tolerated: the most common adverse event (AE) was sedation, with no incidence of serious AEs and no clinically significant changes in vital signs, weight (mean gain 0.5 kg at week 12) or laboratory assessments. Conclusion The results of this small pilot trial suggest that quetiapine adjunctive to traditional therapy may be a useful treatment in patients with GAD or treatment-resistant GAD, and warrant further investigation.

Erratum: Diminished GABAA Receptor Binding Capacity and a DNA Base Substitution in a Patient with Treatment-Resistant Depression and Anxiety

Correction to: Neuropsychopharmacology (2004) 29, 347–350. doi: 10.1038/sj.npp.1300353 The abstract of this article was reproduced with typesetting errors. The correct version of the abstract is presented below. In this report, we describe the case of a Caucasian male patient, aged 42, suffering from severe treatment-resistant generalized anxiety disorder with panic attacks and from severe major depression, for which he was treated with a course of electroconvulsive therapy.