Elevated accuracy in recognition of subliminal happy facial expressions in patients with panic disorder after psychotherapy.

Background: Individuals with anxiety disorders (ADs) often display hypervigilance to threat information, although this response may be less pronounced following psychotherapy. This study aims to investigate the unconscious recognition performance of facial expressions in patients with panic disorder (PD) post-treatment, shedding light on alterations in their emotional processing biases. Methods: Patients with PD (n=34) after (exposure-based) cognitive behavior therapy and healthy controls (n=43) performed a subliminal affective recognition task. Emotional facial expressions (fearful, happy, or mirrored) were displayed for 33 ms and backwardly masked by a neutral face. Participants completed a forced choice task to discriminate the briefly presented facial stimulus and an uncovered condition where only the neutral mask was shown. We conducted a secondary analysis to compare groups based on their four possible response types under the four stimulus conditions and examined the correlation of the false alarm rate for fear responses to non-fearful (happy, mirrored, and uncovered) stimuli with clinical anxiety symptoms. Results: The patient group showed a unique selection pattern in response to happy expressions, with significantly more correct "happy" responses compared to controls. Additionally, lower severity of anxiety symptoms after psychotherapy was associated with a decreased false fear response rate with non-threat presentations. Conclusion: These data suggest that patients with PD exhibited a "happy-face recognition advantage" after psychotherapy. Less symptoms after treatment were related to a reduced fear bias. Thus, a differential facial emotion detection task could be a suitable tool to monitor response patterns and biases in individuals with ADs in the context of psychotherapy.

Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.

OBJECTIVE: Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults). METHODS: Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis. RESULTS: Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents. CONCLUSIONS: Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

Differential Psychological Treatment Effects in Patients With Late-Life Depression and a History of Childhood Maltreatment.

OBJECTIVE: This is the first interventional study to assess the impact of childhood maltreatment (CM) on psychological treatment outcomes in patients with late-life depression (LLD). METHODS: This is a secondary analysis of a multicenter, randomized controlled trial with 251 participants aged ≥60 years with moderate to severe depression. Participants were randomly assigned to cognitive behavioral therapy for late life depression (LLD-CBT) or to a supportive intervention (SUI). Treatment outcomes were measured by changes in the Geriatric Depression Scale (GDS). RESULTS: In the intention-to-treat sample (n = 229), both LLD-CBT (n = 115) and SUI (n = 114) significantly reduced depressive symptoms in patients with CM, with large effects at post-treatment (d = 0.95 [95% CI: 0.65 to 1.25] in LLD-CBT; d = 0.82 [95% CI: 0.52 to 1.12] in SUI). A significant treatment group*CM interaction (F(1,201.31) = 4.71; p = .031) indicated greater depressive symptom reduction in LLD-CBT compared to SUI at week 5 and post-treatment for patients without CM, but not at 6-month follow-up. Across both treatments, higher severity of the CM subtype 'physical neglect' was associated with a smaller depressive symptom reduction (F(1,207.16) = 5.37; p = .021). CONCLUSIONS: Specific and non-specific psychotherapy effectively reduced depressive symptoms in older individuals with depression and early trauma. For patients without early trauma, LLD-CBT may be preferable over SUI. Considering early trauma subtypes may contribute to develop personalized treatment approaches.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Reduced contrast sensitivity, pattern electroretinogram ratio, and diminished a-wave amplitude in patients with major depressive disorder.

The electroretinogram (ERG), a non-invasive electrophysiological tool used in ophthalmology, is increasingly applied to investigate neural correlates of depression. The present study aimed to reconsider previous findings in major depressive disorder (MDD) reporting (1) a diminished contrast sensitivity and (2) a reduced patten ERG (PERG) amplitude ratio, and additionally, to assess (3) the photopic negative response (PhNR) from the flash ERG (fERG), with the RETeval® device, a more practical option for clinical routine use. We examined 30 patients with a MDD and 42 healthy controls (HC), assessing individual contrast sensitivity thresholds with an optotype-based contrast test. Moreover, we compared the PERG ratio, an established method for early glaucoma detection, between both groups. The handheld ERG device was used to measure amplitudes and peak times of the fERG components including a-wave, b-wave and PhNR in both MDD patients and HCs. MDD patients exhibited diminished contrast sensitivity together with a reduced PERG ratio, compared to HC. With the handheld ERG device, we found reduced a-wave amplitudes in MDD, whereas no significant differences were observed in the fERG b-wave or PhNR between patients and controls. The reduced contrast sensitivity and PERG ratio in MDD patients supports the hypothesis that depression is associated with altered visual processing. The findings underscore the PERG's potential as a possible objective marker for depression. The reduced a-wave amplitude recorded with the RETeval® system in MDD patients might open new avenues for using handheld ERG devices as simplified approaches for advancing depression research compared to the PERG.

Chronic insomnia, REM sleep instability and emotional dysregulation: A pathway to anxiety and depression?

The world-wide prevalence of insomnia disorder reaches up to 10% of the adult population. Women are more often afflicted than men, and insomnia disorder is a risk factor for somatic and mental illness, especially depression and anxiety disorders. Persistent hyperarousals at the cognitive, emotional, cortical and/or physiological levels are central to most theories regarding the pathophysiology of insomnia. Of the defining features of insomnia disorder, the discrepancy between minor objective polysomnographic alterations of sleep continuity and substantive subjective impairment in insomnia disorder remains enigmatic. Microstructural alterations, especially in rapid eye movement sleep ("rapid eye movement sleep instability"), might explain this mismatch between subjective and objective findings. As rapid eye movement sleep represents the most highly aroused brain state during sleep, it might be particularly prone to fragmentation in individuals with persistent hyperarousal. In consequence, mentation during rapid eye movement sleep may be toned more as conscious-like wake experience, reflecting pre-sleep concerns. It is suggested that this instability of rapid eye movement sleep is involved in the mismatch between subjective and objective measures of sleep in insomnia disorder. Furthermore, as rapid eye movement sleep has been linked in previous works to emotional processing, rapid eye movement sleep instability could play a central role in the close association between insomnia and depressive and anxiety disorders.

Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes.

INTRODUCTION: Psychotic syndromes can have autoimmune-mediated causes in some patients. Thus, this retrospective work aims to investigate the role of rheumatological markers in the development of psychosis. PATIENTS AND METHODS: In total, 224 patients with psychotic syndromes receiving a "rheumatological laboratory screening" (including C-reactive protein [CRP], immunofixation, complement factors, rheumatoid factor [RF], antiphospholipid antibodies [APAs], antineutrophil cytoplasmic antibodies [ANCAs], and antinuclear antibodies [ANAs]) were analyzed. A further diagnostic work-up included investigations of neuronal antibodies and cerebrospinal fluid (CSF), as well as electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain. ANA testing was routinely performed in all patients using serum on human epithelioma-2 (Hep2) cells, and a subset of patients (N = 73) also underwent tissue-based assays from serum and CSF. The number of cases with autoimmune psychotic syndromes was descriptively collected, and ANA-positive and -negative patients were compared in detail. RESULTS: CRP was elevated in 9 % of patients, immunofixation identified alterations in 8 %, complement factor C3 was decreased in 14 %, RF was elevated in 1 %, APAs were elevated in 7 %, ANCAs were not clearly positive, and ANAs were positive in 19 % (extractable nuclear antigen [ENA] differentiation resulted in positive findings in 14 patients). From the 73 patient samples additionally investigated using tissue-based assays, there were 26 positive results for some kind of ANA (36 %), and overall using both methods, 54 patients (24 %) were considered positive for ANAs. A neuropsychiatric evaluation revealed a possible autoimmune psychotic syndrome in seven patients (3 %) and a probable autoimmune psychotic syndrome in two patients (1 %). ANA-positive patients were more frequently treated with antidepressants (p = 0.040) and had a higher number of somatic comorbidities (p < 0.001). In addition, (chronic) inflammatory MRI lesions (p = 0.008) and focal atrophies (p = 0.012) were found more frequently in ANA-positive than ANA-negative patients. DISCUSSION: Rheumatological screening led to suspicion of a possible or probable autoimmune psychotic syndrome in 4%. ANAs were associated with MRI pathologies. Therefore, rheumatological processes may contribute to the development of psychotic syndromes in rare cases.

Perceived Physical Health and Cognitive Behavioral Therapy vs Supportive Psychotherapy Outcomes in Adults With Late-Life Depression: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Physical diseases co-occur with late-life depression (LLD). The influence of physical diseases and the subjective perception of physical health (PPH) on treatment outcome in LLD, however, is not well understood. Objective: To assess the association of physical diseases and PPH with the outcomes of 2 different types of psychotherapy in LLD. Design, Setting, and Participants: This post hoc secondary analysis of a multicenter, observer-blinded, controlled, parallel-group randomized clinical trial assessed participants 60 years or older with moderate to severe depression recruited at 7 psychiatric-psychotherapeutic outpatient trial sites in Germany from October 1, 2018, to November 11, 2020. Data analysis was performed from April 1 to October 31, 2023. Interventions: Patients received LLD-specific cognitive behavioral therapy (LLD-CBT) or supportive unspecific intervention (SUI). Main Outcomes and Measures: Depression severity, response, and remission were measured during treatment and at 6-month follow-up by the change in the 30-item Geriatric Depression Scale (GDS) score. Physical health and PPH were assessed by the number of physical diseases, Charlson Comorbidity Index (CCI), and the World Health Organization Quality of Life Brief Version physical health subscale. Results: A total of 251 patients were randomized to LLD-CBT (n = 126) or SUI (n = 125), of whom 229 (mean [SD] age, 70.2 [7.1] years; 151 [66%] female) were included in the intention-to-treat analysis. Patients with low and moderate PPH at baseline had significantly less reduction in the GDS score across both treatment groups than patients with high PPH (estimated marginal mean difference [EMMD], 2.67; 95% CI, 0.37-4.97; P = .02 for low PPH and EMMD, 1.82; 95% CI, 0.22-3.42; P = .03 for moderate vs high PPH). Higher PPH at baseline was associated with higher likelihood of response (odds ratio [OR], 1.04; 95% CI, 1.00-1.06; P = .009) and remission at the end of treatment (OR, 1.04; 95% CI, 1.02-1.08; P = .002) and response (OR, 1.05; 95% CI, 1.02-1.08; P < .001) and remission at follow-up (OR, 1.06; 95% CI, 1.03-1.10; P < .001) across both treatment groups. However, a significant interaction of PPH with treatment group was observed with low PPH at baseline being associated with significantly larger reduction in GDS scores in SUI compared with LLD-CBT at the end of treatment (EMMD, -6.48; 95% CI, -11.31 to -1.64; P = .009) and follow-up (EMMD, -6.49; 95% CI, -11.51 to -1.47; P = .01). In contrast, patients with high PPH at baseline had a significantly greater reduction in GDS scores in LLD-CBT compared with SUI at all time points (week 5: EMMD, -4.08; 95% CI, -6.49 to -1.67; P = .001; end-of-treatment: EMMD, -3.67; 95% CI, -6.72 to -0.61; P = .02; and follow-up: EMMD, -3.57; 95% CI, -6.63 to -0.51; P = .02). The number of physical diseases or CCI at baseline did not have an effect on the change in GDS score, response, or remission, neither across both groups nor within either group. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, subjective PPH was associated with treatment outcome, response, and remission in psychotherapy of LLD. Patients with LLD responded differently to LLD-CBT and SUI, depending on their baseline PPH score. Treatment approaches for patients with LLD should address PPH in personalized interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT03735576; Deutsches Register Klinischer Studien Identifier: DRKS00013769.

[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.

Mental health improvement after the COVID-19 pandemic in individuals with psychological distress.

The COVID-19 pandemic and associated countermeasures had an immensely disruptive impact on people's lives. Due to the lack of systematic pre-pandemic data, however, it is still unclear how individuals' psychological health has been affected across this incisive event. In this study, we analyze longitudinal data from two healthy samples (N = 307) to provide quasi-longitudinal insight into the full trajectory of psychological burden before (baseline), during the first peak, and at a relative downturn of the COVID-19 pandemic. Our data indicated a medium rise in psychological strain from baseline to the first peak of the pandemic (d = 0.40). Surprisingly, this was overcompensated by a large decrease of perceived burden until downturn (d = - 0.93), resulting in a positive overall effect of the COVID-19 pandemic on mental health (d = 0.44). Accounting for this paradoxical positive effect, our results reveal that the post-pandemic increase in mental health is driven by individuals that were already facing psychological challenges before the pandemic. These findings suggest that coping with acute challenges such as the COVID-19 pandemic can stabilize previously impaired mental health through reframing processes.

Digital cognitive behavioural therapy for insomnia reduces insomnia in nurses suffering from shift work disorder: A randomised-controlled pilot trial.

Insomnia is a primary symptom of shift work disorder, yet it remains undertreated. This randomised-controlled pilot trial examined the efficacy of a digital, guided cognitive behavioural therapy for insomnia adapted to shift work (SleepCare) in nurses with shift work disorder. The hypothesis was that SleepCare reduces insomnia severity compared with a waitlist control condition. A total of 46 unmedicated nurses suffering from shift work disorder with insomnia (age: 39.7 ± 12.1 years; 80.4% female) were randomised to the SleepCare group or the waitlist control group. The primary outcome measure was the Insomnia Severity Index. Other questionnaires on sleep, mental health and occupational functioning, sleep diary data and actigraphy data were analysed as secondary outcomes. Assessments were conducted before (T0), after the intervention/waitlist period (T1), and 6 months after treatment completion (T2). The SleepCare group showed a significant reduction in insomnia severity from T0 to T1 compared with the control condition (ß = -4.73, SE = 1.12, p < 0.001). Significant improvements were observed in sleepiness, dysfunctional beliefs about sleep, pre-sleep arousal, sleep effort, self-reported sleep efficiency and sleep onset latency. No significant effect was found in actigraphy data. Depressive and anxiety symptoms, cognitive irritation and work ability improved significantly. Overall, satisfaction and engagement with the intervention was high. SleepCare improved insomnia severity, sleep, mental health and occupational functioning. This is the first randomised-controlled trial investigating the efficacy of digital cognitive behavioural therapy for insomnia in a population suffering from shift work disorder with insomnia. Future research should further explore these effects with larger sample sizes and active control conditions.

[Treatment-resistant obsessive-compulsive disorders]. / Therapieresistente Zwangsstörungen.

BACKGROUND: Obsessive-compulsive disorders (OCD) are mainly treated with disorder-specific cognitive behavioral therapy using exposure and response management and/or selective serotonin reuptake inhibitors; however, a significant subgroup of patients does not sufficiently benefit from this approach. OBJECTIVE: This article provides an overview of treatment-resistant OCD. MATERIAL AND METHODS: In this narrative review the definition, causes, diagnostic and therapeutic approaches to treatment-resistant OCD are addressed. RESULTS: Treatment resistance can be assumed in the absence of clinically relevant improvement under therapy, in the sense of a reduction of < 25% on the Yale-Brown obsessive-compulsive scale and a score of 4 (no change) on the clinical global impression-improvement scale. The number of unsuccessful treatment attempts required to establish treatment resistance is defined differently. Causative factors include misdiagnosis, a high severity, comorbid disorders, substance use, specific symptom constellations, organic causes, environmental factors, and aggravating factors in psychotherapy and pharmacotherapy. Suggestions for diagnostic and therapeutic approaches based on the German S3 guideline on OCD are presented. CONCLUSION: For patients with treatment resistance to first-line therapy, useful diagnostic and therapeutic recommendations are available (psychotherapeutic, psychopharmacological and neurostimulation procedures).

Obsessive-compulsive symptoms and brain lesions compatible with multiple sclerosis.

Autoimmune-mediated obsessive-compulsive disorder (OCD) can occur in multiple sclerosis (MS). Here, a well-studied case study of a patient with OCD and MS-compatible diagnostic findings is presented. The 42-year-old female patient had displayed OCD symptoms for 6 years. Magnetic resonance imaging (MRI) identified several periventricular and one brainstem lesion suggestive of demyelination. Cerebrospinal fluid (CSF) analyses detected an increased white blood cell count, intrathecal immunoglobulin (Ig) G and IgM synthesis, CSF-specific oligoclonal bands, and a positive MRZ reaction. Neopterin was increased, but sarcoidosis was excluded. In the absence of neurological attacks and clues for MRI-based dissemination in time, a radiologically isolated syndrome, the pre-disease stage of MS, was diagnosed. Neurotransmitter measurements of CSF detected reduced serotonin levels. In the absence of visible strategic demyelinating lesions within the cortico-striato-thalamo-cortical circuits, OCD symptoms may relate to reduced intrathecal serotonin levels and mild neuroinflammatory processes. Serotonin abnormalities in MS should be studied further, as they could potentially explain the association between neuroinflammation and mental illnesses.

D-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity.

The partial N-methyl-D-aspartate receptor (NMDAR) agonist D-Cycloserine (DCS) has been evaluated for the treatment of a wide variety of psychiatric disorders, including dementia, schizophrenia, depression and for the augmentation of exposure-based psychotherapy. Most if not all of the potential psychiatric applications of DCS target an enhancement or restitution of cognitive functions, learning and memory. Their molecular correlate is long-term synaptic plasticity; and many forms of synaptic plasticity depend on the activation of NMDA receptors. Here, we comprehensively examined the modulation of different forms of synaptic plasticity in the hippocampus by DCS and its mechanism. We found that DCS positively modulates NMDAR-dependent forms of long-term synaptic plasticity (long-term synaptic potentiation, LTP, and long-term synaptic depression, LTD) in hippocampal brain slices of juvenile rats without affecting basal synaptic transmission. DCS binds to the D-serine/glycine binding site of the NMDAR. Pharmacological inhibition of this site prevented the induction of LTP, whereas agonism at the D-serine/glycine binding site augmented LTP and could functionally substitute for weak LTP induction paradigms. The most probable origin of endogenous D-serine are astrocytes, and its exocytosis is regulated by astrocytic metabotropic glutamate receptors (mGluR1). Functional eradication of astrocytes, inhibition of mGluR1 receptors and G-protein signaling in astrocytes adjacent to postsynaptic neurons prevented the induction of NMDAR-dependent forms of LTP and LTD. Our results support the enhancement of a bidirectional range of NMDAR-dependent hippocampal synaptic plasticity by DCS and D-serine-mediated gliotransmission. Therefore, the D-serine/glycine-binding site in NMDAR is a major target for psychopharmacological interventions targeting plasticity-related disorders.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Ketamine in multiple treatment-resistant depressed inpatients: A naturalistic cohort study.

BACKGROUND: Ketamine has emerged as an effective treatment option for patients with treatment-resistant depression. However, there is limited evidence of the benefits of ketamine in inpatients with multiple treatment resistance (MTR), who far exceed the formal criteria for treatment resistance and suffer from extensive psychiatric comorbidities. OBJECTIVE: The aim of this naturalistic study was to provide preliminary evidence for the use of ketamine in the treatment of MTR depression in a naturalistic inpatient setting. METHODS: Seventy-seven patients (mean age 45.1 ± 13.8 years) were treated with intravenous or intranasal ketamine (1068 administrations) twice weekly for five weeks, followed by maintenance therapy if clinically indicated. Treatment effects were assessed with the BDI, and side effects were assessed by clinicians. We analyzed dose- and route of application-related changes in depression severity, response and remission rates as well as effects on suicidality and frequency of adverse events. RESULTS: Depression severity and suicidality decreased in the acute treatment phase and these changes persisted during the maintenance therapy phase. A total of 28.9 % of the patients met the criteria for response, and 15 % met the criteria for remission. The initial treatment response was highly predictive of the outcome at the end of the acute treatment phase. None of the reported side effects required medical intervention. High-dose intravenous ketamine (0.75-1 mg/kg) resulted in the most pronounced clinical effects. LIMITATIONS: This observational, retrospective, and naturalistic study may be subject to bias and did not allow control of external variables. CONCLUSIONS: We outlined a clinically feasible, high-dose ketamine treatment regimen for hospitalized patients with MTR depression.