Search

IntroductionTreatment resistant depression (TRD) affects approximately 10–30% of patients with major depressive disorder, and most patients with TRD do not respond to real-world treatments (RWT). Treatment with esketamine nasal spray (NS) plus a selective serotonin or serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) has significant long-term clinical benefit over RWT in patients with TRD. However, the impact on patient-reported function remains to be determined.MethodsThe ICEBERG analysis was an indirect treatment comparison performed using data from two studies of patients with TRD: SUSTAIN-2 (esketamine NS; NCT02497287) and the European Observational TRD Cohort (EOTC; RWT; NCT03373253; clinicaltrials.gov). Here, patient−reported functional remission, assessed using the Sheehan Disability Scale (SDS), was defined as SDS ≤6 at Month 6. Analyses were conducted using propensity score re−weighting and multivariable models based on 18 covariates.ResultsAt Month 6, the probability of functional remission in esketamine NS−treated patients from SUSTAIN-2 (n=512) was 25.6% (95% confidence interval [CI] 21.8–29.4), while the adjusted probability for RWT patients from the EOTC (n=184) was 11.5% (95% CI 6.9–16.1; relative risk: 2.226 [95% CI 1.451–3.416]; p=0.0003). In the total combined population (N=696), patients who did not achieve clinical response or remission had a low probability of achieving functional remission (5.84% and 8.76%, respectively). However, for patients who did achieve clinical response or remission, the probability of achieving functional remission was greater (43.38% and 54.15%, respectively), although many still did not achieve this status.ConclusionsFor patients with TRD, esketamine NS had a significant functional benefit versus RWT after 6 months of treatment. Irrespective of treatment, achievement of clinical response or remission was insufficient to attain functional remission. Nevertheless, clinical remission increased the likelihood of achieving functional remission, further supporting an important role for clinical remission in for the path towards functional recovery.

BackgroundTranscranial Magnetic Stimulation (TMS) is used for in vivo assessment of human motor cortical excitability, with application of TMS pulses over the motor cortex resulting in muscle responses that can be recorded with electromyography (EMG) as Motor Evoked Potentials (MEPs). These have been widely explored as potential biomarkers for neuropsychiatric disorders but methodological heterogeneity in acquisition, and inherent high variability, have led to constraints in reproducibility. Normalization, consisting in scaling the signal of interest to a known and repeatable measurement, reduces variability and is standard practice for between-subject comparisons of EMG. The effect of normalization on variability of MEP amplitude has not yet been explored and was assessed here using several methods.MethodsThree maximal voluntary isometric contractions (MVICs) and 40 MEPs were collected from the right hand in healthy volunteers, with a retest session conducted 4 to 8 weeks later. MEP amplitude was normalized using either external references (MVICs) or internal references (extreme MEPs). Iterative re-sampling of 30 normalized MEPs per subject was repeated 5,000 times to define, for each normalization method, distributions for between-subject coefficients of variation (CV) of the mean MEP amplitude. Intra-class correlation coefficients (ICC) were used to assess the impact of normalization on test–retest stability of MEP amplitude measurements.ResultsIn the absence of normalization, MEPs collected from the right hand of 47 healthy volunteers were within reported values regarding between-subject variability (95% confidence intervals for the CV: [1.0567,1.0577]) and showed good temporal stability (ICC = 0.77). Internal reference normalization substantially reduced between-subject variability, by values of up to 64%, while external reference normalization had no impact or increased between-subject variability. Normalization with the smallest references reduced test–retest stability, with use of the largest references resulting in slight reduction or improvement of ICCs. Internal reference normalization using the largest MEPs was found to be robust to several sensitivity analyses.ConclusionInternal, but not external, reference normalization reduces between-subject variability of MEP amplitude, and has a minimal impact on within-subject variability when conducted with the largest references. Additional research is necessary to further validate these normalization methods toward potential use of MEPs as biomarkers of neuropsychiatric disorders.

BackgroundTreatment resistant depression (TRD) affects 10–30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking.MethodsICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were.ResultsPatients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6–53.9]) and remission (33.6% [95% CI 29.7–37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5–31.4] and 18.2% [95% CI 13.9–22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034–3.733], p

BackgroundThe efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known.MethodICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling.ResultsEsketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6–53.9]) and remission (33.6% [95% CI 29.7–37.6]) versus RW polypharmacy (26.8% [95% CI 21.0–32.5] and 19.4%, [95% CI 14.2–24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474–2.345; p

IntroductionObsessive-compulsive disorder (OCD) is a highly prevalent chronic disorder, often refractory to treatment. While remaining elusive, a full understanding of the pathophysiology of OCD is crucial to optimize treatment. Transcranial magnetic stimulation (TMS) is a non-invasive technique that, paired with other neurophysiological techniques, such as electromyography, allows for in vivo assessment of human corticospinal neurophysiology. It has been used in clinical populations, including comparisons of patients with OCD and control volunteers. Results are often contradictory, and it is unclear if such measures change after treatment. Here we summarize research comparing corticospinal excitability between patients with OCD and control volunteers, and explore the effects of treatment with repetitive TMS (rTMS) on these excitability measures.MethodsWe conducted a systematic review and meta-analysis of case-control studies comparing various motor cortical excitability measures in patients with OCD and control volunteers. Whenever possible, we meta-analyzed motor cortical excitability changes after rTMS treatment.ResultsFrom 1,282 articles, 17 reporting motor cortex excitability measures were included in quantitative analyses. Meta-analysis regarding cortical silent period shows inhibitory deficits in patients with OCD, when compared to control volunteers. We found no statistically significant differences in the remaining meta-analyses, and no evidence, in patients with OCD, of pre- to post-rTMS changes in resting motor threshold, the only excitability measure for which longitudinal data were reported.DiscussionOur work suggests an inhibitory deficit of motor cortex excitability in patients with OCD when compared to control volunteers. Cortical silent period is believed to reflect activity of GABAB receptors, which is in line with neuroimaging research, showing GABAergic deficits in patients with OCD. Regardless of its effect on OCD symptoms, rTMS apparently does not modify Resting Motor Threshold, possibly because this measure reflects glutamatergic synaptic transmission, while rTMS is believed to mainly influence GABAergic function. Our meta-analyses are limited by the small number of studies included, and their methodological heterogeneity. Nonetheless, cortical silent period is a reliable and easily implementable measurement to assess neurophysiology in humans, in vivo. The present review illustrates the importance of pursuing the study of OCD pathophysiology using cortical silent period and other easily accessible, non-invasive measures of cortical excitability.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020201764], identifier [CRD42020201764].

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that was cleared by the Food and Drug Administration (FDA) for the treatment of Obsessive-Compulsive Disorder (OCD) in 2018. The approved protocol includes individualized symptom provocation before each stimulation session, to elicit a moderate level of obsessional distress. Although symptom provocation can be a delicate, demanding, and uncomfortable procedure, structured training methods for those who are going to apply it are not available. Here, we describe a model for training in symptom provocation for TMS technicians, developed at the Champalimaud Clinical Centre in Lisbon, Portugal. Our programme includes two-sessions dedicated to clinical communication and symptom provocation techniques from a theoretical and practical perspective. Additionally, supervision meetings are conducted during treatment of patients, allowing regular case discussion and redefinition of symptom provocation hierarchy, as needed. In addition to having a strong practical component, our training program is short and pragmatic, allowing for easy implementation and fluid transition to clinical practice. By sharing our experience, we hope to contribute to systematize training procedures required for symptom provocation in the context of TMS, and to qualitatively describe a methodology that can be used for implementation of TMS programmes for the treatment of OCD.

Guidance about treatment-resistant depression (TRD) in Portugal is very limited, even though depression prevalence is among the highest in European countries. A questionnaire was conducted, followed by two advisory boards with seven Portuguese psychiatry experts, to characterize and discuss MDD and TRD epidemiology, diagnosis, patient journey, treatment options, and unmet clinical needs. Consensus was reached on the main issues. In daily practice, TRD can be defined as moderate to severe MDD episodes with insufficient clinical improvement after two antidepressant treatments, taken in adequate doses and duration. TRD diagnosis and treatment are mostly decided by psychiatrists at public hospitals. Treatment type and duration must be adjusted to characteristics of the patient and the depressive episode, including symptoms, number of previous episodes, comorbidities, and previous treatment response and side effects. The most relevant objectives of TRD treatment are reaching response and remission, prevention of suicide, and improvement of quality of life, functionality, and wellbeing. Regarding pharmacotherapy, antidepressant switch occurs more frequently with non-response, while optimization, combination, and augmentation are considered for patients with partial response. Psychotherapy should be considered in parallel to pharmacological treatment. Brain stimulation techniques are underused. Lifelong treatment is required for recurrent or more chronic TRD episodes, but patient adherence is also poorer in these cases. In Portugal, TRD management is limited by lack of access to specialist care and to many treatment options. These aspects highlight that conventional pharmacotherapy does not lead to remission in many patients and that optimization strategies are frequently necessary to achieve satisfactory treatment outcomes.

Introduction: Hypomania symptoms are best described as a continuum, ranging beyond Bipolar Spectrum Disorders (BSD). Other nosological entities, such as major depressive disorder, schizoaffective disorder, or borderline personality disorder, may also share symptoms with BSD, raising challenges for differential diagnosis. While the Hypomania Checklist-32 is one of the most widely used tools for screening hypomania, there is limited evidence describing its use in a real-world outpatient psychiatric clinical setting.Methods: Here we tested the psychometric properties of a European Portuguese adaptation of the HCL-32, establishing its factor structure, reliability and construct validity. Furthermore, we analyzed differences in hypomanic symptoms among several clinical groups and in a non-clinical sample. Data was obtained retrospectively in an ecological setting from a clinical sample of an outpatient psychiatry and psychology clinic, comprising 463 Portuguese individuals, 326 of whom had a psychiatric diagnosis, namely BSD (n = 66), major depressive disorder (n = 116), or other psychiatric disorders (n = 144). A separate non-clinical sample was also collected among healthy volunteers (n = 62). A battery of self-report measures of affective symptoms was applied, and in a subset of patients, diagnosis was established using a structured diagnostic interview.Results: Psychometric properties of the HCL-32 were adequate, with good internal consistency (Cronbach's α = 0.86) and test-retest stability (ICC = 0.86), and two subscores (“active/elated” and “risk-taking/irritable”) defined by Principal Component Analysis. Receiver Operating Characteristic curve analysis demonstrated that the test score discriminated moderately between patients with BSD and other clinical samples as well as healthy volunteers, with a cut-off score of 17 for the total score of the HCL-32 rendering the best combination of sensitivity and specificity. When compared to the HCL-32 total score, the risk-taking/irritable subscore seems to provide additional benefit in discriminating between different clinical groups, namely regarding specificity in the discrimination from patients with a diagnosis of major depressive disorder that was low for the full scale and the alternate subscale.Conclusions: HCL-32 can be used as a screening tool for BSD among adult patients presenting in an outpatient psychiatric clinical setting.

Background: While the Yale-Brown Obsessive-Compulsive Scale Second Edition (Y-BOCS-II) is the gold-standard for measurement of obsessive-compulsive (OC) symptom severity, its factor structure is still a matter of debate and, most importantly, criterion validity for diagnosis of OC disorder (OCD) has not been tested. This study aimed to clarify factor structure and criterion validity of the Y-BOCS-II.Methods: We first validated and quantified the psychometric properties of a culturally adapted Portuguese translation of the Y-BOCS-II (PY-BOCS-II). The PY-BOCS-II and other psychometric instruments, including the OCD subscale of the Structured Clinical Interview for the DSM-IV, used to define OCD diagnosis, were administered to 187 participants (52 patients with OCD, 18 with other mood and anxiety disorders and 117 healthy subjects). In a subsample of 20 OCD patients and the 18 patients with other diagnoses, PY-BOCS-II was applied by clinicians blinded to diagnosis.Results: PY-BOCS-II had excellent internal consistency (Cronbach's α = 0.96) and very good test-retest reliability (Pearson's r = 0.94). Exploratory factor analysis revealed a two-factor structure with loadings consistent with the Obsessions and Compulsions subscales, and there was good to acceptable convergent and divergent validity. Importantly, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve suggested elevated accuracy in discriminating between patients with OCD and control subjects (AUC = 0.96; 95% confidence interval [CI]: 0.92–0.99), that was retained in comparisons with age, gender and education matched controls (AUC = 0.95; 95% CI: 0.91–0.99), as well as with patients with other mood and anxiety disorders (AUC = 0.93; 95% CI: 0.84–1). Additionally, a cut-off score of 13 had optimal discriminatory ability for the diagnosis of OCD, with sensitivity ranging between 85 and 90%, and specificity between 94 and 97%, respectively when all samples or only the clinical samples were considered.Conclusion: The PY-BOCS-II has excellent psychometric properties to assess the severity of obsessive-compulsive symptoms, reflecting obsessive, and compulsive dimensions, compatible with currently defined subscales. Furthermore, we found that a cut-off of 13 for the Y-BOCS-II total score has good to excellent sensitivity and specificity for the diagnosis of OCD.