Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression.

BACKGROUND: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. METHODS: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient's response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). RESULTS: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. CONCLUSIONS: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response.

Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression.

BACKGROUND AND OBJECTIVE: Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine. METHODS: We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery-Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model. RESULTS: There were significant effects for time on item 10 Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited. CONCLUSIONS: Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings.

Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.

BACKGROUND: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression. METHODS: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion. RESULTS: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups. LIMITATIONS: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings. CONCLUSION: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials.

A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression.

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine.

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression.

INTRODUCTION AND OBJECTIVES: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. METHODS: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. RESULTS: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. CONCLUSIONS: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.

[Review of the guidelines of the Brazilian Medical Association for the treatment of depression (Complete version)]. / Revisão das diretrizes da Associação Médica Brasileira para o tratamento da depressão (Versão integral).

OBJECTIVE: Depression is a frequent, recurrent and chronic condition with high levels of functional disability. The Brazilian Medical Association Guidelines project proposed guidelines for diagnosis and treatment of the most common medical disorders. The objective of this paper is to present a review of the Guidelines Published in 2003 incorporating new evidence and recommendations. METHOD: This review was based on guidelines developed in other countries and systematic reviews, randomized clinical trials and when absent, observational studies and recommendations from experts. The Brazilian Medical Association proposed this methodology for the whole project. The review was developed from new international guidelines published since 2003. RESULTS: The following aspects are presented: prevalence, demographics, disability, diagnostics and sub-diagnosis, efficacy of pharmacological and psychotherapeutic treatment, costs and side-effects of different classes of available drugs in Brazil. Strategies for different phases of treatment are also discussed. CONCLUSION: The Guidelines are an important tool for clinical decisions and a reference for orientation based on the available evidence in the literature.

Seasonality of three dimensions of mania: psychosis, aggression and suicidality.

BACKGROUND: To investigate the existence of a seasonal distribution of three dimensions of mania, psychosis, aggression and suicidality, during psychiatric hospitalizations, in a Brazilian sample, correlating these findings with local climatic variables. METHODS: Charts of 425 admissions of 269 ICD-10 manic patients, from 1996-2000 were reviewed for the occurrence of these symptom dimensions. Seasonality was assessed using Cosinor Analysis. When a harmonic seasonal distribution was not present, chi-square tests comparing the peak months with the rest of the year for each specific feature were performed. Correlations were performed between the three mania features and the index and previous months' predictor climatic variables (mean temperature, hours of sunshine, duration of days, relative humidity and rainfall). RESULTS: Cosinor regressions showed non-significance. However, rates of aggression were significantly higher in January-March than in the rest of the year (62 vs. 50%; p=0.007), and suicidality was significantly more frequent in December and January (20 vs. 10%; p=0.019). Suicidality was significantly correlated to rapidly increasing temperatures (rs=0.28; p<0.05). Psychosis was positively correlated with hours of sunshine of index month and with increasing hours of sunshine (rs=0.40 and 0.35; p<0.01); but negatively correlated with relative humidity of index month and with difference from previous to index month (rs=-0.25 and -0.30; p<0.05). Climatic variables studied were not significantly correlated with aggression. LIMITATIONS: Retrospective study on a single institution. CONCLUSION: Climatic conditions correlated differently with each dimension of mania.

[Depression and stress: is there an endophenotype?]. / Depressão e estresse: existe um endofenótipo?

OBJECTIVE: To review the new findings about stress, hypothalamic-pituitary-adrenal axis and depression trying to explain a possible endophenotype prone to depression. METHOD: Nonsystematic review of the literature based on the endophenotype hypothesis. RESULTS: Depression is linked to hypercortisolemia in many patients, but not all patients present these hypothalamic-pituitary-adrenal axis dysfunction. The dexamethasone suppression test is not the most accurate test to measure the hypothalamic-pituitary-adrenal axis function, and its use in the first studies published probably jeopardized the results. Hypercortisolemia frequently occurs in patients with severe depression, melancholic, either psychotic or nonpsychotic type; it is linked to the presence of a polymorphism in the promoter of the serotonin transporter gene, with a history of childhood abuse or neglect, or other significant stressful experiences like the loss of a parent during childhood and temperament leading to alterations in the response to stress. CONCLUSIONS: The alterations of the hypothalamic-pituitary-adrenal axis depend on many factors like severity and type of depression, genotype, history of exposure to stress, temperament, and probably resilience. All these factors together result in an endophenotype thought to be prone to depression.

Seasonality of admissions for mania in a psychiatric hospital of Belo Horizonte, Brazil.

BACKGROUND: Seasonality of mania has been previously reported in several world regions. A spring and/or summer peak has been the most frequent finding, correlating to climatic variables, especially luminosity. There are, however, no South American studies on this association. METHODS: The charts of 269 manic patients admitted from 1996 to 2000 in a psychiatric hospital at Belo Horizonte, Brazil, were reviewed. Seasonality was assessed with Cosinor Analysis. Correlations of the rate of admissions for mania to climatic variables were performed, including lagged and differenced data. RESULTS: A circannual pattern was evident, with a late winter-spring peak and a late summer-autumn trough. The rate of admissions for mania correlated positively to: (a) average index and previous months' hours of sunshine, and (b) differenced mean temperature; and negatively to: (a) index and previous months' rainfall, (b) index months' relative humidity, and (c) previous months' duration of days and mean temperature. Altogether, climatic variables explained 23.7% of the variance in the rate of admissions for mania. LIMITATIONS: This was a retrospective study conducted in a single institution. CONCLUSIONS: The fact that climatic variables are associated to the course of bipolar disorder even in subtropical regions indicate that this effect may be more subtle and extent than previously thought. Further exploration of the biological mechanisms of this association is necessary.

Activity/rest rhythm of depressed adolescents undergoing therapy: case studies.

INTRODUCTION:: Disorders of circadian rhythms have been reported in studies of both depressed children and of depressed adolescents. The aim of this study was to evaluate whether there is a relationship between the 24-hour spectral power (24h SP) of the activity/rest rhythm and the clinical course of depression in adolescents. METHODS:: Six 14 to 17-year-old adolescents were recruited for the study. They were all suffering from major depressive disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria, as identified by the Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Depressive symptoms were assessed using the Children's Depression Rating Scale - Revised (CDRS-R) and clinical evaluations. Locomotor activity was monitored over a period of 13 consecutive weeks. Activity was measured for 10-minute periods using wrist-worn activity monitors. All patients were prescribed sertraline from after the first week up until the end of the study. RESULTS:: We found a relationship between high CDRS values and low 24-hour spectral power. CONCLUSIONS:: The 24h SP of the activity/rest rhythm correlated significantly (negatively) with the clinical ratings of depression.

Eye-hand preference dissociation in obsessive-compulsive disorder and dyslexia.

Dyslexia may be a development disturbance in which there are alterations in visual-spatial and visual-motor processing, while obsessive-compulsive disorder (OCD) is a psychiatric disease in which there are alterations in memory, executive function, and visual-spatial processing. Our hypothesis is that these disturbances may be, at least partially, the result of a crossed eye and hand preference. In the present study 16 controls, 20 OCD (DSM-IV criteria) and 13 dyslexic adults (Brazilian Dyslexia Association criteria) were included. All had a neurological examination, the Yale-Brown scale for obsessive-compulsive symptoms application and the Zazzó evaluation for laterality, abridged by Granjon. Results showed a right hand preference for 100% of controls, 84.6% of dyslexics, and 75% of OCD patients and a right eye preference for 73.3% of controls, 69.2% of dyslexics, and 35% of OCD patients. The left eye preference was significantly higher in OCD when compared with the two other groups (p = 0.01) and the left hand preference of OCD patients (25%) was also significant when compared to Brazilian population (4%) or British population (4.5%). It is possible that this crossed preference may be partially the reason for visual-spatial and constructive disturbances observed in OCD.

[Bipolar disorder: evolution of the concept and current controversies]. / Evolução do conceito e controvérsias atuais sobre o transtorno bipolar do humor.

The author reviews the evolution of the concept of bipolar disorder as an ongoing process. Its roots can be found in the work of Araeteus of Capadocia, who assumed that melancholia and mania were two forms of the same disease. The modern understanding of bipolar disorder began in France, through the work of Falret (1851) and Baillarger (1854). The pivotal concepts of Emil Kraepelin changed the basis of psychiatric nosology, and Kraepelin's unitary concept of manic-depressive insanity was largely accepted. Kraepelin and Weigandt's ideas on mixed states were the cornerstone of this unitary concept. After Kraepelin, however, the ideas of Kleist and Leonhard, in Germany, as well as the work of Angst, Perris and Winokur, emphasized the distinction between unipolar and bipolar forms of depression. More recently, the emphasis has shifted again to the bipolar spectrum, which, in its mild forms, expanded to the limits of normal temperament. In concluding, the author summarizes the polemic aspects concerning the nosology of bipolar disorder and its boundaries in comparison with those of with schizophrenia, schizoaffective disorders and cycloid psychosis.

[Update on neurosurgical treatment for obsessive compulsive disorder]. / Atualização sobre o tratamento neurocirúrgico do transtorno obsessivo-compulsivo.

Responses to pharmacotherapy and psychotherapy in obsessive-compulsive disorder (OCD) range from 60 to 80% of cases. However, a subset of OCD patients do not respond to adequately conducted treatment trials, leading to severe psychosocial impairment. Stereotactic surgery can be indicated then as the last resource. Five surgical techniques are available, with the following rates of global post-operative improvement: anterior capsulotomy (38-100%); anterior cingulotomy (27-57%); subcaudate tractotomy (33-67%); limbic leucotomy (61-69%), and central lateral thalamotomy/anterior medial pallidotomy (62.5%). The first technique can be conducted as a standard neurosurgery, as radiosurgery or as deep brain stimulation. In the standard neurosurgery neural circuits are interrupted by radiofrequency. In radiosurgery, an actinic lesion is provoked without opening the brain. Deep brain stimulation consists on implanting electrodes which are activated by stimulators. Literature reports a relatively low prevalence of adverse events and complications. Neuropsychological and personality changes are rarely reported. However, there is a lack of randomized controlled trials to prove efficacy and adverse events/complication issues among these surgical procedures. Concluding, there is a recent development in the neurosurgeries for severe psychiatric disorders in the direction of making them more efficacious and safer. These surgeries, when correctly indicated, can profoundly alleviate the suffering of severe OCD patients.

[Guidelines of the Brazilian Medical Association for the treatment of depression (complete version)]. / Diretrizes da Associação Médica Brasileira para o tratamento da depressão (versão integral).

OBJECTIVE: Depression is a frequent and chronic condition with high levels of functional disability. Brazilian Medical Association Guidelines project proposed guidelines for diagnosis and treatment of the most common medical disorders. The objective of this paper is to present the original document that originated the abbreviated version available at the electronic address of Brazilian Medical Association. METHODS: This paper was based on guidelines developed in other countries and systematic reviews, randomized clinical trials and when absent, observational studies and recommendations from experts. Brazilian Medical Association proposed this methodology for the whole project. RESULTS: The following aspects are presented: prevalence, demographics, disability, diagnostics and sub-diagnosis, efficacy of pharmacological and psychotherapeutic treatment, costs and side-effects of different classes of available drugs in Brazil. Planning of different phases of treatment is22 also discussed. CONCLUSIONS: Guidelines are a good tool helping clinical decisions and are a reference for an attitude based on levels of evidence.

Cross validation with the mood disorder questionnaire (MDQ) of an instrument for the detection of hypomania in Brazil: The 32 item hypomania symptom check-list, first Revision (HCI-32-R1).

BACKGROUND: Bipolar disorders are frequently diagnosed and treated as unipolar depression initially and accurate diagnosis is often delayed by 8 to 10years. It has been demonstrated that the bipolar spectrum disorders are associated with notable disability and that the current diagnostic gold standard, the Structured Clinical Interview for DSM-IV (SCID) is not sufficiently sensitive to the diagnosis of hypomania or subthreshold manic states. There is a need for better and simpler ways to identify these conditions. METHODS: Hirschfeld et al. (2000) developed and tested a self-report scale for bipolar disorder: the Mood Disorder Questionnaire (MDQ). Recently, another scale has been developed by Angst to assess hypomanic symptoms and to increase the detection of suspected and of manifest, but undertreated, cases of bipolar disorders. In this Brazilian study, 200 patients with the putative diagnosis of "depression" were interviewed using the Structured Clinical Interview for DSM-IV, Axis I Disorders - Clinician Version (SCID-CV; First et al., 1997), as modified by Benazzi and Akiskal (2003) to increase the sensitivity to BP II disorders. Before the interview patients were screened by both HCI-32-R(1) and MDQ and asked to complete them. RESULTS: The HCI-32-R(1) showed a sensitivity of 79.8% and a specificity of 60.5% for the cut-off of 14. A sensitivity of 68.1% and a specificity of 63% were obtained for the Mood Disorder Questionnaire for the cut-off of 7. LIMITATIONS: Although not showing a good specificity, the MDQ seems to be a useful instrument for the screening phase, in which it is important that "cases" are recognized. The HCI-32-R(1) does not distinguish between BP I and BP II disorders. The sample size of patients should be increased in further studies. CONCLUSIONS: The HCI-32-R(1) demonstrated two main factors identified as "active-elated" hypomania and "risk-taking/irritable" hypomania and showed to be a sensitive instrument for hypomanic symptoms. It is a simple and easy-to-use tool for the self-assessment of hypomanic symptoms and may be a valuable supplement to the clinician's interview. The Mood Disorder Questionnaire is a useful screening instrument for bipolar I, bipolar II disorders and other manifestations of bipolar spectrum. As such, this scale might increase the detection of under-treated cases of bipolar disorders. Further studies are needed to verify the accuracy of these tools in non-psychiatric settings and in the general population.

Assessment of obsessive beliefs: Comparing individuals with obsessive-compulsive disorder to a medical sample.

Cognitive behavior models for Obsessive-Compulsive Disorder (OCD) are based currently on the presence of specific beliefs associated with the disorder. Among these beliefs are inflated responsibility, concerns over thought-action fusion, and overimportance of thoughts. The aim of this study was to compare scores from the subscales of the Obsessive Beliefs Questionnaire (OBQ-87), developed by the Obsessive-Compulsive Cognitions Working Group (OCCWG, 2001), in 24 patients from an OCD clinic (OCD) and 24 patients from a Medical Clinic (MC) for ambulatory and chronic diseases. All OCD patients were diagnosed using the SCID, and the OCD portion of the SCID was used to rule out patients with OCD from the MC group. The Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Dysfunctional Attitudes Scale (DAS) were also administered. The results indicated that, contrary to predictions, in the domains of Tolerance for Uncertainty, Threat estimation, Responsibility and Perfectionism, the MC group presented higher scores than the OCD group. The same findings occurred with DAS, which was significantly correlated with the OBQ. Possible explanations for these findings are discussed, as well as suggestions for future research with both groups.

Activity/rest rhythm of depressed adolescents undergoing therapy: case studies / Ritmo de atividade e repouso em adolescentes deprimidos durante terapia: estudos de caso

Abstract Introduction: Disorders of circadian rhythms have been reported in studies of both depressed children and of depressed adolescents. The aim of this study was to evaluate whether there is a relationship between the 24-hour spectral power (24h SP) of the activity/rest rhythm and the clinical course of depression in adolescents. Methods: Six 14 to 17-year-old adolescents were recruited for the study. They were all suffering from major depressive disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria, as identified by the Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Depressive symptoms were assessed using the Children's Depression Rating Scale - Revised (CDRS-R) and clinical evaluations. Locomotor activity was monitored over a period of 13 consecutive weeks. Activity was measured for 10-minute periods using wrist-worn activity monitors. All patients were prescribed sertraline from after the first week up until the end of the study. Results: We found a relationship between high CDRS values and low 24-hour spectral power. Conclusions: The 24h SP of the activity/rest rhythm correlated significantly (negatively) with the clinical ratings of depression.

Resumo Introdução: Distúrbios do ritmo circadiano têm sido relatados em estudos com crianças e adolescentes deprimidos. O objetivo deste estudo foi avaliar se existe relação entre a potência espectral de 24 horas do ritmo de atividade e repouso e sintomas clínicos de depressão em adolescentes. Métodos: Seis adolescentes com idade entre 14 e 17 anos foram recrutados para o estudo. Eles foram diagnosticados com depressão maior de acordo com os critérios do Manual Diagnóstico e Estatístico de Transtornos Mentais, 4ª edição (DSM-IV), identificados utilizando-se o instrumento Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Os sintomas depressivos foram avaliados pelo questionário Children's Depression Rating Scale - Revised (CDRS-R) e por avaliações clínicas. A atividade motora foi monitorada por um período de 13 semanas consecutivas e registrada a cada 10 minutos utilizando-se monitores de atividades usados no pulso. Todos os pacientes utilizaram o antidepressivo sertralina começando após a primeira semana até o final do estudo. Resultados: Foi observada uma relação entre escores altos no CDRS-R e valores baixos de potência espectral de 24 horas no ritmo de atividade e repouso. Conclusão: A potência espectral de 24 horas do ritmo de atividade e repouso apresentou uma correlação significativa (negativa) com os sintomas clínicos de depressão.

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting.

UNLABELLED: The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for the treatment of MDD. RESULTS: The state-of-art of neuromodulation techniques was reviewed and discussed in four sections: [1] epidemiology and pathophysiology of MDD; [2] a comprehensive overview of the neuromodulation techniques; [3] using neuromodulation techniques in MDD associated with non-psychiatric conditions; [4] the main challenges of neuromodulation research and alternatives to overcome them. DISCUSSION: ECT is the first-line treatment for severe depression. TMS and tDCS are strategies with a relative benign profile of side effects; however, while TMS effects are comparable to antidepressant drugs for treating MDD; further research is needed to establish the role of tDCS. DBS and VNS are invasive strategies with a possible role in treatment-resistant depression. In summary, MDD is a chronic and incapacitating condition with a high prevalence; therefore clinicians should consider all the treatment options including invasive and non-invasive neuromodulation approaches.

Hypomania: a transcultural perspective.

This study examined the transcultural robustness of a screening instrument for hypomania, the Hypomania Checklist-32, first revised version (HCL-32 R1). It was carried out in 2606 patients from twelve countries in five geographic regions (Northern, Southern and Eastern Europe, South America and East Asia). In addition, GAMIAN Europe contributed data from its members. Exploratory and confirmatory factor analyses were used to examine the transregional stability of the measurement properties of the HCL-32 R1, including the influence of sex and age as covariates. Across cultures, a two-factor structure was confirmed: the first factor (F1) reflected the more positive aspects of hypomania (being more active, elated, self-confident, and cogni-tively enhanced); the second factor (F2) reflected the more negative aspects (being irritable, impulsive, careless, more substance use). The measurement properties of the HCL-32 R1 were largely invariant across cultures. Only few items showed transcultural differences in their relation to hypomania as measured by the test. F2 was higher among men and in more severe manic syndromes; F1 was highest in North and East Europe and lowest in South America. The scores decreased slightly with age. The frequency of the 32 items showed remarkable similarities across geographic areas, with two excep-tions: South Europeans had lower symptom frequencies in general and East Europeans higher rates of substance use. These findings support the interna-tional applicability of the HCL-32 R1 as a screening instrument for hypomania.