Vortioxetine in major depressive disorder : from mechanisms of action to clinical studies. An updated review

Introduction: Vortioxetine is a multimodal-acting antidepressant that provides improvements on cognitive function aside from antidepressants and anxiolytic effects. Vortioxetine has been found to be one of the most effective and best tolerated options for major depressive disorder (MDD) in head-to-head trials. Areas covered: The present review intends to gather the most relevant and pragmatic data of vortioxetine in MDD, specially focusing on new studies that emerged between 2015 and 2020. Expert opinion: Vortioxetine is the first antidepressant that has shown improvements both in depression and cognitive symptoms, due to the unique multimodal mechanism of action that combine the 5-HT reuptake inhibition with modulations of other key pre- and post-synaptic 5-HT receptors (agonism of 5-HT receptor, partial agonism of 5-HT receptor, and antagonism of 5-HT, 5-HT and 5-HT receptors). This new mechanism of action can explain the dose-dependent effect and can be responsible for its effects on cognitive functioning and improved tolerability profile. Potential analgesic and anti-inflammatory properties observed in preclinical studies as well as interesting efficacy and tolerability results of clinical studies with specific target groups render it a promising therapeutic option for patients with MDD and concomitant conditions (as menopause symptoms, pain, inflammation, apathy, sleep and/or metabolic abnormalities)

Unhappy while depressed : examining the dimensionality, reliability and validity of the subjective happiness scale in a spanish sample of patients with depressive disorders

Altres ajuts: Banco de Instrumentos del Centro de Investigación Biomé-dica en Red de Salud Mental (BICIBERSAM), grant number 11BI02.Despite the considerable amount of research evidence on the significant role of subjective happiness on mental health, there is no psychometric study of the Subjective Happiness Scale (SHS) in psychiatric samples. This study was aimed at exploring the psychometric properties of the SHS in a Spanish sample of patients with depressive disorders. Participants were 174 patients with a depressive disorder (70% diagnosed as major depressive disorder) who completed the SHS, the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), and the EQ-5D Visual Analogue Scale (EQ-5D VAS). Depressive symptoms were also assessed by means of the 17-item Hamilton Depression Rating Scale (HDRS17) and the Clinical Global Impression-Severity (CGI-S) Scale. Dimensionality, internal consistency reliability, construct validity, and responsiveness to change of the SHS were examined. Confirmatory factor analysis replicated the original one-factor structure of the scale. The SHS exhibited good-to-excellent results for internal consistency (α = 0.83) and for convergent [EQ-5D VAS (r = 0.71)] and divergent [QIDS-SR16 (r = −0.72), HDRS17 (r = −0.60) and CGI-S (r = −0.61)] construct validity. The ability of the SHS to differentiate between depression severity levels as well as its responsiveness to clinical change were both highly satisfactory (p < 0.001 in both cases). The SHS retained the soundness of psychometric properties showed in non-clinical samples in a sample of patients with depressive disorders, which supports its use as a reliable and valid outcome measure in the treatment of such disorders

If you feel you can’t, you won’t: the role of subjective and objective cognitive competence on psychosocial functioning in depression

BackgroundThe purpose of this exploratory study is to examine the role of sociodemographic, clinical, and cognitive - both objective and subjective - factors in overall and in specific domains of psychosocial functioning, in patients with depression at different clinical states of the disease (remitted and non-remitted).MethodsA sample of 325 patients with major depressive disorder, 117 in remission and 208 in non-remission, were assessed with a semi-structured interview collecting sociodemographic, clinical, cognitive (with neuropsychological tests and the Perceived Deficit Questionnaire), and functional (Functioning Assessment Short Test) characteristics. Backward regression models were conducted to determine associations of global and specific areas of functioning with independent factors, for both clinical states.ResultsResidual depressive symptomatology and self-appraisal of executive competence were significantly associated with psychosocial functioning in remitted patients, in overall and some subdomains of functioning, particularly cognitive and interpersonal areas. While depressive symptoms, executive deficits and self-appraisal of executive function were significantly related to functional outcomes in non-remitted patients, both in overall functioning and in most of subdomains.DiscussionThis study evidences the strong association of one's appraisal of executive competence with psychosocial functioning, together with depressive symptoms, both in remitted and non-remitted patients with depression. Therefore, to achieve full recovery, clinical management of patients should tackle not only the relief of core depressive symptoms, but also the cognitive ones, both those that are objectified with neuropsychological tests and those that are reported by the patients themselves

Testing the efficacy of INtegral Cognitive REMediation (INCREM) in major depressive disorder : study protocol for a randomized clinical trial

Given the limitation of pharmacological treatments to treat cognitive symptoms in patients with Major Depressive Disorder (MDD), cognitive remediation programs has been proposed as a possible procognitive intervention but findings are not conclusive. This study investigates the efficacy of an INtegral Cognitive REMediation (INCREM) that includes a combination of a Functional Remediation (FR) strategy plus a Computerized Cognitive Training (CCT) in order to improve not only cognitive performance but also the psychosocial functioning and the quality of life. A single blind randomized controlled clinical trial in 81 patients with a diagnosis of MDD in clinical remission or in partial remission. Participants will be randomized to one of three conditions: INCREM (FR + CCT), Psychoeducation plus online games and Treatment As Usual (TAU). Intervention will consist in 12 group sessions, of approximately 110 min once a week. The primary outcome measure will be % of change in psychosocial functioning after treatment measured by the Functional Assessment Short Test (FAST); additionally, number of sick leaves and daily activities will also be recorded as pragmatic outcomes. To our knowledge, this is the first randomized controlled clinical trial using a combination of two different approaches (FR + CCT) to treat the present cognitive deficits and to promote their improvements into a better psychosocial functioning. Clinical Trials . Date registered 10th of August 2018 and last updated 24th August 2018

Testing the efficacy of INtegral Cognitive REMediation (INCREM) in major depressive disorder: study protocol for a randomized clinical trial

Background: Given the limitation of pharmacological treatments to treat cognitive symptoms in patients with Major Depressive Disorder (MDD), cognitive remediation programs has been proposed as a possible procognitive intervention but findings are not conclusive. This study investigates the efficacy of an INtegral Cognitive REMediation (INCREM) that includes a combination of a Functional Remediation (FR) strategy plus a Computerized Cognitive Training (CCT) in order to improve not only cognitive performance but also the psychosocial functioning and the quality of life. Methods: A single blind randomized controlled clinical trial in 81 patients with a diagnosis of MDD in clinical remission or in partial remission. Participants will be randomized to one of three conditions: INCREM (FR + CCT), Psychoeducation plus online games and Treatment As Usual (TAU). Intervention will consist in 12 group sessions, of approximately 110 min once a week. The primary outcome measure will be % of change in psychosocial functioning after treatment measured by the Functional Assessment Short Test (FAST); additionally, number of sick leaves and daily activities will also be recorded as pragmatic outcomes. Discussion: To our knowledge, this is the first randomized controlled clinical trial using a combination of two different approaches (FR + CCT) to treat the present cognitive deficits and to promote their improvements into a better psychosocial functioning. Trial registration: Clinical Trials NCT03624621 . Date registered 10th of August 2018 and last updated 24th August 2018

Marcadores de recurrencia y resistencia al tratamiento en depresión: estudio de espectroscopia y tensor de difusión por resonancia magnética nuclear

La depresión mayor es una enfermedad con elevado riesgo de recurrencia y una respuesta al tratamiento no siempre satisfactoria, que asocia grandes tasas de discapacidad, deterioro psicosocial, morbimortalidad y elevados costes sanitarios. Algunas evidencias señalan que los cambios cerebrales que tienen lugar durante los propios episodios depresivos podrían dejar trazas residuales que aumentaran progresivamente el riesgo de refractariedad y la vulnerabilidad a sufrir nuevas recaídas. En las últimas décadas, el desarrollo e implantación de diversas técnicas de neuroimagen aplicadas a investigación han permitido desgranar al menos parte de las anomalías neuroanatómicas y funcionales subyacentes en depresión, aunque las alteraciones relacionadas con el curso evolutivo han sido menos exploradas. El objetivo del presente trabajo de tesis ha sido el de ampliar el conocimiento en torno al sustrato neural relacionado con los procesos de recurrencia y cronicidad, es decir aquellas anomalías identificables mediante técnicas de neuroimagen que se asociarían a la recaída o al fracaso del tratamiento, incluso aquellas que podrían acumularse a lo largo del curso de la enfermedad impidiendo la recuperación clínica. En particular, las dos técnicas en las que se centran los estudios presentados son la Espectroscopia y el Tensor de Difusión por Resonancia Magnética Nuclear. La tesis se estructura en tres artículos publicados en revistas internacionales indexadas en las bases de datos científicas más populares [1-3]. Los dos primeros evalúan las alteraciones de la neuroquímica celular asociadas a la refractariedad y a la historia de recurrencias en la corteza prefrontal ventromedial (CPFvm) e hipocampo, dos áreas claves en la fisiopatología de los trastornos afectivos y sensibles a los efectos potencialmente perniciosos del estrés crónico. El tercer trabajo evalúa las alteraciones en la microestructura de sustancia blanca en los circuitos cortico-corticales y cortico-subcorticales, incluyendo la conectividad fronto-límbica. Los estudios, basados en muestras representativas de un amplio espectro de gravedad de la enfermedad, constatan alteraciones de los niveles de glutamato-glutamina y otros metabolitos en CPFvm e hipocampo y anormalidades generalizadas de la microestructura de sustancia blanca en los pacientes depresivos claramente sobrerrepresentadas entre aquellos con peor respuesta clínica, antecedentes de episodios previos o mayor duración de enfermedad. Estos hallazgos son altamente sugestivos del potencial neurotóxico de los estados depresivos y justifican la puesta en marcha de estudios longitudinales que confirmen la posible progresión de estos marcadores en subgrupos de pacientes de peor pronóstico a lo largo del curso de la enfermedad.Major depression is a prevalent mental disorder with a high risk of recurrence and unsatisfactory treatment response, which associates high rates of disability, psychosocial impairment, excess of morbidity and mortality and high healthcare costs. Some evidence suggests that brain changes occurring during depressive episodes may leave residual traces which progressively increase the risk of refractoriness and vulnerability to further relapses. In recent decades, development and implementation of neuroimaging techniques have help to identify at least part of the underlying neuroanatomical and functional abnormalities in depression, although alterations related to clinical course have been less explored. The aim of the current thesis was to gain knowledge about the neural substrate of recurrence and chronicity, ie those neuroimaging abnormalities that would be associated with relapse or treatment failure, even those that may accumulate along the course of the illness interfering with clinical recovery. Studies were based on two particular techniques: Proton Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging. This thesis is composed by three articles published in international journals indexed on most popular scientific databases [1-3]. The first two works assess neurochemical alterations associated with refractoriness and history of recurrences in ventromedial prefrontal cortex (vmPFC) and hippocampus, two keys areas in the pathophysiology of affective disorders, sensitive to the potentially harmful effects of chronic stress. The third study evaluates changes in the white-matter microstructure in the cortico-cortical and cortico-subcortical pathways, including the fronto- limbic connectivity. Studies, based on representative samples of a wide spectrum of disease severity, show changes in glutamate-glutamine and other metabolites levels within vmPFC and hippocampus and widespread abnormalities of white matter microstructure in depressive patients clearly overrepresented among those with worst clinical response, history of previous episodes or longer illness duration. Findings are highly suggestive of the neurotoxic potential of depressive states and warrant longitudinal studies to confirm the possible progression of these markers in subgroups of patients with the worst prognosis over the course of the illness

Marcadores de recurrencia y resistencia al tratamiento en depresión: estudio de espectroscopia y tensor de difusión por resonancia magnética nuclear

La depresión mayor es una enfermedad con elevado riesgo de recurrencia y una respuesta al tratamiento no siempre satisfactoria, que asocia grandes tasas de discapacidad, deterioro psicosocial, morbimortalidad y elevados costes sanitarios. Algunas evidencias señalan que los cambios cerebrales que tienen lugar durante los propios episodios depresivos podrían dejar trazas residuales que aumentaran progresivamente el riesgo de refractariedad y la vulnerabilidad a sufrir nuevas recaídas. En las últimas décadas, el desarrollo e implantación de diversas técnicas de neuroimagen aplicadas a investigación han permitido desgranar al menos parte de las anomalías neuroanatómicas y funcionales subyacentes en depresión, aunque las alteraciones relacionadas con el curso evolutivo han sido menos exploradas. El objetivo del presente trabajo de tesis ha sido el de ampliar el conocimiento en torno al sustrato neural relacionado con los procesos de recurrencia y cronicidad, es decir aquellas anomalías identificables mediante técnicas de neuroimagen que se asociarían a la recaída o al fracaso del tratamiento, incluso aquellas que podrían acumularse a lo largo del curso de la enfermedad impidiendo la recuperación clínica. En particular, las dos técnicas en las que se centran los estudios presentados son la Espectroscopia y el Tensor de Difusión por Resonancia Magnética Nuclear. La tesis se estructura en tres artículos publicados en revistas internacionales indexadas en las bases de datos científicas más populares [1-3]. Los dos primeros evalúan las alteraciones de la neuroquímica celular asociadas a la refractariedad y a la historia de recurrencias en la corteza prefrontal ventromedial (CPFvm) e hipocampo, dos áreas claves en la fisiopatología de los trastornos afectivos y sensibles a los efectos potencialmente perniciosos del estrés crónico. El tercer trabajo evalúa las alteraciones en la microestructura de sustancia blanca en los circuitos cortico-corticales y cortico-subcorticales, incluyendo la conectividad fronto-límbica. Los estudios, basados en muestras representativas de un amplio espectro de gravedad de la enfermedad, constatan alteraciones de los niveles de glutamato-glutamina y otros metabolitos en CPFvm e hipocampo y anormalidades generalizadas de la microestructura de sustancia blanca en los pacientes depresivos claramente sobrerrepresentadas entre aquellos con peor respuesta clínica, antecedentes de episodios previos o mayor duración de enfermedad. Estos hallazgos son altamente sugestivos del potencial neurotóxico de los estados depresivos y justifican la puesta en marcha de estudios longitudinales que confirmen la posible progresión de estos marcadores en subgrupos de pacientes de peor pronóstico a lo largo del curso de la enfermedad.Major depression is a prevalent mental disorder with a high risk of recurrence and unsatisfactory treatment response, which associates high rates of disability, psychosocial impairment, excess of morbidity and mortality and high healthcare costs. Some evidence suggests that brain changes occurring during depressive episodes may leave residual traces which progressively increase the risk of refractoriness and vulnerability to further relapses. In recent decades, development and implementation of neuroimaging techniques have help to identify at least part of the underlying neuroanatomical and functional abnormalities in depression, although alterations related to clinical course have been less explored. The aim of the current thesis was to gain knowledge about the neural substrate of recurrence and chronicity, ie those neuroimaging abnormalities that would be associated with relapse or treatment failure, even those that may accumulate along the course of the illness interfering with clinical recovery. Studies were based on two particular techniques: Proton Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging. This thesis is composed by three articles published in international journals indexed on most popular scientific databases [1-3]. The first two works assess neurochemical alterations associated with refractoriness and history of recurrences in ventromedial prefrontal cortex (vmPFC) and hippocampus, two keys areas in the pathophysiology of affective disorders, sensitive to the potentially harmful effects of chronic stress. The third study evaluates changes in the white-matter microstructure in the cortico-cortical and cortico-subcortical pathways, including the fronto- limbic connectivity. Studies, based on representative samples of a wide spectrum of disease severity, show changes in glutamate-glutamine and other metabolites levels within vmPFC and hippocampus and widespread abnormalities of white matter microstructure in depressive patients clearly overrepresented among those with worst clinical response, history of previous episodes or longer illness duration. Findings are highly suggestive of the neurotoxic potential of depressive states and warrant longitudinal studies to confirm the possible progression of these markers in subgroups of patients with the worst prognosis over the course of the illness

A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: A pilot study of relapse prevention

© 2015 8872147 Canada Inc. Background: To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation. Methods: We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON–OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF–ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation. Results: We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (X2 1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria. Limitations: The small sample size limited the statistical power and external validity. Conclusion: These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects. Trial registration: NCT01268137 (ClinicalTrials.gov).This study was funded by several grants of the Fondo de Investigación Sanitaria (FIS, PI 06/0662, PS 09/00580) from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) intramural funding (P91G), the ‘VI Plan Nacional I+D+I 2008–2011’, and the ‘Iniciativa Ingenio 2010, programa CONSOLIDER, acción CIBER’. M. Portella is funded by the Ministerio de Ciencia e Innovación of the Spanish Government and by the Instituto de Investigación Carlos III through a “Miguel Servet” research contract (CP10/00393), co-financed by the European Regional Development Fund (ERDF) (2007-2013). J. de Diego- Adeliño is funded by the Instituto de Salud Carlos III through a “Río Hortega” Spanish government research fellowshipPeer Reviewe

Deep brain stimulation of the subcallosal cingulate gyrus: Further evidence in treatment-resistant major depression

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short-and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-μs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Ãsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ≤7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD. © 2011 CINP.This study is funded by the Fondo de Investigación Sanitaria (FIS: PI 06/0662, PS 09/00580), Instituto Carlos III, and by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) intramural funding (P91G), the “VI Plan Nacional I+D+I 2008-2011”, and the “Iniciativa Ingenio 2010, programa CONSOLIDER, acción CIBER”. Support from grant SAF2007-62378 is also acknowledged. Dr. Portella is funded by the Spanish Ministry of Science and Innovation and the Instituto de Investigación Carlos III through a “Miguel Servet” research contract, co-financed by the European Regional Development Fund (ERDF) (2007-2013).Peer Reviewe