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BACKGROUND: Ablative surgery using bilateral anterior capsulotomy (BAC) is an option for treatment resistant depression (TRD) and obsessive-compulsive disorder (TROCD). The location and extent of the lesion within anterior limb of the internal capsule (ALIC) remains uncertain. Accumulating evidence has suggested that the lesion should be located ventrally while limiting the dorsal extent. Our center is now targeting specific fiber tracts within the lower half of the ALIC. METHOD: Presurgical diffusion tensor Magnetic Resonance Imaging (MRI) was used to identify individual fibre tracts within the ventral aspect of the ALIC in the last two patients who underwent BAC at our center. One patient had TRD and the other had both TROCD and TRD. Radiofrequency-induced thermal lesions were created in the identified targets with lesion volumes between 20 and 229 mm3 (average 95 mm3). FINDINGS: Both patients were responders with neither experiencing significant side effects including compromised executive functions. LIMITATIONS: The generalizability of our findings is limited because the outcome is based on two subjects. CONCLUSION: This work suggests that BAC can be individually tailored and more limited to the ventral aspect of the ALIC and is effective and safe for TRD and TROCD. Accumulating data also suggests that to be clinically effective the length of the capsulotomy should be about 10mm. BAC's use may increase with the growing utilization and mastery of magnetic resonance guided focused ultrasound.
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Trastorno Depresivo Resistente al Tratamiento , Trastorno Obsesivo Compulsivo , Humanos , Depresión , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/cirugía , Trastorno Depresivo Resistente al Tratamiento/patología , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Trastorno Obsesivo Compulsivo/cirugía , Trastorno Obsesivo Compulsivo/patología , Función Ejecutiva , Imagen por Resonancia Magnética , Cápsula Interna/diagnóstico por imagen , Cápsula Interna/cirugía , Cápsula Interna/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Evidence has shown a rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression (TRD) and prominent suicidal ideation (SI). The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in the TRD pathomechanisms. OBJECTIVE: Whether the structural and functional changes of the DLPFC, particularly Brodmann area 46, are associated with the antidepressant and antisuicidal effects of ketamine infusion among such patients is unknown. METHODS: We randomized 48 patients with TRD and SI into groups receiving a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating Scale were used to assess symptoms. Positron emission tomography (PET)-magnetic resonance imaging was conducted prior to infusion and on Day 3 postinfusion. We performed longitudinal voxel-based morphometry (VBM) analysis to evaluate the gray matter (GM) volume changes of the DLPFC. The standardized uptake value ratio (SUVr) of 18F-fluorodeoxyglucose PET images was calculated using the SUV of the cerebellum as a reference region. RESULTS: The VBM analysis revealed a small but significant volumetric reduction in the right DLPFC in the ketamine group compared with that in the midazolam group. A greater reduction in depressive symptoms was associated with a smaller decrease in right DLPFC volumes (p = 0.025). However, we found no SUVr changes of the DLPFC between baseline and post-Day 3 ketamine infusion. DISCUSSION: The optimal modulation of the right DLPFC GM volumes may play an essential role in the antidepressant neuromechanisms of low-dose ketamine.
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Trastorno Depresivo Resistente al Tratamiento , Ketamina , Humanos , Corteza Prefontal Dorsolateral , Midazolam/uso terapéutico , Imagen por Resonancia Magnética , Antidepresivos/uso terapéutico , Método Doble Ciego , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/patología , Tomografía de Emisión de Positrones , Resultado del TratamientoRESUMEN
BACKGROUND: A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD. METHODS: 35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons. RESULTS: The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation. CONCLUSIONS: This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression.
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Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Resistente al Tratamiento/patología , Habénula/fisiopatología , Anhedonia/fisiología , Estudios de Casos y Controles , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/terapia , Habénula/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Ideación SuicidaRESUMEN
It is possible to consider the stimulation of the cingulate gyrus in its portion below the corpus callosum (SCC, or subcallosal cingulate cortex) as an effective, promising, and safe alternative intervention for treatment-resistant depression. In studies with deep brain stimulation - DBS, when follow-on with functional magnetic resonance imaging and/or PET-CT (Positron emission tomography-computed tomography) is performed, it is observed an increase in the blood supply and glucose metabolism in this region, which is the anterior part of the limbic system. This same location has good experimental results also for the treatment of anorexia nervosa. The hypotheses suggest a greater activation of the reward system, a greater sense of well-being, and a consequent reduction in depressive symptoms, the objective of the treatment. Over the last 20 years, multicenter studies have shown symptomatic improvement in 50-60% of patients, and about a third even reach criteria for remission of the depressive disorder.
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Estimulación Encefálica Profunda , Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Estimulación Encefálica Profunda/métodos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/patología , Trastorno Depresivo Resistente al Tratamiento/terapia , Giro del Cíngulo/fisiología , Humanos , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.
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Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Ketamina/farmacología , Administración Intranasal , Antidepresivos/administración & dosificación , Trastorno Depresivo Resistente al Tratamiento/patología , Humanos , Ketamina/administración & dosificación , Prevención SecundariaRESUMEN
Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.
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Trastorno Depresivo Resistente al Tratamiento/genética , Exosomas/genética , MicroARNs/genética , Adolescente , Adulto , Anciano , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN/métodos , Adulto JovenRESUMEN
OBJECTIVES: Antidepressants are first-line treatments for major depressive disorder (MDD), but 40-60% of patients will not respond, hence, predicting response would be a major clinical advance. Machine learning algorithms hold promise to predict treatment outcomes based on clinical symptoms and episode features. We sought to independently replicate recent machine learning methodology predicting antidepressant outcomes using the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) dataset, and then externally validate these methods to train models using data from the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) dataset. METHODS: We replicated methodology from Nie et al (2018) using common algorithms based on linear regressions and decision trees to predict treatment-resistant depression (TRD, defined as failing to respond to 2 or more antidepressants) in the STAR*D dataset. We then trained and externally validated models using the clinical features found in both datasets to predict response (≥50% reduction on the Quick Inventory for Depressive Symptomatology, Self-Rated [QIDS-SR]) and remission (endpoint QIDS-SR score ≤5) in the CAN-BIND-1 dataset. We evaluated additional models to investigate how different outcomes and features may affect prediction performance. RESULTS: Our replicated models predicted TRD in the STAR*D dataset with slightly better balanced accuracy than Nie et al (70%-73% versus 64%-71%, respectively). Prediction performance on our external methodology validation on the CAN-BIND-1 dataset varied depending on outcome; performance was worse for response (best balanced accuracy 65%) compared to remission (77%). Using the smaller set of features found in both datasets generally improved prediction performance when evaluated on the STAR*D dataset. CONCLUSION: We successfully replicated prior work predicting antidepressant treatment outcomes using machine learning methods and clinical data. We found similar prediction performance using these methods on an external database, although prediction of remission was better than prediction of response. Future work is needed to improve prediction performance to be clinically useful.
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Algoritmos , Antidepresivos/uso terapéutico , Biomarcadores/análisis , Ensayos Clínicos como Asunto/estadística & datos numéricos , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Resistente al Tratamiento/patología , Aprendizaje Automático , Adulto , Canadá/epidemiología , Conjuntos de Datos como Asunto , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/epidemiología , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.
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Benzodiazepinas/uso terapéutico , Encéfalo/metabolismo , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Fluoxetina/uso terapéutico , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/metabolismo , Encéfalo/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/metabolismo , Trastorno Depresivo Resistente al Tratamiento/patología , Combinación de Medicamentos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
A growing number of recent studies has suggested that the neuroplastic effects of electroconvulsive therapy (ECT) might be prominent enough to be detected through changes of regional gray matter volumes (GMV) during the course of the treatment. Given that ECT patients are difficult to recruit for imaging studies, most publications, however, report only on small samples. Addressing this challenge, we here report results of a structural imaging study on ECT patients that pooled patients from five German sites. Whole-brain voxel-based morphometry (VBM) analysis was performed to detect structural differences in 85 patients with unipolar depression before and after ECT, when compared to 86 healthy controls. Both task-independent and task-dependent physiological whole-brain functional connectivity patterns of these regions were modeled using additional data from healthy subjects. All emerging regions were additionally functionally characterized using the BrainMap database. Our VBM analysis detected a significant increase of GMV in the right hippocampus/amygdala region in patients after ECT compared to healthy controls. In healthy subjects this region was found to be enrolled in a network associated with emotional processing and memory. A region in the left fusiform gyrus was additionally found to have higher GMV in controls when compared with patients at baseline. This region showed minor changes after ECT. Our data points to a GMV increase in patients post ECT in regions that seem to constitute a hub of an emotion processing network. This appears as a plausible antidepressant mechanism and could explain the efficacy of ECT not only in the treatment of unipolar depression, but also of affective symptoms across heterogeneous disorders.
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Afecto , Corteza Cerebral , Conectoma , Trastorno Depresivo Mayor , Terapia Electroconvulsiva , Sustancia Gris , Imagen por Resonancia Magnética , Red Nerviosa , Adulto , Afecto/fisiología , Anciano , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/patología , Trastorno Depresivo Resistente al Tratamiento/fisiopatología , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Evaluación de Resultado en la Atención de SaludRESUMEN
Electroconvulsive therapy (ECT) is a rapid and highly effective treatment option for treatment-resistant major depressive disorder (TRD). The neural mechanisms underlying such beneficial effects are poorly understood. Exploring associations between changes of brain structure and clinical response is crucial for understanding ECT mechanisms of action and relevant for the validation of potential biomarkers that can facilitate the prediction of ECT efficacy. The aim of this explorative study was to identify cortical predictors of clinical response in TRD patients treated with ECT. We longitudinally investigated 12 TRD patients before and after ECT. Twelve matched healthy controls were studied cross sectionally. Demographical, clinical, and structural magnetic resonance imaging data at 3 T and multiple cortical markers derived from surface-based morphometry (SBM) analyses were considered. Multiple regression models were computed to identify predictors of clinical response to ECT, as reflected by Hamilton Depression Rating Scale (HAMD) score changes. Symptom severity differences pre-post-ECT were predicted by models including demographic data, clinical data and SBM of frontal, cingulate, and entorhinal structures. Using all-subsets regression, a model comprising HAMD score at baseline and cortical thickness of the left rostral anterior cingulate gyrus explained most variance in the data (multiple R2 = 0.82). The data suggest that SBM provides powerful measures for identifying biomarkers for ECT response in TRD. Rostral anterior cingulate thickness and HAMD score at baseline showed the greatest predictive power of clinical response, in contrast to cortical complexity, cortical gyrification, or demographical data.
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Corteza Cerebral/patología , Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Terapia Electroconvulsiva , Adulto , Corteza Cerebral/diagnóstico por imagen , Estudios Transversales , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/patología , Trastorno Depresivo Resistente al Tratamiento/fisiopatología , Femenino , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/patología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , PronósticoRESUMEN
Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a >50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures. Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.
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Estimulación Encefálica Profunda , Trastorno Depresivo Resistente al Tratamiento/patología , Trastorno Depresivo Resistente al Tratamiento/terapia , Sustancia Gris/patología , Giro del Cíngulo/patología , Evaluación de Resultado en la Atención de Salud , Sustancia Blanca/patología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/patología , Biomarcadores , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Femenino , Sustancia Gris/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tálamo/diagnóstico por imagen , Tálamo/patología , Sustancia Blanca/diagnóstico por imagenAsunto(s)
Amígdala del Cerebelo/patología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/patología , Ketamina/uso terapéutico , Adulto , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Femenino , HumanosRESUMEN
BACKGROUND: Increasing evidence suggests that infusion of a subanesthetic dose of ketamine exerts antidepressant and antisuicidal effects in patients with treatment-resistant depression (TRD). AIMS: In this investigation, we used the resting functional connectivity magnetic resonance imaging (fcMRI) to determine the effects of ketamine on the functional connectivity (FC) of prefrontal cortex (PFC)-related circuits in patients with TRD. METHODS: Forty-eight patients with TRD were recruited and randomly divided into three groups on the basis of ketamine infusion dose: 0.5â¯mg/kg (standard dose), 0.2â¯mg/kg (low dose), or normal saline (a placebo infusion). Resting functional MRI data and clinical data were recorded at the baseline and on the third day after ketamine infusion treatment. RESULTS: The standard-dose group showed a reduction in the FC of the left dorsal anterior cingulate cortex (dACC) and right dorsolateral (dl)PFC with the other frontal regions. The low-dose group demonstrated a more pervasive reduction of FC in the bilateral dACC with other frontal and parietal regions. A negative correlation was observed between the reduction in suicidal ideation and the reduction in the FC between the left dACC and right ACC regions in the standard-dose group, whereas a positive correlation was observed between the reduction in suicidal ideation and the increase in the FC between the right dlPFC and left superior parietal region in the low-dose group. CONCLUSIONS: Our results support the hypothesis that PFC-related circuit modulation is crucial to the antidepressant and antisuicidal effects of the ketamine infusion treatment.
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Antidepresivos/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Ketamina/uso terapéutico , Corteza Prefrontal/patología , Adulto , Trastorno Depresivo Resistente al Tratamiento/patología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Giro del Cíngulo/patología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Corteza Prefrontal/efectos de los fármacos , Descanso , Resultado del TratamientoRESUMEN
INTRODUCTION: 20-30% of depressed patients experience Treatment Resistant Depression (TRD). Electroconvulsive Therapy (ECT) remains the treatment of choice for TRD. However, the exact mechanism of ECT remains unclear. We aim to assess grey matter changes in patients with TRD undergoing bilateral ECT treatment at different points during and after treatment. METHODS: Patients are recruited at the University Hospital of Toulouse. Eligibility criteria include a diagnosis of TRD and an age between 50 and 70 years old. Patients received clinical assessments (Hamilton Depression Rating Scale) and structural scans (MRI) at three points: baseline (within 48â¯h before the first ECT); V2 (after the first ECT considered effective); and V3 (within 1 week of completing ECT). RESULTS: At baseline, controls had significantly higher cortical thickness than patients in the fusiform gyrus, the inferior, middle and superior temporal gyrus, the parahippocampal gyrus and the transverse temporal gyrus (respectively: t(35)=2.7, pâ¯=â¯0.02; t(35)=2.89, pâ¯=â¯0.017; t(35)=3.1, pâ¯=â¯0.015; t(35)=3.6, pâ¯=â¯0.009; t(35)=2.37, pâ¯=â¯0.031; t(35)=2.46, pâ¯=â¯0.03). This difference was no longer significant after ECT. We showed an increase in cortical thickness in superior temporal gyrus between (i) baseline and V3 (t(62)=-3.43 pâ¯=â¯0.009) and (ii) V2 and V3 (t(62)=-3.42 pâ¯=â¯0.009). We showed an increase in hippocampal volume between (i) baseline and V3 (t(62)=-5.23 p < 0.001) and (ii) V2 and V3 (t(62)=-5.3 p < 0.001). CONCLUSION: We highlight that there are grey matter changes during ECT treatment in a population with TRD compared to a healthy control population. These changes seem to occur after several rounds of ECT.
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Trastorno Depresivo Resistente al Tratamiento/patología , Trastorno Depresivo Resistente al Tratamiento/terapia , Terapia Electroconvulsiva , Sustancia Gris/patología , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Femenino , Sustancia Gris/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Giro Parahipocampal/diagnóstico por imagen , Giro Parahipocampal/patología , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patologíaRESUMEN
There is considerable diversity in how treatment-resistant depression (TRD) is defined. However, every definition incorporates the concept that patients with TRD have not benefited sufficiently from one or more adequate trials of antidepressant treatment. This review examines the issues fundamental to the systematic evaluation of antidepressant treatment adequacy and resistance. These issues include the domains of interventions deemed effective in treatment of major depressive episodes (e.g., pharmacotherapy, brain stimulation, and psychotherapy), the subgroups of patients for whom distinct adequacy criteria are needed (e.g., bipolar vs. unipolar depression, psychotic vs. nonpsychotic depression), whether trials should be rated dichotomously as adequate or inadequate or on a potency continuum, whether combination and augmentation strategies require specific consideration, and the criteria used to evaluate the adequacy of treatment delivery (e.g., dose, duration), trial adherence, and clinical outcome. This review also presents the Antidepressant Treatment History Form: Short-Form (ATHF-SF), a completely revised version of an earlier instrument, and details how these fundamental issues were addressed in the ATHF-SF.
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Antidepresivos/uso terapéutico , Estimulación Encefálica Profunda/métodos , Trastorno Depresivo Resistente al Tratamiento/diagnóstico , Trastorno Depresivo Resistente al Tratamiento/terapia , Psicoterapia/métodos , Encuestas y Cuestionarios , Trastorno Depresivo Resistente al Tratamiento/patología , Humanos , Resultado del TratamientoRESUMEN
INTRODUCTION: Pharmacotherapy for the treatment of depressive disorders in Alzheimer's Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8-12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects. AREAS COVERED: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine. EXPERT OPINION: The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Enfermedad de Alzheimer/patología , Antipsicóticos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Ensayos Clínicos como Asunto , Trastorno Depresivo Resistente al Tratamiento/complicaciones , Trastorno Depresivo Resistente al Tratamiento/patología , Humanos , Nimodipina/uso terapéutico , Piperazinas/uso terapéutico , Sertralina/uso terapéutico , Sulfuros/uso terapéutico , VortioxetinaRESUMEN
Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD17) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Hipocampo/diagnóstico por imagen , Adulto , Factores de Edad , Citalopram/uso terapéutico , Estudios de Cohortes , Preparaciones de Acción Retardada , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/patología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Reconocimiento de Normas Patrones Automatizadas , Pronóstico , Escalas de Valoración Psiquiátrica , Inducción de Remisión , Sertralina/uso terapéutico , Clorhidrato de Venlafaxina/uso terapéuticoRESUMEN
BACKGROUND: A single low-dose ketamine infusion exhibited a rapid antidepressant effect within 1h. Despite its short biological half-life (approximately 3h), the antidepressant effect of ketamine has been demonstrated to persist for several days. However, changes in brain function responsible for the persistent antidepressant effect of a single low-dose ketamine infusion remain unclear METHODS: Twenty-four patients with treatment-resistant depression (TRD) were randomized into three groups according to the treatment received: 0.5mg/kg ketamine, 0.2mg/kg ketamine, and normal saline infusion. Standardized uptake values (SUVs) of glucose metabolism measured through 18F-FDG positron-emission-tomography before infusion and 1day after a 40-min ketamine or normal saline infusion were used for subsequent whole-brain voxel-wise analysis and were correlated with depressive symptoms, as defined using the Hamilton Depression Rating Scale-17 (HDRS-17) score RESULTS: The voxel-wise analysis revealed that patients with TRD receiving the 0.5mg/kg ketamine infusion had significantly higher SUVs (corrected for family-wise errors, P = 0.014) in the supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC) than did those receiving the 0.2mg/kg ketamine infusion. The increase in the SUV in the dACC was negatively correlated with depressive symptoms at 1day after ketamine infusion DISCUSSION: The persistent antidepressant effect of a 0.5mg/kg ketamine infusion may be mediated by increased activation in the SMA and dACC. The higher increase in dACC activation was related to the reduction in depressive symptoms after ketamine infusion. A 0.5mg/kg ketamine infusion facilitated the glutamatergic neurotransmission in the SMA and dACC, which may be responsible for the persistent antidepressant effect of ketamine much beyond its half-life.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Giro del Cíngulo/patología , Ketamina/uso terapéutico , Adulto , Encéfalo/efectos de los fármacos , Trastorno Depresivo Resistente al Tratamiento/metabolismo , Trastorno Depresivo Resistente al Tratamiento/patología , Femenino , Giro del Cíngulo/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Corteza Motora , Tomografía de Emisión de Positrones , Factores de TiempoRESUMEN
BACKGROUND: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). RESULTS: Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. CONCLUSION: Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Ketamina/uso terapéutico , Adolescente , Adulto , Anciano , Amígdala del Cerebelo/patología , Antidepresivos/uso terapéutico , Atrofia/patología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Resistente al Tratamiento/patología , Método Doble Ciego , Femenino , Genotipo , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Tálamo/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Although treatment-resistant and nontreatment-resistant depressed patients show structural brain anomalies relative to healthy controls, the difference in regional volumetry between these two groups remains undocumented. METHODS: A whole-brain voxel-based morphometry (VBM) analysis of regional volumes was performed in 125 participants' magnetic resonance images obtained on a 1.5 Tesla scanner; 41 had treatment-resistant depression (TRD), 40 nontreatment-resistant depression (non-TRD), and 44 were healthy controls. The groups were comparable for age and gender. Bipolar/unipolar features as well as pharmacological treatment classes were taken into account as covariates. RESULTS: TRD patients had higher gray matter (GM) volume in the left and right amygdala than non-TRD patients. No difference was found between the TRD bipolar and the TRD unipolar patients, or between the non-TRD bipolar and non-TRD unipolar patients. An exploratory analysis showed that lithium-treated patients in both groups had higher GM volume in the superior and middle frontal gyri in both hemispheres. CONCLUSIONS: Higher GM volume in amygdala detected in TRD patients might be seen in perspective with vulnerability to chronicity, revealed by medication resistance.