Abnormal expression profile of plasma-derived exosomal microRNAs in patients with treatment-resistant depression.

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.

Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review.

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.

Neuroanatomical predictors of response to subcallosal cingulate deep brain stimulation for treatment-resistant depression

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.

Exploring cortical predictors of clinical response to electroconvulsive therapy in major depression.

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.

Increased hippocampal tail volume predicts depression status and remission to anti-depressant medications in major depression.

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.

Amygdala and regional volumes in treatment-resistant versus nontreatment-resistant depression patients.

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.

A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control.

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. It has previously been proposed that this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral anterior cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy control subjects. Using the Ekman 60 faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received anterior cingulotomy were impaired in recognizing negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with this hypothesis, we found that larger volume lesions predicted more impairment in recognizing fear, disgust and anger, and no impairment in recognizing facial expressions of surprise or happiness. However, we found no impairment in recognizing expressions of sadness. Also consistent with the hypothesis, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman's meta-analysis-derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimizing behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. While the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes.

A Prospective, Longitudinal Study of the Effect of Remission on Cortical Thickness and Hippocampal Volume in Patients with Treatment-Resistant Depression.

BACKGROUND: Magnetic resonance imaging studies have provided evidence of structural modifications in cortical-limbic regions in major depressive disorder. To date, however, few studies have tracked structural changes in patients during treatment. This prospective, longitudinal imaging study investigated associations between brain structure and clinical responsiveness in a sample of patients with treatment-resistant major depressive disorder during an approximate 1-year follow-up period. METHODS: FreeSurfer software was used to extract volume or cortical thickness values from 6 regions of interest (hippocampus, rostral middle frontal gyrus, orbitofrontal cortex, rostral and caudal anterior cingulate cortices, and inferior temporal gyrus) in patients (n = 26) and matched healthy controls (n = 28). Regions of interest were selected based on previous evidence of potential associations between morphometric characteristics in these regions and treatment response or remission. Analyses were conducted to compare volume and cortical thickness in patients and controls at baseline imaging, determine whether patients' brain structure at treatment initiation was associated with response over follow-up, and compare longitudinal changes in volume and cortical thickness in patients who achieved sustained 6-month remission (Montgomery-Åsberg Depression Rating Scale Score ≤12) with nonremitters. RESULTS: Patients and controls showed no structural differences at baseline. Among patients, thicker right caudal anterior cingulate cortex at baseline was associated with greater symptom improvement over follow-up. Remitters and nonremitters showed subtle changes in volume and thickness over time in opposing directions, with increased hippocampal volume and cortical thickness in the rostral middle frontal gyrus, orbitofrontal cortex, and inferior temporal gyrus in remitters, and decreased volume or thickness in these regions in nonremitters. CONCLUSIONS: The results suggest that longitudinal structural trajectories may differ in major depressive disorder patients according to their clinical response to treatment.

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.

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 (χ(2)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).

Impact of monoamine-related gene polymorphisms on hippocampal volume in treatment-resistant depression.

OBJECTIVE: In major depressive disorder (MDD), single nucleotide polymorphisms (SNPs) in monoaminergic genes may impact disease susceptibility, treatment response, and brain volume. The objective of this study was to examine the effect of such polymorphisms on hippocampal volume in patients with treatment-resistant MDD and healthy controls. Candidate gene risk alleles were hypothesised to be associated with reductions in hippocampal volume. METHODS: A total of 26 outpatients with treatment-resistant MDD and 27 matched healthy controls underwent magnetic resonance imaging and genotyping for six SNPs in monoaminergic genes [serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), serotonin 1A and 2A receptors (HTR1A and HTR2A), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF)]. Hippocampal volume was estimated using an automated segmentation algorithm (FreeSurfer). RESULTS: Hippocampal volume did not differ between patients and controls. Within the entire study sample irrespective of diagnosis, C allele-carriers for both the NET-182 T/C [rs2242446] and 5-HT1A-1019C/G [rs6295] polymorphisms had smaller hippocampal volumes relative to other genotypes. For the 5-HTTLPR (rs25531) polymorphism, there was a significant diagnosis by genotype interaction effect on hippocampal volume. Among patients only, homozygosity for the 5-HTTLPR short (S) allele was associated with smaller hippocampal volume. There was no association between the 5-HT2A, COMT, and BDNF SNPs and hippocampal volume. CONCLUSION: The results indicate that the volume of the hippocampus may be influenced by serotonin- and norepinephrine-related gene polymorphisms. The NET and 5-HT1A polymorphisms appear to have similar effects on hippocampal volume in patients and controls while the 5-HTTLPR polymorphism differentially affects hippocampal volume in the presence of depression.

Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression.

BACKGROUND: Although white-matter abnormalities have been reported in middle-aged patients with major depressive disorder (MDD), few data are available on treatment-resistant MDD and the influence of relevant variables related to clinical burden of illness is far from being well established. METHOD: The present study examined white-matter microstructure in a sample of 52 patients with MDD in different stages (treatment-resistant/chronic MDD, n = 18; remitted-recurrent MDD, n = 15; first-episode MDD, n = 19) and 17 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. Groups were comparable in age and gender distribution, and results were corrected for familywise error (FWE) rate. RESULTS: Widespread significant reductions of fractional anisotropy (FA) - including the cingulum, corpus callosum, superior and inferior longitudinal fascicule - were evident in treatment-resistant/chronic MDD compared with first-episode MDD and controls (p < 0.05, FWE-corrected). Decreased FA was observed within the ventromedial prefrontal region in treatment-resistant/chronic MDD even when compared with the remitted-recurrent MDD group (p < 0.05, FWE-corrected). Longer duration of illness (ß = -0.49, p = 0.04) and higher depression severity (at a trend level: ß = -0.26, p = 0.06) predicted lower FA in linear multiple regression analysis at the whole-brain level. The number of previous episodes and severity of symptoms were significant predictors when focused on the ventromedial prefrontal area (ß = -0.28, p = 0.04; and ß = -0.29, p = 0.03, respectively). Medication effects were controlled for in the analyses and results remained unaltered. CONCLUSIONS: Our findings support the notion that disruptions of white-matter microstructure, particularly in fronto-limbic networks, are associated with resistance to treatment and higher current and past burden of depression.

Ventral targeted anterior capsulotomy for treatment-resistant depression and obsessive-compulsive disorder: A treatment method with cases.

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.

Refractory major depression successfully treated with electroconvulsive therapy in a patient with Addison disease.

This report describes a 55-year-old woman who had 1 previous episode of major depression that responded favorably to treatment with tricyclic antidepressants. After the development of Addison disease, she experienced a new episode of major depression that failed to respond to adequate treatment with imipramine and was subsequently successfully treated with electroconvulsive therapy (ECT) with steroid cover. The patient did not experience adrenal crisis or adverse effects. After 9 ECT sessions, she attained full remission. These findings support the suggestion that ECT treatment is safe in patients with Addison disease when using 100 mg intravenous hydrocortisone as prophylaxis.

Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: A randomized, double-blind, midazolam-controlled PET-MRI clinical trial.

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.

Hippocampal volumetrics in treatment-resistant depression and schizophrenia: the devil's in de-tail.

Studies of patients with major depressive disorder (MDD) and schizophrenia (SCH) have revealed reduced hippocampal volumes, but findings have been inconsistent due to sample and measurement differences. The current study sought to measure this structure in a large sample of MDD, SCH, and healthy subjects, using a strict measurement protocol, to elucidate morphological-specific volumetric differences. Patients with treatment-resistant MDD (N = 182) and treatment-resistant SCH with auditory-verbal hallucinations (N = 52), and healthy controls (N = 76) underwent psychiatric assessments and brain MRI. The findings indicate that (1) MDD and SCH patients have reduced total hippocampal volume which was marked in the tails (more so in patients with MDD), (2) region of interest estimation protocols and sample characteristics may help explain volumetric differences between previous SCH studies.

Cognitive and volumetric predictors of response to repetitive transcranial magnetic stimulation (rTMS) - a prospective follow-up study.

As the prevalence of treatment resistant depression (TRD) continues to rise, it remains a clinically important issue to identify neurobiological-, patient- and treatment-related factors that could potentially predict response to treatment. Medial temporal lobe (MTL) structures, in particular the hippocampus and amygdala have been implicated in inferior treatment response. The role of related structures such as the entorhinal cortex and the impact of MTL abnormalities on neurocognitive function, however, have not been systematically examined. The current study investigated MTL abnormalities and neurocognitive characteristics of eventual treatment responders and non-responders to a course of repetitive transcranial magnetic stimulation (rTMS) in order to identify potential predictors of treatment outcome. Prior to rTMS treatment all patients underwent magnetic resonance imaging (MRI) and neuropsychological assessment. MRI analysis was conducted using FreeSurfer 5.0. There was a 50% response rate following up to a 6-week course of daily rTMS treatments. Treatment response was defined as 50% reduction in Hamilton Depression Rating Scale and BDI-II scores from baseline. There was no difference in pre-treatment neurocognitive profiles and MTL volumes between eventual treatment responders and non-responders. Smaller pre-treatment left hippocampus volume showed a trend towards predicting eventual subjective improvement in depressive symptomatology. Although preliminary, our findings suggest that structural abnormalities may have some potential for predicting outcome to rTMS.

Abnormal habenula functional connectivity characterizes treatment-resistant depression.

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.

Molecular basis and clinical perspectives of deep brain stimulation for major depressive disorder.

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.

Replication of machine learning methods to predict treatment outcome with antidepressant medications in patients with major depressive disorder from STAR*D and CAN-BIND-1.

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.

A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

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.