Electroconvulsive Therapy Versus Aripiprazole Addition to Clozapine in Patients with Clozapine-Resistant Symptoms (EMECLO): A Protocol of a Single-Blind, Multicenter, Randomized-Controlled Feasibility Trial.

BACKGROUND: Currently, guidance on the most effective treatment for patients with clozapine-resistant schizophrenia-spectrum disorders (SSD) is lacking. While augmentation strategies to clozapine with aripiprazole and electroconvulsive therapy (ECT) have been demonstrated to be effective in patients with clozapine-resistant schizophrenia spectrum disorders (CRS), head-to-head comparisons between these addition strategies are unavailable. We therefore aim to examine the feasibility of a larger randomized, single-blind trial comparing the effectiveness, cost-effectiveness, and safety of aripiprazole addition vs. ECT addition in CRS. METHODS: In this multi-center, randomized, single-blind feasibility study, the feasibility of recruiting 20 participants with CRS who will be randomized to either aripiprazole or bilateral ECT addition will be assessed. The main endpoint is the number of patients willing to be randomized. The number of screened individuals and reasons to decline participation will be recorded. Effects will be estimated for the benefit of the foreseen larger trial. To that end, differences between both arms in symptom severity will be assessed using blinded video assessments. In addition, tolerability (e. g., cognitive functioning), safety, quality of life, recovery, and all-cause discontinuation will be compared. The follow-up period is 16 weeks, after which non-responders will be given the option to switch to the other treatment. DISCUSSION: Strengths of this feasibility trial include maintaining blinding with video assessment, a possibility to switch groups in case of non-response, and a broad set of outcome measures. Identification of factors contributing to non-participation and drop-out will generate valuable information on trial feasibility and may enhance recruitment strategies in a follow-up RCT. TRIAL REGISTRATION: The study has been approved by the Medical Research Ethics Committee of the Amsterdam University Medical Center, location AMC, and was registered on 1 May 2022 in the EU Clinical Trials Register (EudraCT) under the trial name 'EMECLO' (2021-006333-19).

Study protocol of a randomized, double-blind, placebo-controlled, multi-center trial to treat antipsychotic-induced weight gain: the Metformin-Lifestyle in antipsychotic users (MELIA) trial.

BACKGROUND: Antipsychotic-induced Weight Gain (AiWG) is a debilitating and common adverse effect of antipsychotics. AiWG negatively impacts life expectancy, quality of life, treatment adherence, likelihood of developing type-2 diabetes and readmission. Treatment of AiWG is currently challenging, and there is no consensus on the optimal management strategy. In this study, we aim to evaluate the use of metformin for the treatment of AiWG by comparing metformin with placebo in those receiving treatment as usual, which includes a lifestyle intervention. METHODS: In this randomized, double-blind, multicenter, placebo-controlled, pragmatic trial with a follow-up of 52 weeks, we aim to include 256 overweight participants (Body Mass Index (BMI) > 25 kg/m2) of at least 16 years of age. Patients are eligible if they have been diagnosed with schizophrenia spectrum disorder and if they have been using an antipsychotic for at least three months. Participants will be randomized with a 1:1 allocation to placebo or metformin, and will be treated for a total of 26 weeks. Metformin will be started at 500 mg b.i.d. and escalated to 1000 mg b.i.d. 2 weeks thereafter (up to a maximum of 2000 mg daily). In addition, all participants will undergo a lifestyle intervention as part of the usual treatment consisting of a combination of an exercise program and dietary consultations. The primary outcome measure is difference in body weight as a continuous trait between the two arms from treatment inception until 26 weeks of treatment, compared to baseline. Secondary outcome measures include: 1) Any element of metabolic syndrome (MetS); 2) Response, defined as ≥5% body weight loss at 26 weeks relative to treatment inception; 3) Quality of life; 4) General mental and physical health; and 5) Cost-effectiveness. Finally, we aim to assess whether genetic liability to BMI and MetS may help estimate the amount of weight reduction following initiation of metformin treatment. DISCUSSION: The pragmatic design of the current trial allows for a comparison of the efficacy and safety of metformin in combination with a lifestyle intervention in the treatment of AiWG, facilitating the development of guidelines on the interventions for this major health problem. TRIAL REGISTRATION: This trial was registered in the Netherlands Trial Register (NTR) at  https://www.trialregister.nl/trial/8440 as NTR NL8840 on March 8, 2020.

Pharmacological Elevation of Catecholamine Levels Improves Perceptual Decisions, But Not Metacognitive Insight.

Perceptual decisions are often accompanied by a feeling of decision confidence. Where the parietal cortex is known for its crucial role in shaping such perceptual decisions, metacognitive evaluations are thought to additionally rely on the (pre)frontal cortex. Because of this supposed neural differentiation between these processes, perceptual and metacognitive decisions may be divergently affected by changes in internal (e.g., attention, arousal) and external (e.g., task and environmental demands) factors. Although intriguing, causal evidence for this hypothesis remains scarce. Here, we investigated the causal effect of two neuromodulatory systems on behavioral and neural measures of perceptual and metacognitive decision-making. Specifically, we pharmacologically elevated levels of catecholamines (with atomoxetine) and acetylcholine (with donepezil) in healthy adult human participants performing a visual discrimination task in which we gauged decision confidence, while electroencephalography was measured. Where cholinergic effects were not robust, catecholaminergic enhancement improved perceptual sensitivity, while at the same time leaving metacognitive sensitivity unaffected. Neurally, catecholaminergic elevation did not affect sensory representations of task-relevant visual stimuli but instead enhanced well-known decision signals measured over the centroparietal cortex, reflecting the accumulation of sensory evidence over time. Crucially, catecholaminergic enhancement concurrently impoverished neural markers measured over the frontal cortex linked to the formation of metacognitive evaluations. Enhanced catecholaminergic neuromodulation thus improves perceptual but not metacognitive decision-making.

The minimal important difference in obsessive-compulsive disorder: An analysis of double-blind SSRI trials in adults.

BACKGROUND: The change in symptoms necessary to be clinically relevant in obsessive-compulsive disorder (OCD) is currently unknown. In this study, we aimed to create an empirically validated threshold for clinical significance or minimal important difference (MID). METHODS: We analyzed individual participant data from short-term, double-blind, placebo-controlled registration trials of selective serotonin reuptake inhibitors in adult OCD patients. Data were collected from baseline to week 12. We used equipercentile linking to equate changes in the Clinical Global Impression (CGI) scale to changes in the Yale-Brown Obsessive-Compulsive Scale (YBOCS). We defined the MID as the YBOCS change linked to a CGI improvement of 3 (defined as "minimal improvement"). RESULTS: We included 7 trials with a total of 1216 patients. The CGI-scores and YBOCS were moderately to highly correlated. The MID corresponded to 4.9 YBOCS points (95% CI 4.4-5.4) for the full sample, or a 24% YBOCS-decrease compared to baseline. The MID varied with baseline severity, being lower in the group with mild symptoms and higher in the group with severe symptoms. CONCLUSIONS: By linking the YBOCS to the CGI-I, this is the first study to propose an MID in OCD trials. Having a clearly defined MID can guide future clinical research and help interpretation of efficacy of existing interventions. Our results are clinician-based; however, there is further need for patient-reported outcomes as anchor to the YBOCS.

Autonomic nervous system function before and after trauma-focused psychotherapy in youth with (partial) posttraumatic stress disorder.

While trauma-focused psychotherapies have been shown effective in youth with PTSD, the relationship between treatment response and alterations in the autonomic nervous system (ANS) associated with PTSD, remains incompletely understood. During neutral and personalized trauma script imagery heart rate (HR), pre-ejection period (PEP) and respiratory sinus arrhythmia (RSA) were recorded in youth aged 8-18 with PTSD or partial PTSD (n = 76) and trauma-exposed controls (TEC) (n = 27) to determine ANS activity and stress reactivity. Within the patient group, 77.6% met the full DSM-IV diagnostic criteria for PTSD, the remaining 22.4% met the criteria for partial PTSD. Youth with (partial) PTSD were subsequently treated with eight sessions of either trauma-focused cognitive behavioral therapy or eye movement desensitization and reprocessing. PTSD severity was assessed using the Clinician-Administered PTSD scale for Children and Adolescents to divide patients into responders and non-responders. Youth with (partial) PTSD relative to TEC had higher overall HR during both neutral and trauma imagery (p = .05). Youth with (partial) PTSD showed RSA decrease during trauma imagery relative to neutral imagery, the reverse of TEC (p = .01). Relative to non-responders, responders demonstrated a significant baseline to posttreatment increase of RSA response to stress only when employing a ≥ 50% response criterion (p = .05) and not with the primary ≥ 30% criterion (p = .12). Our results suggest overall higher HR and sympathetic nervous system activity as well as vagal withdrawal in response to stress in youth with (partial) PTSD and only provide partial support for normalization of the latter with successful trauma-focused psychotherapy.

Distinct saliva DNA methylation profiles in relation to treatment outcome in youth with posttraumatic stress disorder.

In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome. Thereby gaining a deeper molecular understanding of how psychotherapy (reflecting a change in the environment) relates to epigenetic changes and the adaptability of individuals. To date, limited research is done in clinical samples and no studies have been conducted in youth. Therefore we conducted a study in a Dutch cohort of youth with and without PTSD (n = 87, age 8-18 years). We examined the cross-sectional and longitudinal changes of saliva-based genome-wide DNA methylation (DNAm) levels, and salivary cortisol secretion. The last might reflect possible abbreviations on the hypothalamic-pituitary- adrenal (HPA) axis. The HPA-axis is previously linked to DNAm and the development and recovery of PTSD. Youth were treated with 8 sessions of either Eye Movement Reprocessing Therapy (EMDR) or Trauma Focused Cognitive behavioral Therapy (TF-CBT). Our epigenome wide approach showed distinct methylation between treatment responders and non-responders on C18orf63 gene post-treatment. This genomic region is related to the PAX5 gene, involved in neurodevelopment and inflammation response. Additionally, our targeted approach indicated that there were longitudinal DNAm changes in successfully treated youth at the CRHR2 gene. Methylation at this gene was further correlated with cortisol secretion pre- and post-treatment. Awaiting replication, findings of this first study in youth point to molecular pathways involved in stress response and neuroplasticity to be associated with treatment response.

Internet-based behavioural activation therapy versus online psychoeducation for self-reported suicidal ideation in individuals with depression in Indonesia: a secondary analysis of an RCT.

BACKGROUND: Southeast Asia has the highest suicide mortality worldwide. To improve our knowledge on the effectiveness of interventions for suicidal ideation (SI) in individuals with depression in Indonesia, we conducted a secondary analysis of a randomised controlled trial. OBJECTIVE: We explored whether an internet-based behavioural activation (BA) intervention ('Guided Act and Feel Indonesia' (GAF-ID)) was superior in targeting SI compared with online-delivered psychoeducation (PE). METHODS: In total, 313 participants were randomised between treatment allocation. The SI item of the Patient Health Questionnaire-9 was the primary outcome measure. Mediation analyses were conducted to identify if BA at week 10 mediated the relationship between intervention and SI at week 24. FINDINGS: The GAF-ID intervention was not superior in reducing SI compared with online minimal PE at week 10 (OR 0.61, 95% CI (0.37 to 1.01)), nor at week 24 (OR 0.84, 95% CI (0.47 to 1.52)). SI at week 24 was not mediated by BA at week 10 (b=-0.03, 95% CI (-0.05 to 0.00), p=0.07). CONCLUSIONS: In individuals with depression in Indonesia, the GAF-ID intervention was not superior in reducing self-reported SI compared with PE. Also, the association between treatment condition and SI at week 24 was not mediated via BA at week 10. CLINICAL IMPLICATIONS: This study supports the need for further research on the efficacy of psychological treatments targeting SI in the Southeast Asia context.

Using neurobiological measures to predict and assess treatment outcome of psychotherapy in posttraumatic stress disorder: systematic review.

BACKGROUND: Trauma-focused cognitive-behavioral therapy (TF-CBT) and eye movement desensitization and reprocessing (EMDR) are effective treatments for posttraumatic stress disorder. However, little is known about their neurobiological effects. The usefulness of neurobiological measures to predict the treatment outcome of psychotherapy also has yet to be determined. METHODS: Systematic review of randomized controlled trials (RCTs) focused on neurobiological treatment effects of TF-CBT or EMDR and trials with neurobiological measures as predictors of treatment response. RESULTS: We included 23 publications reporting on 16 separate trials. TF-CBT was compared with a waitlist in most trials. TF-CBT was associated with a decrease in heart rate and blood pressure and changes in activity but not in volume of frontal brain structures and the amygdala. Neurobiological changes correlated with changes in symptom severity. EMDR was only tested against other active treatments in included trials. We did not find a difference in neurobiological treatment effects between EMDR and other treatments. Publications on neurobiological predictors of treatment response showed ambiguous results. CONCLUSION: TF-CBT was associated with a reduction of physiological reactivity. There is some preliminary evidence that TF-CBT influences brain regions involved in fear conditioning, extinction learning and possibly working memory and attention regulation; however, these effects could be nonspecific psychotherapeutic effects. Future trials should use paradigms aimed specifically at these brain regions and physiological reactivity. There are concerns regarding the risk of bias in some of the RCTs, indicating that methodologically more rigorous trials are required. Trials with neurobiological measures as predictors of treatment outcome render insufficient results to be useful in clinical practice.

Catecholaminergic neuromodulation and selective attention jointly shape perceptual decision-making.

Perceptual decisions about sensory input are influenced by fluctuations in ongoing neural activity, most prominently driven by attention and neuromodulator systems. It is currently unknown if neuromodulator activity and attention differentially modulate perceptual decision-making and/or whether neuromodulatory systems in fact control attentional processes. To investigate the effects of two distinct neuromodulatory systems and spatial attention on perceptual decisions, we pharmacologically elevated cholinergic (through donepezil) and catecholaminergic (through atomoxetine) levels in humans performing a visuo-spatial attention task, while we measured electroencephalography (EEG). Both attention and catecholaminergic enhancement improved decision-making at the behavioral and algorithmic level, as reflected in increased perceptual sensitivity and the modulation of the drift rate parameter derived from drift diffusion modeling. Univariate analyses of EEG data time-locked to the attentional cue, the target stimulus, and the motor response further revealed that attention and catecholaminergic enhancement both modulated pre-stimulus cortical excitability, cue- and stimulus-evoked sensory activity, as well as parietal evidence accumulation signals. Interestingly, we observed both similar, unique, and interactive effects of attention and catecholaminergic neuromodulation on these behavioral, algorithmic, and neural markers of the decision-making process. Thereby, this study reveals an intricate relationship between attentional and catecholaminergic systems and advances our understanding about how these systems jointly shape various stages of perceptual decision-making.

Accelerated intermittent theta burst stimulation in major depressive disorder: A systematic review.

BACKGROUND: Major depressive disorder [MDD] is expected to be the leading cause of overall global burden of disease by the year 2030 [WHO]. Non-response to first line pharmacological and psychotherapeutic antidepressive treatments is substantial, with treatment-resistant depression [TRD] affecting approximately one third of depressed patients. There is an urgent need for rapid acting and effective treatments in this population. Repetitive Transcranial Magnetic Stimulation [rTMS] is an non-invasive treatment option for patients with MDD or TRD. Recent studies have proposed new paradigms of TMS, one paradigm is accelerated intermittent Theta Burst Stimulation [aiTBS]. OBJECTIVE: This systematic review assesses the efficacy, safety and tolerability of aiTBS in patients with MDD. METHODS: This review was registered with PROSPERO [ID number: 366556]. A systematic literature review was performed using Pubmed, Web of Science and PsycINFO. Case reports/series, open-label and randomized controlled trials [RCTs] were eligible for inclusion if they met the following criteria; full text publication available in English describing a form of aiTBS for MDD or TRD. aiTBS was defined as at least three iTBS treatments sessions per day, during at least four days for one week. RESULTS: 32 studies were identified describing aiTBS in MDD, 13 studies described overlapping samples. Six articles from five unique studies met eligibility criteria; two open-label studies and three RCTs [two double blind and one quadruple blind]. Response rates directly after treatment ranged from 20.0% to 86.4% and remission rates ranged from 10.0 to 86.4%. Four weeks after treatment response rates ranged from 0.0% to 66.7% and remission rates ranged from 0.0% to 57.1%. Three articles described a significant reduction in suicidality scores. aiTBS was well tolerated and safe, with no serious adverse events reported. CONCLUSIONS: aiTBS is a promising form of non-invasive brain stimulation [NIBS] with rapid antidepressant and antisuicidal effects in MDD. Additionally, aiTBS was well tolerated and safe. However, the included studies had small samples sizes and differed in frequency, intersession interval, neuro localization and stimulation intensity. Replication studies and larger RCTs are warranted to establish efficacy, safety and long term effects.

Gender differences in the response to antipsychotic medication in patients with schizophrenia: An individual patient data meta-analysis of placebo-controlled studies.

OBJECTIVE: To determine whether gender and menopausal status moderate the response to antipsychotic medication in patients with schizophrenia. METHODS: We analyzed data of 22 short-term placebo-controlled registration trials of antipsychotic medications, which included 5,231 patients with schizophrenia. We applied two-step individual patient data meta-regression analyses to establish the influence of gender and menopausal status on treatment response in mean difference in symptom severity and difference in response (>30% symptom reduction). Analyses were performed both with and without correction for baseline (negative) symptom severity. RESULTS: Antipsychotic treatment is associated with larger mean symptom reduction in women than in men with schizophrenia. The number needed to treat (NNT) for a response in women was 6.9, in men 9.4. Although, we found an age by gender effect, the gender by treatment effect was independent of premenopausal status and baseline (negative) symptom severity. CONCLUSION: In the treatment of schizophrenia we found evidence of a higher response to antipsychotic medication in women relative to men. We found no evidence that this effect was driven by menopausal status, or baseline (negative) symptom severity. Despite the impact of gender and age on effect size in acute antipsychotic treatment, efficacy was clinically relevant in all subgroups.

Perceived ethnic discrimination, suicidal ideation and mastery in a multi-ethnic cohort: the HELIUS study.

BACKGROUND: The association between perceived ethnic discrimination (PED) and mental health conditions is well studied. However, less is known about the association between PED and suicidal ideation, or the role of positive psychosocial factors in this association. AIMS: To examine the association between PED and suicidal ideation among ethnic minority groups in Amsterdam, The Netherlands, and investigate whether ethnicity and mastery (people's extent of feeling in control of their lives and environment) moderate this association. METHOD: Cross-sectional data from the multi-ethnic HELIUS study were analysed (n = 17 053) for participants of South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin. PED was measured using the Everyday Discrimination Scale, suicidal ideation using item 9 of the Patient Health Questionnaire-9 and mastery using the Pearlin-Schooler Mastery Scale. RESULTS: Logistic regression analyses demonstrated a small positive association between PED and suicidal ideation (OR = 1.068, 95% CI 1.059-1.077), which did not differ among ethnic minority groups. Mastery did not moderate the association between PED and suicidal ideation among the ethnic minority groups. CONCLUSIONS: Our findings support the hypothesis that PED is associated with suicidal ideation and this association does not significantly vary between ethnic minority groups. Although higher levels of mastery were associated with lower suicidal ideation, mastery did not moderate the relationship between PED and suicidal ideation. Besides targeting ethnic discrimination as a societal problem, future longitudinal research is needed to investigate whether interventions aimed at improving mastery could reduce suicidal ideation in ethnic minority groups.

Ethnic differences in response to atypical antipsychotics in patients with schizophrenia: individual patient data meta-analysis of randomised placebo-controlled registration trials submitted to the Dutch Medicines Evaluation Board.

BACKGROUND: Little is known about the effect of ethnicity on the response to antipsychotic medication in patients with schizophrenia. AIMS: To determine whether ethnicity moderates the response to antipsychotic medication in patients with schizophrenia, and whether this moderation is independent of confounders. METHOD: We analysed 18 short-term, placebo-controlled registration trials of atypical antipsychotic medications in patients with schizophrenia (N = 3880). A two-step, random-effects, individual patient data meta-analysis was applied to establish the moderating effect of ethnicity (White versus Black) on symptom improvement according to the Brief Psychiatric Rating Scale (BPRS) and on response, defined as >30% BPRS reduction. These analyses were corrected for baseline severity, baseline negative symptoms, age and gender. A conventional meta-analysis was performed to determine the effect size of antipsychotic treatment for each ethnic group separately. RESULTS: In the complete data-set, 61% of patients were White, 25.6% of patients were Black and 13.4% of patients were of other ethnicities. Ethnicity did not moderate the efficacy of antipsychotic treatment: pooled ß-coefficient for the interaction between treatment and ethnic group was -0.582 (95% CI -2.567 to 1.412) for mean BPRS change, with an odds ratio of 0.875 (95% CI 0.510-1.499) for response. These results were not modified by confounders. CONCLUSIONS: Atypical antipsychotic medication is equally effective in both Black and White patients with schizophrenia. In registration trials, White and Black patients were overrepresented relative to other ethnic groups, limiting the generalisability of our findings.

Suicidal ideation in remitted major depressive disorder predicts recurrence.

INTRODUCTION: Each year almost 800.000 people die from suicide, of which up to 87% are affected by major depressive disorder (MDD). Despite the strong association between suicidality and MDD, it remains unknown if suicidal symptoms during remission put remitted recurrent MDD patients (rrMDD) at risk for recurrence. METHODS: At baseline we compared sociodemographic characteristics and suicidal symptoms in un-medicated rrMDD participants to matched never-depressed controls. We used the HDRS17 and IDS-SR30 to assess suicidal symptoms and depressive symptomatology. Next, we studied the longitudinal association between baseline suicidal symptoms and time to recurrence(s) in rrMDD during a 2.5-year follow-up period using cox regression analyses. Further, we studied with longitudinal data whether suicidal symptoms and depressive symptomatology were cross-sectionally associated using mixed model analysis. RESULTS: At baseline, rrMDD participants (N = 73) had higher self-reported suicidal symptoms than matched never-depressed controls (N = 45) (χ2 = 12.09 p < .002). Self-reported suicidal symptoms were almost four times higher (27.9% versus 6.9%) compared to clinician-rated suicidal symptoms in rrMDD at baseline. Self-reported baseline suicidal symptoms, but not clinician-rated symptoms, predicted earlier MDD-recurrence during follow-up, independent of other residual depressive symptoms (χ2 = 7.26, p < .026). Higher suicidal symptoms were longitudinally related to higher depressive symptoms (HDRS17; F = 49.87, p < .001), IDS-SR30; (F = 22.36, p < .001). CONCLUSION: This study showed that self-reported - but not clinician-rated - suicidal symptoms persist during remission in rrMDD and predict recurrence, independent from residual symptoms. We recommend to monitor both suicidal and depressive symptomatology during remission in rrMDD, preferably also including self-reported questionnaires apart from clinician-rated. It would be beneficial for future research to assess suicidality using questionnaires primarily designed for measuring suicidal ideation.

Associations Between Child Maltreatment, Inflammation, and Comorbid Metabolic Syndrome to Depressed Mood in a Multiethnic Urban Population: The HELIUS Study.

Background: Child maltreatment is a common negative experience and has potential long-lasting adverse consequences for mental and physical health, including increased risk for major depressive disorder (MDD) and metabolic syndrome. In addition, child maltreatment may increase the risk for comorbid physical health conditions to psychiatric conditions, with inflammation as an important mediator linking child maltreatment to poor adult health. However, it remains unresolved whether experiencing child maltreatment increases the risk for the development of comorbid metabolic syndrome to MDD. Therefore, we investigated whether child maltreatment increased the risk for comorbid metabolic syndrome to depressed mood. Subsequently, we examined whether C-reactive protein (CRP), as an inflammatory marker, mediated this association. In addition, we investigated whether effects differed between men and women. Methods: Associations were examined within cross-sectional data from the multiethnic HELIUS study (N = 21,617). Adult residents of Amsterdam, Netherlands, self-reported on child maltreatment (distinct and total number of types experienced before the age of 16 years) as well as current depressed mood (PHQ-9 score ≥ 10), and underwent physical examination to assess metabolic syndrome. The CRP levels were assessed in N = 5,998 participants. Logistic and linear regressions were applied for binary and continuous outcomes, respectively. All analyses were adjusted for relevant demographic, socioeconomic, and lifestyle characteristics, including ethnicity. Results: A higher number of maltreatment types as well as distinct types of emotional neglect, emotional abuse, and sexual abuse were significantly associated with a higher risk for current depressed mood. Child maltreatment was not significantly associated with the risk for metabolic syndrome in the whole cohort, nor within individuals with depressed mood. As child maltreatment was not significantly associated with the CRP levels, subsequent mediation analyses were not performed. No significant moderating effects by sex were observed. Conclusion: In this multiethnic urban cohort, child maltreatment was associated with a higher risk for depressed mood. Contrary to our expectations, child maltreatment was not significantly associated with an increased risk for metabolic syndrome, neither in the whole cohort nor as a comorbid condition in individuals with depressed mood. As the data were cross-sectional and came from a non-clinical adult population, longitudinal perspectives in relation to various stages of the investigated conditions were needed with more comprehensive assessments of inflammatory markers.

Individual prediction of trauma-focused psychotherapy response in youth with posttraumatic stress disorder using resting-state functional connectivity.

Randomized controlled trials have shown efficacy of trauma-focused psychotherapies in youth with posttraumatic stress disorder (PTSD). However, response varies considerably among individuals. Currently, no biomarkers are available to assist clinicians in identifying youth who are most likely to benefit from treatment. In this study, we investigated whether resting-state functional magnetic resonance imaging (rs-fMRI) could distinguish between responders and non-responders on the group- and individual patient level. Pre-treatment rs-fMRI was recorded in 40 youth (ages 8-17 years) with (partial) PTSD before trauma-focused psychotherapy. Change in symptom severity from pre- to post-treatment was assessed using the Clinician-Administered PTSD scale for Children and Adolescents to divide participants into responders (≥30% symptom reduction) and non-responders. Functional networks were identified using meta-independent component analysis. Group-differences within- and between-network connectivity between responders and non-responders were tested using permutation testing. Individual predictions were made using multivariate, cross-validated support vector machine classification. A network centered on the bilateral superior temporal gyrus predicted treatment response for individual patients with 76% accuracy (pFWE = 0.02, 87% sensitivity, 65% specificity, area-under-receiver-operator-curve of 0.82). Functional connectivity between the frontoparietal and sensorimotor network was significantly stronger in non-responders (t = 5.35, pFWE = 0.01) on the group-level. Within-network connectivity was not significantly different between groups. This study provides proof-of-concept evidence for the feasibility to predict trauma-focused psychotherapy response in youth with PTSD at an individual-level. Future studies are required to test if larger cohorts could increase accuracy and to test further generalizability of the prediction models.

Trauma-focused psychotherapy response in youth with posttraumatic stress disorder is associated with changes in insula volume.

Randomized controlled trials have shown efficacy of trauma-focused psychotherapies in youth with posttraumatic stress disorder (PTSD), but little is known about the relationship between treatment response and alternations in brain structures associated with PTSD. In this study, we longitudinally examined the association between treatment response and pre-to posttreatment changes in structural magnetic resonance imaging (MRI) scans using a voxel-based morphometry approach. We analyzed MRI scans of 35 patients (ages 8-18 years, 21 female) with PTSD (80%) or partial PTSD (20%) before and after eight weekly sessions of trauma-focused psychotherapy. PTSD severity was assessed longitudinally using the Clinician-Administered PTSD scale for Children and Adolescents to divide participants into responders and non-responders. Group by time interaction analysis showed significant differences in grey-matter volume in the bilateral insula due to volume reductions over time in non-responders compared to responders. Despite the significant group by time interaction, there were no significant group differences at baseline or follow-up. As typical development is associated with insula volume increase, these longitudinal MRI findings suggest that treatment non-response is associated with atypical neurodevelopment of the insula, which may underlie persistence of PTSD in youth. The absence of structural MRI changes in treatment responders, while in need of replication, suggest that successful trauma-focused psychotherapy may not directly normalize brain abnormalities associated with PTSD.

Magnetic resonance imaging for individual prediction of treatment response in major depressive disorder: a systematic review and meta-analysis.

No tools are currently available to predict whether a patient suffering from major depressive disorder (MDD) will respond to a certain treatment. Machine learning analysis of magnetic resonance imaging (MRI) data has shown potential in predicting response for individual patients, which may enable personalized treatment decisions and increase treatment efficacy. Here, we evaluated the accuracy of MRI-guided response prediction in MDD. We conducted a systematic review and meta-analysis of all studies using MRI to predict single-subject response to antidepressant treatment in patients with MDD. Classification performance was calculated using a bivariate model and expressed as area under the curve, sensitivity, and specificity. In addition, we analyzed differences in classification performance between different interventions and MRI modalities. Meta-analysis of 22 samples including 957 patients showed an overall area under the bivariate summary receiver operating curve of 0.84 (95% CI 0.81-0.87), sensitivity of 77% (95% CI 71-82), and specificity of 79% (95% CI 73-84). Although classification performance was higher for electroconvulsive therapy outcome prediction (n = 285, 80% sensitivity, 83% specificity) than medication outcome prediction (n = 283, 75% sensitivity, 72% specificity), there was no significant difference in classification performance between treatments or MRI modalities. Prediction of treatment response using machine learning analysis of MRI data is promising but should not yet be implemented into clinical practice. Future studies with more generalizable samples and external validation are needed to establish the potential of MRI to realize individualized patient care in MDD.

Ethnic discrimination and depressed mood: The role of autonomic regulation.

Perceived ethnic discrimination (PED) is thought to underlie increased prevalence of depressed mood in ethnic minorities. Depression is associated with increased sympathetic and decreased parasympathetic activity. We investigated a biopsychosocial model linking PED, disrupted sympathovagal balance and depressed mood. Baseline data of HELIUS, a cohort study on health among a multi-ethnic population, was used. Heart rate variability (HRV), baroreflex sensitivity (BRS), PED (evaluated with the Everyday Discrimination Scale) and presence of depressed mood (evaluated with the Patient Health Questionnaire-9) were assessed. Associations of PED, HRV/BRS and depressed mood were analyzed with linear and logistic regression analyses. Mediation of the association of PED and depressed mood by HRV/BRS was assessed in a potential outcomes model and four steps mediation analysis. Of 9492 included participants, 14.7% fulfilled criteria for depressed mood. Higher PED was associated with depressed mood (P < .001). Lower autonomic regulation indexes were associated with depressed mood (deltaR2 = 0.4-1.1%, P < .001) and at most weakly with PED (deltaR2 = 0.2-0.3%, P < .001). A very modest mediating effect by HRV/BRS in the association between PED and depressed mood was attenuated after adjustment for socioeconomic status. To conclude, we found no support for the hypothesis that autonomic regulation relevantly mediates the association between PED and depression.