Sleep predicts the response to rTMS and CBT in patients with OCD: an open label effectiveness study.

Background: Although many OCD patients benefit from repetitive transcranial magnetic stimulation (rTMS) as treatment, there is still a large group failing to achieve satisfactory response. Sleep problems have been considered transdiagnostic risk factors for psychiatric disorders, and prior work has shown comorbid sleep problems in OCD to be associated with non-response to rTMS in OCD. We therefore set out to investigate the utility of sleep problems in predicting response to rTMS in treatment resistant OCD. Method: A sample of 61 patients (treated with 1-Hz SMA or sequential 1-Hz SMA+DLPFC rTMS, combined with cognitive behavioral therapy) were included. Sleep disturbances were measured using the PSQI, HSDQ and actigraphy. Treatment response was defined as a decrease of at least 35% in symptom severity as measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: 32 of 61 patients (52.5%) responded to rTMS, and trajectories of response were similar for both rTMS protocols. Three PSQI items (Subjective Sleep Quality; Sleep Latency and Daytime Dysfunction) and the HSDQ-insomnia scale were found to predict TMS response. A discriminant model yielded a significant model, with an area under the curve of 0.813. Conclusion: Future replication of these predictors could aid in a more personalized treatment for OCD.

rTMS combined with CBT as a next step in antidepressant non-responders: a study protocol for a randomized comparison with current antidepressant treatment approaches.

BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders, however, current treatment options are insufficiently effective for about 35% of patients, resulting in treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that is effective in treating TRD. Not much is known about the comparative efficacy of rTMS and other treatments and their timing within the treatment algorithm, making it difficult for the treating physician to establish when rTMS is best offered as a treatment option. This study aims to investigate the (cost-)effectiveness of rTMS (in combination with cognitive behavioral therapy (CBT) and continued antidepressant medication), compared to the next step in the treatment algorithm. This will be done in a sample of patients with treatment resistant non-psychotic unipolar depression. METHODS: In this pragmatic multicenter randomized controlled trial 132 patients with MDD are randomized to either rTMS or the next pharmacological step within the current treatment protocol (a switch to a tricyclic antidepressant or augmentation with lithium or a second-generation antipsychotic). Both groups also receive CBT. The trial consists of 8 weeks of unblinded treatment followed by follow-up of the cohort at four and 6 months. A subgroup of patients (n = 92) will have an extended follow-up at nine and 12 months to assess effect decay or retention. We expect that rTMS is more (cost-)effective than medication in reducing depressive symptoms in patients with TRD. We will also explore the effects of both treatments on symptoms associated with depression, e.g. anhedonia and rumination, as well as the effect of expectations regarding the treatments on its effectiveness. DISCUSSION: The present trial aims to inform clinical decision making about whether rTMS should be considered as a treatment option in patients with TRD. The results may improve treatment outcomes in patients with TRD and may facilitate adoption of rTMS in the treatment algorithm for depression and its implementation in clinical practice. TRIAL REGISTRATION: This trial is registered within the Netherlands Trial Register (code: NL7628 , date: March 29th 2019).

Is a Negative Attentional Bias in Individuals with Autism Spectrum Disorder Explained by Comorbid Depression? An Eye-Tracking Study.

Heightened attention towards negative information is characteristic of depression. Evidence is emerging for a negative attentional bias in Autism spectrum disorder (ASD), perhaps driven by the high comorbidity between ASD and depression. We investigated whether ASD is characterised by a negative attentional bias and whether this can be explained by comorbid (sub) clinical depression. Participants (n = 116) with current (CD) or remitted depression (RD) and/or ASD, and 64 controls viewed positively and negatively valenced (non-)social pictures. Groups were compared on three components of visual attention using linear mixed models. Both CD individuals with and without ASD, but not remitted depressed and never-depressed ASD individuals showed a negative bias, suggesting that negative attentional bias might be a depressive state-specific marker for depression in ASD.

Automatic approach-avoidance tendencies as a candidate intermediate phenotype for depression: Associations with childhood trauma and the 5-HTTLPR transporter polymorphism.

Depression risk genes in combination with childhood events have been associated with biased processing as an intermediate phenotype for depression. The aim of the present conceptual replication study was to investigate the role of biased automatic approach-avoidance tendencies as a candidate intermediate phenotype for depression, in the context of genes (5-HTTLPR polymorphism) and childhood trauma. A naturalistic remitted depressed patients sample (N = 209) performed an Approach-Avoidance Task (AAT) with facial expressions (angry, sad, happy and neutral). Childhood trauma was assessed with a questionnaire. Genotype groups were created based on allele frequency: LaLa versus S/Lg-carriers. The latter is associated with depression risk. We found that remitted S/Lg-carriers who experienced childhood trauma automatically avoided sad facial expressions relatively more than LaLa homozygotes with childhood trauma. Remitted LaLa-carriers who had not experienced childhood trauma, avoided sad faces relatively more than LaLa homozygotes with childhood trauma. We did not find a main effect of childhood trauma, nor differential avoidance of any of the other facial expressions. Although tentative, the results suggest that automatic approach-avoidance tendencies for disorder-congruent materials may be a fitting intermediate phenotype for depression. The specific pattern of tendencies, and the relation to depression, may depend on the genetic risk profile and childhood trauma, but replication is needed before firm conclusions can be drawn.

Decreased Cognitive Functioning After Electroconvulsive Therapy Is Related to Increased Hippocampal Volume: Exploring the Role of Brain Plasticity.

OBJECTIVE: Electroconvulsive therapy (ECT) is still the most effective treatment of severe and therapy-refractory major depressive disorder. Cognitive side effects are the major disadvantage of ECT. Cognitive deficits are generally temporary in nature and may be mediated by the hippocampus. Recent studies have shown a temporary increase in hippocampal volume and a temporary decrease in cognitive functioning post-ECT compared with pre-ECT. This study investigates whether these volumetric changes are related to changes in cognitive functioning after ECT. METHODS: Nineteen medication-free patients with treatment-resistant major depressive disorder underwent a whole-brain magnetic resonance imaging scan and a neuropsychological examination (including the Rey auditory verbal learning task, Wechsler Memory Scale Visual Reproduction, fluency, Trail Making Task) within 1 week before and within 1 week after the course of ECT. Electroconvulsive therapy was administered twice a week bitemporally with a brief pulse. A matched healthy control group (n = 18) received the same neuropsychological examination and at a similar interval to that of the patients. RESULTS: Hippocampal volumes increased significantly from pretreatment to posttreatment in patients. Mean performance on cognitive tasks declined, or remained stable, whereas performance in controls generally improved because of retesting effects. The increase in hippocampal volume was related to changes in cognitive performance, indicating that this increase co-occurred with a decrease in cognitive functioning. CONCLUSIONS: Our findings tentatively suggest that the temporal increase in hippocampal volume after treatment, which may result from neurotrophic processes and is thought to be crucial for the antidepressive effect, is also related to the temporary cognitive side effects of ECT.

ADHD symptoms in healthy adults are associated with stressful life events and negative memory bias.

Stressful life events, especially Childhood Trauma, predict ADHD symptoms. Childhood Trauma and negatively biased memory are risk factors for affective disorders. The association of life events and bias with ADHD symptoms may inform about the etiology of ADHD. Memory bias was tested using a computer task in N = 675 healthy adults. Life events and ADHD symptoms were assessed using questionnaires. The mediation of the association between life events and ADHD symptoms by memory bias was examined. We explored the roles of different types of life events and of ADHD symptom clusters. Life events and memory bias were associated with overall ADHD symptoms as well as inattention and hyperactivity/impulsivity symptom clusters. Memory bias mediated the association of Lifetime Life Events, specifically Childhood Trauma, with ADHD symptoms. Negatively biased memory may be a cognitive marker of the effects of Childhood Trauma on the development and/or persistence of ADHD symptoms.

Childhood trauma and negative memory bias as shared risk factors for psychopathology and comorbidity in a naturalistic psychiatric patient sample.

BACKGROUND: Both childhood trauma and negative memory bias are associated with the onset and severity level of several psychiatric disorders, such as depression and anxiety disorders. Studies on these risk factors, however, generally use homogeneous noncomorbid samples. Hence, studies in naturalistic psychiatric samples are lacking. Moreover, we know little about the quantitative relationship between the frequency of traumatic childhood events, strength of memory bias and number of comorbid psychiatric disorders; the latter being an index of severity. The current study examined the association of childhood trauma and negative memory bias with psychopathology in a large naturalistic psychiatric patient sample. METHODS: Frequency of traumatic childhood events (emotional neglect, psychological-, physical- and sexual abuse) was assessed using a questionnaire in a sample of 252 adult psychiatric patients with no psychotic or bipolar-I disorder and no cognitive disorder as main diagnosis. Patients were diagnosed for DSM-IV Axis-I and Axis-II disorders using a structured clinical interview. This allowed for the assessment of comorbidity between disorders. Negative memory bias for verbal stimuli was measured using a computer task. RESULTS: Linear regression models revealed that the frequency of childhood trauma as well as negative memory bias was positively associated with psychiatric comorbidity, separately and above and beyond each other (all p < .01). CONCLUSIONS: The results indicate that childhood trauma and negative memory bias may be of importance for a broader spectrum of psychiatric diagnoses, besides the frequently studied affective disorders. Importantly, frequently experiencing traumatic events during childhood increases the risk of comorbid psychiatric disorders.

Implicit and explicit self-esteem in remitted depressed patients.

BACKGROUND AND OBJECTIVES: Low self-esteem is a symptom of depression and depression vulnerability. Prior research on self-esteem has largely focused on implicit (ISE) and explicit self-esteem (ESE) as two separate constructs, missing their interaction. Therefore, the current study investigated the interaction between ISE and ESE in a depression-vulnerable group (remitted depressed patients; RDs), compared to never-depressed controls (ND). METHODS: Seventy-five RDs and 75 NDs participated in the study. To measure ESE, the Rosenberg Self-Esteem Scale (RSES) was used. The Implicit Association Test (IAT) and the Name Letter Preference Task (NLPT) were used to assess ISE. RESULTS: RDs reported lower ESE than NDs. However, the two groups did not differ on ISE. RDs exhibited a damaged self-esteem or a low-congruent self-esteem, similar to what has been found in currently depressed patients. Moreover, damaged self-esteem was associated with residual depressive symptoms. LIMITATIONS: The results need to be interpreted with care because the IAT and NLPT did not reveal the same associations with the clinical measures. CONCLUSIONS: Implicit and explicit self-esteem may be different constructs in depression and studying the combination is important. The present study provides evidence indicating that damaged self-esteem may be more detrimental than low congruent self-esteem.

Childhood abuse and deprivation are associated with distinct sex-dependent differences in brain morphology.

Childhood adversity (CA) has been associated with long-term structural brain alterations and an increased risk for psychiatric disorders. Evidence is emerging that subtypes of CA, varying in the dimensions of threat and deprivation, lead to distinct neural and behavioral outcomes. However, these specific associations have yet to be established without potential confounders such as psychopathology. Moreover, differences in neural development and psychopathology necessitate the exploration of sexual dimorphism. Young healthy adult subjects were selected based on history of CA from a large database to assess gray matter (GM) differences associated with specific subtypes of adversity. We compared voxel-based morphometry data of subjects reporting specific childhood exposure to abuse (n=127) or deprivation (n=126) and a similar sized group of controls (n=129) without reported CA. Subjects were matched on age, gender, and educational level. Differences between CA subtypes were found in the fusiform gyrus and middle occipital gyrus, where subjects with a history of deprivation showed reduced GM compared with subjects with a history of abuse. An interaction between sex and CA subtype was found. Women showed less GM in the visual posterior precuneal region after both subtypes of CA than controls. Men had less GM in the postcentral gyrus after childhood deprivation compared with abuse. Our results suggest that even in a healthy population, CA subtypes are related to specific alterations in brain structure, which are modulated by sex. These findings may help understand neurodevelopmental consequences related to CA.

Interaction of the 5-HTTLPR and childhood trauma influences memory bias in healthy individuals.

The tendency to recall more negative and less positive information has been frequently related to the genetic susceptibility to depression. This memory bias may be associated with depression candidate genes especially in individuals who experienced stressful childhood events. The serotonin transporter gene, SLC6A4/5-HTT, regulates the reuptake of serotonin. The 5-HTTLPR polymorphism in the gene's promoter region has a short (S) and a long (L) allele, of which L contains a further SNP (rs25531), resulting in a triallelic polymorphism: La, Lg, and S. Both S and Lg result in increased serotonin signaling (to simplify, we refer to both alleles as 'S'), which in turn appears associated with depression vulnerability, specifically in individuals with stressful events. In non-depressed individuals (N=1083), we examined the interaction between the 5-HTTLPR genotype (LaLa, SLa, and SS) and stressful childhood events in association with explicit verbal memory bias (positive, negative). Two types of stressful childhood events were studied, namely childhood adverse events (e.g. parental loss) and interpersonal traumatic childhood events (e.g. abuse). Less positive memory bias was found for individuals with the SS genotype who had experienced interpersonal childhood traumatic events. No general association of genotype with memory bias was found, nor was there a significant interaction between genotype and childhood adverse events. Our results suggest that the depression-susceptibility genotype of the 5-HTTLPR is associated with depressive information processing styles when occurring in combination with traumatic childhood events. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising.

Depressed patients in remission show an interaction between variance in the mineralocorticoid receptor NR3C2 gene and childhood trauma on negative memory bias.

BACKGROUND: Genetic, environmental, and cognitive factors play a role in the development and recurrence of depression. More specifically, cognitive biases have been associated with depression risk genes and life events. Recently, the mineralocorticoid receptor NR3C2 gene, and in particular the rs5534 polymorphism, has been associated with negative memory bias, at least in healthy individuals who experienced severe life adversity. The current study examined the interaction between the rs5534 genotype and different types of adverse life events in a sample of depressed patients in remission. MATERIALS AND METHODS: A total of 298 depressed patients in remission performed an incidental emotional memory task (negative and positive words). Life adversity, childhood trauma, and recent adversity were measured using a self-report questionnaire. NR3C2 rs5534 by life adversity, as well as childhood trauma and recent adversity interactions were analyzed for negative and positive memory bias using analyses of covariance. RESULTS: The significant interaction between rs5534 and childhood trauma on negative memory bias (P=0.046) indicated that risk 'A' allele carriers with childhood trauma tended to show more negative memory bias compared to individuals homozygous for the G allele who had experienced childhood trauma and A allele carriers without childhood trauma. No interaction effects with life adversity or recent adversity were found. Also, no main effect of rs5534 on memory bias was found, although we had insufficient power for this analysis. CONCLUSION: An association of the NR3C2 gene and childhood trauma with negative memory bias was found in depressed patients in remission, which extends previous findings in a healthy population.

No evidence for the association between a polymorphism in the PCLO depression candidate gene with memory bias in remitted depressed patients and healthy individuals.

The PCLO rs2522833 candidate polymorphism for depression has been associated to monoaminergic neurotransmission. In healthy and currently depressed individuals, the polymorphism has been found to affect activation of brain areas during memory processing, but no direct association of PCLO with memory bias was found. We hypothesized that the absence of this association might have been obscured by current depressive symptoms or genetically driven individual differences in reactivity to stressful events. Experiencing stressful childhood events fosters dysfunctional assumptions that are related to cognitive biases, and may modulate the predisposition for depression via epigenetic effects. The association between PCLO and memory bias, as well as interaction between PCLO and childhood events was studied in patients remitted from depression (N = 299), as well as a sample of healthy individuals (N = 157). The participants performed an emotional verbal memory task after a sad mood induction. Childhood trauma and adversity were measured with a questionnaire. The Genotype main effect, and Genotype by Childhood Events interaction were analyzed for memory bias in both samples. PCLO risk allele carrying remitted depressed patients did not show more negatively biased memory than non-risk allele carriers, not even patients with stressful childhood events. A similar pattern of results was found in healthy individuals. Memory bias may not be strongly associated with the PCLO rs2522833 polymorphism. We did not find any support for the PCLO-childhood events interaction, but the power of our study was insufficient to exclude this possibility.

Linking genetic variants of the mineralocorticoid receptor and negative memory bias: interaction with prior life adversity.

Substantial research has been conducted investigating the association between life adversity and genetic vulnerability for depression, but clear mechanistic links are rarely identified and investigation often focused on single genetic variants. Complex phenotypes like depression, however, are likely determined by multiple variants in interaction with environmental factors. As variations in the mineralocorticoid receptor gene (NR3C2) have been related to a higher risk for depression, we investigated whether NR3C2 variance is related to negative memory bias, an established endophenotype for depression, in healthy participants. Furthermore, we explored the influence of life adversity on this association. We used a set-based analysis to simultaneously test all measured variation in NR3C2 for an association with negative memory bias in 483 participants and an interaction with life adversity. To further specify this interaction, we split the sample into low and high live adversity groups and repeated the analyses in both groups separately. NR3C2 variance was associated with negative memory bias, especially in the high life adversity group. Additionally, we identified a functional polymorphism (rs5534) related to negative memory bias and demonstrating a gene×life adversity interaction. Variations in NR3C2 are associated with negative memory bias and this relationship appears to be influenced by life adversity. As negative memory bias is implicated in the susceptibility to depression, our findings provide mechanistic support for the notion that variations in NR3C2 - which could compromise the proper function of this receptor - are a risk factor for the development of mood disorders.

Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study.

Electroconvulsive therapy (ECT) is the most potent biological therapy in depression. Animal studies suggest that ECT acts via neuroplasticity effects on limbic structures involved in the pathophysiology of depression but in vivo evidence at the human system level is scarce. Therefore, the aim of the present study was to investigate the effect of ECT on hippocampus and amygdala volume in 15 antidepressant-free patients with treatment refractory depression (seven males, range 42-63 years). ECT treatment was successful as indexed by a significant decrease in depressive symptoms (t14=13.6; p<0.001). Analysis of normalized volumetric data before and after ECT treatment revealed a significant volume increase of both hippocampus and amygdala (minimum p<0.005) with no evidence for a change in global brain volume. Though this change in volume cannot be clearly related to treatment effects, ECT is associated with broader neurotrophic effects other than mere adult neurogenesis in the hippocampus, which has been previously suggested as a core mechanism on the basis of animal data.

[Neurosyphilis, the great imitator: a diagnostic challenge]. / De grote imitator neurosyfilis: een diagnostische uitdaging.

BACKGROUND: Neurosyphilis is a tertiary form of syphilis and is caused by the spirochete Treponema pallidum. Today, more than one type of neurosyphilis often manifest simultaneously, which can pose difficulties to the diagnostic process. CASE DESCRIPTION: A 45-year-old man presented with an attack of stammering and loss of strength in the right half of his body. Diagnostic testing led to a suspected TIA and the man was treated as such. It was only a few months later, when he had developed more neurological symptoms, that the diagnosis of 'neurosyphilis' was made. Despite treatment with benzyl penicillin, he also developed symptoms of a psychiatric nature. CONCLUSION: The patient described in this article had symptoms consistent with both meningovascular syphilis and generalised paresis. Detailed history-taking was necessary to make the diagnosis (the patient had a history of gonorrhoea). A seemingly insignificant detail - an elevated estimated sedimentation rate - was an important clue.

Approach and Avoidance of Emotional Faces in Happy and Sad Mood.

Since the introduction of the associative network theory, mood-congruent biases in emotional information processing have been established in individuals in a sad and happy mood. Research has concentrated on memory and attentional biases. According to the network theory, mood-congruent behavioral tendencies would also be predicted. Alternatively, a general avoidance pattern would also be in line with the theory. Since cognitive biases have been assumed to operate strongly in case of social stimuli, mood-induced biases in approach and avoidance behavior towards emotional facial expressions were studied. 306 females were subjected to a highly emotional fragment of a sad or a happy movie, to induce either a sad mood or a happy mood. An Approach-Avoidance Task was implemented, in which single pictures of faces (with angry, sad, happy, or neutral expression) and non-social control pictures were presented. In contrast to our expectations, mood states did not produce differential behavioral biases. Mood-congruent and mood-incongruent behavioral tendencies were, however, present in a subgroup of participants with highest depressive symptomatology scores. This suggests that behavioral approach-avoidance biases are not sensitive to mood state, but more related to depressive characteristics.