Mental illness and cardiovascular health: observational and polygenic score analyses in a population-based cohort study.

BACKGROUND: Individuals with serious mental illness have a markedly shorter life expectancy. A major contributor to premature death is cardiovascular disease (CVD). We investigated associations of (genetic liability for) depressive disorder, bipolar disorder and schizophrenia with a range of CVD traits and examined to what degree these were driven by important confounders. METHODS: We included participants of the Dutch Lifelines cohort (N = 147 337) with information on self-reported lifetime diagnosis of depressive disorder, bipolar disorder, or schizophrenia and CVD traits. Employing linear mixed-effects models, we examined associations between mental illness diagnoses and CVD, correcting for psychotropic medication, demographic and lifestyle factors. In a subsample (N = 73 965), we repeated these analyses using polygenic scores (PGSs) for the three mental illnesses. RESULTS: There was strong evidence that depressive disorder diagnosis is associated with increased arrhythmia and atherosclerosis risk and lower heart rate variability, even after confounder adjustment. Positive associations were also found for the depression PGSs with arrhythmia and atherosclerosis. Bipolar disorder was associated with a higher risk of nearly all CVD traits, though most diminished after adjustment. The bipolar disorder PGSs did not show any associations. While the schizophrenia PGSs was associated with increased arrhythmia risk and lower heart rate variability, schizophrenia diagnosis was not. All mental illness diagnoses were associated with lower blood pressure and a lower risk of hypertension. CONCLUSIONS: Our study shows widespread associations of (genetic liability to) mental illness (primarily depressive disorder) with CVD, even after confounder adjustment. Future research should focus on clarifying potential causal pathways between mental illness and CVD.

Effects of deep brain stimulation on cognitive functioning in treatment-resistant depression: a systematic review and meta-analysis.

Deep brain stimulation (DBS) is a promising intervention for treatment-resistant depression (TRD). Effects on cognitive functioning are unclear since they have been studied in small samples. We aim to estimate the impact of DBS on cognitive functioning in TRD with a systematic review and meta-analyses. After systematically searching PubMed we included 10 studies which compared standardized neuropsychological tests before and after DBS or between active and sham DBS in TRD. Different random-effects meta-analyses were done for different cognitive (sub-)domains and for different follow-up time windows (<6 months, 6-18 months, and >18 months). We found no significant differences in cognitive functioning up to 6 months of DBS. After 6-18 months of DBS small to moderate improvements were found in verbal memory (Hedge's g = 0.22, 95% CI = [0.01-0.43], p = 0.04), visual memory (Hedge's g = 0.37, 95% CI = [0.03-0.71], p = 0.04), attention/psychomotor speed (Hedge's g = 0.26, 95% CI = [0.02-0.50], p = 0.04) and executive functioning (Hedge's g = 0.37, 95% CI = [0.15-0.59], p = 0.001). Not enough studies could be retrieved for a meta-analysis of effects after >18 months of DBS or for the comparison of active and sham DBS. Qualitatively, generally no differences in cognitive functioning between active and sham DBS were found. No cognitive decline was found in this meta-analysis up to 18 months of DBS in patients with TRD. Results even suggest small positive effects of DBS on cognitive functioning in TRD, although this should be interpreted with caution due to lack of controlled data.

[Consensus Statement on deep brain stimulation for treatment-resistant obsessive-compulsive disorder]. / Consensusverklaring diepe hersenstimulatie bij obsessieve-compulsieve stoornis.

BACKGROUND: Since 2013, deep brain stimulation (DBS) has been reimbursed in the Netherlands as a proven effective treatment for treatment-resistant obsessive-compulsive disorder (OCD). Nevertheless, DBS is still rarely applied, and a national Dutch treatment protocol is lacking. AIM: To prepare a nationwide multidisciplinary treatment protocol for the application of DBS in the treatment of treatment-resistant OCD. METHOD: Formulation of recommendations for the execution and application of DBS in OCD regarding indication, implantation, optimization of stimulation parameters, and consolidation of long-term effects, based on literature research and consensus among experts represented in the multidisciplinary Dutch DBS in Psychiatry working group. RESULTS: Following indication, DBS electrodes are bilaterally implanted in white matter tracts in the anterior limb of the internal capsule. In previously highly treatment-resistant patients with severe OCD, this leads to an average 66% response rate after optimization of stimulation parameters. Placebo-controlled effects are significant (Hedges’ g = 0.9). The main reported side effects are transient hypomanic symptoms, fatigue, and subjective cognitive complaints. Perioperative complications are rare. Positive effects remain stable during years of follow-up. DBS is cost-effective and leads to increased quality of life and functional recovery. Nevertheless, DBS is applied infrequently relative to the estimated number of patients with treatment-resistant OCD. CONCLUSION: By adhering to the described recommendations regarding indication, implantation, optimization, and consolidation, DBS is an effective and safe treatment option for treatment-resistant OCD. A nationwide multidisciplinary treatment protocol can contribute to the implementation of DBS with more and earlier referrals, allowing more patients to benefit from this treatment more quickly.

Instrumental learning in a mouse model for obsessive-compulsive disorder: Impaired habit formation in Sapap3 mutants.

It has been hypothesized that maladaptive habit formation contributes to compulsivity in psychiatric disorders such as obsessive-compulsive disorder (OCD). Here, we used an established animal model of OCD, Sapap3 knockout mice (SAPAP3-/-), to investigate the balance of goal-directed and habitual behavior in compulsive individuals and if altered habit formation is associated with compulsive-like behavior. We subjected 24 SAPAP3-/- and 24 wildtype littermates (WT) to two different schedules of reinforcement in a within-subjects design: a random-ratio (RR) schedule to promote goal-directedness, and a random-interval (RI) schedule, known to facilitate habitual responding. SAPAP3-/- acquired responding under both schedules, but showed lower response rates and fewer attempts to collect food pellets than WT, indicative of altered reward processing. As expected, WT were sensitive to sensory-specific satiety (outcome devaluation) following RR training, but not RI training, demonstrating schedule-specific acquisition of goal-directed and habitual responding, respectively. In contrast, SAPAP3-/- were sensitive to outcome devaluation after both RR and RI training, suggesting decreased engagement of a habitual response strategy. No linear relation was observed between increased grooming and behavior during the outcome devaluation test in SAPAP3-/-. Together, our findings demonstrate altered reward processing and impaired habit learning in SAPAP3-/-. We report a diminished propensity to form habits in these mice, which albeit inconsistent with the predominant idea of excessive habit formation in OCD, nonetheless points at dysregulation of behavioral automation in the context of compulsivity. Thus, the habit hypothesis of compulsivity should be updated to state that an imbalance of habitual and goal-directed responding in either direction can contribute to the development of compulsive behavior.

[Electroconvulsion therapy for persistent depression in the Netherlands; very low application rate]. / Elektroconvulsietherapie bij persisterende depressie in Nederland; zeer lage toepassingsgraad.

BACKGROUND: Of all depressive disorders, 20% has a persistent course. For persistent depressive patients, electroconvulsive therapy (ect) is recommended for this patient population, since it is the most potent treatment for depression. The Dutch depression guideline advises the use of ect for persistent depressive disorder at approximately 12 months after inadequate efficacy of psychotherapy and/or pharmacological treatment.
AIM: To quantify the use of electroconvulsive therapy in persistent depressive patients in the Netherlands.
METHOD: Quantitative research using the Dutch registration system (diagnosis-treatment-combination; dbc) information system (dis) of the Dutch Healthcare Authority (nza).
RESULTS: Of the patients within the dbc system (in 2014) with the main diagnosis of unipolar depression, 23,597 (26%) were registered for more than two years and could be classified as having a persistent depressive episode. Of these latter patients, only 278 (1.2%) received ect.
CONCLUSION: In the Netherlands, only 1.2% of patients with a persistent depression received ect, whereas this treatment could have been considered for 26% of this group. The low application rate might be caused by professionals' inadequate knowledge about ect and the premature use of the handicap model.

[Reaction on 'Persistant underuse of ECT for persistant depressive disorder?'] / Reactie op 'Persisterend ondergebruik van ECT bij persisterende depressieve stoornis?'.

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[Does psychiatry revert to subjectivity?] / Keert nieuwe psychiatrie terug naar de betekenis?

BACKGROUND: Psychiatry is currently challenged by two main issues, subjectivity and non-exclusivity.
AIM: The re-appraisal of phenomenological psychiatry.
METHOD: Personal reflection.
RESULTS: Phenomenology may contribute to psychiatry by 1. offering a method, 2. focusing on descriptive observation, and 3. taking a neutral stance.
CONCLUSION: By emphasizing the subjective experience, phenomenology offers psychiatry an opportunity to become proficient and to distinguish itself from other disciplines through the continued development of insight and understanding of mental disorders.

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression.

BACKGROUND: Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation. METHOD: To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase. RESULTS: TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially. CONCLUSIONS: vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory.

[Deep brain stimulation in psychiatry]. / Diepe hersenstimulatie in de psychiatrie.

BACKGROUND: Deep brain stimulation (DBS) is now used regularly to treat therapy-refractory obsessive-compulsive disorders, and is being applied experimentally for refractory depression, Tourette syndrome, addiction, eating disorders, post-traumatic stress disorder, autism and schizophrenia. AIM: To review the effects and mechanisms of dbs and to consider the future opportunities for this type of treatment in psychiatry. METHOD: We reviewed the literature using PubMed. RESULTS:  DBS is effective and safe to use in the treatment of therapy-refractory OCD and has produced encouraging results in cases of refractory depression and Tourette syndrome. However, further investigations are needed with regard to the use of DBS for treating other psychiatric disorders. DBS influences brain networks that are relevant for a whole range of psychiatric symptoms. CONCLUSION:  DBS should always be considered as possible treatment for therapy-refractory OCD. DBS often leads to marked and rapid improvement in mood, anxiety, behaviour and other psychiatric symptoms, making it a promising intervention for a variety of refractory patient groups. The development of DBS for psychiatry will benefit from our increased knowledge about how specific brain networks relate to psychiatric dysfunctioning.

A functional MRI marker may predict the outcome of electroconvulsive therapy in severe and treatment-resistant depression.

Electroconvulsive therapy (ECT) is effective even in treatment-resistant patients with major depression. Currently, there are no markers available that can assist in identifying those patients most likely to benefit from ECT. In the present study, we investigated whether resting-state network connectivity can predict treatment outcome for individual patients. We included forty-five patients with severe and treatment-resistant unipolar depression and collected functional magnetic resonance imaging scans before the course of ECT. We extracted resting-state networks and used multivariate pattern analysis to discover networks that predicted recovery from depression. Cross-validation revealed two resting-state networks with significant classification accuracy after correction for multiple comparisons. A network centered in the dorsomedial prefrontal cortex (including the dorsolateral prefrontal cortex, orbitofrontal cortex and posterior cingulate cortex) showed a sensitivity of 84% and specificity of 85%. Another network centered in the anterior cingulate cortex (including the dorsolateral prefrontal cortex, sensorimotor cortex, parahippocampal gyrus and midbrain) showed a sensitivity of 80% and a specificity of 75%. These preliminary results demonstrate that resting-state networks may predict treatment outcome for individual patients and suggest that resting-state networks have the potential to serve as prognostic neuroimaging biomarkers to guide personalized treatment decisions.

Net gain analysis, an addition to responder analysis--The case of antipsychotic treatment of acute mania.

Net Gain Analysis (NGA) is proposed as an alternative to Responders Analysis (RA) as a more comprehensive method to tap clinical relevance of the effect of treatment. NGA is the group difference in responders minus the group difference in deteriorators; while RA is the group difference in responders. We examined the performance of these two methods in a dataset consisting of individual patient data from 10 randomized controlled trials (N = 2666) of five different antipsychotics in patients with acute mania by comparing the rank ordering of the five compounds according to both systems (NGA and RA). The rank order did not differ between the 2 systems but the inferiority of one compound was revealed more evidently by the NGA in comparison to the RA.

Cognitive-behavioural therapy augments the effects of deep brain stimulation in obsessive-compulsive disorder.

BACKGROUND: Deep brain stimulation (DBS) is a promising new treatment for patients with treatment-refractory obsessive-compulsive disorder (OCD). However, since most DBS patients only show a partial response, the treatment still needs to be improved. In this study we hypothesized that cognitive-behavioural therapy (CBT) could optimize the post-operative management in DBS and we evaluated the efficacy of CBT as augmentation to DBS targeted at the nucleus accumbens. METHOD: A total of 16 patients with treatment-refractory OCD were treated with DBS targeted at the nucleus accumbens. After stabilization of decline in OCD symptoms, a standardized 24-week CBT treatment programme was added to DBS in an open-phase trial of 8 months. Changes in obsessive-compulsive, anxiety and depressive symptoms were evaluated using the Yale-Brown Obsessive Compulsive Scale, Hamilton Anxiety Scale and Hamilton Rating Scale for Depression. RESULTS: Following the addition of CBT to DBS, a significant decrease in obsessive-compulsive symptoms was observed, but not in anxiety and depressive symptoms. In a subsequent double-blind phase, in which stimulation was discontinued, OCD symptoms returned to baseline (relapse) and anxiety and depressive symptoms worsened (rebound) compared with baseline. CONCLUSIONS: The results of this explorative study suggest that a combined treatment of accumbens DBS and CBT may be optimal for improving obsessive-compulsive symptoms in treatment-refractory OCD. However, a subsequent randomized controlled trial is necessary to draw firm conclusions. It seems that DBS results in affective changes that may be required to enable response prevention in CBT. This may indicate that DBS and CBT act as two complementary treatments.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

A multicenter double-blind randomized crossover study comparing the impact of dorsal subthalamic nucleus deep brain stimulation versus standard care on apathy in Parkinson's disease: a study protocol.

BACKGROUND: Neuroimaging studies suggest an association between apathy after deep brain stimulation (DBS) and stimulation of the ventral part of the subthalamic nucleus (STN) due to the associative fibers connected to the non-motor limbic circuits that are involved in emotion regulation and motivation. We have previously described three patients with severe apathy that could be fully treated after switching stimulation from a ventral electrode contact point to a more dorsal contact point. OBJECTIVES: To determine whether more dorsal stimulation of the STN decreases apathy compared to standard care in a multicenter randomized controlled trial with a crossover design. METHODS: We will include 26 patients with a Starkstein Apathy Scale (SAS) score of 14 or more after subthalamic nucleus (STN) deep brain stimulation (DBS) for refractory Parkinson's disease. This is a multicenter trial conducted in two teaching hospitals and one university medical center in the Netherlands after at least 3 months of STN DBS. Our intervention will consist of 1 month of unilateral dorsal STN stimulation compared to treatment as usual. The primary outcome is a change in SAS score following 1 month of DBS on the original contact compared to the SAS score following 1 month of DBS on the more dorsal contact. Secondary outcomes are symptom changes on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor part III, Montgomery-Åsberg Depression Rating Scale, 39-item Parkinson's disease questionnaire, Parkinson's disease impulsive-compulsive disorders questionnaire, changes in levodopa-equivalent daily dosage, apathy rated by the caregiver, and burden and quality of life of the caregiver. TRIAL REGISTRATION: ClinicalTrials.gov NL8279. Registered on January 10, 2020.

Self-reported suicidal ideation among individuals with first episode psychosis and healthy controls: Findings from the international multicentre EU-GEI study.

INTRODUCTION: Suicidal ideation is common among individuals with first episode psychosis (FEP), with prevalence estimates up to 56.5 %. Despite its high prevalence, relatively little is known about how sociodemographic, clinical and/or developmental characteristics contribute to the experience of suicidal ideation in individuals with FEP. METHODS: In this cross-sectional study (FEP n = 551 and controls n = 857), univariate logistic regression analyses were performed to study the associations of sociodemographic, clinical, and developmental factors with suicidal ideation in individuals with FEP as well as controls. Suicidal ideation was assessed using the Community Assessment of Psychic Experiences (CAPE). In addition, multivariate logistic regression analyses were conducted based on a stepwise approach. RESULTS: In FEP, only depressive symptoms remained significantly associated with suicidal ideation when all correlates were integrated into one model. In the multivariate model in controls, depressive symptoms, positive symptoms, and traumatic childhood experiences were significantly associated with suicidal ideation. CONCLUSIONS: This study showed that depressive symptoms are an important factor relating to suicidal ideation in individuals with FEP, over and above other clinical, sociodemographic, and developmental factors. This underscores the relevance of screening for suicidal ideation in individuals with FEP, and highlights the need for a better understanding of the diagnostic uncertainty and course of mood symptoms in early psychosis. LIMITATIONS: Cross-sectional study design, self-reported questionnaires.

Test-retest reliability of task-related pharmacological MRI with a single-dose oral citalopram challenge.

Non-invasive assessment of human neurotransmitter function is a highly valuable tool in clinical research. Despite the current interest in task-based pharmacological MRI (phMRI) for the assessment of neural correlates of serotonin (5-HT) function, test-retest reliability of this technique has not yet been established. Using a placebo-controlled crossover design, we aimed to examine the repeatability of task-related phMRI with a single dose of oral citalopram in twelve healthy female subjects. Since we were interested in the drug's effect on neural correlates of 5-HT related cognitive processes, a sensorimotor and an emotional face processing paradigm were used. For both paradigms, we found no significant effects of the oral citalopram challenge on task-positive brain activity with whole-brain analysis. With ROI-based analysis, there was a small effect of the challenge related to emotional processing in the amygdala, but this effect could not be reproduced between sessions. We did however find reproducible effects of the challenge on task-negative BOLD-responses, particularly in the medial frontal cortex and paracingulate gyrus. In conclusion, our data shows that a single oral dose of citalopram does not reliably affect emotional processing and sensorimotor activity, but does influence task-negative processes in the frontal cortex. This latter finding validates previous studies indicating a role for 5-HT in suppression of the task-negative network during goal-directed behavior.

Deep brain stimulation and the role of astrocytes.

Deep brain stimulation (DBS) has emerged as a powerful surgical therapy for the management of treatment-resistant movement disorders, epilepsy and neuropsychiatric disorders. Although DBS may be clinically effective in many cases, its mode of action is still elusive. It is unclear which neural cell types are involved in the mechanism of DBS, and how high-frequency stimulation of these cells may lead to alleviation of the clinical symptoms. Neurons have commonly been a main focus in the many theories explaining the working mechanism of DBS. Recent data, however, demonstrates that astrocytes may be active players in the DBS mechanism of action. In this review article, we will discuss the potential role of reactive and neurogenic astrocytes (neural progenitors) in DBS.

Deep brain stimulation in addiction: a review of potential brain targets.

Deep brain stimulation (DBS) is an adjustable, reversible, non-destructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS is currently investigated in psychiatry for the treatment of refractory obsessive-compulsive disorder, Tourette syndrome and depressive disorder. Although recent research in both animals and humans has indicated that DBS may be an effective intervention for patients with treatment-refractory addiction, it is not yet entirely clear which brain areas should be targeted. The objective of this review is to provide a systematic overview of the published literature on DBS and addiction and outline the most promising target areas using efficacy and adverse event data from both preclinical and clinical studies. We found 7 animal studies targeting six different brain areas: nucleus accumbens (NAc), subthalamic nucleus (STN), dorsal striatum, lateral habenula, medial prefrontal cortex (mPFC) and hypothalamus, and 11 human studies targeting two different target areas: NAc and STN. Our analysis of the literature suggests that the NAc is currently the most promising DBS target area for patients with treatment-refractory addiction. The mPFC is another promising target, but needs further exploration to establish its suitability for clinical purposes. We conclude the review with a discussion on translational issues in DBS research, medical ethical considerations and recommendations for clinical trials with DBS in patients with addiction.