Dynamic reconfigurations of brain networks in depressive and anxiety disorders: The influence of antidepressants.

Major Depressive Disorder (MDD) and anxiety disorders are highly comorbid recurrent psychiatric disorders. Reduced dynamic reconfiguration of brain regions across subnetworks may play a critical role underlying these deficits, with indications of normalization after treatment with antidepressants. This study investigated dynamic reconfigurations in controls and individuals with a current MDD and/or anxiety disorder including antidepressant users and non-users in a large sample (N = 207) of adults. We quantified the number of subnetworks a region switched to (promiscuity) as well as the total number of switches (flexibility). Average whole-brain (i.e., global) values and subnetwork-specific values were compared between diagnosis and antidepressant groups. No differences in reconfiguration dynamics were found between individuals with a current MDD (N = 49), anxiety disorder (N = 46), comorbid MDD and anxiety disorder (N = 55), or controls (N = 57). Global and sensorimotor network (SMN) promiscuity and flexibility were higher in antidepressant users (N = 49, regardless of diagnosis) compared to non-users (N = 101) and controls. Dynamic reconfigurations were considerably higher in antidepressant users relative to non-users and controls, but not significantly altered in individuals with a MDD and/or anxiety disorder. The increase in antidepressant users was apparent across the whole brain and in the SMN when investigating subnetworks. These findings help disentangle how antidepressants improve symptoms.

Glucocorticoid Receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma: protocol of the RESET-medication randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. METHODS: The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology-Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. DISCUSSION: The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. TRIAL REGISTRATION: The trial protocol has been registered 01-02-2022 on ClinicalTrials.gov with ID "NCT05217758".

Efficacy of celecoxib add-on treatment for immuno-metabolic depression: Protocol of the INFLAMED double-blind placebo-controlled randomized controlled trial.

Introduction: As the role of (neuro)inflammation in depression pathophysiology is emerging, augmentation of antidepressant treatments with anti-inflammatory drugs have shown beneficial results, but not consistently across all studies. Inconsistencies may be due to depression biological and clinical heterogeneity. Immuno-Metabolic Depression (IMD) has been put forward as a form of depression characterized by the clustering of low-grade inflammation, metabolic dysregulations and atypical, energy-related symptoms (overeating, weight gain, hypersomnia, fatigue and leaden paralysis). IMD features are present in ∼30% of patients with Major Depressive Disorder (MDD). By selecting these specific patients, directly targeting inflammation may reduce depressive symptoms. Methods: and analysis INFLAMED is a double-blind randomized controlled trial. 140 MDD patients with IMD characteristics (MDD with Inventory of Depressive Symptomatology (IDS) ≥ 26, IDS atypical, energy related symptoms ≥6, C-Reactive Protein (CRP) > 1 mg/L) will receive either 400 mg celecoxib per day or matching placebo for a period of 12 weeks. Biological, physical and interview data will be collected after 2, 6 and 12 weeks of starting the intervention. Questionnaires will be sent out bi-weekly during the study period. The main study outcome is the IDS (30-item self-report) total score during 12-week follow-up. Secondary study outcomes include response, remission, adverse side effects, symptom profiles (atypical, energy-related symptoms), fatigue, food craving, sleep, anxiety symptoms, functioning, pain, and optionally, microbiome composition. Explorative analyses will be performed on the role of CRP, IL-6, TNF-α, cholesterol, triglycerides, glucose, BMI, waist and hip circumference. Ethics and dissemination: This protocol has been approved by the Medical Ethics Review Board of the Amsterdam UMC, location VUmc (2022.0015) on 2-6-2022, as well as by the competent authority in The Netherlands: CCMO, on 3-8-2022. Registration details: Trail registration numbers NCT05415397, EudraCT 2021-003850-21.

[Guided discontinuation of antidepressants: approach and first results of a Dutch multidisciplinary outpatient clinic]. / Werkwijze en eerste resultaten van multidisciplinaire afbouwpoli anti-depressiva.

BACKGROUND: Discontinuation of antidepressant medication can be difficult due to withdrawal symptoms and relapse risk. Scientific evidence on the questions of who, when, and how to stop antidepressants is limited. In Amsterdam a multidisciplinary outpatient clinic was started to provide advice and guidance. AIM: To substantiate the design of the clinic. Central questions relate to knowing which patients are referred, the background of their request, and their experiences with the outpatient clinic. METHOD: The first 51 patients of the clinic were described on the basis of file research, in addition a survey was conducted into patient experiences. RESULTS: Half of the patients (55%) actually started discontinuation, 39% were advised not to do so (yet). Patients at the clinic had used antidepressants for an average of 10 years, and 76% had previously attempted to stop. 21% had now successfully stopped and 25% were satisfied with a lower dose. One patient relapsed during tapering. CONCLUSION: So far, patients with long-term antidepressant use and multiple quit attempts have been referred. Our experiences are aimed at helping individual patients but can also result in more knowledge about who can stop at what moment, and how this should be done.

The STRESS-NL database: A resource for human acute stress studies across the Netherlands.

Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6-99 years, mean age 27.7 ±â€¯16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts.

[How the DSM helps psychiatry move forward]. / Hoe de DSM de psychiatrie verder kan helpen.

The prospect of 'disease' in psychiatry has been debated for centuries. In the 21st century, this discussion often focusses on the usefulness of DSM classifications, the diagnostic manual of psychiatry. This criticism on the DSM is exemplary for our struggle to understand, classify and treat psychiatric problems. However, we tend to forget that the DSM system has provided a wealth of knowledge and structure to psychiatric care and science. Moreover, there is no elaborated alternative and an abolishment of the DSM will lead to confusion and polarisation. We should not throw the baby out with the bathwater. In this perspective, we argue how we can build on decades of experience with the DSM and how historical weighting and accurate use of the DSM can offer fertile grounds for refinement and precision of diagnostics in psychiatry.

Dorsal attention network centrality increases during recovery from acute stress exposure.

Stress is a major risk factor for the development of almost all psychiatric disorders. In addition to the acute stress response, an efficient recovery in the aftermath of stress is important for optimal resilience. Increased stress vulnerability across psychiatric disorders may therefore be related to altered trajectories during the recovery phase following stress. Such recovery trajectories can be quantified by changes in functional brain networks. This study therefore evaluated longitudinal functional network changes related to stress in healthy individuals (N = 80), individuals at risk for psychiatric disorders (healthy siblings of schizophrenia patients) (N = 39), and euthymic bipolar I disorder (BD) patients (N = 36). Network changes were evaluated before and at 20 and 90 min after onset of an experimental acute stress task (Trier Social Stress Test) or a control condition. Whole-brain functional networks were analyzed using eigenvector centrality as a proxy for network importance, centrality change over time was related to the acute stress response and recovery for each group. In healthy individuals, centrality of the dorsal attention network (DAN; p = 0.007) changed over time in relation to stress. More specifically, DAN centrality increased during the recovery phase after acute stress exposure (p = 0.020), while no DAN centrality change was observed during the initial stress response (p = 0.626). Such increasing DAN centrality during stress recovery was also found in healthy siblings (p = 0.016), but not in BD patients (p = 0.554). This study highlights that temporally complex and precise changes in network configuration are vital to understand the response to and recovery from stress.

[Antipsychotics with no dopamine receptor blockade; promise or hype?] / Antipsychotica zonder dopaminereceptorblokkade.

Over twenty different antipsychotics are available in the treatment of schizophrenia. All antipsychotics are generally effective, although differences exist in terms of efficacy but also in side effect profile. So far, all antipsychotics block the dopamine-2 (D2) receptor in the brain, including recently available antipsychotics such as lurasidone, cariprazine and brexpiprazole. However large differences exist in binding strength to the D2 receptor that influence dosage ranges. Thus, there seems to be a rock-solid law of antipsychotics: D2 receptor blockade is necessary for an antipsychotic to be effective. Hitherto, the effects of molecules that do not block the D2 receptor for the treatment of psychotic disorders are either disappointing or equivocal, e.g. glutamate system modulators as the metabotropic mGLu2/3 agonist LY2140023. This is disappointing because there is a great need for antipsychotics with novel mechanisms of action. This is pivotal as a proportion of patients with schizophrenia do not sufficiently benefit from currently available dopamine-blocking antipsychotics with limited effects on negative and cognitive symptoms of schizophrenia. In addition, side effects of antipsychotics sometimes prevent its long-term use. Recently, a randomized controlled trial evaluated SEP-363856 for the treatment of acute schizophrenia, a molecule that does not bind to the D2 receptor but binds to trace amine-associated (TAAR) receptors and 5-HT1A receptors. SEP-363856 was more effective compared to placebo after 4 weeks of treatment (effect size 0.45). This is encouraging, although the duration of the RCT and relatively selected group of patients preclude firm conclusions on its efficacy. We may be hopeful that antipsychotics with a novel mechanism of action are investigated, but only the future will learn whether SEP-363856 will have true added value to improve the life of patients suffering from psychotic disorders.

[The underestimated value of science in psychiatry]. / De onderschatte waarde van wetenschap in de psychiatrie.

BACKGROUND: Psychiatry is a special but complicated medical specialty as it focuses on the most elusive of all suffering in medicine: mental suffering.
AIM: Description of the (desired) role of science in psychiatry.
METHOD: Essay based on relevant literature.
RESULTS: Science constitutes the basis of psychiatry and is essential for daily practice. A methodologically broad view on science can provide new knowledge and better care in psychiatry without falling prey to reductionism. The doubt and nuance inherent in science is also valuable to avoid unnecessary ideological debates in psychiatry and to give room to meaningful discussions. Nevertheless, investments in science within psychiatry are relatively limited, particularly in view of the suffering and costs related to psychiatric disorders.
CONCLUSION: Psychiatry has greatly benefited from science. However, science should also lead to modesty and doubt about the current state of knowledge. This paradox should be an incentive to embrace science as the basis of psychiatry while avoiding reductionism. This essay discusses a number of ways how this could be realized.

Phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients (from the OPTiMiSE cohort).

OBJECTIVE: Antipsychotic-induced weight gain (AiWG) is a debilitating adverse effect of most antipsychotics. First-episode psychosis patients are particularly vulnerable to the detrimental consequences of AiWG. Amisulpride has good efficacy and tolerability. We here aimed to identify the phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients. METHOD: Data were collected from the Optimization of Treatment and Management of Schizophrenia in Europe trial. Multivariable regression models with various phenotypic variables (N = 305) were performed with absolute AiWG and clinically relevant AiWG (≥7% AiWG) as outcomes. RESULTS: Four weeks of amisulpride treatment increased body weight from 69.7 to 72.4 kg (P < 0.001). In the regression model of absolute AiWG, unemployment (ß = 0.94, P = 0.016), younger age (ß = -0.07, P = 0.031) and absence of current comorbid major depression disorder (ß = -1.61, P = 0.034) were positively associated with absolute AiWG. In the regression model of clinically relevant AiWG, unemployment (OR = 2.83, P = 0.001), schizophreniform disorder (OR = 2.00, P = 0.025) and low baseline weight (OR = 0.97, P = 0.032) increased the likelihood of clinically relevant AiWG. CONCLUSIONS: Clinicians prescribing amisulpride should consider the relatively high susceptibility to AiWG in unemployed first-episode patients with psychosis, in particular young subjects with a diagnosis of schizophreniform disorder. We advise to carefully monitor these patients and, when needed, implement weight-reducing strategies.

[Too early for pharmacogenetics in psychiatric practice]. / Te vroeg voor farmacogenetica in de psychiatrische praktijk.

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[Reaction on 'Hypomania induced by intranasal corticosteroid fluticasone spray']. / Reactie op 'Hypomanie geïnduceerd door intranasaal corticosteroïd fluticasonspray'.

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The Role of Stressful Parenting and Mineralocorticoid Receptor Haplotypes on Social Development During Adolescence and Young Adulthood.

The development of social behavior could be affected by stressful parenting. The mineralocorticoid receptor, one of the two main receptors for the stress hormone cortisol, plays a vital role in adequate responses to stress. Therefore, the effects of stressful parenting on social development (i.e., empathic concern, perspective taking and prosocial behavior) may be moderated by functional genetic variation in mineralocorticoid receptor haplotypes (a combination of alleles). A group of 343 adolescents (44.3% females) was followed from the age of 13 until 24 years. Growth curve analyses showed lower levels of prosocial behaviors and a slower increase in empathic concern and perspective taking in adolescents who reported more stressful parenting. In contrast, relatively higher levels of prosocial behavior, empathic concern and perspective taking were present in combination with stress resilient mineralocorticoid receptor haplotypes. Despite sex differences in social development with earlier social development for girls, no consistent sex differences were found with regard to mineralocorticoid receptor haplotypes. The current study showed that genetic variation in mineralocorticoid receptor impacts the social development during adolescence and young adulthood.

Increased responses of the reward circuitry to positive task feedback following acute stress in healthy controls but not in siblings of schizophrenia patients.

Acute stress is known to affect the way we process rewards. For example, during, or directly after stress, activity within key brain areas of the reward circuitry is reduced when a reward is presented. Generally, the effects of stress on the brain are time-dependent, changing neural and cognitive processing in the aftermath of stress to aid recovery. Such a dynamic response to stress is important for resilience on the longer term. However, relatively little is known about reward processing during the recovery phase of stress and whether this is changed in individuals at increased risk for stress-related psychopathology. Healthy male individuals (N = 40) and unaffected siblings of schizophrenia patients (N = 40) were randomized to either an acute stress task (Trier Social Stress Test) or a no-stress task. Neural responses during reward anticipation and reward feedback (monetary gain or no gain) were examined 50 min later using an fMRI monetary incentive delay task. The ventral striatum and orbitofrontal cortex (OFC) were used as predefined hypothesis-driven regions of interest. Neural responses following stress differed between controls and siblings during reward feedback (group × stress interaction OFC p = 0.003, ventral striatum p = 0.031), showing increased ventral striatum and OFC responses following stress in healthy controls only. Exploratory analyses revealed that this effect was most pronounced during hit trials (compared to when a reward was omitted), and independent of monetary value. Stress did not affect subsequent reward processing in siblings of schizophrenia patients. We found no significant differences between controls and siblings in ventral striatum and OFC responses during reward anticipation following stress. This study shows that ventral striatum and OFC responses to positive task feedback are increased in the aftermath of stress in healthy male controls, regardless of monetary value. This indicates a dynamic shift from previously reported reduced responses in the striatum and OFC to reward feedback directly after stress to increased responses to both reward and non-reward feedback during the recovery phase of stress. These increased neural responses following stress were absent in siblings of schizophrenia patients. Together, these findings indicate that stress recovery is affected in this at-risk group, particularly in responses to positive feedback following stress.

Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia.

Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently, we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation, we exposed human fibroblasts to nutritional deprivation. In the famine-exposed schizophrenia patients, we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N = 153, p = 0.01). In this sample, DUSP22 methylation was also significantly higher in patients independent of famine exposure (p = 0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control samples not exposed to famine using DNA from whole blood (N = 64, p = 0.03) and postmortem brains (N = 214, p = 0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p = 0.048) and expression (p = 0.019) in response to nutritional deprivation (N = 10). These results highlight an epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early-life exposure to famine and that is relevant for a major psychiatric disorder.

At-risk individuals display altered brain activity following stress.

Stress is a major risk factor for almost all psychiatric disorders, however, the underlying neurobiological mechanisms remain largely elusive. In healthy individuals, a successful stress response involves an adequate neuronal adaptation to a changing environment. This adaptive response may be dysfunctional in vulnerable individuals, potentially contributing to the development of psychopathology. In the current study, we investigated brain responses to emotional stimuli following stress in healthy controls and at-risk individuals. An fMRI study was conducted in healthy male controls (N = 39) and unaffected healthy male siblings of schizophrenia patients (N = 39) who are at increased risk for the development of a broad range of psychiatric disorders. Brain responses to pictures from the International Affective Picture System (IAPS) were measured 33 min after exposure to stress induced by the validated trier social stress test (TSST) or a control condition. Stress-induced levels of cortisol, alpha-amylase, and subjective stress were comparable in both groups. Yet, stress differentially affected brain responses of schizophrenia siblings versus controls. Specifically, control subjects, but not schizophrenia siblings, showed reduced brain activity in key nodes of the default mode network (PCC/precuneus and mPFC) and salience network (anterior insula) as well as the STG, MTG, MCC, vlPFC, precentral gyrus, and cerebellar vermis in response to all pictures following stress. These results indicate that even in the absence of a psychiatric disorder, at-risk individuals display abnormal functional activation following stress, which in turn may increase their vulnerability and risk for adverse outcomes.

[In- and out-of-hospital emergency psychiatry: what is the best approach?] / Acute psychiatrie binnen en buiten het ziekenhuis.

A range of clinical syndromes may present with psychiatric symptoms, both in and out of hospital settings. In such situations agitation, suicidality, communication difficulties and legal aspects often play a role, making diagnosis and treatment a challenge. Based on several case studies, we illustrate how the recently-published Dutch open access source 'Acute Psychiatry' (www.acutepsychiatrie.com) can be of help in acute psychiatric presentations both within and outside psychiatric hospitals.