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".

A new approach to drug intravenous compatibility research: the case of obstetric parenteral drugs.

OBJECTIVES: The product information and literature does not provide confirmation of compatibility for co-administration of all commonly used drug pairs in obstetrics. However, there is a need for co-administration of these drugs over one lumen for this group of patients. Therefore, this study focuses on Y-site compatibility. Since different conditions between clinical and laboratory settings can lead to discrepancies in results, a novel approach for drug intravenous compatibility testing was designed to reflect clinical conditions. The aim was to study the compatibility of nine commonly used drug pairs in obstetrics and to evaluate the clinical value of the designed method. METHODS: The clinical situation was reflected by using different temperature ranges (20°C and 37°C), actual Y-site flow ratios, clinically relevant drug pairs and an observation time of 120 min. The clinically relevant drugs pairs include atosiban, nicardipine, amoxicillin/clavulanic acid, oxytocin, remifentanil, labetalol and magnesium sulpfate. Drug pairs were visually assessed according to the European Pharmacopoeia (Ph. Eur.) and pH was measured. When incompatibility of a drug pair seemed likely based on literature review or observed abnormalities during visual assessment, subvisual analysis was performed using a particle counter. Y-site compatibility applied for drug pairs when no visual changes occurred or when no additional particles were formed during the observation time. RESULTS: Eight of the nine combinations showed no visual changes or noticeable changes in pH during the observation time. The amoxicillin/clavulanic-acid-oxytocin combination showed a colour change at 37°C at the actual Y-site flow ratio. However, subvisual particle counting showed no formation of additional particles. CONCLUSIONS: Y-site compatibility was established for all tested drug pairs. The new clinical approach for analysing Y-site compatibility provides a high certainty of outcomes for clinical practice. In this way, clinical complications and use of several additional intravenous catheters can be avoided.

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.

Does a short course of etanercept influence disease progression and radiographic changes in patients suspected of non-radiographic axial spondyloarthritis? Three -years follow- up of a placebo-controlled trial.

OBJECTIVE: To study the long-term effect of 16 weeks of etanercept treatment on disease activity and radiographic changes in patients with suspected non-radiographic axial spondyloarthritis (nr-axSpA). METHOD: Eighty patients with inflammatory back pain and suspected nr-axSpA, with a Bath Ankylosing Disease Activity Index (BASDAI) ≥ 4, received etanercept (n = 40) 25 mg twice weekly or placebo (n = 40) for 16 weeks. They were followed without treatment restrictions after 24 weeks, for up to 3 years. Comparisons were made between patients who received etanercept or placebo in the first period, and changes in BASDAI, Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Metrology Index (BASMI), function, and radiographic changes in the spine [according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)] and sacroiliac joints (Bath Ankylosing Spondylitis Radiology Index (BASRI). RESULTS: After 3 years of follow-up, 84% of the patients were diagnosed with SpA, predominantly axSpA. Biological treatment was started after 24 weeks in 30% of patients. Disease activity scores after 3 years did not reveal significant differences between the initial randomization groups in mean BASDAI scores (mean difference 0.9, 95% CI -1.1;0.7, p = 0.6) and ASDAS (mean ASDAS 0.3, 95% CI 0.6;3.1, p = 0.5). BASMI and function scores remained stable over 3 years. No differences in radiographic changes of the sacroiliac joints or spine were observed over 3 years between the two groups. CONCLUSION: A short course of etanercept in patients with suspected nr-axSpA did not affect disease activity, the chance of biological treatment, or radiographic progression after 3 years of follow-up.

[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.

Policy and Practice Review: A First Guideline on the Use of Pharmacogenetics in Clinical Psychiatric Practice.

Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.

[Carbamazepine and quetiapine: a neglected, but highly relevant interaction]. / Carbamazepine en quetiapine: een onderbelichte, maar zeer relevante interactie.

We describe a case of concomitant use of carbamazepine and quetiapine, with a highly relevant interaction that requires attention. The combination of these drugs can be prescribed in psychiatry, for example in bipolar disorder, but also in other disciplines. Pharmacotherapy is one of the cornerstones in the treatment of bipolar disorders, and a combination of drugs is frequently used. Carbamazepine, an anti-epileptic drug that is effective as a mood stabilizer, and quetiapine, a second-generation antipsychotic, are both recommended in the Dutch guideline. Besides monotherapy is a combination of both drugs possible. It is striking that carbamazepine and quetiapine have a strong pharmacokinetic interaction via the metabolizing liver enzyme, CYP3A4. This interaction results in a factor 10 reduction of quetiapine blood levels. This may result in a possible loss of clinical efficacy of quetiapine.

[Discontinuing venlafaxine by switching to fluoxetine]. / Stoppen met venlafaxine door omzetting naar fluoxetine.

Patients wanting to discontinue their antidepressant use may experience antidepressant discontinuation syndrome (ADS). This is characterized by symptoms such as nausea, vomiting, diarrhea, headaches and sweating. Withdrawal symptoms can discourage patients from permanently discontinuing antidepressants. We present the case of a 48-year-old visually impaired woman where, after a first attempt failed, venlafaxine was successfully discontinued after a switch to fluoxetine. Fluoxetine mediated discontinuation is a simple, effective and inexpensive method for patients who suffer from withdrawal symptoms when tapering off antidepressants.

A common polymorphism in the ABCB1 gene is associated with side effects of PGP-dependent antidepressants in a large naturalistic Dutch cohort.

The drug efflux transporter permeability glycoprotein (PGP) and cytochrome P450 (CYP) 2C19 are important for eliminating antidepressants from the brain and body. The ABCB1 gene, encoding for PGP, and CYP2C19 gene have several variants that could influence enzyme function and thereby the effect of PGP- and 2C19-dependent antidepressants. We investigated the association of antidepressant side effect and common genetic variation in 789 antidepressant users. In PGP-dependent antidepressant users, the A-allele of the rs2032588 single-nucleotide polymorphism (SNP) was associated with a lower number of side effects after adjusting for gender, age, dosage and duration of use, (B=-0.44, q=4.6 × 10(-3)). This association was different from and absent in non-PGP-dependent antidepressant users. Other SNP associations as well as an interaction analysis between the rs2032588 SNP and the CYP2C19 SNPs were not statistically significant after adjusting for covariates and multiple comparisons. The association of rs2032588 with antidepressant side effects suggests the involvement of the ABCB1 genotype in the clinical pharmacology of PGP-dependent antidepressants.

ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder.

P-glycoprotein (P-gp), an ATP-driven efflux pump in the blood-brain barrier, has a major impact on the delivery of antidepressant drugs in the brain. Genetic variants in the gene ABCB1 encoding for P-gp have inconsistently been associated with adverse effects. In order to resolve these inconsistencies, we conducted a study in a large cohort of patients with major depressive disorder with the aim to unravel the association of ABCB1 variants with adverse effects of antidepressants and in particular with selective serotonin reuptake inhibitors (SSRIs), which display affinity as substrate for P-gp. The Netherlands Study of Depression and Anxiety (NESDA) study was used as a clinical sample. For 424 patients data were available on drug use, side effects. We selected six ABCB1 gene variants (1236T>C, 2677G>T/A, 3435T>C, rs2032583, rs2235040 and rs2235015) and analyzed them for association with adverse drug effects using multinomial regression analysis for both single variants and haplotypes. We found a significant association between the number of SSRI-related adverse drug effects and rs2032583 (P=0.001), rs2235040 (P=0.002) and a haplotype (P=0.002). Moreover, serotonergic effects (sleeplessness, gastrointestinal complaints and sexual effects) were significantly predicted by these variants and haplotype (P=0.002/0.003). We conclude that adverse drug effects with SSRI treatment, in particular serotonergic effects, are predicted by two common polymorphisms of the ABCB1 gene.

[The syndrome of inappropriate antidiuretic hormone secretion (SIADH) during treatment with the antipsychotic agents haloperidol and quetiapine]. / Het syndroom van inadequate secretie van antidiuretisch hormoon (SIADH) tijdens het gebruik van de antipsychotica haloperidol en quetiapine.

A 45-year-old man with paranoid schizophrenia repeatedly developed hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), both after treatment with haloperidol and after taking quetiapine. This side effect did not occur subsequently during clozapine treatment. SIADH has been described in connection with almost all psychotropic drugs. Since the risk of developing SIADH is increased with increasing age, comorbid somatic disorders and polypharmacy, and the mean age of the psychiatric patient will further increase in the years to come, the physician should be alert to the risk factors and the clinical symptoms of disturbances in water balance; moreover, the proper differential diagnostic deliberations should be made. In case of increased risk, it is recommended to monitor the serum sodium during the first 2-4 weeks of pharmacotherapy.

[Medicinal cannabis for diseases of the nervous system: no convincing evidence of effectiveness]. / Medicinale cannabis voor aandoeningen van het zenuwstelsel: geen overtuigend bewijs voor effectiviteit.

--In 1996, the Netherlands Health Council issued a negative recommendation regarding the use of medication on the basis of cannabis (marihuana). However, interest in medicinal cannabis has certainly not waned since. --The neurological diseases for which cannabis could presently be used therapeutically are: multiple sclerosis, chronic (neuropathic) pain and the syndrome of Gilles de la Tourette. --Since September 2003, the Dutch Ministry of Health, Welfare and Sport delivers medicinal cannabis to Dutch pharmacies, so that now for the first time, medicinal cannabis can be given to patients on a prescription basis within the framework of the Opium Law. The result of this is that doctors and patients now assume that this is a medication for which the efficacy and safety have been established. --The question arises whether new scientific data have become available since 1996 that provide scientific support for the current Governmental policy. --In a recent clinical trial that has aroused much discussion, patients with multiple sclerosis and problematic spasticity were treated with oral cannabis or a placebo. There was no significant effect of treatment on the primary outcome measure, i.e. objectively determined spasticity. Nevertheless, it was concluded that the mobility was improved and that the pain was subjectively decreased. --Until now, convincing scientific evidence that cannabinoids are effective in neurological conditions is still lacking. --However, it is also not possible to conclude definitely that cannabinoids are ineffective; still, this is no basis for official stimulation of their use.

Toxicokinetics of nortriptyline and amitriptyline: two case reports.

Two cases are presented of intentional intoxications with the tricyclic antidepressants (TCAs) nortriptyline (NT) and amitriptyline (AT). The peak plasma concentrations were 2290 microg/L and 2900 microg/L, respectively. The active metabolites E-10-hydroxynortriptyline (EHNT) and Z-10-hydroxynortriptyline (ZHNT) profiles were quite different as monitored for 5 to 10 days after presumed drug intake. In conclusion, these cases illustrate that (1) metabolite formation and elimination after intake of an overdose dose of NT and AT are stereoselective, and (2) NT and EHNT toxicokinetics and toxicodynamics are quite different. It also shows that a patient with a severe TCA overdose can still survive if he or she receives appropriate and quick supportive care, even if the prognostic markers QRS time, coma grade, and serum TCA levels predict poor outcome.

Cytokine profiles during clinical high-flux dialysis: no evidence for cytokine generation by circulating monocytes.

Secretion of cytokines by monocytes has been implicated in the pathogenesis of dialysis-related morbidity. Cytokine generation is presumed to take place in two steps: induction of mRNA transcription for cytokines by C5a and direct membrane contact, followed by lipopolysaccharide (LPS)-induced translation of mRNA (priming/second signal theory, Kidney Int 37: 85-93, 1990). However, the in vitro conditions on which this theory was based differed markedly from clinical dialysis. To test this postulate for routine hemodialysis, 13 patients were studied cross-over with high-flux cuprammonium (CU), cellulose triacetate (CTA), and polysulfon dialyzers, using standard bicarbonate dialysate, as well as CTA with filtered dialysate (fCTA). Besides leukocytes, C3a, C5a, and limulus amebocyte lysate reactivity, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-1RA, soluble TNF receptors, and IL-1 beta mRNA were assessed. Only during dialysis with CU did C5a increase significantly (561 to 8185 ng/ml, P < 0.001). Endotoxin content of standard bicarbonate was higher than filtered dialysate (median, 24.3 and < 5 pg/ml respectively, P = 0.002), whereas limulus amebocyte lysate reactivity was not detected in the blood, except in the case of CU. TNF-alpha levels were elevated before, and remained stable during, dialysis, independent of the modality used. IL-1 beta, IL-6, and mRNA coding for IL-1 beta could not be demonstrated. IL-1RA and soluble TNF receptors (p55/p75) were markedly elevated compared with normal control subjects, but showed no differences between fCTA and CTA. To summarize, no evidence was found for production and release of cytokines by monocytes during clinical high-flux bicarbonate hemodialysis, neither with complement-activating membranes nor with unfiltered dialysate. Therefore, this study sheds some doubt on the relevance of the "priming/second signal" theory for clinical practice. The data presented suggest that reluctance to prescribe the use of high-flux dialyzers, as advocated in many reports, may not be warranted.