Blended-ALMAMAR app for inpatient mental health care for refugees: study protocol for a multicenter implementation study within the I-REACH consortium (Internet based REfugee mentAl healtH Care).

BACKGROUND: Refugees are at high risk for developing mental illnesses. Due to language and cultural barriers, there is need for specifically adapted therapeutic procedures for refugees in inpatient mental health care settings. Internet-based applications in refugee mother tongues have the potential to improve the outcomes of mental health care for this vulnerable population. The key research question of the present implementation study is whether the newly developed "blended ALMAMAR" app for Arabic and Farsi speaking refugees in Germany is used and accepted by patients and professionals in routine inpatient mental health care (blended care). METHODS: We present the design of an observational, prospective multicenter implementation study in eight psychiatric hospitals. We plan to recruit 100 Farsi or Arabic speaking refugees receiving in-patient treatment due to depression, anxiety disorder, posttraumatic stress disorder or substance use disorders. These patients will get access to the "blended ALMAMAR" app during their inpatient stay in a blended-care approach. We will assess the usage (e.g., duration and frequency of use of the app) as well as subjective acceptability and usability of the intervention. To identify sociodemographic and clinical factors associated with "blended ALMAMAR" usage, we will also perform clinical and questionnaire assessments. DISCUSSION: The newly developed "blended ALMAMAR" app may help to close communication gaps for the hard-to reach and vulnerable group of refugees in inpatient mental health care. It is the first blended-care intervention that addresses severely mentally ill refugees in an inpatient psychiatric setting in Germany. TRIAL REGISTRATION: The trial was registered in the German Clinical Trials Register on November 11, 2021 (DRKS00025972) and adapted on November 14, 2023.

Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

BACKGROUND: Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS: A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS: Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION: The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING: German Federal Ministry of Education and Research.

Glatiramer Acetate Treatment in Multiple Sclerosis-Associated Fatigue-Beneficial Effects on Self-Assessment Scales But Not on Molecular Markers.

Although fatigue is a common symptom in multiple sclerosis (MS), its pathomechanisms are incompletely understood. Glatiramer acetate (GA), an immunomodulatory agent approved for treatment of relapsing-remitting MS (RRMS), possesses unique mechanisms of action and has been shown to exhibit beneficial effects on MS fatigue. The objective of this study was to correlate clinical, neuropsychological, and immunological parameters in RRMS patients with fatigue before and during treatment with GA. In a prospective, open-label, multicenter trial, 30 patients with RRMS and fatigue were treated with GA for 12 months. Inclusion criterion was the presence of fatigue as one of the most frequent and disabling symptoms. Before and during treatment, fatigue was assessed using the Fatigue Severity Scale (FSS), the MS-FSS, and the Modified Fatigue Impact Scale (MFIS). In addition, fatigue and quality of life were assessed using the Visual Analog Scales (VAS). Laboratory assessments included screening of 188 parameters using real-time PCR microarrays followed by further analysis of several cytokines, chemokines, and neurotrophic factors. Fatigue self-assessments were completed in 25 patients. After 12 months of treatment with GA, 13 of these patients improved in all three scales (with the most prominent effects on the MFIS), whereas 5 patients had deteriorated. The remaining 7 patients exhibited inconsistent effects within the three scales. Fatigue and overall quality of life had improved, as assessed via VAS. Laboratory assessments revealed heterogeneous mRNA levels of cytokines, chemokines, and neurotrophic factors. In conclusion, we were not able to correlate clinical and molecular effects of GA in patients with RRMS and fatigue.

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

Soluble CSF interleukin 2 receptor as indicator of neurosarcoidosis.

Neurosarcoidosis (NS) represents an important differential diagnosis of multiple sclerosis (MS). However, thus far no reliable laboratory marker of neurosarcoidosis exists. The objective of this study was to evaluate whether cerebrospinal fluid (CSF) levels of soluble interleukin 2 receptor (sIL2-R) distinguish NS and other inflammatory disorders of the central nervous system. For this purpose, 139 paired CSF and serum samples from 11 patients with NS, 21 with MS, 10 with CNS vasculitis, 22 with bacterial meningitis, 17 with viral meningitis/encephalitis, seven with neurotuberculosis, and 18 healthy donors were assessed for sIL2-R using an enzyme-linked immunosorbent assay. We found that sIL2-R CSF levels above 150 pg/ml identified untreated NS patients with an overall accuracy of 93% against a group of non-infectious CNS-diseases. Furthermore, an increase in sIL2-R in the CSF was associated with and preceded the outbreak of new neurological symptoms. In conclusion, these findings suggest that sIL2-R measurement in the CSF may be a valuable tool in the diagnosis and follow-up of patients with suspected and proven neurosarcoidosis.

Impact of immunomodulatory treatment on leukocyte cytokine production in multiple sclerosis patients and healthy donors.

OBJECTIVES: Treatment with interferon(IFN) beta, glatiramer acetate (GLAT) and intravenous immunoglobulins (IVIG) alters the cytokine production in multiple sclerosis (MS) patients. To date, it is not clear whether the effect on cytokines varies among these drugs. Therefore, we analyzed the effects of these drugs on the cytokine profiles of MS patients as well as healthy controls. METHODS: The in vitro effects of IFNbeta, GLAT and IVIG on leukocyte subsets producing the p40 subunit of interleukin 12 (IL12p40), IFNgamma, tumor necrosis factor (TNF) and interleukin (IL) 10 were assessed in 21 MS patients and 11 healthy volunteers using flow cytometry. RESULTS: In peripheral vein blood of healthy volunteers, IVIG reduced IL12p40-producing monocytes (p = 0.003) and IFNgamma in CD4+ lymphocytes (p = 0.003). IFNbeta treatment increased the proportion of IFNgamma-producing CD4+ lymphocytes (p = 0.003) whereas GLAT reduced TNF production (p = 0.012). In MS patients, IVIG induced a suppression of leukocytes producing IL12p40 (p < 0.001) and IFNgamma (p = 0.001). IFNbeta decreased monocytes producing IL12p40 (p < 0.001) and increased IL10 (p = 0.005). GLAT reduced IL12p40 (p < 0.001), IFNgamma (p = 0.001 in CD4+ and CD8+ lymphocytes) and TNF production of leukocytes (p < 0.001). In addition, the baseline cytokine patterns were inherently different between individual MS patients. CONCLUSIONS: IFNbeta, GLAT and IVIG had different effects on cytokine patterns, which might point towards different mechanisms of action. Since the baseline cytokine patterns differed among MS patients, the evaluation of the cytokine pattern might serve as a surrogate marker before starting immunomodulatory treatments and might be helpful to tailor MS therapy effectively to the needs of each individual patient.

Use of rituximab in multiple sclerosis: current progress and future perspectives.

In recent years, new insights into the immunological pathways in multiple sclerosis (MS) have been detected. This increasing knowledge has led to more distinct treatment options in modifying the disease course of MS. In 2006, natalizumab, an alpha4-integrin monoclonal antibody, introduced a new era of MS treatment. Another promising drug is the monoclonal CD20-antibody rituximab, which depletes CD20(+) cells, pre-B cells and mature B cells. Rituximab is approved for the treatment of a number of autoimmune diseases other than MS, such as rheumatoid arthritis and non-Hodgkin's lymphoma. Early-phase trials in the autoimmune-driven disorders Sjögren's syndrome, vasculitis and thrombocytopenic purpura confirmed the use of rituximab in B-cell-mediated diseases. Another autoimmune disease affecting the CNS is neuromyelitis optica (NMO). NMO is characterized by having some similarities with MS and several studies demonstrated successful therapy of NMO using rituximab. In addition, numerous case reports in MS patients showed a stabilization of the course with a reduction of the relapse rate and MRI pathologies in MS patients. To date, one Phase II clinical trial in MS patients confirmed the results from these case reports. In this article, we will focus on the role of B cells in MS and the immunomodulatory pathways of rituximab. Recent data from experimental and clinical trials, as well as safety aspects, are discussed. A future perspective is given regarding the possible role of rituximab, as well as possible other candidates for treating MS.

Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients - follow-up and clinical implications.

BACKGROUND: An intrathecal polyspecific antibody response is a well known finding in multiple sclerosis. However, little is known about the evolution of intrathecal antibodies over time and their impact on the disease progress. Therefore, we focused in this study on the intrathecal polyspecific antibody response in multiple sclerosis. METHODS: Here we present a follow-up study of 70 patients with multiple sclerosis over 1 to 106 months. Serum and cerebrospinal fluid sample pairs were obtained from 1 to 5 consecutive lumbar punctures. CSF cell count, the IgG index, local IgG synthesis, oligoclonal bands and the antibody index for measles, rubella or varicella zoster were calculated. Results were analysed with regard to clinical characteristics of the patients. RESULTS: Once an intrathecal antibody response was established, it persisted. De novo antibody response against measles virus developed in 7% of the patients between the first and the second spinal tap. In two of seven patients where 5 consecutive CSF samples were available, the intrathecal antibody response expanded from one to three antigens. Furthermore, an intrathecal measles antibody production was associated with a rapid progression of the disease. CONCLUSION: These data stress the importance of activated B cells for the disease process and the clinical outcome in multiple sclerosis.