Weight gain, gender, and antipsychotics: a disproportionality analysis of the FDA Adverse Event Reporting System database (FAERS).

INTRODUCTION: Side effects are a very important aspect of antipsychotic treatments. Weight gain is an important side effect that jeopardizes the uninterrupted therapy administration, especially in patients with psychiatric conditions. This case-non-case pharmacovigilance study aims at investigating in a real-world adverse event reporting system whether several antipsychotics increase the risk of weight gain reporting, and the differences among men and women as far as weight gain as a reported adverse event is concerned. AREAS COVERED: Adverse event reports submitted to the FDA Adverse Event Reporting System of the Food and Drug Administration of the United States (FAERS) of 24 major antipsychotics were extracted, cleaned, and analyzed to determine which of these drugs were correlated with weight gain. The Reported Odds Ratio (ROR) and the adjusted Reported Odds Ratio (aROR) were calculated for each antipsychotic using logistic regression models. Demographics like age, gender, and concomitant insulin use were taken into consideration for each drug. EXPERT OPINION: Women had a statistically significant increase in weight gain reporting compared to men, while the men's group was associated with a reduced weight gain reporting in every antipsychotics in the logistic regression analyses. Out of the 24 antipsychotics included in our analysis, Aripiprazole, Brexpiprazole, Olanzapine, and Haloperidol had statistically significantly more weight increase reporting compared to the others.

Safety and Monitoring of the Treatment with Disease-Modifying Therapies (DMTs) for Multiple Sclerosis (MS).

BACKGROUND: Disease-Modifying Therapies (DMTs) for Multiple Sclerosis (MS) are widely used given their proven efficacy in the relapsing form of the disease, while recently, Siponimod and Ocrelizumab have been approved for the progressive forms of the disease. Currently, 22 diseasemodifying drugs are approved by the FDA, while in 2012, only nine were present in the market. From March 2019 until August 2020, six new drugs were approved. This rapid development of new DMTs highlighted the need to update our knowledge about their short and long-term safety. OBJECTIVE: This review summarizes the available safety data for all the Disease-Modifying Therapies for Multiple Sclerosis and presents the monitoring plan before and during the treatment. METHODS: A literature search was conducted using PUBMED and COCHRANE databases. Key journals and abstracts from major annual meetings of Neurology, references of relevant reviews, and relative articles were also manually searched. We prioritized systematic reviews, large randomized controlled trials (RCTs), prospective cohort studies, and other observational studies. Special attention was paid to guidelines and papers focusing on the safety and monitoring of DMTs. CONCLUSION: Data for oral (Sphingosine 1-phosphate (S1P) receptor modulators, Fumarates, Teriflunomide, Cladribine), injectables (Interferons, Glatiramer acetate, Ofatumumab), and infusion therapies (Natalizumab, Ocrelizumab, Alemtuzumab) are presented.

Effects of GABAergic Agents on Multiple Sclerosis. A Narrative Review of In-vivo Models.

BACKGROUND: Multiple sclerosis (MS) is a lifelong deteriorating disease characterized by multiple heterogeneous symptoms. Being an autoimmune disease of the central nervous system, mainly affecting the myelin sheath of the nerves ordinarily results in neurological symptoms. GABA has numerous effects on the immune cells, altering cytokine production, cell migration and proliferation. Immune cells express GABA receptors making GABA an inflammation modulator. Therefore, GABAergic- associated agents could provide a compatible add-on therapy for MS patients alleviating their symptoms and providing better quality years. OBJECTIVE: This review aims to highlight and provide evidence of the potential benefits of a secondary treatment option in MS patients, aiming to better manage this disease. METHODS: We conducted a literature search through PubMed, Scopus and Google Scholar for GABA agonists, antagonists and modulators used in the in vivo model of experimental autoimmune encephalomyelitis (EAE), taking into consideration certain inclusion and exclusion criteria. RESULTS: In vivo studies for GABA-a and GABA-b agonists and modulators showed regulation of the autoimmune response in EAE mice. Increased preservation of myelinated sensitive fibers and diminished axonal damage in the CNS was also demonstrated. Further, decreased mononuclear inflammatory infiltration, pro-inflammatory cytokines reduction and reduced levels of Reactive oxygen species (ROS) were also reported. Biological results included decreased peak disease severity, duration, clinical scores and EAE incidence in the treatment groups. CONCLUSION: GABA agonists and modulators efficiently challenged different aspects of disease pathophysiology in vivo models of EAE. The studies showed a significant relevance of neuroprotection via modulation of the autoimmune response in EAE rats, indicating that they should be considered proper therapeutic candidates for clinical use, while also further clinical studies could empower their administration in clinical practice.

S1P receptor modulators in Multiple Sclerosis: Detecting a potential skin cancer safety signal.

INTRODUCTION: S1P receptor modulators are oral Disease-Modifying Therapies (DMTs) for Multiple Sclerosis, which were associated with cases of basal cell carcinoma in clinical trials. This study aims at investigating in a real-world adverse event reporting system whether S1P receptor modulators increase the risk of skin cancer reporting, compared to other DMTs. METHODS: Adverse event reports from the FDA Adverse Event Reporting System (FAERS) were extracted, cleaned, and analyzed from 2004Q1 until 2020Q4. The crude and adjusted Reported Odds Ratios (cROR, aROR) for the outcomes: basal cell carcinoma, squamous cell carcinoma, or melanoma were calculated for all DMTs. In a sensitivity analysis, we looked at each outcome separately. RESULTS: The aROR (95%CI) of siponimod was: 9.68 (5.48-15.79) and of fingolimod 4.54 (3.86-5.32), indicating a safety signal of S1P receptor modulators for skin cancer. Ozanimod had only 52 complete reports without any cases. In the sensitivity analysis, siponimod showed a signal only for basal cell carcinoma: 22.83 (12.27-38.83), while fingolimod for all outcomes separately, including melanoma: 3.02 (2.31-3.89). Notably, among the other DMTs, alemtuzumab: 4.40 (2.98-6.25) and cladribine: 3.28 (1.17-7.13) presented also a signal for disproportionate reporting, while ocrelizumab showed a signal in the sensitivity analysis only for melanoma 2.55 (1.21-4.65). CONCLUSIONS: S1P receptors seem to increase skin cancer reporting on FAERS, and the association is strongest for basal cell carcinomas. Therefore, close dermatologic surveillance before- and during therapy is needed. Whether fingolimod and ocrelizumab also increase the risk of melanoma needs further investigation.

Atypical antipsychotics in multiple sclerosis: A review of their in vivo immunomodulatory effects.

INTRODUCTION: The high efficacy of atypical antipsychotics (AAP) in treating diverse psychiatric disorders has been partly attributed to their capacity to curb neuroinflammation, a shared aspect of these diseases. These immunomodulatory properties of AAP have lately been explored in the context of multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS. METHODS: This study aimed to review in vivo studies reporting on the therapeutic effects of AAP both in EAE, the main animal model of MS and in cuprizone-induced demyelination. For that matter we conducted a literature search and a screening process that eventually yielded 8 eligible studies. RESULTS: All studies agreed on the efficiency of AAP to dramatically reduce EAE severity and delay its onset, while suppressing the production of numerous inflammatory cytokines. Clozapine showcased similar yet more intense effects than risperidone, quetiapine and olanzapine, significantly attenuating CD4 T cell infiltration and myeloid cell activation, while upregulating Tregs. Clozapine also downregulated chemokines responsible for the migration of immune cells in the CNS and caused dopamine receptor levels in the brain of EAE mice to rise. DISCUSSION: Taken together, these findings unanimously attest to the anti-inflammatory and immunomodulatory properties of AAP, suggesting that their therapeutic potential expands beyond their current neuropsychiatric applications. Despite the salutary effects of AAP in MS reported in vivo, a clinical trial of clozapine on MS patients failed to confirm preclinical findings due to low acceptability of AAP and early participant withdrawal. CONCLUSION: Although preclinical evidence unquestionably supports the multifaceted beneficial properties of AAP in MS, further investigation is required to elucidate the pharmacodynamic profile of these agents and allow for their proper clinical testing on MS patients.

Disease-modifying agents for multiple sclerosis and the risk for reporting cancer: A disproportionality analysis using the US Food and Drug Administration Adverse Event Reporting System database.

AIM: While the efficacy of disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is established, little is known about their long-term safety. Cancer-risk after DMT use remains unclear. This study aimed to investigate whether the prescription of DMTs for patients with MS increases the risk of reporting cancer. METHODS: Data from the Food and Drug Administration Adverse Event Reporting System were extracted from 2004 to 2020. After data cleaning, the crude and adjusted reported odds ratios (cROR and aROR) for cancer were calculated for DMTs with Interferon beta-1a as the reference drug. Sensitivity analyses investigated the group of reports with multiple registered DMTs, the effect of indication restriction and the results when using the rest of the DMTs as reference. RESULTS: For malignant tumours, aROR (95% confidence interval [CI]) values were Cladribine 0.46 (0.18-0.95), Dimethyl fumarate 0.30 (0.27-0.34), Fingolimod 0.61 (0.53-0.70), Glatiramer 0.50 (0.43-0.58), Alemtuzumab 0.84 (0.64-1.08), Interferon beta-1b 0.49 (0.42-0.56), Natalizumab 0.36 (0.34-0.39), Ocrelizumab 0.48 (0.29-0.74), Peginterferon beta-1a 0.35 (0.26-0.48), Siponimod 0.89 (0.47-1.54) and Teriflunomide 0.25(0.21-0.30) adjusted to age, gender and concomitant medications. In the sensitivity analysis, when the rest of the drugs were used as a reference, Interferon beta-1a and Peginterferon beta-1a had aROR (95% CI) 2.60 (2.47-2.74, P < .001) and Alemtuzumab had aROR 1.47 (1.13-1.88, I = .003). CONCLUSIONS: No safety signal for increased cancer risk was detected among the approved DMTs. A potential safety signal detected in the sensitivity analysis concerning Interferon beta-1a and Alemtuzumab requires further evaluation with more robust evidence.