Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review

Gasim, Majid; Bernstein, Çharles N.; Graff, Lesley A.; Patten, Scott B.; El‐Gabalawy, Renée; Sareen, Jitender; Bolton, James M.; Marriott, James; Fisk, John D.; Marrie, Ruth Ann

doi:10.1016/j.msard.2018.09.008

Cited by 35 publications

(21 citation statements)

References 82 publications

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“…In clinical trials, anxiety has been observed as a rare ADR to the combination product nicotinic acid and laropiprant 22 . However, no increased risk of psychiatric ADRs has been identified for dimethyl fumarate 23 . Therefore, further research seems warranted.…”

Section: Discussionmentioning

confidence: 97%

“…22 However, no increased risk of psychiatric ADRs has been identified for dimethyl fumarate. 23 Therefore, further research seems warranted. HCA 2 is present in microglial cells of all brain areas and might mediate neuroprotective effects of dimethyl fumarate in patients with MS. 3,24 As glial cells are involved in the pathogenesis of anxiety disorders, 25 Increased liver enzymes were identified as similarly distributed to dimethyl fumarate and nicotinic acid in our analysis.…”

Section: Discussionmentioning

confidence: 99%

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Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA₂‐mediated adverse reactions? A combined epidemiological‐experimental approach

Dubrall

Pflock

Kosinska

et al. 2021

Brit J Clinical Pharma

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Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA 2 ) and induce flushing. It is not known whether HCA 2 mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA 2 -mediated.Methods: We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA 2 expression.Results: Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" ) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA 2 was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]). Conclusion:The gastrointestinal ADRs common to both substances may be mediated by HCA 2 . Other ADRs not common to both substances are compound or indicationspecific reactions and likely do not involve HCA 2 .Diana Dubrall, René Pflock, Markus Schwaninger and Bernhardt Sachs contributed equally.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA₂‐mediated adverse reactions? A combined epidemiological‐experimental approach

Dubrall

Pflock

Kosinska

et al. 2021

Brit J Clinical Pharma

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“…Regarding treatment of MS depression, immunomodulatory and immunosuppressive drugs, namely disease modifying therapies (DMTs), such as oral dimethyl fumarate, teriflunomide, fingolimod, and intravenous drugs, such as natalizumab, and alemtuzumab (Kirzinger et al, 2013;Hunter et al, 2016;Montanari et al, 2016;Gasim et al, 2018) seem to modulate depressive symptoms in MS. Furthermore, some of these DMT drugs exert a direct beneficial effect on glutamatergic and GABAergic synaptic transmission by modulating inflammatory mediators (Gentile et al, 2016(Gentile et al, , 2018Mandolesi et al, 2017).…”

Section: Clinical Insights For Cytokine Theorymentioning

confidence: 99%

Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis

Bruno

Dolcetti

Rizzo

et al. 2020

Front. Cell. Neurosci.

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In the past years, several theories have been advanced to explain the pathogenesis of Major Depressive Disorder (MDD), a neuropsychiatric disease that causes disability in general population. Several theories have been proposed to define the MDD pathophysiology such as the classic “monoamine-theory” or the “glutamate hypothesis.” All these theories have been recently integrated by evidence highlighting inflammation as a pivotal player in developing depressive symptoms. Proinflammatory cytokines have been indeed claimed to contribute to stress-induced mood disturbances and to major depression, indicating a widespread role of classical mediators of inflammation in emotional control. Moreover, during systemic inflammatory diseases, peripherally released cytokines circulate in the blood, reach the brain and cause anxiety, anhedonia, social withdrawal, fatigue, and sleep disturbances. Accordingly, chronic inflammatory disorders, such as the inflammatory autoimmune disease multiple sclerosis (MS), have been associated to higher risk of MDD, in comparison with overall population. Importantly, in both MS patients and in its experimental mouse model, Experimental Autoimmune Encephalomyelitis (EAE), the notion that depressive symptoms are reactive epiphenomenon to the MS pathology has been recently challenged by the evidence of their early manifestation, even before the onset of the disease. Furthermore, in association to such mood disturbance, inflammatory-dependent synaptic dysfunctions in several areas of MS/EAE brain have been observed independently of brain lesions and demyelination. This evidence suggests that a fine interplay between the immune and nervous systems can have a huge impact on several neurological functions, including depressive symptoms, in different pathological conditions. The aim of the present review is to shed light on common traits between MDD and MS, by looking at inflammatory-dependent synaptic alterations associated with depression in both diseases.

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“…If 36–54% of PwMS are confronted with anxiety and studies have clearly shown that anxiety (and depression) is also associated with cognitive impairment,90 therapy counseling “in an open and honest partnership” with our PwMS is a conditio sine qua non 91. The questionable association between “depression” and “DMT therapy” was investigated by Gasim et al (side effects of DMT with regard to psychiatric comorbidities in natalizumab, dimethylfumarate, teriflunomide and alemtuzumab) 92. DMTs have not been associated with an increased risk of adverse psychiatric effects and some may even reduce the incidence of depressive symptoms.…”

Section: Maximizing Therapeutic Opportunities To Delay the Transitionmentioning

confidence: 99%

“…DMTs have not been associated with an increased risk of adverse psychiatric effects and some may even reduce the incidence of depressive symptoms. This may reflect either a positive direct effect of immune modulation or an indirect effect resulting from a positive influence on disease activity or course 92. PwMS with progressive course of MS also showed an increase in pain and disability 93.…”

Section: Maximizing Therapeutic Opportunities To Delay the Transitionmentioning

confidence: 99%

<p>Comorbidities in multiple sclerosis—a plea for interdisciplinary collaboration to improve the quality of life of MS patients</p>

Goischke¹

2019

DNND

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The negative influence of comorbidities on the quality of life of people with multiple sclerosis is evident and the problem is increasingly acknowledged by numerous international studies in long-term care. One therapeutic option would be an add-on therapy with vitamin D (VD), with the aim of achieving a therapeutically effective dose. The individually required VD dose must be tested, since the response to a certain dose is subject to variations between individuals. A possible toxicity with increased 1.25(OH)D3 (active VD metabolite) is largely prevented by increased activity of 24-hydroxylase ( CYP24A1 ). Monitoring of serum VD levels as well as serum calcium and phosphate levels (optional Ca excretion in 24-hour urine, Ca creatinine ratio in urine) provides safety and is necessary because possible mutations on the (catabolic) CYP24A1 gene can lead to a partial or total loss of 24-hydroxylase activity and provoke hypercalcemia/hyperphosphatemia. The main therapeutic objective is to maintain functional and social independence by using drugs with a high safety profile. The prevention and optimal management of comorbidities can influence the quality of life of patients with MS (PwMS) when included in patient care. Adequate measures can reduce the burden of MS only if the risk of comorbidity is reduced through targeted monitoring, early detection and diagnosis. Such a strategy will contribute to influencing the premature mortality of patients with MS. If VD is recognized as a “multipurpose steroid hormone”, it could also be used to maintain cognitive function and prevent premature possible dementia, especially as there is evidence that VD deficiency correlates with brain atrophy (hippocampus). At present, MS therapy is still a balancing act between therapeutically efficient action and the management of unexpected side effects, with VD add-on therapy being almost unproblematic and most likely to be accepted by PwMS.

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Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review

Cited by 35 publications

References 82 publications

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA₂‐mediated adverse reactions? A combined epidemiological‐experimental approach

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA₂‐mediated adverse reactions? A combined epidemiological‐experimental approach

Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis

<p>Comorbidities in multiple sclerosis—a plea for interdisciplinary collaboration to improve the quality of life of MS patients</p>

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Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review

Cited by 35 publications

References 82 publications

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA2‐mediated adverse reactions? A combined epidemiological‐experimental approach

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA2‐mediated adverse reactions? A combined epidemiological‐experimental approach

Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis

<p>Comorbidities in multiple sclerosis—a plea for interdisciplinary collaboration to improve the quality of life of MS patients</p>

Contact Info

Product

Resources

About

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA₂‐mediated adverse reactions? A combined epidemiological‐experimental approach

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA₂‐mediated adverse reactions? A combined epidemiological‐experimental approach