Insights into the pathophysiological mechanisms governing neuropsychiatric symptoms of multiple sclerosis

In a recent study published in Translational Psychiatry, researchers pursued insights into the pathophysiological mechanisms governing neuropsychiatric symptoms of multiple sclerosis (MS).

The study reviewed all advancements in common neuropsychiatric symptoms in MS, major depressive disorder (MDD), anxiety, and cognitive impairment, their clinical and magnetic resonance imaging (MRI) characteristics, and treatment approaches currently available or in development.

Study: Depressive symptoms, anxiety and cognitive impairment: emerging evidence in multiple sclerosis.  Image Credit: UnderhilStudio/Shutterstock.comStudy: Depressive symptoms, anxiety and cognitive impairment: emerging evidence in multiple sclerosis.  Image Credit: UnderhilStudio/


Mood disorders, like depression and anxiety, are often overlooked in clinical practice, even though their effect on patient's daily activities and quality of life (QoL) is profound.

Emerging evidence of neuropsychiatric symptoms, including cognitive impairment, clinical depression, and anxiety in MS, has given valuable insights into the pathophysiology of the disease.

It has established the need for evaluating neuropsychological batteries and scales alongside the irreversible physical disability that characterizes MS. The application of MRI measures has helped researchers identify and visualize structural and functional aberrations in relevant brain regions and networks of an MS patient.

It has enabled the development of novel therapeutic targets for MS patients' management, with particular attention to improving their QoL.

About the study

In the present review, experts describe an updated overview of the most common neuropsychiatric symptoms of MS patients and their pathophysiology.

Moving on to treatment approaches, both currently available or under investigation, they describe and evaluate pharmacological and rehabilitative approaches with beneficial effects on MS-related cognitive functioning, mood disorders, and fatigue.

Ultimately, the researchers gathered knowledge on MS pathophysiology might help develop tools to develop a basis for a personalized treatment approach for each MS patient. 

MDD, anxiety disorders, and cognitive impairment: epidemiology, pathophysiology, and treatment

The prevalence of MDD in MS patients is three to 10 times the rate in the general population for periods exceeding 12 months. In fact, it is one of the most prevalent comorbidity in MS that generally peaks in patients aged 45 to 59 years.

Another worrisome observation is that MS patients with depressive symptoms have worse cognitive outcomes. The Beck Depression Inventory (BDI) scale clinically assesses depression in MS patients.

The pathogenesis of MS-related depressive symptoms is multifactorial, with genetic and immunological players. Studies suggest that the Apolipoproteinε2 allele plays a protective role and decreases the incidence of depression.

Likewise, studies have linked proinflammatory cytokines to the onset of depressive symptoms. Studies have also demonstrated that structural and functional abnormalities in frontotemporal and limbic cortices of the brain worsen depression in MS patients.

The treatment of MS-triggered depression follows the same guidelines as for the general population. First-line treatment comprises serotonin reuptake inhibitors, and psychotherapy is another important treatment approach for MS-related depression.

Among non-pharmacological treatments, clinicians widely use transcranial magnetic stimulation to treat cognitive and mood symptoms. Drugs like natalizumab and fingolimod also have a positive effect on depression.

Anxiety disorders in MS patients vary with age, with an age-standardized prevalence of up to 35.6% reported in MS patients compared to 29.6% in the general population. Several brain regions, including the amygdala, hippocampus, and medial prefrontal cortex, have been implicated in MS-triggered modulation of anxiety disorders.

MS-related anxiety usually co-occurs with depressive symptoms. So, there is no specific treatment for these disorders, even though natalizumab and fingolimod treatment have been shown to improve anxiety symptoms.

The prevalence of cognitive impairment in MS patients ranges between 34% and 91%. Even though cognitive deficits in MS patients are highly variable, data processing speed, attention, learning, and memory remain the most frequently involved domains, with male patients showing more cognition deficits than females.

Nonetheless, these precede the appearance of inflammatory-demyelinating lesions of the CNS seen on MRI. Cognitive deficits are also widespread in cases of pediatric-onset MS (in >50% of cases).

Being shorter, the Brief International Cognitive Assessment for multiple sclerosis (BICAMS) and the Symbol Digit Modalities Test (SDMT) are more useful in clinical settings and provide critical data on executive functions, verbal fluency, and working memory.

Recent studies challenged the traditional dichotomous classification of cognitive functioning. They identified distinctive cognitive phenotypes in MS. Defining these five phenotypes would be a step toward tailored treatment approaches for MS-related cognitive changes.

The MRI evaluation of White Matter (WM) and grey matter (GM) damage has helped predict cognitive outcomes in MS; however, the role of additional factors, such as brain reserve and cognitive reserve, cannot be overlooked. 

MS patients with higher intracranial volume (ICV) showed better cognitive scores in the SDMT, but this protective effect was unrelated to memory functions. Likewise, cognition-enriching leisure activities and life experiences had a protective effect against cognitive decline in MS patients independent of ICV. 

Here it is also noteworthy that children have a greater capacity to compensate for brain damage through neural plasticity. Thus, MS-triggered cognitive decline is more common in older than younger people.

Nonetheless, therapeutic approaches should target cognitive reserve, i.e., a modifiable factor, to prevent or slow down cognitive deterioration in MS patients. An ongoing randomized clinical trial is evaluating cognitive rehabilitation and aerobic exercise together.

Cognitive rehabilitation trains people to improve and regain skills lost during MS progression, apart from helping them develop compensatory strategies for lost abilities.

There is no evidence for each therapeutic strategy for treating cognitive impairment. Thus, a multifaceted approach combining symptomatic treatments and cognitive rehabilitation with a healthy lifestyle could be the most rewarding approach toward the preservation of 'cognitive integrity' in MS patients.


Cognitive impairment, clinical depression, and anxiety are highly prevalent in MS patients versus the general population. These symptoms manifest much-early during MS progression, even before the clinical diagnosis of MS. Hence, early diagnosis of MS is crucial to prevent neuropsychiatric disorders and related complications.

Given definitive treatment guidelines do not exist in MS, more studies are warranted to study the intricate interplay between MS and its neuropsychiatric symptoms.

It might help uncover the effect of sex, lesion location, neuroendocrine factors, etc., on this interplay. 

Furthermore, randomized controlled trials on larger cohorts might reveal the effectiveness of pharmacological and psychotherapies in MS patients.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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