Neuroprotective Benefits of Antidepressants in Multiple Sclerosis: Are We Missing the Mark?

Stress is an important biological function that in small amounts is adaptive and has the ability to help motivate us to achieve goals. Sustained or uncontrollable stress, however, may lead to depression, especially in individuals who are predisposed (20). Unsurprisingly, a review of studies that have assessed the relationship between stress and depression in PwMS has found the link to be robust, with a proposed moderate to large effect (5).

The relationship between stress and disease progression has gained considerable research attention because of the long-considered view among many PwMS that significant stressful life events are involved in the onset of disease and occurrence of relapses, as well as the transient worsening of existing symptoms. Animal studies have shown a relationship between induced stress and disease onset and progression in mice infected with experimental autoimmune encephalomyelitis, the mouse model of MS (21). However, the relationship is complex and dependent on factors including gender, timing, duration, and type of induced stress. Additionally, severe stress has been shown to improve disease, whereas milder stress progressed it (22). An association dependent on the severity of a stressful relationship has also been shown in a human study. Brown et al. (23) recruited 101 consecutive PwMS through two MS clinics and followed them over a 2-year period. They reported acute stress, measured as stressful events of less than 6 months, to be related to exacerbation, whereas chronic stress, measured as stressful events of more than 6 months duration, was not. A review of research investigating the relationship between stress and disease onset or progression deduced that there is evidence of stress influencing disease onset and clinical course, although “no secure conclusions could be drawn” (24). There have been contrasting results from studies about the relationship between stress and exacerbation; however, the majority have found a relationship (for a review, see Mitsonis et al. [25]), which was reported to be moderate in a meta-analysis that included results of 14 studies (effect size, Cohen’s d=0.53) (26). Clearly, the relationship between stress and disease onset, progression, or exacerbation is not straightforward and is likely mediated or moderated by a range of psychosocial factors, including depression and anxiety (25, 27).

Research suggests there is also a relationship between depression and relapse/progression in MS. A study of 132 PwMS reported a correlation between higher depressive symptoms and exacerbation, with depressive symptoms remaining 6 months after the MS relapse (28). Furthermore, a retrospective assessment of 2,312 PwMS found that women (but not men) who had experienced a psychiatric illness (depression, anxiety, or bipolar) within a 10-year period had significantly higher scores on the Expanded Disability Status Scale than those who had not (β=0.31, p=0.0004) (29), which is consistent with an earlier animal study that found a greater stress-progression response in female mice infected with experimental autoimmune encephalomyelitis (30). However, depression was not related to greater disability progression at 10-year follow-up in another smaller study (N=96), despite depression remaining stable in people assessed at baseline (10). It is possible this study was underpowered, although the difference in psychiatric measurements may also be responsible for the contrasting results. Koch et al. (10) recruited through an MS clinic and used the Center for Epidemiological Studies Depression scale (CES-D), with a score of 16 or greater determining depressive symptoms in PwMS. The CES-D ranges between 0 and 60. By comparison, McKay et al. (29) identified psychiatric disorder from physician and hospital claim files (≥ five physician claims or ≥ one hospital claim), suggesting PwMS in this sample had a greater severity of psychiatric difficulties, given that they were seeking health care management in relation to them.

The experience of stress activates the hypothalamo-pituitary-adrenal (HPA) axis through the secretion of corticotrophin releasing hormone from the hypothalamus, which activates the pituitary gland and secretes adrenal corticotrophin, stimulating cortisol production from the adrenal gland; among other things, it helps regulate stress and immune response. Cortisol receptors provide a negative feedback loop to regulate cortisol production and the cortisol-to-cortisone ratio (20, 31). Production of cortisol is regulated by circadian rhythms, with highest levels in the morning and a reduction of cortisol throughout the day. Regulation of cortisol is important for both physical and psychological health. However, the natural rhythm of cortisol production is altered with HPA-axis disruption (31). HPA-axis dysregulation and inflammation have been related to psychiatric pathology (32). Increased cortisol levels, modulated by the HPA axis, have been associated with acute and chronic stress and depression in people with and without MS (33, 34). Dysregulation of the HPA axis is well established in PwMS; hyperactivity correlates with the clinical course of MS, such that mild hyperactivity is seen in relapsing remitting MS (RRMS), whereas primary-progressive MS (PPMS) shows the most pronounced changes. It is proposed that HPA-axis dysregulation may be driven by inflammation in RRMS but by neurodegeneration in secondary progressive MS (SPMS) (35–37). A study that assessed cortisol awakening response (CAR) in people with RRMS and SPMS in comparison to healthy controls found that CAR was significantly higher in people with RRMS than the control group, but not people with SPMS. Additionally, in people with RRMS, increased CAR at baseline was predictive of greater disability 9 months later (38). Prior studies have also found cortisol hyperresponsiveness and HPA-axis dysregulation predicted clinically measured disease progression in PwMS (39). It is possible that glucocorticoid-insensitive immune cells may be responsible for excessive inflammatory response seen in RRMS, whereas glucocorticoid-insensitivity is absent or reduced in people with chronic disease types SPMS and PPMS (39). Taken together, the reregulation of the HPA-axis may be time critical for people with RRMS, before irreversible neuronal damage that causes dysregulation in the absence of inflammation. Importantly, treatment with antidepressant medication has shown attenuation of HPA-axis function in depression (40), and HPA-axis hyperactivity in MS is attenuated by immunomodulatory medications (35).

There is a well-established association between immune system inflammation and severity of depression (41, 42). The MS disease-modifying medication fingolimod, which has anti-inflammatory effects, has recently displayed antidepressant effects, including hippocampal neurogenesis in mice exposed to either chronic unpredictable stress or depressive symptoms induced by chronically treated corticosterone (43). Fingolimod increases brain-derived neurotropic factors (BDNF). BDNF support neurons and glial cells within the central nervous system and are important to neuronal survival and plasticity. BDNF are expressed in immune system cells and have been linked to inflammation. Other immunomodulatory therapy used in MS, including glatiramer acetate and hematopoietic stem cell therapy, have been shown to modulate BDNF. BDNF are similarly reduced in people experiencing depression, and fluoxetine has been found to increase BDNF in cultured mouse astrocytes (44–46).

A number of neurotransmitters have been shown to be altered in both MS and depression. For example, norepinephrine, known for its anti-inflammatory and neuroprotective effects, has been found to be reduced in PwMS (47, 48), as have serotonin transporters and platelet content (49, 50). Excessive glutamine, known to have neurotoxic effects, has been shown in PwMS (51). Serotonin or norepinephrine depletion has long been considered a factor in depression, and this is supported by antidepressant medications that act to increase the synaptic availability of these neurotransmitters to treat depression (52, 53). Glutamate has similarly been implicated in depression, and there is evidence that chronic antidepressant administration reduces the presynaptic release of glutamate (54). These commonalities between neurotransmitter disturbance in MS and depression may point to a potential overlap in disease mechanisms.

An important consideration for interpreting human studies that assess the relationship between antidepressant administration and exacerbation or progression in PwMS is that they excluded people with moderate to severe depressive symptoms. Excluding people with depressive symptoms is problematic, given that depression is a symptom of MS with a biological basis beyond that of reactive depression (5). The inclusion of people with depressive symptoms in a double-blind randomized-controlled study provides a layer of complexity because, once identified, the randomization of people experiencing moderate to severe depressive symptoms to the placebo arm raises ethical concerns. However, there is precedent for this practice when assessing antidepressant efficacy (72). Alternatively, a single-blind randomized control trial would provide participants in the placebo arm with autonomy to discontinue the trial if they chose to seek treatment for depressive symptoms, while still blinding study outcome evaluation.

Furthermore, studies that are limited to PPMS or SPMS, both characterized with ongoing progression of disability and brain atrophy in the absence of, or with minimal, inflammation, may limit the ability to detect an effect or require a larger sample to detect a smaller effect. Inflammation is a common mechanism associated with both MS and depression (41, 42) and is therefore a potential common mechanism by which antidepressant medication may exert an effect to reduce progression. Similarly, a shared disruption to neurotransmitters, including serotonin, norepinephrine, and glutamate, as well as to BDNF and HPA-axis activity in PwMS and people with depression supports the inclusion of PwMS and comorbid depression (35, 40, 50, 53, 73), especially given the ability of antidepressant medication to reregulate BDNF levels and HPA-axis activity in people experiencing depression (40, 74). Thus, if there is a link between depression and disease progression in MS, exclusion of participants with comorbid depression may be considered a systematic sampling error, because it risks not finding a neuroprotective relationship from SSRI use (or any antidepressant in general) when there is one, if results are generalized to the broader MS population.

Although there is a high priority to find neuroprotective agents for SPMS and PPMS given the dearth of therapeutics currently available for these subtypes, it is remiss to exclude people with RRMS, who often still experience neurological damage with current therapeutics. These people may be granted a greater level of neuroprotection, and therefore quality of life, if the addition of antidepressant medication offers neuroprotective benefits.

Given the high prevalence of depression and other emotional disorders in PwMS, and the similarities of neurotransmitter, BDNF, and HPA-axis dysregulation in PwMS and people experiencing stress and depression, it is vital that studies assessing the neuroprotective benefits of antidepressant medication in PwMS include people who are also experiencing depressive symptoms, and people with RRMS subtype, where inflammation is a key disease component. Should current research assessing the neuroprotective benefits of antidepressants in MS miss a signal because the study design excludes the very PwMS who would have shown a neuroprotective benefit, it risks the MS research community losing enthusiasm for this line of research. Thus, a potential opportunity to improve the quality of life for people living with MS and to reduce health care expenditure resulting from greater physical and psychological disability progression will also be lost.