Depression Called a 'Core Symptom' of MS

Nancy A. Melville

June 14, 2019

SEATTLE — Because brain imaging studies increasingly show that depression experienced by patients with multiple sclerosis (MS) may be linked as much to brain changes caused by the disease itself as to external psychological stresses, careful consideration should be given to the appropriate of choice of treatment, experts say.

"I think the evidence we see from emerging brain imaging indicates that depression can be viewed as a core symptom of MS," said Anthony Feinstein, MD, PhD, a professor of psychiatry at the University of Toronto and Sunnybrook Health Sciences Center, Canada.

"I say this not to minimize the role of external factors, but the findings on this issue are pretty consistent," he said.

The link between depression and MS was discussed here at the Consortium of Multiple Sclerosis Centers (CMSC) 2019 Annual Meeting.

Depression can affect nearly half of MS patients over a lifetime, the researchers note. Evidence supporting this link include MRI studies that show alterations of the structural connectome in the limbic system of people with MS, as well as a link between brain lesion volume and atrophy and depression.

An MRI study published in Brain in 2009 showed that even in MS patients who were cognitively intact, there was a greater lack of functional connectivity between two prefrontal areas and the amygdala, a subcortical region linked to negative feelings, compared to healthy control persons.

"When you look at the imaging data, we see that brain volume metrics can account for nearly 50% of the depression variance in MS, and this suggests that depression is very much linked to the brain pathology in some MS patients, so for me, that says it's indeed a core feature of MS," Feinstein told Medscape Medical News.

The conclusion underscores the need for more studies of the treatment of depression in MS, and particularly randomized controlled trials of antidepressants for patients with the disease. According to a recent Cochrane review, there are currently only three such trials; they involve the tricyclic antidepressant desipramine (multiple brands) and the selective serotonin reuptake inhibitors paroxetine (multiple brands) and sertraline (Zoloft, Pfizer), Feinstein explained.

For a more comprehensive discussion of treatment options, one review, published in 2017 in Multiple Sclerosis and Related Disorders, offers some important insights on antidepressants recommended for MS on the basis of patients' medical symptoms.

For patients with depression and fatigue (a symptom that is highly prevalent among MS patients), the authors recommend the norepinephrine/dopamine-reuptake inhibitor bupropion (multiple brands).

Patients with depression and symptoms of nausea and insomnia may benefit from mirtazapine (Remeron, Organon); for those with sexual dysfunction, mirtazapine as well as bupropion may be ideal choices; for pain, duloxetine (Cymbalta, Lilly) and possibly venlafaxine (multiple brands) are suggested; for urinary symptoms, including overactive bladder, duloxetine may be helpful; and for those with variable compliance, fluoxetine (multiple brands) may be of benefit, the review authors recommend.

CBT Before Meds

Before turning to antidepressants, however, Feinstein said the first treatment option for depression should not include medication.

"The treatment of choice for depressed people with MS is cognitive- behavioral therapy [CBT] — this is the American Academy of Neurology recommendation," he said.

The data regarding CBT are very extensive and show that CBT offers important, though not always substantial, benefits, Feinstein noted.

"CBT in the literature is quite optimistic, whether it's individually, group, or computerized, and we see effect sizes invariably are positive, albeit modest," he said. "CBT works in MS — not dramatically, but it's compelling."

Internet-based CBT interventions can be effective, he noted. A randomized controlled trial published in 2015 in the Lancet showed that among 90 patients with MS who were randomly assigned in a 1:1 ratio either to be on a wait list for 9 weeks or to receive a fully automated, Internet-based CBT program (Deprexis, Gaia AG), those in the intervention group had significant improvements in Beck Depression Inventory scores (P = .01; effect size, d = 0.53).

Exercise regimens, though beneficial for depression in the general population, are not well studied in people with MS.

"The trouble is, depression is always added on as a secondary outcome measure, so there is no good study with depression representing the key outcome of the exercise," Feinstein said.

ECT an Option in MS

For particularly severe depression, Feinstein noted that clinicians should not rule out electroconvulsive therapy (ECT).

"You can't talk about treatment of depression without mentioning ECT," he noted.

"I run a clinic and see people who have tried multiple therapies and failed, and once or twice a year we get someone who is acutely suicidal and at acute risk and has tried multiple therapies, and we will resort to ECT, and the results are usually quite good.

"The big question is whether ECT makes patients worse from a neurological perspective, and the answer is no," he said.

Feinstein recommended that if there are concerns of aggravating the neurologic condition with ECT, clinicians should obtain a gadolinium-enhanced MRI scan prior to the ECT treatment.

"If there are no enhanced lesions on the MRI, then it would appear this therapy is completely safe from a neurological perspective," he said.

"That doesn't mean you can't get cognitive fallout from ECT, particularly with respect to autobiographical memory, but you're dealing with people here who are getting a therapy that is completely lifesaving," he said.

Psychiatric Treatment Considerations in MS

Laura T. Safar, MD, who gave a separate talk on psychopharmacology in MS at the meeting, offered a few notable additional recommendations on psychiatric conditions beyond depression in an interview with Medscape Medical News.

With antipsychotics, she noted, clinicians should use caution with risperidone (Risperdal, Janssen) or other antipsychotics: "The drugs may cause rigidity and gait problems," said Safar, who is director of MS neuropsychiatry at Brigham and Women's Hospital, Boston, Massachusetts.

"If you already have motor and gait problems due to MS or Parkinson's disease, those patients will be more sensitive to those side effects," she said.

Bupropion, she noted, may increase the risk for seizures in people with MS.

The drug memantine (multiple brands), used to treat dementia in patients with Alzheimer disease, is associated with worsening physical and neurologic symptoms in patients with MS, and trials have been interrupted early owing to worsened psychiatric symptoms, Safer explained.

In her talk, Safar noted that some disease-modifying therapies for MS have themselves been linked to depression, including interferon beta-1a and 1b and natalizumab (Tysabri, Biogen). However, some drugs may also have therapeutic psychiatric effects.

Safar agreed that CBT should at least be attempted before recommending antidepressants.

"I completely agree that it should be CBT first, with efforts such as therapy, exercise, and sleep hygiene prior to writing a prescription," Safar said.

"It's also about building up a resiliency in patients," she added. "Going to CBT can help patients learn new ways of thinking about behavioral activation, and it can teach how patients can help themselves activate their mind to fight depression.

"If they're just taking medication, they're not necessarily building resiliency," she said.

A positive trend is that psychiatric problems in MS appear to be gaining much-needed attention, Safar noted.

"Part of the reason why there are so few clinical trials of psychopharmacological treatments in MS is that there has been a split between mental health and neurological care. But that appears to be one of the directions in which the field is growing," she said.

"There is less stigma because patients are bringing these things up more often, and there is higher integration [with mental health care providers] among the teams. It's happening slowly, but it's the way to go," she said.

Feinstein receives grant support from the MS Society of Canada and the Progressive MS Alliance. He receives honoraria from Merck-Serono, Teva, Novartis, Biogen, and Sanofi-Genzyme. Safar has disclosed no relevant financial relationships.

Consortium of Multiple Sclerosis Centers (CMSC) 2019 Annual Meeting: Presented May 30, 2019.

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