Hippocampal Atrophy, High Cortisol Found in Depressed MS Patients

Janis C. Kelly

July 09, 2010

July 9, 2010 — Multiple sclerosis (MS) patients have a lifetime depression risk as high as 50%, and new imaging studies suggest that the cause may be both physical and psychological.

Magnetic resonance imaging (MRI) studies by Stefan M. Gold, MD, Nancy L. Sicotte, MD, and colleagues document smaller hippocampal volumes in MS subjects than in normal controls. Among the MS subjects, those with depressive symptoms (Beck Depression Inventory [BDI] score >13) had smaller volumes of the dentate gyrus (CA23DG) and also had higher cortisol levels.

"Depression is a common problem in MS that may result from structural changes due to the disease," Dr. Sicotte said. "Depressive symptoms are undertreated in MS," she added.

The studies are reported online July 1 in Biological Psychiatry.

Subregional Specificity

The researchers studied anatomically defined hippocampal subregional volumes (cornu ammonis 1-3 [CA1-CA3], CA23DG, subiculum, and entorhinal cortex) using MRI in 29 patients with relapsing-remitting MS and 20 matched healthy control subjects. They measured salivary cortisol at awakening, 4 pm, and 9 pm on 2 consecutive days and had all subjects complete the BDI.

"There may be subregional specificity of hippocampal involvement in multiple sclerosis: CA1 atrophy in all MS patients and CA23DG atrophy in depressed MS patients," Dr. Sicotte, who is associate professor of neurology at the University of California–Los Angeles, told Medscape Medical News. "This may provide markers for disease-specific effects in MS, which could be used to monitor disease progression and/or treatment effects."

Dr. Sicotte said that she was surprised at how robust and consistent the findings were in a relatively small number of patients.

"Interestingly, this idea of a link between excessive activity of the HPA [hypothalamic-pituitary-adrenal] axis and reduced brain volume in the hippocampus hasn't received a lot of attention, despite the fact that the most consistently reproduced findings in psychiatric patients with depression (but without MS) include hyperactivity of the HPA axis and smaller volumes of the hippocampus," Dr. Sicotte said. "So the next step is to compare MS patients with depression to psychiatric patients with depression to see how the disease progresses in each."

Another surprise was that hippocampal volumes were essentially normal in MS patients whose depression was well-controlled with selective serotonin reuptake inhibitors (SSRIs).

"We have to be careful not to draw conclusions from such small subgroups assessed in an exploratory and cross-sectional manner, but it suggests testable possibilities. It could be that folks without hippocampal atrophy are the ones who respond to SSRIs or that the SSRIs lead to a normalization of previously affected hippocampal subregional volume. To answer this, we will need to do a longitudinal treatment study," Dr. Sicotte said.

Implications Potentially Great

Marino Zorzon, MD, who also studies MRI changes in MS, pointed out that the actual number of MS depressed patients is rather small (n = 8), that the correlation between BDI-II scores and the volume of the CA23DG region is weak (r = −0.38, P = .04), and the number of depressed MS patients who were taking SSRIs was even smaller (n = 5).

Still, Dr. Zorzon said, "The clinical implications are potentially great and fascinating: treating the depression you can modify cerebral areas implicated in the developing of depressive symptoms and you can observe this in vivo." Dr. Zorzon is professor of neurology and neurorehabilitation and director of the Multiple Sclerosis Center, University of Trieste, Italy.

Anthony Feinstein, MD, professor of psychiatry at the University of Toronto, Ontario, Canada, who has also studied brain abnormalities in MS patients with major depression, commented that this is a well-conducted imaging analysis but needs to be replicated.

Dr. Feinstein also noted that cortisol abnormalities have been reported in MS patients without depression and that the threshold for determining depression on the BDI was low at 13. "It would be interesting to see what the results show if the bar is raised. A cutoff of 13 on the BDI signifies mild depression," Dr. Feinstein said.

Funding was provided by the National Multiple Sclerosis Society, the National Institutes of Health, the UCLA Cousins Center for Psychoneuroimmunology, and Claire and William Vaughn. Dr. Sicotte, Dr. Feinstein, and Dr. Zorzon have disclosed no relevant financial relationships.

Biol Psychiatry. Published online July 1, 2010.

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