Deborah Brauser

March 26, 2012

March 26, 2012 (Washington, DC) — Despite the stigma it seems to have for some patients and their families, lithium is just as effective for treating mania in older patients with bipolar disorder (BD) as the more commonly used valproate, new research suggests.

In one of the first large studies to examine late-life mania, patients older than 60 years with BD who received lithium and those who received valproate both showed significant antimanic responses.

Both treatments were also considered "well tolerated," investigators reported during a session devoted to initial findings of the Geriatric BD (GERI-BD) study here at the American Association for Geriatric Psychiatry (AAGP) 2012 Annual Meeting.

"Both drugs worked very well, with scores coming down very nicely," coinvestigator Martha Sajatovic, MD, professor of psychiatry at Case Western Reserve University School of Medicine in Cleveland, Ohio, and director of the Neurological Outcomes Center at University Hospitals Case Medical Center, reported during the presentation, which was given to a standing-room-only crowd of attendees.

"We just need to realize that treatment response can take time," she added.

Coinvestigator John L. Beyer, MD, told Medscape Medical News after the session that although "we're still early in the analysis of this study," the main point for clinicians is that the treatments are equally beneficial.

"It's a reminder that our current medications are good and effective. And even monotherapy can be very effective," said Dr. Beyer, assistant professor of psychiatry and director of the Mood Disorder Clinic at Duke Medical Center in Durham, North Carolina.

"I think this is the only prospective, randomized controlled trial for bipolar mania in geriatrics, so it's also actually ground-breaking."

Limited Evidence

According to the investigators, "despite the importance of safe and effective management of bipolar in late life," there is currently a limited evidence base on which to base practice.

"We really don't know how to treat geriatric mood disorder patients, but especially geriatric [BD] patients," said Dr. Beyer.

The selection of lithium and valproate, which are both mood stabilizers, for inclusion in this study was based on the frequency of their use in this population and on the reported benefits from past research involving small patient numbers or with open-label designs.

However, according to Dr. Beyer, a recent study found that there has been a marked decrease in the prescribing of lithium for elderly patients with mania and an increase in prescribing valproate over the last few years.

"Why do we practice like this? There just isn't a lot of evidence to back that up," he said.

For this study, 2408 older adult patients with bipolar 1 disorder were initially screened at 6 North American sites.

However, after screening and consent withdrawals, only 224 were selected for randomization. Of these, 112 received 0.80 to 0.99 mEq/L of lithium carbonate (50% men; mean age, 67.6 years) and 112 received 80 to 99 μg/ml of valproate (53% men; mean age, 68.3 years) for 9 weeks.

"We wanted to push them to a therapeutic level, and if they could tolerate it, they could go down," explained Dr. Beyer.

After 3 weeks of treatment, risperidone could be added for any patient who did not show improvement. Risperidone and lorazepam were given as rescue medications if needed. All participants were in a manic or hypomanic state at baseline and had a score of 18 or higher on the Young Mania Rating Scale (YMRS). None were found to have rapid cycling or dementia.

The YMRS and the Clinical Global Impressions of Bipolar Disorder scale (CGI-BP) were used to assess antimanic effects at days 4, 9, 15, 21, and then weekly.

Tolerability of treatment was assessed at the same time; assessment included use of the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale, laboratory tests, electrocardiograms, and the checking of vital signs.

Secondary outcome measures included change in depressive symptoms, as shown on the Montgomery Åsberg Depression Scale (MADRS) and the Hamilton Depression Rating Scale (HDRS).

No Significant Differences

At baseline, the mean YMRS scores were 27.1 for the lithium group and 25.5 for the valproate group. The baseline mean MADRS scores were 11.4 vs 11.9, respectively.

At the 3-week point, the YMRS scores for those who completed the study were significantly better among both groups of participants (decreasing in the range of 50%), although there were no statistically significant between-group differences.

There were also no significant between-group differences in depression or CGI-BP scores, and there were no significant differences in need for augmentation (19 of those treated with lithium vs 16 of these treated with valproate) or rescue medications.

"Only about 1 out of 5 or 6 patients had to be on an atypical. So at least a third could be treated with monotherapy," said Dr. Sajatovic.

The number of serious adverse events for those treated with lithium was 21 compared with 19 for those treated with valproate, which was not significantly different.

The most common treatment-related adverse events reported were diarrhea (17 vs 10 for lithium vs valproate, respectively, at 3 weeks and 13 vs 8 at 9 weeks), sleepiness (10 vs 10 at 3 weeks, 11 vs 8 at 9 weeks), and tremor (3 vs 2 at 3 weeks, 8 vs 2 at 9 weeks).

There were 29 premature terminations for any reason, but this was not deemed statistically significant between the groups (19 in the lithium group vs 10 in the valproate group).

"Both lithium and valproate were adequately tolerated, and side effects were not the primary reason for attrition. There was no 'smoking gun' for one treatment or the other," reported coinvestigator Benoit Mulsant, MD, professor and vice-chair in the Department of Psychiatry at the University of Toronto in Ontario, Canada, during his presentation.

More Work to Do

Principal investigator Robert C. Young, MD, professor of psychiatry at Weill Cornell Medical College in White Plains, New York, and creator of the YMRS, noted that "tolerability is certainly essential for benefit. This study showed that patients can respond to monotherapy and conservative target blood levels."

He reported that the investigators "have a lot more work to do" with this study, including assessing outcomes from the World Health Organization Disability Assessment Schedule (WHO-DAS), the 12-Item Short Form Health Survey (SF-12), clinical laboratory measures, and cognitive measures.

"We also want to better examine the attrition outcomes," said Dr. Young.

During the question-and-answer session after the presentation, the investigators were asked about the long-term use of atypical antipsychotics as supplementation in light of the US Food and Drug Administration's black box warning about their use in the elderly.

"That is only for people with dementia, which none of our patients had," replied Dr. Mulsant. "Still, it's good if they don't have to be on it. Monotherapy with lithium or valproate, as long as it's tolerated, is best."

"This study challenges us in how we think about our treatment of patients because of the large number who did respond to monotherapy," added Dr. Beyer.

"The question is: are we patient enough to treat patients with monotherapy? That's something to think about when other studies have found that a combination of treatments may be faster. I think it comes down to how we weigh risks and benefits."

Essential Data

"This particular study revealed to us that lithium is a well-tolerated and very effective management for elderly bipolar disorder patients. It gives us another option to use," Mark Burns, MD, geriatric psychiatrist and adjunct associate professor of psychiatry at the University of Texas Health Science Center in San Antonio, told Medscape Medical News.

Dr. Burns, who was not involved with this research, noted that residents and fellows in training often underutilize lithium in this patient population.

"I think they have a reluctance to use it for a number of reasons, including concerns over toxicity and tolerability. Also, many of them started their training at a time when we were getting a lot of information about divalproex sodium [valproate], which was the new kid on the block," he said.

"Even clinicians out there in the community aren't reaching for lithium probably as often as they should, given the important findings of this study. We have to remember that it's really a proven, safe, and effective treatment."

He also noted that he was happy to see the discussion on monotherapy as a first-line treatment, especially because elderly patients are often on so many other medications.

"I once saw a woman who was extremely manic and psychotic and thought to even be delirious from a neurological condition. But she actually had what we call 'manic delirium.' And she responded to lithium monotherapy beautifully."

Dr. Burns said he was "very grateful" to the investigators for doing this study because there has not been much previous research in the area of elderly mania.

"We need this data. And going forward, it's essential and very welcomed."

This study was supported by grants from the National Institute of Mental Health. In addition, Janssen provided risperidone to some study sites. Dr. Sajatovic reported having received research support from AstraZeneca, Merck, Pfizer, and Novartis. Dr. Beyer reported having received research support from AstraZeneca, Lilly, Forest, and Takeda. Dr. Burns reported being on speaker's bureaus for Takeda and Forest.

American Association for Geriatric Psychiatry (AAGP) 2012 Annual Meeting. Session 111. Presented March 16, 2012.

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