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Two-drug combination helps older adults with hard-to-treat depression

September 28, 2015

TORONTO, September 28, 2015 - More than half of older adults with clinical depression don't get better when treated with an antidepressant. But results from a multicentre clinical trial, including researchers at the Centre for Addiction and Mental Health (CAMH) in Toronto, indicate that adding a second drug - an antipsychotic medication - to the treatment regimen helps many of those patients.

The findings, from a study of 468 people over age 60 diagnosed with depression, are published in The Lancet. This is the first study of its kind ever undertaken in older people with depression.

Previous research in younger patients with depression showed that adding a low dose of the antipsychotic drug aripiprazole (brand name Abilify) helped relieve symptoms of depression when an antidepressant alone wasn't effective. But the new study is the first to show that the same strategy also works in older adults. The two-drug combination relieved depression in a significant number of patients and also reduced the likelihood that they would have suicidal thoughts.

"This is a rare study because it looks at depression specifically in older adults," says Dr. Benoit Mulsant, a co-author of the study and Senior Scientist at CAMH. "It's important to treat older adults effectively, especially given that adults with late-life depression are at an increased risk of developing dementia. Our research demonstrates that older adults respond to treatment for depression."

"It's important to remember that older adults may not respond to medications in the same way as younger adults," says Dr. Eric J. Lenze, first author of the study and Director of the Healthy Mind Laboratory at Washington University School of Medicine in St. Louis. "There are age-related changes in the brain and body that suggest certain treatments may work differently, in terms of benefits and side effects, in older adults. Even when a strategy works for patients in their 30s, it needs to be tested in patients in their 70s before it can be considered effective in older patients."

At least 1 to 3 per cent of Canadians age 65 and older experience major depressive disorder, and another 8 to 16 per cent have clinically significant depressive symptoms, according to the 2009 report Improving the Management and Outcomes of Late-Life Depression in Canada led by St. Mary's Hospital Centre in Montreal. Non-psychiatric physicians recognize depression in only about one in three affected seniors, and most depressed seniors receive inadequate treatment or no treatment at all.

The consequences are costly: Elderly patients with clinical depression use more health care, and depression reduces their ability to function independently. Further, older Canadians have a high risk of suicide, particularly among males. Depression is also a risk factor for dementia.

"Depression among older Canadians is a huge public health problem," says Dr. Daniel Blumberger, a co-author of the study, Head of the Late-Life Mood Disorders Clinic at CAMH and Clinician-Scientist in CAMH's Brain Stimulation and Geriatric Mental Health Services. "Late-life depression is a mental illness, not a normal part of aging."

Dr. Mulsant and Dr. Blumberger, both part of the Campbell Family Mental Health Research Institute at CAMH, were the principal investigators in Toronto, and conducted their research out of CAMH's Late-Life Mood Disorders Clinic. Patients were also treated at Washington University School of Medicine and the University of Pittsburgh School of Medicine.

Each study participant received an extended-release formulation of the antidepressant drug venlafaxine (brand name Effexor XR) for 12 weeks. About half of these patients still were clinically depressed after 12 weeks of treatment.

For the second phase of the study, patients who initially did not respond to the venlafaxine continued to receive the drug along with aripiprazole or a placebo. Aripiprazole often is prescribed to treat schizophrenia and manic episodes associated with bipolar disorder.

The two-drug combination led to a remission of depression in 44 per cent of the treatment-resistant patients, compared to only 29 per cent of those who had received the placebo.

"This study is a major advance in support of evidence-based care for older adults with depression," says Dr. Charles F. Reynolds, a co-author of the study and the UMPC Endowed Professor in Geriatric Psychiatry at the University of Pittsburgh. "By publishing our findings in The Lancet, we hope particularly to reach primary care physicians, who provide most of the treatment for depressed older adults. The excellent safety and tolerability profile of aripiprazole, as well as its efficacy, should support its use in primary care, with appropriate medical monitoring."

Some patients who took the two-drug combination experienced restlessness. Others developed some stiffness, called mild Parkinsonism. But the side effects tended to be mild and short-lived, and the researchers say the potential benefits of the two-drug combination outweighed the side effects.

As well, side effects that the researchers expected to see, such as weight gain and metabolic problems, never occurred. Antipsychotic medications can cause increasing amounts of fat, increasing blood sugar and potentially contributing to diabetes. But aripiprazole was no more likely than the placebo to produce increased fat in these patients and had no effect on blood sugar, insulin or lipids.

The key remaining question, the researchers agree, involves predicting which older patients with depression are likely to benefit from the two-drug combination. Learning the answer is a goal for future research.
This study was funded by the National Institute of Mental Health (NIMH) and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), both in the U.S. Additional funding was provided by the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry, the Taylor Family Institute for Innovative Psychiatric Research at Washington University and the Washington University Institute of Clinical and Translational Sciences, and the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH) in Toronto. Bristol-Meyers Squibb contributed aripiprazole and placebo tablets, and Pfizer contributed venlafaxine extended-release capsules.

In related research, Dr. Mulsant and Dr. Blumberger are leading a study that combines two innovative non-drug treatments with the goal of preventing Alzheimer's dementia in older adults with depression or early memory problems. Interested participants can learn more about the PACt-MD study and how they can join by emailing or calling 416-583-1350.

The Centre for Addiction and Mental Health (CAMH) is Canada's largest mental health and addiction teaching hospital, as well as one of the world's leading research centres in the area of addiction and mental health. CAMH combines clinical care, research, education, policy development and health promotion to help transform the lives of people affected by mental health and addiction issues. CAMH is fully affiliated with the University of Toronto, and is a Pan American Health Organization/World Health Organization Collaborating Centre. For more information, please visit or follow us on Twitter @CAMHnews or @CAMHResearch.

Centre for Addiction and Mental Health

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