New Therapies Show Promise for Vascular Depression; Heart, Metabolic, Risks of Some Antipsychotic Medications Flagged

May 7, 2008 • Science Update

WASHINGTON, DC, May 7 — Researchers see new treatments on the horizon for a type of depression related to blood vessels that affects the elderly, and have discovered why some elderly people fail to respond to current medications. In other studies, scientists urge caution regarding use of antipsychotics (usually for schizophrenia or other psychosis) in this and other populations to minimize metabolic, heart, and stroke risks.

The scientists spoke today at a press conference involving speakers from two symposia sponsored by National Institute of Mental Health (NIMH), a part of the National Institutes of Health, during the American Psychiatric Association Annual Meeting here.

"Mental health practitioners and patients should be aware of the relationship between vascular problems and depression, and should understand the value of preventing vascular changes that might lead to difficult-to-treat depressions, for example through early recognition and treatment of high blood pressure" says John Newcomer, MD, of Washington University in St. Louis.

Drugs Show Promise for Vascular Depression

New treatment possibilities are being explored for vascular depression, a recently recognized type of depression that usually develops in patients older than age 60 and is associated with loss of blood supply to the brain. This condition is a serious problem for elderly patients and highly effective treatments have yet to be developed, but several research teams now report progress in understanding and treating this condition.

George Alexopoulos, MD^* of the Weill Cornell Medical College in White Plains, NY, and his colleagues, are investigating the specific brain abnormalities linked to blood vessel problems. Using a new magnetic resonance imaging technique called diffusion tensor imaging, Alexopoulos and his team have found that, in late life depression, higher blood pressure readings are linked to tiny white matter abnormalities, mainly in the brain's frontal lobes and in subcortical areas. Some of these structural abnormalities were linked to impairment in specific frontal lobe functions.

The researchers are also studying the brain abnormalities preventing depressed older patients from responding to antidepressant medication. In a study of 112 elderly patients with major depression treated with the antidepressant citalopram, they found that patients were less likely to recover from their depression if they had cardiovascular disease or performed poorly on a 'response inhibition' task testing an aspect of cognition requiring frontal lobe function. This timed task asks a person to suppress the reading of a word (e.g., the word red) and identify the color of ink by which the word is written (e.g., blue). In a subsequent study of 48 depressed older patients treated with the antidepressant escitalopram, which is more potent than citalopram, Alexopoulos and his colleagues showed, for the first time, that patients who failed to achieve remission had more of the tiny structural abnormalities in several areas of frontal lobe and in subcortical structures compared with those who got well.

"With further refinement, the findings may improve physicians' ability to predict who will fail to respond to antidepressants," Alexopoulos says. "Such patients may need close follow-up and different treatments such as psychotherapy or novel medications. Second, our findings can be used in the development of new treatments for those who do not respond to classical antidepressants."

Alexopoulos is now working to pinpoint activation and processing abnormalities in frontal and subcortical brain structures that predict failure to respond to antidepressants. He is studying how parts of the frontal lobe are activated when depressed patients perform cognitive tasks known to engage this area. "Preliminary findings show that depressed older patients cannot activate these frontal lobe parts as efficiently as non-depressed older adults," Alexopoulos, says.

Stimulation Therapy Tested for Vascular Depression

In other treatment strategies, Robert Robinson, MD, a professor of psychiatry at the University of Iowa, and his colleagues have found for the first time that vascular depression can be effectively treated with repetitive transcranial magnetic stimulation (rTMS), an experimental technique that also has been tested in other psychiatric disorders.

Among 92 depressed people with an average of three prior treatment failures, the researchers found that rTMS produced better remission rates than those associated with standard medication treatment. They also found that increasing the number of magnetic pulses delivered significantly improved remission rates. "These findings suggest that this new method of treatment may be particularly useful for these late life onset depressions and that even greater response rates might be achieved by utilizing more pulses of magnetic stimulation," Robinson says. The findings of this study were published in the March 2008 issue of the Archives of General Psychiatry.

The study participants had clinical or imaging evidence indicating lack of blood flow in the brain, and had failed to respond to standard treatments for depression. They were given either 12,000 or 18,000 pulses of rTMS or a sham (inactive) treatment over a two-week period. Neither the patient nor the examiner knew if the treatment was actual rTMS or sham, thus removing any possible bias. Improvement of depression was documented by scores on the Hamilton Depression Scale. The next step in this research is to determine precisely how many magnetic stimulations will achieve the maximum response among patients with vascular depression.

Metabolic and Cardiovascular Risks Linked to Depression

Newcomer and his colleagues have studied the risk of adverse cardiometabolic side-effects during treatment with different antipsychotic medications in two NIMH-funded studies, one in children with disorders that include autism and pervasive developmental disorder and one involving adults with schizophrenia.

Preliminary results indicate that children undergoing their first 12-week exposure to antipsychotic medications routinely experience an increase in total body fat, which can vary in magnitude with individual medications and may be accompanied by increases in blood fat levels. In contrast, chronically treated adults with schizophrenia can experience increases or decreases in total body fat during a new 12-week course of antipsychotic treatment, depending on the individual medications involved.

In general, body fat is highly correlated with tissue insulin sensitivity, the body's ability to control blood sugar. Increases in fat mass tend to result in decreases in insulin sensitivity, producing risk for conditions such as diabetes and cardiovascular disease. "Fortunately, progress in understanding these conditions and potential side-effects of treatment should inform the best ways to lower risk and improve treatment outcomes," Newcomer says.

In another study, very preliminary findings from an NIMH-sponsored trial of 450 patients in San Diego County "indicate a surprisingly high prevalence of metabolic abnormalities in patients with post traumatic stress disorder who have psychotic symptoms," says Dilip Jeste, MD, of the University of California at San Diego.

The randomized, controlled trial is looking at the effects of long-term use of four atypical antipsychotics — aripiprazole, olanzapine, quetiapine, and risperidone — in middle-aged and elderly psychiatric patients.^** This is a longitudinal, prospective study with serial clinical and laboratory assessments of adverse effects.

Results of the preliminary PTSD study findings should be available by early May; and the overall study results by the end of 2010 For now, Jeste stresses the importance of shared decision-making between the caregiver and patient or legally authorized representative, and caution in using medications for all older patients.

Since their introduction during the past 15 years, the newer "atypical" antipsychotics have been increasingly used for the management of a variety of psychotic disorders and severe behavioral disturbances in older patients. The main reason for this common off-label use of atypical antipsychotics is their lower risk of producing persistent abnormal movement side-effects, compared with conventional antipsychotics. However, in the last several years there has been a growing concern that these medications present a different set of potentially serious adverse effects, specifically weight gain, blood lipid increase, and insulin resistance that can raise the risk for metabolic conditions like diabetes mellitus, and for cardiovascular diseases like coronary heart disease and cerebrovascular disease.

Recently, based on an analysis of 17 double-blind randomized placebo-controlled trials among elderly people with dementia, the US Food and Drug Administration added a 'black box' warning label on these medications to alert the public about the potential increased risk of strokes and death for patients with dementia.

^* Alexopoulos has received research grants from Cephalon and Forest Pharmaceuticals and served in the advisory board of Forest. He is on the speakers bureau of Jannsen, Forest, Bristol-Myers-Squibb, and Eli Lilly.

^** AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen donate atypical antipsychotic medications for this study.