NARSAD Young Investigator Grantees Bring Fresh Ideas to Mental Health Research for Older Patients

Carmen Andreescu, M.D. - Brain & behavior research expert on anxiety
Carmen Andreescu, M.D.

As America ages, more and more young scientists are awakening to the increasingly urgent public health issue of late-life mental illness. NARSAD Young Investigator Grantees bring fresh ideas to help answer some long-standing questions, pointing the way toward improved therapies targeted specifically to the needs of older patients.

Asking such questions as: How does increasing age exacerbate treatment-resistant depression? The rate of depression can range from 55 to 81 percent in the older population. Persistent, unrelieved depression can result in severe functional disability, cognitive decline and often suicide. Elevated rates of suicide are also associated with bipolar disorder, current treatments for which are often only partially effective for geriatric patients and can have significant side effects.

For these young scientists, their research presents the possibility of helping to ease the enormous burden of mental illness on society and often requires an innovative, multidisciplinary approach to successfully treat the aging population.

Carmen Andreescu, M.D.

2009 NARSAD Young Investigator Grant: “Neural Markers of Treatment Response in Late-life Generalized Anxiety Disorder”

Objective of research: To identify biological predictors of treatment response in elderly patients with generalized anxiety disorder (GAD) to further development of personalized and effective treatments.

According to Carmen Andreescu, M.D., 2009 NARSAD Young Investigator Grantee, late-life generalized anxiety disorder (GAD) is associated with cognitive impairment and poorer recovery after events such as strokes. Its onset may reflect age-specific stressors and brain changes and she says, “late-life GAD is relatively understudied and arguably the least treated brain and behavior disorder in the elderly.”

A research assistant professor in the department of psychiatry at the University of Pittsburgh, Dr. Andreescu was trained in medicine and psychiatry in her native Romania. She completed a residency in psychiatry and a geriatric psychiatry fellowship at the University of Pittsburgh’s Western Psychiatric Institute and Clinic, before receiving her current appointment. With her NARSAD Grant, she is exploring age-related neuroanatomical changes that may interfere with responses to treatment for GAD in the elderly, which until recently has been under-diagnosed and under-treated due to poor screening and limited awareness.

GAD is as prevalent as late-life depression, and here, too, effective treatments are lacking. Several brain areas appear to be involved in initiating and maintaining the pathological worry of GAD, particularly interactions between the amygdala and the rostral anterior cingulate, regions that, among other functions, help process emotions and the brain’s reward system. During healthy worry suppression, the rostral anterior cingulate inhibits neural output from the amygdala. Dr. Andreescu conjectures that in the elderly this mechanism might be defective due to disconnection between the two structures caused by age-related vascular changes and neurodegeneration.

Aided by structural and functional magnetic resonance imaging (MRI) technology, she is investigating amygdala-rostral anterior cingulate interaction in patients treated with selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants.

Daniel M. Blumberger, M.D.

2010 NARSAD Young Investigator Grant: “A Prospective Study of Cortical Inhibition in Treatment-Resistant Late-Life Depression”

Objective of research: To clarify the pathophysiology of late-life depression and provide early identification of treatment-resistant patients.

“I was able to help a number of older adults recover from serious depressions. The experience was extremely rewarding. I then became interested in learning more about the biology of depression in older adults and this has become   a focus of my research career,” states Daniel M. Blumberger, M.D., 2010 NARSAD Young Investigator Grantee.

Dr. Blumberger is a research fellow at the University of Toronto’s Centre for Addiction and Mental Health, one of three centers involved in a National Institute of Mental Health (NIMH) study to test the efficacy of the antidepressant venlafaxine (trade name Effexor) with or without aripiprazole (Abilify) as a treatment for late-life treatment-resistant depression. With the support of his 2010 NARSAD Grant, Dr. Blumberger is using the opportunity offered by the availability of the NIMH study participants to investigate cortical inhibition, an important brain function that shows   a specific pattern of disturbance in depressed patients who do not respond to antidepressant treatment.

The aging process leads to a decrease in cortical inhibition. By comparing depressed older patients and healthy controls, Dr. Blumberger wants to determine whether deficits in cortical inhibition predict treatment resistance in late-life depression. He is using a method called repetitive transcranial magnetic stimulation (rTMS) to evaluate levels of cortical inhibition. Pioneered by Brain & Behavior Research Foundation Scientific Council Member Mark S. George, M.D., rTMS is a non-invasive form of brain stimulation that probes neuronal circuits regulating mood (see 2011 Highlights, p.2).

Brent P. Forester, M.D.

2008 NARSAD Young Investigator Grant: “31P MR Spectroscopy Magnetization Transfer Study of CoEnzyme Q10 (coQ10) in Geriatric Bipolar Depression”

Objective of research: To explore the use of a novel compound, coQ10, as a treatment for older patients with bipolar disorder. CoQ10 is known to enhance cellular energy metabolism in patients with neurodegenerative disorders such as Parkinson’s disease.

The disease mechanisms of bipolar disorder remain unclear overall. Dr. Forester, director of the Mood Disorders Division of the Geriatric Psychiatry Research Program at McLean Hospital, a Harvard-affiliated psychiatric facility, and a psychiatry instructor at Harvard Medical School, is exploring abnormalities in cellular energy metabolism that have been implicated in bipolar disorder. He is testing a novel compound that may normalize aberrant energy in older patients with this disorder.

Mitochondria are the structures, or organelles, within cells that serve as the cellular powerhouse: they generate energy. Studies have shown the presence of altered energy parameters, reflecting impaired mitochondrial function, in bipolar disorder patients, but these studies have not included older bipolar patients. Dr. Forester is using magnetic resonance spectroscopy (MRS), a potent and safe technology for investigating brain biochemistry. With this technology, he is able to test the effects of coQ10 with older patients who have bipolar disorder. CoQ10 is known to enhance mitochondrial function in patients with neurodegenerative disorders such as Parkinson’s disease. To assess coQ10’s effectiveness, he will compare energy parameters and mood before and after treatment.

Jordan F. Karp, M.D.

2010 NARSAD Young Investigator Grant: “Buprenorphine for Late-Life Treatment-Resistant Depression”

Objective of research: To test the safety and efficacy of buprenorphrine, a kappa opiate receptor antagonist, for treatment-resistant depression in older adults, and to translate functional magnetic resonance imaging (fMRI) results into more precise treatment planning.

I am interested in geriatric mental health “because it transcends psychiatry, psychology, medicine and cognitive neuroscience. I’m drawn to the multidisciplinary approach required to both treat and prevent psychiatric illness in late life,” says Jordan F. Karp, M.D., 2010 NARSAD Young Investigator Grantee.

Dr. Karp is an associate professor of psychiatry, anesthesiology and clinical and translational science at the Western Psychiatric Institute and Clinic of the University of Pittsburgh School of Medicine. His particular interest is in the treatment of older people with comorbid—co-existing—depression and chronic pain. His NARSAD Grant research is aimed at identifying and testing more effective medications for patients with late-life depression for whom currently available antidepressants don’t work. This treatment resistance may be complicated by other problems associated with aging, such as cerebrovascular disease or incipient Alzheimer’s disease, which may compromise brain neurocircuitry.

Based on studies suggesting that opioid drugs may exert antidepressant effects, Dr. Karp is conducting a trial to determine the potential of a compound called buprenorphine as a treatment for late-life depression. Buprenorphine acts on brain structures rich in opiate receptors, which are critical to reward circuits.

Jian-Min Zhang, M.D., Ph.D.

2008 NARSAD Young Investigator Grant: “Testosterone, Androgen Receptor Genotype and Late-Life Depression”

Objective of research: Dr. Zhang’s goal is to identify genetic markers that will determine which men will benefit from testosterone treatment for late-life depression—and which men will not and should be exempted from this treatment due to its potential side effects.

Dr. Zhang is an assistant professor of psychiatry and director of the Geriatric Psychiatry Division at the University of Maryland in Baltimore, and directs the geriatric psychiatry service at the University of Maryland Medical Center. In his NARSAD Grant-supported project, begun in 2008, he has focused on depression in the elderly male population.

Hypogonadism—a deficiency in the hormone testosterone—affects 30 percent of men over the age of 55. Hypo- gonadal men are three times more likely to suffer from depression and are more likely to become treatment resistant. Testosterone as a treatment for hypogonadism has had mixed results, which may reflect lack of attention to the functional status of androgen receptors (AR), the cellular receptors for testosterone, which must be working properly for testosterone to have the appropriate effects in the body and the brain.

Dr. Zhang is studying differences in AR genes among elderly men to see whether these differences are associated with response to testosterone. His goal is to determine whether AR receptor gene types can be used as genetic markers for men who will benefit from testosterone treatment and exempt those who would not, since testosterone therapy carries a potential increased risk for prostate cancer.