The Genetic Bases of Mood and Anxiety Disorders: Current Research at the NIMH Mood and Anxiety Disorders Program

Director, Mood and Anxiety Disorders Program, Chief, Laboratory of Molecular Pathophysiology, NIMH

This interview was conducted on March 8, 2007 by Peter Cook.

Introduction

This is the first of a two-part series focusing on current research being conducted by the NIMH’s Mood and Anxiety Disorders program. As such, it will focus on the goals of the program and recent advances in the understanding of the etiology of depression and anxiety. Next week’s installment will focus on novel targets for treating depression, and will include and overview of other current research.

Formation of the Mood and Anxiety Disorder Group

“Traditionally, research on specific psychiatric disorders at the National Institutes of Health (NIH) has been at multiple levels independently,” says Dr. Husseini Manji, director of the NIH Mood and Anxiety Disorders program. “Depression research, for example, comprised a number of groups, each focused on different aspects of the disorder: genetics, new treatments, phenotypic variation, etc. It was recognized that these complex diseases might best be tackled by undertaking the research at multiple levels in an integrated manner. Thus, in 2000, the idea of combining related research under the aegis of one program was brought forth, and, in 2001, the Mood and Anxiety Disorders program was created.”

The program was created from both existing groups at the NIH as well as a number of new people—including Dr. Manji—brought in to head up new labs. The new program was judged a success, and when  original director Dennis Charney, MD left for Mt. Sinai Medical School in 2004, Dr. Manji was selected first as acting director, and then later as permanent director.

The Goals of the Mood and Anxiety Disorders Program

“Our explicit mission is to try and make a real and positive difference in severe mood and anxiety disorders,” Dr. Manji says. “We believe this can be done first by truly understanding the operation of the major disorders, whether in terms of predisposing genes, patient resilience, or brain circuitry, and second, and most importantly, by devising novel and effective treatments. Furthermore, we attempt to integrate our child/adolescent and adult studies, because our major illnesses undoubtedly have a major developmental component.”

As Dr. Manji explains, recently industry has become relatively conservative. “The majority of drug companies today are focusing less on designing new treatments, and more on producing enhanced versions of successful agents or producing another SSRI with a more favorable side effect profile.” The researchers at the Mood and Anxiety Disorders program have taken this as a challenge. “We’ve set out to see if we can demonstrate the utility of some completely novel agents,” Dr. Manji says, “with the hope that once we do we can partner with industry to develop these agents as real medications. Dr. Carlos Zarate has been spearheaded these efforts, and so far this approach has turned out to be very successful.”

The group, notably Drs. Pine, Leibenluft and Towbin, is also interested in enhancing early recognition of psychiatric disorders. “Most of these severe mood and anxiety disorders don’t suddenly appear out of thin air when one turns 40,” Dr. Manji says. “If we can identify these disorders—even in a prodromal phase—in childhood there’s a chance we can lessen the long-term impact, or even prevent the illness entirely.”

Research Into Genetic Bases for Mood and Anxiety Disorders

A good deal of the research coming out of the Mood and Anxiety Disorders program has been based on the theory that many psychiatric disorders are affected by/related to the turning on and turning off of various genes. “This idea sounds more radical than it is. Learning entails turning on and off genes, as does building muscle. The trick is to ascertain which genes are involved in a particular disorder,” Dr. Manji explains. With over 30,000 genes, isolating the relevant genes has been, until quite recently, extremely difficult. However, advances in recent years, such as microarray technology and differential displays, now allow researchers to examine all the genes at the same time.

“Once we were able to widen our view from just those genes involved in serotonin and dopamine production and uptake, we realized that the main classes of treatments for bipolar disorder and depression were actually turning on genes we traditionally thought of as specific to cell-growth and maintenance,” Dr. Manji says. “This was quite surprising, as psychiatry has generally not regarded mood disorders as similar to the classical neurodegenerative disorders.” While neural degeneration is by no means as pronounced in mood disorders as in Alzheimer’s disease and Huntington’s disease, mounting evidence from brain scans and post-mortem studies indicates consistent shrinkage of certain nerve cells, suggesting that current treatments work on those genes that restore damaged nerve cells to normal health. “This has opened up a whole range of new targets we’ve begun to investigate. Opened up a whole number of new targets we’ve begun to investigate, and has led to the idea that perhaps we shouldn’t be focusing solely on increasing serotonin or norepinephrine at the synapse or norepinephrine at synapse, but should rather be working on these molecules related to synaptic plasticity and cellular resilience.

One gene Dr. Manji and colleagues have identified is BCL2, which is turned on by certain treatments for bipolar disorder. “Our studies have indicated,” Dr. Manji says, “that, at least in rats, this gene is involved in regrowing and establishing connections between neurons, as well as protecting against ischemia and free radicals. If we can demonstrate that BCL2 is involved in neuroprotection in humans, it will be good evidence that protecting the brain is more than a prophylactic against long-term cognitive decline; neuro-protective agents may be critical in pathways involved in the resolution of depression.” Not only has this research led to excitement regarding early intervention, it has lead to the testing of novel treatments mimicking growth factors, many of which are now ready to begin testing.

The genetics group in the program, headed by Dr. Francis McMahon, are also involved in gathering genetic information from probands in a number of studies. Most recently, Dr. Manji and Dr. McMahon have collaborated with the STAR*D study.

“We were able to obtain DNA from roughly half of the 4,000 patients enrolled in STAR*D,” Dr. Manji says, “and this has enabled us to match particular sets of genes to treatment response, remission, and side effects.”

One paper has already been published identifying a variant in a 5-HT_2A receptor that predicts response to SSRIs. “This variant, which is associated with good response, is ~7 times less common in African Americans,” Dr. Manji says. “Typically, African Americans have done poorly in antidepressant studies in comparison to whites. It is quite possible that the frequency of a particular genetic subpopulation within a particular race may account for the findings.” 

The Mood and Anxiety Disorders group has also identified two other genes that appear to be strong predictors of remission in response to treatment with antidepressants. The research group is also intent on searching for genes associated with particularly troubling side effects.

“The identification of biomarkers of treatment response and/or serious side effects has caught the attention of the FDA,” Dr. Manji says. These sorts of tests would also have obvious applications in treatment selection for regular patients. “If a treatment takes 8-12 weeks to begin working, a clinician is going to be a great deal more likely to prescribe this treatment if they know it has a 90% probability of being effective as opposed to a 20% chance,” Dr. Manji says. “Increasing advances in genetic profiling of treatment response will allow us to increasingly tailor treatment to fit the patient, as opposed to the hit-or-miss strategy we’re stuck with now.”

Disclosure: Dr. Manji reports no affiliations with or financial interests in any organization that may pose a conflict of interest.