New Targets for Treatment: 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.

This is the second and concluding part of Psychiatry Weekly’s two-issue series, authored by Dr. Husseini Manji, on recent and ongoing research out of the NIMH’s Mood and Anxiety Disorders Program. The first part—focusing on advances in genetic research into mood and anxiety disorders—was published last week and is available  here.

Introduction

Created in 2001, the explicit mission of the NIMH Mood and Anxiety Disorders program is, in the words of director Dr. Husseini Manji, “to make a real and positive difference in severe mood and anxiety disorders.” Dr. Manji believes this can be achieved by “truly understanding the operation of the major disorders—whether in terms of predisposing genes, patient resilience, or brain circuitry—and by devising novel and effective treatments.” In addition to exploring the etiology of mood and anxiety disorders, the program also attempts to find new and more effective targets for treatment.

Delayed Treatment Effect

“It’s been evident for some years now that most of the agents that have been shown effective for treating mood and anxiety disorders take days, or even weeks, to start working,” Dr. Manji says. “An agent may initially increase serotonin at the synapse, but the changes most relevant to treatment response occur later, and, likely, at a different site. This could account for both the delay in treatment response as well as the delay in symptom reemergence following treatment discontinuation.” Which particular changes resulting from medication actually produce patient improvement is one of the questions Dr. Manji and his colleagues are attempting to answer.

Prediction of treatment response is a related area of research. “Say the most salient downstream change produced by an SSRI is in the glutamate system,” Dr. Manji says. “There could be numerous steps between the original effects on the serotonin system and the treatment-relevant effects an agent finally produces in the glutamate system. If there’s a problem (eg, genetically determined) in any one of those multiple steps between the serotonin and glutamatergic systems, the patient isn’t going to respond to an SSRI.”

Dr. Manji and colleagues hope to identify the most relevant targets and design medication that can hit them directly. “A great deal of our work is translational. Molecular and cellular studies can implicate specific molecules in the symptoms of mood and anxiety disorders. If we can target these molecules we can likely improve treatment and eliminate response lag.”

Recent Advances

One of the most promising studies to have come out of the Mood and Anxiety Disorders program involves targeting
the NMDA receptors in patients with depression. The NMDA receptors, a subtype of the glutamate system, have been implicated in learned helplessness animal studies. Learned helplessness is a common animal model of human depression, and researchers have discovered that antidepressants, when successful at alleviating the symptoms of learned helplessness in animals, begin to affect the NMDA receptors several weeks after dosing (around the same time treatment response typically begins). Further, direct manipulation of the NMDA receptors has produced antidepressant-like effects in rats and mice.

Based on the animal findings as well as a small previous study at Yale, Dr. Manji, Dr. Carlos Zarate, and colleagues designed a pilot study examining the effects of ketamine (which has been shown to target the NMDA receptors) on patients with severely refractory depression.

“We enrolled patients who hadn’t responded to traditional medications,” Dr. Manji says. “Our thinking was mainly that if a patient was going to respond to a more traditional treatment, that’s what he or she should be receiving instead of an experimental treatment. In addition, individuals who have failed at least two previous treatment trials are far less likely to be placebo-responsive, significantly lowering the sample size required to detect a signal that the treatment works.”

The patients enrolled had failed an average of 6 previous antidepressants, and some had failed ECT as well. The average history of depression was 24 years, and the average current episode was 3 years in length. “In this extremely treatment-resistant population, one very low dose of IV ketamine produced an extraordinary antidepressant response,” Dr. Manji says. “Antidepressant effects were seen as early as two hours, and at 24 hours 75% of patients had responded and 30% met criteria for remission. After 1 week, with no readministering of ketamine, 35% of patients were still responders. The results were particularly intriguing in that, not only could we hit the NMDA receptors and see a rapid effect, but we saw a sustained effect as well.” Building off of the striking results of the ketamine study, Dr. Manji, Dr. Zarate, and colleagues set out to find out how ketamine was working and how they could improve treatment response even more.

As Dr. Manji explains, one theory was that increasing the signal through AMPA receptors relative to NMDA receptors was at the heart of the antidepressant effects. “We gave rats AMPA blockers along with ketamine, and found that, unlike in previous ketamine studies sans AMPA blockers, the ketamine produced no antidepressant effects,” Dr. Manji says. “We’re currently looking into ways to more directly increase activity at AMPA receptors relative
to NMDA receptors.”

A related avenue of research involves further honing NMDA receptor-specific treatment. “Ketamine can trigger psychosis and/or temporary depersonalization in people,” Dr. Manji says. “Ketamine affects all types of NMDA receptors (of which there are at least 4 subytpes), so Dr. Zarate in the Mood and Anxiety Disorders Program has begun to explore the possibility that some receptor subtypes are responsible for antidepressant response, while others may be responsible for the negative side effects of ketamine.” Animal studies have indicated that an NR2B subtype blocker has robust antidepressant effects, and early (and unrelated) studies on patients with Parkinson’s (who are, in general, prone to developing psychosis) have so far suggested that NR2B blockers do not produce psychosis. “If this compound produces antidepressant effects in humans it could be extremely useful, as it doesn’t appear to have the baggage that ketamine does,” Dr. Manji says.

The Mood and Anxiety Disorders program is also exploring the possibility of using ketamine to get patients quickly out of depression, and then maintaining treatment response with other, safer compounds. “Riluzole, which is used to treat Lou Gherig’s disease, has been shown to increase AMPA receptor function in rats, and we’re currently conducting a study in which patients are treated first with ketamine, and then maintained with riluzole,” Dr. Manji says. “The study is in the early stages, but, so far, the results are promising.”

Conclusion

The Mood and Anxiety Disorders program is also running a host of other promising studies. They’ve identified a molecule—protein kinase C—that appears to be an ideal target for rapid treatment of manic episodes, and an antagonist—substance P—that looks to be extremely effective in treating PTSD-like symptoms in animals. In addition, building off of evidence that short-term sleep deprivation has powerful and rapid antidepressant effects, Dr. Manji and his colleagues are conducting a study attempting to target the relevant neurons without waking the patients up. Numerous studies are ongoing, and many are in need of patient participants.

“It doesn’t matter where the patients are coming from,” Dr. Manji says. “If they qualify, we’ll bring the patients to us. In some cases, because the compounds being investigated are so novel, we do have stringent exclusionary criteria. However, in many of the studies, comorbid diagnoses do not necessarily preclude participation. We want to know whether our treatments work or not—comorbidity is rampant in the real world, and we want our studies to reflect that.”

For information regarding participating in an NIMH Mood and Anxiety Disorders Program study, please call 301-402-9347. Information about the program can also be found online at: http://intramural.nimh.nih.gov/mood/.

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