David Baxter PhD
Late Founder
Updates from the NIMH: Current Research in Mood and Anxiety Disorders
July 7, 2008
by Husseini Manji, MD
Director, Mood and Anxiety Disorders Program; Chief, Laboratory of Molecular Pathophysiology, NIMH
Psychiatry Weekly, Volume 3, Issue 24, on July 7, 2008
This interview was conducted on April 21, 2008 by Peter Cook
There is a growing consensus in the field of psychiatry that many of the psychiatric illnesses, and almost certainly depression, are the product of different biological mechanisms in different patients,? says Dr. Husseini Manji. ?Just as hypertension and elevated blood pressure can be caused exclusively by defects in the heart, blood vessels, or kidneys, many psychiatric illnesses may have diverse causes.? Dr. Manji notes that it is also not uncommon to have two patients who both meet DSM-IV criteria for depression but share no symptoms in common?one may sleep too much while the other sleeps too little, one may eat too much while the other eats too little, etc.
?It is increasingly clear that a one-size-fits-all philosophy of treatment is severely limited,? Dr. Manji says. ?Our group has become increasingly focused on identifying biomarkers?everything from genes and proteins to brain imaging?that are associated with particular subtypes of psychiatric illness. Accurate subtyping has a host of implications, diagnostically, but, more importantly, in terms of tailoring treatment to each individual patient.?
Biomarkers
Dr. Manji and his team have been searching for biomarkers of use in distinguishing bipolar from unipolar depression. ?When someone first presents with a depressive episode, especially a young person, there is no reliable way to determine whether this person is depressed or bipolar and waiting to have his or her first manic episode,? he says. This is an area of particular concern, as treatment for unipolar depression?antidepressants?can sometimes destabilize bipolar illness, triggering manic episodes or rapid cycling. ?We are conducting a collaborative study using proteomics, which allows us to look at different cellular proteins and how they are modified chemically, looking for a signature that might allow us to better predict whether a patient has unipolar or bipolar depression. The work is promising, and, although it is unlikely to be completely definitive, may ultimately lead to better informed treatment decisions.?
?We?re building this notion of biomarkers into all the NIMH mood and anxiety disorder studies,? Dr. Manji says, ?both for distinguishing patient subtypes and in terms of predicting treatment effectiveness and side effect profiles. The Experimental Therapeutics group at NIMH has been looking at ketamine for refractory depression, and it has shown a great deal of promise. Now we are trying to identify biomarkers that would help us predict which patients are likely to respond better the drug.? Toward that end, Manji and colleagues are conducting functional brain imaging studies, and have found notable dissimilarities in brain activation that appear to be related to responsiveness to ketamine.
A Better Ketamine
?The NIMH group is also working on coming up with a better ketamine, which, although it works very well, tends to produce rather unpleasant side effects. Dr. Carlos Zarate has been looking at NR2B antagonists. NR2B is a subtype of the NMDA receptor, and our hope is that by blocking just the subtype, instead of, as with ketamine, all NMDA receptors, we might be able to get the beneficial effects without some of the side effects.?
It will be some time before the data on NR2B blockers are available, and, in the meantime, Dr. Manji?s group is considering the possibility of ?jump-starting? treatment with ketamine and then maintaining patients on some less aversive drug. ?Riluzole is looking very promising,? he says. ?Riluzole increases AMPA receptor throughput, and we think that the AMPA and NMDA balance is what?s important. We may be able to get people better by blocking NMDA receptors with some substance such as ketamine and then keep people better by increasing AMPA receptor function. Part of the appeal of a ketamine/riluzole combination treatment, Dr. Manji explains, is that these substances are already FDA-approved for other indications. If strong evidence supports the effectiveness of such a treatment course, refractory patients could receive the benefits in the very near future.
Resilience
Manji and colleagues are also examining resilience to psychiatric illness. ?Clinicians and researchers tend to focus on what makes people ill, but it may at times be equally productive to study what protects people from getting ill or allows more rapid recovery,? he says. ?If we better understood these protective mechanisms, we might be able to tap into them for treatment.
?Currently, there is much exciting work in this area, and researchers are identifying molecules related to the glucocorticoid receptors (critical in stress responses). A group at Emory has just looked at one such molecule, FKBP5, and found that genetic variations in this molecule are strongly associated with the likelihood of developing PTSD. This is an important finding, and the NIMH and Max-Plank genetics groups have found evidence that FKBP5 plays a role both in both the likelihood of developing depression and the rate of onset of antidepressant response.?
Another molecule of interest to Dr. Manji and his colleagues is BAG1, which also talks to the glucocorticoid receptors, and appears to be turned on by mood stabilizers like lithium and valproate. ?Genetically engineered animals that have more BAG1 are amazingly resilient to stress. While a normal animal might take weeks to recover from induced depression, one of these modified animals recovers in just 2?3 days. The modified animals also appear to be very resistant to mania. It may be possible that there are different molecules that work best for symptomatic treatment?ketamine is one example?and other molecules may be involved in long-term relapse prevention and remaining well in the face of stressors?we think that FKBP5 and BAG1 might represent the latter.?
Time Course to Available Treatments
The use of ketamine and riluzole for initial treatment and maintenance could in the near future, if researchers can definitively show that such a strategy works, become a very real part of treatment for patients with refractory depression. Other treatments that might result from this research are still some years from possible availability. ?Science is slow,? Dr. Manji says, ?but it is essential that we validate our findings and that they are replicated independently. In terms of identifying molecules that increase resilience, technology has gotten much better, and if a pharmaceutical company is working with a specific target?say BAG1?it can quickly screen millions of compounds, find out what turns on BAG1, then do the toxicity test on a smaller subgroup. Clinical trials, however, still take a number of years. We?re at least 5?10 years from having any treatments that specifically augment resilience.?
July 7, 2008
by Husseini Manji, MD
Director, Mood and Anxiety Disorders Program; Chief, Laboratory of Molecular Pathophysiology, NIMH
Psychiatry Weekly, Volume 3, Issue 24, on July 7, 2008
This interview was conducted on April 21, 2008 by Peter Cook
There is a growing consensus in the field of psychiatry that many of the psychiatric illnesses, and almost certainly depression, are the product of different biological mechanisms in different patients,? says Dr. Husseini Manji. ?Just as hypertension and elevated blood pressure can be caused exclusively by defects in the heart, blood vessels, or kidneys, many psychiatric illnesses may have diverse causes.? Dr. Manji notes that it is also not uncommon to have two patients who both meet DSM-IV criteria for depression but share no symptoms in common?one may sleep too much while the other sleeps too little, one may eat too much while the other eats too little, etc.
?It is increasingly clear that a one-size-fits-all philosophy of treatment is severely limited,? Dr. Manji says. ?Our group has become increasingly focused on identifying biomarkers?everything from genes and proteins to brain imaging?that are associated with particular subtypes of psychiatric illness. Accurate subtyping has a host of implications, diagnostically, but, more importantly, in terms of tailoring treatment to each individual patient.?
Biomarkers
Dr. Manji and his team have been searching for biomarkers of use in distinguishing bipolar from unipolar depression. ?When someone first presents with a depressive episode, especially a young person, there is no reliable way to determine whether this person is depressed or bipolar and waiting to have his or her first manic episode,? he says. This is an area of particular concern, as treatment for unipolar depression?antidepressants?can sometimes destabilize bipolar illness, triggering manic episodes or rapid cycling. ?We are conducting a collaborative study using proteomics, which allows us to look at different cellular proteins and how they are modified chemically, looking for a signature that might allow us to better predict whether a patient has unipolar or bipolar depression. The work is promising, and, although it is unlikely to be completely definitive, may ultimately lead to better informed treatment decisions.?
?We?re building this notion of biomarkers into all the NIMH mood and anxiety disorder studies,? Dr. Manji says, ?both for distinguishing patient subtypes and in terms of predicting treatment effectiveness and side effect profiles. The Experimental Therapeutics group at NIMH has been looking at ketamine for refractory depression, and it has shown a great deal of promise. Now we are trying to identify biomarkers that would help us predict which patients are likely to respond better the drug.? Toward that end, Manji and colleagues are conducting functional brain imaging studies, and have found notable dissimilarities in brain activation that appear to be related to responsiveness to ketamine.
A Better Ketamine
?The NIMH group is also working on coming up with a better ketamine, which, although it works very well, tends to produce rather unpleasant side effects. Dr. Carlos Zarate has been looking at NR2B antagonists. NR2B is a subtype of the NMDA receptor, and our hope is that by blocking just the subtype, instead of, as with ketamine, all NMDA receptors, we might be able to get the beneficial effects without some of the side effects.?
It will be some time before the data on NR2B blockers are available, and, in the meantime, Dr. Manji?s group is considering the possibility of ?jump-starting? treatment with ketamine and then maintaining patients on some less aversive drug. ?Riluzole is looking very promising,? he says. ?Riluzole increases AMPA receptor throughput, and we think that the AMPA and NMDA balance is what?s important. We may be able to get people better by blocking NMDA receptors with some substance such as ketamine and then keep people better by increasing AMPA receptor function. Part of the appeal of a ketamine/riluzole combination treatment, Dr. Manji explains, is that these substances are already FDA-approved for other indications. If strong evidence supports the effectiveness of such a treatment course, refractory patients could receive the benefits in the very near future.
Resilience
Manji and colleagues are also examining resilience to psychiatric illness. ?Clinicians and researchers tend to focus on what makes people ill, but it may at times be equally productive to study what protects people from getting ill or allows more rapid recovery,? he says. ?If we better understood these protective mechanisms, we might be able to tap into them for treatment.
?Currently, there is much exciting work in this area, and researchers are identifying molecules related to the glucocorticoid receptors (critical in stress responses). A group at Emory has just looked at one such molecule, FKBP5, and found that genetic variations in this molecule are strongly associated with the likelihood of developing PTSD. This is an important finding, and the NIMH and Max-Plank genetics groups have found evidence that FKBP5 plays a role both in both the likelihood of developing depression and the rate of onset of antidepressant response.?
Another molecule of interest to Dr. Manji and his colleagues is BAG1, which also talks to the glucocorticoid receptors, and appears to be turned on by mood stabilizers like lithium and valproate. ?Genetically engineered animals that have more BAG1 are amazingly resilient to stress. While a normal animal might take weeks to recover from induced depression, one of these modified animals recovers in just 2?3 days. The modified animals also appear to be very resistant to mania. It may be possible that there are different molecules that work best for symptomatic treatment?ketamine is one example?and other molecules may be involved in long-term relapse prevention and remaining well in the face of stressors?we think that FKBP5 and BAG1 might represent the latter.?
Time Course to Available Treatments
The use of ketamine and riluzole for initial treatment and maintenance could in the near future, if researchers can definitively show that such a strategy works, become a very real part of treatment for patients with refractory depression. Other treatments that might result from this research are still some years from possible availability. ?Science is slow,? Dr. Manji says, ?but it is essential that we validate our findings and that they are replicated independently. In terms of identifying molecules that increase resilience, technology has gotten much better, and if a pharmaceutical company is working with a specific target?say BAG1?it can quickly screen millions of compounds, find out what turns on BAG1, then do the toxicity test on a smaller subgroup. Clinical trials, however, still take a number of years. We?re at least 5?10 years from having any treatments that specifically augment resilience.?
