Revered researcher speaks about harnessing the brain’s own biological assets to treat bipolar and mood disorders

From The Quarterly, Summer 2011

Brain & Behavior Research Foundation Scientific Council Member, Dr. Husseini Manji, is one of the leading contemporary explorers of the brain ─ that remarkable 3-pound organ which he reminds us is “the very basis of human society and civilization” ─ so complex and capable, yet so delicate and vulnerable.



What he calls the “exquisite inner balances” that enable our brains to work efficiently are in various ways disturbed in brain and behavior disorders. But, he stresses, “our research is showing us something that fills us with hope. We now have reason to believe that we can use the brain’s own biological assets ─ its inherent plasticity ─ to help restore that balance in a number of disorders.”



“For complex brain illnesses,” he states, “it will not be a question of finding the magic bullet that will make life fine. It is important to ‘think beyond the pill.’ It's going to take what I call a holistic solution.” He explains, “Some of that may involve drug-device combinations; some of the future treatments will be neurotrophic ─ that is, they will help nerve cells restore their health or allow them to grow and communicate better.  But you can't think of that like ‘brain fertilizer’ that you can sprinkle over the brain and hope for the best.” Dr. Manji insists that it’s necessary to “activate specific circuits upon which the brain's self-nurturing and self-repairing capacities can act.”

“We now have reason to believe we can use the brain’s own biological assets ─ its inherent plasticity ─ to help restore that balance.”

A former NARSAD Independent Investigator Grantee and winner of the organization’s Outstanding Achievement Prize in Mood Disorders , Dr. Manji now  helps select the most promising ideas for NARSAD Grants in his role on the Scientific Council. “The funding of innovative ideas helps generate  data to demonstrate merit, which can then lead to much more significant NIH funding. There’s a large multiplier effect,” which starts by choosing “the most promising ideas” in psychiatric research.



Dr. Manji for much of his career conducted cutting-edge research at the National Institute of Mental Health as chief of NIMH’s Mood and Anxiety Disorders Program, where he was responsible for coordinating the work of 450 researchers in 18 groups. He has published hundreds of scientific articles on a remarkable diversity of subjects, mostly pertaining to causes and treatments for the mood disorders, specifically major depressive disorder (MDD) and bipolar disorder.  He is now the Global Therapeutic Area Head for Neuroscience at Johnson & Johnson.



What do we know today about bipolar disorder ─ which Dr. Manji has written about more than any other topic ─ that we did not know as recently as 10 years ago? “Something we began thinking about a decade ago now seems absolutely convincing,” he reports. “Bipolar disorder, we now believe, isn’t a disease of too much or too little serotonin or dopamine. It is not about the ‘chemical soup’ of neurotransmitters in the brain, but rather it is about synaptic and neural plasticity.”



Plasticity is the attribute that enables the billions of nerve cells in the brain to change and adapt on a millisecond-by-millisecond basis in response to the many inputs that are continually being processed. “What we’ve learned in the last 10 years is that whether we’re talking about memory or mood or movement, all advanced brain functions involve changes in the ability to convey information between synapses in different circuits.”

“Bipolar disorder, we now believe, isn’t a disease of too much or too little serotonin or dopamine. We now think of the problem as being in the machinery of signal transmission.”

And this ability, he says, is the crux of the problem in mood disorders. “Rather than too much of this neurochemical or too little of that one, we now think of the problem as being in the machinery of signal transmission.” Not only is this machinery engaged in information processing; says Dr. Manji, “the same machinery seems also to be involved in helping nerve cells survive and grow.”



While there is atrophy or shrinkage of neurons in certain brain areas in individuals with mood disorders, the neurons are not dead. Neurons normally have a profusion of tree-like branches, and they communicate with one another by forming a multitude of synapses between these branches. Synapses are tiny gaps across which the neuron that is sending information transmits signals to the neuron that is receiving it. “If that branch shrivels up, you lose synaptic contacts,” Dr. Manji observes. “And how can you expect to have communication when that happens?”



Dr. Manji and others helped demonstrate in the 1990s that the drug lithium, which is the oldest and most successful mood-stabilizer for bipolar disorder, has “neuroprotective” effects. The discovery that it boosts levels of proteins that help neurons maintain their function and other proteins that help neurons and their treelike branches grow seems to explain the fact that lithium is effective over long periods of time. It doesn’t, in other words, simply address a short-term problem but contributes to the long-term maintenance of the machinery within nerve cells that enables signals to pass properly from one cell to the next.



Not only did the discovery of lithium’s neuroprotective qualities help explain resilience; it also provided plausible answers to another mystery. “The plasticity that the drug revealed also helped us theorize why it might take several weeks for SSRI antidepressant drugs to take effect,” says Dr. Manji. People with bipolar disorder provided vivid proof that depression can rapidly cease. “If a bipolar patient is sleep-deprived, for example, they can go from depression to mania literally overnight. Other patients spontaneously flip from one polarity of mood to the other. This suggests that maybe our antidepressant drugs don’t work rapidly because they are going after the wrong target!”



The drugs, in other words, [antidepressants] address the balance of neurotransmitters, while the real anti-depressant action might come from modifying synaptic plasticity. This was an interesting hypothesis, but the idea generated greater excitement when ketamine, an agent long used as an anesthetic, was given to people with severe depression.  In many cases, the depression melted away in a few hours.



Understanding how this might be possible has shed further light on how better to control the symptoms of bipolar disorder and MDD. “One of the major mechanisms by which neurons bring about plasticity is that they move things called AMPA and NMDA receptors into and out of certain synapses,” says Dr. Manji. “This has the effect of making the connection between nerve cells stronger or weaker.”



“Research suggests that you want to increase the AMPA type or reduce the NMDA type of receptors in specific synapses to treat MDD. It happens that ketamine blocks NMDA receptors.” Once this was demonstrated, Dr. Manji and others conducted trials in which ketamine was given to severely depressed patients who had failed other forms of treatment, including antidepressants and electroconvulsive therapy (ECT). “It was remarkable—people who had failed six different drugs and also ECT and had been continuously depressed for 3 years started to respond within two hours. Within 24 hours, 70% had responded to the ketamine.”

“We don’t need to know everything about the brain to arrive at better treatments,” he says. “I believe our recently gained knowledge is moving us close to some important improvements.”

Ketamine is a controversial treatment not currently approved by the FDA, in part because of its potential side effects, which can include hallucinations and dissociation (feeling “unreal” for brief periods). But as a research tool, it has raised hopes. According to Dr. Manji, a single infusion of low-dose ketamine (much lower than used in anesthesia), given over 40 minutes, continues to show therapeutic antidepressant effects a week and sometimes two weeks later, long after the drug has left the body. In small studies, it has also proved surprisingly effective as an agent to reduce suicidal thinking. As with all experimental treatments, more work is needed to validate its use in non-research settings.



Dr. Manji and others now look for other ways of doing what ketamine does; agents that “will enable us to fine-tune the balance between the AMPA and NMDA receptors.” He notes that pioneering treatments by his colleagues on the Scientific Council, Dr. Helen Mayberg, and separately, Dr. Fritz Henn, have also suggested that there may be ways to “switch” severe depression “off” in very short order. Drs. Mayberg and Henn have used precisely targeted electrical stimulation delivered via surgically implanted probes to rapidly reverse refractory depression in a limited number of clinical trial patients. Dr. Manji notes that Area 25, which Dr. Mayberg and colleagues have pinpointed, happens to be a brain region rich in NMDA receptors.



The research goes forward. Piecing together new knowledge gained over the last decade, Dr. Manji offers this metaphoric account of what goes wrong in bipolar disorder. “We think that in bipolar disorder, one of the problems is that a very finely-tuned system, almost like a thermostat, is faulty. When a person with MDD is coming out of a depressive episode, the cellular thermostat should and does prevent mood from ‘overshooting’ in the other direction. But in bipolar disorder, the thermostat inside the nerve cell is sluggish, it is not well-tuned, and so when you come out of your depression, you overshoot over to the manic side of the mood continuum.”



Scientists don’t yet have enough factual data to prove this hypothesis, but Dr. Manji is adamant about the importance of it not being overwhelming. Rather than thinking of fixing all dysfunctions with new pills, Dr. Manji suggests we keep our focus on moving toward the notion of harnessing the brain’s own capacities for plasticity and restoration: “Not, ‘let’s block this receptor,’ but ‘could we use this capacity that nerve cells already have ─ could we activate it in a person with bipolar disorder in whom the program has been shut down or is somehow broken?” He concludes, “We don’t need to know everything about the brain to arrive at better treatments,” he says. “I believe our recently gained knowledge is moving us close to some important improvements.”