Solving Treatment-Resistant Depression

Based on a webinar offered by Dr. Fritz Henn on September 8, 2015, exclusively for the Foundation



Each year about 15 million people in America experience the debilitating effects of depression. About one patient in seven doesn’t respond to treatment. Fritz Henn, M.D. Ph.D., is working hard to solve this problem. He’s a professor of psychiatry at Mount Sinai School of Medicine and a member of the Foundation’s Scientific Council.



Most drug treatments for depression have centered on a single chemical messenger in the brain, serotonin. Drugs targeting this neurotransmitter have been magically effective for some, but others show marked resistance. Henn has focused his research on identifying additional pathways in the brain – beyond serotonin and related chemical messengers – that control depression.



He and his colleagues took advantage of an animal model for depression, known as “learned helplessness.” Many animals, like people, are resilient when faced with adversity. But for those suffering from depression, problems can seem intractable, to the point where an individual feels hopeless.



How does this human experience look in an animal? Most rats will learn to stop harmless, if annoying, foot shocks by pressing a lever. But some will never learn -- even if they inadvertently press the lever. These animals are displaying learned helplessness. It’s behavior analogous to that of depressed people who don't take action to alter or avoid a negative stimulus. Intriguingly, animals displaying this “helpless” behavior respond to antidepressant treatments, Henn says, and are thus good models of depression in people.



Henn wanted to know what distinguished helpless and resilient animals. He used PET scans to compare them and found that a tiny region called the lateral habenula becomes very active in only the helpless animals.



The lateral habenula had been largely unstudied. It’s so small that researchers often haven’t trusted data associated with it. The few existing studies have implicated it in anticipating negative events, like punishment. Henn hypothesized that “turning off” activity in the lateral habenula might relieve depression.



In animals, that’s precisely what he found. He used a method called deep brain stimulation (DBS) to inhibit the lateral habenula in rats and the animals became resilient to stress.



The method has had mixed results in human trials. Henn and his colleagues successfully used DBS to treat a woman who had struggled with severe depression for more than 25 years. After six months, she remained completely well with no manic symptoms. Still, clinical trials at Mount Sinai have seen more measured success, with the treatment failing entirely for another patient.



Despite the potential of DBS, it is a highly invasive treatment. Henn’s primary goal is to identify drug-based therapies that can mimic DBS and inhibit the lateral habenula. To do this, he drilled down into the lateral habenula to identify the specific type of cell that was hyperactive. The culprit, he discovered, was a type of neuron that scientists call glutamatergic; these neurons are specifically responsive to the chemical neurotransmitter glutamate – the most common chemical signal in the brain, responsible for carrying nerve impulses from one cell to another.



Henn found that glutamate-sensitive neurons in the tiny lateral habenula become overly excited due to an overabundance of glutamate. He reasoned that lowering the amount of glutamate in the region might be an effective treatment for depression.



Glutamate in the brain is highly regulated – active neurons release it and molecular machines known as transporters are responsible for clearing it once a signal has been transmitted. But there is a known class of drugs that can increase the amount of glutamate transporters; one, called diazoxide, is FDA-approved and marketed for pediatric hypoglycemia.



As a treatment for depression, the drug is promising but will need more work, Henn says. In animal models, it’s able to reverse “learned helplessness” so that stressed rats become resilient. But in human clinical trials, the drug appears to be less effective. It’s possible that higher doses will be needed and yet Henn and his colleagues have concerns about side effects. They are working to identify other more effective chemicals in the same drug class to target the lateral habenula and glutamatergic neurons in particular. This new pathway represents a promising avenue for the development of new treatments for depression.