Manji Develops Novel Treatment for Major Depressive Disorder
Photo: Marleen Van Den Neste
Major depressive disorder is a debilitating, chronic disease that afflicts more than 300 million people worldwide, one-third of whom don’t improve after trying different antidepressants. At long last, many in this cohort of treatment-resistant patients may soon find some relief.
Dr. Husseini Manji, global head of neuroscience at Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, has pioneered a ketamine-based nasal spray that, in multiple clinical trials, has swiftly alleviated depressive symptoms in patients who have not responded to other medications. This treatment, the first neuroscience drug to receive “breakthrough therapy” designation from the Food and Drug Administration, is the first new treatment for major depressive disorder in decades.
Just days before esketamine nasal spray would receive FDA approval, Manji spoke at an NIMH Director’s Innovation Speaker Series lecture in the Neuroscience Center.
“Developing a new medication for anything is very, very difficult,” said Manji, a former NIMH fellow, lab chief and director of NIH’s Mood and Anxiety Disorders Program. “Drug failure rates are in the 90-plus percent range. For complex neuropsychiatric conditions, [the failure rate] is even worse.”
Yet there’s an enormous need for better treatments. Mental illnesses tend to strike people when they’re young and the conditions are so incapacitating because they’re generally lifelong, said Manji. Across North America and Europe, “We were struck to find mental illnesses were the most disabling conditions in the 15-44 age group,” he said.
In the United States, major depression has become the leading cause of disability and can be fatal. Suicide claims the lives of more than 45,000 Americans annually.
Despite the need for new therapies, many pharmaceutical companies have abandoned the mental health field altogether, investing instead in other areas that have higher success rates. As mental illnesses become more pervasive, Manji and his team remain determined to find solutions.
The drug ketamine, a powerful anesthetic, has been studied for some time for its antidepressant properties. The drug works by disinhibiting certain neurons while triggering others. In clinical trials in the early 1990s, many patients responded quickly to low-dose ketamine administered intravenously.
Manji wanted to find a way to help millions and started thinking about a more expedient delivery method than IV infusion. When he arrived at Janssen, he wondered, “Is there a way we can make this a safe, effective, FDA-approved convenient medication?”
Photo: Marleen Van Den Neste
As they began to explore an intranasal version, they searched for a potent form of ketamine that might work with the tiny volume emitted by a nasal spray. Esketamine showed rapid and robust antidepressant effects at a low dose. Encouraged to see patients improve quickly, Manji and his team also wanted to explore how to keep them better longer.
“What drug do we have that a single dose lasts forever?” he asked. Surprisingly, though, they found a single dose helped keep people well for several days.
The strategy was to give patients esketamine twice a week for the first month, then administer the treatments every 1-2 weeks to help maintain the effects. After conducting a series of clinical trials, including 6 phase-3 studies, the positive data generated from 1,700 patients led to the treatment’s FDA approval.
“Our data showed,” said Manji, “that with intranasal administration, we can get treatment-resistant depressed patients better faster and, with intermittent dosing, keep them well.”
Ketamine has serious side effects—and some abuse potential—so even the nasal spray version is not a take-home drug. Esketamine must be administered in a clinic under a health care professional’s supervision. The two major side effects—hallucinations and increased blood pressure—usually peak within 30-40 minutes and disappear shortly after, explained Manji. The patient remains at the clinic for a couple of hours after treatment for monitoring, then gets discharged but is not permitted to drive for the rest of the day due to the drug’s drowsy effects.
“If this is going to be a life-saving, life-altering treatment,” Manji said, “let’s make sure we do it correctly.”
Whereas other treatments can take weeks to work, esketamine is effective within hours and can be useful in acute crisis. The rapid response is particularly important for helping those at imminent risk of suicide. There are ongoing phase-3 studies of this second proposed indication for esketamine. Also encouraging, long-term studies consistently showed that patients had a significantly reduced risk of relapse with intermittent esketamine treatment.
Developing treatments for mental illness involves a complex web of advanced genetics, protein engineering, biomarker identification, neuroimaging and data mining. These are diseases of synapses and circuits, said Manji, so it’s possible to make advances by finding and manipulating the right pathways, even if every gene involved can’t yet be identified.
Within that circuitry, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, which are found all over the brain and regulate excitability, remain an ongoing area of research.
“We think AMPA receptors, being so ubiquitously expressed, are going to lend themselves to novel therapeutic development,” said Manji. “We now have novel ways to target them in specific circuits, rather than throughout the brain.”
We need a massive effort, he said, in which scientists, advocates, companies and the government come together to address mental illness. “I think if we can work together as a society, we can make a big difference for our patients.”