Treatment-resistant depression can be very debilitating for patients who have tried a number of different antidepressants with no relief. Mark Niciu, MD, PhD, assistant professor of psychiatry and one of the newest members of the Iowa Neuroscience Institute, is studying the antidepressant mechanisms of an experimental drug that has shown to bring patients relief within hours.
Specializing in psychiatry wasn’t even on Niciu’s radar until he started taking neuroscience and psychopharmacology courses during his MD, PhD training at the University of Connecticut.
“I also love the multidisciplinary aspects of psychiatry and the opportunity to spend more time with patients than typically permitted in other areas of medicine,” he said.
During his medical training, Niciu developed an interest in the intersection between mood and alcohol use disorders, which have high comorbidity and mechanistic similarities, including effects on the excitatory neurotransmitter glutamate. And later during his residency training at Yale University, he began looking into ketamine as a therapy for treatment-resistant depressive disorders.
Niciu then went on to work as a Clinical Fellow at the National Institute of Mental Health with Carlos Zarate Jr., MD, Chief of the Experimental Therapeutics and Pathophysiology Branch. Zarate has made great strides in understanding the antidepressant effects of ketamine, although the long-term effects of the drug are still unknown.
“If someone with depression received an IV infusion of ketamine, they might feel better within hours as opposed to standard antidepressant medications, which often take weeks-to-months of daily use for efficacy,” Niciu said.
The first study of ketamine’s rapid-acting antidepressant effects was completed at Yale in 2000. In 2006, Zarate replicated the findings and since then, “the field has just exploded,” Niciu said.
Although still an off-label or experimental therapy, ketamine clinics have popped up all over the country for the treatment of depression and other psychiatric conditions. Another major focus has been the development of alternatives to IV administration. One potential option is an intranasal spray. The University of Iowa, led by William Coryell, MD, professor of psychiatry, recently participated in a multisite industry-sponsored clinical trial examining the efficacy of intranasal esketamine in treatment-resistant depression.
In his clinical and translational research, Niciu has been particularly intrigued by the finding that patients with a family history of alcohol use disorder have an enhanced and longer antidepressant response to ketamine, compared to those without familial risk for alcoholism.
“If you have a first degree relative with alcoholism and you received ketamine, your antidepressant efficacy on average may be improved,” he said.
Niciu has been working to understand the mechanisms and develop biomarkers of ketamine’s fast-acting antidepressant response, especially in this particular patient population where the effect seems to be stronger and longer-lasting. In animal models of depression and clinical populations, ketamine has rapid effects on brain circuitry and synaptic plasticity.
“In depressive illness there’s an overall weakening of synaptic contacts,” Niciu said, adding that ketamine has been shown to increase the strength of connections in key areas of the brain that have been shown to play a role in mood disorders, such as the prefrontal cortex and hippocampus.
How ketamine does this so quickly is still a contested issue. One idea is that ketamine leads to a glutamate surge in the brain which ultimately strengthens the synaptic connections between neurons.
Niciu hypothesizes that patients who have a family history of alcohol abuse have a more pronounced glutamate release leading to enhanced synaptic plasticity. In addition to this clinical research, he will continue to investigate ketamine’s cellular and molecular effects in stem cell-derived “brain in a dish” models, which he started during his fellowship at the NIMH.