Scientists may have found a target in the brain that could selectively interact with ketamine to provide only the beneficial aspects of the drug to treat depression, according to research published in Molecular Psychiatry.
While ketamine is able to relieve depression within two hours and its beneficial effect may last as long as a week, the party drug “Special K” is also addictive and may cause hallucinations and delusions in recreational users. Some have experienced disorientation referred to as the “K-hole.”
Because of the potential for misuse and addiction, “you have a novel, highly effective treatment for depression, but you can’t give it to people to take at home or on a routine basis,” said Daniel Lodge, PhD, of The University of Texas Health Science Center at San Antonio in a statement.
A fast-acting, long-lasting treatment for depression is highly desirable because current antidepressants usually take two weeks to show any effect, and not all patients benefit. A fast-acting drug could reduce the risk of suicide. The difficulty with ketamine is that it acts on receptors throughout the brain, making it difficult to control its effects.
To attempt to identify a brain circuit that delivers the beneficial aspects of ketamine, Dr Lodge and colleagues from the Health Science Center’s Department of Pharmacology tested the activation and inactivation of a brain circuit between the hippocampus and prefrontal cortex in rats.
The researchers found that optogenetic and pharmacogenetic specific activation of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine. Notably, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not achieve this effect. They also found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to the sustained antidepressant response in ketamine.
They also found that inactivation of the vHipp with lidocaine prevented the sustained (but not acute) antidepressant-like effect of ketamine, and that optogenetic inactivation of the vHipp/mPFC pathway completely reversed the antidepressant effect of ketamine.
“These data demonstrate that activity in the vHipp–mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine,” the authors wrote.
“The idea is, if one part of the brain contributes to the beneficial effects of ketamine, and another part contributes to its abuse and effects such as hallucinations, now we can come up with medications to target the good part and not the bad,” said lead author of the study Flavia R. Carreno, PhD, in a statement.
Identifying this mechanism gives scientists a target, Dr Lodge explained. “The next step is finding a drug that interacts selectively with it. And we have some ideas how to do that.”
Carreno FR, et al. Activation of a ventral hippocampus–medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psychiatry. 2015; doi:10.1038/mp.2015.176.