Unraveling schizophrenia drug mechanism
Rakesh Karmacharya spends one day each week treating severely ill psychotic patients as the medical director of the Schizophrenia and Bipolar Disorder Research Clinic at McLean Hospital, a Harvard psychiatric hospital in Belmont, MA. The rest of his professional week is spent at the Broad Institute where he works as a physician-scientist in the Chemical Biology Program. For several years, Rakesh has been bringing these two worlds together in the form of a project to identify how clozapine, the main drug used for treatment of schizophrenia, exerts its therapeutic effects.
Similar to the story I told a few weeks ago about lithium, the best drug available for treating bipolar disorder, researchers do not know how clozapine works, though it is the most effective drug for schizophrenia and the only drug shown to help people who do not respond to other treatment options. And even then, it is a tricky drug to give to this patient group since it requires weekly blood monitoring. Clozapine can lead to a serious blood disorder indicated by a drop in certain blood cell types.
But in a paper published in an early online edition of Brain Research, Rakesh and his colleagues reported that clozapine’s biological effects may be related to interactions with trace amines, compounds found in mammalian brains at much lower concentrations than other similar compounds, including the neurotransmitters serotonin and dopamine. Working with the microscopic roundworm C. elegans, an organism used routinely in basic research to study biological pathways, the team wanted to see if they could identify new pathways that clozapine may be interacting with. “I thought it would make sense to start with C. elegans since we knew that it has a functioning nervous system with many of the human neurotransmitters and that many signaling pathways are conserved between C. elegans and mammals,” Rakesh explains. (Read more about why the Broad loves C. elegans here.)
Teaming up with C. elegans geneticist Edgar Buttner and psychopharmacologist Bruce Cohen at McLean Hospital, Rakesh and his colleagues sought to identify if clozapine produced any unique effects in C. elegans using a variety of well-characterized behavioral tests. “We found that when we exposed C. elegans to clozapine, they laid eggs like crazy,” Rakesh explains relating to one of these behavior tests. Egg laying is an extensively studied C. elegans behavior that is regulated by intricate neural mechanisms. But when they tested the older typical antipsychotic haloperidol or a newer atypical one, olanzapine, this effect on egg laying was not observed. Rakesh adds, “This finding meant we had identified a behavioral effect in C. elegans that was specific to clozapine.”
Eventually they found that a lesser-known trace amine called tyramine was involved. For clozapine to have its effect of increased egg laying in C. elegans, the worm needed to have a functioning tyramine system.
That’s interesting to see this effect in worms, but Rakesh and colleagues wanted to see if the same pathway modulated clozapine’s effects in a higher-order model using mice. They collaborated with Spencer Lynn and Gregory Miller at the New England Primate Research Center to test clozapine’s effects on behavioral assays in rodents. Their research confirmed that the trace amine pathway is involved in clozapine’s effect.
“This is the first time anyone has shown that antipsychotics, especially clozapine, and trace amines are even related, that they are interacting at the cellular level,” Rakesh adds. Admittedly, there is a big leap from work on C. elegans and mice to humans but it does represent a significant first step in identifying a novel pathway that is modulated by clozapine.
Going forward, Rakesh and colleagues are working on creating human inducible pluripotent stem (iPS) cells to create cellular models for testing these findings. “iPS cells provide us with the exciting possibility of studying psychiatric disease biology in human neuronal cultures in vitro, starting from patients’ skin cells,” Rakesh explains. Generally, lack of access to live neuronal tissue with the patients’ genetic makeup has been a serious impediment in the study of psychiatric neurobiology. Patient-derived human iPS cells open the doors to carry out studies to determine the biological pathways involved in psychiatric illnesses and medication effects. In April, Rakesh was awarded a coveted Harvard Stem Cell Institute seed grant to carry out studies aimed at the identification of cellular signatures in schizophrenia using patient-derived iPS cells.
If further studies validate the role of the trace amine pathway, the idea will be to search for small molecules that retain or improve on the therapeutic effects of clozapine while minimizing its harmful side effects. Ideally, new therapeutic leads would not only treat the positive symptoms of schizophrenia (hallucinations, delusions) but also lessen the negative symptoms (lack of affect, social withdrawal) and cognitive impairments that have a profound effect on patients’ lives in the long run. “Society at large is much more aware of and concerned with the positive symptoms but as a practicing doctor I can tell you that these other domains severely hamper the lives of people with schizophrenia,” Rakesh adds. “There is a lot of room for improvement to help severely ill patients for whom there are few choices that are helpful.”
Karmacharya R, et al. Behavioral effects of clozapine: Involvement of trace amine pathways in C. elegans and M. musculus. Brain Res. 2011 Jun 1;1393:91-9. Epub 2011 Apr 9.