The National Centre for Biological Sciences (NCBS) has established the causes of sedation in the antipsychotic drug clozapine. The scientists have delved into how this side effect can be modulated without more medication.
The research results indicate that the serotonin receptor 5-HT2A is partially responsible for the sedative effects of clozapine, and can be reduced by stimulating an organism simply by introducing something novel into its environment.
The findings were driven by the experience of a family whose teenage son, was diagnosed of bipolar disorder. Once therapy started, it became apparent that standard drugs which were effective in most cases were not working in this case. So the doctors turned to a less preferred drug, clozapine. Though effective in controlling the manic-depressive cycles, one of its side effects was extreme sleepiness and fatigue. Currently mechanisms of side effects occur are poorly understood and options to treat are limited.
Prof. Mitradas Panicker’s group at NCBS has proven that the molecule 5-HT2A in the brain is partially responsible for the sedative effects of clozapine. Furthermore, the team led by Radhika Joshi, a doctoral student in Panicker’s laboratory has also discovered that the drug-induced sedation can be affected by environmental factors.
The drug clozapine helps manage symptoms of depression and anxiety by binding to receptor molecules in the brain that respond to neurotransmitters used by nerve cells to communicate with each other. Clozapine mainly targets receptors for the neurotransmitters serotonin and dopamine. Amongst these, 5-HT2A is a serotonin receptor that was identified to be partially responsible for the sedative effects of clozapine.
Radhika in collaboration with Dr. Rupasri Ain and co-workers Rolen Quadros, and Michael Drumm were formerly affiliated NCBS generated and characterized a genetically modified mice to test if the 5-HT2A receptor involved in the sedative side effects of clozapine. When given clozapine, mutant mice lacking the 5-HT2A receptor were found to be more active and less sensitive to sedation than normal mice. But while conducting these studies, the researchers also noticed that the environment played a role in modulating these effects.
“While most drugs focus on improving the therapeutic effects, side effects are often ignored. Sometimes side effects can be severe enough to result in non-compliance and require secondary medication. Our observations indicated that the environment can modulate the side effect of an antipsychotic. This has not been reported before, and so we investigated,” she said.
When either normal mice or mice without the 5-HT2A receptor were given clozapine in a home environment in cages where they are normally housed, these were less active and sensitive to sedation. However, when the drug was given in a cage where a toy was placed, the mice were less somnolent, particularly the 5-HT2A knockout mice. Having something different in their surroundings served to decrease the drowsy effects of clozapine and this effect was more pronounced in the mice lacking the 5-HT2A receptor. Further investigations also revealed that clozapine sedation could be reduced if the mice were given caffeine before the drug.
“We believe that a novel environment is often stimulating to organisms to overcome the sedation by an antipsychotic. Our results are one of the first few steps towards designing of drugs that are safer and with lesser side effects, though a lot more work is needed before we can expect better drugs,” said Joshi.
The work is published as a paper titled ‘Sedative effect of clozapine is a function of 5-HT2A and environmental novelty’ in the journal European Neuropsychopharmacology.