Researchers at the MRC Toxicology Unit have found that the antipsychotic drug aripiprazole impairs fertility in male fruit flies. Aripiprazole damages the mitochondria in adult male testes, resulting in increased levels of reactive oxygen species (ROS) and loss of the precursor cells that give rise to sperm.
Aripiprazole is a third-generation antipsychotic that is used to treat mental health conditions like schizophrenia and bipolar disorder. It is also prescribed to young children for irritability associated with autism and Tourette syndrome. It works by binding to dopamine receptors in the brain and has fewer side effects than previous generations of antipsychotics.
Aripiprazole reaches throughout the body, even though it is designed to act on the brain. In fact, one study found that there was a higher level of aripiprazole in the testes compared to the brain of normal male mice.
Scientists at the MRC Toxicology Unit previously identified that aripiprazole is toxic to mitochondria, the centre of energy production, in cells in the brain, muscle, and intestine of fruit flies. This could help explain some of the common side effects from this drug including headaches, insomnia, indigestion, and nausea.
Different cells in our bodies have different requirements for their mitochondria, meaning that they will respond to mito-toxic drugs in different ways. Mitochondria are very important at all stages of sperm production and allow the sperm to swim and fertilise the egg.
To understand how aripiprazole affects mitochondria in the testes, the scientists provided food supplemented with the drug to a species of fruit fly called Drosophila melanogaster and examined the different stages of sperm production. Drosophila are a useful model to test the effect of drugs as they have many molecular and cellular pathways common to humans.
Dr Amrita Mukherjee, lead author on this study said “We found that aripiprazole interfered with sperm production and resulted in less offspring in Drosophila. Aripiprazole impaired a key component of mitochondrial respiration resulting in increased production of molecules called reactive oxygen species (ROS).”
ROS triggered pathways in the cell are important in sperm production, but excess ROS can also stop cells from functioning properly. High levels of ROS are linked to 30-80% of cases of infertility in men.
High levels of mitochondrial ROS caused by aripiprazole triggered the JNK (c-Jun N-terminal kinase) stress response pathway resulting in the death of the precursor cells that give rise to sperm. The researchers also found that these effects could be reversed by giving the flies an antioxidant supplemented diet along with aripiprazole.
Whilst safety data suggests that aripiprazole doesn’t cause any reproductive or developmental defects, patients treated with aripiprazole have shown reduced sperm counts and sperm motility.
Amrita said “Aripiprazole is a valuable tool in treating psychiatric conditions, as it has fewer side effects than other antipsychotic medication. However, methods to reduce drug related side-effects should be investigated as stopping treatment may not be an option for many patients. More research is needed to understand when these side effects occur and if combinations with other treatments such as antioxidants can be beneficial.”
The paper ‘Oral intake of aripiprazole compromises male fertility in Drosophila’ was published on the 11th November in the Journal Biology Direct. Read the full publication here.