Monoaminergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) take weeks to months to take effect and do not work for more than one in three patients. For patients diagnosed with treatment-resistant depression, or in immediate crisis, access to safe, effective, rapid-acting antidepressants can improve lives and decrease suicide. WHO report estimated around 800,000 people die from suicide annually. Though it cannot be said how many reach this choice for depression or unresponsive depression, this number is unacceptable for clinicians as well as for our society. Besides, for the 280 million people worldwide suffering from depression relief cannot wait. One current possibility being investigated is ketamine, which can improve depression, even in treatment-resistant patients. Ketamine is an anesthetic used for over 50 years, but it has serious side-effects, including dependence, hallucinations and delusions.
This is due to its interaction with a surface receptor called NMDAR, one of the receptor subtypes used by glutamate in nervous system. Therefore, while preclinical studies have shown that a single dose of ketamine can have beneficial long-term effects on mental health and is only used to treat depression as a last resort. There are good reasons to be cautious; in addition to the side-effects, the way ketamine alters brain chemistry is not fully understood. If the biological mechanisms in the brain that ketamine influences are discovered, new drugs could be developed to target the beneficial antidepressant effect specifically. The study demonstrated ketamine treatment led to an increase in insulin-like growth factor 1 (IGF-1). This is a peptide growth factor essential for brain developent since the embryonal stages; in the adult, it partially mediates insulin bodily effects and is also a known antidepressant brain molecule.
However, scientists did not know if this was linked to previously ketamine-induced antidepressant molecules like brain-derived neutrophic factor (BDNF). They confirmed IGF-1 produced an antidepressant effect then demonstrated that they could switch it off by blocking it with a neutralizing antibody against IGF-1. After having demonstrated they could switch off IGF-1, the researchers followed up with a separate experiment. Previous studies have shown that ketamine increases BDNF, another growth factor produced in the brain that promotes nerve growth, solidify neural contacts, enhances memory and may also influence neural stem cell committment toward mature neurons. This is why scientists wanted to check if IGF-1 and BDNF were working together or separately. They tested whether IGF-1 and BDNF neutralizing antibodies blocked the other proteins antidepressant effect, they did not, leading the researchers to conclude that IGF-1 and BDNF work through their own independent pathways.
A strenghtening event is that IGF-1 and ketamine effects are partially abolished by rapamycin, a known inhibitor of the activation of the cellular mTORC1 complex. After all, this is a well known concept in the biology of growth factors. All hormones and peptide growth factors mediate their effects through plasma membrane receptors. Each growth factors may have even two or more subtype of receptors, which converge downstream with the activation of several known signaling pathways, like MAP-kinases, calcium-dependent protein kinases, phospho-inositide or sphingolipide signaling and stress kinases like JNK and p38. However, not all receptors activate these transduction pathways, neither for timing, nor for types or sequence of events. This may be the case for IGF-1 and BDNF: mTORC1 complex indeed, is not just used to control protein synthesis; it is also necessary for lipid synthesis and to control cellular autophagy, the process of cellular partial erasing to supply molecular building blocks.
Indeed, this last process could be important for stabilize neural contacts and dendritic spines for important brain events of learning and memory. The hypothesis that depression could be viewed as a malfunctioning learning and scrambling of the correct neural patterns is not new. Maybe ketamine will unravel the essence of this hypothesis and new cutaways of the biology of depression. This could be furtherly strenghtened by the latest discovery of how ketamine may affect mood in animals by activating the production of mature neurons form precursors (stem-like enhancement).
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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