Research in the Lab of Neurotherapeutics
Dr. Tomi Rantamäki has been interested in antidepressant treatments from the very beginning of his career. Practically all antidepressants have been found by chance, yet the exact neurobiological basis underlying their actions remains obscure. Still, millions of people are using these medications every year. Everybody knows – many through own experience – something about them. They act super slowly but can produce annoying side effects early on. Although there is plenty to choose from, not one of them is above others. Quite often the first try at medication doesn´t fit to you. Very often even the second choice is not good enough and you end up with other options. One of the most powerful options is the electroconvulsive therapy (ECT), developed already more than 80 years ago. ECT is largely based on, again serendipitous, observations demonstrating the therapeutic effects of chemically evoked seizures in psychiatric (schizophrenia) patients. Thus in essence ECT is seizure therapy, but a controlled one. ECT is also delivered under light anesthesia. Why and how do seizures bring about antidepressant effects is less understood than the mechanism of action of world famous antidepressant Prozac®.
In early 1990´s repeated administration of antidepressants (including ECT) was shown to upregulate the expression of neurotrophin BDNF (brain-derived neurotrophic factor) in brain areas implicated in depression – stress did the opposite. These hallmark studies moved antidepressant investigations from acute chemical changes into gradually evolving changes on neuronal plasticity. Tomi´s main contribution to these studies came from his observations demonstrating that all antidepressant drugs, regardless of their primary pharmacological action, activate the BDNF receptor in the adult rodent brain. However, the effects of antidepressants on TrkB are apparent very quickly – well before the upregulation of BDNF is noticeable. Moreover, ECT did not seem to activate TrkB, rather the opposite. Even after extensive studies, the precise mechanism how antidepressant drugs activate TrkB remained unclear. Altogether, our efforts have been only able to exclude some of the most plausible possibilities, including BDNF.
Meanwhile important studies were conducted to investigate the ultimate functional significance of antidepressant-induced neuronal plasticity. It was demonstrated that antidepressants produced a plastic state in the adult brain – a kind of sensitive period – which allows the rewiring of neuronal connections guided by environmental cues. Now it made much more sense: 1) it takes time for the brain to achieve this plastic state and even more time is need for the rewiring of the connections; 2) antidepressant don´t work if the environment is not supporting the rewiring (e.g. lack of rehabilitation); 3) antidepressants have therapeutic effects against several nervous system pathologies since they facilitate plasticity in several cortical structures. Notably, the early findings that formed the basis of the network hypothesis of antidepressant actions came from studies conducted using the visual cortex as a model system! But no matter how much one likes this idea, the network hypothesis of antidepressant drug action, it has not been fully proofed right and conceptualized in preclinical – not to mention clinical – settings.
Then ketamine came into the picture: a dissociative anesthetic and a drug of abuse. A subanesthetic dose of ketamine was shown to ameliorate depressive symptoms almost immediately. So can depression be treated quickly in the end? Probably not, since the effects of ketamine cease within weeks or even days after the treatment. Even with this limitation, ketamine raised new hope to generate drugs that could alleviate depressive symptoms early on during treatment. In particular, if the mechanism of these intriguing effects of ketamine could be revealed, novel drugs targeting these same systems could be developed. Interestingly, emerging experimental data suggests that the neurobiological events implicated in Prozac´s actions, namely up-regulation of BDNF-TrkB signaling and plasticity, are underlying also the rapid therapeutic effects of ketamine. Except that the effects of ketamine are topped up with additional alterations, such as facilitation of mTor signaling and dampening of GSK3β signaling. Ketamine is also shown to rapidly regulate synaptogenesis. What are these new synaptic connections doing?