Q&A with Eero Castrén. Questions by Schizophrenia Research Forum.
Q: What prompted you to do this study?
A: The clinical effects of antidepressants appear with a delay, and increased neuronal plasticity and alterations in network structure have been suggested to underlie this delay (Castrén, 2005). However, a direct demonstration that antidepressants would functionally alter neuronal networks has been lacking.
Q: How did you tackle this problem?
A: We used the visual cortex, a classical model structure for developmental plasticity, to examine the effects of fluoxetine on cortical network rearrangements in rats. Our results demonstrate that fluoxetine reactivates the critical period plasticity in the adult visual cortex and facilitates functional recovery of miswired neuronal networks.
Q: Can you give us some background on this model?
A: Plasticity in the visual cortex is high during a critical period of postnatal development, when inputs from the two eyes compete for the innervation of the visual cortex and the functional networks are laid down (Hensch, 2005). If one eye is deprived of vision during the critical period, the inputs of the active open eye occupy the visual cortex and those from the closed eye are withdrawn, leaving the eye poor in vision, a condition known as amblyopia. Opening the eye and patching of the better eye during the critical period allows the weaker eye recovery of its connectivity and visual acuity. In adulthood, after the end of the critical period, plasticity is more restricted and closure of one eye no longer leads to the loss of innervation; conversely, an amblyopic eye not treated with patching of the better eye during the critical period remains poor in vision.
Q: So what was the main finding?
A: We found that peroral fluoxetine treatment for three weeks reopens the critical period plasticity in the adult visual cortex and closure of one eye leads to the shift in the cortical innervation to favor that of the open eye. Furthermore, if an amblyopic eye covered during the critical period is reopened in adulthood, vision improved in the weaker eye to finally equal that of the healthy eye when fluoxetine treatment was combined with covering the better eye.
Q: What is the basis for this renewed plasticity?
A: The enhanced plasticity was associated with increased BDNF expression in the visual cortex, and infusion of BDNF into visual cortex mimicked the effects of fluoxetine. Intracortical inhibition, which is known to regulate critical period plasticity, was reduced and increasing inhibition by intracortical infusion of diazepam blocked the effects of fluoxetine on plasticity. Thus, BDNF signaling and cortical GABAergic networks play a critical role in the mechanisms through which antidepressants facilitate cortical plasticity.
Q: What does this work tell us about the action of antidepressants?
A: These experiments convincingly demonstrate that antidepressants induce plasticity in the visual cortex and facilitate functional rearrangements leading to a recovery of a faulty network miswired due to imbalanced environmental stimuli during the postnatal development.
Q: Does this have any relevance to human conditions?
A: Antidepressants may have similar effects also in the human visual cortex. Normann et al. showed recently that while neuronal plasticity in the visual cortex of depressed patients was reduced, treatment of healthy volunteers with another SSRI, sertraline, enhanced plasticity over that seen in untreated controls (Normann et al., 2007).
It is important to note, however, that fluoxetine did not repair the network on its own; it merely enhanced plasticity to facilitate the ability of environmental cues to guide the rearrangement of the connectivity. Maffei’s lab has previously shown that raising rats in an enriched environment has effects equivalent to those of fluoxetine: an enriched environment enhances plasticity in adult visual cortex and allowed a recovery of an amblyopic eye in adults (Sale et al., 2007).
Q: What about other areas of the cortex, such as those involved in mood regulation. Is it possible that fluoxetine and other antidepressants might have analogous effects there?
A: That remains to be seen. If this was the case, antidepressants, through BDNF signaling, might facilitate the recovery of dysfunctional cortical networks miswired by disruptive early life experiences or perhaps during extended stress. However, in this case, too, beneficial environmental cues, such as rehabilitation or talk therapy, would be required to guide rearranging networks for functional recovery, which is consistent with the observations that antidepressants and psychotherapy together work better than either one alone.
Q: Is there any reason for clinicians to be concerned about the use of antidepressants in schizophrenia, which is pretty common? A prominent body of work in schizophrenia revolves around the idea of GABA hypofunction in prefrontal cortex. If fluoxetine further depresses GABA function, then might not these drugs counteract any psychotherapeutic interventions?
A: For the schizophrenia, it is true that the GABAergic system is implicated; however, this system is multifaceted and complicated. I would be very cautious about rushing into any direct conclusions based on our study. On the contrary, there are decades of clinical experience about using antidepressants in schizophrenics—if something alarming would happen, that would be known by now.
Incidentally, there is an interesting review from the McGuire lab in Lancet (Fusar-Poli et al., 2007) reviewing data that suggest that antidepressant treatment might protect against the first episode of schizophrenia in at-risk people. Whether this has anything to do with the plasticity found in our study remains to be seen. However, it seems to me that it is not useful, and might even be harmful, to strictly label drugs into slots such as "antidepressants" and "antipsychotics," etc. It should be evident already (they are useful for a variety of neuropsychiatric disorders), and further emphasized by our study, that antidepressants do something very different than simply counteracting depression. A fresh look is what is needed.