Why Antidepressants Cause Cognitive Dysfunction

Neuroscientists have long been focused on the mystery of how learning (the formation of memories) is encoded in the brain.  Following the maxim of Donald Hebb, that neurons that fire together wire together, neuroscientists have focused on the relationship between two types of receptors for the neurotransmitter glutamate: AMPA receptors and NMDA receptors.  The story on long term potentiation (the term for memory formation) has pretty much been worked out.  It involves coordinated activity of the AMPA and NMDA receptors.

With the knowledge of the particular mechanism for learning, Joe Tsien began making modifications of the relevant proteins involved in the process and ended up with the “Doggie Howser” mouse: a super-smart mouse that out performed all of the other mice on memory tasks.  What Tsien did was to over-express a particular version of a subunit of the NMDA receptor: the NR2B subunit.  (Tsien manipulated the neuron’s DNA so that more of the NR2B protein was produced.)

Elsewhere other researchers have paid attention to the impact of antidepressants (Selective Serotonin Reuptake Inhibitors) on which versions of the NMDA receptor subunits are used to create the NMDA receptor.  Turns out long term use of antidepressants decreases the supply of these NR2B subunits so that NMDA receptors rely on NR2A instead of NR2B version of the protein at least in the amygdala.  With aging, the brain does increase its use of NR2A subunits, but antidepressants (Selective Serotonin Reuptake Inhibitors) accelerate this effect.

The impact of long term antidepressants on decreasing NR2B subunits does have functional consequences.  Joe LeDoux is the neuroscientist who has worked out the particulars in the amygdala on how a rat learns to associate a light with shock when the two stimuli are repeatedly paired.  (This is called fear conditioning.)  Initially, LeDoux and colleagues showed that antidepressants impair the acquisition of fear memories.  (Perhaps a positive outcome.)  It is also known that unlearning the association between the light and the shock, called extinction, also involves new learning.  According to a study by LeDoux and colleagues, long term exposure to antidepressants makes it harder to unlearn fear memories as well.  Moreover, in their study, the deficit capacity to unlearn the association was correlated with deficit amounts of NR2B subunits.  LeDoux and colleagues concluded that the addition of antidepressants to exposure therapy, for extinguishing fear memories, is counter-productive.

LeDoux et al. did not examine whether similar reliance on NR2A rather than NR2B subunits is happening elsewhere in the brain when an organism is exposed to antidepressants.  However, others have examined the impact of long term exposure to antidepressants and found NR2B deficits in other brain areas besides the amygdala.  Both studies by Ampuero et al. and Boyer et al. suggest that a decrease in NR2B proteins is found in the cortex as well after long term exposure to antidepressants.  However, there are not many studies.  Future work promises to identify those areas of the brain and those types of learning where the composition of the NMDA receptor units matter.

Naturally, with aging, more NR2A subunits replace the NR2B subunits.  Perhaps accelerated aging in cognitive capacity should be added to the list of antidepressant side effects.  This area of research has yielded some useful findings as well.  Dietary consumption of Magnesium threonate can increase NR2B subunits.  For brain health and optimal functioning, we’re once again back to the topic of diet.


Abumaria, N., Yin, B., Zhang, L., Li, X. Y., Chen, T., et al. (2011).  Effect of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala.  Journal of Neuroscience, 31, 14871-14881.

Abumaria, N., Luo, L., Ahn, M., & Liu, G.  (2013).  Magnesium supplement enhances spatial-context pattern separation and prevents fear overgeneralization.  Behavioral Pharmacology, 24, 255-263.

Ampuero, E., Rubio, F. J., Falcon, R., Sandoval, M., Diaz-Veliz, G., Gonzalez, R. E., Earle, D., Dagnino-Subiabre, A., Aboitiz, F., Orrego, F., & Wyneken, U.  (2010).  Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex.  Neuroscience, 169 (1), 98-108.

Boyer, P. A., Skolnick, P., & Fossom, L. H.  (1998).  Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNA in mouse brain: a quantitative in situ hybridization study.  Journal of Molecular Neuroscience, 10, 219-233.

Burghardt, N. S., Sigurdsson, T., Gorman, J. M., McEwen, B. S.  & LeDoux, J. E. (2013).  Chronic antidepressant treatment impairs the acquisition of fear extinction.  Biological Psychiatry, 73(11), 1078-1086.

Jacobs, S., Cui, Z., Feng, R. Wang, H., Wang, D. & Tsien, J. Z.  (2014).  Molecular and genetic determinants of the NMDA receptor for superior learning and memory functions.  PLOS One, 9 (10), e111865

Wang, D., Jacobs, S. A., & Tsien, J. Z.  (2015).  Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline.  Expert Opinion and Targeted Therapeutics, 18 (10), 1121-1130.