Effect of Selective Serotonin Reuptake Inhibitors (SSRIs)

Lynnette Chan

Do Selective Serotonin Reuptake Inhibitors (SSRIs) Negatively Affect Memory?

Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants prescribed to treat moderate to severe depression. SSRIs increase serotonin (5-hydroxytryptamine, 5-HT) levels in the brain by blocking serotonin reuptake. Compared to other antidepressants such as tricyclic antidepressants (TCAs), SSRIs are more selective and have fewer side effects. In addition to affecting emotional moods, SSRIs can also affect food and sex related behaviors, resulting in side effects such as weight gain and reduced sexual drive (Mayo Clinic). However, recent studies indicate that serotonin also plays a “significant role in learning and memory” (Buhot, Martin, & Segu 210). Given serotonin’s lack of specialized function, can SSRIs negatively affect memory function as a side effect? To answer this question, this paper will establish the association between SSRIs and serotonin levels, and then examine the relationship between SSRI use and impaired or improved memory.

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Since depression has been linked to a shortage of serotonin neurotransmissions, antidepressants should increase 5-HT levels. But in a comprehensive review on the serotonergic and noradrenergic systems of the hippocampus, R. Mongeau, P. Blier, and C. de Montigny found that successful SSRI treatments show both an increase and decrease of 5-HT neurotransmissions (178). This finding is unusual because SSRIs inhibit 5-HT reuptake to increase 5-HT levels and should not result in decreased 5-HT neurotransmissions. As decreased 5-HT levels do appear in successful treatments utilizing SSRIs, there must be additional factors involved in mood elevation within the serotonergic system. Regardless of the exact mechanism that allow SSRIs to treat depressive symptoms, SSRIs do increase and decrease 5-HT neurotransmissions in the brain.

While the exact mechanism of how 5-HT levels affect mood remains unclear, SSRI use and changes in 5-HT levels have been linked to memory impairment. In a study investigating the role of serotonin in memory impairment, Marie-Christine Buhot, Stephanie Martin, and Louis Segu found that serotonergic activity in the brain affects memory and learning differently depending on the stimulation or inhibition of different 5-HT receptor subtypes. This study found that stimulation of the 5-HT_2A/2C or 5-HT₄ receptor subtypes, or inhibition of the 5-HT_1A or 5-HT₃ or 5-HT_1B receptor subtypes improved memory and learning in high-cognitive activities (210). 5-HT receptor subtypes are differentiated by their relative distributions in the brain and their cellular locations, differentiations that explain the various effects of 5-HT receptor subtypes. For example, the 5-HT_1A receptor subtype is largely concentrated in the hippocampus and interacts with the noradrenergic, dopaminergic, and GABAergic systems (Buhot, Martin, & Segu 214). As a result, stimulating 5-HT_1A receptors impairs memory. The Buhot study confirms that serotonin affects memory function and is dependent on the stimulation or inhibition of different 5-HT receptor types or subtypes.

The Buhot study examined the neurotransmitter mechanisms of serotonin and memory, but it did not examine the effect of specific SSRI antidepressants on memory. In a study on the effect of short-term use of SSRIs on cognitive brain function, Jeroen A. J. Schmitt, Monique J. Kruzinga, and Wim J. Riedel found that the positive and negative effects SSRIs have on memory is caused by interactions with external neurotransmitter systems. The study conducted tests with sertraline and paroxetine, the two “most potent inhibitors of serotonin reuptake” available at the time of the study (Schmitt, Kruzinga, & Riedel 173). They found that paroxetine contributed to long-term memory impairment, an effect attributed to paroxetine’s additional anticholinergic properties. On the other hand, sertraline only slightly improved verbal fluency, an effect attributed to sertraline’s additional dopaminergic effects. Although this study agrees with the Buhot study that additional neurotransmitter interactions in serotonergic pathways contribute or prevent memory impairment, the Buhot study attributes memory functions to serotonin while the Schmitt study does not.

Both the Buhot and Schmitt studies argue that SSRIs influence memory, but the two studies disagree on the mechanism that causes memory improvement and impairment. In a study examining the short-term use of the SSRI citalopram and the SNRI (serotonin-norepinephrine reuptake inhibitor) reboxetine and their effect emotional memory and perception, Catherine J. Harmer, Nicholas C. Shelley, Philip J. Cowen, and Guy M. Goodwin found that both citalopram and reboxetine decreased the memory and perception of negative emotions in comparison to positive emotion. Additionally, citalopram use lowered startle responses to displays of negative emotion. Unlike the Buhot and Schmitt study, this study claims that SSRI’s side effect on emotional memory and perception is actually the mechanism that makes SSRIs effective antidepressants. Perhaps SSRIs help strengthen memories of positive emotions with increased 5-HT concentrations and weaken memories of negative emotions with decreased 5-HT concentrations at different 5-HT receptor subtypes to contribute to mood elevation and regulation.

SSRIs have a recognized role in memory and learning. The Buhot study argues that memory can be strengthened or weakened depending on the inhibition or stimulation of different 5-HT receptor subtypes, characterized by location and neurotransmitter pathways. On the other hand, the Schmitt study argues that SSRIs effect on memory is not caused by 5-HT levels, but by the additional effects of other neurotransmitter systems. In contrast, the Harmer study argues that the strengthening and weakening of emotional memory and perception contributes to the antidepressant properties of SSRIs. In conclusion, SSRIs can both impair and improve memory, depending on the SSRI type and their interactions with 5-HT receptor subtypes and other neurotransmitter pathways.

SSRIs have been confirmed to affect memory and cognitive function, but further research is required to determine the exact mechanism of how different SSRIs affect neurotransmitters and mood. Research can explore the degree of memory impairment caused by SSRIs, and examine the neurotransmitter systems that interact most with the serotonergic system to better define neurotransmitter function. Future research can also focus on developing new antidepressants by exploring the neurotransmission systems that interact with SSRIs. Hopefully, a more comprehensive understanding of the mechanisms of memory and the role of neurotransmitters can also provide better insight on neurodegenerative disorders that affect memory, such as Alzheimers disease.

Works Cited

Buhot, Marie-Christine, Stéphanie Martin, and Louis Segu. “Role of Serotonin in Memory Impairment.” Annals of Medicine 32.3 (2000): 210-21. Informa Healthcare. Web. 26 Feb. 2015. <http://informahealthcare.com/doi/abs/10.3109/07853890008998828>.

Harmer, Catherine J., Nicholas C. Shelley, Philip J. Cowen, and Guy M. Goodwin. “Increased Positive Versus Negative Affective Perception and Memory in Healthy Volunteers Following Selective Serotonin and Norepinephrine Reuptake Inhibition.” American Journal of Psychiatry 161.7 (2004): 1256-263. American Journal of Psychiatry. Web. 26 Feb. 2015. <http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.161.7.1256>.

Mayo Clinic. “Depression (major Depressive Disorder).” Selective Serotonin Reuptake Inhibitors (SSRIs). January 1, 2015. Accessed March 18, 2015. http://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825.

Mongeau, R., P. Blier, and C. De Montigny. “The Serotonergic and Noradrenergic Systems of the Hippocampus: Their Interactions and the Effects of Antidepressant Treatments.” Brain Research Reviews 23.3 (1997): 145-95. Science Direct. Web. 26 Feb. 2015. <http://www.sciencedirect.com/science/article/pii/S0165017396000173>.

Schmitt, Jeroen A. J., Monique J. Kruizinga, and Wim J. Riedel. “Non-serotonergic Pharmacological Profiles and Associated Cognitive Effects of Serotonin Reuptake Inhibitors.” Journal of Psychopharmacology 15.3 (2001): 173-79. Sage Journals. Web. 26 Feb. 2015. <http://jop.sagepub.com/content/15/3/173.short>.