Antidepressants And Memory Function - Understanding The Impact And Managing Potential Issues

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Introduction

Developed in the 1950s, antidepressants are medications that are commonly prescribed to treat clinical depression. However, they can also be used to treat other mental health conditions and long-term chronic pain. One of the concerns surrounding the use of antidepressants is their potential side effects and adverse effects - such as memory loss, as reported by some studies.¹ ² ³

Types of antidepressants

Antidepressants alter the function of multiple neurotransmitters. Neurotransmitters are the chemicals that allow neurons (nerve cells) to communicate with each other throughout the body.

There are various types of antidepressants which can be carefully selected to best meet each patient’s needs. Types of antidepressants include:

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin-noradrenaline reuptake inhibitors (SNRIs)
  • Tricyclic antidepressants (TCAs)
  • Monoamine oxidase inhibitors (MAOIs)
  • Noradrenaline and specific serotonergic antidepressants (NASSAs)
  • Serotonin antagonists and reuptake inhibitors (SARIs)

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs target the neurotransmitter serotonin. Low serotonin levels are often associated with depression, and SSRIs are designed to increase levels of serotonin. To achieve this, they prevent neurons from reabsorbing serotonin, increasing the levels of serotonin in the gaps between neurons (synaptic cleft). This allows serotonin receptors to be activated for a longer time, restoring normal brain functions. SSRIs typically work by inhibiting the serotonin transporters (SERTs) in neurons.

SSRIs are commonly prescribed, as they typically cause fewer side effects than other antidepressants. They have little or no effect on other chemical signalling molecules such as dopamine, norepinephrine, histamine, and acetylcholine. As a result, SSRIs do not cause side effects associated with other antidepressants, such as xerostomia (dry mouth due to reduced saliva production), sedation, constipation, urinary retention, and cognitive impairments. However, the FDA did issue a warning in 2004, as SSRIs have been associated with an increased risk of suicidal thoughts in paediatric and young adult (up to 25 years old) patients. Moreover, they can affect and dysregulate parts of the cardiac cycle (which controls your heartbeat), which could lead to fatal arrhythmia.

SSRI antidepressants include:

  • Fluoxetine
  • Sertraline
  • Paroxetine
  • Fluvoxamine
  • Citalopram
  • Escitalopram
  • Vilazodone

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs are designed to prevent the reabsorption of serotonin and norepinephrine (or noradrenaline) into neurons from the synaptic cleft.,¹⁰ This increases the concentration of both serotonin and norepinephrine in the synaptic cleft and prolongs the activation of their receptors, restoring normal neuron and brain function. 

Like SSRIs, SNRIs are associated with less severe side effects than other antidepressants. However, they can cause anxiety, insomnia and restlessness, sexual dysfunction, headaches, nausea, insomnia, dry mouth, and in rare cases, elevated blood pressure.

Some examples of SNRIs:

Tricyclic antidepressants (TCAs) 

Tricyclic antidepressants are designed to prevent the reabsorption of neurotransmitters such as serotonin and norepinephrine.¹¹,¹² In terms of side effects, TCAs cause similar ones to the SSRIs and SNRIs; these include: dry mouth, slight blurring of vision, constipation, problems passing urine, drowsiness, dizziness, weight gain, excessive sweating (especially at night), arrhythmias, such as noticeable palpitations or a fast heartbeat (tachycardia).

Some examples of TCAs:

  • Imipramine
  • Trimipramine
  • Amitriptyline
  • Nortriptyline
  • Desipramine
  • Protriptyline
  • Doxepin
  • Amoxapine

Monoamine oxidase inhibitors (MAOIs) 

Monoamine oxidase inhibitors inhibit the activity of the monoamine oxidase enzyme, which breaks down different types of neurotransmitters from the brain such as norepinephrine, serotonin, dopamine, and tyramine.¹³ As such, MAOIs inhibit the breakdown of these neurotransmitters, increasing their levels and allowing them to continue to influence the activity of neurons. 

MAOIs are a separate class from other antidepressants, as they treat different forms of depression and other disorders such as panic disorder, social phobia, and depression with atypical features. Whilst they were the first antidepressants introduced, they are not the first choice in treating mental health disorders due to several dietary restrictions, side effects, and safety concerns. Therefore, they are only prescribed when all other medications are unsuccessful. The most common side effects caused by MAOIs are dry mouth, nausea, diarrhoea, constipation, drowsiness, insomnia, dizziness, and lightheadedness.

Some examples of MAOIs:

  • Isocarboxazid
  • Phenelzine
  • Selegiline
  • Tranylcypromine

How do antidepressants affect memory? 

Before delving into how antidepressants affect memory function, we first must understand what memory is and how it works. 

Memory is the ability to encode, store, and recall information in our brain. It can be categorised into sensory, short-term, and long-term memory. Sensory memory, the considered first stage of memory, involves registering large amounts of information from our environment within a short period of time. This type of memory is associated with the 5 senses: haptic (touch), echoic (hearing), iconic (eyesight), olfactory (sense of smell), and gustatory (taste). 

Sensory information is only transferred into the short-term memory if you pay attention to your surroundings. Short-term memory is responsible for holding information for ten to fifteen seconds, and undergoes “maintenance rehearsal” (repetition) - otherwise, information is forgotten. If “elaborate rehearsal” (continual repetition) occurs, then the information is transferred to the long-term memory. Long-term memory is where information is stored for a longer time. When long-term memories form, the hippocampus (the part of the brain responsible for learning and memory) retrieves information from short-term memory, triggering changes in the brain’s physical neural wiring. The more times a specific memory is retrieved, the stronger the neural connections become. Similarly, if specific memories are rarely revisited and retrieved,  it is thought that the neural connections decay over time.¹⁴,¹⁵

Antidepressants and memory function

As mentioned above, the various types of antidepressants each act and affect the brain differently. In this section, we will explore different studies that have been conducted relating antidepressants to memory loss.

A case study published in 2003 looked at how fluoxetine, an SSRI, caused severe memory loss in an 82-year-old female. The family of the patient reported a decline in memory after two weeks of treatment. However, two weeks after discontinuing treatment, the mental status of the patient improved. This correlates to the half-life of the drug (the amount of time that it takes for the drug to decay to half its original concentration within the body). From this, they concluded that fluoxetine causes reversible memory loss. They claim that many other case reports verify these findings, but manufacturer data indicates that there is a less than one per cent chance of this memory loss occurring.¹⁶

Another study conducted in 2008 selectively reviewed several studies testing the effects of antidepressant drugs on animals. The results showed that MAOIs tend to have either no effect on memory (or actually improve it) and that most other antidepressant types have no effect on memory, besides trazodone, which impairs it.¹⁷

One further study conducted in 2001 looked at the relationship between depression, antidepressants and the shrinking of the hippocampus. They stated that major depression was associated with the atrophy (shrinking) of the hippocampus (the area in the brain responsible for learning and memory), explaining the cognitive deficits caused by major depression. Using data from animal studies to support their findings, this study determined that the shrinking of the hippocampus (and memory loss) was due to depression itself, whilst antidepressants reverse it - effectively restoring normal memory.¹⁸ In contrast, a 2016 study suggested that patients who took SSRIs for consecutive weeks demonstrated a gradual cognitive decline.¹⁹

These contradicting results demonstrate how much more research needs to be done in order to understand the relationship between antidepressants and memory loss. However, it is also important to note that the results of these studies might not be completely applicable to humans, especially since some are based on animal models. 

Summary

The relationship between antidepressants and memory is a complex and nuanced subject that requires further exploration and understanding. The diverse classes of antidepressants, such as SSRIs, SNRIs, TCAs, and MAOIs, exhibit varying effects on neurotransmitter function and may have different implications for memory.

While some studies suggest reversible memory loss is associated with certain antidepressants, others suggest that prolonged SSRI use can trigger cognitive decline over time, and others suggest that there is no relationship at all. These conflicting findings highlight the need for more comprehensive research to better understand the link between depression, antidepressant usage, and memory.

The contrasting results from different studies also highlight the importance of considering individual variations and potential discrepancies between animal and human systems. The impact of antidepressants on memory appears to be multifaceted, with factors like drug type, duration of use, and underlying mental health conditions influencing outcomes.

It is crucial for healthcare professionals to weigh the potential benefits of antidepressant treatment against the reported risks, including impacts on memory function. As our understanding evolves, further research is essential to refine our knowledge of how antidepressants affect memory and to develop strategies for managing potential cognitive issues associated with their use.

References

  1. Cleveland Clinic. Antidepressants [Internet]. 2023 [cited Jan 25 2024]. Available from: https://my.clevelandclinic.org/health/treatments/9301-antidepressants-depression-medication
  2. NHS. Overview - Antidepressants [Internet]. 2021 [cited Jan 24 2024]. Available from: https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/antidepressants/overview/
  3. ‌Joss JD, Burton RM, Keller CA. Memory Loss in a Patient Treated with Fluoxetine. Ann. Pharmacother. 2003 Dec;37(12):1800–3.
  4. ‌Hyttel J. Pharmacological characterization of selective serotonin reuptake inhibitors (SSRIs). Int. Clin. Psychopharmacol. [Internet]. 1994 [cited 2024 Jan 20];9:19. Available from: https://journals.lww.com/intclinpsychopharm/Abstract/1994/03001/Pharmacological_characterization_of_selective.4.aspx?casa_token=fg79aMeSToIAAAAA:pCeMTb8dAZ6Puuic8iO5JGmUiQRKHEnfHfVWZgqKYC79tk4RYNCthMqTxh9GMexM5OczyMfgETS7PpYnl-93WF7c8mc
  5. ‌Sheffler ZM, Reddy V, Pillarisetty LS. Physiology, neurotransmitters. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK539894/
  6. ‌NHS. Overview - Antidepressants [Internet]. 2021 [cited Jan 23 2024]. Available from: https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/antidepressants/overview/
  7. Chu A, Wadhwa R. Selective serotonin reuptake inhibitors. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK554406/
  8. Talha B, Swarnkar SA. Xerostomia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. http://www.ncbi.nlm.nih.gov/books/NBK545287/
  9. Fanelli D, Weller G, Liu H. New serotonin-norepinephrine reuptake inhibitors and their anesthetic and analgesic considerations. Neurol. Int. 2021;13(4): 497–509. https://doi.org/10.3390/neurolint13040049.
  10. Santarsieri D, Schwartz TL. Antidepressant efficacy and side-effect burden: a quick guide for clinicians. Drugs Context. 2015;4: 212290. https://doi.org/10.7573/dic.212290.
  11. Moraczewski J, Awosika AO, Aedma KK. Tricyclic antidepressants. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557791/
  12. NHS. Side Effects - Antidepressants [Internet]. 2021 [cited Jan 24 2024]. Available from: https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/antidepressants/side-effects/
  13. Sub Laban T, Saadabadi A. Monoamine oxidase inhibitors(Maoi). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK539848/
  14. BrainGymmer. How the human memory works [Internet]. [cited Jan 25 2024]. Available from: https://www.braingymmer.com/en/blog/memory/
  15. Lesley University. Becker B. How Memories Are Made: Stages of Memory Formation [Internet]. 2023 [cited Jan 25 2024]. Available from: https://lesley.edu/article/stages-of-memory#:~:text=When%20long%2Dterm%20memories%20form
  16. Joss JD, Burton RM, Keller CA. Memory Loss in a Patient Treated with Fluoxetine. Ann. Pharmacother. 2003;37:1800–3.
  17. Monleón S, Vinader-Caerols C, Arenas MC, Parra A. Antidepressant drugs and memory: Insights from animal studies. ENP. 2008 Apr;18(4):235–48.
  18. Sapolsky RM. Depression, antidepressants, and the shrinking hippocampus. PNAS. 2001;98:12320–12322. 
  19. Sayyah M, Eslami K, AlaiShehni S, Kouti L. Cognitive function before and during treatment with selective serotonin reuptake inhibitors in patients with depression or obsessive-compulsive disorder. Psychiatry J. 2016;2016:5480391. 

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Érica Ramos Lopes Sousa

Medical Undergraduate - MBBS / BSc , Imperial College London

Érica, a first-year medical student at Imperial College London, is already displaying a keen interest in the fields of neurosurgery and genetics. Her foundation in academic writing, acquired during her International Baccalaureate studies, serves as a strong platform for her goal of crafting informative health-related articles for the general public. As she progresses through her medical education, she harbours ambitions of further enhancing her expertise and insights, with the ultimate aim of contributing to significant advancements in the field of medicine.

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