The Effect of Long-Term Antidepressant Usage on the Brain

Phoebe Amakiri – phoebeamakiri@gmail.com

September 4th, 2025

Edited by the YNPS Publications team.

Abstract 

Depression is a leading global health concern and is commonly treated with antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs). While these drugs are effective in alleviating depressive symptoms, concerns have emerged regarding the long-term effects of their use on brain function and overall well-being. This paper synthesises existing literature on the neurological and behavioural impacts of prolonged antidepressant use, drawing on both animal and human studies. Findings suggest that extended use of SSRIs and SNRIs is associated with persistent adverse effects, including sexual dysfunction, cognitive impairment, and motor deficits. These results highlight the need for further longitudinal research to better understand the mechanisms and mitigate these effects.

Keywords: antidepressants, SSRIs, SNRIs, long-term use, neuroplasticity, cognitive impairment, depression treatment

Introduction

Depression is a major global health problem, bringing with it significant mental disability and social obstacles. The World Health Organisation (WHO) attributes it as the leading cause of ill health and disability (WHO, 2017). Due to the significant challenges brought by depression and the prevalence of the condition, treatment remains a significant focus in fields focusing on mental health and neurology. Antidepressant drugs are the most common and effective method of treatment in patients (Marasine et al., 2021), and advancements continue to occur, driven by the rise in affected patients. For example, while TCAs (tricyclic antidepressants) were the preferred method of treatment for many years, they have gradually been replaced by Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)  (Marasine et al., 2021). While TCAs work similarly to both SSRIs and SNRIs, inhibiting the reuptake of certain neurotransmitters associated with mood fluctuations, TCAs are associated with more adverse effects and more overdose cases, making SSRIs and SNRIs a safer alternative for patients. SSRIs and SNRIs are also preferred among patients because of their better tolerability and milder side effects. However, antidepressant prescription is largely done on an individual basis, focusing on the needs of the patient (Moraczewski et al., 2023). 

This paper will focus on the use of Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs), as they are the most commonly prescribed class of antidepressants. 

Serotonin, often known as the “feel-good” neurotransmitter, deficiencies and imbalances are strongly associated with the onset of depression. Antidepressants thus focus on regulating the amount of serotonin available to the brain’s neural pathways by preventing reabsorption (reuptake), effectively increasing serotonin availability. This prevents the mood imbalances that cause depression (Marasine et al., 2021). Norepinephrine also plays a role in depression, with low levels causing low arousal and excitement and contributing to depression (Moret & Briley, 2011). This increased modulation has a significant impact on the brain, raising questions about the effects of prolonged use. This is especially relevant because an increasing number of people are diagnosed with and treated for depression in the modern era. Therefore, this paper aims to summarise and synthesise the existing literature on the effects of long-term antidepressant usage, with a focus on SSRIs and SNRIs.

Scholarship

Earlier scholarship focused on identifying similarities between the effects of antidepressants and other brain-modulating drugs such as opiates, analgesics, and hypnotic pills. Withdrawal effects are associated with long-term use of most drugs. A specific study focused on the possibility of persistent adverse effects of antidepressants (Moncrieff, 2019). It raised concerns about the possibility of permanent restructuring. Antidepressants not only prevent serotonin reabsorption, but they also encourage activity in neural pathways. Short-term studies on the effects of selective serotonin reuptake inhibitors also show that they promote neurogenesis, the creation of new neurons (Segi-Nishida, 2017). Moncrieff’s study draws on Segi-Nishida’s, analysing the long-term effect of antidepressants on the brain, proven through increased neuroplasticity through the lens of previous brain-modulating drugs. The study concluded, based on patient surveys and previous literature analysis, that cases of antidepressant withdrawals followed a similar pattern to benzodiazepines (benzos) and were common. The study also found that prolonged SSRI use was associated with sexual dysfunction lasting from months to years in patients (Moncrieff, 2019). Another study assessed patients following long-term treatment with SSRIs with a special focus on their cognition. Over 20% reported cognitive decline following treatment, including fatigue, memory impairment, lack of concentration, and muted emotions (Popovic et al., 2015). Another study aimed to study the effects of antidepressant usage in mothers on their children. It found that newborn rats treated with SNRI antidepressants exhibited poorer motor function compared to the control group. While they performed far below average, this performance was able to be improved with repetition and practice (Lee & Lee, 2012).

Methodology

This synthesis and summary included mostly published and scientific papers, except for a cited WHO report. The included papers were restricted to those focusing on Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs). Additionally, papers were sourced from between 2010-2025; older papers were excluded because they did not include relevant information about new advancements in antidepressants and emerging side effects. Of the three studies included, two worked with rats to test the effects of long-term antidepressant use–that is, a longitudinal study–while two surveyed participants who had been through long-term depression treatment taking antidepressants on the after effects of treatment. Studies with larger sample sizes were preferred. Moncrieff’s study included 50 rats raised from adolescence and dosed with antidepressants, and it also surveyed 532 participants of varying age and gender on their experiences with antidepressant withdrawals and perceived impairment–cognitive and sexual–following antidepressant use. The study done by Popovic et al. (2015) surveyed 67 consecutive participants who had been successfully treated for at least six months with antidepressants, assessing them for side effects with a special focus on cognition. Lee & Lee’s study raised 60 rat pups from the day of birth, treating them with SSRIs from the day of birth to postnatal day 4 before assessing motor function.

Results

All studies found a significant link between prolonged antidepressant use and adverse side effects in patients. Sexual dysfunction was found among both rats and humans (Moncrieff, 2019). Participants across all studies reported a level of cognitive impairment affecting characteristics like memory, concentration, emotions, and motor function. The rats surveyed in Lee and Lee’s study exhibited significantly reduced motor function compared to the control group after exposure to antidepressants, specifically SSRIs, since birth. Commonly, all participants across all examined studies exhibited some form of impairment in correlation with long-term antidepressant use. Lee and Lee’s study found that the negative effects could be corrected, but the same was not replicated in the other studies. 

Implications & Discussion

The findings from the reviewed studies indicate that while SSRIs and SNRIs remain an effective treatment for depression, their long-term use raises several concerns that should not be overlooked. Most notably, adverse effects such as sexual dysfunction, cognitive impairment, and motor deficits suggest that the benefits of these drugs may come with significant costs when used over an extended period. The persistence of some of these side effects demonstrates that discontinuation does not always guarantee full recovery, particularly in the case of sexual dysfunction  (Moncrieff, 2019). This raises important questions about whether these drugs induce structural or functional changes in the brain, causing the changes and side effects to linger.

Another key implication is the potential impact on quality of life after treatment. While the primary goal of antidepressant therapy is to restore emotional stability, impairments in memory, attention, and emotional responsiveness, as reported in Popovic et al. (2015), can hinder daily functioning. These side effects may even discourage patients from remaining adherent to treatment, complicating long-term management of depression. The reduced motor function observed in Lee and Lee’s rat study also suggests that developmental exposure to antidepressants could have lasting consequences, which is particularly relevant for prescribing SSRIs or SNRIs during pregnancy or early life.

Clinically, these findings underscore the importance of balancing the benefits of antidepressant therapy with the risks of prolonged use. Healthcare providers should take a personalised approach, regularly evaluating whether continued medication is necessary and considering tapering strategies or alternative interventions when possible. This is especially critical given that antidepressant prescriptions are often indefinite, even after symptoms have stabilised.

Finally, these results point to the need for more longitudinal studies that examine the neurological and behavioural effects of antidepressants beyond the acute treatment phase. Research should also explore strategies to mitigate these adverse effects, such as drug holidays, adjunct therapies, or developing compounds that provide therapeutic benefits without long-term drawbacks. Addressing these questions is essential, not only for improving clinical practice but also for ensuring that treatment for depression does not create a new set of challenges for patients over time.

Limitations

Although all studies included had good sample sizes, the results could have been stronger with consistently sized groups of 100 people or more. Additionally, the study done by Popovic et al. (2015) lacked a control group, as it focused on those already treated for depression. The study could have been strengthened if data could have been found on the effects of long-term SSRI usage on those without depression initially, because it would help extricate lingering symptoms of depression from the side effects of long-term antidepressant use. Ethics and the low willingness of a control group to participate in such a study prevent further studies from advancing in this area. The literature on the effect of long-term antidepressant use is further limited by the novelty of the question. Antidepressants and the treatment of depression as a disease are relatively new advancements in medicine. As usual, medicine has been slow to question the potential side effects of a largely positive innovation. The stigma associated with depression also previously deterred people from seeking diagnosis and treatment, limiting the size and diversity of study samples. Future studies could build upon existing literature by growing their sample size and extending the time spent following participants of a study. 

Conclusion

Long-term use of SSRIs and SNRIs remains a complex issue in the treatment of depression. While these medications are highly effective in alleviating depressive symptoms, the evidence reviewed suggests that their prolonged use may lead to significant adverse effects, including sexual dysfunction, cognitive impairment, and, in some cases, developmental consequences. These side effects raise critical questions about the structural and functional changes that antidepressants may induce in the brain and highlight the importance of carefully weighing risks against benefits when considering extended treatment. 

References

Lee, L. J., & Lee, L. J. (2012). Neonatal fluoxetine exposure alters motor performances of adolescent rats. Developmental neurobiology, 72(8), 1122–1132. https://doi.org/10.1002/dneu.20942

Marasine, N. R., Sankhi, S., Lamichhane, R., Marasini, N. R., & Dangi, N. B. (2021). Use of Antidepressants among Patients Diagnosed with Depression: A Scoping Review. BioMed research international, 2021, 6699028. https://doi.org/10.1155/2021/6699028

Moncrieff J. (2019). Persistent adverse effects of antidepressants. Epidemiology and psychiatric sciences, 29, e56. https://doi.org/10.1017/S2045796019000520

Moraczewski, J., Awosika, A. O., & Aedma, K. K. (2023). Tricyclic Antidepressants. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/sites/books/NBK557791/

Moret, C., & Briley, M. (2011). The importance of norepinephrine in depression. Neuropsychiatric disease and treatment, 7(Suppl 1), 9–13. https://doi.org/10.2147/NDT.S19619

Popovic, D., Vieta, E., Fornaro, M., & Perugi, G. (2015). Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRi antidepressants. Journal of affective disorders, 173, 211–215. https://doi.org/10.1016/j.jad.2014.11.008

Segi-Nishida E. (2017). The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors. Frontiers in cellular neuroscience, 11, 142. https://doi.org/10.3389/fncel.2017.00142

World Health Organisation. (2017). “Depression: let’s talk” says WHO, as depression tops list of causes of ill health. http://Www.who.int. https://www.who.int/news/item/30-03-2017–depression-let-s-talk-says-who-as-depression-tops-list-of-causes-of-ill-health