The SSRI debate -Some thoughts

Submitted by Michael C. LaFerney RN, PMHCNS, BC, Ph. D

Tags: depression Psychiatry serotonin SSRI

The SSRI debate -Some thoughts

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Depression is a mental illness seen in 5 % of people in the world globally and in the United States nearly 1 in 5 people report having been diagnosed with depression at some point in their lifetime. Depression rates can vary from state to state . There is difference of depression rates between some states or more than 15 per cent. Depression rates also vary based on sex -women . Women are diagnosed more than twice the rate of men.(1) There ares several types of depression-these include major depression seasonal affective disorder, dysthymic disorder and bipolar disorder, depressed. A major treatment for depression is psychopharmacology.

There are several classes of antidepressants with SSRI's (selective serotonin reuptake inhibitors) being the most used . They operate on the theory that depression is caused by low levels of serotonin concentrations and activity and SSRIs can correct this imbalance. Studies indicate at best ,SSRIs have a moderate success rate. It is estimated that antidepressants have an efficacy or around 42-53 percent (2). ( This can vary in different studies depending on what the efficacy criteria is and the type of depression being treated. It is estimated that 30 percent of patients with Major depression do not respond to SSRI use at all.(3) The role of serotonin in depression has a been a subject of debate for many years but as of this date the debate has recently intensified. A study in 2022 by researchers in the UK suggested that after an exhaustive review there was no evidence that low serotonin levels were a cause of depression The researchers concluded that telling patients using that SSRIs would aid their depression was giving the patient false hope based on a false theory (4) Is this the same as when we provide cholinesterase inhibitors for patient with Alzheimer disease? These drugs may shown some statistical improvement but translate in to little real clinical benefit. When we prescribe an antibiotic for an infection and we have the right sensitivity we expect an almost 100 percent cure rate. Many psychiatric practitioners and drug companies have come to the rescue of the serotonin theory and point out what they feel were shortcomings in the research and offer evidence based examples of research and testimonies from patients who feel they were helped by the SSRIs Others point out the SSRI theory has been helpful and research into other neurotransmitter and their role in depression treatment is being explored.

So what are some other factors in depression and SSRIs to be considered?

Depression is felt to be caused by hereditary, psycho-social, chemical and biological factors. So when we use use antidepressants alone as many in practice do we are not addressing the other contributing factors. The antidepressant won't override a bad relationship, job or other psycho-social factors. If the serotonin theory is correct it might give the patient more ability to deal or change their situation. If the person has a hereditary disposition to depression will increasing serotonin impact their genetic makeup? Can biology and environment overcome our genetic predisposition? There is some evidence to support treatments that increase serotonin have some efficacy.

Other therapies are used to treat depression as ECT are shown to increase serotonin levels and patients do often improve dramatically with treatment. (5)Transcranial magnetic stimulation (TMS) has shown improvement into some patients who have failed antidepressant use benefit.(6) Some patients on SSRI therapy have improvement but do not totally recover from all their depressive symptoms. I would call these patients partial responders. Light therapy increases serotonin levels in patients with SAD and there is improvement.(7)

Some other factors to consider. There are different types of depression. Treatment may vary on the type. We have developed specific medications now for bipolar depression rather than those major depression now. A new antidepressant has just been approved for Post partum depression ( (Zulleso/Brexanolone)( 8)We augment SSRIs with other medications as mood stabilizers and anti psychotics which sometimes improve depressive symptoms. This indicates that other neurotransmitters , interaction between various neurotransmitters and various pathways in the brain may be more prominent in depression.

We often may fail to diagnose the correct types as we do with distinguishing Bipolar based depression from Major Depression. The fact that woman are diagnosed at higher rates of depression than men may suggest hormonal or psycho-social factors s more prominent. The fact that depression rates may vary by state indicates psycho-social factors as poverty, politics, wealth, and infrastructure that provide for opportunity may be more the factor than chemical imbalance or perhaps the chemical imbalance is caused by these. I meet many patients who voice being depressed but when we look at the DSM -5 criteria we find they are eating well. Sleeping, engaged in activity with no suicidal ideation. They do not meet the criteria .We have to make sure what they are calling depression is not actually something else as unhappiness in their current situation or another mental health issue as a personality disorder. The factor to me that impacts the serotonin theory of depression is the placebo effect. Multiple studies have indicated a significant number of patients who respond to SSRIs do so because they believe they will work. Many studies have replicated the original studies that showed benefit was more likely due to patent beliefs than changes in serotonin levels.(9) An important factor in drug research is that statistical significance does not mean real clinical evidence based response. This is true in medications used for Alzheimer's disease and may be for depression.

In Summary we know that depression is caused by a multitude of factors that includes heredity, the environment, psycho-social, substance abuse, our definitions of depressive symptoms, and structural and chemical changes in the brain. SSRIs alone are not sufficient for treatment. This is why we have have multiple types of psychotherapies and other treatments to treat and augment. We can tell our patients that the cure rate of testicular cancer is 95 percent.(10) We can't tell our patient what the cure rate will be be when we treat depressive disorders given the multitude of factors. We continue to make progress toward this. We may soon be able to devise medications that work on our genetic makeup for depression and we are making headway in understanding not only the neurotransmitters involved in depression but also the transport mechanisms and brain pathways. For now it seems that SSRIs are still a major part of our arsenal of tools.

  1. (2023) Howard, Jacqueline, CNN, Nearly 1 in 5 US adults have been diagnosed with depression and the prevalence varies dramatically by state, CDC report finds Taken from the WWW July 22 , 2023 at: %20new%20report%20published%20Thursday,to%2027.5%25%20in%20West%20Virginia.
  2. Taliaz, D., Spinrad, A., Barzilay, R. et al. Optimizing prediction of response to antidepressant medications using machine learning and integrated genetic, clinical, and demographic data. Transl Psychiatry 11, 381 (2021).
  3. (2019) Paddock,Catherine Medical news today Why do some antidepressants fail for some? Taken for the WWW July 2023 at: cell-response-to-SSRIs
  4. (2002) Moncrieff, J., Cooper, R.E., Stockmann, al.The serotonin theory of depression: a systematic umbrella review of the evidence.Mol Psychiatry(2022).
  5. (2017) Science Digest European Psychiatry Volume 41, Supplement, April 2017, Page S138 P.Agha Mohammad Hasan and al.Effect of electroconvulsive therapy on serum serotonin level in patients with treatment–Resistant major depressive disorder Taken for the WWW at: sion,following%20ECT%20in%20MDD%20patients.
  6.  (2017) Dubin, M. Imaging TMS: Antidepressant mechanisms and treatment optimization Taken for the WWW at:
  7. (20210Otman, H., Michigan Medicine, Seeing the Light of an Improved Mood Taken from the WWW July 2023 at: text=%22Morning%20bright%20light%20is%20an,the%20brain%20that %20regulate%20mood.
  8. (2023)Zullesso, Each Day Matters,taken from the WWW July 20203 at:
  9.  (2018)Stilman, Steinert, World Psychiatry ., 2018 Feb; 17(1): 114–115.Published online 2018 Jan 19 Chance of response to an antidepressant: what should we say to the patient , Taken from the WWW July 2023 at:
  10. (2022)Testicular cancer statistics , Cancer. Net taken from the WWW July22, 2023 at: