The Recent Headlines on Depression, Serotonin, and Antidepressants: What You Need to Know

In the past weeks, you may have seen headlines about recent articles that call
into question the “serotonin theory” of depression. One of the papers that is
frequently being referenced in the media is a July 2022 summary of systematic
reviews on the possible association between serotonin and depression,
published in the Journal of Molecular Psychiatry (1). The overarching message of
this paper is that there is inadequate evidence that lowered/heightened levels of
serotonin cause depression, and as such, greater caution should be practiced by
doctors who prescribe antidepressants to clients, who may form “lifelong
dependence on these drugs” (Moncrieff et al., 2022).

As a psychologist, I have heard several people express concern about this recent
paper and what they are hearing about it in the news. This is an understandable
reaction: if you are not prescribed an antidepressant, there is a large chance that
someone close to you has a prescription for them. More than one in ten people
in the United States are prescribed antidepressants (2),  and that number is likely on the rise: according to the pharmacy benefit management organization Express
Scripts, prescriptions in antidepressants increased by over 18% at the outset of
the COVID-19 pandemic (3). Moreover, antidepressant prescriptions to children as young as the age of five have been increasing in Western countries over the
course of the last two decades (4, 5).

Given the worry that the aforementioned studies have been causing many
individuals, I would like to take a moment to review some of the science, history,
and more specific concerns around antidepressants, and next steps to consider if
you are wondering whether antidepressants are appropriate for you or a loved
one.

What is the “serotonin theory,” and how does it relate to antidepressants?

The study of serotonin’s role in depression dates back to the mid-20 th century.
The monoamine hypothesis of depression originated in the 1960s, which put
forward that individuals suffering from depression had decreased levels of
monoamine neurotransmitters, including serotonin, norepinephrine, and
dopamine. Many classes of antidepressants were developed over the course of
the 20th century in order to restore the aforementioned chemical messengers,
although the more acute side effects of drugs such as monoamine oxidase
inhibitors (MAOIs) and tricyclics were cause for concern. In the late 1960s and
1970s, increased attention was given to the potential role that serotonin plays in
depression. Some researchers began to posit that serotonin in particular played
a more significant role in major depressive disorder (MDD): for
instance, postmortem studies of individuals with depression who had died by
suicide showed that they had lower serotonin levels (6), while other researchers
found that serotonin precursors (supplements such as amino acids that can
increase the production of neurotransmitters) seemed to enhance the
performance of existing antidepressants (7). Consequently, neuroscientists and
drug manufacturers began to work to develop treatments that both targeted
serotonin levels and diminished serious side effects for users. History was made
in 1987 when the Food and Drug Administration (FDA) approved the first
“selective serotonin reuptake inhibitor” (SSRI) to be marketed in the U.S. by the
pharmaceutical company Eli Lilly. The drug, fluoxetine, was given the brand
name Prozac. Since then, SSRIs have become the most commonly prescribed
antidepressants.

For a more detailed understanding of the history of the monoamine hypothesis of
depression, the serotonin (5-hydroxytryptamine, or 5HT) theory, and the history
of antidepressant development, I recommend the articles by Pereira and Hiroaki-
Sato (2018) (8), Hillhouse and Porter (2015) (9), and Wong et al. (2005).

If the serotonin theory is being called into question, then how do SSRIs
work? Or do they work at all?

There is a large agreement in the scientific community that the boiled-down,
oversimplified, but commonly used explanation of how SSRIs work (i.e. “They
increase serotonin levels in the brain”) is inaccurate. Some speak to their more
nuanced effects over time, such as Dr. David Curtis of the University College
London Genetics Institute:

Their immediate action is to alter the balance between serotonin
concentrations inside and outside neurons but their antidepressant effect is
likely due to more complex changes in neuronal functioning which occur
later as a consequence of this. It is very clear that people suffering from
depressive illness do have some abnormality of brain function, even if we
do not yet know what this is, and that antidepressants are effective
treatments for severe depression whereas interventions such as exercise
and mindfulness are not (10).

Other researchers, including Dr. Joanna Moncrieff – one of the lead authors of
the main article being discussed – posit that improvements experienced after
taking SSRIs are more likely due to an “amplified placebo effect or through their
ability to restrict or blunt emotions in general,” which indeed are phenomenons
that have been confirmed in clinical trials (Graziosi, 2022; Montclieff et al., 2022).
The fact of the matter is that experts across the board are engaged in ongoing
debates and research as to how exactly antidepressants work (especially when
taken consistently over a long period of time), and even argue over how effective
they are; to illustrate, read the February 2018 article in Psychology Today written
by Health Sciences Clinical Professor Dr. Joseph M. Pierre entitled, Do
Antidepressants Work? Yes, No, and Yes Again (11)! Depending on the studies you
read, you may walk away with varied opinions. At the very least, what most
psychiatric experts agree is that antidepressants, including SSRIs, do create
some level of psychological change in the people that take them.

Are SSRIs dangerous? If researchers are expressing concerns about
lifelong dependence, should I be worried?

Like any medication, SSRIs can come with side effects; the more commonly
identified symptoms associated with these medications include but are not limited
to dizziness, drowsiness, headaches, impact on appetite, nausea, sexual
problems, and weight gain. Some studies have pointed to an association between increased suicidal thoughts or attempts with SSRI use, particularly in younger
populations, but doctors of psychiatry and pharmacology such as Nischal et al.
(2012) note that,

This risk can be anticipated and managed clinically. Clinicians are,
therefore, advised to maintain a close follow-up during the initial treatment
periods and remain vigilant of this risk. This advisory, however, should not
deter clinicians from the use of effective dosages of antidepressants for a
sufficient period of time, in every age group of patients, when clinically
needed, and if found suitable otherwise (12).

To be clear, SSRIs do not have addictive properties in the way that substances
like alcohol or nicotine do. However, they are being prescribed for longer, more
extended periods: data from the National Center for Health Statistics (NCHS)
found in a National Health and Nutrition Examination Survey that one-fourth of
persons who took antidepressant medications did so for a decade or more (Pratt
et al., 2017). This is an area of concern for many psychiatric researchers, who
note that most clinical drug trials of SSRIs only last up to a few months, and as of
yet there is little knowledge about the effects of their long-term use (13). Some
studies suggest greater association between antidepressant use and health risks
over time (i.e. heart attacks, stroke, dementia) (14). Still others have found that
approximately 25% of individuals on SSRIs will experience a decrease in their
efficacy, a condition known as tachyphylaxis (a.k.a. “Prozac poop-out”), which in
turn has brought up questions related to whether individuals develop tolerance to
these drugs over time (15).

Should I bother with SSRIs in light of this data, or should I discontinue my
current medication regimen?

In terms of whether or not SSRIs or any antidepressants should be considered in
light of the Moncrieff et al. (2022) paper, this is a personal decision that should
be made after consulting with healthcare providers. Many doctors will continue
to prescribe SSRIs, and research psychologists such as Dr. Gemma Lewis of the
University College London state that there is “strong evidence that
antidepressants can be effective for people experiencing a wide range of depressive symptoms” (Moyer, 2022). In my review of the existing literature,
there are scant (if any) legitimate researchers or clinicians out there stating that
antidepressants should be entirely avoided. Rather, the point that researchers
like Dr. Moncrieff are making – and rightfully so – is that both clinicians and the
public need to be aware of what they DON’T know regarding SSRIs, that the
neuropsychological mechanisms of depression and intervention treatments are
complex, and that given the existing gaps in our knowledge base of the long-term
effects of SSRIs, their prescriptions should be made cautiously and carefully
monitored over time. This is especially true given the very high rate at which
SSRIs are prescribed.

This is a lot of information to take in, even with my attempts to summarize a large
topic as succinctly as possible. Accordingly, for the remainder of this post, I’d
like to give my thoughts about what to keep in mind with this information, and
what not to do with it. The “what not to do” section is more clear-cut, so I’ll start
there:

• Do not, under any circumstance, stop taking antidepressants without the guidance of a medical professional. Discontinuation effects are well documented in studies, particularly when SSRIs are stopped abruptly, with symptoms varying from dizziness, fatigue, headaches, and insomnia to aggression, anxiety, irritability, mood changes, and panic attacks (16). Pharmacologists believe that these discontinuation symptoms can likely be attributed to the elimination half-life of SSRIs; in other words, how long it takes for the drugs to be metabolized and eliminated from the body (Weir, 2020).
• Do not demonize mental health medication, judge the individuals or
  families who choose to use them, or fall into a thinking trap of viewing
  psychiatric medications as either “all good” or “all bad.” I believe the public
  is more aware of the existence of MDD than it used to be, and fortunately
  the stigma around it is decreasing. However, it is difficult to put into words
  how acutely painful MDD is for the individuals who suffer from it and for the
  loved ones who witness their suffering. While there is much that still needs
  to be learned about antidepressants, they are a possible source of support
  for people and families who are desperately searching for relief from
  depression. I think Pies and Dawson (2022) said it best: “Many effective
  drugs used in general medicine, neurology, and oncology act through
  unknown or multiple mechanisms, and this is not an indictment of the
  drugs or those who prescribe them" (17).

What to keep in mind:

• Any mental health professional worth their salt can tell you that depression
  is an extraordinarily complex illness that cannot be boiled down to a mere
  chemical imbalance. In this respect, clinicians are stating that the
  Moncrieff et al. (2022) paper isn’t exactly “new” news (Pies & Dawson,
  2022). Yes, a myriad of chemical reactions can contribute to MDD, but
  brain chemistry is but one part of depression’s many contributors, which
  can include but are not limited to brain structure, chronic pain, pre- or co-
  occurring medical or psychiatric diagnoses, family history, and genetics,
  medications, social factors, ongoing life stressors (i.e. financial problems,
  difficulty in relationships), substance use, and/or trauma. To that end,
  while some may benefit from psychiatric medications alone, ongoing
  research has found that a combination of psychiatric medication and
  psychotherapy is associated with significantly better outcomes in
  ameliorating MDD, particularly in cases of more acute or re-occurring
  depression (18, 19, 20). Furthermore, there are also somatic therapies (i.e.
  electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve
  stimulation) and complementary treatments (i.e. acupuncture, folate, light
  therapy, meditation) that may help to decrease depressive symptoms.
• Personally speaking, I am wary of the clinician that focuses primarily on
  medication without taking interest in an integrative, tailored treatment plan
  for patients who are diagnosed with, or may be suffering from, depression.
  How many, if any, complex health concerns can you think of that are
  ameliorated by only one approach? Heart disease, skin conditions,
  diabetes, or any number of illnesses are rarely improved by just
  medications; doctors encourage patients to make ongoing adjustments to
  their lifestyles and behaviors. Why should illnesses involving the brain –
  the most intricate and complicated organ in our body – be the exception?
  What I am writing may seem painfully obvious, but at times I am still
  surprised and saddened by medical professionals I come across who are
  dismissive or diminish the importance of the psychological profession. Fortunately, these instances in my career are the exception rather than the
  rule. However, when one considers what has been discussed in this post
  – that antidepressants can have limited effectiveness, that individuals may
  want to decrease or stop taking their medications at some point, that
  depression has multiple and personal contributors beyond chemical
  imbalances – the coping skills and insight that an individual with
  depression learns through psychotherapy becomes a fundamental part of
  the treatment plan for MDD rather than just an “option.” It is simple to find
  a plethora of research that backs me up on this.
• Be an effective healthcare advocate for yourself, and don’t be afraid to ask
  questions. When I refer clients for a psychiatric referral, I do so
  thoughtfully because I very much want them to live their healthiest lives,
  and believe that medication combined with psychotherapy may be the best
  way for them to achieve that goal. At the same time, I like when clients
  have many questions about mental health treatments, because their
  questions tell me that they are thoughtful about their self-care. As is
  evident by the Moncrieff et al. (2022) paper and the resulting wide
  coverage, the fields of psychiatry and neuropsychology are complicated
  and ever-evolving. When it to comes to medications and what you put in
  your body, I firmly believe that there is no such thing as a stupid question:
  you are valuable, and your health and how it is managed is an essential
  part of a life well-lived. Write a list of your medication-related questions
  and bring it to your doctor. If you don’t understand their explanations,
  speak up. If you feel rushed, ask for times to follow up and/or
  supplementary informational resources to refer to in between visits. If you
  feel dismissed or your doctor becomes defensive, find another practitioner.
  You and your healthcare provider(s) may have a difference of opinion on
  what may be most helpful, and you may be asked to keep an open mind
  when considering different treatments, but your feelings about your
  healthcare regimen are important and deserve to be treated with respect.
• If the article discussed in this post or some of the alarmist-tone media
  headlines you have seen associated with it have you feeling anxious or
  hopeless, take a moment to pause, take a deep breath from your
  diaphragm, and consider my favorite title on this issue that I’ve seen thus
  far, featured in The New Republic: It’s Good When Science Confirms That
  Depression is Complicated (21). Yes, there are gaps in our knowledge about
  depression and its treatment, just as uncertainty exists in many of life’s
  most complicated challenges. Analyses of studies like those written by Moncrieff et al. (2022) increase discourse in both public and professional
  arenas and lead us to ask questions that make us better health advocates,
  clinicians, and researchers. Our understanding of MDD has evolved
  exponentially over the course of the past century, and this evolution will
  continue as lifelong learners pursue degrees in mental health, medicine,
  and various sciences. Uncertainty is not reason for despair or
  catastrophizing. If you are suffering from depression, there are many
  treatment options to consider. Likewise, there are psychologists,
  psychiatrists, and other professionals who are eager to welcome you to
  their office, are humbled by the trust their clients place in them, and are
  passionate about supporting individuals and families on the path to
  wellness. I know from experience.

References

1 Moncrieff, J., Cooper, R.E., Stockmann, T., Amendola, S., Hengartner, M.P. & Horowitz, M.A. (2022). The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry. https://www.nature.com/articles/s41380-022-01661-0

2 Pratt, L.A., Brody, D.J., & Gu, Q. (2017). Antidepressant use among persons aged 12 and over: United States, 2011– 2014. NCHS Data Brief, 283. https://www.cdc.gov/nchs/products/databriefs/db283.htm

3 Express Scripts. (2020). America’s state of mind report. https://www.express-scripts.com/corporate/americas-state-of-mind-report

4 Bachmann, C.J., Aagaard, L., Burcu, M., Glaeske, G., Kalverdijk, L.J., Petersen, I., Schuiling-Veninga, C.C.M., Wijlaars, L., Zito, J.M., & Hoffman, F. (2016). Trends and patterns of antidepressant use in children and adolescents
from five Western countries, 2005-2012. European Neuropsychopharmacology, 26(3), 411-419. https://pubmed.ncbi.nlm.nih.gov/26970020/

5 Sarginson, J., Webb, R.T., Stocks, S.B., Esmail, A., Garg, S., & Ashcroft, D.M. (2017). Temporal trends in antidepressant prescribing to children in UK primary care, 2000 – 2015. Journal of Affective Disorders, 210, 312-318. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458802/

6 Shaw, D.M., Camps, F.E., & Eccleston, E.G. (1967). 5-Hydroxytryptamine in the hind-brain of depressive suicides.
The British Journal of Psychiatry, 113(505), 1407-1411. https://pubmed.ncbi.nlm.nih.gov/6078496/

7 Wong, D.T., Perry, K.W., & Bymaster, F.P. (2005). The discovery of fluoxetine hydrochloride (Prozac). Nature Reviews Drug Discovery, 4, 764-774. https://www.nature.com/articles/nrd1821#ref-CR40

8 Pereira, V.S. & Hiroaki-Sato, V.A. (2018). A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatrica, 30(6), 307-322. https://www.cambridge.org/core/journals/acta-
neuropsychiatrica/article/brief-history-of-antidepressant-drug-development-from-tricyclics-to-beyond- ketamine/B5C9D55C6299BC41B237187DB609DB68

9 Hillhouse, T.M. & Porter, J.H. (2015). A brief history of the development of antidepressant drugs: From monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1), 1- 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428540/ 

10 Graziosi, G. (2022, August 1). What a new study on depression does – and does not – tell us about antidepressants and serotonin. The Independent.
https://www.independent.co.uk/news/world/americas/depression-serotonin-levels-antidepressants-pills-side-effects-b2135378.html

11 Pierre, J. (2018). Do antidepressants work? Yes, no, and yes again! Psychology Today. https://www.psychologytoday.com/us/blog/psych-unseen/201802/do-antidepressants-work-yes-no-and-yes-again

12 Nischal, A., Tripathi, A., Nischal, A., & Trivedi, J.K. (2012) Suicide and antidepressants: What current evidence indicates. Mens Sana Monographs, 10(1), 33-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353604/ 

13 Moyer, M.W. (2022, April 2). How much do antidepressants help, really? The New York Times. https://www.nytimes.com/2022/04/21/well/antidepressants-ssri-effectiveness.html

14 Petersen, A. (2019, August 28). New concerns emerge about long-term antidepressant use. The Wall Street Journal. https://www.wsj.com/articles/new-concerns-emerge-about-long-term-antidepressant-use-11567004771 

15 Targum, S.D. (2014). Identification and treatment of antidepressant tachyphylaxis. Innovations in Clinical Neuroscience, 11(3), 24-28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008298/

16 Weir, K. (2020). How hard is it to stop antidepressants? American Psychological Association Monitor on Psychology, 51(3). https://www.apa.org/monitor/2020/04/stop-antidepressants

17 Pies, R.W., & Dawson, G. (2022). The serotonin fixation: Much ado about nothing. Psychiatric Times. https://www.psychiatrictimes.com/view/the-serotonin-fixation-much-ado-about-nothing-new

18 Cuijpers, P., Berking, M., Andersson, G., Quigley, L., Kleiboer, A., & Dobson, K.S. (2013). A meta-analysis of cognitive-behavioral therapy for adult depression, alone and in comparison with other treatments. The Canadian
Journal of Psychiatry, 58(7). https://journals.sagepub.com/doi/10.1177/070674371305800702

19 American Psychiatric Association. (2010). Practice guideline for the treatment of patients with major depressive disorder (3 rd ed.). https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd-1410197717630.pdf

20 Anxiety & Depression Association of America. (October 2020). Understand anxiety & depression: Treatment and management. https://adaa.org/understanding-anxiety/depression/treatment-management

21 Cummins, E. (2022, August 10). It’s good when science confirms that depression is complicated. The New Republic. https://newrepublic.com/article/167367/depression-serotonin-chemical-imbalance