In the 1970s, the discovery that serotonin played a
significant role in mood disorders initiated efforts to develop Selective
Serotonin Reuptake Inhibitors (SSRIs). Monoamine oxidase (MAO) inhibitors and
tricyclic antidepressants (TCA) had been used to treat major depressive
disorder since the late 1950s. Both of these classes of drugs were developed
serendipitously; MOAs were discovered originally for treatment of tuberculosis
and TCAs were initially intended for patients suffering from schizophrenia. MAO
enzymes break down amines such as neurotransmitters, and their inhibition results
in the increase of neurotransmitter concentrations in the presynaptic terminal.
TCAs contain a core of three benzene rings and inhibit both neurotransmitter
transporter and receptor functions. Although these medications were mildly
effective, they had a narrow therapeutic index and long list of serious side
effects.1
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Figure 1.
Mechanism of Action of Selective Serotonin Reuptake Inhibitors7
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In the clinic, SSRIs proved to be
much more tolerable than MAO inhibitors and TCAs for patients based on their
specificity for serotonin receptors.2 They bind only serotonin
transporters and increase the amount of serotonin in the synapse. Over time, the
serotonin receptor 5HT1A is downregulated and even more serotonin is released. This
mechanism explains why these medications take a few weeks to show full effect.3
SSRIs were initially thought to be free of side effects and could be used by
children and elderly populations.
However, as
clinical use increased, the side effects of SSRIs became more apparent. It is
possible that the dosages used in early clinical trials were relatively low and
at levels that did not exert observable side effects. It is also possible that
side effects were not reported as they relied on self-report measures which
often lack accuracy. The most significant adverse side effects of SSRIs are serotonin
syndrome, sexual dysfunction, and weight gain, but appetite and sleep may be
affected. Serotonin syndrome can result from overdose and presents with muscle
spasms, increased heart rate, and possible psychosis. If a patient abruptly
stops taking SSRIs, discontinuation syndrome may ensue. This is similar to
withdrawal, so patients should be weaned off these medications.2 A
2005 study showed patients who tapered their SSRI medications exhibited half
the symptoms of discontinuation syndrome than those who stopped taking them
abruptly. Tapering schedules were developed by patients, general practitioners,
and psychiatrists, with periods varying from two weeks to four months.4
The
controversy on the efficacy of SSRIs prevails. Irving Kirsch is a psychologist
and a researcher of the Placebo Studies Program at Harvard Medical School. In a
60 Minutes special, Kirsch argued
that the placebo effect, not the actual chemical substance of antidepressants,
accounted for patients’ improvement By performing a meta-analysis, he concluded
that SSRIs were only effective with severe levels of depression. However, Dr.
Michael Thase of the University of Pennsylvania School of Medicine disagreed,
saying that by focusing on research, Kirsch was overlooking the success of
SSRIs seen in clinic. Although the efficacy Thase observes is low, more success
is seen in the mildly and moderately depressed than what is shown in the research.5
A newer meta-analysis conducted by Hieronymus et al. compared paroxetine and
citalopram (information was requested for fluoxetine and sertraline but was not
received) and refuted this placebo effect. More research is needed to provide
conclusive evidence on SSRI efficacy, but this study was able to provide
support for the pharmacodynamic effects of these drugs.6
- Hillhouse, T. M., & Porter, J. H. (2015). A brief history on the development of antidepressant drugs: From monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1). http://doi.org/10.1037/a0038550
- Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Effects and Tolerability. The Primary Care Companion to the Journal of Clinical Psychiatry, 3(1), 22-27. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181155/#i1523-5998-003-01-0022-b11
- Guzman, F. (n.d.). Mechanism of Action of SSRIs. Retrieved from https://psychopharmacologyinstitute.com/antidepressants/ssris/mechanism-action-ssris/
- van Geffen, E. C. G., Hugtenberg, J. G., Heerdink, E. R., van Hulten, R. P., & Egberts, A. C. G. (2005). Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. European Journal of Clinical Pharmacology, 61, 303-307. https://doi.org/10.1007/s00228-005-0921-x
- Stahl, L. (Interviewer), Kirsch, I. & Thase, M. (Interviewees). (2012, February 19). Treating Depression: Is there a Placebo Effect? [Interview Transcript]. Retrieved from https://www.cbsnews.com/news/treating-depression-is-there-a-placebo-effect/
- Hieronymus, F., Lisinski, A., Nilsson, S., & Eriksson, E. (2017). Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Molecular Psychiatry. https://doi.org/10.1038/mp.2017.147
- Lattimore, K. A. , Donn, S., Kaciroti, N., Kemper, A. R., Neal, C. R., & Vázquez, D. (2005). Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis. Journal of Perinatology, 25, 595-604. doi:10.1038/sj.jp.7211352.
By Catie White, Master of Medical Sciences Student, University of
Kentucky
I found this blog to be very informative on Selective Serotonin Reuptake Inhibitors (SSRI’s). I have learned about neurotransmitters and the nervous system in general, however, I was unaware that there is still issues about SSRI medications and disagreements over the efficacy of them. Not only the efficacy seems to be the problem, but also each individual’s interpretation on which severity levels of depression SSRI’s can treat. At the end of this blog, another question that came to mind was how does a psychologist or physician assess the level of depression?
ReplyDeleteThe NHS at South West London Health and Care Partnership gave some insight by providing a chart on the assessment and treatment of depression in adults within primary care. Two systems are used to diagnose the severity of depression, DSM-IV and ICD-10 (Taylor et al., 2014). The PHQ-9 is a diagnostic tool that is also used, which scores each of DSM-IV’s 9 criteria in a range of 0 to 3 (0 meaning not at all and 3 meaning nearly every day) (Taylor et al., 2014). If an individual displays mild depression, they will have 4 of the 10 symptoms in ICD-10, in the DSM-IV, few symptoms of the 5 result in only minor practical deficiency, and the PHQ-9 score ranging from 5 to 9 (Taylor et al., 2014). Displays of moderate depression include 5 to 6 of the 10 symptoms in ICD-10, symptoms contribute between mild and severe functional impairment in the DSM-IV, and the PHQ-9 score between 10 to 14 (Taylor et al., 2014). Lastly, patients with severe depression have 7 or more symptoms in ICD-10, a majority of the symptoms in the DSM-IV hinder function, and the PHQ-9 scores of above a 20 (Taylor et al., 2014).
The NHS does warn about the possible adverse effects of SSRI’s but still recommends it as a first line treatment (Taylor et al., 2014). They also advise patients with mild depression to not take antidepressants due to the poor risk to benefit ratio (Taylor et al., 2014). This statement contradicts Dr. Michael Thase’s in the blog, saying that even though efficacy is low, there is more success observed in patients who are mildly or moderately depressed. In my opinion, the whole SSRI’s class of drugs should just be avoided and instead, researchers should work to just find an alternative way to increase serotonin levels in the synaptic cleft.
Reference:
Taylor, D., Payton, C., & Kapur, S. (2014, November). Protocol for assessment and treatment of depression in primary care. Retrieved October 18, 2018, from https://www.nice.org.uk/media/default/sharedlearning/624_croydondepressionguidelinefinal1dec11.pdf
Mental health is such an important aspect of overall health and general well-being. With World Mental Health Day being recognized recently (October 10), this is a very fitting topic to discuss. While there is still much controversy and debate surrounding the use of SSRI’s to treat depression, I became interested in analyzing natural ways to increase serotonin levels without the use of pharmaceuticals.
ReplyDeleteAn article published in 2007 highlighted several non-pharmacologic strategies for raising serotonin levels – most of which need further investigation and research. Factors that were mentioned included self-induced changes in mood, exposure to sunlight, along with diet and exercise.1
Studies analyzing the relationship between serotonin synthesis and various mood inductions showed “the possibility that the interaction between serotonin synthesis and mood may be 2-way, with serotonin influencing mood and mood influencing serotonin.” Attempting to change one’s mood (with positive thoughts) can not only affect the brain microenvironment but may also lead to changes in social behavior and overall better health outcomes.
Another mechanism mentioned, exposure to sunlight, was proven via several independent studies. One study investigated levels of serotonin during summer and winter seasons in postmortem brains, showing that people who died during summer (with more sunlight exposure) had higher levels of serotonin in the brain.1 A different study assessed serotonin-metabolite levels in venous flow of the brain, “showing a positive correlation between serotonin synthesis with hours of sunlight, independent of season.”1
There are known benefits of diet and exercise in overall health outcomes, however, they may have major implications in serotonin levels and brain chemistry as well. Researchers have been exploring ways to introduce tryptophan across the blood brain barrier, as it is the precursor to serotonin. Tryptophan from our diet is not purified and is unable to have substantial plasma increases in the brain due to “competition between various amino acids for the transport system.”1 “The possibility that mental health could be improved by increasing the dietary intake of tryptophan relative to the dietary intake of other amino acids remains an interesting idea that should be explored.”1
The studied effects of exercise on serotonin is thought to work via two different mechanisms: 1. “motor activity increases the firing rates of serotonin neurons, and this results in increased release and synthesis of serotonin” and 2. there is an increase in the brain of the serotonin precursor tryptophan that persists after exercise”1
I found these to be highly interesting approaches and hope to see more data about this in the future. The goal is to find more natural ways to cure ailments and diseases rather than pumping patients full of artificial processed products of which we do not fully understand the effects and mechanisms.
Young, S. N. (2007). How to increase serotonin in the human brain without drugs. Journal of Psychiatry & Neuroscience : JPN, 32(6), 394–399.
Modern advances in medicine have been able to treat or relieve many of the physical ailments. But the ailments of the mind still remain elusive. Like Caitlin mentioned in her post, we should perhaps shift our attention from developing a “pill” to alternative approaches. Improving sleep hygiene, maintaining a balanced diet, adequate physical activity and limiting unnecessary stressors have all been reported to improve one’s mental and physical well being. Recent studies have shed light the on the association between gut-brain axis and depression. Certain strains of our gut microbiota may play, either a pathogenic or protective role, in the development of depression and other disorders of the CNS. Studies also reports narrowing of microbiome diversity in individuals diagnosed with depression compared to the normal population. There is even emerging evidence that the microbiome could be using microRNAs to alter how DNA is transcribed and how proteins are synthesized in our neurons. Studies have also shown that diets consisting of variety of food groups: fruits, vegetables, whole grains, and those rich in macro and micro nutrients to be positively correlate with microbiome diversity.
ReplyDeleteWe should start by changing our attitudes towards diet. Food should be viewed as more than energy, it should be recognized as nourishment for our physical health and mental vitality.
References:
How bacteria are changing your mood
https://www.bbc.com/news/health-43815370
The Gut-Brain Axis: The Missing Link in Depression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662178/
While doing a little research on mood disorders, one interesting fact that I kept coming across was that women are more commonly affected by mood disorders than men. In fact, women have twice the risk of developing a mood disorder as compared to men. Why is this the case? According to an article posted on the Harvard Health website, there are many different theories that may explain the phenomenon. For example, one theory is that women are more likely than to openly discuss their feelings and seek help, and are thus more likely to be diagnosed with a mood disorder. Other biological factors may also come into play such as genetics and hormones.
ReplyDeleteSome depressive disorders are unique to women, such as premenstrual dysphoric disorder, postpartum depression, and postmenopausal depression. These events all correlate with extreme hormonal changes, which supports the theory that hormones, and estrogen in particular, play a significant role in depression. One theory is that hypoestrogenic states such as those mentioned above are correlated with an increased risk of developing depression. Another theory proposes that dramatic fluctuations in hormone levels, rather than absolute levels, are more likely to result in increased risk for depression. Clearly, more research needs to be done in this area to further examine the possible connection between reproductive hormones and depression.
References:
Soares, C. N., & Zitek, B. (2008). Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability?. Journal of psychiatry & neuroscience : JPN, 33(4), 331-43.
Harvard Health Publishing. (n.d.). Women and depression. Retrieved from https://www.health.harvard.edu/womens-health/women-and-depression
I am in complete agreement that mental health is a very important topic in today's society. I believe mental health is not taken as seriously as it should be and those suffering deserve better treatment. After watching the TED talk in class yesterday, I feel more educated on the prevalence of mental disorders. It makes sense that the majority of individuals suffering from mental disorders will show signs by the age of 24. Being 24 years old myself, I can understand those statistics. As a young adult, we are faced with many stressful and important life choices that may contribute to the development of anxiety, depression and even OCD.
ReplyDeleteWhether or not SSRI's are effective in treating mental disorders is a hot topic for debate. A study published by BMC Psychiatry highlighted a study conducted in 2015, which found that only 13% of the United States population was prescribed SSRI's and of that group, 69% did not meet the criteria for any major depressive disorder (Simons, 2017). This begs the question as to if American's are being over prescribed SSRI's. Another article published in 2016 by Scientific American, described the results of a study which discovered that treatment with SSRI's contributed significantly to an increase in suicidal thoughts and aggression (Simons, 2017). There is also a significant withdrawal effect that may cause numerous physical and mental problems. Are the potential benefits of treatment with SSRI's outweighed by the harmful effects?
There is no right or wrong answer to this question. Further research is needed in order to truly determine the efficacy of SSRI's. However, I do know many people who are prescribed SSRI's and have been taking them for years. Those individuals no longer report symptoms of anxiety or depression, but do admit that if they forget to take their medication, there are serious withdrawal symptoms. Would you want to become that drug dependent?
References:
Simons P. New Data Show Lack of Efficacy for Antidepressants. Mad in America. https://www.madinamerica.com/2017/02/new-data-showslack-efficacy-antidepressants/. Published February 27, 2017. Accessed October 25, 2018.
Across the board, it seems many agree there are a number of variables involved in an individuals depression symptoms. In addition, medications seem to affect different individuals with even the same symptoms in different ways. One may respond better to a drug similar to bupropion (a dopamine re-uptake inhibitor) vs. an SSRI, for example. Even norepinephrine availability is thought to be a piece of the depression puzzle and still SNRI's or pure NRI's are routinely prescribed to help treat. It seems, the more complicated the disease, the less likely a blanket treatment is available to patients. I realize this is not a profound statement but whatever the treatment, it should ultimately be "individualized" with medications being prescribed by only a specialist to help optimize each patient's response and decrease the possibility of any sort of deleterious side effects.
ReplyDeleteThe prescription of SSRI's or any other pill which either does not help or makes the depression worse may cause the patient to lose hope and stop all treatments sending them into even a more downward spiral.
There is depression involved in 7% to 15% of all pregnancies. Being a new mom recently, I had to find out what is the effect of these antidepressants on newborn if these were used in prenatal or postpartum depression. I actually found out published studies claiming that babies who were exposed to SSRIs through their mother had lower birth weight & less gestational age than the babies who were not exposed to SSRIs. More importantly there were significant reports of adverse neonatal symptoms (respiratory distress, jaundice, convulsions, feeding difficulties etc). Concerns about neonatal symptoms led the Food and Drug Administration and Health Canada to issue warnings in 2004 regarding third-trimester SSRI use.
ReplyDeleteNeonatal Outcomes After Prenatal Exposure to Selective Serotonin Reuptake Inhibitor Antidepressants and Maternal Depression Using Population-Based Linked Health Data
https://jamanetwork-com.ezproxy.uky.edu/journals/jamapsychiatry/fullarticle/668200
I thought it was intriguing that the first study you found attributed all progress made with SSRIs and anti-depressants just to be the placebo effect. With about 30 million people taking anti-depressants in the U.S., it seems odd that the effect may be completely in patient's head. A study I found examining the efficacy of antidepressants showed that anywhere from 20-40% of patients taking a placebo felt an improvement in depression symptoms in 6-8 weeks.1 This same study found SSRIs and other anti-depressants had anywhere from 40-60% effectiveness in the study group.
ReplyDeleteThe study goes further, saying that 50 out of 100 people taking a placebo had a depression relapse within 2 years, while only 23 of 100 on antidepressants had a relapse. Undoubtedly, as Katie said, more research is really necessary to show if these SSRIs are worth the possible harm that they can cause, from dizziness, heart problems, or even withdrawal.
Another thing that was intriguing is that SSRIs are reported to increase suicidal thoughts and attempts at taking one's life in teenagers. It is scary that these medications meant to limit depression and mood disorders can escalate them so far.
Reference:
Informed Health Online [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Depression: How effective are antidepressants? 2015 Jan 28 [Updated 2017 Jan 12]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK361016/
I find it very interesting how SSRI's were initially thought to have no side effects and were supposedly safe for use in children and the elderly. In today's medical community, it is generally accepted that you are almost guaranteed to have at least one side effect from taking an SSRI. The Mayo Clinic states that some of the most common side effects are dizziness, sexual dysfunction, drowsiness, nausea, and insomnia, among others (Mayo Clinic, 2018). However, most, if not all of these side effects are expected to go away within a few weeks. One particularly disturbing aspect of SSRI's is their withdrawal symptoms. Having taken SSRI's myself, I have experienced this firsthand. I once ran out of my medication for several days due to extenuating circumstances and I remember very vividly how ill I became. I was so dizzy that I could barely see, felt so hot (as if I was running a fever), became extremely nauseated, and the whole right side of my body would randomly twitch violently. Once I finally took my medication, I was completely back to normal in about an hour. Hopefully, there will be medications developed that aren't just a "serotonin bath" for your brain and that do not have withdrawal symptoms.
ReplyDeleteReference:
Selective serotonin reuptake inhibitors (SSRIs). (2018, May 17). Retrieved from https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825
In a video that I recently watched on social media, a doctor was talking about the overprescription of SSRIs and the like stating that doctors are quick to write a pill, but not to run the necessary tests to see if its a chemistry problem or a life problem. His suggestion was a change in mindset could be the key to living a depression/anxiety free life even when living with the constant stressors we have daily. While that may not be exactly true, I think it is a good approach to a growing problem. Of course, there are more serious matters that require a more serious approach such as those cases of PTSD. However, they are not 100% effective against the disorder.
ReplyDeleteA study showed that 60% of PTSD cases responded to treatment using SSRIs while only 20-30% showed complete effects of the treatment (Alexander, 2012). While SSRIs are commonly used with other therapies in these cases, it is safe to say that some disorders require them. The fact still remains that the necessity is relative to the recipient and the physician. Until we understand mental illness better, there may not be a treatment that doesn't involve messing with the body's natural chemistry.
Reference:
Walter Alexander. (2012).Pharmacotherapy for Post-traumatic Stress Disorder In Combat Veterans Focus on Antidepressants and Atypical Antipsychotic Agents. Pharmacy and Therapeutics, 37(1): 32-38.
As advanced as medicine has become in this day and age, one of the few things that have, arguably, not advanced are the use of SSRI's. Some people will argue that their antidepressants are essential to their every day functioning while others admit that they are not helpful and struggle to find an effective treatment. According to Informed Health Online, these medications are only meant to treat moderate and severe chronic mood disorders, probably not mild cases. So what of that for the mild cases? Well, it comes down to a series of trial and error of medications. When one proves to be ineffective, another one is prescribed in hopes of working. As someone who suffers from anxiety, this can be a very frustrating and hopeless process. Most of the SSRI's I was prescribed made me extremely sick to my stomach. Although SSRI's may not work for some, a recent study shows that 29 out of 32 individuals favored an SSRI in elevating their mood, which are fantastic odds. Because the stigma on mental health is finally starting to diminish, I am confident there will be an advance on alternative treatments.
ReplyDeleteInformed Health Online [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Depression: How effective are antidepressants? 2015 Jan 28 [Updated 2017 Jan 12]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK361016/