History of Antidepressant Medications
While we here at the Counseling Center Group focus on the behavioral side of healthcare, it’s still very important for us and our clients to understand the world of medicine and how it applies to mental health. In this vein, I wanted to spend this post exploring the history of medications that are most widely used for treating depression so that we can make the most informed choices when exploring treatment options. We’ll cover the history of medications used for depression, the current landscape for treatment options, and some exciting new developments within the pharmacological space.
While this blog post draws heavily from the article “Ketamine and the Future of Rapid-Acting Antidepressants” by Riggs et al., I’ve done my best to make the information there a bit more presentable. I go on to mention Ketamine briefly towards the end of this article, which you can read more about in this very well written article. I am also writing a second blog post that goes into detail about one other promising medication that has already garnered a lot of excitement, psilocybin.
Monoamine Oxidase Inhibitors
The history of modern depression medication largely started in the 1950s when researchers noticed that the tuberculosis medication Iproniazid had the unintended side effect of improving patients’ moods. When scientists began to notice how this effect was being caused, they found that the drug was limiting the decay (ie oxidation) of the neurotransmitters Dopamine, Serotonin, and Norepinephrine (all belonging to the subclass Monoamines). This first wave of medications was, therefore, dubbed Monoamine Oxidase Inhibitors (MAOIs). Physicians quickly moved to start implementing the new medication, with 600,000 prescriptions issued in the first year they became available. However, they quickly found that the MAOIs had catastrophic side effects, including strokes and heart palpitations. This led the medical establishment to quickly begin searching for a less harmful alternative.
Tricyclics and SSRIs
In the 1960’s the next wave of antidepressants entered the market that proved to be more effective and less harmful than MAOI’s. Dubbed ‘Tricyclics’ due to their circular chemical structure, these medications targeted preventing reuptake instead of decay. Tricyclics were the first truly viable antidepressant and are still widely used today. However, they still prevented reuptake for all three Monoamines (Serotonin, Norepinephrine, and Dopamine) and thus created significant side effects such as dizziness, hypotension, blurred vision, and memory impairment.
Searching for ways to make further improvements, scientists looked at MAOIs in the 1950s and noticed that they had a larger effect on Serotonin decay than the other two monoamines. These observations led to the “Serotonin Hypothesis”, which posited that depression was linked to specifically Serotonin networks within the brain. The next major class of medications developed in the 1980s would be dubbed Selective Serotonin Reuptake Inhibitors (SSRIs), with a smaller class of meds called Selective Norepinephrine Inhibitors (SNRIs) developed as well for similar reasons. These medications selectively target serotonin or norepinephrine receptors and leave the other two monoamines largely unaffected, thus causing less overall disruption to the brain. Overall, this strategy has been largely effective, as SSRIs constitute the foundation of our current medical interventions for depression.
Where We Are Now
These medications have represented a dramatic improvement from previous generations and remain some of the most prescribed medications in the world. Once it was demonstrated that SSRIs and SNRIs were safe and effective, they exploded into the psychiatric space. According to the CDC, 15% of American adults have used SSRIs in the past 30 days and antidepressants are the most prescribed class of medication in the US. While, for the rest of this post, I’ll spend the majority of my time discussing the limitations these drugs still have, it is hard to overstate just how much of a positive impact they make. SSRIs are still the most scientifically supported FDA approved medications available for depression, and are responsible for changing the lives of millions of people all over the world. If you are experiencing significant and sustained depression symptoms, they should be one of the potential treatment options you discuss with your psychiatrist and therapist.
Limitations of Current Medications
That said, SSRI’s are still far from perfect in many ways. Even though SSRIs were a step up from their predecessors in terms of being more effective and having fewer side effects, they still do not work for everyone and can have harmful side effects such as nausea, irritability, insomnia, and sexual dysfunction. Patients starting medications typically have to wait several weeks for positive effects to occur and it is also common to have to try multiple medications before finding a good fit. This means that patients who are struggling can be made to endure up to 1-2 months of medication juggling before receiving relief from depression symptoms, all the while possibly experiencing considerable side effects. Furthermore, while it is generally accepted that around 33% of patients don’t respond to SSRIs at all (Riggs, 2021), a meta analysis of the original qualifying studies for SSRIs came to the controversial conclusion that the data from them does not demonstrate any significant benefit for any level of depression except for the most severe (Fournier, 2010). While there is still a widespread consensus that SSRIs are a beneficial treatment, these drawbacks demonstrate that there is still substantial room for improvement in the tools we have to treat depression.
Searching for Alternatives
Due to the limitations of current psychopharmacology, researchers have been searching for alternative medications since SSRIs were developed in the 80’s. However, until recently there had not been any real progress in the field for decades. Most antidepressant medications had initially been developed for other uses and had only been applied to mental health after other effects had been noticed. Subsequent attempts to develop medications according to the so-called “Serotonin Hypothesis” have not proved as fruitful as expected, which has led many researchers to begin to question whether the levels of serotonin and the other monoamines dopamine and norepinephrine are really the main explanations for depression. According to leading scholar Dr. Robert M. A. Hirschfeld of Cornell University, there has been a lack of convincing evidence in support of the predictions made based on the serotonin hypothesis, and as a result, it is generally accepted that the serotonin hypothesis cannot fully explain depression symptomatology or lead to treatments that will be widely effective (2000). It is important to remember that our understanding of depression in the brain is largely shaped by finding medications that work, seeing how they affect the brain, and then building our understanding of depression based on that. But just because something affects the symptoms of a disorder, that doesn’t mean it is related to the root cause. If I have a headache, take an ibuprofen, and then feel better, it does not mean my headache was caused by an ibuprofen deficiency. It seems increasingly likely that we made a similar misstep with SSRIs.
Exciting potential
Because of this, in recent years researchers have started to look more outside of the box for potential treatments, and the results are very promising. Some of the main contenders, which you have probably heard of, are LSD, psilocybin, MDMA, and ketamine. Interestingly, all but ketamine have similar histories of being discovered and then widely studied throughout the early twentieth century before being outlawed and heavily stigmatized. In many ways, therefore, we are returning to the work that we started in the 1970s and building an understanding of how these compounds can be used to help a variety of conditions including depression. The last 10 years have seen the start of clinical trials to determine how they work and how effective they are, many producing very exciting results. Unlike our current FDA approved medications, this most recent wave seems to produce immediate results after a single administration – a marked improvement over the delayed response of SSRIs. Effect sizes seem to be high and studies have failed to find any significant lasting side effects or abuse potential. Also, given their different mechanisms of action, these medications present an amazing opportunity to learn more about how depression functions in the brain. Ketamine in particular does not even affect serotonin receptors at all, indicating entirely new alternatives to the ‘Serotonin Hypothesis’. While it is always good to remain cautious about new experimental treatments, these new compounds do seem to have the potential to revolutionize our treatment of depression and our understanding of how it functions in the brain.
I am excited to talk more about this new wave of treatments and have already started a post on psilocybin therapy, so stay tuned!
References
Riggs, L. M., & Gould, T. D. (2021). Ketamine and the Future of Rapid-Acting Antidepressants. Annual Review of Clinical Psychology, 17(1), 207–231. https://doi.org/10.1146/annurev-clinpsy-072120-014126
Hirschfeld RM. 2000. History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61(Suppl. 6):4–6
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA, 303(1), 47–53.
About the Author
Matt Korbon, LGPC
Matt serves clients of all ages and backgrounds and is a Licensed Graduate Professional Counselor (LGPC) in the State of Maryland. Matt weaves together various treatments, including Cognitive Behavioral Therapy ...
