Wondering why you can’t tolerate antidepressants? SSRIs can cause Serotonin SyndromeRuslan Dorfman, PhD, MBA
Last updated March 19, 2021
Many people diagnosed with depression cannot tolerate antidepressants even at low doses. To treat the symptoms of depression, patients often try different medications to no avail; nothing seems to work, or they cause intolerable side effects. In the worst-case scenario, a severe adverse reaction to antidepressants, such as commonly prescribed SSRIs, can include a potentially fatal condition known as ‘Serotonin Syndrome.’ Here we explain why some people have problems finding optimal treatment for depression, anxiety and other mental health conditions and how understanding your genetics can help.
What is an SSRI?
SSRI is an acronym for ‘Selective Serotonin Reuptake Inhibitor’, a class of drugs for treating mental health conditions. It includes some of the most commonly prescribed antidepressants. SSRIs are prescribed for depression, anxiety disorders and other conditions such as Obsessive-Compulsive Disorder (OCD).
Serotonin is one of the essential chemical messengers of brain cells. It regulates mood, emotion, social behaviour, sleep, memory, learning and other functions. It is thought that people who suffer from depression have lower levels of serotonin in the brain. SSRIs work by blocking the reabsorption of serotonin, causing the level of serotonin in the brain to increase over time, enhancing communication between neural cells. In general, depression symptoms are relieved once an appropriate level of serotonin is achieved. This is why it takes several weeks before patients and their doctors can know whether or not a treatment plan is working. However, having too much serotonin in the brain also leads to significant mental health problems.
Some patients with bipolar disorder, schizophrenia, or personality disorders have elevated levels of neural transmitters in the brain, including serotonin, leading to severe mood swings and anxiety.
What is Serotonin Syndrome?
When treated with SSRIs, people may be at risk for a serious drug reaction called Serotonin Syndrome, which can be triggered by the use of other drugs and supplements that further increase serotonin levels. Serotonin Syndrome symptoms include:
- rapid heart rate
- agitation / restlessness / panic attacks
- twitching muscles
- loss of muscle coordination
- heavy sweating
- high fever
There can be a range in the severity of symptoms. In the case of mild symptoms, the side effects are usually alleviated once the medication is stopped. Some patients, however, experience severe symptoms which can be fatal if left untreated. Interactions between SSRIs, other types of antidepressants, as well as some supplements can trigger Serotonin syndrome. When switching between different types of antidepressants, the current drug must be slowly tapered down over a few weeks, followed by a washout period before new antidepressants can be started to reduce the risk of Serotonin Syndrome. Consult with your doctor and pharmacist about the best way to start new medications safely.
What causes SSRI intolerance?
The answer is in your genes.
Not all patients experiencing mood swings or depression have abnormally low levels of serotonin in the brain. Even though they have normally functioning liver enzymes that metabolize SSRIs properly, they are still unable to tolerate these medicines, even at low concentrations. They can experience side effects within a few hours of getting the first doses. People who experience such symptoms frequently carry a mutation in one of the genes that make proteins involved in the clearance of serotonin from the body, resulting in accumulated high levels of serotonin.
An excess of serotonin is commonly found in patients with bipolar disorder and other inherited mental health conditions which have anxiety and depression as part of the initial clinical presentation. The trouble for these people begins when they start taking an SSRI in combination with other medications that further elevate serotonin levels. Some patients cannot tolerate even the first few doses of SSRIs.
Based on our experience with mental health patients, we note that most of the patients with bipolar disorder and schizophrenia have normal activity of both enzymes that process SSRIs. In fact, new CANMAT guidelines for treatment of Bipolar I disorder recommend avoiding SSRIs due to high risk of symptom worsening.
If you experience worsening anxiety symptoms, rapid heartbeat and difficulty breathing after taking one or two doses of your antidepressant, SSRIs might not be the right medication for you.
What to do if your SSRI is not working, and you are concerned about adverse side effects?
- Talk to your doctor, pharmacist or other trusted healthcare provider. Describe your side effects in detail, as well as any family history of mental illness.
- If Serotonin Syndrome is suspected, the recommendation would be to discontinue SSRIs and start a different type of antidepressant that does not affect serotonin.
What else should you consider?
The majority of side effects occur when medication concentration in the bloodstream is too high. This can happen even if you are taking a regular drug dose, but your liver is not able to eliminate the drug out of your body. Most of the commonly used antidepressants are metabolized primarily by two liver enzymes. If one of these enzymes is not working, i.e. you are a Poor Metabolizer, the level of antidepressant increases in the blood, which leads to significant side effects. If antidepressants metabolize too quickly, i.e. you are a Rapid or Ultrarapid Metabolizer, the drug is eliminated too fast. It does not achieve a high enough concentration in the blood to be effective.
The STAR*D study demonstrated that only one-third of patients respond to the first line of treatment with antidepressants. The majority of patients with depression have to undergo multiple drug trials to find the most effective medication. The ultimate goal of pharmacogenetics is to improve treatment outcomes by predicting a patient’s response to specific drugs – before they are prescribed. This approach allows us to move away from the traditional “trial method” of prescribing medicines and shift towards a more evidence-based, personalized approach.
Pharmacogenetic testing helps optimize treatment for depression
A Pharmacogenetic (PGx) test, such as Pillcheck, can help you know in advance whether or not you are at risk for adverse side effects or if you may not benefit from specific medications due to inherited altered drug metabolism. There are some people with a serotonin imbalance who cannot tolerate SSRIs even though their liver enzymes function normally. In other words, they may experience SSRI-induced side effects even though their Pillcheck report shows that this medication is appropriate for them. However, knowing how your body processes medications can significantly reduce the time to remission, decrease the risk of adverse side effects, improve drug efficacy and lead to overall better treatment outcomes.
Want to know more about Pillcheck and how it can help you?
Drug-Induced Serotonin Syndrome. Bartlett D et al. Crit Care Nurse. (2017) https://www.ncbi.nlm.nih.gov/pubmed/28148614
Serotonin syndrome (serotonin toxicity) https://www.uptodate.com/contents/serotonin-syndrome-serotonin-toxicity
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512908/
Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. https://www.ncbi.nlm.nih.gov/pubmed/27997040
Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder https://pubmed.ncbi.nlm.nih.gov/29536616/