Australia is one of the highest consumers of antidepressants, but these medications can have unwanted side effects if not used wisely.
Gene Dosage is a monthly column by Janan Arslan that finds out what genome science is uncovering about each individual's unique response to drugs and pharmaceuticals. Janan is a graduate student and pharmacogenomics researcher with a keen interest in personalised medicine.
It was a sunny day in Melbourne. I had just finished work, and was waiting for my bus in front of the Royal Melbourne Hospital, where I found an elderly gentlemen sitting on the bench, deep in thought. I don’t remember how our conversation even started, but somehow there we were, talking. The man pointed to a row of burn scars along his leg that had just begun healing. He had been prescribed antidepressants, he told me, and these had had a horrendous effect on him. The effect was so bad that he ended up causing bodily harm to himself — the scars were the product of his ghastly experience.
Having just started in the field of pharmacogenomics, I remember thinking what a coincidence it was for him to be sharing his story with a scientist invested in personalising treatments, an area so relevant to his experience. Serendipity, perhaps. It hit home that day how many others might be in this man’s situation, and I can honestly say the experience solidified my passion for the field. Paying homage to that day, this month’s column will focus on antidepressants.
So, what are antidepressants? Antidepressants are a class of psychotropic medications, which also include anxiolytics, sedatives, antipsychotics, mood stabilisers, and attention-deficit hyperactivity disorder (ADHD) medications. Antidepressant use can vary from a few months to years, but their objective is simple: they are supposed to make you feel better by reducing the effect of depression.
In 2013, the Organisation for Economic Co-operation and Development (OECD) released its Health at a Glance report, within which Australia ranked second highest in the level of antidepressant consumption amongst OECD member countries. In fact, the report noted a general increase in antidepressant consumption across all OECD nations. As depression is estimated to affect 350 million people globally, it is not surprising that antidepressant use is on the rise. The OECD report attributed this rise to several potential factors, such as: greater intensity and duration of treatments; and the use of antidepressants for milder forms of depression, generalised anxiety disorders or social phobia.
The OECD report says the latter reason has “raised concerns about appropriateness.” This to me suggests that psychiatrists may either unnecessarily or over-prescribe antidepressants.
Psychiatrists have traditionally used empirical approaches to treat their patients, often adopting a trial-and-error method, which usually sees the patients trying a few medications to find the best fit. It is within this period of trial-and-error that we may see unnecessary or even over-prescribing. “Let’s try this, and that. That didn’t work, maybe this.”
This approach is tricky and the psychiatrist needs to keep an eye out for clinical signs and side effects of concern, including nausea, agitation, aggression, sedation and weight gain. One of the worst side effects of antidepressant use is the increased risk of suicidal behaviour. This is perhaps what the elderly gentlemen had gone through during the course of his treatment, and perhaps why he harmed himself. Naturally, this process seems counter-intuitive as the objective is, after all, to help the patient feel better, not to bring them to the precipice of their sanity.
The incorporation of pharmacogenomics into psychiatry, therefore, seemed to be the next rational step. It takes out the guesswork for psychiatrists, isn’t co-dependent on purely clinical manifestation, and finds the right treatment for their patients with considerable ease. I can only imagine the relief it must bring for patients (and their psychiatrists) not to have all these antidepressants catapulted at them.
The most widely prescribed antidepressants are the selective serotonin reuptake inhibitors (SSRIs), due to their improved efficacy and tolerability. Sertraline (Zoloft), citalopram (Cipramil), escitalopram (Lexapro), paroxetine (Aropax), fluoxetine (Prozac), and fluvoxamine (Luvox) are all SSRIs. Only last month, the Clinical Pharmacogenetics Implementation Consortium (CPIC), a global community of pharmacogenomics researchers, released a publication about these SSRIs. As the CPIC is essentially the Holy Grail of this field, the genes I mention here will be straight out of their publication.
The gene CYP2C19 is the major metabolic pathway involved in the metabolism of sertraline, citalopram and escitalopram. In patients who are considered to be poor metabolisers (that is, their ability to metabolise the medication is significantly hindered), psychiatrists either reduce the dose of these medications by half, or try an alternative SSRI. Otherwise, the patient may experience unwanted side effects. At the opposite end of the spectrum, if the patient is an ultrarapid metaboliser (their rate of metabolism is considerably accelerated), they metabolise the drug so quickly that it may not have an effect, so their psychiatrist may consider switching to an alternate SSRI entirely.
Citalopram is also partially metabolised by the gene CYP2D6, which happens to be the major metabolic pathway of other SSRIs paroxetine and fluvoxamine. Similar to the aforementioned drugs, patients who are poor metabolisers for CYP2D6 are at greater risk of side effects than those who are considered normal metabolisers. And ultrarapid metabolisers, due to their ability to quickly clear the drug, may have no benefit from taking either medication. Fluvoxamine also has minor metabolic pathways, such as CYP2C19 and CYP1A2.
30-40% of patients who take fluoxetine do not respond to the treatment, and this is most likely linked to genetic variation. Although several genes are involved in the metabolism of fluoxetine, such as CYP2C9, CYP3A4 and CYP2C19, the most significant gene is CYP2D6. Its method of metabolism is very complex, as it is converted to two counterparts: R-norfluoxetine (CYP2D6 and CYP2C9), and S-norfluoxetine (CYP2D6 only). S-norfluoxetine is considered to be more effective, as it is 20 times more potent in modulating serotonin re-uptake than the R-norfluoxetine.
A considerable amount of time, energy, and resources have gone into standardising prescribing practices in psychiatry. Besides the CPIC, the US Food and Drug Administration (FDA) had to incorporate several warnings into antidepressant drug labels to make consumers aware of potential side effects, in particular suicide ideation. When pharmacogenomics became more accessible, these warnings were upgraded to suggest the incorporation of genomic testing into prescribing methods.
As I conclude this column, my mind wanders back to the final words I exchanged with the elderly gentlemen. Thinking that I could help, I told him about the availability of pharmacogenomics testing. He merely nodded at my words, and we sat in silence for a moment. I suspect we both wondered whether all of his pain could have been avoided. The sad answer to that question is, yes, it probably could have been. Here’s to hoping that in the near future, we can avoid this happening to others.