Why most Antidepressants don't work for me: turns out I have a nonfunctional gene
Hello all,
So I have had anxiety and depression related issues since I was in middle school at least, and for the past few years have been trying to manage it with medication. Last year, I was prescribed Escitalopram/Lexapro, but since I seemed to be experiencing Serotonin Syndrome (muscle spasms, dilated eyes, heightened anxiety, racing heart rate), I decided to stop after my second dose. This experience made me very afraid of trying medication, but then about two months ago, my PCP said that Lexapro may have just been too "harsh" of an option and that Citalopram/Celexa might work better for me. So she prescribed me some. However, I was so scared of experiencing the same side effects I felt before that I decided not to take it.
Turns out that that was a very good choice. Go anxiety brain!
After my refusal to take Citalopram, my PCP asked me if I would like to have a Genetic test done to determine what medications would work best for me and with the least side effects. I accepted, got my mouth swabbed, and got my results a few weeks later. I found out that I have a totally non-functional Cytochrome P450 2D6 enzyme which basically means that my body does not metabolize a good portion of commonly prescribed medications, including a majority of Antidepressants. Instead, they just sit there and accumulate each time I take one, resulting in overdose and other not-pleasant side effects.
I can't safely take: fluoxetine/Prozac, venlafaxine/Effexor, escitalopram/Lexapro, sertraline/Zoloft, amitryptyline/Elavil, clomipramine/Anafranil, desipramine/Norpramin, doxepin/Sinequan, imipramine/Tofranil, nortriptyline/Pamelor, vortioxetine/Trintellix, citalopram/Celexa, paroxetine/Paxil, selegiline/Emsam, vilazdone/Viibryd, bupropion/Wellbutrin, miratripzine/Remeron, trazodone/Desyrel, duloxetine/Cymbalta, or fluvoxamine/Luvox.
The only two antidepressants that I may be able to safely take are: desvenlafaxine/Pristiq and levomilnacipran/Fetzima.
My PCP wants me to start taking Pristiq to see if it works. Needless to say, I am terrified to try medication after what I just found out, even if it is medication that shouldn't negatively effect me like Lexapro did. I know that none of you on here are qualified to give me advice, but I just needed to let this off my chest.
I also found out that the mutation that I have makes me unable to process Codeine (and potentially other opioids), which explains why I felt so terrible taking Codeine after I got my Wisdom Teeth Removed. The terrible nightmares and facial numbness weren't due to anxiety, they were due to the gene-medication interactions. It's kind of nice to know that all the weird side effects that I experience from taking certain meds might not be anxiety. It makes me feel validated, like it wasn't all in my head.
Re: Why most Antidepressants don't work for me: turns out I have a nonfunctional gene
Quote:
Originally Posted by
AbyssalStars
I was prescribed Escitalopram/Lexapro, but since I seemed to be experiencing Serotonin Syndrome (muscle spasms, dilated eyes, heightened anxiety, racing heart rate)
These are not symptoms of serotonin syndrome, but of heightened serotonin activity which all serotonergic antidepressants trigger initially. It is what they are supposed to do. However, after a while bio-feedback kicks-in downregulating serotonin synthesis and expression in areas of the brain associated with anxiety (also depression) to well below baseline.
My guess is that you were started on 10mg/day. For anxiety a 5mg starting dose for the first 7-8 days is preferred.
BTW-most of what you find online about serotonin syndrome/toxicity is wrong. Many medical journals and even drug regulators such as the WHO, FDA and MHRA get it wrong (not my opinion, but that of one of the two leading SS/ST experts, Dr Ken Gillman who used to spend a large part of his semi retirement trying to correct this misinformation until the futility of it all became overwhelming (he details some of it here).
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my PCP said that Lexapro may have just been too "harsh" of an option and that Citalopram/Celexa might work better for me. So she prescribed me some. However, I was so scared of experiencing the same side effects I felt before that I decided not to take it.
Turns out that that was a very good choice.
Perhaps, but not for the reason you think. Citalopram and escitalopram share the same active chemical, the 'S' isomer of citalopram, aka escitalopram. Citalopram also contains the 'R' mirror image isomer which is a poorer fit biologically and so is mostly inactive. Escitalopram is more refined and only contains the 'S' isomer. There can be subtle differences in the side-effects each med produces because of that 'R' isomer in citalopram, but in terms of efficacy and how they are metabolised there is little difference.
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my PCP asked me if I would like to have a Genetic test done to determine what medications would work best for me and with the least side effects.
Gene testing is still very much in its infancy and not that reliable a guide. One of the hurdles may be that not only DNA may affect drug metabolising, so may epigenetic changes and other environmental factors. It's main advantage atm is fattening wallets. See, or example:
"Unfortunately, genome-wide association studies (GWAS) of antidepressant response have yet to consistently replicate any individual single-nucleotide polymorphisms (SNPs) that meet genome-wide significance.
"...One of the criticisms of universal PGx testing to predict antidepressant response is the variability in the gene variants comprising each company’s panel. Of the four companies that have published RCTs of PGx-guided treatment versus usual care, each company tests for a different panel of pharmacokinetic and pharmacodynamic candidate genes and SNPs. These differences lead to varying antidepressant recommendations in the proprietary PGx report. Therefore, a positive finding in one study does not indicate that all pharmacogenetic testing is useful. Unfortunately, no head-to-head trials of different PGx testing platforms have been conducted, so we have no idea whether any one company yields superior results.
"...Of course, gene structure is only one piece of the puzzle that contributes to inter-individuality of antidepressant response. Personal or environmental variables, such as concomitant medications, ethnicity, gender, smoking status, and comorbidities, are important as well. We are hopeful that future research with candidate genes such as the corticotropin-releasing hormone binding protein, norepinephrine transporter, and FKBPs, as well as inflammatory biomarkers and epigenetics, will lead to platforms with clinical utility for predicting antidepressant response.
Smith TL, Nemeroff CB,
Pharmacogenomic testing and antidepressant response: problems and promises, Braz J Psychiatry. 2020 Mar-Apr; 42(2): 116–117.
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"Despite the small number of clinically actionable variants, private industry has reached far beyond the evidence base to combine dozens of variants, many of dubious significance, into sweeping proprietary algorithms advertised to match a patient with the right drug. The literature supporting the clinical implementation of this testing is entirely industry-sponsored and highly biased. A few randomized controlled trials have been performed, but the majority have not met their primary outcomes."
Nurmi EL.
Panacea, placebo or poison? Genetically guided treatment for depression, Braz J Psychiatry. 2020 Mar-Apr; 42(2): 118–119.
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"The implementation of pharmacogenetic testing in psychiatry is underway but is not yet standard protocol. Barriers to pharmacogenetics becoming standard practice are the lack of translation of evidence-based recommendations and standardization of genetic testing panels. As for the latter, there are currently no regulatory standards related to the gene and allele content of testing panels used to derive medication selection and dosing advice."
Bousman C, Al Maruf A, Muller DJ,
Towards the integration of pharmacogenetics in psychiatry: a minimum, evidence-based genetic testing panel, Curr Opin Psychiatry. 2019 Jan;32(1):7-15.
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Even the Mayo Clinic which developed the GeneSight AD gene test says these tests shouldn't guide med selection:
"Choosing antidepressants based on your health history and symptoms is still the standard that health care providers use when prescribing these medications. Routine genetic testing isn’t recommended at this time."
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I found out that I have a totally non-functional Cytochrome P450 2D6 enzyme which basically means that my body does not metabolize a good portion of commonly prescribed medications, including a majority of Antidepressants.
Most ADs are metabolised by at least two enzyme pathways, so while lacking activity of one may increase a med's plasma levels it doesn't necessarily mean the med shouldn't be prescribed, or that it won't work, but that a lower dose will do the job. For example, citalopram and escitalopram are primarily metabolised by P-450 CYP3A4 and CYP2C19 isoenzymes with CYP2D6 having a minor role (it does have the primary role in metabolizing some secondary es/citalopram metabolites).
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I can't safely take: fluoxetine/Prozac, venlafaxine/Effexor, escitalopram/Lexapro, sertraline/Zoloft, amitryptyline/Elavil, clomipramine/Anafranil, desipramine/Norpramin, doxepin/Sinequan, imipramine/Tofranil, nortriptyline/Pamelor, vortioxetine/Trintellix, citalopram/Celexa, paroxetine/Paxil, selegiline/Emsam, vilazdone/Viibryd, bupropion/Wellbutrin, miratripzine/Remeron, trazodone/Desyrel, duloxetine/Cymbalta, or fluvoxamine/Luvox
As per above, citalopram and escitalopram, or primarily metabolised by non CYP2D6 isoenzymes. This is also true for sertraline which is primarily metabolised by P450 CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Vilazodone is mainly metabolized by cytochrome P450 CYP3A4 and to minor extents by CYP2C19 and CYP2D6. Mirtazapine is metabolised by CYP1A2, CYP2D6 and CYP3A4 isoenzymes with only about 25% of the drug metabolised by CYP2D6.
Re: Why most Antidepressants don't work for me: turns out I have a nonfunctional gene
Thank you for the reply, Panic_down_under. I haven't yet read your entire post, but I will soon. I just wanted to say that what I have read has calmed me down a bit. And after some of my own research, I found out that there are many many Cytochromes that all perform overlapping roles, so they sort of pick up each other's slack. And I guess this means that what I thought was a serious issue is probably not as serious as I first thought.
I made this post right after I was handed the results and told that a majority of antidepressants wouldn't work well for me. Now that I have had some time to relax, I think I can look at it more logically. I will definitely take what you said into consideration.
Edit: I finished reading your post! Thank you for all of your information. It's definitely valuable to know that I wasn't experiencing Serotonin Syndrome. It definitely felt scary in the moment. And I think that you are right about Genetic Testing being in its infancy.
Re: Why most Antidepressants don't work for me: turns out I have a nonfunctional gene
Quote:
Originally Posted by
AbyssalStars
And after some of my own research, I found out that there are many many Cytochromes that all perform overlapping roles, so they sort of pick up each other's slack. And I guess this means that what I thought was a serious issue is probably not as serious as I first thought.
Not only are there usually at least one other isoenzyme to metabolise a med there are over 100 alleric variants of CYP2D6 and I wonder how many were included in the test you had given some are difficult/expensive to sequence. But even if your liver was completely unable to metabolise meds via CYP2D6, it doesn't mean the drug would accumulate exponentially. The body has alternative ways of eliminating it.
Around 8-10% of Caucasians are non CYP2D6 metabolisers (~2% for Africans, <1% for Asians) and I'm guessing about as many again are poor responders which suggests there should be a large niche market for desvenlafaxine and levomilnacipran yet both are well down the sales rankings.
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It's definitely valuable to know that I wasn't experiencing Serotonin Syndrome. It definitely felt scary in the moment.
Understandable given that most of the information about it online is male bovine manure. Serotonin syndrome is rarely an issue when taking a single SSRI, even in massive overdose. It normally isn't even a problem when taking two SSRIs/SNRIs, or a SSRI/SNRI and TCA at appropriate doses, for example when cross tapering from one to another. It is usually only when taking a MAOI class AD with another serotonergic med that serious issues arise.
Which isn't to say that the side-effects are not due to serotonin. They are, but not because of serotonin toxicity as such. The problem is that serotonin isn't the 'feel good' transmitter of popular myth. It's just the opposite as you experienced. Nor are these symptoms only experienced when serotonin activity is increased by ADs. Despite the other common myth, anxiety and depression aren't caused by too little serotonin. In fact brain serotonin levels rise when we are anxious, or at least it does in rats which are a good model for what happens in humans (Rex A, 2005; Rueter LE, 1997). We and the anxious lab rats already have more serotonin in our brains than 'normies'/controls (Frick A, 2015; Zangen A, 1997). The first few weeks on ADs just compounds this until bio-feedback kicks-in.
