I am, admittedly, not very good at keeping up with social media in any capacity. The pages for the Lethal Dose Podcast are kept barely alive by the ability to schedule posts on Instagram and because my co-host, Venus, maintains the TikTok account. I’m not even sure if my personal or fiction author TikTok accounts are even still around, or if they’ve been deleted. For anyone keeping up with this blog, that likely comes as no surprise.
It’s not that I haven’t wanted to do any non-fiction writing to supplement the fiction that I’ve been putting out or the true crime stories that I research for the podcast, it’s just that, frankly, I’ve had a fucked up year.
In April, we covered serotonin as the poison of interest in the case of Libby Zion, and I mentioned in the episode that I’d recently put prescribed a selective serotonin reuptake inhibitor (SSRI) that worked well until it didn’t. When the medication made me hyponatremic and gave me debilitating migraines, I looked deeper into the side effects of antidepressants and the mechanism of action for serotonin and found that since the 1990s researchers knew that serotonin was not the only biochemical responsible for depression and so the use of SSRIs in depression treatment was perhaps not the most effective way to do things. Not that SSRIs are totally ineffective, either. I mentioned all of this in the episode and noted that many people do feel better when prescribed an SSRI – even I did, for a short time. Further research into the complexity of the biochemistry behind depression is certainly justified and needed.
That first medication was Lexapro (escitalopram). In the months to follow, I tried several more SSRIs and SNRIs (selective norepinephrine reuptake inhibitors) including Cymbalta (duloxetine), Luvox (fluvoxamine), Zoloft (sertraline), Remeron (mirtazapine), and the tricyclic antidepressant amitriptyline.
With all these drugs except sertraline, I experienced severe side effects before reaching a therapeutic dose. The sertraline was prescribed in August, and I told my psychiatrist and therapist that if it didn’t work for me I wasn’t going to try any more medications. Even at a therapeutic dose, it wasn’t working to in any way enhance my mood, and although I wasn’t experiencing ‘severe’ side effects, the drug caused dysphoria that ultimately resulted in me not using it. Rather than stopping altogether, my dose was lowered and I was instructed to take it with mirtazapine, which I’d already taken before and which did not work for me. This combination did not prevent the dysphoria, so I tapered off both drugs completely.
Now, there had been times over the course of this year when I’d tapered off to no medication, and when I’d tapered off one medication and onto another. I knew it was important to do this correctly because my doctors had warned me about antidepressant discontinuation syndrome, or antidepressant withdrawal. If you know me, you know I love mnemonic acronyms, and the acronym for antidepressant withdrawal is FINISH1:
FINISH:
Flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal
Honestly, this isn’t a very good acronym because it’s so general. These descriptions encompass a gamut of symptoms from muscle aches to nightmares to “brain zaps” to the involuntary jerky movements also seen in serotonin syndrome. I knew that any and all of these symptoms were possible side effects of even tapering off drugs and that I would just have to power through them for a week or two after my final dose.
So, when I started to experience the muscle aches, insomnia, brain zaps, intense nausea, dizziness, fatigue, and irritability, I wasn’t surprised. One week turned into two and I figured I was nearing the end of my suffering.
Then the migraines came. The pain felt like my brain was pushing my eyes from my skull and my cheeks felt swollen like I had a sinus infection. At first, they struck without warning and I would suddenly be sensitive to light, sound, and even smell. All I could do was lay in the dark, in the quiet, and try not to move too much. The migraines caused the nausea to worsen – or maybe my clenching my jaw from the nausea caused the migraines to worsen, it was hard to tell sometimes.
Two weeks turned into three. Three turned into five and I was still barely able to get myself to the office to work. I could manage maybe one day a week where I wasn’t in a dark room with my computer’s nightlight up and screen brightness down to just barely scrape by and avoid using up all my sick time. I contacted my primary care physician and she told me that there wasn’t much she could do for headaches except maybe prescribe me something else.
At this point in the story, I do want to be clear about something that I’ve repeated on the podcast: sick people should go to the doctor if they need help. Doctors, especially specialists, have a wealth of knowledge that we can benefit from. However, doctors are also people and are fallible. And, as was pointed out as the main problem in Libby Zion’s case, doctors are overworked and spread thin. In the age of COVID and in the United States, I can attest that this is still true in and some cases possibly worse now. But even before COVID, I noticed that, when presented with an especially complex problem, doctors demur and appear to have no more insight into the manner than you do as the patient with the problem.
One particularly vivid memory I have when my mother was experiencing problems requiring a specialist’s insight was a doctor’s office visit that ended with the recommendation that we search PubMed to see what we could find. I was perhaps 15 at the time and had never heard of PubMed. Not that it would have done me much good to look it up, given that most of the papers were behind a paywall and I hadn’t learned about any sort of Sci Hub.
Now I am older and wiser and have a VPN, and so I followed the doctor’s advice and did what doctors on the internet hate for people to do. I Googled it.
What I Learned
Doctors and academics have known about antidepressant withdrawal since the 1990s,2 around the same time they realized that serotonin manipulation was a sketchy way to treat depression. Despite the many issues presented by SSRIs, including serotonin overdose and withdrawal, the volume of these prescriptions increased threefold between 1995 and 2007 in the US and UK.
Attempts have been made to better understand the role of serotonin in depression, but until the last couple of years almost no one made any attempt to investigate the mechanism of action for antidepressant withdrawal.3 Although not everyone experiences withdrawal with all drugs, approximately 20% of patients who discontinue antidepressants taken for at least a month do experience withdrawal symptoms,1 which is not a negligible amount of people considering that 6-16% of the population of Europe and North America are estimated to be taking antidepressants (roughly 79-212 million people).4
There was resistance to even recognize the symptoms brought on by cessation of antidepressants as withdrawal and not simply ‘discontinuation syndrome,’ which placed the onus more on the patient than the drug.5 If pill manufacturers and prescribers admitted to a withdrawal syndrome from their product, it meant that the product is in some way addictive – which it is.4 There’s nothing which distinguishes antidepressants from any other psychotropic drug, like benzodiazepines, which have the potential for addiction and withdrawal symptoms upon cessation. Placing the blame on the patient also precludes the need to investigate the discontinuation syndrome, and it was often written off as a relapse or recurrence of the original mental illness from which the patient suffered before medication.6 While it is true that patients coming off antidepressants might be familiar with the agitation, sleep disturbances, or suicidal thoughts that accompany discontinuation of the drug, I can attest that the brain zaps and migraine headaches are an entirely new sensation and not part of the anxiety or depression I experienced prior to being medicated.
Examination of the withdrawal syndrome by one group in 2015 suggested three different types of withdrawal: new symptoms and rebound syndromes which are both acute and short-lasting, and then persistent withdrawal syndromes.5 The first two are the kind which are almost exclusively discussed by doctors and in literature prior to the 2010s. They encompass with FINISH symptoms and a return of the symptoms the patient experienced prior to medication but at a greater intensity, and are transient and reversible, and tend to stop spontaneously within a few weeks (1-2) of drug cessation and last no more than six weeks.
Persistent or protracted withdrawal symptoms are those which last longer than six weeks, in some cases the symptoms last for years. Because of the paucity of information regarding protracted withdrawal syndrome (PWS), providers may believe that the symptoms cannot possibly be caused by the antidepressants, leading to misdiagnosis and improper treatment for what can be a “severe and debilitating condition” that can, and has, led sufferers to suicide.4
Severity of symptoms appears to be unrelated to dose or duration of medication, once a person has been on a drug for at least a month. Rather, withdrawal symptoms appear to be worse in high-potency drugs and drugs with a short elimination half-life from the body.5 The worst culprits among antidepressants identified by user self-reporting appear to be sertraline,4, 7 venlafaxine,4, 6, 7 escitalopram,4, 7 paroxetine,1, 4-7 citalopram,4, 8 and fluoxetine4, 7. These drugs have elimination half-lives of 22-36 hours, 4 hours, 27-33 hours, 21 hours, 24-48 hours, and 1-4 days, respectively.
As with any drug, sample data is useful when considering a sample of the population, but may not exactly describe the experience of any one person. The half-life of venlafaxine, for instance, is quite short but is suspected to precipitate fewer withdrawal symptoms than sertraline, and fluoxetine’s long half-life is recommended in some instances for assisting in tapering off of antidepressants,1, 8 yet it suspected to precipitate symptoms more often than mirtazapine or duloxetine,4 which are considered by another group to be “high risk” drugs for PWS, while fluoxetine is considered “low risk”7. It is also best to keep in mind that only examining half-life of a drug is as overly simplistic way of examining the susceptibility of a drug to cause withdrawal symptoms in the same way that it is overly simplistic to think that adjusting serotonin alone will cure depression.
In my own experience, I struggled with anger at my doctors for prescribing me sertraline when I said I’d only be trying one more drug because I was clearly sensitive to the side effects of drugs, and sertraline has a short half-life. My time spent as a child of the night, alone in the dark and battling migraines, I had to remind myself that the information I’d uncovered on PWS is still relatively new, and disputed because of the small samples of data available and the apparent biases of the researchers.
For instance, the largest quantitative analysis of case reports regarding PWS, conducted in 2020 and examining 69 individuals on an internet forum specifically about antidepressant withdrawal help, included the founder of the internet forum, Adele Framer, as one of the researchers. Identifying bias and conflict of interest is important in any study, but it seems important to not discredit this woman for sounding the alarm based on her own awful personal experience that caused her to create the online community SurvivingAntidepressants.org and reach out to professionals in the field, like Michael P. Hengartner and Lukas Schulthess from the University of Zurich. Sixty-nine internet users is also not a great sample size for crediting or discrediting a hypothesis, but prior to their investigation the largest previous study on PWS only looked at seven case reports.
Still, some researchers have been accused of overstating the scope and severity of the problem.2 While more research is certainly needed – both for the sake of figuring out the frequency, severity, and mechanism of PWS, but also because people who are suffering need to be listened to and helped and because we need to be more aware of the risks of antidepressants – researchers have started to see the shape of the problem from case reports, as well as literature reviews of the scant data available using call center data and user surveys.
Discontinuation of antidepressants needs to be addressed in the same manner as discontinuation of any other drug that the body becomes dependent on, because that is truly what is happening. Moving the onus from the user to the drug raises the hackles of drug makers and prescribers because admitting that a drug causes withdrawal often gives people the impression that a drug is addictive, but addiction and dependence are different. Addiction indicates use based on drug-seeking behavior, while dependence refers to an adaptation of the central nervous system based on drug use. Remove this drug, and the effects of the adaptation are seen in the withdrawal symptoms, like with caffeine, alcohol, opioids, or benzodiazepines.
There is now too much evidence to ignore that antidepressants cause withdrawal because the of the body’s dependence, and the withdrawal symptoms can be dealt with in the same manner that withdrawal from alcohol or benzodiazepines is managed.5
To begin with, patients who wish to stop a psychotropic drug like an antidepressant need to taper off much more gradually than just over the course of a few weeks. Members of SurvivingAntidepressants.org recommend a 10% decrease every month until they reach approximately 2.5% of the original dose.8 Tapering even this conservatively may still result in acute withdrawal symptoms, but may not produce rebound or PWS.
In some cases, it may be beneficial to taper off one drug and onto another with a shorter half-life, and then taper off that drug.1 However, this gets into another strange problem that internet forum users have noticed and which creates another similarity to alcohol and benzodiazepine withdrawal, and that’s hyper-reactivity and kindling.
Kindling describes the hyperexcitability in the brain caused by stimulus that produces epileptic seizures, but which has also been seen in alcoholics when they cease or suddenly decrease their alcohol consumption.9, 10 Researchers believe this happens when repeated chemical or electrical stimulus causes the brain to become hypersensitive. This may be a reason that repeated alcohol withdrawal may present with worsened symptoms after each period of binging and abstinence, even to the point of causing seizure activities. Similarly, individuals suffering from antidepressant withdrawal may experience hyper-reactivity to seemingly weak stimulus, including alcohol, antibiotics, caffeine, B vitamins, and even fish oil, as well as to light and sound. They may also find that consecutive instances of antidepressant withdrawal, even over a number of years, may result in worse and worse symptoms each time.
I’ll admit that the notion of kindling felt like a stretch to me, even if I conceded that my body had developed a dependence on antidepressants. But like many people driven to the internet for help from strangers, I was willing to try anything, and stopping caffeine didn’t seem like it would kill me. That was during week 5 of my symptoms.
It’s been two weeks since then. I’ve stopped taking my daily B vitamin and stopped drinking alcohol and caffeine, and I’ve focused on exercising when I can (it seems to keep the headaches away) as well as eating regularly and getting enough sleep. Boiler plate stuff, sure, but I do feel better. I’m still getting headaches, but they rarely become migraines anymore and they aren’t coming as frequently. It could be that I’m getting past my withdrawal symptoms gradually, or that I’m just generally taking better care of myself and very little of what I’ve written above has any impact on me as an individual, but I think that’s part of the problem.
Serotonin, antidepressants, PWS – all of it needs to be researched more thoroughly, by anyone who is willing to put in the time to do it. If someone with resources out there thinks that Adele Framer is full of shit, then by all means prove her wrong with a sufficiently large and meaningful 6+ month long study and tell the world what you find. Maybe kindling isn’t a thing. And maybe PWS isn’t as common of a problem as some researchers have found, but even if that’s the case and there’s a minority of people suffering, those people still deserve answers and solutions to their ailments, and patients considering starting a regimen of antidepressants deserve to know what they might be getting into.
(1) Gabriel, M.; Sharma, V. Antidepressant discontinuation syndrome. CMAJ 2017, 189 (21).
(2) Hengartner, M. P.; Davies, J.; Read, J. Antidepressant withdrawal – the tide is finally turning. Epidem Psych Sci 2019, 29.
(3) Frost, L.; Lal, S. Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors. Am J Psy 1995, 152 (5), 810a-810.
(4) Hengartner, M. P.; Schulthess, L.; Sorensen, A.; Framer, A. Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum. Ther Adv Psychopharmacol 2020, 10, 1-13.
(5) Chouinard, G.; Chouinard, V.-A. New classification of selective serotonin reuptake inhibitor withdrawal. Psychother Psychosom 2015, 84 (2), 63-71.
(6) Cosci, F.; Chouinard, G. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychother Psychosom 2020, 89 (5), 283-306.
(7) Horowitz, M. A.; Framer, A.; Hengartner, M. P.; Sørensen, A.; Taylor, D. Estimating risk of antidepressant withdrawal from a review of published data. CNS Drugs 2022, 37, 143-157.
(8) Framer, A. What I have learnt from helping thousands of people taper off antidepressants and other psychotropic medications. Ther Adv Psychopharmacol 2020, 11, 1-18.
(9) Becker, H. C. Kindling in alcohol withdrawal. Alcohol Health Res World 1998, 22 (1), 25-33.
(10) Kraus, J. E. Sensitization phenomena in psychiatric illness: Lessons from the kindling model. J Neuropsy Clin Neurosci 2000, 12 (3), 328-343.
Kayla Woods 