“I too, feel depressed,” I texted my mother from an island rock perched in crystalline Lake Tahoe.

My mother’s passing feeling of depression was referring to two suitcases in the back of a storage closet. They hadn’t been used in twenty-three years, relics from the trip she and I were on when my father died. My feeling of depression wasn’t so much wrapped up in luggage, although the reminder didn’t help. Instead, it was—is—caught in the tendrils of a long, ongoing list of personal and professional misfires capped off with a full ACL tear. (I am in surgery as we speak. Or as you read, rather.)

Although nothing about my career, relationships, or general life satisfaction is thriving, most of my inner torture is attached to the actions of someone else. Without getting into specifics, I am waiting on a response to an inquiry that could change my entire life. I have formally been waiting since March, but really, I’ve been waiting for a year and a half. What began as a zygote of an idea grew into curiosity and was then fed with just enough fodder and uncertainty to create a perfect storm of compulsion, passion, and confusion. The torture is less about what answer comes from the inquiry and more about the insanity over why this is happening in the first place. Is it destiny? Life purpose? Misguided desperation? I fixate on concrete interactions that brought me here and then fight the delusion that comes from dreaming so big in the first place. I search Twitter and Google News for updates and extrapolate data from folks who have no idea they’re supplying breadcrumbs to someone desperate for a nourishing meal. The whole thing has pulled a melancholic veil over my world, something that even a Wednesday lounge by the blue waters of Tahoe couldn’t lift.

I came home from the lake and turned to my coping mechanism—oil painting—until it got dark. Mid brushstroke, egged on by the minor chords of Shane Smith and the Saints’ “Little Bird,” I failed to fight back tears of exhaustion, longing, and frustration. While chewing on a (bad) idea I thought might take the edge off the ache, I remembered an old journal scribbled with something relevant to the bad idea and, upon cleaning my brushes, went looking for whatever I’d written down.

In big letters, I’d written a word I’d never heard of and had never bothered to look up: limerence.

A quick Google took me to The Attachment Project’s definition of limerence:

The experience of having an uncontrollable desire for someone – an obsession that consumes the limerent person’s thoughts, feelings, and behaviors. It usually involves two people: the person who desires the other (the limerent) and the desired person (the limerence object or LO).

Essentially, limerance is a state of being stuck between uncertainty and hope: will they or won’t they return the sentiment? For instance, perhaps this person hasn’t rejected them entirely, but they haven’t confessed their love either. 

This state of irresolution causes the limerent to become preoccupied with the LO, closely analyzing their behavior and body language to look for signs of reciprocation. They may also ruminate about past encounters with the LO and fantasize about what might happen between them in the future. The key feature of limerence is that these thoughts and yearnings are uncontrollable and all-consuming. 

As I went down a limerence rabbit hole, I wondered how I’d gone 38 years without learning this word. Limerence is usually associated with romantic love, but it doesn’t have to be. Friendship, family, mentor/mentee—any relationship involving two people can go wayward with limerence. For me, it explained everything.

Instantly, I felt better. I even looked dog and said, “Holy shit, that’s it!” How good it felt to be seen, to have the irrationality explained, to read accounts of other folks on r/limerence whose crazy was just as bad (and worse) than my own.

The epiphany gave me odd permission to do all the things I knew I needed to do but couldn’t quit. I unsubscribed from news platforms that might carry a snippet of information, unfollowed a few players in the space, and muted decision-makers. I will get an answer this year. Everyone involved has each other’s phone numbers. That was true before and is still true now. The difference is that in putting a name to the crazy, I am now able to shift into waiting without being consumed by thoughts.

It didn’t take long for me to draw a parallel between my elation over having a name for my distress and the (sometimes literal) party people throw for themselves when, after years of suffering, they get a formal mental disorder diagnosis. Twitter is full of tweets (and arguments) over adults to celebrate the ADHD, AuADHD (Autism/ADHD), or bipolar diagnosis they receive in midlife. People become so enmeshed with their diagnosis that it ends up in their bio, right next to their other primary descriptors: proud mom of 3, chemist, AuADHD.

I am, admittedly, quite judgemental over this kind of behavior. I can’t pinpoint exactly what bothers me, but it lies somewhere in the space of over-medicalization + over identification + taking resources away from folks who actually need it. Marcia, the offbeat, fiftysomething part-time jewelry maker may feel quirky and “off” in the world, but if she lives independently, pays her bills on time, and contributes to society, is she really “disordered”?

Hell, my sensory issues, mood swings, and general frustration with people land me on the spectrum of high-functioning autism. More than one person has asked me if I’m neurodivergent, which pisses me off. Again, I can’t pinpoint exactly why. Perhaps it’s because the suggestion itself indicates that someone wants to force me into a box, which, if you know me even a little bit, is the quickest way to make sure we never speak again. My gut reaction to the question is even less attractive. It’s something along the lines of: Who gives a shit? Stop searching for trendy explanations and go create something with your life.

And yet, learning the meaning limerence was like someone taking off mental handcuffs.

I am well aware of my bias. After seven years in the antidepressant withdrawal and overmedicalization space, the three words most likely trigger an eye roll are stigma, treatment, and validation. Drug makers are advocacy groups biggest donors, which puts a damper on “awareness” and “anti-stigma” campaigns. May may be “Mental Health Awareness Month” but if it were honest, it would be called “Psych Drug Advertisement Month.”

Treatment is a sneaky little way of using common languange to medicalizing a psycho/social/emotional issues. Just like Eli-Lilly’s clever 2023 tagline rebrand from “Powered by Purpose” to “A Medicine Company,” it’s about treating the patient, or ensuring access to treatment. What sort of monster wouldn’t want someone suffering to get the treatment they deserve? “Treatment” is medical care for an injury or illness, synonomous with drugs and diagnosis. It is not healing, building resilience, facing issues, making difficult decisions, or daring to accept that sometimes you are the problem.

And then there’s validation, both a powerful force for positive change and destruction. Validation when it comes to sorting out an issue and being understood by another human? Good. Validation from external sources and the constant need to have feelings recognized? Not so good.

The difference, I think, is what happens after validation is received. Productive validation identifies an issue and, through the act of recognition, diffuses its intensity. I recognized myself in the definition of limerence and used the tools provided to quiet the symptoms. Unproductive validation is righteous and only intensifies the feedback loop. Had I seen the definition of limerence, felt seen but not taken action, all I’d be doing is shifting the blame. A lightbulb that illuminates the whole picture versus a spotlight that blinds everything outside a defined edge.

Or, as Oxford researcher Lucy Foulkes recenty said in her New York Times opinion piece, “High-Functioning Anxiety isn’t a Medical Diagnosis. It’s a hashtag” :

All this awareness oversimplifies and maybe even popularizes mental disorder…and over interpretation can become a self-fulfilling prophecy…if everyone is ill, no one is.

Ever since MAY CAUSE SIDE EFFECTS was published in 2022, I’ve done as much press as I can without bankrupting my savings account or my soul. Podcasts are my favorite outlet, and after years of refusing, I finally caved and got on TikTok with the intent of reaching a withdrawal-specific audience. 

A few weeks ago, I shared a clip from my episode of Relatable with Allie Beth Stuckey, a massive podcast with loyal listeners. On both Instagram and TikTok, the post blew up, launching me into the weird world of internet virality. In many ways, I’ve been training for this since I started speaking publicly on antidepressant withdrawal in 2018. I’ve honed my message, backed up my personal story with research, and learned how to talk about it without treading into the litigious world of formal medical advice.

Still, nothing quite prepares you for the onslaught of notifications when a post goes viral. Instagram has a short half-life. Viral posts die within a week or so. TikTok is different. The algorithm keeps feeding it back into the funnel, like riding the same ride at the carnival over and over again. Combined, the clip has over half a million views with around two thousand comments. 

What I am most surprised by is the lack of pushback compared to the volume of psychiatric horror stories. Typically, anti-antidepressant content generates a decent amount of criticism. Whether it’s my work or someone else’s, you see a lot of, “Antidepressants save lives!” and “Stop shaming people for seeking the treatment they need.” Point out the FDA-supported data suggesting that antidepressants actually take lives in people under 24 and have no effect on suicidality for those 24-65, and I’m usually met by a reductionist, personal anecdote that culminates in, “What you’re doing is DANGEROUS.”

Sometimes people get cranky because I’m not a doctor or researcher, to which they say, “and what are ur credentials?” Unbeknownst to them, this is the one line that makes me doubt what I’m doing, so much so that after some rando made this comment I started researching online masters programs to see if I could get a quickie degree. I’m not bothered because I don’t have letters after my name. I’m bothered because I don’t know what I don’t know. I wonder if my bias is causing me to miss something that could hurt someone. Somehow, my lizard brain thinks having an advanced degree would protect me from that bias, which is ironic because the whole problem with the current standard of care in mental health is that clinicians are blind to the pharma/diagnostic bias programmed into them during their advanced degrees. 

Credentials buy you an expensive certificate that says, “I’m good at memorizing the stuff required to pass a test.” The art of medicine or therapy—and the critical thinking required to question why people aren’t getting better despite more intervention—only comes with time and practice. And after 10+ years of by-the-book education, very few practitioners have the self-awareness or balls to say, “I don’t know what I don’t know. I wonder if my bias is causing me to miss something that could hurt someone?” 

Thus, millions of people around the world are being hurt by people with letters after their names, yet somehow I’m the problem. 

When these comments get to me, I try to remember that being an MD doesn’t shield you from bullshit. Dr. Will Cole, a major player in the functional medicine space, recently shared a post on Instagram about the evidenced-based placebo effect with antidepressants. It garnered so many negative comments that the post is now deleted. Will told me in a podcast we did together that the response made him not want to talk about the topic at all. 

For my posts that went viral, the ratio of positive/like minded comments to nasty ones is about 100:1. Whether it’s sample bias from the algorithm or people finally feeling safe to air their grievances about shit doctors and bad drugs, I don’t know. But in the comments of one video, there are over 1600 horror stories just about Effexor. If this were in a specialty that uses lab tests to determine disease, that would be a class action lawsuit. It’s not a class action lawsuit in psychiatry because there aren’t any empirical tests to measure mental and emotional symptoms. A group of people claiming Effexor-induced suicidality cannot prove that Effexor was at fault, and all the pharmaceutical lawyers have to do is point to the patients’ clinical history and blame their suicidality on the depression diagnosis the patient inevitably received. Clever, innit?

The deluge of comments does inspire me to keep chugging along, though. Many folks talk about how they thought they were alone until they stumbled upon my post. This work can feel meaningless because it feels like the needle isn’t moving, and I often wonder if I’m wasting my time. I needed this boost as much as the folks in the comments did. 

So, if you’re new to my substack from one of these podcasts, thank you for being here. I’ll keep doing the work if you do. 

On March 8, 2017, I published a post on Medium entitled, “Finding Happiness Through Factual Optimism (Even When Life Goes Sideways.)”

The essay, even with its amateur prose that now makes me cringe, explained the system I created for myself to objectively track my progress when I was healing from antidepressant withdrawal and fifteen years of chronic depression.

At the time, I recognized two things:

So I did what I do best—go in a completely different direction and find a way to quantify the shit out of my feelings, then measure them against a very low bar of success! Because fuck gratitude, right? To quote myself from my book, on page 100 of MAY CAUSE SIDE EFFECTS: Gratitude is the bow we tie around our brand of shit to convince ourselves our particular pile of shit is a pretty pile of shit.

My feelings have changed on this, as I’ll address later, but at the time, rejecting gratitude was a form of taking back my power. I was just trying to survive. Gratitude was too advanced, and I needed to aim lower.

The lowest bar, I reasoned through a black and white lens, was that life would be worth living if it trended positive 51% of the time. That’s 2.6 “good” days per week, where “good” is defined by having the day itself trend 51% positive. String enough 51% days together, and you’ve got a 51% life objectively worth living. How’s that for data you can’t argue?

With a yardstick in place, I set about tracking and quantifying the data with the objective of a 51% Lifetime Happiness Average, whereby my choices were validated by default. My goal was never to reach a Utopic level of constant joy. I knew 100% Lifetime Happiness was impossible, but even 80% felt like a stretch. The gratitude gurus lived at 80. I just wanted to dig myself out of 20.

So, at the end of each day, I opened a journal and assigned myself a Daily Happiness Rating based on how the hell I was feeling at that moment. I used a 0-100 scale to allow for nuance. The difference between 49 and 51 was monumental, so it seemed right to give respect to the weight of each integer. Still, knowing that feelings aren’t facts, I didn’t overthink the number. Good morning, bad evening? Give it a 48. Horrific day filled with intrusive thoughts? It gets a 10. A window in the world of withdrawal, in which I didn’t break down in tears? Assign the day a 60 and hope for a 61 tomorrow.

Then, I plotted it all on a line graph.

The drop in February occurred when I went into antidepressant withdrawal. The uptick in August happened when I boarded a one-way plane to Malaysia and was temporarily spellbound by the thrill of a new place. Then, predictably, the high wore off leading to a September crash, followed by an uptick.

When zoomed out, this looks like a person healing. Which, it was. But zoomed in, the day-to-day felt volatile because it was:

My monthly charts from 2016 would reflect a much lower day to day experience, but in February 2017, nearly a year into withdrawal, I was having more 51% days than not. Still, when I went down, I went down hard.

Plotting this over a lifetime, as defined from the year my father died when I was 15 up until the end of 2017:

This is how I proved to myself that I was, objectively, getting better. I could not argue with the system I put in place. The only metric was how I felt, and I didn’t need to rationalize why I felt one day was a 38 while another was a 64. They just were, and that was good enough.

This process allowed me to have bad days, even bad weeks, while knowing that the only goal was a 51% lifetime average. This low bar both took all the pressure off and allowed me to look at individual decisions and determine how they’d affect my overall happiness average. Some decisions were easy. Making my bed certainly contributed to increasing my chances of a 51% day, and so would going to the gym rather than getting ice cream.

Other decisions were more nebulous or didn’t seem to have a clear upside. When those choices came up, I trusted that I’d banked enough smaller 51% decisions (like making the bed) to make up for a choice that might lower the overall average. Over time, I became better at recognizing when a choice was good for me while also forgiving myself for the days when things just fucking sucked.

I stopped tracking in early 2018, when I stabilized enough for the graphs to get boring. When the graphs got boring, something magical happened: I recognized gratitude.

What I’d missed about gratitude is that it is a feeling, not a thought. You cannot think yourself into it, which is why gratitude journals never worked for me. I was too full of muck for the feeling to appear, but once I cleared enough of the muck and analyzed all my little day-to-day choices, I began to notice the little spark of gratitude—a lazy moment in the sun with my dog, the smell of coffee, the color of a flower—all of which eventually grew into a campfire.

That is when I finally understood that gratitude is the way out of suffering. Because once you build that campfire, the world is filled with logs to keep it burning. Even in during painful experiences or crushing, a strong fire stays lit.

It is this duality that makes for a life truly lived at 100. For a long time, I thought a Lifetime Happiness Average of 100 was unattainable because no one can be happy all the time. This is true, of course, but what I know now is that the 100 contains within it all human emotions and experiences. To live at 100 is to experience the full depth of despair and uncertainty because it is matched by intense awe and love.

I know this because I now know love in a way I didn’t before. I know how love is all at once the most painful and beautiful experience, one that simultaneously makes you want to hold on to every moment and also die immediately, just to stop the ache of losing it. It is extreme and all-encompassing, encasing all the meaning of 0-100 within it.

What a gift it is to feel it, to not only want to live in a world bigger than 51%, but to welcome the extremes on either end. Where black and white, dark and light, good and bad are no longer opposites, but integrated expressions of a life well lived.

Inevitably, when you write a book about a growing global concern like antidepressant withdrawal, people reach out with questions. And even though I’ve received hundreds of inquiries in the year and a half since MAY CAUSE SIDE EFFECTS came out, I haven’t bothered to create an FAQ. As much as general themes repeat, people’s stories are unique, and canned answers rarely come in handy.

Instead, I try to answer each person individually and at the very least, ensure that they feel heard for a moment. In most cases—80%—this is all that’s needed. When people have been gaslit by doctors or have spent the majority of their lives under the influence of powerful psychiatric drugs, sometimes the difference maker is nothing more than someone validating their experience. That little bit of encouragement is enough to keep them on course and usually, I never hear from them again.

The remaining 20%, like all 80/20 relationships, take up most of my correspondence time. Typically these are the more complicated cases, usually from folks whose friends likely describe them as “a little neurotic.” These are the overachievers, the philosophers, the Type-As control freaks who did not schedule antidepressant withdrawal into their five-year plan.

This phenotype wants to do everything in their power to make withdrawal go away as fast as possible and can be found furiously googling and going down unhelpful rabbit holes on withdrawal forums. They also usually have money—depression is a privilege as it turns out—and are willing to spend it if they only knew what tests to get.

Of course, their doctor doesn’t have a clue, so when a basic blood panel comes out clean, the prescriber dismisses the idea of running more tests. The patient, though, knows something is amiss. Inn googling, these people find me and fill my DMs, which leads me the meandering point of this issue: every medical test I’ve been through to heal myself after fifteen years of antidepressants.

I took my last antidepressant in 2016, considered myself fully through antidepressant withdrawal in 2018, and spent the better part of 2021 – 2023 healing my body from the ordeal. I spent 2019 and 2020 tinkering with my diet in hopes of figuring out what was causing my gut issues and general I-feel-like-shit issues. I cut gluten or dairy or coffee. I ate less protein. I ate more protein. I juiced celery and drank fennel tea. I went to gastroenterologists who looked at me over a clipboard and said, “We can schedule a colonoscopy?”

Finally, in 2021, I called Andy Galpin, PhD., an old friend who, along with nutrition savant Dan Garner, was working with professional athletes to heal their lingering issues and improve their physical performance. Dan & Andy let me go through their program, which kicked off a two years of lab work and serious dietary changes that have finally allowed my body to heal and perform its best.

(I’ll cover my diet and the results of these tests in another issue. I’m on the road doing press for the paperback release of MAY CAUSE SIDE EFFECTS.)

Over a two year period, I’ve spent well over $10,000 out of pocket on lab tests. It is no small amount of money, especially given my super-lucrative career as a freelance writer and chef. (I recently received a royalty check for the amount of thirteen cents!)

Insurance hasn’t covered a dime, and still, it’s the best money I’ve ever spent on myself because I actually feel better. The key is to get all the testing done in a 1-2 week time period so you have a full picture of your health, all at once. This allows for the Dan Garners of the world to connect the dots between the body’s different systems, rather than isolating the endocrine/gut/blood labs in a vacuum and assuming nothing is connected, like allopathic medicine likes to do.

So, have at it folks. Go forth and figure out your shit. Literally.

Food Sensitivity:

MRT test

Hormones:

Dutch Test

Gut/GI:

GI Map

Heavy Metals:

Doctor’s Data Toxic & Essential Elements: Hair

Genetic:

GeneSight

Blood:

Complete metabolic blood panel

HNK1 (CD57) panel

Microscopic examination

Urinalysis, complete

C-Reactive Protein, Cardiac

Ferritin

Fibrinogen Activity

GGT

Hemoglobin A1C

Homocyst(e)I’ve

LDH

Lipid Panel with Chol/HDL Ratio

Magnesium

Phosphorus

Reverse T3, serum

Thyrogobulin Antibody

Thyroid Peroxidase TPO Ab

Thyroid Profile II

Thyroxine (T4) Free, Direct

Triiodothyronine (T3), Free

Uric Acid

Vitamin D, 25-Hydroxy

For months, I’ve felt like I just got on one of those carnival rides where you sit down, strap in, and let a rusty elevator take you to the top of a tower. Even though the elevator is gently taking you away from familiar ground, you know that at some point, the elevator will stop, open its doors, and give you a view of the world you’re about to drop into. And then, just as you relax into the view, the floor will fall away and gravity will take over, leaving you with no option other than to feel the rush.

I keep waiting for the elevator doors to open and show me a new world. It is coming. I can feel it and I’ve been feeling it for months. In October, I lost my main client and most of my work evaporated overnight. I challenged myself to simply wait, as itchy as it was because I could feel this something coming. I could feel myself standing in line, putting on a seatbelt, and waiting to move.

Every few years I seem to come back here, to a place of uncomfortably long stagnancy with no clear direction. The last time this happened was in August 2017. I was at the tail end of both a year of international travel and a year and some months of antidepressant withdrawal. I didn’t have a job or an address, but I had signed a flimsy book deal for a book called LADYBALLS. Though I still love the title, that book never came to be, but its existence contained the zygote of what would eventually become MAY CAUSE SIDE EFFECTS.

On a rooftop in Buenos Aires, I wrote myself a letter and dated it January 1, 2018. Why I thought six months was an appropriate open date, I don’t remember. But I do remember that when the new year rolled around, I looked at the unopened letter and knew it wasn’t time to read it. Days before, the book deal for LADYBALLS fell apart. I fired my agent and my publisher in a blind move that turned out to be the best career decision I’ve ever made. I couldn’t remember the specifics of the letter, but I knew if I opened it, I would only feel frustration and shame. So I stuffed it in a folder and forgot about it.

Until yesterday.

My strategy for dealing with general overwhelm is to spontaneously deep clean my home. Typically, a stressor appears—good, bad, doesn’t matter—and within a day, I decide my house is unacceptable. I am already known to vacuum in the middle of a dinner party, but this takes it to another level. In the words of Monica Gellar, the compulsive chef on Friends: “Not just health department clean. Monica clean.”

Yesterday, I signed a contract with a new client, thereby imbuing me with all sorts of problems to solve. After attempting—and failing—to solve all those problems in one morning, I came home and began scrubbing the screws on my toilet. Which led to re-lining drawers. And going through my closet. And cleaning out my desk, where I found a brittle, unopened yellow envelope dated January 1, 2018.

I smiled, sure that inside the letter was something about a $50,000 book deal that never materialized. Enough time had passed and I figured I could handle whatever was in there, even if what was in there was nothing but disappointment.

The back side:

I chuckled at the line, “By the time you read this, you’ll know where you’re going to live.” That is the only bit in there that isn’t quite settled. Something on the carnival ride feels like I’m not staying put much longer.

Everything else, though, has manifested. I wrote the book. And it’s good. And I finished on time, and I am happy with the words I wrote and the things I believe. The money came, too. And that independence. Real independence, because that year and these years gave me the gift of confidence and a voice—a true voice.

By the time I opened this, I had an address to come home to. And I can pay for it. And I am surrounded by people who love me. The negativity that followed me is a distant memory. I am me. And I am paid to be me. I am content, happy, full, and free.

I can’t remember if, when I wrote the letter, I really believed any of it would come true. I knew I wanted to believe, and that I’d seen glimpses of light during antidepressant withdrawal that at least taught me I was capable of experiencing a life I never imagined.

I share this with you because I can feel that I’m reaching the top of the elevator and that when it opens up and the ride truly begins, I know my story is going to reach even more people. So far, I’ve been able to keep up with the amount of correspondence I receive from people suffering from antidepressant withdrawal. Sometimes it takes a while, but I get there. I don’t know how much longer I’m going to be able to respond to everyone.

So, for everyone who is suffering, let this letter serve as an example of possibility. This can be your future if you keep the course and keep doing the work. Most times, the hard way is actually the easy way. Let it be hard. Feel it. Process it. Because at the other end is light.

Light

Light

Light

Light

Light

Light

Light

Joy

Love

Acceptance.

Hi friends,

When you’re reading this, I will be on my way to another continent to celebrate both my mom’s and my birthdays. And on the day of my birthday—February 1—I will have 16,715 more days to live. 

Maybe. Hopefully.

My father died suddenly when he was 54. That means he was halfway through at 27 and still had 13 years of living before I came along. I don’t have the vocabulary to express how much that twists my mind, and yet it’s been a constant thought over this year. I don’t know if it’s because 54 no longer feels all that old or far away, or because no one ever knows when they’re halfway done. 

I turn to numbers for comfort. Always have. Even as a girl, when I felt overwhelmed, I would quietly calm myself by counting ceiling tiles or cars passing in the other direction. 

In the depths of depression—despite years of antidepressants—I took a dozen life expectancy tests, sourced from life insurance companies and accounting firms. I averaged the results for a total of 83 years, 9 months, and 6 days on this planet. Or 30,595 sunsets.

I didn’t want those sunsets until I got off all the antidepressants and came out of a year of severe antidepressant withdrawal. But after all the suffering and all the deep work, finally, I want time. I want all the days I never thought I’d have. 

If I am so lucky to see them all, that means I get to watch the leaves turn 46 more times. 

And read just 920 more books. 

And watch 11 more Summer Olympics. 

There will be maybe 138 more pizzas and 33,430 cups of coffee. Assuming there’s always a canine by my side, I’ll take 66,860 more walks with 4 more dogs. 

I’ll hug that friend I only see once every few years about 15 more times. 

And feel lucky if I laugh until I cry 92 more times. 

Maybe I get half a dozen moments of complete and utter awe. 

And one great love. 

Maybe. Hopefully. 

All this to say: 

I don’t know how many more mother/daughter trips I have left, especially grand international ones. I will be happily unavailable for a few weeks and want to make sure you have your fill of the latest news on antidepressant withdrawal, so I have compiled a bunch of recent articles below.

There was a time when maybe one article was written on the topic every three months, and now I’m starting to see weekly (and even daily) headlines. Something is shifting. I can feel it, and I welcome it.

The STAR*D trial, once considered a landmark study in psychiatry, is now mired in controversy due to findings of protocol violations, inflated remission rates, and a general lack of accountability from its investigators.

One of the largest and longest studies on antidepressants, the trial initially reported a 67% effectiveness rate for antidepressants, which became the basis for the pharmaceutical focus that has shaped much of modern psychiatric “care.” However, the trial has come under scrutiny for several reasons, revealing a far different picture of its findings:

A new study on publication bias of the benzodiazepine Xanax has been released. According to researchers from Harvard, Massachusetts General Hospital, McLean Hospital, and former FDA reviewer Eric Turner, four of the five original studies on the effectiveness of alprazolam (Xanax) found it to be no better than a placebo. Furthermore, only one of the five studies reviewed by the FDA showed a positive result. It is curious when you consider that the FDA “expects that the drug maker will submit results from two well-designed clinical trials to be sure that the findings from the first trial are not the result of chance or bias.”

Publication bias is the practice of picking and choosing what gets published and how it gets published. This is extremely common across all hard and soft scientific disciplines, and it’s a big reason why relying on published, peer-reviewed research should not be the be-all, end-all of human existence.

Negative and neutral trials, for example, often don’t make it into literature. Not only do the researchers not want to draw attention to a failed hypothesis, but journals don’t want to waste space on science that doesn’t work. Furthermore, the media rewards breakthroughs, not duds. Thus, an unknown amount of research is left on the cutting room floor.

The problem with this is that when you look at the body of research that does get published, it tells a very different story. British physician Ben Goldacre explains it well. I’ve fast-forwarded to the most relevant part for your convenience:

This is exactly what happened in the Xanax approval process. The FDA received data on five Phase 2 and Phase 3 trials. They considered four of them to be negative but approved the drug due to the strength of Study 2. Furthermore, the results of Study 1 were spun to look positive, despite the FDA statistician determining the study failed because improvement was not noted in all seven primary endpoints (the FDA deems “studies positive only if all primary endpoints achieve statistical significance”).

Studies 3, 4, and 5 failed or were nonsignificant, and none of these studies were published.

Thus, the published literature reflected that Xanax was a successful intervention for panic disorder, which led to a frenzy of prescriptions thanks to media and marketing departments that use published literature for headlines and campaigns.

And here we are, thirty years later, with a raging global opioid crisis, in part thanks to the misuse of benzodiazepines.

You know Big Pharma is prepping to push a new class of drugs when the narrative starts changing around the golden pharmaceutical children of yore.

Drug patents in the United States typically last 20 years, and given that there’s been no meaningful pharmacological advance in the mechanism of antidepressants during that time, most SSRIs and SNRIs have fallen off the patent cliff and are available in generic form. Generics, of course, don’t bring in the dough. So, pharmaceutical companies use a variety of tactics to bury generic competition, including but not limited to:

Two themes are appearing in the media that make me think we’re heading for a classic shift. First, we’re seeing headlines about new antidepressants, specifically Zurzuvae (zuranolone) and Zulresso (brexanolone), both of which act on GABA receptors (like benzodiazepines) and are being targeted at vulnerable new mothers with postpartum depression.

Zulresso, by the way, costs $34,000.

The New York Times reported on these new drugs on August 4, 2023. On November 9, 2023, the New York Times also reported on Post SSRI Sexual Dysfunction, a devastating and often permanent side-effect of antidepressants that can rob people not their libdo, function, and feeling in their genitals. Chemical castration, effectively.

Both articles include a pithy offer of journalistic objectivity, adding a quote or two from the “opposition” to satisfy the reader with an attempt at balance. But the tone of each article is clear: New shiny drugs, good! Old generic drugs, beware!

Curioser and curioser.

In good news, SNOMED (Systematized Nomenclature of Medicine Clinical Terms) has created code 1285639002 for “Protracted antidepressant withdrawal syndrome (disorder).”

SNOMED is a non-profit organization responsible for determining global standards for health terminology. It is designed to support a wide range of healthcare processes, including clinical documentation, decision support, and data analysis. It encompasses a broad spectrum of clinical concepts, relationships between them, and associated terms. This standardized terminology helps ensure consistency and interoperability in health information systems.

Without a formal code, an ailment essentially doesn’t exist. That means that prior to code 1285639002, precisely 0 cases of protracted withdrawal have been formally recorded because there wasn’t a way to do it.

In the UK, doctors have to activate the code in order to use it. Once that happens, researchers will be able to start tracking case rates. In the US, it’s irrelevant because of our dumbass system. I’m told that we likely won’t have a code until the DSM recognizes it, which would lead to a bit of the emperor has no clothes situation. But SNOMED is a start, and I’ll take it.

“When humans do not assume they have rather complete control of their experience, they do not so deeply fear those who have appeared to have lost it.”

—Juli McGruder, anthropologist

As of late, I’ve been learning about the different expressions of perceived mental illness around the world. I use “perceived” in this context because the more I learn, the more I understand that symptoms of mental/emotional distress are tied to cultural expectations. (See the TikTok tics from issue 105.) Said another way, the lifecycle of mental illness is influenced by the macro and micro-level beliefs that surround it. What’s considered crazy in one culture is accepted in another.

On a macro level, the prevalence and intensity of schizophrenia vary from place to place. Men living in urban areas of Sweden, for example, are at a 68% higher risk of being admitted for psychosis than those who live in the countryside. This is also true for urban settings in the United States and Europe, and it remains constant even when migration, drug use, and poverty are taken out of the equation.

Furthermore, a 25 year study conducted by the World Health Organization that began in the 1960s found that people diagnosed with schizophrenia in developing countries have better outcomes, longer periods of remission, and higher levels of social functioning than those in industrialized nations. Known as the International Pilot Study of Schizophrenia, the data showed that over time, 40% of schizophrenics in countries like the United States, Denmark, and Taiwan were considered “severely impaired” compared to 24% of people in countries like India, Nigeria, and Columbia.

Of course, these findings ignited a hot debate because the results are counterintuitive. You’d think all the money, research, and resources would lead to better outcomes. But alas, the data showed the opposite to be true.

(Side note, half a century later, our use of psychotropic medicine continues to reflect what we knew in the 1960s and 1970s. Are poor nations tragically underserved by psychiatry? Or have they avoided the crosshairs?)

This debate is the heart of cross-cultural psychiatry research. While it’s interesting in its own right and the conclusions are, to me, dead obvious, I find the micro influences to be even more interesting. It’s not just about the culture we live in. But the roof we live under.

Expressed emotion (EE) is a term used to describe the way that family members and caregivers interact with a person. High EE is characterized by critical, hostile, and emotionally overinvolved behaviors. Low EE is characterized by warm, supportive, and accepting behaviors. While expressed emotion is not the cause of distress, it can influence the course and outcome in an individual.

We all know that when our actions are met with criticism or hostility, we don’t fare as well. But emotional over-involvement requires more explanation.

Emotional over-involvment is characterized as a range of dramatic behaviors ranging from self-sacrifice, extreme devotion, overprotectiveness, or intrusiveness over a person’s life. Control, essentially.

Ethan Watters uses an example in his book, Crazy Like Us, that describes a mother who was so emotionally over involved with her son’s schizophrenia that she “dropped all other interests from her life. Her sole activity, she reported, was to take care of him and protect him, ‘like a pearl of a diamond.’ This same mother said that she often became so distraught over her son’s plight that she considered committing suicide by throwing herself down the family staircase.”

In addition to raising stress levels in the sufferer—which in this case, could trigger schizophrenic episodes—this maligned strategy is a constant reminder to the person suffering that those around him perceive him to be ill, which in turn, reinforces the idea that something is wrong.

Watters gives a contrasting example of a family in Zanzibar with a schizophrenic daughter, Kimwana, who overdosed her medication and nearly died. Juli McGruder, an anthropologist who witnessed the scene said, “There was no noisy woe-is-me talk or dramatic wringing of hands. [The family] seemed to take it in stride like everything else…When I asked what I could do, [the mother] told me I could take a carton of milk to Kimwana in the hospital.”

The ability for the family unit to keep calm and carry on benefitted Kimwana. The family’s perspective, in part because of Zanzibarian beliefs include spiritual possession, allowed everyone to embrace the idea that difficulties—and even voices in the head—are a natural part of life. Therefore, disruptive behavior as a result of these difficulties was more understandable and forgivable. Kimwana wasn’t viewed as other, or as someone to be feared. She was viewed as a strong expression of what we all have inside of us. This kept her within the social group.

Anglo-Americans have the highest level of expressed emotion compared to different groups around the world. Given that we no longer let our kids have sleepovers, have unsupervised play, or breathe without parental supervision, this shouldn’t be surprising. According to researcher Jill Hooley, Anglo-Americans have a strong “locus of control,” which means they believe a person can be master of their own fate and control their own issues through force of will. The critical, hostile, and emotionally over involved actions stemming from this locus of control aren’t necessarily cruel in intent, but are instead an expression of assumed (and flawed) human nature.

Cultures with more fatalistic or spiritual values place less focus and/or blame on those with mental and emotional distress. Conversely, in cultures that value personal accountability and individualism, highly emotionally involved relatives are actually more hopeful about the disease because they are convinced recovery is a matter of will—both on their part and the part of the sufferer.

But as they say in football (soccer), “It’s the hope that kills you.”

Watters says, “One typical father described his reaction to the schizophrenic break of his son: ‘I went to the library and began reading books about mental illness…I thought: “No, I’m going to fix this.” That is your first instinct as a parent. You’re going to fix it. I thought, “I can get him help. I can get him cured.”…That intense focus, even when it springs from a hopeful engagement of the problem, might be the very thing that exacerbates the illness.”

Furthermore, our obsession with the biomedical model of mental illness only exacerbates emotional over involvement. Take the following Euro-American norms:

By applying these norms to an individual, we separate them from the group by labeling them as Other, all while promoting the idea that recovery is never really possible. How could it be, if mental illness is nothing more than a stroke of bad luck and questionable genetics?

In 1997, Sheila Mehta of Auburn University got curious about whether or not the “brain disease” narrative of mental illness actually reduced stigma, as promised.

In her experiment, she paired up people for what test subjects thought was a simple learning experiment. Unbeknownst to the test subjects in the study, their partners were actors and were instructed to inform the test subjects during the get-to-know-you phase that they suffered from mental illness.

The actor told the test subject that the distress occurred because of the “things that happened to me when I was a kid or that they had “a disease just like any other, which affected my biochemistry.”

In the experiment, the test subject was assigned to teach the actor a pattern of button presses. When the actor got the pattern wrong, the test subject was told to give the actor a “barely discernible” to “somewhat painful” electric shock.

Test subjects who believed their partner had a “disease like any other” increased the severity of shocks at a faster rate than those paired with the actor whose issues were caused by childhood events.

Mehta said, “The results of the study suggest that we may actually treat people more harshly when their problem is described in disease terms. Viewing those with mental disorders as diseased sets them apart and may lead to our perceiving them as physically distinct. Biochemical aberrations make them almost a different species.“

And what is our instinct when we encounter Other? Critical, hostile, and emotionally over-involved behaviors.

So it goes.

As of late, I’ve become fascinated with the idea that mental illness is contagious.

The fascination started with a New York Times article about a wave of thousands of female and gender-nonbinary teens who developed Tourette’s-like tics during the pandemic—because of TikTok.

Arriving in the zeitgeist when people were forced to stay home, TikTok exploded during the pandemic. Videos of people claiming to have Tourettes multiplied on the platform, and because TikTok’s algorithm is built on showing users a wide variety of content—regardless of the user’s preferred interests—Tourette’s videos began popping up on people’s feeds. As of this writing, #Tourettes on TikTok has 8.7 billion views.

Like mental illness, there aren’t any scans or biological markers to diagnose or identify Tourettes. However, Tourettes is categorized as a movement and neurological disorder marked by uncontrolled physical or verbal tics, not a mental illness. It typically presents in males and first appears in childhood, with waxing and waning symptoms.

For the girls with “TikTok Tics,” however, the Tourettes-like symptoms arrived suddenly, with a wave of new cases popping up all over the world. Notably, though, when life began to regain some normalcy and the stress of the pandemic waned, the wave of TikTok Tics receded as well. Thus, it is hypothesized that the unique stress of the pandemic + the unique vulnerability of teenage girls created a tinderbox of stress that manifested in psychologically contagious tics.

This isn’t the first time we’ve observed psychological contagion. This phenomenon repeats itself across both time and cultures. In the Middle Ages, it was believed that humans could be possessed by the spirits of demonic animals, leading a group of nuns at a French convent to meow like cats.

In the 1800s, “hysteria” was a known psychological diagnosis that afflicted women. It included a diverse range of symptoms, including paralysis, stomach pain, amnesia, and day blindness. Hysteria was almost worshiped and certainly fetishized by popular magazines, newspapers, and even public hygiene literature. Much like today, male doctors and scholars of the time filled lecture halls and pontificated on the “quintessential illness of womanhood,” as Ethan Watters said in his book, Crazy Like Us. But by the time the 20th century rolled around, hysteria had largely evaporated from the collective consciousness. Women stopped reporting paralysis and leg weakness, and the symptoms of psychosomatic illness moved on to other expressions.

Even the human reaction to war is tied to the cultural temperature. Medical records of war veterans show that the psychological and even physical effects of war are a reflection of time and place. For British soldiers in the Boer War, the psychological trauma manifested as muscle weakness and joint pain, while American soldiers during the Civil War complained of a weak heartbeat and an aching in the left side of the chest. During World War I, both British and American soldiers experienced “shell shock,” with symptoms that included tremors, ticks, and sensory disturbances. Today, addiction affects veterans of modern war.

As Watters explains, “Although the potential psychic damage of war is indisputable, the process by which that damage becomes an outward symptom is a reflection of the cultural beliefs in a particular time and place.”

Said another way, whether as a PTSD response to war or TikTok, people will unconsciously produce symptoms that reflect the culture’s prevailing cultural diagnosis of the time. The TikTok Tics were not so much a measurable illness, but a subconscious yearning for recognition of internal distress.

The implications of viewing mental illness through this lens, in my opinion, destabilize the entire foundation of psychiatry and psychology. I know, for example, that as a young ballet dancer, the eating disorders I experienced as a teenager were created through community. Anorexia is rampant in ballet not just because thinness is an aesthetic ideal, but because everyone else is doing it. Toss in the death of my father and the emergence of the internet in the early 2000s, and the fixation on thinness festered as a direct result in order to satisfy a need to belong to something while expressing suffering. There wasn’t ever anything wrong with my brain. If anything, it was a sign that my psyche was doing exactly what it should be expected to do in times of great stress. I was simply exhibiting symptoms consistent with the time—no different than if I had started meowing with nuns in the Middle Ages.

For an affliction to be pathological, it seems to me that it should ring true across both time and culture. A cancerous mass viewed under a modern microscope looks the same in Taiwan as it does in the United States. But if mental illness and psychological distress cannot be separated from the culture in which it is experienced, how is a blanket biomedical response ever going to be the answer?

In the 100th issue of Happiness Is A Skill, I revealed that I underwent genetic testing through GeneSight in order to get an insight into how my body metabolizes psychiatric drugs. My results are in, and we’re going to take a look at them together in order to better understand this technology, while also examining some of the limitations and concerns around this type of testing.

I recommend reading through issue 100 before diving in here.

Please note that I have no affiliation with GeneSight, and this is in no way an advertisement or medical advice.

The GeneSight report focuses on three different aspects of psychiatric drug metabolism: psychotropic, which indicates how a person is likely to metabolize a wide variety of psychiatric drugs; genotype and phenotype, which is the organism’s genetic information and its observable traits; and a gene-drug interaction chart.

In theory, this information aims to optimize medication choices by reducing trial-and-error prescribing. Given that I’m not in the business of taking psychiatric drugs ever again, I’m more interested in the insight this gives me into my own body, and what it might mean for psychiatric drug withdrawal. Big emphasis on might. I won’t be running any double blind, placebo controlled trials on the hypothesis any time soon, but seeing this information and understanding what it means does make me think twice about blindly taking prescription drugs. Personally, I think that’s the power of a test like this. It shows the layperson that pharmaceutical intervention is extremely complicated, while also increasing the patient’s medical literacy. Given that on average, doctors only spend 17 minutes with each patient—and 4.5 hours per day on electronic medical records—it behooves the patient to have some basic medical literacy before walking into an appointment.

Genesight gives psychotropic results for five drug categories: antidepressants, anxiolytics and hypnotics (anti-anxiety and sedatives), antipsychotics, mood stabilizers, stimulants & non stimulants.

The results are coded in green (use as directed), yellow (moderate gene-drug interaction), and red (significant gene-drug interaction.)

Intuitively, you can gather that green medications are not associated with any known genetic issues that would be expected to change patient medication outcomes; yellow medications may require dose adjustments in order to have the desired effect and may be less likely to work/may cause side effects; and red mediations are likely to require significant dose adjustments in order to have the desired effect, or they not work at all, and may cause side effects.

The number to the right indicates the rationale for the reason why a drug is in the yellow or red column. This is where things get interesting when viewed through the lens of my personal history.

Before my child psychiatrist landed on a combination of Wellbutrin XL and Effexor XR, he gave me at least two other drug that created obvious, immediate side effects. I don’t remember which drugs they were and the medical records have long been destroyed, but given the antidepressant market in 2001/2002, it was likely to be Prozac, Celexa, or Zoloft—all of which exist in my yellow column.

Effexor, too, is on my yellow list. While I know I didn’t have immediate side effects from my 37.5mg dose, Effexor withdrawal was pure hell. While there aren’t any clinical studies looking at the relationship between the CYP450 system and psychiatric drug withdrawal, it doesn’t seem like a radical leap to assume that someone’s ability to metabolize a drug also affects the body’s ability to get the drug out of the system. Anecdotally, this hypothesis is further bolstered by my relative ease when it came to getting off the Wellbutrin, a drug in my green column. I know this isn’t the whole story, but it seems unlikely that it’s not somehow related.

Another reason why I find this test valuable is because of the information buried in the anxiolytics and hypnotics results. Many of these drug are commonly prescribed as part of surgical procedures in hospitals. If I ever needed major surgery, I’d want my anesthesiologist to have these results. Whether or not they’d take them into consideration is another matter, but I’ve given a copy to my emergency contact, just in case.

The genotype and phenotype type results show specific variants for each gene. These results explain why drugs end up in the green/yellow/red column.

It is broken down into two categories: Pharmacodynamic and pharmacokinetic.

Pharmacodynamic genes provide insights into how medications interact with the body. Variations in these genes can impact the likelihood of response or the risk of side effects with certain medications.

While it is important to note that many genes—including ones not tested by GeneSight—are involved in the process of metabolizing psychiatric drugs, GeneSight has identified a handful of issues known to come with specific gene variants. SLC6A4, for example, encodes for the serotonin transporter, which is the main site of action for SSRIs. People have either a long allele (variation) or short allele of SLC6A4. According to GeneSight, “Studies have shown that the short [SLC6A4] allele results in less serotonin transporters than the long allele. Individuals who have the short allele may be less likely to respond to certain SSRIs based on this genotype.” Thus, my short SLC6A4 allele contributes to the reason why SSRIs like Celexa, Paxil, and Zoloft are on my yellow list.

The same goes for pharmacokinetic genes, which provide information about how the body processes medications.

What stands out here is my CYP2D6 and CYP1A2. CYP2D6 is involved in a wide range of drug metabolism, psychiatric and otherwise. My intermediate metabolizer status indicates that I metabolize these drugs more slowly than normal. This is important because it means that while I may not have immediate adverse reactions, I am more likely to encounter them long term as the drug slowly builds up in my system.

On the other end of the spectrum, I am an ultra rapid metabolizer for CYP1A2. CYP1A2 is involved in the metabolism of a not only some antipsychotics, but also melatonin and caffeine. This explains two things I’ve known to be true about myself: I can drink caffeinated coffee or tea late in the day without it affecting my sleep, and melatonin has little to no effect on me. This makes sense—thanks to my quick CYP1A2, both caffeine and melatonin rush right through my system.

Additionally, vegetables like cabbages, cauliflower and broccoli are known to increase levels of CYP1A2, whereas spices like turmeric and cumin inhibit CYP1A2. So much so that a Sydney based researcher concluded that the “different diets and lifestyles of South Asians compared to Europeans could lead to the two groups requiring very different doses of medicines commonly used to treat illnesses such as depression and psychosis.”

Said another way: diet affects drug metabolism.

Of course, most of us aren’t thinking about how that chai tea affects the efficacy of our Rx cocktail. For the majority of people, it’s this particular quirk probably irrelevant. But for others—say, someone living in a Sri Lankan household who is struggling with a particular prescription drug—the knowledge might be more akin to low hanging fruit.

Furthermore, it speaks to the nuance of drug prescription that is all but ignored. Now, I know that any drug or supplement I take should be crossed checked to see if it’s metabolized by CYP1A2 or CYP2D6. If so, maybe I need to stay away from Indian food while I take it or consider a change in dose.

The last chunk of the GeneSight test is a handy chart outlining gene-drug interaction. The chart is supplementary, and only tells you which genes are involved in metabolizing each drug.

The real limitation here is that the second multiple drug are involved, all of this goes out the window.

You now know that a drug-gene interaction occurs when a person’s genetic makeup affects how their body metabolizes or responds to a medication. A drug-drug-gene interaction occurs when the effects of two or more medications are altered by a person’s genetic makeup.

For example, someone who is an intermediate metabolizer for CYP3A4—one of the enzymes involved in Zoloft (sertraline) metabolizatoin—may have no issue with the Zoloft alone, even as an intermediate metabolizer. But serotonin toxicity, also know n as serotonin syndrome, becomes a real risk if they start taking the antibiotic erythromycin. Erythromycin uses the CYP3A4 pathway and therefore inhibits the metabolism of Zoloft, leading increased and potentially toxic Zoloft levels in the body.

While the Zoloft or the erythromycin individually may not create an issue, combine them together with an intermediate or slow metabolizer, and you’ve got a problem.

GeneSight isn’t of any help when it comes to drug-drug-gene interaction, a giant limitation given how many people are on multiple drugs. But again, it gives us more information than we had before, which I think is a net positive.

In general, I went down the GeneSight rabbit hole for no reason other than pure curiosity. I have no plans to take psychiatric drugs in the future, nor do I know how my trajectory might have been different had I had this information back when I was medicated in 2001.

There is plenty of debate about the use of genetic testing in the world of mental health, most of it focusing on questions about privacy, accuracy, over interpretation of the results, lack of FDA approval, and cost.

From my perspective, there’s not enough compelling evidence to convince me that people shouldn’t take it into consideration. We do all sorts of things that aren’t approved by the FDA—drinking wine and taking multivitamins, for example—so that argument is moot. Privacy concerns are ubiquitous these days, but I personally don’t care what they do with my results. Some think that the results could inhibit people from getting insurance to pay for psychiatric care down the line, but again, I haven’t seen direct evidence of this.

Like anything, it’s up to the individual to decide what’s best for them.

It’s the 100th issue of Happiness Is A Skill, and I’m marking the occasion by going down a rabbit hole of genetic testing through GeneSight. This isn’t your usual, turns out I’m 1% Korean type of genetic testing (true story). It’s relatively new science that analyzes the body’s ability to process psychiatric drugs through the cytochrome P450 system (CYP), a group of enzymes responsible for metabolizing many medications and other substances in the body.

Though I personally have zero plans to ever swallow a psychiatric drug again, the more time I spend in the world of antidepressant withdrawal, the more interested I am in the why of it all. Why is it that some people have no issue stopping psychotropic drugs cold-turkey, while other people, like the man I wrote about in Issue 99, have permanent brain damage from psychiatric drug use and withdrawal?

My hunch is that it has something to do with genetics and the CYP system. Though there are no known studies on the CYP system and withdrawal specifically, there is some emerging research on CYP system and medication side effects. My assumption is that if the CYP system affects how a daily dose of drugs is metabolized, it’s likely involved in clearing the drug out of the system even when a daily dose is no longer being taken.

Hopefully we’re not too far from formal research on the subject, but in the meantime, I’m going to share what I’ve learned about this genetic testing and my results.

The CYP450 pathway is a group of enzymes found in the liver that are responsible for the metabolism of a wide variety of drugs, including antidepressants and antipsychotics. Specifically, the CYP450 enzymes are involved in the breakdown of these drugs in the liver, which can affect their efficacy and potential side effects.

Most antidepressants are metabolized by the CYP450 enzymes through variant alleles (versions) of the CYP450 pathways. For example, allele CYP2C19 is primarily responsible for metabolizing citalopram/Celexa and escitalopram/Lexapro while allele CYP2D6 is primarily responsible for fluoxetine/Prozac, paroxetine/Paxil, and venlafaxine/Effexor.

By looking at the genetic variations in these alleles, we can see how the body metabolizes psychiatric drugs via the CYP450 pathway. Everyone falls into one of the following categories: extensive (normal) metabolizer, intermediate metabolizer, poor metabolizer, rapid or ultra-rapid metabolizer.

An extensive metabolizer is a person with normal enzyme activity levels, meaning they can metabolize drugs normally, and therefore require standard doses of medications.

In contrast, an intermediate metabolizer has reduced activity levels of the CYP enzyme, which means they metabolize drugs slower than expected. As a result, intermediate metabolizers may experience higher overall drug levels or longer exposure to drugs, which can lead to increased risk of side effects or toxicity.

Poor metabolizers have significantly reduced or absent activity of a specific CYP enzyme, which leads to impaired drug metabolism. As a result, poor metabolizers may need to avoid certain drugs altogether due to the risk of adverse effects.

Conversely, ultra rapid metabolizers are individuals with increased activity levels of CYP enzymes, which means they metabolize drugs faster than expected, potentially leading to lower overall drug levels and reduced or absent effectiveness of medications.

The work of Selma Eikelenboom-Schieveld, a Dutch forensic scientist based out of New Mexico, focuses on the association between genetic variants of the CYP450 enzymes and violence-related adverse drug reactions in patients receiving psychoactive medication.

In her 2016 research paper “Psychoactive Medication, Violence, and Variant Alleles for Cytochrome P450 Genes,” Eikelenboom-Schieveld compared 55 violent individuals—whose behavior ranged from an altered emotional state (30 subjects), to assault, attempted or completed suicide and homicide (25 subjects)—against 58 persons with no history of violence as the controls.

In the nonviolent group, 38 subjects did not use prescription medication. In the violent group, all the subjects were on prescription medication. Of the 75 subjects on medication, 52 (almost 70%) were on three or more medications.

Her research showed that there is an “association between prescription drugs, most notably antidepressants and other psychoactive medication; having variant alleles for CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4; and the occurrence of an altered emotional state or acts of violence. Based on these results, genotyping patients for these six CYP450s would provide information as to who might be susceptible to adverse drug reactions, e.g., the development of an altered emotional state or assault/suicide/homicide.”

To say it another way: if someone is a normal metabolizer or has limited CYP gene variations and is only on one medication, chances are acts of violence are also limited. But in someone with many variants and many medications, the enzymatic pathway effectively gets clogged up, causing a buildup of drugs in the system that can lead to an altered emotional state or violence. These undesirable actions are often mistaken for mental illness, so more drugs added, increasing the likelihood of violence.

Welcome to Science Corner by Happiness Is A Skill, where I take a few minutes to teach you about the relevant neuroscience of antidepressants and antidepressant withdrawal. No more half assed assumptions without evidentiary support, like the whole chemical imbalance theory of mental illness. The idea that “too little” serotonin causes depression? Or that “too little” dopamine causes ADHD? Obsolete, oversimplified, hogwash conveniently packaged by marketing departments of pharmaceutical companies in order to convince you to “talk to your doctor about Zoloft, because when you know more about what’s wrong, you can help make it right.”

That’s the actual tagline for Zoloft by the way, from 2001. Brilliant, isn’t it? Here’s a very simple explanation for your distress. It has nothing to do with your life or your choices or the bad things that happened to you, but instead has to do with some chemicals in your brain you can’t control. So take this pill and the sun will shine and flowers will bloom and scary thoughts will go away and we’ll all be content. Right? Right? 

If one could die of bullshit overload, I would long be gone.

Instead, let’s talk serotonin transporter (SERT) occupancy, something researchers have actually measured and analyzed in labs.

Let’s start with some background information. The serotonin transporter is a protein in the brain that helps regulate levels of serotonin. When someone takes an antidepressant, the drug binds to the SERT protein and blocks it from transporting serotonin out of the brain, disturbing the brain’s longstanding homeostasis by increasing the amount of serotonin available. When early test subjects reported an elevated mood after taking antidepressants in clinical trials, the assumption was that the increase in serotonin was responsible for this relief, therefore thus forming the basis of the serotonin theory of depression. If more serotonin = happier people, then less serotonin = sad people. And that’s how Prozac was born!

Too bad it was all a pipe dream.

Over time, the brain adapts to the presence of the drug and learns to produce less serotonin on its own. The body is always trying to get back to homeostasis, remember. The pharmaceutical industry spends billions of dollars trying to convince you that they can override hundreds of thousands of years of evolutionary physiology, but the bottom line is the body has to remain in equilibrium to stay alive. If you’re hot, you sweat to cool down. If you’re cold, you shiver to warm up. If either of those systems don’t work like they should, you die.

So let’s say you’ve been on 20mg Prozac (fluoxetine) for ten years and you decide it’s time to come off. Your doctor drops you to 10mg for a few weeks and you tolerate it. Maybe you’re a little emotional and antsy but you can handle it. Your doctor has heard about all this withdrawal stuff so he thinks he’s got it all figured out and tells you not to drop from 10mg to 0, but to instead cut the capsule in half and take 5mg for a week or two. You don’t feel great and wonder if it’s the depression coming back. But you figure you’ll drop to zero and give it a few weeks to know for sure. After all, 5mg is miniscule. Smaller than the smallest dose on the market! They give 5mg of Prozac to six year olds!

You drop to zero and all hell breaks loose—akathisia, huge emotional swings, paranoia, brain fog, gut issues. Back to the doctor you go, because clearly you’re sick and how stupid you were to think that you could operate without the Prozac. So you go back on 20mg. Hell, make it 40mg this time. Clearly, you need it. Your doctor suggests an antipsychotic as well because the paranoia suggests an emergence of Bipolar Disorder. Life, now, is all about managing symptoms.

Where did everyone go wrong? A fundamental misunderstanding of SERT occupancy.

Let’s look at the following graphs, courtesy of researcher Mark Horowitz:

The black curve is the measure of SERT occupancy as determined through brain-imaging techniques called PET scans that allow researchers to see the biological workings of the body. As you can see, at 25mg of fluoxetine, 80% of the serotonin transporters are occupied.

Figure (a) is a representative of the conventional line of thinking for linear tapering of antidepressants. Rather, the idea of lowering dosages by equal, measured steps—5mg, in the case of this graph. The problem is that if you lower the dose of Prozac from 20mg to 5mg—a 75% reduction—SERT occupancy only reduces by 20%. This means that not only are there fewer operating receptors, there is also less serotonin in the brain because the body long ago lowered its production. It is likely that withdrawal occurs at least in part because of this chemical imbalance created through linear tapering. And yes, it is ironic that this time, a true chemical imbalance is responsible.

Due to the hyperbolic nature of SERT occupancy, this dissonance is even more extreme at lower dosages, as seen in Figure (b). At 2.5mg of Prozac—20% of the lowest dose available on the market—SERT occupancy is 40%, just half of what it is at a robust dose of 25mg. This explains why it can be more difficult for people taper as they get closer and closer to zero.

Though SERT occupancy occurs with all antidepressants, the levels of SERT occupancy vary from drug to drug, as shown by this systematic analysis of 10 different psychiatric drugs, done by Anders Sorenson, et al.

The reason why you need to know about this is because it’s likely your prescriber is completely unaware. More understanding of SERT occupancy, as well as more robust research (especially when multiple drugs are involved), would lead to better de-prescribing practices that will likely lessen or eliminate severe withdrawal effects.

In the fictional example I gave above, our now “bipolar” patient needed a much slower taper that followed the hyperbolic curve and was adjusted only once she stabilized from the previous dose reduction. Had she tolerated a 10% reduction—from 10mg to 9mg to 8.1mg to 7.29mg and so on to 0—her brain likely would have had much more time to fire up dormant receptors and naturally ramp up serotonin production, leading to a more gentle, symptom-free re-introduction into a world without SSRIs.

Instead, when she was pulled off too quickly, her system went haywire because neurotransmitters are responsible for regulating the entire body. Instead of recognizing this as withdrawal, both she and her doctor assumed it was mental illness and plunked her back in the system with a shiny new diagnosis. This happens all the time. All. The. Time.

I hope you’ve enjoyed this Science Corner issue of Happiness Is A Skill. Please keep in mind that we are very much in the infancy of antidepressant withdrawal research, and that no single piece of information is the whole answer. But as they say on NBC, the more you know! Ding ding dong!