The serotonin theory of depression: a systematic review of the evidence (2022)

Important to note that the serotonin theory of depression doesn't have to be strictly true for SSRIs to be effective. People who having passing familiarity with neuroscience often assume that psychiatric medications work by correcting deficiencies, but this isn't true. It's also not accurate to say that SSRIs "give you more serotonin" or any of the other variations on that theme.

Neurotransmitters aren't simple levels in the brain that go up and down, despite how much podcasters and fitness influencers talk about them like that. Neurotransmitter dynamics are complex and the long-term adaptations after taking medications like an SSRI can't be simply described in terms of "levels" going up and down. There are changes in frequency, duration, and movement of Serotonin across synapses that are much more complex. There are also adaptations to the receptors, including auto-receptors which modulate release of neurotransmitters (side note: some newer antidepressants also directly target those autoreceptors with possibly slight improvements in side effect profile).

So keep that in mind when reading anything about the serotonin theory of depression. This is often brought up as a strawman argument to attack SSRIs, but we've known for decades that the serotonin theory of depression never fully explained the situation. We've also known that some conditions like anxiety disorders are associated with increased serotonin activity in parts of the brain, which SSRIs can normalize.

Exactly this - SSRI's efficacy was established based on improvements in reports from depressed people and we formed a theory about the mechanism based on the interactions we understood. As we try to prove that theory out it turns out our theories don't hold - but people who are depressed still improve when on SSRIs! So we're still working on the mechanism (which we always knew was incomplete at best) but this work isn't about the underlying efficacy of the drugs on the condition. It's about the nerdy explanation for why SSRIs work.

SSRIs aren’t shown to be much better than placebo and are shown to be about as effective as therapy — which is actually durable.

There’s also rates of sexual side effects in excess of 70% [1] and they cause weight gain which is separately associated with depression.

In fact industry data shows a smaller gap between SSRIs and placebo than FDA data. See Figure 1. [2]

The problem with SSRIs is that serotonin receptors are all over the body including in the gonads and they play a large role in appetite regulation.

They do something but it’s not nearly what people assume.

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6007725/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/

I read this sort of critique often, but what are people living with debilitating depression supposed to do? SSRIs are barely better than placebo, but so is psychotherapy; SSRIs have side-effects, but at least they're cheap and readily available. Exercise is also barely better than placebo, if you're actually capable of maintaining that effort. Everything else in the armamentarium is some combination of less effective, more risky and/or prohibitively expensive.

Do we need better treatments for depression? Yes, desperately. Are some people with mild, self-limiting illness taking SSRIs unnecessarily? Probably, in some places. Are many people with serious depressive illness not trying drugs that might help them? Definitely. Does denigrating the least-worst treatment for most people actually help anyone?

For me, I found Bupropion slightly effective, and Dextroamphetamine very effective for my depression.

I had severe depression during Covid, manifesting as involuntary and passive suicidal ideation. Basically a hours long whirlpool of daydreaming about dying in some way, because it was the only thing which brought comfort to what I would best describe as a sort of mental agony, but without pain. Just the constant need to escape existing. Passive meaning at no point was I actively intending to act on it, but obviously this was not something to be allowed to continue.

The depression basically severely reduced my ability to mitigate my ADHD symptoms, causing them to become very apparent, essentially being co-morbid with each other. With that context, I first did some non-stimulant preliminary alternatives like:

* Bupropion HCL. This provided partial mitigation of the depression. Basically it was manageable and not threatening to implode my ability to do basic life tasks. No effect on my ADHD.

* And Atomoxetine (Strattera) which within the week had brought back my involuntary hours long daydreams of dying, and really fucked up my dick/physical and mental sexual response, which lingered for a few months after despite quickly ending treatment. As a male, I severely underestimated how much having a healthy sexual response contributes to overall wellbeing.

After that I tried extended release Dextroamphetamine.

The very first day, I wasn’t what I would consider euphoric, but I had a distinct calm sort of sense of wellbeing that was very much in contrast to the previous several months. Basically I could actually start to feel that things could be better, rather than trying to brute force reason while suffering. I liken it to what you feel when the pain from when you stub your toe fades, and you have some minor lingering endorphins.

After that first day, I didn’t feel anything else directly connected to taking the pill after that. I’d typically forget if I already took the pills 2-3 times a week (meaning skip the dose). All I could notice after resuming after skipping a day, was being slightly more chatty, and feeling like I was slightly worse at driving. The few times I probably doubled up, I’d feel this sort of mild head pressure.

But the overall effect of Dextroamphetamine within 3 days was the complete elimination of my passive ideation. Intrusive thoughts are like flies, they land on everyone, but healthy people can brush them away. I still had to take care not to voluntarily sustain negative thoughts, but it was actually voluntary now.

I later moved to Lisdexamfetamine ER because the supply of dex at the time was severely constrained, but it was basically identical. Supposedly less addictive/abusable too, though for me either felt as addictive as a collagen supplement.

After a few months, I had the dose lowered, and several months later, I halted taking stimulants. They didn’t really do much for my ADHD symptoms, and I felt that whatever had triggered my depression had cleared up so I could manually deal with the symptoms like I always have.

So that left some mild side effects of slight head pressure, probably being a slightly worse driver, probably being a slight detriment to my sleep, and possibly increasing jaw clenching (I now have a fitted nightguard), so I had zero reason to continue.

But it’s very reassuring that if I get another severe depression episode for some reason, I now have a first response tool I can use.

Thanks for your personal empircal revelations.

I'm sure you know Bupropion doesn't affect seratonin, its a dopamine re-uptake inhibitor.

As someone who also doesn't seem to respond much to seratonin related meds, Burproprion worked somewhat but I suffer from increased insomnia as a side effect. I actually respond better to things mostly affecting GABA and NMDA rather than the 'classic' anti-depressents.

That said I was trialled on methylphenidate and all it did was make me procrastinate waaaay faster, so personally I'm avoiding any stimulants stronger than caffeine.

bupropion does...a lot of things (including mildly doing what dextroamphetamine does...). A lot of these drugs don't just hit one receptor type...(don't get a pharmd started on receptor affinity binding profiles...)