#i am far from being a chemist and know that literally basically nothing makes sense here I humbly request you indulge me.

[hogoflight]

WHAT IF. blood of the Earth ≈ oil. therefore the Greek gods’ ichor was composed of a high concentration of crude oil?? THE GODS BLEED BLACK???? Maybe translations got a bit weird with a prophecy mentioning something about “oil / ichor (for containing oil) being worth as much as gold” in the future. And over time stories eventually mentioned that ichor looked like gold? If this was the case, ichor would of course have other stuff in it. Maybe White Phosphorus would be fun just because magic. white ichor that glows sickly green in the dark and is also toxic! ichor being toxic is mentioned several times in myths!!! this gets WILDER when you think about the Byzantines’ Greek fire also “setting the water on fire”. KIND OF LIKE HOW OIL DOES. (The implications of Greek fire containing the Gods’ blood is WILD. Like what happened for the gods to give them their blood for a weapon?? Did the gods do so to protect their country and nation? Did commanders strike a deal with their old gods of the land to protect their current one? Also super metal.) ALSO GODS’ BLOOD BEING FLAMMABLE. AOAUGHGAUGH. the image of two gods fighting badly, covered in deep black gashes and surrounded by pools and spills of viscous oil. Being injured and heavily coughing up spurts of the stuff. This could also work for gods’ eyes turning black when angry (crude oil?) but also maybe being white (white phosphorus)???? MAGIC LOGIC GO WITH IT

[thenormativesuperintendent]

The Schwarzschild radius

One of the most common complaints among people who begin treatment with SSRI's is that they reduce their ability to feel, and that this is definitely a bad thing, and therefore all psychiatric drugs are bad, Prozac is bad, Zoloft is bad, Big Pharma is bad, and then the patient gets depressed again and now feels even worse because, like, I can't take sertraline, can I? I wouldn't feel anything! "I knew I had to get off Zoloft because I couldn't even cry at my brothers wedding!" - Random woman whose name I can't recall. I can sympathise, this would indeed be a little jarring and disconcerting, but you know what else is bad? Depression. I don't mean to make a mockery of her plight, I understand what it's like to suffer from depression, but my annoyance at the time came from her anger towards the drug. I understand you were upset you couldn't feel that happy for your brother, but this is how SSRI's work, ok? Numbing to initiate action, action to improve your circumstances.

I'm going to palm this off to my favourite blog, and probably one of the smartest/most insightful people alive, Hotel Concierge, in this essay here, because he's written a far more eloquent, well articulated set of reasons as to why emotional analgesia is a good thing, and how this effect is leveraged to facilitate therapy. Also, if you have ever undergone the burden of mental illness, this essay is literally, for me, life-saving. I sincerely hope that it helps you too.

Second point: I find alarming the claim that, fundamentally, most antidepressants work via the same mechanism. I debated whether to tap out this text file on the point of not wanting to offend anyone/appear to be a pedantic asshole, but recently, this, courtesy Slate Star Codex:

“Increasing BDNF is the best option we have” NO[1]

Can I write "disagree" and then underline it, and then highlight it several times? I think this view -that it’s really just a landscape of SSRI’s- is flat-out wrong - I don't think it's necessarily dangerous per se, but it vastly misrepresents the state of play in psychopharmacology, and I want to put forward my arguments to rectify that.

Firstly, from the wonder of modern pedagogy that is Stahl:

Complex.

The idea behind these diagrams (the textbook is brilliant) is to give you a visual representation of the various binding affinities these compounds have for different receptors; the larger the shape, the greater the binding affinity.

Now let’s take a look at two similar antidepressants from the SSRI class: Lexapro and Zoloft (escitalopram and sertraline) The primary mechanism of action in both is occupancy of SERT (the serotonin transporter); normally serotonin gets slurped back up into pre-synaptic neuron, now it can’t because said slurpy protein is full, this leads to serotonin lingering in the synaptic cleft for longer which leads to an increased chance for it to bind to serotonin receptors on the post synaptic neurone. Voila, more activity in serotonergic neurons. Could be inhibitory, excitatory, changing receptor expression in the surface of the neuron: a multitude of downstream effects. Give two weeks for gene translation to occur and there you have it.

Serotonin is involved, in a broad, upstream kind of way, in regulating mood. More specifically, if thoughts[2] are constituted of different circuits or clusters of neurons firing, then serotonin plays a role in regulating affect by changing the activity of these cells (by the probability that they release/don’t release an impulse) that are poorly understood.

Posteriori, it’s no surprise that “pure” SSRI’s compress your emotional bandwidth concomitant to dose; we developed the saying “carrot and stick” for a reason; if emotional circuitry is closely related to System 1 thinking (Kahneman & Taversky - please don’t make me cite) then we need happiness and reward as well as sadness and grief. The two in partnership give us a map to help steer our actions away from what might harm us and towards what might be beneficial. If depression isn’t sadness (it isn’t) then lower serotonin levels lead to loss of any feeling, and your subjective cognitive interpretation of this is depression. You feel, not nothing, but hopeless. You lie there doing nothing; there’s no carrot, there’s no stick, everything just sucks. You’re not sad, you’re not crying, there’s just no point doing anything. Going upstream to jack up extracellular serotonin levels makes sense; sure, you might cap out your happiness by increasing the overall activity of all those serotonin pathways, but now the affective system has some life in it, you can get up and move about, think and cognise. Hooray, now therapy can work.

Except what if we could do better? We recognise that blocking the transporter means more serotonin everywhere, serotonin everywhere = emotional numbing. What if we could go further downstream and just target the receptors we want directly? Don’t jump to the conclusion that morphine is a good thing right now, if you’re suffering from depression and thumbing through your contact book to find a dope dealer, you have my sympathies, and far bigger issues than I can help you with. I wish you luck.

But there is no such thing as a pure SSRI; Zoloft has a weak, but clinically significant effect on other proteins (transporters and receptors); Lexapro is about as close to a pure SSRI as we currently have, but Zoloft seems to have some decent dopamanergic action going on in the frontal cortex.

And this is exactly the issue. I’m not debating that the primary mechanism of effect in both these drugs is interfering with serotonin metabolism, I’m saying that the subjective experience of being on sertraline is going to be different to the subjective experience of being on escitalopram. How do you quantify a slight uptick in dopamine? Chemists and pharmacists might say “well, it’s nothing, it’s really just an SRI�� except: how in gods name do you qualify the subjective difference of “minor increase in dopamine”?

This isn’t a theoretical consideration; what appears on paper to be a bunch of drugs with minor differences, will, I am confident, have wildly different effects on different patients. Forget neurotransmitters, forget HAM-D scales. What if you just gave each patient four weeks on each of these different drugs and asked them to keep a daily journal of their subjective experiences? Which pill would they prefer? My best guess is no clear answer would emerge: minor differences on paper lead to concrete differences to different patients, and this is a very real, tangible, beneficial phenomena. Vortioxetine is indeed exciting: heavily antagonising HT2C sub-receptors tends to have good clinical effects, as evidenced by the fact Agomelatine seems to work well for some people. “But couldn’t that just be its beneficial effects on sleep and MT1/MT2 agonising?” Sure, except melatonin decreases dopamine release, which is the current leading hypothesis of seasonal affective disorder. Try popping 20mg of melatonin and tell me how you feel the next morning. Not enough dopamine means a malfunctioning reward/motivation pathway and shoddy cognition[3]. Combining SERT occupancy with serotonin antagonism on certain sub-receptors is a legitimately neat development. Mirtazapine is a potent drug, perhaps makes some a little too edgy or sedated (sedation can be a useful tool, see: insomnia) and it just antagonises the bejesus out of histamine, adrenergic, and serotonergic receptors.

The problem is that once people see “SERT” on a drug, everything else gets sucked into that vacuum, compressed into a black hole and all nuance is lost, and in the delicate balance of various ratios of neurotransmitter levels, nuance is everything. There’s no way to qualify the subjective experience of “minor increase/decrease in transmitter X/Y/Z” so stop pretending that these drugs are all basically the same; similarity on paper != similarity of experience.

(Endnote: SNRI’s tend to work well, slightly paradoxically, on anxiety. Why? Because increasing norepinephrine levels leads to agonising the alpha-2 autoreceptor, this shuts down the firing of the pre-synaptic neuron. Of course, individual mileage may vary and standard disclaimers apply. Just don’t be surprised if you fall asleep in class six hours after you’ve taken your Cymbalta)

I hope I haven’t offended anyone - my aim is simply to push back against a perceived hopelessness at making new antidepressants, and to argue that there are demonstrable, subjective (which in psychiatry is almost everything?) differences in each and every anti-depressant out there.

[1] It was (still is?) trendy to say that increasing BDNF ameliorates depression, but I’m pretty confident BDNF has very little to do directly with depression. Yes, depressed people show low levels of BDNF, and drugs like Zoloft can increase BDNF and synaptogenesis (they can also not do that) So does exercise. And yet exercise is much more efficacious at doing so than Zoloft, but no-one successfully gets through clinical depression by doing laps across Greece like 300 lives depend on it. Don’t get me wrong, exercise is fantastic, for mental and physical health. I’m just saying that nothing increases BDNF like exercise, and yet it doesn’t work as well as antidepressants in most cases. That NSI-189 failed to differentiate from placebo is perhaps the most unsurprising result since Karl Popper put pen to paper.

[2] Ontology question: what’s a thought?

[3] My leading cause of frustration with the nootropic/biohacking/transhumanist community: “give me all the dopamine you can!” Oh, so you want schizophrenia? Dude, you don’t need pills, you need to stop avoiding study. To quote Hotel Concierge, “your rationalism is inseparable from your anxiety”