Again the long purposeful rants? Always.

Conclusions

Teaser it is.

🧬 Despite a lot of psychiatrists betting on the negative side of genetic testing - I’m slightly pro-testing: the costs are dwindling + there’s a lot of data to mitigate side effects/make settling on a scheme faster

🫘 Lithium’s role in renal dysfunction is still eluding science’s grasp; it does influence some processes, but it looks like the real nephrotoxic or not debate brings a bit of reverse causation

💉 Concerning thyroid effects of lithium: it not only competes for iodine transporter, but has weird immunomodulatory effects that can pour some oil to the autoimmune processes present

Genetic testing in psychiatry

I believe ranting about Psychopharmacology Institutes’ takes and publications is my semi-recurring rubric. Not to say anything - they’re awesome, and have a bunch of clinical experience.

From a good overview on depression/inflammation duo paper

However, I couldn’t skip ranting their overview of genetic testing in psychiatry:

• It seems the outcomes are no better with genetic guidance. → I’ve mentioned that ABCB1, multidrug resistance gene, can predict and influence outcomes for its substrates, a lot

• The theory suggested that having the short arm of the serotonin transporter gene means a person won't respond well to serotonin-based antidepressants like SSRIs. However, this theory didn't pan out. → inb4 tying the response to directly related gene. Luckily we now know that SSRI therapeutic effects are tied to:

  • increased neuroplascitity (as the linked overview suggests)

  • decreased stress-induced inflammation, previously covered in 2019

• Chris Aiken, M.D.: We've known for years that checking blood serum levels of antidepressants does not improve outcomes, which is surprising. → given that occupancy is often high enough with even subclinical doses (“For citalopram at 20 mg and escitalopram at 10 mg, occupancy increased from 73% and 74% to 80% and 77%, respectively, after 25 days”), and the usual scheme is getting to recommended doses - I can’t see this a factor.

  • the concentration of e.g. escitalopram can change

• In the rare event of a slow or rapid metabolizer, we've lowered or raised the dose accordingly and achieved decent outcomes. It seems the outcomes are no better with genetic guidance. → another good one.

  • Given that recent studies show metabolizer status does influence response (figure from the article) → namely, poor metabolizers CYP2C19 get better response

  • Also, starting is, again, rougher for PMs: gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden

• Not only P450 and ABCB1 do influence response - take lithium, for example: it’s an almost-silver-bullet for bipolar depression, preventing a whole lot of bad outcomes (made an overview here) via e.g. GSK-3β (NOT GlaxoSmithKline…) inhibition. Yet lithium is one of those meds you definitely want to check plasma levels on.

  

  • Lithium overdose is not pretty at all (that post is also a good example the importance of genetic testing: “crazily enough they were “just above” therapeutic but my body just cannot metabolize lithium the way it’s supposed to be metabolized for some reason”

  • This paper tries to do a deep dive in lithium’s genetics: the usual GSK-3β, inositol INPP1, BDNF, XBP1 (X-box binding protein! C allele has 3x OR for lithium response), NR1D1 (T allele → 3.56x OR for poor response)

  • Turns out there’s a separate consortium for investigating the genetics’ effect on lithium response and metabolism, ConLiGen (Consortium on Lithium Genetics)!

Continuing on lithium’s side effects…

Going renal!

Lithium’s awesome - yet it poses its risks, and is feared by many practitioners. First and foremost, the kidneys. As per the awesome image by PsychSceneHub (above):

• ⬇️ Antidiuretic hormone + ⬇️ Aquaporin 2 (AQP2) → polyuria (⬆️ increased urination)

• ⬇️ Epithelial Sodium Channel → ⬆️ sodium excretion

• ⬇️ antidiuretic effect of Vasopressin (source) → more polyuria! Yay

So, pretty much a lot of polyuria and less sodium left. Yet, according to the same review and our title source - it’s inconclusive if lithium itself causes renal damage. The NNH (number needed to harm) is 300, i.e. you’d get one patient one of 300 getting serious problems.

Apparently managing side effects in psychopharmacology equals:

• monitoring plasma levels so they don’t get toxic

• using diuretics in case levels get risky-high

• discontinuing if renal function gets icky-bad

• be accurate with long workouts/sweating ( ͡° ͜ʖ ͡°)

• don’t use caloric beverages for polyuria-caused polydipsia (that’s just thirst…) → and remember that diabetes risks are 65% higher by a recent Monash Uni study (actually increased by 38% vs 23%, but I love drama) with artificial sweeteners compared to sugar

(and thyroid)

Adding to the infographics’:

• lithium concentrates in thyroid at 3-4x plasma levels, and likely competes with iodine transporter for uptake

• goiter occurs in roughly the half of all patients

• hypothyroidism occurs in 20-30% of all patients and is most common in women over 45 → given that lithium accelerates antibody titre increases (as per ScienceDirect) and the fact that ~17.5% of adult women have Hashimoto’s already…

P.S. As per the paper, HT prevalence of female adults was 3.86 adult males times (17.5 vs. 6.0%). I’m an idiot but 6×3.86=23.16… Okay, that’s actually not prevalence but ORs compared with weights, but the wording is unclear.

Given that lithium apparently stimulates B lymphocyte activity (hence the thyroid autoimmunity exacerbation) → we may speculate it may jump-start other autoimmune conditions caused by B-cell-produced antibodies, right?

There are also papers that evaluate lithium’s immunomodulatory activity in bipolar, namely:

• ⬇️ pro-inflammatory cytokines, i.e. TNF-α, IFN-γ, IL-6, IL-1β, IL-2 → suppressing inflammation and proliferation

• ⬆️ anti-inflammatory IL-10 → increasing immunoregulatory activity

At the same time, immune cells are getting a boost:

• ⬆️ G-CSF (granulocyte colony-stimulating factor), Neutrophil count and B-cell activity

Response is correlated to decreases in TNF-α and increases in IGF1 expression (IGF1 gene was significantly overexpressed in BD patients taking lithium but only in those responding to therapy.)

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Next?

Next pharmaBS episode:

• autism phenotypes, I just wanna dissect that study

• post-GLP obesity pills (when will exercise mimetics explode instead of those? This one’s creatine-dependent thermogenesis activator…)

• melatonin vs. trazodone vs. doxepin vs. benzos for sleep

Next VC episode:

• 2025 updates in VC/PE performance

• appealing to the funds

• fellowships and internships

Next in viz:

• a lot of funny visualizations and tutorials

Next in doing something (not gonna happen and we know it):

• maybe a hackathon

• maybe a finishing paper scoring engine, finally

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