# Pharma, Jun-Jul(and a bit of Aug)'25 Again the long purposeful rants? **Always**. # Conclusions Teaser it is. šŸ§¬ Despite a lot of psychiatrists betting on the negative side of genetic testing - Iā€™m slightly pro-testing: the **costs are dwindling** + thereā€™s a lot of data to **mitigate side effects/make settling on a scheme faster** šŸ«˜ Lithiumā€™s role in renal dysfunction is still eluding scienceā€™s grasp; it **does** influence some processes, but it looks like the real *nephrotoxic or not* debate brings a bit of reverse causation šŸ’‰ 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](https://psychopharmacologyinstitute.com/publication/the-role-of-genetic-testing-in-psychiatry-interview-2873) I believe ranting about Psychopharmacology Institutesā€™ takes and publications is my semi-recurring rubric. Not to say anything - theyā€™re awesome, and have a bunch of clinical experience. ![The Bidirectional Relationship of Depression and Inflammation: Double Trouble: Neuron](https://www.cell.com/cms/10.1016/j.neuron.2020.06.002/asset/a8d602dc-38ba-4369-90be-be7eecf86288/main.assets/gr1_lrg.jpg align="center") *From a good overview on* [*depression/inflammation duo paper*](https://www.cell.com/neuron/fulltext/S0896-6273%2820%2930431-1) However, I couldnā€™t skip ranting their [overview of genetic testing in psychiatry](https://psychopharmacologyinstitute.com/publication/the-role-of-genetic-testing-in-psychiatry-2873): * `It seems the outcomes are no better with genetic guidance.` ā†’ Iā€™ve [mentioned](https://t.me/ohmyboi/1118) that ABCB1, multidrug resistance gene, can predict and [influence outcomes for its substrates](https://www.gatewaypsychiatric.com/abcb1-predicts-antidepressant-response/), **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.` ā†’ inb4 tying the response to directly related gene. Luckily we now know that SSRI therapeutic effects are tied to: * [increased neuroplascitity](https://scitechdaily.com/brain-plasticity-ssris-breakthrough-on-how-antidepressants-work-why-they-take-weeks-to-kick-in/) (as the linked overview suggests) * decreased stress-[induced inflammation](https://t.me/ohmyboi/630), previously [covered in 2019](https://t.me/ohmyboi/448) * `Chris Aiken, M.D.: We've known for years that checking blood serum levels of antidepressants does not improve outcomes, which is surprising.` ā†’ given that occupancy is [often high enough with even subclinical doses](https://pmc.ncbi.nlm.nih.gov/articles/PMC8960396/#Sec7) (*ā€œFor citalopram at 20ā€‰mg and escitalopram at 10ā€‰mg, occupancy increased from 73% and 74% to 80% and 77%, respectively, after 25 daysā€),* and the usual scheme is getting to recommended doses - I canā€™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.` ā†’ another good one. * Given that recent studies show [metabolizer status **does** influence response](https://www.nature.com/articles/s41398-024-02981-1#Sec9) ([figure](https://i.imgur.com/LWzVkCE.png) from the article) ā†’ namely, poor metabolizers CYP2C19 get better response * Also, starting is, again, [rougher for PMs](https://pubmed.ncbi.nlm.nih.gov/30135031/): *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: itā€™s an almost-silver-bullet for bipolar depression, preventing a whole lot of bad outcomes (made an overview [here](https://posts.teleogenic.com/going-mediterranean#heading-lithiums-mechanismhttpsreadwiseioreadershared01gr7jwz0c2jnhpsdvgkvpa7sq)) via e.g. [GSK-3Ī²](https://selfhacked.com/blog/gsk3b-inhibition-potent-pathway-improve-brain-function-mood/) (NOT GlaxoSmithKlineā€¦) inhibition. Yet lithium is one of those meds you definitely **want to check plasma levels** on. ![](https://i.imgur.com/KaDLzfA.png align="center") * Lithium overdose is [not pretty at all](https://www.reddit.com/r/bipolar/comments/19dpsof/lithium_toxicity/) (that post is also a good example the importance of genetic testing: ā€œ*crazily enough they were ā€œjust aboveā€ therapeutic but my body just* ***cannot metabolize lithium the way itā€™s supposed to be metabolized*** *for some reasonā€* * [This paper](https://pmc.ncbi.nlm.nih.gov/articles/PMC8836013/) tries to do a deep dive in lithiumā€™s genetics: the usual GSK-3Ī², inositol INPP1, BDNF, XBP1 (X-box binding protein! C allele has **3x OR for lithium response**), NR1D1 (T allele ā†’ **3.56x OR for poor response**) * Turns out thereā€™s a [separate consortium](https://www.pharmgkb.org/literature/6482732) for investigating the geneticsā€™ effect on lithium response and metabolism, ConLiGen (*Consortium on Lithium Genetics*)! ## Continuing on lithiumā€™s side effectsā€¦ ### [Going renal](https://psychopharmacologyinstitute.com/section/managing-renal-side-effects-of-lithium-therapy-2889-5870)! ![](https://i.imgur.com/r4xMhVV.png align="center") Lithiumā€™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](https://psychscenehub.com/psychinsights/lithium-induced-renal-dysfunction/) (above): * ā¬‡ļø Antidiuretic hormone + ā¬‡ļø Aquaporin 2 (AQP2) ā†’ **polyuria** (ā¬†ļø increased urination) * ā¬‡ļø Epithelial Sodium Channel ā†’ ā¬†ļø **sodium** excretion * ā¬‡ļø antidiuretic effect of Vasopressin ([source](https://pmc.ncbi.nlm.nih.gov/articles/PMC4456600/#:~:text=Acute%20lithium%20treatment%20reduces%20the%20antidiuretic%20effect%20of%20vasopressin%20\(Singer%20et%20al.%201972\).)) ā†’ more **polyuria**! Yay So, pretty much a **lot of polyuria** and **less sodium** left. Yet, according to the same review and our title source - itā€™s inconclusive if lithium itself causes renal damage. The *NNH (number needed to harm) is 300*, i.e. youā€™d get one patient one of 300 getting serious problems. Apparently **managing side effects** in psychopharmacology equals: * monitoring plasma levels so they donā€™t get toxic * using diuretics in case levels get risky-high * discontinuing if renal function gets icky-bad * be accurate with long workouts/sweating ( Ķ”Ā° ĶœŹ– Ķ”Ā°) * donā€™t use caloric beverages for polyuria-caused polydipsia (thatā€™s just thirstā€¦) ā†’ and remember that [diabetes risks are 65% higher](https://www.monash.edu/news/articles/one-can-of-artificially-sweetened-soft-drink-daily-may-increase-diabetes-risk-by-more-than-a-third) by a recent Monash Uni study (actually increased by 38% vs 23%, but I love drama) with artificial sweeteners compared to sugar ### (and thyroid) ![how does lithium affect the thyroid](https://www.verywellhealth.com/thmb/CkPajwFiRwdA_mJi_WuaDjIL0uc=/1500x0/filters:no_upscale():max_bytes(150000):strip_icc():format(webp)/lithium-and-thyroid-disease-3233148-033255da0a6a473ab07e08870c4abc16.jpg align="left") Adding to the infographicsā€™: * lithium concentrates in thyroid at 3-4x plasma levels, and likely [competes with iodine transporter for uptake](https://www.mdpi.com/1424-8247/17/11/1425#:~:text=Lithium%20is%20concentrated%20in%20the%20thyroid%20at%20levels%20three%20to%20four%20times%20higher%20than%20in%20the%20plasma%20%5B21%5D.%20This%20drug%20reduces%20the%20uptake%20of%20radioiodine%20in%20the%20thyroid%20of%20rats%20and%20other%20species%2C%20suggesting%20that%20it%20may%20compete%20for%20iodide%20transport%20%5B22%5D) * goiter occurs in roughly the [half of all patients](https://www.verywellhealth.com/lithium-and-thyroid-disease-3233148#:~:text=most%20common%20thyroid%2Drelated%20side%20effect%20of%20lithium%2C%20occurring%20in%20approximately%2040%20percent%20to%2050%20percent%20of%20all%20patients.) * hypothyroidism occurs in 20-30% of all patients and [is most common in women over 45](https://www.verywellhealth.com/lithium-and-thyroid-disease-3233148#:~:text=It%20is%20most%20common%20in%20women%20over%20the%20age%20of%2045%20and%20in%20people%20with%20a%20family%20history%20of%20thyroid%20disease.) ā†’ given that lithium accelerates antibody titre increases (as per [ScienceDirect](https://www.sciencedirect.com/science/article/abs/pii/S1521690X09000724#:~:text=%E2%80%A2,Patients%20taking%20lithium)) and the fact that [~17.5% of adult women have Hashimotoā€™s already](https://pmc.ncbi.nlm.nih.gov/articles/PMC9608544/#s3:~:text=HT%20prevalence%20of%20female%20adults%20was%203.86%20adult%20males%20times%20\(17.5%20vs.%206.0%25\))ā€¦ P.S. As per the paper, `HT prevalence of female adults was 3.86 adult males times (17.5 vs. 6.0%)`. Iā€™m an idiot but *6Ɨ3.86=23.16*ā€¦ Okay, thatā€™s actually not prevalence but [ORs compared with weights](https://i.imgur.com/4BErlrB.png), but the wording is unclear. Given that lithium apparently [stimulates B lymphocyte activity](https://www.researchgate.net/publication/270515387_Review_of_lithium_effects_on_immune_cells#:~:text=Further%2C%20lithium%20may%20stimulate%20immunoglobulin%20production%20in,increase%20T%2Dlymphocyte%20proliferation%2C%20and%20affect%20proinflammatory%20cytokine) (hence the thyroid autoimmunity exacerbation) ā†’ we may speculate it may jump-start other autoimmune conditions caused by B-cell-produced antibodies, right? ![Figure 2](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d57b/10469704/b4881c44909c/fnins-17-1213766-g002.jpg align="left") There are also [papers that evaluate lithiumā€™s immunomodulatory activity](https://pmc.ncbi.nlm.nih.gov/articles/PMC10469704/#sec8) in bipolar, namely: * ā¬‡ļø pro-inflammatory cytokines, i.e. *TNF-Ī±, IFN-Ī³, IL-6, IL-1Ī², IL-2* ā†’ suppressing inflammation and proliferation * ā¬†ļø anti-inflammatory *IL-10* ā†’ increasing immunoregulatory activity At the same time, **immune cells are getting a boost**: * ā¬†ļø G-CSF (granulocyte colony-stimulating factor), Neutrophil count and B-cell activity Response is correlated to [decreases in TNF-Ī±](https://www.mdpi.com/1422-0067/25/24/13277) and increases in IGF1 expression ([`IGF1 gene was significantly overexpressed in BD patients taking lithium but only in those responding to therapy.`](https://pmc.ncbi.nlm.nih.gov/articles/PMC10469704/#sec8:~:text=Squassina%20et%20al,responding%20BD%20patients)) --- ## 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 oneā€™s creatine-dependent thermogenesis activatorā€¦) * 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 --- Welcome to **Teleogenic**ā£ļø Other places I cross-post (not always) to: * [**Hashnode**](https://posts.teleogenic.com) * [**Medium**](https://baldr.medium.com/) * [**Telegram**](https://t.me/ohmyboi) * [**Twitter**](https://twitter.com/ZakharKogan) * [**LinkedIn**](https://www.linkedin.com/in/zakhar-kogan/)