The polygenic risk score approach is pretty smart for catching subthreshold bipolar cases that don't fit the DSM boxes. If someone's genetics scream bipolar but they never hit the full mania checklist, you're basically guessing blind on lithium unless you look at family history. Running PRS before trial and error could probably cut down those multi-year journeys through failed antidepressants.
I like guanfacine as a longterm heart health replacement for Vyvanse - for myself; but consider that depression leaves lasting degenerative cognitive symptoms (whether natural or pharmaK treated iatrogenic side FX , no?) - stimulants can be helpful to balance that out 😉
Theories of depression polarization and categories are always interesting! Thanks! ☺️
Glad you found it interesting! The biomarker-guided approach is what I find most promising - matching specific etiology to specific treatments rather than trying different options sequentially. Thanks for your engagement
This was a very interesting presentation, but I somehow was hoping it would move to a discussion of transmagnetic stimulation. Does this mean you do not see this as having a “future” within this context, despite its “trendy” aspects? I have had patients with serious refractory forms of depression who I have presented to Grand Rounds & in each case received recommendations for TMS, and in both cases was quite surprised by the outcome. Any thoughts?
Oh I definitely see neurostimulation as part of the toolkit. I was just covering these two recent advances here. Will definitely be doing deep dives on neurostimulation for depression (and other conditions) in the future. Thanks for the thoughtful comment.
This is incredibly interesting. Thank you. Here is something to add to the conversation.
I think you might find this relevant. The summary below was synthesised by AI that has a very detailed longitudinal dataset on my symptoms, drug responses, and functional profile. I’m highly resistant to multiple medication classes; ethanol functions as a stimulant for me; and my system is hyper-regulated by a single dopamine-modulating agent (you can probably guess which one).
I’ve also included a link to a report describing a non-psychotic, form-stable hallucination I experienced for over 20 years — a good example of the architecture–symptom mismatch you’re discussing here.
Diagnostic Summary:
Highly atypical phenotype marked by dopaminergic variability, executive-circuit hypofunction, and intact frontal reality testing, resulting in chronic misclassification within DSM mood categories. Despite longstanding “treatment-resistant depression,” affective symptoms are minimal; episodes manifest instead as cognitive depletion, anhedonia, and executive dysfunction, consistent with the cognitive biotype described in recent circuit-based depression research. Substance responses suggest reward-prediction error instability: ethanol acts as a stimulant, historical “self medication agent” reliably modulated functioning, and aripiprazole abruptly extinguished alcohol craving, indicating upstream dopaminergic dysregulation rather than classical addiction biology. The patient also reports a 20-year, form-consistent perceptual phenomenon (“The Eye”) occurring only under cognitive strain, with preserved insight and no psychotic features, aligning with predictive-processing overload, not psychosis.
Collectively, this profile reflects a dopaminergic–executive architecture that diverges sharply from symptom-based diagnosis, underscoring the need for biology-guided treatment selection in atypical cases.
Here’s the Eye piece — a 20-year non-psychotic hallucination that shows exactly how architecture can diverge from symptoms:
Given that the diagnosis of depression is about as useful a guide to underlying etiology as "pain" I don't think antidepressants are too shabby frankly!
The polygenic risk score approach is pretty smart for catching subthreshold bipolar cases that don't fit the DSM boxes. If someone's genetics scream bipolar but they never hit the full mania checklist, you're basically guessing blind on lithium unless you look at family history. Running PRS before trial and error could probably cut down those multi-year journeys through failed antidepressants.
Looks like it, yes. Thanks for your comment.
I like guanfacine as a longterm heart health replacement for Vyvanse - for myself; but consider that depression leaves lasting degenerative cognitive symptoms (whether natural or pharmaK treated iatrogenic side FX , no?) - stimulants can be helpful to balance that out 😉
Theories of depression polarization and categories are always interesting! Thanks! ☺️
Glad you found it interesting! The biomarker-guided approach is what I find most promising - matching specific etiology to specific treatments rather than trying different options sequentially. Thanks for your engagement
Very interesting read! Thanks for your contribution!
This was a very interesting presentation, but I somehow was hoping it would move to a discussion of transmagnetic stimulation. Does this mean you do not see this as having a “future” within this context, despite its “trendy” aspects? I have had patients with serious refractory forms of depression who I have presented to Grand Rounds & in each case received recommendations for TMS, and in both cases was quite surprised by the outcome. Any thoughts?
Oh I definitely see neurostimulation as part of the toolkit. I was just covering these two recent advances here. Will definitely be doing deep dives on neurostimulation for depression (and other conditions) in the future. Thanks for the thoughtful comment.
This is incredibly interesting. Thank you. Here is something to add to the conversation.
I think you might find this relevant. The summary below was synthesised by AI that has a very detailed longitudinal dataset on my symptoms, drug responses, and functional profile. I’m highly resistant to multiple medication classes; ethanol functions as a stimulant for me; and my system is hyper-regulated by a single dopamine-modulating agent (you can probably guess which one).
I’ve also included a link to a report describing a non-psychotic, form-stable hallucination I experienced for over 20 years — a good example of the architecture–symptom mismatch you’re discussing here.
Diagnostic Summary:
Highly atypical phenotype marked by dopaminergic variability, executive-circuit hypofunction, and intact frontal reality testing, resulting in chronic misclassification within DSM mood categories. Despite longstanding “treatment-resistant depression,” affective symptoms are minimal; episodes manifest instead as cognitive depletion, anhedonia, and executive dysfunction, consistent with the cognitive biotype described in recent circuit-based depression research. Substance responses suggest reward-prediction error instability: ethanol acts as a stimulant, historical “self medication agent” reliably modulated functioning, and aripiprazole abruptly extinguished alcohol craving, indicating upstream dopaminergic dysregulation rather than classical addiction biology. The patient also reports a 20-year, form-consistent perceptual phenomenon (“The Eye”) occurring only under cognitive strain, with preserved insight and no psychotic features, aligning with predictive-processing overload, not psychosis.
Collectively, this profile reflects a dopaminergic–executive architecture that diverges sharply from symptom-based diagnosis, underscoring the need for biology-guided treatment selection in atypical cases.
Here’s the Eye piece — a 20-year non-psychotic hallucination that shows exactly how architecture can diverge from symptoms:
https://open.substack.com/pub/entropicart/p/the-third-eye-a-mind-that-never-looks?r=6rzpyd&utm_medium=ios
Given that the diagnosis of depression is about as useful a guide to underlying etiology as "pain" I don't think antidepressants are too shabby frankly!
I don’t disagree but we should do better on both fronts…