Metabolic Psychiatry?

[LurkerNow]

Unlurking for this one. There's a new theory of mental illness conceptualization and tx called metabolic psychiatry. The basic idea is that much of what we call mental illness can be conceptualized as a metabolic disorder of the brain. It's the bio part of a new biopsychosocial model (the psychosocial part is not ignored).

Emerging evidence suggests that by addressing brain metabolism through lifestyle factors (principally but not exclusively through "ketogenic metabolic therapy," or KMT) many of those suffering from serious mental illness (e.g. SZ, BD) experience dramatic outcomes at least on par, if not exceeding the outcomes of traditional tx's (drugs and therapy). The research base supporting metabolic psychiatry and KMT extends over a wide swath of different disciplines, including neurology, genetics, metabolic, and clinical research. Stanford has created a "metabolic psychiatry" clinic, and Harvard now has a "metabolic and mental health" program. The book "Brain Energy" by Chris Palmer breaks down the theoretical and research underpinnings. The research is still in its infancy, with around 12 controlled trials examining KMT for MI still in various stages of completion. There is a lot of buzz in this area.

Whenever I ask colleagues for their opinion about it they typically dismiss it out of hand as quackery, but without even a superficial understanding of the theory or the science behind it. Personally, I think this is a game changer and will revolutionize how we conceptualize and treat mental illness. But I could be wrong, time will tell.

I am curious to know if anyone on this board has heard of this, and your opinion about it. Specifically, if you think it's bunk, please tell me why. Here are a couple of articles to introduce yourself to the topic. The first is from the J of Psychiatric Brain Science, the second is a NPR article, but with lots of research links:

The Role of Ketogenic Metabolic Therapy on the Brain in Serious Mental Illness: A Review

Patients say keto helps with their mental illness. Science is racing to understand why​

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[PsyDr]

ketogenic diets are an established intervention for seizure disorders. It makes sense to use analogous interventions for other brain based disorders.

The problem with this idea is that:
a. twin studies don't support it,
b. interventions, that have metabolic side effects similar to the claim cause, show efficacy.
c. Usually people whose behavior is erratic, by definition, have trouble with adhering to a behavioral change to their diet
d. the entire orthopsychiatry literature has created barriers to this. And Breggin starting testifying for a religion that believes that a space alien threw a bunch of other aliens into the volcanoes in Hawaii, and that is the course of all mental illness.

 

[Ollie123]

I certainly think the metabolic system has a stronger role in neurobiology than we'd realized until recently (hence all the new gut-brain axis work). Heck, I'm in the process of writing a large federal grant to study GLP-1As I was working on just a couple hours ago.

So in a very general sense, I think the notion has substantial merit. However, I also think "revolutionize" is more than a bit off the deep end. As PsyDr already alluded to, diets that are notoriously challenging to adhere to for a psychiatrically healthy population are going to be extra challenging for this population. Even putting adherence issues aside - first off, if any diet as well-established as the ketogenic diet reliably eliminated psychiatric symptoms, we would certainly already know that. It is common enough that even with adherence issues we would have no doubt have already figured out the "miracle cure". Could there be a subset of patients with SMI who actually have a previously known metabolically-induced subtype of the disorder? Sure, but for the same reasons as above I'd bet it is relatively rare. The other piece to this is effect size. Depending on the precise population you are discussing, our treatments don't work that great in the first place. Equivalence or even beating them completely does not mean restoration to normal functioning. The standard american diet is terrible for nearly everything else, so it shouldn't be surprising it is bad for the brain too and changing that diet can make people somewhat better. So I guess it depends where you draw the line for revolutionize.

Long story short, research on metabolic influences on psychiatry = good and has substantial promise, claims that psychiatric disease is a direct result of diet and we can eliminate psychiatric disease solely through dietary manipulation = quackery.

An NPR article and a narrative review published in an extremely-sketchy-looking journal (that didn't even have an IF that I could find?) do little to help convince me otherwise.

 

[LurkerNow]

ketogenic diets are an established intervention for seizure disorders. It makes sense to use analogous interventions for other brain based disorders.

The problem with this idea is that:
a. twin studies don't support it,
b. interventions, that have metabolic side effects similar to the claim cause, show efficacy.
c. Usually people whose behavior is erratic, by definition, have trouble with adhering to a behavioral change to their diet
d. the entire orthopsychiatry literature has created barriers to this. And Breggin starting testifying for a religion that believes that a space alien threw a bunch of other aliens into the volcanoes in Hawaii, and that is the course of all mental illness.

Yes, and many anti-seizure medications are now used both on and off label for a wide variety of SMI. That KMT is effective in treating tx-resistant epilepsy hints that that similar mechanisms of action of KMT for SMI may be in play. Teasing out those mechanisms is the hard part, but efforts are underway.

a. are you referring to MZ concordance rates? How would that either support or negate it? Maybe you are referring to another area of twin studies?
b. Yes, this is a common argument against MP and thank you for bringing it up! Gynecomastia (i.e. man-boobs) or weight gain in general are examples of metabolic side effects from efficacious interventions. If MP is valid, how can a treatment that harms metabolism end up improving mental health? Well, it turns out the brain is pretty complex. Chris Palmer has answered this question, and I'll humbly (and hopefully not bumblingly) take a crack at summing up his response. Basically, the "mitochondrial (MT) funx paradox" entails that some medications appear to work by improving mt funx, and others ameliorate mh sx's by impairing mt funx. Wait, what? It boils down to out-of-control hyperexcitable cells being responsible for a variety of sx's (mania, a/h, anxiety, insomnia, etc.), and shutting down the mt in those cells which powers them down. This results in short term reduction of sx's, but at the long-term cost of metabolic dysregulation. It gets complicated fast, because some medications appear to improve mt funx of some cells, while impairing mt funx of others. It is also well known that meds often lose their effectiveness over time, and the explanation above helps explain why--short term relief of sx's by impairing mt funx, but long term worsening because, it turns out, mt are kind of important for overall health. The following review article breaks down the mitochondrial paradox: Effect of neuropsychiatric medications on mitochondrial function; for better or for worse
c. Very true, another astute point! For sure, lifestyle changes are hard for anyone, and those with SMI have even more obstacles than the rest of us. But some people, even those with SMI can adhere; emerging research bears that out: Pilot study of a ketogenic diet in bipolar disorder.
d. I have no idea WTF you are talking about : P

 

[LurkerNow]

I certainly think the metabolic system has a stronger role in neurobiology than we'd realized until recently (hence all the new gut-brain axis work). Heck, I'm in the process of writing a large federal grant to study GLP-1As I was working on just a couple hours ago.

So in a very general sense, I think the notion has substantial merit. However, I also think "revolutionize" is more than a bit off the deep end. As PsyDr already alluded to, diets that are notoriously challenging to adhere to for a psychiatrically healthy population are going to be extra challenging for this population. Even putting adherence issues aside - first off, if any diet as well-established as the ketogenic diet reliably eliminated psychiatric symptoms, we would certainly already know that. It is common enough that even with adherence issues we would have no doubt have already figured out the "miracle cure". Could there be a subset of patients with SMI who actually have a previously known metabolically-induced subtype of the disorder? Sure, but for the same reasons as above I'd bet it is relatively rare. The other piece to this is effect size. Depending on the precise population you are discussing, our treatments don't work that great in the first place. Equivalence or even beating them completely does not mean restoration to normal functioning. The standard american diet is terrible for nearly everything else, so it shouldn't be surprising it is bad for the brain too and changing that diet can make people somewhat better. So I guess it depends where you draw the line for revolutionize.

Long story short, research on metabolic influences on psychiatry = good and has substantial promise, claims that psychiatric disease is a direct result of diet and we can eliminate psychiatric disease solely through dietary manipulation = quackery.

An NPR article and a narrative review published in an extremely-sketchy-looking journal (that didn't even have an IF that I could find?) do little to help convince me otherwise.

Many good points here. Yes, GLP-1 agonists appear to be helpful in Alz D, Parkinson's, and depression due to their brain glucose lowering effects. Also interesting that KMT lowers blood glucose so much that combining KMT with GLP-1 can lower BG to dangerous levels. This suggests that KMT should be considered as a medical intervention, similar to GLP-1 but without the cost/side effects.
I also agree we should hold off on the "miracle cure" talk for now. But, I guess I draw the line for "revolution" differently than you. I never heard anything about the role of neuronal MT funx, brain glucose hypometabolism, or insulin resistance of the brain in the etiology of mental disorders in graduate school. Instead, we talked about unscientific, mythical case formulations that vary wildly, depending on your theoretical orientation (IMHO, standard CFs typically amount to fairy tales designed to sell the clinician's expertise and to sell a story to the patient about why they are mentally ill and how the clinician can successfully treat them. That's not to say they don't work sometimes in "remoralizing" the patient and even resulting in positive outcomes, but that doesn't make them scientifically valid).
Our field really doesn't have a valid scientific theory about what causes any of it. The best we can say is, "We really don't know." If it turns out that disordered brain metabolism is indeed an important driver, even a root cause, of some cases of mental illness, how is a paradigm shift of that magnitude not revolutionary? We both seem to agree it may be a subset, I suspect the subset may be quite large. In any event, maybe "revolution" isn't the right word. Maybe, "Kuhnian paradigm shift" connotes less hype
At the same time, I think it makes sense to be skeptical about all this. I get it. There is wisdom in not getting too excited yet. For me though, the wide swath of extant neurological/metabolic/psychological research appears to coalesce into a compellingly united theory of mental illness (at least for some cases).

 

[Ollie123]

I don't disagree that the prototypical case formulation entails a not-insignificant amount of voodoo, but at the same time I beg to disagree on valid scientific theories on causes. I think we lack primary biologic scientific theories for many disorders, at least any that seem to be universally true, but that's only one level of analysis and not one that necessarily addresses true root causes (though again, given the state of the DSM I question whether "universally true" is even a reasonable goal).

I guess I've just been through this too many times already even in my fairly short career to believe we're on the verge of some united theory. We're way early. There are a few half-baked theories and some crappy pilot studies. I'm not seeing how this is any different from the early "Depression = not enough serotonin because probably genetics or something" path the field was on for a while. While I would be genuinely delighted to be wrong about this, I strongly suspect this is more "Another piece of the puzzle....and probably not even a corner piece" territory than "Revolutionary" territory. Its plausible we'll find viable subtypes, though that hasn't borne out well for us in the past. I do think integration of metabolic considerations will push the field forward (the only reason I feel justified asking for 3-4 million of my/our tax dollars to find out!). I'm just very, very skeptical that we're on the verge of something that will change the field versus something that helps inform future research, maybe gives us a couple additional tools in our treatment toolbox and maybe yields a net gain in treatment efficacy of 10% (but definitely not 500%) - but more likely just provides an equally effective alternative to existing treatments.

 

[psych.meout]

At the same time, I think it makes sense to be skeptical about all this. I get it. There is wisdom in not getting too excited yet. For me though, the wide swath of extant neurological/metabolic/psychological research appears to coalesce into a compellingly united theory of mental illness (at least for some cases).

Is it a "united theory" or is it not?

 

[tr]

Peripheral metabolic markers are only weakly associated with psychiatric effects on a population level, in ways that mostly suggest trivial mechanisms related to mood and eating behaviors.

CNS insulin dynamics and brain cell fatty acid metabolism, on the other hand, seem quite likely to have very powerful pathophysiologic connections with mood. The problem is that it's quite difficult to measure brain cell metabolism in living humans so the most relevant work comes from animals, and there is a lot of difficulty with direct translation to the clinic.

These are nice papers though:

https://www.pnas.org/doi/abs/10.1073/pnas.1801609115

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance - Molecular Psychiatry

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite...

www.nature.com

 

[PsyDr]

Yes, and many anti-seizure medications are now used both on and off label for a wide variety of SMI. That KMT is effective in treating tx-resistant epilepsy hints that that similar mechanisms of action of KMT for SMI may be in play. Teasing out those mechanisms is the hard part, but efforts are underway.

a. are you referring to MZ concordance rates? How would that either support or negate it? Maybe you are referring to another area of twin studies?
b. Yes, this is a common argument against MP and thank you for bringing it up! Gynecomastia (i.e. man-boobs) or weight gain in general are examples of metabolic side effects from efficacious interventions. If MP is valid, how can a treatment that harms metabolism end up improving mental health? Well, it turns out the brain is pretty complex. Chris Palmer has answered this question, and I'll humbly (and hopefully not bumblingly) take a crack at summing up his response. Basically, the "mitochondrial (MT) funx paradox" entails that some medications appear to work by improving mt funx, and others ameliorate mh sx's by impairing mt funx. Wait, what? It boils down to out-of-control hyperexcitable cells being responsible for a variety of sx's (mania, a/h, anxiety, agitation, etc.), and shutting down the mt in those cells powers down the hyperexcitable cells resulting, in short term reduction of sx's, but at the long-term cost of metabolic dysregulation. But it all gets very complicated very fast, because some medications appear to improve the mitochondria of some cells, while impairing the mt of others! It is also well known that psychiatric medications often lose their effectiveness over time, and the explanation above helps explain why--short term relief of sx's by impairing hyperexcitable cell mt funx, but long term worsening because, it turns out, mt are kind of important for overall health and funx! The following review article breaks down the mitochondrial paradox: Effect of neuropsychiatric medications on mitochondrial function; for better or for worse
c. Very true, another astute point! For sure, lifestyle changes are hard for anyone, and those with SMI have even more obstacles than the rest of us. Emerging research, however, refutes the claim that adherence for this population is a non-starter: Pilot study of a ketogenic diet in bipolar disorder.
d. I have no idea WTF you are talking about : P

Many of your points intersect with an old area of psychiatry called orthopsychiatry. This area was started by a psychiatrist who believed that dietary intervention worked. But then he said that mental illness was caused by an invisible cosmic energy that caused rain and ufo sighting, and could be released by sitting in a box and having sex.

Some of your other points intersect with the anti psychiatry movement. I doubt you are aware of that. But that area is highly promulgated by a certain religion whose leader was unsuccessfully treated by psychiatry, and a psychiatrist who testifies for said religion.

 

[borne_before]

It is kind of interesting that GLP-1 agonists seem to reduce other compulsive behaviors (e.g., gambling/drinking).

 

[smalltownpsych]

My experience with this is family members of people with psychotic disorders buying into this and being almost delusional in their own focus to the detriment of treatment.

 

[DaphneDoc]

Nutritional psychology/psychiatry is a growing field....there is some merit (or seems to be growing data, anyways)....but it's on the assumption that those with poor diets/metabolic issues have the ways/means to change their diets (think $, motivation, ability to stay on diet plan, etc.).

Given the correlations with poverty and SMI, I am curious how the field will evolve.... Plus, the chicken or egg phenomenon...SMI folks often take meds that create metabolic issues....or were the metabolic issues there prior? Will be interesting to watch over the next couple decades....

 

[clausewitz2]

Nutritional psychology/psychiatry is a growing field....there is some merit (or seems to be growing data, anyways)....but it's on the assumption that those with poor diets/metabolic issues have the ways/means to change their diets (think $, motivation, ability to stay on diet plan, etc.).

Given the correlations with poverty and SMI, I am curious how the field will evolve.... Plus, the chicken or egg phenomenon...SMI folks often take meds that create metabolic issues....or were the metabolic issues there prior? Will be interesting to watch over the next couple decades....

Given the evidence for lipid abnormalities in many drug-naive people diagnosed with schizophrenia, probably something was going on prior a lot of the time.

 

[Ollie123]

It is kind of interesting that GLP-1 agonists seem to reduce other compulsive behaviors (e.g., gambling/drinking).

Hope to be able to tell you more about why that might be happening in something like 5-7 years

 

[borne_before]

As an aside, magnesium glycinate.

 

[psych.meout]

As an aside, magnesium glycinate.

 

[LurkerNow]

It is kind of interesting that GLP-1 agonists seem to reduce other compulsive behaviors (e.g., gambling/drinking).

Also interesting that both anti-seizure meds (e.g. benzos, topiramate) and KMT can reduce alcohol withdrawals and cravings. Again, suggests that they share similar mechanisms of action.

A recent inpatient RCT found that the KMT group (compared to standard diet group) had reduced withdrawal side effects, reduced cravings, and needed fewer detox meds. And in the parallel preclinical study, the KMT rats drank less alcohol! It’s thought that acetone (a type of ketone body) is similar to acetate, the energy molecule derived from alcohol (converted by the liver). A brain used to getting acetate reduces its use of glucose, and ends up acetate dependent. Take away their alcohol (acetate) and misery ensues (brain isn’t getting enough energy). But acetone (ketone body) can be used by the acetate-dependent brain better than glucose, thus reducing withdrawals and cravings for those on KMT. Interesting!

Again, caution abounds, this is only the first RCT to look at this, but more research is underway. Also, these were inpatients; would people not locked up be able to do this on their own? Another word of caution is that the state of ketosis results in lowered tolerance to alcohol (and many drugs, both street and prescription, which is whole ‘nother discussion). Thus, if a heavy drinker gets into ketosis and then resumes drinking, a given amount of alcohol will result in more intoxication/impairment than usual. KMT benefits abound, but so do risks. Either way, how can you not be intrigued by this S___?

It bears mentioning that KMT isn't just healthy eating, and it's not just a list of foods. It's any way of eating (and living, e.g. fasting, extreme exercise, etc.) that lowers insulin/depletes glycogen to the point that the liver starts producing ketones from fatty acids.

 

[WisNeuro]

Also interesting that both anti-seizure meds (e.g. benzos, topiramate) and KMT can reduce alcohol withdrawals and cravings. Again, suggests that they share similar mechanisms of action.

A recent inpatient RCT found that the KMT group (compared to standard diet group) had reduced withdrawal side effects, reduced cravings, and needed fewer detox meds. And in the parallel preclinical study, the KMT rats drank less alcohol! It’s thought that acetone (a type of ketone body) is similar to acetate, the energy molecule derived from alcohol (converted by the liver). A brain used to getting acetate reduces its use of glucose, and ends up acetate dependent. Take away their alcohol (acetate) and misery ensues (brain isn’t getting enough energy). But acetone (ketone body) can be used by the acetate-dependent brain better than glucose, thus reducing withdrawals and cravings for those on KMT. Interesting!

Again, caution abounds, this is only the first RCT to look at this, but more research is underway. Also, these were inpatients; would people not locked up be able to do this on their own? Another word of caution is that the state of ketosis results in lowered tolerance to alcohol (and many drugs, both street and prescription, which is whole ‘nother discussion). Thus, if a heavy drinker gets into ketosis and then resumes drinking, a given amount of alcohol will result in more intoxication/impairment than usual. KMT benefits abound, but so do risks. Either way, how can you not be intrigued by this S___?

It bears mentioning that KMT isn't just healthy eating, and it's not just a list of foods. It's any way of eating (and living, e.g. fasting, extreme exercise, etc.) that lowers insulin/depletes glycogen to the point that the liver starts producing ketones from fatty acids.

Easy answer, by and large, no. No, they wouldn't. Even in individuals with epilepsy, the compliance rate when trying something like a ketogenic diet is pretty low. I can't imagine the compliance rate would be higher in a population with impulse control issues in a non-controlled setting.