Why Physicians and Clinics Are At Least As Important as Randomized Clinical Trials

Year (month)	Medication	Key milestone	Dosing interval
1968	Fluphenazine decanoate (Prolixin Decanoate)	First FDA-approved LAI antipsychotic (oral fluphenazine approved 1959)	q2–4+ wk, IM/SC
1986	Haloperidol decanoate (Haldol Decanoate)	Only other first-generation LAI approved in the US; one source cites 1984, likely reflecting non-US availability	q4 wk, IM
Oct 2003	Risperidone microspheres (Risperdal Consta)	First second-generation LAI; bipolar I added May 2009	q2 wk, IM
Aug 2009	Paliperidone palmitate 1-month (Invega Sustenna)	First monthly second-generation LAI; schizoaffective disorder added Nov 2014	q4 wk, IM
Dec 2009	Olanzapine pamoate (Zyprexa Relprevv)	REMS required for post-injection delirium/sedation syndrome	q2–4 wk, IM
Feb 2013	Aripiprazole monohydrate (Abilify Maintena)	Bipolar I maintenance added Jul 2017	q4 wk, IM
May 2015	Paliperidone palmitate 3-month (Invega Trinza)	First LAI dosed beyond monthly	q3 mo, IM
Oct 2015	Aripiprazole lauroxil (Aristada)	Prodrug; 6- and 8-week regimens available	q4–8 wk, IM
2018	Aripiprazole lauroxil (Aristada Initio)	Single-day initiation regimen	Initiation only
Jul 2018	Risperidone ER SC (Perseris)	First subcutaneous LAI antipsychotic	Monthly, SC
2021	Paliperidone palmitate 6-month (Invega Hafyera)	Longest dosing interval of any LAI	q6 mo, IM
2023	Risperidone ER IM (Rykindo)	Additional IM risperidone LAI	q2 wk, IM
Apr 2023	Risperidone ER SC (Uzedy)	Schizophrenia; bipolar I added Oct 2025	q1 or q2 mo, SC
2023	Aripiprazole 2-month (Abilify Asimtufii)	Schizophrenia and bipolar I maintenance	q2 mo, IM
2024 (available Apr 2025)	Paliperidone palmitate (Erzofri)	Single 351 mg initiation injection; no day-8 dose	Monthly, IM
References Rowland D. Should we be prescribing fluphenazine long-acting injectable formulation? Curr Psychiatry Rep. 2025. Jann MW, Penzak SR. Long-acting injectable second-generation antipsychotics: an update and comparison between agents. CNS Drugs. 2018. Abbas F, Rajab T, Alsamarrai O, et al. Fluphenazine decanoate (timing of administration) for people with schizophrenia. Cochrane Database Syst Rev. 2017. Food and Drug Administration. Fluphenazine decanoate [package insert]. 2025. Kane JM, McEvoy JP, Correll CU, Llorca PM. Controversies surrounding the use of long-acting injectable antipsychotic medications for the treatment of patients with schizophrenia. CNS Drugs. 2021. Benarous X, Cottin G, Lahaye H, et al. Efficacy, tolerability, and acceptance of long-lasting antipsychotics in children and adolescents: a systematic review. J Child Adolesc Psychopharmacol. 2022. Food and Drug Administration. Haloperidol decanoate [package insert]. 2026. Rauch AS, Fleischhacker WW. Long-acting injectable formulations of new-generation antipsychotics: a review from a clinical perspective. CNS Drugs. 2013. García-Carmona JA, Simal-Aguado J, Campos-Navarro MP, Valdivia-Muñoz F, Galindo-Tovar A. Long-acting injectable antipsychotics: analysis of prescription patterns and patient characteristics in mental health from a Spanish real-world study. Clin Drug Investig. 2020. Mauri MC, Paletta S, Di Pace C, et al. Clinical pharmacokinetics of atypical antipsychotics: an update. Clin Pharmacokinet. 2018. Edinoff AN, Doppalapudi PK, Orellana C, et al. Paliperidone 3-month injection for treatment of schizophrenia: a narrative review. Front Psychiatry. 2021. U.S. Food and Drug Administration. Orange Book: approved drug products with therapeutic equivalence evaluations. Silver Spring (MD): U.S. Department of Health and Human Services. Pahwa M, Sleem A, Elsayed OH, Good ME, El-Mallakh RS. New antipsychotic medications in the last decade. Curr Psychiatry Rep. 2021. Food and Drug Administration. Invega Hafyera (paliperidone palmitate) [package insert]. 2025. Merenlender Wagner A, Perlstein I, Farkas P, et al. A phase 1 open-label study assessing the safety and pharmacokinetics of TV-46000, an extended-release injectable suspension of risperidone for subcutaneous use. CNS Drugs. 2026. Food and Drug Administration. Abilify Asimtufii (aripiprazole) [package insert]. 2025. Chen Y, Hu L, Meyer JM, et al. Population pharmacokinetics and dosing simulations for paliperidone palmitate 351 mg as alternative maintenance doses in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2026. Food and Drug Administration. Erzofri (paliperidone palmitate) extended-release injectable suspension [package insert]. 2026.

Note: Abilify Maintena is listed by one review as February 2015, but other reviews give February 2013. Exact months for Aristada Initio (June 2018), Invega Hafyera (August 2021), Rykindo (January 2023), Abilify Asimtufii (April 2023), and Erzofri (July 2024) should be verified against Drugs@FDA. Fluphenazine enanthate (circa 1966–67, since withdrawn) and non-US depots (flupentixol, zuclopenthixol) are excluded.

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I finished a memoriam to a colleague today.  He was one of the best psychiatrists I have known and I know a lot of excellent psychiatrists.  He was able to integrate the technical and humanistic aspects of the field to provide very high-quality care and consultation to his colleagues.  We both worked in the same acute care setting for a period of about 11 years.  I was primarily an inpatient psychiatrist and he was outpatient.  We both ran clinical trials but he was much more active in that area.

 

I am mentioning him here because of his innovative practices that preceded widespread adoption by years if not decades.  The first innovation was a large clinic for long-acting injectable antipsychotic medications or LAIs.  The above table lists all of the current LAIs with their approval dates in the left column. My colleague worked at our hospital from 1981-2002, so his LAI clinic probably only had two available options fluphenazine decanoate and haloperidol decanoate.  The older LAIs had a more significant side effect burden.  For optimal use, careful dose adjustment and in some cases therapeutic drug monitoring was necessary. There was also a reluctance to prescribe these medications because of a bias that most people would not want intramuscular injections on a regular basis. He had a very large clinic of patients taking these medications and none of those factors were a problem. As an inpatient specialist at the time – his patients were rarely hospitalized.  We had monthly quality assurance (QA) meetings that seemed more like surgical morbidity and mortality conferences, but at no time did we discuss different outcomes by physician or clinic or the potential advantages of the LAI clinic.  The QA meetings were focused on criticizing care rather than optimizing it.

 

When clozapine came out in 1990, it was strictly regulated in the state of Minnesota.  The only indication was treatment resistant schizophrenia and a normal absolute neutrophil count (ANC).  For the first several years it also required approval by a PharmD at the state level. There had to be documentation that the patient failed on 2 antipsychotics before they were allowed to use clozapine.  Clozapine also had a Risk Evaluation and Mitigation Strategy (REMS) before they existed.  Clozapine had a risk of agranulocytosis and therefore every patient had to have a weekly blood draw and normal ANC before they could get the next week supply of clozapine.  Over the next decade, my colleague built up and maintained what was probably the largest clozapine clinic in the state.  He was adept at treating all of the side effects of this medication as well as administrative complications. I can recall calling him in a panic one day when I found out that a patient I had discharged on clozapine to another state missed the weekly ANC determination but was still given the next week supply of medication.

 

Both of these clinics were early innovations based on both current discussions and how LAIs are discussed in treatment guidelines.  Clozapine is now widely regarded as the most effective antipsychotic medication with secondary applications in movement disorders. The REMS strategy has been reduced to the point that it is done but is no longer mandatory and it is no longer for the entire period of time while using clozapine. Some guidelines have incorporated additional indications such as one failed antipsychotic or significant suicide risk.  Since better tolerated second generation LAIs have been developed the indications have expanded to include bipolar disorder.  I have personally seen patients with clear bipolar disorder who have been stabilized on newer LAIs when nothing else worked.   

 

My main point in discussing these two clinics is that they were in place and working 10-15 years before these modalities were being discussed as not being widely enough deployed or not being utilized early enough in treatment.  My colleague was focused on providing that level of care and establishing therapeutic relationships with his patients. He was always available for consultation and discussion.  We had humorous conversations about the personal embarrassment of polypharmacy but how some people seemed to need it.  We discussed the best ways to treat depression with comorbid schizophrenia.  We covered movement disorders that were barely discussed in the literature (tardive torticollis) and patients with hematological malignancies who needed clozapine.  Acute care psychiatry can become a series of desperate situations and it is always good to have a colleague who can reassure you that there is nothing else that can be done. 

 

In addition to the clinics my colleague was also an investigator in 80 clinical trials for Alzheimer’s Disease, Schizophrenia, Obsessive Compulsive Disorder, Major Depression, Tourette’s Syndrome, Post Traumatic Stress Disorder, and Generalized Anxiety Disorder. Although most were medication trials many involved psychotherapy and quality of life outcomes.  He was also a speaker and between 1991 and 2001 gave over 200 invited presentations for grand rounds, regional psychiatric and community meetings, and pharmaceutical presentations.

 

It was not until after I had finished writing my tribute that I thought of a piece written by Atul Gawande, MD about another Minnesota physician.  In that piece he describes how pediatrician Warren Warwick may have made the Minnesota Cystic Fibrosis Center at Fairview-University Children’s hospital – the top center in the country.  He had that discussion after a long introduction of how physicians were rated on outcomes, the need for transparency in those ratings, and how most physicians would either not want to see the results or be reluctant to accept the results. Evidence Based Medicine (EBM) is introduced as the standard, but it takes more than that.  All of the top cystic fibrosis centers used the same guidelines, procedures, and medicines. Why was it that Warwick had consistently better results in terms of much lower mortality rates?

 

Gawande observed a couple of Warwick’s sessions with patients. In the dialogue he is doing much more than a review of symptoms. He is actively exploring and confronting the patient about their CF care.  Gawande suggests that “more nebulous factors like aggressiveness and consistency and ingenuity can matter.”  As I read about the interaction it seemed like supportive psychotherapy to me. The only element missing was an explicit statement about the therapeutic alliance, but that was implied by Dr. Warwick’s: “What have you been doing to make us the best CF program in the country?’

 

I am sure that my colleague was much less direct.  He knew what his patients needed and he knew that it included more than medicine.  He was able to discuss anything with them. Years after he left, those same people would approach me in the hallways and ask: “Have you heard from him?  How is he doing?”  They all knew he wanted the best for them and that they could problem solve with him and get his support.

 

Gawande’s piece still contains important observations 22 years later.  It also has implications for psychiatry. Gawande was writing at that time about a country wide network of 117 CF centers.  Even before his essay these centers had reduced CF mortality significantly from an average life expectancy of 10 years in 1962 to 33 years in 2003.  At the best center - lifespan was 47 years.  The questions come down to: can the reasons for these differences be measured reliably, is it a question of a bell curve distribution of outcomes and how static is that curve, and how important are the intangibles?

Gawande seems to have been using the bell-shaped curve literally in this essay and that is problematic.  A normal or Gaussian distribution has to have certain characteristics that typically do not exist in medical outcomes data.  For example, in a normal distribution the data have to be continuous, symmetrical about the mean, and the mean, median, and mode all have to coincide. Counted outcomes based on medical interventions do not have that kind of distribution.  The distribution will generally be skewed in the direction of the intervention with a long tail of outliers. That has led to modeling outcomes like surgery and length of stay with the Poisson distribution or modifications of that distribution. It has also led to predictive analytics with machine learning being used to select the most relevant variable and use those to predict outcomes.  

 

I was in a managed care organization that attempted to measure process outcomes.  One of the criticisms of psychiatry is that there are no “hard outcomes.”  Having completed an extensive review of antidepressants and suicide risk I know that is not true.  Death and hospitalization are both hard outcomes in psychiatry. The paradox in current healthcare measurement-based care is that all care in the US is based on rationing.  No amount of rationalization will convince me that rationed care has quality or optimizing outcomes as a goal.  Care in many of these settings is observably bad - even compared with care I personally received in 1969.

 

But what would happen if we approached care like my late colleague?  What if we developed networked clinics based on LAIs or clozapine, or specific diagnostic groups?  What if the goal was cooperative elevation of the field and enhanced collegial consultation instead of avoiding difficult problems and rationing care?  What if it was possible to learn intangibles and psychotherapy that would enhance the treatment process instead of the continued silo based practices?

These are additional thoughts I had as I commemorated my colleague.  They are things I wished I had asked him when he was around.

 

     

George Dawson, MD, DFAPA

 

 

 Reference:

Gawande A.  The Bell Curve.  The New Yorker.  November 29, 2004:  https://www.newyorker.com/magazine/2004/12/06/the-bell-curve

Graphics Credit: 

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How To Painlessly Pass A Primary Care Dietary Screening with Flying Colors...

 

Every year when I go in for my annual primary care visit – they give me the 2-item test for fruit and vegetable consumption.  It asks for an estimate of how many servings of fruit and vegetables are consumed every day. I can’t recall the breakpoints my health plan uses but the scale runs from zero servings per day up to ≥ 5.  If you research these screenings, some studies will use half measures (like 2.5 servings if consumption varies between 2 or 3).  Other studies will get very specific about what constitutes a serving.  That can vary from “one small apple” to “one cup of apples” to “a baseball sized portion.”.  My goal with this post is to illustrate how you can pass this screen by eating one complicated but easy to make salad a day.  I will also illustrate how to record recipes easily using a system invented by an engineer.

I have to add the usual disclaimers that I am not advising you to make and eat this salad like I do – only showing what is possible for educational purposes. If you are a vegetarian for example, I expect that you would easily exceed the upper end of the scale.  There are two additional advantages to the salad I eat almost every day – first it is designed to be palatable for people like me who generally do not like the taste of vegetables.  Second, it minimizes spoilage. The only ingredient susceptible is tri-color slaw and carrots and they are usually consumed by the expiration date on the bag.  The other ingredients are either frozen (berries) or have a long shelf life (apples). 

I stopped trying to use lettuce of any type because it often spoiled before the expiration date.  The paternal side of my family were cabbage (and potato) eaters from central Europe.  It took me a while to figure out why – but then it dawned on me – they could preserve barrels of cabbage as sauerkraut and not need any refrigeration.  Cabbage also has endogenous antioxidants and that is also probably why it lasts longer than lettuce.   Sauerkraut also fundamentally changes the taste of cabbage, leading me to think that many of those relatives may have had the same aversion to vegetables that I do.  As an example, I remember my father eating overcooked boiled potatoes as his main vegetable staple while the rest of us were supposed to be eating a broader selection.

There is a taste receptor specific and non-specific genetic component to taste and it has been studied for both vegetables and food-liking or food fussiness.  Cabbage makes the list in several categories.

 

Gene / variant	What it detects	Functional effect	Consequence for vegetables / diet
TAS2R38 — PAV ("taster")	Glucosinolates/isothiocyanates in Brassica (broccoli, sprouts, cabbage, kale); PROP/PTC	High bitter sensitivity; more PAV mRNA expressed in taste cells correlates with stronger perceived bitterness	Greater bitterness → vegetable avoidance; may shift toward sweeter/fattier foods; "tasters" decreased vegetable intake under minimal dietary counseling
TAS2R38 — AVI ("non-taster")	Same compounds	Low/absent bitter perception	Less aversion; largest increases in vegetable intake with intervention
TAS2R38 — heterozygote (PAV/AVI)	Same compounds	Intermediate sensitivity, widest perceptual range	Variable acceptance; intermediate vegetable intake response
TAS2R16	Bitter β-glucosides (broad glycoside ligands)	Two-faced binding pocket giving high specificity across diverse glycosides	Modulates perception of bitter plant glycosides, contributing to bitter-food preference
TAS2R19	Bitter glycosides (e.g., in grapefruit, other plant foods)	Clusters genetically with bitter-food liking traits	Associated with liking of bitter vegetables/foods
Multiple TAS2R loci (GWAS)	Various bitter compounds	Polygenic influence on bitter-taste pathways	Collectively shape bitter-food preferences and metabolic/sensory pathways
Food-fussiness / food-liking heritability	Not receptor-specific	~50% heritable; genetic correlation ~−0.65 between fussiness and vegetable liking	Some children genetically predisposed to reject vegetables independent of a single gene
1:  A Review of the Associations Between Single Nucleotide Polymorphisms in Taste Receptors, Eating Behaviors, and Health. Critical Reviews in Food Science and Nutrition. 2018. https://pubmed.ncbi.nlm.nih.gov/27247080 2:  Bitter Taste of Brassica Vegetables: The Role of Genetic Factors, Receptors, Isothiocyanates, Glucosinolates, and Flavor Context. Critical Reviews in Food Science and Nutrition. 2017. https://pubmed.ncbi.nlm.nih.gov/28718657   3:  Human Bitter Perception Correlates With Bitter Receptor Messenger RNA Expression in Taste Cells.        The American Journal of Clinical Nutrition. 2013. https://pubmed.ncbi.nlm.nih.gov/24025627 4:  TAS2R38 Predisposition to Bitter Taste Associated With Differential Changes in Vegetable Intake in Response to a Community-Based Dietary Intervention. G3. 2018. https://pubmed.ncbi.nlm.nih.gov/29686110 5:  A Review of the Associations Between Single Nucleotide Polymorphisms in Taste Receptors, Eating Behaviors, and Health. Critical Reviews in Food Science and Nutrition. 2018. https://pubmed.ncbi.nlm.nih.gov/27247080 6:  Human Bitter Perception Correlates With Bitter Receptor Messenger RNA Expression in Taste Cells. The American Journal of Clinical Nutrition. 2013. https://pubmed.ncbi.nlm.nih.gov/24025627 7:  TAS2R38 Predisposition to Bitter Taste Associated With Differential Changes in Vegetable Intake in Response to a Community-Based Dietary Intervention. G3. 2018. https://pubmed.ncbi.nlm.nih.gov/29686110 8:  Human Bitter Perception Correlates With Bitter Receptor Messenger RNA Expression in Taste Cells. The American Journal of Clinical Nutrition. 2013. https://pubmed.ncbi.nlm.nih.gov/24025627 9:  TAS2R38 Predisposition to Bitter Taste Associated With Differential Changes in Vegetable Intake in Response to a Community-Based Dietary Intervention. G3. 2018. https://pubmed.ncbi.nlm.nih.gov/29686110 10: The Bitter Taste Receptor TAS2R16 Achieves High Specificity and Accommodates Diverse Glycoside Ligands by using a Two-faced Binding Pocket. Scientific Reports. 2017. https://doi.org/10.1038/s41598-017-07256-y 11: Genome-Wide Association Analyses of Bitter Food Preferences Link Genetic Loci to Sensory and Metabolic Pathways. The Journal of Nutrition. 2026. https://pubmed.ncbi.nlm.nih.gov/42632617 12: A biologically informed framework for instrument selection in dietary Mendelian randomization using chemosensory genetics. BMC Medicine. 2026. https://doi.org/10.1186/s12916-026-04966-x 13: Genome-Wide Association Analyses of Bitter Food Preferences Link Genetic Loci to Sensory and Metabolic Pathways. The Journal of Nutrition. 2026. https://pubmed.ncbi.nlm.nih.gov/42632617 14:  A biologically informed framework for instrument selection in dietary Mendelian randomization using chemosensory genetics. BMC Medicine. 2026. https://doi.org/10.1186/s12916-026-04966-x 15:  Common Genetic Architecture Underlying Young Children's Food Fussiness and Liking for Vegetables and Fruit. The American Journal of Clinical Nutrition. 2016. https://pubmed.ncbi.nlm.nih.gov/26864359 16:  Large-scale GWAS of food liking reveals genetic determinants and genetic correlations with distinct neurophysiological traits. Nature Communications. 2022. https://doi.org/10.1038/s41467-022-30187-w

   

The implications of the above table seem fairly clear.  If you are one of these folks who prefers fats and sugars to vegetables it seems logical that disguising that taste would make these foods more palatable.  Salt, pepper, sugar and other condiments are commonly used as well as butter.  There are numerous forms of coleslaw made with this shredded slaw mix that add fat, vinegar, and sweetener.  Just a few years ago, I had my first salad with blueberries and that was an eye opener.  I typically use salad dressing to disguise the vegetable taste, but blueberries worked very well.  That is one of the driving forces for the salad I will reveal below.

The other driving force is also genetics.  Several years ago, I learned that I have a risk genotype for pancreatic cancer as well as being in the 100<sup>th</sup> percentile for polygenic risk for amyotrophic lateral sclerosis (ALS).  I would like to try to avoid both of those illnesses if possible.  How and whether or not either of those genotypes get expressed is still a research question.  The answer can only be approximated by epidemiological studies and the results are conflicting.  In terms of exercise, it probably reduces cancer risk but the ALS risk is an open question.  Contact sports and in some cases high exertion athletics can increase risk.  In other cases, non-contact exercise at any level does not seem to have an impact.  Dietary effects on cancer and cardiovascular disease are more well known and the source of recommendations for non-processed fruits and vegetables.  In terms of ALS – higher premorbid intake of fat, trans fat, and cholesterol were higher in a group who developed ALS. Fruit and vegetable intake reduced the risk by 34%.  In a Mendelian randomization study (genotype risk concentration) oily fish, fresh fruit, coffee intake reduced the risk.  There is no definitive prevention path suggested by the studies done so far only the recommendation for larger intervention-based studies.  With current genotyping methods those studies can be done on a pool of subjects with concentrated ALS risk.

At any rate, general dietary guidelines suggest that fruits and vegetables are a critical component of the diet with certain other common components (high added sugar, high saturated fat, trans fat, cholesterol, alcohol) - red flagged.   The dietary landscape has been more confused than ever over the past 2 years based on political misinformation. Against that backdrop I present my personal solution (again not a recommendation to you or medical advice) that allows me to both pass my primary care physician’s fruit and vegetable screening and reassure myself that I can ingest a palatable meal that is probably good for my health.  The salad is also designed to be cost effective since one of the main concerns with fresh produce is how long it will last before it is discarded.

The blueberry salad that started all of this was mixed salad greens, blueberries, and a vinaigrette dressing.  I have not had much luck with mixed greens or even lettuce in my refrigerator.  They generally deteriorate well before the best by date and rapidly discolor.  I decided to substitute mixed slaw (red cabbage, green cabbage, carrots).  Apples last longer and I decided to add that to the mix.   The recipe is presented in graphic form below.  As you can see this is a combination of 3 vegetables and 4 fruits for a total of 7 per day – all in one bowl. 

 

 

That is my salad that I eat most days of the week.  I don't know if there is a gene that allows for eating the exact same food every day - but if it exists I definitely have it.  The cumulative number of fruits and vegetables at the end of the year is impressive and any spoilage is minimal.  A summary of the possible nutritional benefits is listed in the table below.   

Ingredient	Antioxidant capacity	Flavonoids	Dietary fiber	Characteristic phytochemicals
Blackberry	Very high (among highest cellular antioxidant activity of common fruits)	Rich in anthocyanins; flavonols (quercetin)	High (berries ~5–8 g/cup)	Anthocyanins, ellagitannins, hydroxycinnamic acids
Raspberry	Very high; anthocyanin-rich fruits show highest TEAC/FRAP/ORAC	Anthocyanins; quercetin	~8.0 g per cup	Anthocyanins (cyanidin), ellagitannins
Blueberry	Very high cellular antioxidant activity	Anthocyanins; notable seasonal variation in flavonoid content	High (berries)	Anthocyanins (delphinidin, malvidin, petunidin), chlorogenic acid
Red cabbage	Highest among cabbages/vegetables; highest TEAC of the vegetables tested	Highest cabbage flavonoid content (~108 mg catechin eq/100 g); cyanidin predominates	Moderate (cabbage, fermentable)	Anthocyanins (cyanidin), glucosinolates, kaempferol, quercetin
Yellow/green cabbage	Lower than red cabbage but still notable (flavonol-rich)	Kaempferol, quercetin, apigenin predominate (lower total than red)	Moderate (fermentable)	Glucosinolates/isothiocyanates, flavonols
Carrot	Lower than berries/red cabbage	Low flavonol content	~2.8 g/100 g (skin); 4.8 g/cup cooked	Carotenoids (β-carotene), galactose-rich pectin
Apple (with skin)	Lower (hydroxycinnamate-rich fruits lowest antioxidant activity), but a major dietary phenolic contributor	Lowest flavonol content among fruits tested (~460 mg/kg dry); quercetin concentrated in skin	~2.4 g/100 g; 4.4 g per medium apple	Chlorogenic acid, quercetin glycosides, procyanidins

---

References

1. Cellular Antioxidant Activity of Common Fruits. Journal of Agricultural and Food Chemistry. 2008.
2. Synergistic, Additive, and Antagonistic Effects of Food Mixtures on Total Antioxidant Capacities. Journal of Agricultural and Food Chemistry. 2011.
3. Flavonoid Content of U.S. Fruits, Vegetables, and Nuts. Journal of Agricultural and Food Chemistry. 2006.
4. The Antioxidant Activity of Regularly Consumed Fruit and Vegetables Reflects Their Phenolic and Vitamin C Composition. Free Radical Research. 2002.
5. Chronic Constipation in Adults. American Family Physician. 2022.
6. Antioxidant Properties of Raw and Processed Cabbages. International Journal of Food Sciences and Nutrition. 2004.
7. Fibre: The Forgotten Carbohydrate in Sports Nutrition Recommendations. Sports Medicine. 2025.
8. Glucosinolates From Cruciferous Vegetables and Their Potential Role in Chronic Disease: Investigating the Preclinical and Clinical Evidence. Frontiers in Pharmacology. 2021.
9. Does Vegetable Colour Matter? A Comparative Assessment of Bioactive Composition and Biological Properties. Food Chemistry. 2026.
10. Dichotomous effect of dietary fiber in pediatrics: a narrative review of the health benefits and tolerance of fiber. European Journal of Clinical Nutrition. 2024.
11. Flavonols (Kaempeferol, Quercetin, Myricetin) Contents of Selected Fruits, Vegetables and Medicinal Plants. Food Chemistry. 2008.
12. Flavonoids: an overview. Journal of Nutritional Science. 2016. (Erratum: 2025).

 

The table illustrates this this salad adds fruit and vegetable components that are not generally available form other sources. It is complementary rather than complete nutrition because it lacks protein, several vitamins (B-6, B-12, D, E), minerals (Ca, I Zn, Fe, Se), fats and omega-3 FFA, and caloric density.  Some of these deficiencies can be made up by the additional components of the salad (olive oil in vinaigrette, additional nuts, etc). and additional food groups.  This salad is a niche player in the overall diet – but an important one in supplying necessary antioxidants, fiber, and phytochemicals that are not available elsewhere.  It is designed to avoid processed foods and food wasting.        

 

George Dawson, MD, DFAPA

 

Supplementary 1:   The graphic recipe display has two sources.  The first is the engineer Michael Chu's blog "Cooking for Engineers" who came up with the idea in the first place.  The second is the online site Recipe Tables where I was able to convert my recipe to graphic form.  The software named it Wyman’s Berry Salad based on the name of the frozen berries that I use. Any brand will do but I found these were the best prepared and do not require any additional preparation other than defrosting.  I typically use the defrost cycle in my microwave for 2-3 minutes depending on portion size.     

Supplementary 2:  While I am meteing out dietary advice I thought I would also include a place where you can get expert advice including advice that is designed to counter the current misinformation from the US Government.  

Dr. Jessica Knurick https://www.jessicaknurick.com/ An extremely articulate doctorate level nutritionist with both written and visual channels.  She has not only expert dietary advice that seems rare these days but also very good opinions about professional boundaries like the roles of physicians and dieticians and how our current healthcare system is respecting neither profession. 

Supplementary 3:   In the last table TEAC, FRAP, and ORAC are all antioxident assays. 

References:

1:  Goutman, S.A., Savelieff, M.G., Jang, DG. et al. The amyotrophic lateral sclerosis exposome: recent advances and future directions. Nat Rev Neurol 19, 617–634 (2023). https://doi.org/10.1038/s41582-023-00867-2

2:  Huisman MHB, Seelen M, van Doormaal PTC, et al. Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015;72(10):1155–1162. doi:10.1001/jamaneurol.2015.1584

3:  Nieves JW, Gennings C, Factor-Litvak P, et al. Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis. JAMA Neurol. 2016;73(12):1425–1432. doi:10.1001/jamaneurol.2016.3401

4:  Jing Z, Qi X, Teng J. Dietary factors and risk for amyotrophic lateral sclerosis: A two sample mendelian randomization study. Medicine (Baltimore). 2024 Jun 21;103(25):e38473. doi: 10.1097/MD.0000000000038473. PMID: 38905382; PMCID: PMC11191971.

5:  Chapman L, Cooper-Knock J, Shaw PJ. Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence. Brain. 2023 May 2;146(5):1745-1757. doi: 10.1093/brain/awac470. PMID: 36918362; PMCID: PMC10151186.

6:  Westeneng HJ, van Veenhuijzen K, van der Spek RA, Peters S, Visser AE, van Rheenen W, Veldink JH, van den Berg LH. Associations between lifestyle and amyotrophic lateral sclerosis stratified by C9orf72 genotype: a longitudinal, population-based, case-control study. Lancet Neurol. 2021 May;20(5):373-384. doi: 10.1016/S1474-4422(21)00042-9. PMID: 33894192.

Psychiatrists and the Nobel Prize

 

The verdict came in a week ago and the Nobel Prize in Physiology or Medicine was awarded to Karl Diesseroth, MD, PhD, Peter Hegemann, PhD and Georg Nagel, PhD.  The award for the discovery and implementation of optogenetics in neuroscience.  This technique is a revolutionary one for neuroscience and this award was expected for some time for these researchers.  Since the Prize was publicized there has been an explosion of images, videos, and social media posts featuring Diesseroth, his colleagues, and family members.  In this age of social media, there are an army of influencers using the story to get views.  For my part, I will just say congratulations.  The story I want to tell here is more about psychiatrists and the Nobel Prize.

Many years ago, when I worked at an acute care hospital, I was the department member who presented unusual grand rounds.  I gave one on the mathematicians Paul Erdös and Kurt Gödel reviewing their accomplishments, creativity, and eccentricities.  I followed it up with a grand rounds on the first psychiatrist to receive a Nobel Prize in 1927 – Julius Wagner-Jauregg.  He discovered the treatment of dementia paralytica (late-stage neurosyphilis) with malaria.  It is important to recall that this form of neurosyphilis made up 10-20% of all asylum care at the time, this was a pre-antibiotic era and at the time late-stage neurosyphilis (or General Paresis of the Insane/GPI) was a uniformly fatal illness. An estimated 30% of this population recovered with malaria inoculation and subsequent treatment of the malaria with quinine.

The downside to the treatment and controversy was the fact that 10-15% of patients died as a result of the malaria. This therapy did not disappear with the advent of the antibiotic era in the 1940s.  Patients were being treated as recently as 1969 with malaria fever therapy (12).

Wagner-Jauregg is described as a psychiatrist, but the training in those days was not standardized. After medical school he trained with a histopathologist, then in a psychiatric clinic for 4 years, and eventually headed a psychiatric clinic at the University of Graz in Austria.  His academic focus there was on goiter, cretinism, and iodine.  He produced 80 publications during his academic career and succeeded two highly regarded psychiatrists in clinics. 

His career was not without controversy.  First, he was a Nazi sympathizer.  His application to that party was denied because his first wife was Jewish.  Second, he promoted eugenics.  Third, he administered electric shocks to soldiers for “malingering” and several of them died leading to a formal inquest.  Fourth, some did not find the malaria therapy of neurosyphilis that impressive probably because the cure was also fatal to a significant number of patients. Like any infectious disease, outcomes depend on host factors and neurosyphilis lead to significant physiological compromise and deconditioning.  Fifth, he was also credited with calling for the iodination of salt to prevent goiter based on his thyroid studies, but subsequent work determined there was no direct connection to that policy being adopted in Austria as it occurred decades after his research and at least 2 other research groups were credited.  At a more general level, research in this era was before informed consent was adopted after the Nuremberg trials.  That means that malaria fever therapy was probably never presented as a research protocol and there was probably an unclear line when it crossed over to clinical care.  Adequate informed consent would have required determination of whether the GPI patients were competent consenters for high risk protocols that included the possibility of death from malaria (13).    

He had a problematic personality and believed that the usual rules did not apply to him. Although I find century old personality critiques stretching credibility – I agree with several authors that his accomplishments were overshadowed by the controversies.  The best proof of overshadowing is that most people are not aware of his name or accomplishments – even though he won the Nobel and Freud did not, Freud is more widely known and studied to this day.    

Wagner-Jauregg and Freud were contemporaries.  Freud was 1 year older and at times they influenced each other’s career. Wagner-Jauregg was called upon to write a critique of Freud’s work for an academic appointment and Freud provided expert testimony in a hearing where Wagner-Jauregg was accused of killing shell shocked soldiers with some type of electrotherapy.    From 1925-1938, Freud was nominated 12 times for the Nobel Prize in Physiology or Medicine and once for the Nobel Prize in Literature in 1936 but never won the award. In his biography, Peter Gay writes that Freud thought about the award constantly, hoped to get it, and was disappointed when he did not.

Depending on the author, both Freud and Wagner-Jauregg are written about as neurologists or psychiatrists and Freud is occasionally called a psychologist.  This is because of a lack of uniformity in training and credentialling in the 19<sup>th</sup> and early 20<sup>th</sup> century.  When you read about many of these prominent figures you will find that they head neurology and psychiatry clinics interchangeably and in many cases were also neuropathologists, neuroanatomists, and histologists.  A good example if the photo at the top of this post.  It is a photo of Alois Alzheimer (back row 6<sup>th</sup> from the left) with his colleagues in neurology clinic (title Nervenklinik 1910-1911).  The strict translation is “psychiatric clinic or mental hospital”.  At the time this was in the Munich Psychiatric Clinic headed by Emil Kraepelin.

If we think of criteria to apply to determine if a researcher is a psychiatrist or not dating back to that time, I suggest the following:

1) Physicians who made major contributions to neuropsychiatry prior to the formal establishment of the fields of psychiatry and neurology.   Charcot, Wernicke, Alzheimer, Kraepelin, and Freud practiced across both domains.

2) neuropathologists or neurologists who were also psychiatrists or had a major interest in psychiatry; note that Freud was a Privadozent in neuropathology and Adolph Meyer came to the US to work as a neuropathologist.   António Egas Moniz is typically cited as a neurologist who practiced psychiatry.

3) physicians trained in both neurology and psychiatry.  There were really 2 waves of neuropsychiatry.  In the US practically all psychiatrists before 1935 practiced both and it was revived for military psychiatry in WWII. After graduating from medical school in 1901 von Economo spent a year working in an internal medicine clinic and over the next four years worked at various clinics in Europe with Marie, Kraepelin, Alzheimer, and Oppenheim learning psychiatry, neurology, and hypnosis. He returned to the University of Vienna in 1906 and was appointed Professor of Neurology and Psychiatry in 1921.

4) physicians board certified in psychiatry by the ABPN – modern standard – can occur even if the psychiatrist does not practice or see patients.

5)  physicians who headed psychiatric clinics or hospitals – many prominent examples like Franz Nissl who did research with Alzheimer and Kraepelin and is known for histopathological discovery but he eventually replaced Kraepelin as Professor of Psychiatry and Director of the Psychiatric Clinic at the University of Heidelberg.

6) attending physician in psychiatry.

7) physicians trained by self-identified psychiatrists.

With those expanded criteria – we can look at additional Nobel Laureates in the table below:

 

Laureate(s) (year)	Recognized for	Criterion invoked	Basis / caveat
Camillo Golgi & Santiago Ramón y Cajal (1906)	Microscopic structure of the nervous system	1	Pre-specialization neuropsychiatry; foundational to both fields, but neither was a clinical psychiatrist
Julius Wagner-Jauregg (1927)	Malaria therapy for general paresis of the insane	1, 2, 6	Career psychiatrist; the paradigmatic psychiatric laureate
Otto Loewi & Henry Dale (1936)	Chemical neurotransmission	1, 5	Trained in the Central-European neuropsychiatric/physiology milieu; psychiatric mentorship claim is indirect
António Egas Moniz (1949)	Prefrontal leukotomy for psychiatric illness	2	Neurologist whose award was for a psychiatric treatment
John Eccles (1963)	Synaptic physiology	1	Fundamental brain science; no psychiatric certification
Bernard Katz, Julius Axelrod, Ulf von Euler (1970)	Neurotransmitter storage/reuptake	1, 5	Axelrod's catecholamine work underpins biological psychiatry; lineage claim is thematic, not certified
Arvid Carlsson (2000)	Dopamine as a neurotransmitter	2, 5	Central to psychopharmacology/psychiatry; not a psychiatrist
Paul Greengard (2000)	Dopamine signal transduction	2	Molecular basis of psychiatric drug action
Eric Kandel (2000)	Molecular basis of memory	4	Psychiatry-trained; strongest ABPN-type example
Karl Deisseroth (2026)	Optogenetics	4, 6	Psychiatry-trained; ABPN board certified, attending physician inpatient and outpatient.

 

Looking at the table of Nobel laureates Only Wagner-Jauregg and Deisseroth practiced clinical psychiatry.  Kandel was trained and board certified as a psychiatrist but worked as a basic science researcher. I would count all three as psychiatrists. 

Of the remaining laureates the following completed medical degrees Camillo Golgi (University of Pavia 1865), Santiago Ramón y Cajal (University of Zaragoza 1873), Otto Loewi (University of Strassburg -1896), Henry Dale (Cambridge University 1909), António Egas (University of Coimbra 1899), and Ulf von Euler – (Karolinska Institute 1930). 

Two of the laureates were trained as PhD scientists Julius Axelrod (George Washington University - 1955 and Paul Greengard (Johns Hopkins University -1953).  The remaining three laureates were trained as physicians and scientists - John Eccles (MB, BS, MD -University of Melbourne) (Oxford - DPhil 1929), Bernard Katz (MD University of Leipzig – 1934) (PhD University College London – 1938), Arvid Carlsson – (MD, PhD University of Lund – 1951).  The interesting observation in this case is that most of the Nobel awards were to scientists with medical training or combined MD/PhD training.  There is some selection bias since the category is Medicine or Physiology.  

Even though neuroscience is considered a relatively new discipline it has historically had a close relationship to psychiatry for over 100 years.  Psychiatry has developed out of the close relationship with neurology and neuroscience and that seems to be lost by many modern-day critics.  That seems to be semantics more than anything else.  Just because you could not get a BS in Neuroscience in Cajal’s era did not mean neuroscience did not exist.   

In addition to Freud there were several additional neuropsychiatrists or possibly psychiatry adjacent researchers who were nominated but never received the Noble.  Ugo Cerletti (1877–1963) — an Italian neuropsychiatrist had correspondence with the Nobel committee and actively wanted the prize, but controversy about the method as well as conflict with his student Lucio Bini who subsequently patented his own machine may have been a factor in him not getting it.  Others include Joseph Babinski, Vladimir Bekhterev, Henry Head, Eduard Hitzig, and Hans Berger.

One of the fascinating aspects in training and reading about psychiatry is the tremendous diversity in training that occurred.  I previously asked the question whether the field though standardization has become less intellectually stimulating than it was in the past.  I used von Economo’s career as an example.  With standardization you can no longer go through a lab, a neurology clinic, or a psychiatry clinic in 4-year blocks and come out studying and researching whatever you want.  It is rare these days to see an MD doing basic science research, but fairly common to see them doing clinical research.  The neuropsychiatrists of the early 20<sup>th</sup> century are not the neuropsychiatrists of the early 21<sup>st</sup> century.  Before the board certification rule in the US in 1934, all psychiatrists were considered neuropsychiatrists.  Today they come in three forms – double board certified in psychiatry and neurology, psychiatrists with a neuropsychiatry fellowship or neurologists with a behavioral neurology fellowship, or self-proclaimed.  None of the psychiatrists doing this work are very visible. Most of the patients they treat are not seen in routine outpatient practice. They are more likely to be seen in acute care settings and specialty clinics.

The reason why the Nobel is so important in psychiatry is not because of the scorecard.  Having people of that caliber in the field, especially when they take an active role in teaching, mentoring and research brings the field up to a higher level.  I think it worked that way in the early 20<sup>th</sup> century when Warner-Jauregg made a landmark finding in biological psychiatry.  It worked that way when Kandel made similar discoveries in plasticity and memory in the 1970s (8).  I hope it works that way now with the award to Deisseroth.   I hope his work is being studied in psychiatry resident seminars across the country.  

Not that I expect it will stimulate any more MD, PhDs – but I hope it stimulates people to think about what a psychiatrist should know and how it improved our knowledge of the field.  I hope it encourages all of us to expand beyond the roles that have been defined for us by businesses, administrators, or people who otherwise attempt to intellectually restrict the field.

 

George Dawson, MD, DFAPA

 

Supplementary 1:  My suggested criteria for psychiatrist or not is not completely original but borrows heavily from criteria sent to me by Sheldon Benjamin, MD - a neuropsychiatrist and long time educator in that field. I would also like to thank Dr. Benjamin for the reference (13) and discussion of the informed consent issue.

Supplementary 2:  Wagner-Jauregg’s Treatment Malaria Fever Therapy protocol for GPI:

1:  Inoculation of the patient with live Plasmodium vivax (benign tertian) malaria.  This was usually done by intravenous infusion of 4-8 ml of blood from infected patients.  P. vivax was chosen because it was considered a more benign form of the disease. 

2:  Incubation:  It generally took one week before the first episode of febrile illness.

3:  Febrile course: Since the fever was considered the therapeutic component patients were required to cycle through several episodes of fever.  The literature describes this as 5-6 in a series of Viennese patients but as high as 8-12 elsewhere.  The fevers generally occurred in a tertian rhythm meaning thirds as in every third day but the measured intervals were about 31 to 41 hours.  Wagner-Jauregg also used a combined approach adding arsenical anti-syphilitic treatment (Salvarsan/neoarsphenamine).

4:  Termination: with quinine or combination therapy using other antimalarials.

There were some variations in this protocol.  In some cases, mosquitoes (Anopheles spp) were used for the inoculation.  This was problematic because it required keeping a supply of malaria carrying mosquitoes alive.  The blood inoculation required an infected person but that could also be the result of passing the infection through the inoculation route. Blood inoculation bypasses the liver stage of infection and does not result in relapses.  It predictably led to a first episode of fever in a week.  Mosquito bite infections also tended to be more severe and had a more marked inflammatory response even when parasite densities were comparable.     

Graphics Credit:  This is a well known photo reproduced in several texts.  The copyright has expired and it is in the public domain.  For full details as well as identification of other people in the photo - see the full Wikimedia post:  https://commons.wikimedia.org/wiki/File:Alzheimer_with_his_co-workers_Nervenklinik_Munich_1909-1910.JPG

References:

1:  Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci. 2005 Sep;8(9):1263-8. doi: 10.1038/nn1525. Epub 2005 Aug 14. PMID: 16116447.

2:  Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci. 2015 Sep;18(9):1213-25. doi: 10.1038/nn.4091. PMID: 26308982; PMCID: PMC4790845.

3:  Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K. Optogenetics in neural systems. Neuron. 2011 Jul 14;71(1):9-34. doi: 10.1016/j.neuron.2011.06.004. PMID: 21745635.

4:  Deisseroth K, Feng G, Majewska AK, Miesenböck G, Ting A, Schnitzer MJ. Next-generation optical technologies for illuminating genetically targeted brain circuits. J Neurosci. 2006 Oct 11;26(41):10380-6. doi: 10.1523/JNEUROSCI.3863-06.2006. PMID: 17035522; PMCID: PMC2820367.

5:  Deisseroth K. Optogenetics in Sight. N Engl J Med. 2026 Oct 8;395(14):1444-1446. doi: 10.1056/NEJMe2610388. PMID: 42842909.

5:  Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K. Structural and molecular interrogation of intact biological systems. Nature. 2013 May 16;497(7449):332-7. doi: 10.1038/nature12107. Epub 2013 Apr 10. PMID: 23575631; PMCID: PMC4092167.

6:  Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009 Jun 4;459(7247):698-702. doi: 10.1038/nature07991. Epub 2009 Apr 26. PMID: 19396159; PMCID: PMC3969859. 

7:  Whitrow M. Freud and Wagner-Jauregg: a historiographical study. Psychiatric Bulletin. 1990 Jun;14(6):356-8.

8:  Danto EA. Trauma and the state with Sigmund Freud as witness. Int J Law Psychiatry. 2016 Sep-Oct;48:50-56. doi: 10.1016/j.ijlp.2016.06.004. Epub 2016 Jun 17. PMID: 27324417.

9:  Kandel ER. Psychotherapy and the single synapse. The impact of psychiatric thought on neurobiologic research. N Engl J Med. 1979 Nov 8;301(19):1028-37. doi: 10.1056/NEJM197911083011904. PMID: 40128.

10:  Gomes MDM. Franz Nissl (1860-1919), noted neuropsychiatrist and neuropathologist, staining the neuron, but not limiting it. Dement Neuropsychol. 2019 Jul-Sep;13(3):352-355. doi: 10.1590/1980-57642018dn13-030014. PMID: 31555410; PMCID: PMC6753910.

11:  Hansson N, Palmen L, Padrini G, Karenberg A. Babinski, Bektherev, Cerletti, Head, and Hitzig: European Neurologists Nominated for the Nobel Prize 1901-1950. Eur Neurol. 2020;83(5):542-549. doi: 10.1159/000509078. Epub 2020 Jul 30. PMID: 32731244.

12:  Wolff S, Kainz RM, Reimold D, Lagler H, Mischlinger J, Ramharter M. Clinical and Parasitological Characteristics of Plasmodium vivax Malaria in Malaria-Naïve Patients: A Review of Malaria Fever Therapy in Patients with Schizophrenia and Neurosyphilis during the 1950s and 1960s in Vienna, Austria. Am J Trop Med Hyg. 2025 Sep 30;113(6):1249-1255. doi: 10.4269/ajtmh.24-0828. PMID: 41027422; PMCID: PMC12676601.

13:  Tsay CJ. Julius Wagner-Jauregg and the legacy of malarial therapy for the treatment of general paresis of the insane. Yale J Biol Med. 2013 Jun 13;86(2):245-54. PMID: 23766744; PMCID: PMC3670443.