What The Economist doesn’t know about Psychiatry

It is always good to take an in depth look at articles in the popular press about psychiatry – because of the clear antipsychiatry bias. An article from the Economist was posted recently that seemed to get a positive reception in some areas.  In my estimation that reception was not warranted.  Interestingly the same principles of analyzing rhetoric can be applied to this article as the last post on this blog about “doing your own research.”  I will use the same concept by concept approach to examine this article that I used for that video.  At the time the article was posted I read it for free online and I hope it is still available so that any reader here can appreciate the full text.  The author was not listed.

1:  “But her local hospital, in Durham, England, was dismissive, suggesting she had anxiety, a mental-health condition, and that she was probably spending too much time watching videos on TikTok. Her mother describes the experience as “belittling”:

The author begins with a story about an autoimmune condition with many neuropsychiatric manifestations Pediatric Autoimmune-Neuropsychiatric Disorders Associated with Streptococcus (PANDAS).  This is a condition that is known within psychiatry for at least 25 years and is covered in major psychiatric textbooks.  The author proceeds to conflate the lack of a definitive diagnosis with deficiencies in psychiatry as if it is totally unknown in the field. It is not and the pathophysiology and neuropsychiatric manifestations are known and taught within the field.  Secondarily if I had to speculate on the medical specialists who are most likely to see people who are told by a physician or family member that “it’s all in your head” – they would be psychiatrists.  We tend to see more of these people than anybody else.  

2: And infections are one small piece of the puzzle. It is increasingly clear that inflammatory disorders and metabolic conditions can also have sizeable effects on mental health, though psychiatrists rarely look for them. All this is symptomatic of large problems in psychiatry.

Psychiatrists have always been more interested in inflammatory and infectious conditions affecting the brain than most other specialists.  Griesinger mentions inflammation as a mechanism affecting brain function in his 1845 text on psychiatry (2). It is highly likely that in any community - psychiatrists are making more of these diagnoses than primary care physicians because they know the manifestations and they need to rule out physical causes of mental illnesses to make a psychiatric diagnosis.  All psychiatrists are trained in making these diagnoses and not mistaking them for a mental illness occurring in a healthy person or a person with chronic illnesses not affecting brain function.  The only large problem here is the lack of knowledge about how psychiatrists are really trained.

Inflammatory disorders were used as treatments in the early 20^th century.  In the pre-antibiotic era, 5-10% of asylum admissions were due to neurosyphilis and the associated psychiatric manifestations. Some of the early treatments were based on inducing fevers.  Austrian psychiatrist Julius Wagner-Jauregg was awarded the Nobel Prize in Medicine in 1927 for successful treatment of neurosyphilis by inoculating patients with malaria (2).  This work was replicated and additional agents were used to induce fevers by other investigators with similar results. In addition to the experimental results, this represented a sea change in the general attitude of treating psychosis in asylums where a previous biological treatment did not exist.  Subsequent innovations occurred when neuromodulation techniques were introduced in 1932 (5) and psychopharmacology in 1952 (6).

The early focus on gross neuropathology and transition to microanatomy led to the discovery of Alzheimer's Disease in 1906 and Binswanger's Disease a form of vascular dementia in 1894.  Both Alzheimer and Binswanger were considered psychiatrists - Alzheimer by his own designation and training and Binswanger was eventually appointed to head an asylum by age 30.  

As far as "rarely looking for them" goes the top 4 medical conditions I diagnosed in newly seen patients were probably Type 2 diabetes mellitus, hypothyroidism, hypertension, and atrial fibrillation. Any psychiatrist practicing in the last 30 years is aware that psychiatric disorders and pharmacological treatment can be associated with metabolic syndrome and the need to monitor for and prevent that condition. 

3:  Chronic conditions are poorly treated – apparently because they are not cured (paraphrased):

This is always an interesting rhetorical sleight-of-hand. In what other specialty is the expectation that chronic conditions will be cured? It does not take a lot of research to show that nobody is curing most diabetics, hypertensives, asthmatics, arthritics, or patients with a multitude of other chronic conditions. In fact most of these patients remain symptomatic even when they are treated. These are all conditions with clear cut laboratory tests and other disease markers.  These are all conditions where there is at least a speculative biological hypothesis of pathophysiology.  And yet – there is no expectation of cure and in fact much more expected mortality in other specialties. Why is psychiatry different?  It is not.

4:  Some people in the profession believe that biological psychiatry will lead to better characterizations of psychiatric problems including pathophysiology, drug treatment, and pharmacological targets/precision psychiatry (paraphrased):

It is obvious that biological psychiatrists have been at it for decades and much longer.  The journal Biological Psychiatry was founded in 1969 but biology has been a focus of psychiatric research dating back to mid-19^th century when attempts were made to observe brain dissection correlates with behavior.  Griesinger (2) documents efforts by both Pinel and Esquirol to document brain abnormalities in severe mental illnesses. In his text he documents brain diseases leading to psychiatric care and associated organ dysfunction at autopsy in patients identified as having severe mental illness.

In the days of asylum care before biological psychiatry, delirious mania had a mortality rate of 75% (7).  That has essentially been reduced to zero with advances in modern biological psychiatry including electroconvulsive therapy and psychopharmacology.  There is probably no better example of advances due to biological psychiatry occurring over decades.

Like all other medical specialties, biological psychiatry is an active area of research with new journals like Molecular Psychiatry (1997) and Translational Psychiatry (2011) that are focused on the latest innovations in biological psychiatry and potential treatment applications.

5:  The DSM or the Bible of Psychiatry does not specify pathophysiology

Any time you see that the DSM is the “Bible of psychiatry” that is a red flag that indicates the author either lacks knowledge about the Bible or the DSM.  Here is a brief primer on the DSM to correct some misconceptions.  That primer emphasizes that the person using it (typically for diagnostic codes used for administrative purposes) is a trained professional and understands its limitations. Chief among those limitations includes ruling out medical causes of psychiatric symptomatology and understanding that it is not a guide for everyman to use for diagnosis and treatment.  Kendler (8) and others have taken it a step further to point out that it is an index of disorders and therefore a starting point – rather than an actual diagnostic guide.  In other words, meeting criteria for a diagnosis is not that same as having the diagnosis.  This is generally true of all codified systems of medical diagnosis.  An example would be the American College of Rheumatology classification criteria.  There is an extensive discussion of these classification criteria compared with diagnostic criteria and why the ACR currently endorses only the former (9).  It is basically the same discussion that Kendler uses in describing the indexing system – that there is sufficient heterogeneity in clinical presentations over time and geographical areas that every case needs to be individually considered. Here is the rationale from the leading text on systemic lupus erythematosus (SLE) (10):  

“The classification criteria do not contain a complete list of all the possible manifestations of lupus.  The manifestations of SLE often develop over a period of time, sometimes years, making the diagnosis more difficult at initial presentation. The diagnosis of lupus is made on clinical grounds, supported by laboratory data and depends highly on the physician’s knowledge and experience. (author’s emphasis)”

Despite the title, the DSM is not a guide to diagnosis or treatment. People who do not “meet criteria” are not automatically excluded from treatment consideration. Separate knowledge about psychopathology and diagnostic formulation is necessary. Speaking to the author’s concern about the lack of specific etiologies – even the skeletal classification and indexing framework of the DSM has chapters on clear medical, toxicological, and neurological causes of mental disorders.

The Economist dates psychiatry’s “Bible” back to 1952.  That would have been the DSM-I.  I encourage anyone who is interested to read the 6 page Forward to that document.  It started initially to standardize nomenclature. Each training program was using their own version of nomenclature as well as the military.  When trained psychiatrists went out to practice in the community – there was no standard nomenclature being used to described similar phenomenon and the requirements of military and civilian nomenclature were different. The secondary goal was to use this nomenclature to collect statistics that could be used to improve the necessary infrastructure and resources to treat these disorders.  All of this can be done without any specific reference to pathophysiology in both psychiatry and the rest of medicine.    

And here is a news flash from the DSM-5,  my estimate is that 69% of all of the diagnoses listed have a clear pathophysiology or medical test equivalent to any other branch of medicine.  Given the classification problems with all medical diagnoses that overall figure probably compares well with any other branch of medicine.   

Whatever your take away from this post, The Economist knows very little about psychiatry and medicine. But that should not be too surprising.  The tone and factual content clearly resemble much of what you see on the Internet and in the press about psychiatry. That does not make it any less wrong.  If you are really interested in what is going on in the field – I would recommend reading the general literature in the field or summaries about it. The popular press – newspapers and magazines – is clearly not up to the task.

6:  Attempts to find causal mechanisms for mental illnesses have failed (paraphrased):

News flash – that is true of every other complex disease as well as the medication used to treat them.  This post illustrates that fact with medication used to treat multiple sclerosis.  The table lists 18 FDA approved drugs – many of which modify the course of the illness but in every case the specific mechanism of action of the drug is unknown.

7:  Genetics has been a clinical “flop” (paraphrased):

It would probably be a good idea to get the opinion of an expert in psychiatric genetics.  The article seems to focus on the issue of polygenic risk analysis (PRA) and those studies generally have low effect sizes due to the number of genes studied.  Any commercial assessment of a genome will result in hundreds of these profiles – most of them for non-psychiatric illnesses. The example given above illustrates polygenic risk scores (PRS) when the small risk factors (both protective and potentially causative) are summed and compared to a standard sample so that 100% is highest percentile risk in the sample and 0% is the lowest. This is only one approach and there are major psychiatric initiatives in this space doing ongoing research. PRA/PRS is accepted science at this point but the widespread clinical utility is not known for practically all polygenic disorders.

Recent examples given by Kendler (11) in his commentary on whether psychiatric disorders are brain diseases points to the importance of genetics in psychiatry.  To this day there are endless debates, typically by people who are not trained to be psychiatrists that psychiatric disorders are somehow independent of brain substrate. In other words, even though it is widely acknowledged that a brain is required for mental life – there is no evidence at the molecular level that an alteration in brain function causes mental illness. Contrary to The Economist, Kendler states: “I use the most robust empirical findings in all of psychiatry—that genetic risk factors impact causally and substantially on liability to all major psychiatric disorders.”  He quotes the recent literature illustrating that risk variants for schizophrenia are located only in brain tissue.  Similar evidence is accumulating for bipolar disorder and major depression. This correlation of strongest known risk factors and brain substrate location is good evidence of specific genetic effects in the brain. Similar work is being done to identify signaling systems, proteins, and physiological processes underlying the DSM classifiers.  Once again, this is similar to the approaches being taken with all complex non-psychiatric diseases. 

8:  Biology is coming, whether psychiatry is ready or not:

When I saw this caption – it seemed like a joke.  Over the 40 years of my career there has been a constant battle based on the false dichotomy of biological psychiatrists and psychotherapy focused psychiatrists. That left out important additional identities including medical psychiatrists, neuropsychiatrists, and community psychiatrists. Practically all the criticism in the press has been that psychiatrists are too biological. I could probably write a book about this – but in this case suffice it to say that The Economist has not done much homework. The smattering of research projects listed in the last several paragraphs about immunology and metabolism ignores that this type of research has been going on for decades and gradually making progress. 

Every psychiatrist is trained in the biology of medicine and psychiatry - just like me.  We are willing to incorporate the latest research innovations and look forward to them. Biology comes as no surprise.

 

George Dawson, MD, DFAPA

 

 

 

References:

1:  “Many mental-health conditions have bodily triggers: Psychiatrists are at long last starting to connect the dots.:  April 24, 2024.  In the print edition this story is under the general heading "Psychiatry’s blind spots".  No author was listed for the online version that I read.

2:  Griesinger W: Die Pathologie und Therapie der Psychischen Krankheiten: für Aerzte und Studirende. (The pathology and therapy of mental illnesses, for doctors and students). Stuttgart, Germany, Verlagvon Adolph Krabbe, 1845  https://www.deutschestextarchiv.de/book/view/griesinger_psychische_1845?p=47

3:  Wagner-Jauregg J. The treatment of general paresis by inoculation of malaria. J Nerv Ment Dis. 1922;55:369–375. [Google Scholar] [Ref list]

4:  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.

5:  Gazdag G, Ungvari GS. Electroconvulsive therapy: 80 years old and still going strong. World J Psychiatry. 2019 Jan 4;9(1):1-6. doi: 10.5498/wjp.v9.i1.1. PMID: 30631748; PMCID: PMC6323557.

6:  Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007 Aug;3(4):495-500. PMID: 19300578; PMCID: PMC2655089.

7:  Bell, L., 1849. On a form of disease resembling some advanced stage of mania and fever.  Am. J. Insanity 6, 97–127. 

8:  Kendler KS. The Phenomenology of Major Depression and the Representativeness and Nature of DSM Criteria. Am J Psychiatry. 2016 Aug 1;173(8):771-80. doi: 10.1176/appi.ajp.2016.15121509. Epub 2016 May 3. PMID: 27138588.

9:  Aggarwal R, Ringold S, Khanna D, Neogi T, Johnson SR, Miller A, Brunner HI, Ogawa R, Felson D, Ogdie A, Aletaha D, Feldman BM. Distinctions between diagnostic and classification criteria? Arthritis Care Res (Hoboken). 2015 Jul;67(7):891-7. doi: 10.1002/acr.22583. PMID: 25776731; PMCID: PMC4482786.

10:  Rudinskaya A, Reyes-Thomas J, Lahita R.  The clinical presentation of systemic lupus erythematosus and laboratory diagnosis. In: Lahita RG, Costenbader KH, Bucala R, Mani S, Khamashta MA.  Lahita’s Systemic Lupus Erythematosus. 6^th ed.  London, England:  Elsevier, 2021: 316.

11:  Kendler KS. Are Psychiatric Disorders Brain Diseases?-A New Look at an Old Question. JAMA Psychiatry. 2024 Apr 1;81(4):325-326. doi: 10.1001/jamapsychiatry.2024.0036. PMID: 38416478.

How I ended up in a high-risk pancreatic cancer screening clinic

Pancreatic cancer is a scary disease. The pancreas (like the brain) is in a difficult to access space.  It is removed from other anatomical structures so that it does not produce symptoms that lead to early detection.  In medical school they taught us two presentations – waking up with painless jaundice and depression.  The painless jaundice is more of a specific give away than the depression. In either case, prognosis at the time of diagnosis is poor and has not improved significantly in the past decades (1,2,7).

I think about discussions I used to have over lunch with several specialists. Our typical group consisted of 3 GI docs, 1 or 2 Infectious Disease docs, a nephrologist and me.  We usually talked about movies but one day it turned to pancreatic cancer.  The question became – if you could screen for it would you?  This discussion happened back in the 1990s and the consensus at that time was no.  One of the pieces of evidence offered was the poor prognosis after surgical intervention – irrespective of the time of diagnosis.

I personally know 10 people who were diagnosed with pancreatic cancer. Four of them are on the paternal side of my family and one is a first degree relative – my sister. My earliest recollection of the disease was visiting my paternal aunt who lived a few blocks from my family.  Back in the 1950s, there was no useful imaging and diagnoses typically depended on exploratory surgery and direct tissue sampling. People who lived in remote areas did not travel to large referral centers to see specialists. You lived and died based on the skill of local physicians – some who had surgical training but were not technically general surgeons. Blood banking also did not exist and my father and uncle had to donate blood for my aunt. Nine of the 10 people I have known with pancreatic cancer are deceased some of them within weeks to months of the diagnosis.  My sister has been a trail blazer.  After a fortuitous diagnosis while being scanned for gallbladder disease, pancreatic cancer was diagnosed and she underwent radiation therapy, chemotherapy, a Whipple procedure, and maintenance therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor.  She saw an oncologist who recommended genetic testing and discovered she had an ATM gene variant. The genetic counselor she was seeing at the time recommended that all her siblings get tested for the same gene and to see if their children also needed to be tested.

ATM stands for “ataxia telangiectasia mutated.”  Ataxia telangiectasia (AT) is a hereditary degenerative ataxia that occurs in 1 in 20K to 100K live births (3,4).  Gait problems and truncal instability occurs in the first decade of life followed by progressive ataxia. Telangiectasias starts at about age 5 and are most evident in the conjunctive but can occur at various sites on the body. Immunodeficiency is noted with frequent respiratory infections.  Humoral and cell mediated immunity are affected as evidenced by decreased immunoglobulins and lymphocytopenia. AT is also associated with an increased frequency of cancers beginning with hematological malignancies in childhood and different malignancies as adults (6).  Lifespan with AT is decreased but is now more than 25 years with supportive measures. 

The mutations causing AT were discovered as mutations in the ATM gene in the late 20^th century.  The ATM gene is located on chromosome 11, and the gene product is a serine-threonine kinase involved in DNA repair (5). Like most human genes there are a large number of mutations and single nucleotide polymorphisms (SNPs).  Those mutations associated with AT are insertions, deletions, missense, and truncations.  These mutations can lead to absence or loss of function ATM protein.  In my case the lab report read:

 

Variant Details:

ATM, Exon 10, c.1564_1565del (p.Glu522Ilefs*43), heterozygous, PATHOGENIC

This sequence change creates a premature translational stop signal (p.Glu522Ilefs*43) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872).

This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9000145, 9463314, 10330348, 10817650, 12497634, 21965147, 27083775).

In order to appreciate how the ATM protein works – a brief review of cell biology is in order.  Cells reproduce according to a cell cycle with various components. The protein components and cell signaling of that cycle were discovered in the past 40 years.  The cell cycle has checkpoints designed to stop the cycle and repair any DNA that is discovered as defective along the way. ATM is one of the proteins that modulates that process.  Functional ATM protein means that it is less likely that damaged DNA is passed along in new cell lines and that reduces the risk of cancer.  ATM mutations are associated with increase risk for pancreatic, ovarian, breast, and prostate cancer and as previously noted – malignancies associated with AT.  That is the mile high version of checkpoint and checkpoint proteins.  If you want a more detailed explanation, put it in the comments section and I will add more.

This mechanism is interesting to consider when thinking about genomic versus environmental effects. Peak incidence for new diagnoses of pancreatic cancer occurs during the 70s. If you have a defective DNA repair mechanism – is this the time where those defects accumulate to the point of creating malignancy?  How is your history of avoiding carcinogens like alcohol and tobacco smoke relevant to that probability?  What about the protective effects of antioxidants and exercise? At some point does a partially functional ATM protein protect against cancer or is the fully functional protein required?

The referral process in my own primary care clinic went smoothly when I told my internist about my sister’s diagnosis. I got an online appointment with a genetic counselor and when the results came back – she told me there was a 10-15% chance of pancreatic cancer and one clinic that did risk surveillance at Mayo.  She asked me if I was interested and why.  She also advised me that there are currently loopholes in the law that allow some companies to discriminate against you based on genetic testing. After discussing what those companies did – I told her I was not concerned about it and she made the referral.  I met with the gastroenterologist who headed the clinic, signed up for additional research protocols, had an MRI scan and just completed an upper GI endoscopy with ultrasound (US).  The ultrasound device is in the head of the gastroscope and it needs to be positioned in various areas of the stomach and duodenum to visualize the entire pancreas. The US procedure was also set up to proceed with a fine needle biopsy of the pancreas – but no lesions were noted and no biopsy was necessary. If a biopsy is required it is done through the wall of the stomach or duodenum.  Current screening is on an annual basis and the orders have already been placed for next year.

Getting back to the answer to the question posed in the title - it comes down to genes. One of the cultural myths in the US is that you always bear some level of responsibility for your disease. Recall any discussion about this with friends or family: “Did you hear that your classmate died last week from X?”  The next question or comment is likely to be – “well he (smoked, drank, never exercised, was obese, didn’t take care of himself, never saw a doctor, etc.”). There always must be an explanation for your old classmate dying prematurely and it is rarely biological.  Even though everybody in town with the same risk factors – outlived him by 20 years.  The stark reality is that it does not take a risk factor-based analysis. All it takes is a gene (or many genes) that code for the disease either directly or indirectly.

 

George Dawson, MD, DFAPA

 

References:

1:  Armstrong SA, Schultz CW, Azimi-Sadjadi A, Brody JR, Pishvaian MJ. ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications. Mol Cancer Ther. 2019 Nov;18(11):1899-1908. doi: 10.1158/1535-7163.MCT-19-0208. PMID: 31676541; PMCID: PMC6830515.

2:  Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021 Jul;18(7):493-502. doi: 10.1038/s41575-021-00457-x. Epub 2021 May 17. PMID: 34002083; PMCID: PMC9265847.

The risk of death from pancreatic cancer rises dramatically with age from <2 deaths per 100,000 person-years for individuals in the USA aged 35–39 years to >90 deaths per 100,000 person-years for individuals aged >80 years.

3:  Subramony SH, Xia G. Disorders of the cerebellum, including the degenerative ataxias.  In:  Neurology in Clinical Practice (7^th edition). RB Daroff, J Jancovic, JC Mazziotta, SL Pomeroy (eds). Elsevier, London, 2016.  p: 1468-1469.

4:  Rothblum-Oviatt, C., Wright, J., Lefton-Greif, M.A. et al. Ataxia telangiectasia: a review. Orphanet J Rare Dis 11, 159 (2016). https://doi.org/10.1186/s13023-016-0543-7

5:  ATM serine/threonine kinase [ Homo sapiens (human) ]

Gene ID: 472, updated on 12-Mar-2023

https://www.ncbi.nlm.nih.gov/gene/472

6:  Hsu F, Roberts NJ, Childs E, et al. Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene. JAMA Oncol. 2021;7(11):1664–1668. doi:10.1001/jamaoncol.2021.3701

“The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95%CI, 0.8%-1.3%) by age 50 years; 6.3%(95%CI, 3.9%-8.7%) by age 70 years; and 9.5%(95%CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95%CI, 4.5-9.5) in ATM variant carriers compared with noncarriers.”

7:  Trikudanathan G, Lou E, Maitra A, Majumder S. Early detection of pancreatic cancer: current state and future opportunities. Curr Opin Gastroenterol. 2021 Sep 1;37(5):532-538. doi: 10.1097/MOG.0000000000000770. PMID: 34387255; PMCID: PMC8494382.

8:  Oh SY, Edwards A, Mandelson MT, Lin B, Dorer R, Helton WS, Kozarek RA, Picozzi VJ. Rare long-term survivors of pancreatic adenocarcinoma without curative resection. World J Gastroenterol. 2015 Dec 28;21(48):13574-81. doi: 10.3748/wjg.v21.i48.13574. PMID: 26730170; PMCID: PMC4690188.

9:  Overbeek KA, Goggins MG, Dbouk M, Levink IJM, Koopmann BDM, Chuidian M, Konings ICAW, Paiella S, Earl J, Fockens P, Gress TM, Ausems MGEM, Poley JW, Thosani NC, Half E, Lachter J, Stoffel EM, Kwon RS, Stoita A, Kastrinos F, Lucas AL, Syngal S, Brand RE, Chak A, Carrato A, Vleggaar FP, Bartsch DK, van Hooft JE, Cahen DL, Canto MI, Bruno MJ; International Cancer of the Pancreas Screening Consortium. Timeline of Development of Pancreatic Cancer and Implications for Successful Early Detection in High-Risk Individuals. Gastroenterology. 2022 Mar;162(3):772-785.e4. doi: 10.1053/j.gastro.2021.10.014. Epub 2021 Oct 19. PMID: 34678218.

10:  Søreide K, Ismail W, Roalsø M, Ghotbi J, Zaharia C. Early Diagnosis of Pancreatic Cancer: Clinical Premonitions, Timely Precursor Detection and Increased Curative-Intent Surgery. Cancer Control. 2023 Jan-Dec;30:10732748231154711. doi: 10.1177/10732748231154711. PMID: 36916724; PMCID: PMC9893084.

"The overall poor prognosis in pancreatic cancer is related to late clinical detection. Early diagnosis remains a considerable challenge in pancreatic cancer. Unfortunately, the onset of clinical symptoms in patients usually indicate advanced disease or presence of metastasis."

11:  National Center for Biotechnology Information. ClinVar; [VCV000127340.60], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000127340.60 (accessed March 19, 2023).

Graphics:

I drew that genogram of my immediate family using EDraw Max.  I am one of the two siblings that tested positive for the ATM variant. My other siblings have not been tested. 

Patentable Biomarkers of Suicide

From: Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach (reference 1 with permission).

One of the most interesting aspects of biological psychiatry is the attempt to characterize complex biological systems.  It may not have been apparent but complex biological systems factored in a recent post about bronchitis.  Lungs are certainly complex with two different blood supplies and complicated immunology, but the lungs are not thinking organs.  They don't come up with any secondary concepts that need to be analyzed as possible derivatives of the biological substrate.  And even then, basic syndromes that we all learned about in medical school and in clinical rotations, defy more useful classifications.  I have previously posted on endophenotypes and their usefulness in the treatment of asthma and only recently noted that they have proliferated to include an obese endophenotype and how that affects response to therapy.  Diagnostic and treatment approaches to asthma and bronchitis are necessarily crude, largely because the biological complexity in these processes is not fully appreciated and addressed.

The brain is certainly the most complex organ in the body.  Cellular arrays in the brain produce a stream of consciousness, robust unconscious processing, unique conscious states, and all forms of emotional, social and intellectual constructs that can be observed, monitored, and changed.  That brings me to a paper from Molecular Psychiatry on possible biomarkers for suicide.  Not just any paper - at this point it is the most downloaded paper from the top-ranked psychiatry journal (1/140) in the world.  Molecular Psychiatry has an impact factor of 14.496 and that is the highest impact factor of all psychiatry journals.  In part that is probably driven by how absurdly expensive that similar journals like Biological Psychiatry are or other barriers to purchase like needing to be a member of the sponsoring society.  This is a public access journal that uses Creative Commons Licenses for their content.  The authors in this case have provided a 20 pages article and 124 pages in Supplemental Information.

The idea of a biomarker for suicide is very attractive to psychiatrists, because assessing suicide risk is a big part of what we do.  Current clinical guidelines suggest that we need to make that assessment at every patient visit.  The actual prediction of suicide is difficult due to the fact that mental states change over time and people may not be able to communicate their true level of risk.  I have had people tell me in retrospect that they lied about their degree of suicidal thinking and level of control when I asked them about it.  I have had acute care colleagues tell me that they were weary of having to guess about whether a person was going to try to kill themselves or not - many times a day.  The assessment is further complicated by a lack of acceptable acute care options that may further hinder complete self disclosure.  A biomarker would potentially be beneficial.  I qualify that by the fact that the dexamethasone suppression test was once considered a biomarker of suicide (1), but these days it is rarely done and certainly not as part of a suicide assessment.  A study by Coryell, et al (9) notes that the DST was not able to differentiate patients who died from suicide or cardiovascular disease when long term mortality was determined by the National Death Index.  Those authors suggest it may be useful as a predictor of suicide only in patients with depression.

In this article the authors take a look at possible biomarkers in blood that could predict both suicide and some associated markers like risk of hospitalization.  There is a lot going on in this paper.  All the research participants were men.  They studied four different patient cohorts including 217 patients followed longitudinally.  This group was called the Discovery Cohort because markers were discovered based on 37 patients who had a switch from a no suicide state to a high suicide state defined as a score of 2 - 4 on the HAMD question about suicide.  26 deceased patients who committed suicide were used to validate the initial markers.  Two psychiatric cohorts of 108 and 157 to look at prediction of suicidal ideation and hospitalization with the chosen tests.  The flow of these experiments in depicted in the graphic at the top of this post from the original paper.  In the diagram, the designations AP (absent-present) and DE (differential expression) are techniques to capturing genes that are turning of and turning on and off and gradual  changes in gene expression.  The respective genes in this analysis are color-coded based on those properties.  The Convergent Functional Genomic (CFG) Approach is depicted in the box.  Candidate genes are ranked in the triangles according to CFG score.  The CFG score was the sum of various weighted factors including evidence of human brain expression, evidence of human peripheral presence, human genetic evidence and linkage with weighted scores in the CFG box.  Using their discovery and validation sequence the authors were able to pare down the total number of genes down from 412 to 208 to 143 and ultimately to 76 genes.  The supplementary information provides the validation of biomarkers and a table that looks at each gene and prior human genetic evidence, prior evidence of brain expression and prior human evidence of peripheral expression.

The authors discussion of the biological relevance of their findings was interesting.  They did pathway analysis looking at Ingenuity, KEGG, and GeneGO databases.  Of these only the Kyoto Encyclopedia of Genes and Genomes (KEGG) is publicly available without a subscription fee.  It is very useful to know about KEGG because of the relevance of pathway analysis in the psychiatric literature.  As an example, I have been teaching about the mTOR pathway discussed in this article in my neurobiology of addiction lectures for the past 4 years.    

This article is very interesting and can be read at  several levels.  It is premature to consider it definitive at this point and based on this paper and the work of the associated lab these authors are working on additional validation strategies.  If they are  correct,  suicidality may be captured in time as a polygenic event based on a combination of genes that are turned off and on and others that gradually change.  I titled this post as "patentable genes" because the only conflict of interest cited is the lead author is listed as an inventor on a patent application being filed by Indiana University.  For trainees and early career psychiatrists a familiarity with this technology and its potential uses and limitations would be one of the reading goals and including Molecular Psychiatry and its sister journal from the same group Translational Psychiatry (8) is probably a good idea.  Both are potentially good sources of neuroscientific information in psychiatry and if popularity is any indication - fill a niche in the field.  Some of the tools that they developed along the way are useful to think about from a clinical perspective (4, 5).  The thought that the CFI-S Scale was particularly interesting because it is a 22 point binary scale that looks at factors (excluding suicidal ideation) that they determined to be important.  The factors are also classified as to whether they represent increased reasons (IR) or decreased barriers (DB) to suicide.  The emphasis on suicide as a discrete syndrome independent of diagnosis is a research strategy that has been called for recently based on the need to come up with better ways to diagnose and treat the problem.  In a clinical setting I think that clinicians are still frequently surprised by suicide attempts and suicides being able to determine if a patient is in a high risk state based on a blood test independent of their clinical presentation and statements would be useful both in terms of the test but also the associated dialogue.

What I really like about this paper is that it is an attempt to deal with a common psychiatric problem at the appropriate level of complexity.  Clinical trials do exactly the opposite.  As an example, clinical trials in psychiatry will look at heterogeneous groups of patients pulled together under a vague diagnostic category.  There may be rating scales or global ratings just because the rating scales don't seem to have much discriminatory power.  In the end, the entire study is generally collapsed for a very simple statistical analysis.  Getting to those final variables and what has been ignored in the process is always the critical question.  I think it is trendy these days to commiserate about the fact that there are inconclusive, weak and non-reproducible results from the standard clinical trials technology.  I don't know why anyone would expect a different result.  If anything this paper illustrates that a lot of biological information can be considered and analyzed.  The popularity of this paper leaves me hopeful that this is a positive trend for the future.            


George Dawson, MD, DFAPA


References:

1:  Niculescu AB, Levey DF, Phalen PL, Le-Niculescu H, Dainton HD, Jain N,Belanger E, James A, George S, Weber H, Graham DL, Schweitzer R, Ladd TB, Learman R, Niculescu EM, Vanipenta NP, Khan FN, Mullen J, Shankar G, Cook S, Humbert C, Ballew A, Yard M, Gelbart T, Shekhar A, Schork NJ, Kurian SM, Sandusky GE, Salomon DR. Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach. Mol Psychiatry. 2015 Aug 18. doi: 10.1038/mp.2015.112. [Epub ahead of print] PubMed PMID: 26283638.

2:   Lee BH, Kim YK. Potential peripheral biological predictors of suicidal behavior in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):842-7. doi: 10.1016/j.pnpbp.2010.08.001. Epub 2010 Aug 11. Review. PubMed PMID: 20708058.

3:   Collection of references for biomarkers in suicide.

4:  Simplified Affective State Scale (SASS).

5:  Convergent Functional Information for Suicide (CFI-S) Scale.

6:  Laboratory of Neurophenomics Web Site.

7.  Niculescu AB Medline Collection on additional convergent functional genomics references.

8.  Translational Psychiatry Web Site.

9.  Coryell W, Young E, Carroll B.  Hyperactivity of thehypothalamic-pituitary-adrenal axis and mortality in major depressive disorder.  Psychiatry Res. 2006 May 30;142(1):99-104. Epub 2006 Apr 21. PubMed PMID: 16631257.

Attribution:

The figure at the top of the post is from the original article listed completely in reference 1 under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.  To view the condition of that license view it here.

Supplementary:

1.  There is a Mayo Clinic Conference coming up this fall for anyone interested in translational approaches to psychiatric disorders and addictions.  Further information is available at this web site.

2.  There is also the 3rd Annual Update and Advances in Psychiatry conference at the US Madison and one of presentations is by Daniel Weinberger, MD on the neuroscience of schizophrenia and psychotic disorders.   Information on that conference and the conference brochure is available at this web site.

The Stanley Center Grant

 The details of this grant and some of the history of previous grants are given in this press release from the Broad Institute.  A few of the details include the fact that the Broad Institute has about 150 scientists working on the genetics of severe mental illnesses.  That focus includes detailing the genetic basis of these disorders, a more complete elaboration of the the pathways involved and developing molecules that can modify these pathways as a foundation for more effective medical treatment.   The focus of this group is on severe psychiatric disorders including schizophrenia, bipolar disorder, autism and attention deficit-hyperactivity disorder.  It was also the single largest donation for psychiatric research - ever.

Any search on research grants over the past decade will produce thousands of research articles that were funded by the Stanley Foundation.  The press release details the fact that grants from the Stanley Foundation have been incremental and that they are obviously monitored for progress by the grantees who are satisfied with the progress being made.  That has not stopped some critics from suggesting that the money is basically either wasted, that it could be better used for symptom control, or that it would be more useful for research in symptom control.  My goal here is to question some of these arguments about basic psychiatric research in much the same way that I question the arguments that usually attack psychiatric practice and clinical research.    My speculation is that the underlying premises in both cases are very similar.

The basic arguments about whether it is a good idea to fund basic science research as it applies to psychiatry range from speculation about whether or not it might be useful to the fact there are more urgent needs to funding on the clinical side.  Many of these arguments come down to the idea of symptom management versus a more scientific approach to the patient.  There are few areas in medicine that have a purely scientific approach to the patient at this time.   The more clearcut examples would be locating a lesion somewhere in the body, performing a biopsy and making tissue diagnosis.  That is an example of the highly regarded "test" to prove an illness that seems to be a popular idea about scientific medicine.  But in that case the science can run out at several levels.  The  diagnosis depends on correctly sampling the lesion and that can come down to the skill of the sampler.  It depends on the agreement of pathologists making the tissue diagnosis.  The tissue diagnosis may be irrelevant to the health of the patient if there are no treatments for the diagnosed illness.

In many cases in medicine, treatment depends on symptom recognition and monitoring.  In some cases  there are tests of basic anatomy or function.  A good example is asthma.  As I have previously posted here (see Myth 4), the majority of asthmatics have inadequate control of asthma and the approach to asthma is generally symptom control.  The current basic science of asthma depends on identifying genes and gene products that will allow for more specific treatment of the underlying pathophysiology and there are surprising similarities with mental illnesses.  For example, there is no single asthma gene.  The genetics of the various aspects of asthma pathophysiology including the degree to which it can be treated is assumed to be polygenic in the same manner as the genetics of severe psychiatric disorders.  The only difference being that a larger portion of the human genome is dedicated to brain proteins (personal correspondence with experts puts that figure as high as 25%).   Genome wide association studies of severe asthma can have as much difficulty identifying candidate genes that reach statistical significance.   Any thought experiment comparing the reference pathway for asthma to any number of similar pathways that are operative for brain plasticity, human consciousness and the variants we call mental illnesses will show that there are surprising few specific interventions for asthma signaling and that signaling occurring in the brain is even more complex.  The reason why we have impressive brain function is structural complexity at cellular, structural and biochemical pathway levels.   And yet the rhetoric of critics usually considers asthma as a disease to be more legitimate than psychiatric disorders and the lungs are apparently considered a more legitimate target for research funding than the brain.

What are the critics saying?  Allen Frances, MD DSM critic has decided that neuroscience research may be so complicated that the $650 million dollar grant may be a drop in the bucket in sorting out the basic science.  He suggests:

"But there is a cruel paradox when it comes to mental disorders. While we chase the receding holy grail of future basic science breakthrough, we are shamefully neglecting the needs of patients who are suffering right now. It is probably on average worse being a patient with severe mental illness in the US now than it was 150 years ago. It is certainly much worse being a patient with severe mental illness in the US as compared to most European countries."

My experience in psychiatry is clearly much different from Dr. Frances. Although I am probably at least a decade younger, I can remember a time when there was no treatment at all.  As a child I heard the stories of my great aunt working in a county sanatorium full of patients with tuberculosis and severe mental illnesses.  This was state-of-the-art treatment before the era of psychopharmacology.  Large numbers of institutionalized patients went there and many never left unless they had a mood disorder that suddenly remitted or they received electroconvulsive therapy.  Those leaving often ended up on county "poor farms" for the indigent.  Contrary to Dr. Frances observations that was about 50 years ago. Going back earlier than that I consider Shorter to be definitive.  In his text he describes what describes what it was like to have a psychotic disorder before the asylum era in many countries of the world and concludes:

"In a world without psychiatry, rather than being tolerated or indulged, the mentally ill were treated with a savage lack of feeling.  Before the advent of the therapeutic asylum,  there was no golden era, no idyllic refuge for those supposedly deviant from the values of capitalism.  To maintain otherwise is a fantasy."  (p4)     

Even when psychopharmacology became available to people in institutions it took a long time to make it to Main Street. In the small town of 10,000 people where I grew up, I witnessed a generation of people with autism, schizophrenia, post-traumatic stress disorder (from WWII and the Korean War) and bipolar disorder being treated with amitriptyline and benzodiazepines by primary care physicians. They may have been home from the state hospitals but with that treatment the outcomes were not much better.

The only cruel paradox that I find quite offensive is the blatant discrimination of governments at all levels and their business proxies against anyone in this country with an addiction or a mental illness.  I don't understand all of the bluster about a diagnostic manual that clearly has not made a whit of difference since it was released or endless debates about conflict of interest that apply to a handful of physicians when this massive injustice exists and when clinical psychiatrists have to deal with it every day and many times a day.   I don't know who "we" refers to in the post, but I can say without a doubt that the technology and know-how is there to alleviate a significant degree of suffering for people with chronic and severe psychiatric disorders right now and at a very reasonable cost.  That cost will not be the few hundred dollars that it takes to see someone in 4 - 15 minute "med check" clinic visits a year and provide them with (now generic) medications.  No -  one year of care will cost about the same amount as a middle-aged person presenting to the emergency department with chest pain.  The reason why care for people with chronic severe mental illness is better in other countries is that there are no financial incentives in those countries for corporations to make money by denying care for the treatment of mental illness and addiction.  That is the cruel paradox in this country, not neuroscience research occurring at the expense of clinical care.  If a billion dollars was directed to clinical care in this country - my guess is that half of it would end up in the hands of the insurance industry rather than providing medical care.

The image of the "receding holy grail" of a future basic science breakthrough is certainly admirable rhetoric, but it is just that.   We have spent too much time rearranging the deck chairs of DSM technology.  Is there any informed person out there who thinks that it makes sense to keep rearranging diagnostic criteria, while clinicians basically focus on the same handful of disorders?  Is there any informed clinician out there who doesn't see the basic disorders as heterogenous conditions mapped onto unique conscious states?  With those basic premises there are just a couple of possible outcomes.   Continue pretending like the past two decades that everyone with these heterogeneous disorders can be treated the same way with a specific medication or type of psychotherapy.  The alternative is to look for specific subtypes based on more than clinical criteria that will produce better treatments with fewer side effects and better outcomes.  And since when is basic science research done in hopes of a clinical breakthrough?  Basic science research is hypothesis testing in the service of more science.  Science as the process that it is.  Any criticism that initially critiques terminology based psychiatry and suggests that it is a vehicle for the expansion of the pharmaceutical industry while suggesting that research funds should be directed at symptom control based on those crude definitions and research is internally inconsistent and defies logic.

I unequivocally applaud the past and current efforts of the Stanley Foundation.  At a time when mental health research and clinical services are subjected to intensive rationing efforts, it is inspiring when a private foundation comes forward in the face of all of those biases and makes an statement about how important this area of science is.  It is one thing to talk about stigma and quite another to come out and treat basic neuroscience and the associated disorders as seriously as any other major health problem.  Hopefully it will inspire others to provide grants for funding research and the development of clinical neuroscience programs that can be applied and taught to psychiatrists during residency training.



George Dawson, MD, DFAPA


1: Reardon S. Gene-hunt gain for mental health. Nature. 2014 Jul 22;511(7510): 393. doi: 10.1038/511393a. PubMed PMID: 25056042.

2:  Adam D.  Cause is not everything in mental illness.  Nature.  2014 Jul 30; 511(7511): 509

3:  Shorter E,  A History of Psychiatry.  John Wiley & Sons.  New York, 1997.