Real World Evidence and Cannabis Psychosis

 

As readers of this blog know – I am not high on cannabis.  That is based on my experience as an acute care psychiatrist and an addiction psychiatrist. That real world experience was associated with treating hundreds of people for exacerbations of preexisting psychotic disorders as well as seeing psychosis develop in people with no risk factors of family history of psychosis. A significant number of thise people need ongoing treatment for psychosis to stay out of the hospital.  Their course is complicated by cannabis use disorder.  Contrary to the hype – addiction can occur to cannabis with all of the associated problems.

Rhetoric is always a significant factor in the United States, especially when there are large sums of money at stake. Depending on who you read the $38.5B cannabis industry is part of the $1.8T health and wellness industry compared with the total pharmaceutical industry value of $602B.  For twenty years we heard about medical cannabis as though it was a miracle drug.  The first medical application of cannabis may have occurred in the second century AD when a famous Chinese physician mixed it with wine and used it as an analgesic.  The use of cannabis as an intoxicant preceded this medical use by about 800 years (1).  The rise of Taoism, Chinese culture, and the availability of alcohol and opium are thought to have limited its widespread use for that purpose. Hemp was also cultivated as a seed crop but that was supplanted by more effective seed crops much like medical use.  The 20^th century medical rhetoric always ignored that history. I attended many seminars where there was a discussion of the endogenous cannabinoid system as a backdrop to talking about medical applications.  In my home state there was a tortured effort to invent a system parallel to the FDA to approve medical cannabis for certain indications. I use the word tortured because the evidence including collected data was very thin to non-existent.  All of this was an obvious prelude to legalization of cannabis and being able to market it as an intoxicant. The psychiatric side effects and the fact that any intoxicant has major problems associated with it – were minimized. Common minimization rhetoric included the ideas that alcohol was much more dangerous, that cannabis-based crimes were discriminatory, and that the War on Drugs was a failure. There was also the idea that the United States was lagging behind the rest of the world in legalization, when it is only fully legal in 9 countries in the world.

That brings me to a recent paper characterizing the real-world evidence of antipsychotic use to treat cannabis induced psychosis.  I follow two of the authors of this paper (Tiihonen and Taipale) because they are experts in designing observational studies based on registry data that typically does not exist in the US.  In this case they selected a cohort of 1772 patient with a diagnosis of cannabis induced psychosis (CIP) from Swedish registry and insurance data between January 2006 and December 2021.  Exclusion criteria included any previous diagnosis of substance induced psychosis, schizophrenia, or bipolar disorder.  Medication data was collected according to the Anatomical Therapeutic Chemical (ATC) classification.  Medication exposure to antipsychotic and antimanic medications was based on exposures as prescription refills and less than 5 exposures was not counted as an exposure.  Additional psychiatric medications – antidepressants, medications for ADHD and addictions, benzodiazepines and related drugs were also extracted.  The resulting medication list from the supplementary information is listed below along with the effect on the primary outcome (rehospitalization for CIP) by Hazard Ratio.

	Events	Users	Person-years	aHR (95%CI)
Antipsychotics
No exposure	1892	1754	10617,19	Reference
Levomepromazine	30	131	49,64	0.92 (0.59-1.44)
Perphenazine	NA	NA	NA	NA
Perphenazine LAI	9	26	28,58	0.55 (0.25-1.22)
Haloperidol	35	125	69,09	1.01 (0.66-1.54)
Haloperidol LAI	14	22	18,37	1.14 (0.61-2.15)
Flupentixol	5	22	20,42	0.88 (0.31-2.50)
Flupentixol LAI	NA	NA	NA	NA
Zuclopenthixol	10	41	41,29	0.71 (0.32-1.61)
Zuclopenthixol LAI	26	47	45,7	0.77 (0.47-1.26)
Clozapine	28	54	119,25	0.56 (0.34-0.90)
Olanzapine	404	1013	1031,96	0.82 (0.70-0.96)
Olanzapine LAI	13	57	50,1	0.29 (0.16-0.55)
Quetiapine	91	385	405,41	0.94 (0.69-1.27)
Risperidone	72	261	210,27	0.91 (0.66-1.26)
Risperidone LAI	18	40	45,46	0.55 (0.28-1.10)
Aripiprazole	62	331	283,83	0.61 (0.43-0.88)
Aripiprazole LAI	15	69	83,45	0.26 (0.14-0.49)
Paliperidone LAI 1M	32	74	63,03	0.69 (0.45-1.08)
Paliperidone LAI 3M	6	8	10,39	0.43 (0.09-2.03)
AP Polytherapy	423	675	727,23	0.75 (0.64-0.89)
Cariprazine	5	19	9,32	20.88 (1.99-218.64)
Paliperidone oral	5	42	14,8	1.38 (0.48-3.95)
Other SG oral	NA	NA	NA	NA
Other FG oral	NA	NA	NA	NA
ADHD medications
No exposure	3127	1767	13312,32	Reference
Dexamfetamine	NA	NA	NA	NA
Methylphenidate	30	206	307,89	0.67 (0.41-1.11)
Modafinil	NA	NA	NA	NA
Atomoxetine	16	85	59,31	0.64 (0.32-1.26)
Lisdexamphetamine	27	168	223,14	1.10 (0.61-1.98)
ADHD polytherapy	NA	NA	NA	NA
SUD medications
No exposure	3145	1767	13749,18	Reference
Disulfiram	25	79	41,09	0.94 (0.48-1.82)
Acamprosate	NA	NA	NA	NA
Naltrexone	10	60	36,73	1.39 (0.55-3.50)
Buprenorphine	15	24	55,87	0.83 (0.27-2.56)
Methadone	11	17	68,81	3.05 (0.80-11.69)
Multiple SUD drugs	NA	NA	NA	NA
Antidepressants
No exposure	2704	1742	11565,26	Reference
Clomipramine	5	24	30,15	0.57 (0.15-2.12)
Amitriptyline	NA	NA	NA	NA
Nortriptyline	NA	NA	NA	NA
Fluoxetine	22	118	164,43	0.75 (0.41-1.34)
Citalopram	15	109	114,94	0.56 (0.29-1.10)
Paroxetine	12	30	50,26	1.60 (0.67-3.77)
Sertraline	104	447	538,89	0.75 (0.56-1.00)
Fluvoxamine	NA	NA	NA	NA
Escitalopram	60	249	277,43	1.03 (0.71-1.49)
Moclobemide	NA	NA	NA	NA
Mianserin	NA	NA	NA	NA
Mirtazapine	122	449	387,9	0.89 (0.69-1.15)
Bupropion	13	155	86,75	0.94 (0.48-1.82)
Venlafaxine	48	170	217,67	1.15 (0.75-1.76)
Reboxetine	NA	NA	NA	NA
Duloxetine	25	91	101,98	1.30 (0.75-2.27)
Agomelatine	<5	20	9,38	5.28 (0.41-67.42)
Vortioxetine	6	48	36,58	0.67 (0.26-1.73)
Rare antidepressants	NA	NA	NA	NA
Antidepressant polytherapy	65	364	364,42	0.93 (0.62-1.39)
Benzodiazepines and related drugs
No exposure	2817	1755	12756,76	Reference
Any benzodiazepine or related drug	390	732	1231,3	1.19 (1.01-1.40)
Mood stabilizers
No exposure	3020	1768	13280,77	Reference
Carbamazepine	11	41	42,23	0.93 (0.44-1.99)
Valproic acid	89	168	206,7	0.93 (0.70-1.25)
Lamotrigine	15	115	159,81	0.68 (0.34-1.37)
Topiramate	NA	NA	NA	NA
Lithium	60	107	217,85	0.98 (0.67-1.43)
Mood stabilizer polytherapy	8	66	64,51	0.46 (0.20-1.07)

 

The data was analyzed using a stratified Cox regression model.  The advantage to this model is that the assumption that hazard ratios are constant over time are restricted to the stratum occupied by each individual so that hazard ratios between strata may differ based on genetics, age and other factors but they are constant in each stratum.

Of the final sample 84.7% were men and the mean age of onset of the first diagnosis was 26.6 (± 8) years.  About half of the sample had work income at baseline but 5.4% had 90 days sick leave from work in the year before the study and 6.9% were on disability pensions.  

In terms of the primary rehospitalization endpoint – any antipsychotic use was associated with a decreased risk of readmission (aHR 0.75; 95%CI 0.67–0.84).  Some of the antipsychotics associated with less risk like aripiprazole, aripriprazole LAI, olanzapine, olanzapine LAI, and clozapine clozapine,  Any antipsychotic use also reduced the risk of secondary endpoints including hospitalization due to a medical problem (aHR 0.58; 95% CI 0.38–0.89) and hospital admission caused by a substance use disorder (aHR 0.78; 95% CI 0.71–0.87).

The authors include a Forest plot of antipsychotic medications and risk of relapse (see Fig 1.)  The SGA drugs olanzapine, clozapine, and aripiprazole had the best results in both LAI and oral short acting forms.  FGA drugs (pooled) and paliperidone, risperidone, and quetiapine (all SGAs) did not have a statistically significant result.

The authors conclude that AP drugs – especially the LAI version may be effective in preventing rehospitalization following an episode of cannabis induced psychosis – a condition that as a high risk of relapse.  The reduction in risk was about 72%.  Medication effectiveness mirrored effectiveness noted in psychotic disorders for clozapine.  FGA were less effective than noted in studies of first episode psychosis without cannabis use and this may be due to the small numbers being treated with these medications.  They speculate that the effectiveness of aripiprazole may be due to partial dopamine agonist activity with improved cognition and less craving.  They cite one of their previous papers suggesting that the combination of clozapine and aripiprazole may be the best to prevent relapse prevention in schizophrenia and substance use (3).     

In terms of limitations, the authors cite the small subject numbers in some of the studied groups.  They also lacked data on ongoing cannabis use if rehospitalization did not occur. It is always interesting to consider what an ideal randomized controlled clinical trial of this problem would look like.  At the minimum it would involve structured interviews for psychiatric diagnoses, detailed structured interviews on substance use, and possible toxicology screens and measures of medication adherence for oral medications (typically pill counts).  That may be a fundable grant at some point – but the current political atmosphere in the US suggests otherwise. This is a significant strength of the studies from this group.  As I noted in a recent post it also reflects the clinical experience of acute care psychiatrists in the US where substance use is a significant complication of care.   

 This is an excellent observational study of how cannabis use and cannabis use disorder complicates the lives of people. Obviously not everyone who uses cannabis is at risk for these complications – but if they occur and result in hospitalization and the prescription of medications for treating an ongoing psychosis that results in major life disruption and disability.  The less obvious disruption is how both psychosis and cannabis in can impair the insight of the affected individual. Psychosis generally leads to a conscious state where the affected individual cannot accurately assess how they are doing in the environment and take corrective action. With a cannabis use disorder, an individual can experience reinforced use by the biological properties of THC, and continue to use the substance despite negative consequences.  People with those impairments have a much harder time stopping cannabis use often despite very negative consequences.  That pattern of behavior is always a good reason to avoid intoxicants of any kind.  

George Dawson, MD, DFAPA

 

References:

1:  Booth M.  Cannabis – A History. New York. Picador, 2003: 23.

2:  Mustonen A, Taipale H, Denissoff A, Ellilä V, Di Forti M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J, Niemelä S. Real-world effectiveness of antipsychotic medication in relapse prevention after cannabis-induced psychosis. Br J Psychiatry. 2025 May 6:1-7. doi: 10.1192/bjp.2025.72. Epub ahead of print. PMID: 40326094.

3:  Tiihonen J, Taipale H, Mehtälä J, Vattulainen P, Correll CU, Tanskanen A. Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia. JAMA Psychiatry. 2019 May 1;76(5):499-507. doi: 10.1001/jamapsychiatry.2018.4320. PMID: 30785608; PMCID: PMC6495354.

Graphic Credit:

The table and figure used in the above post is taken directly from the authors Supplementary data and original paper per the CC license (reference 2):

Open Access article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.

Phenotypic diversity from dogs to diseases

 

Whether you are trying to keep your neighbor’s German shepherd out of your yard or avoiding that biting Chihuahua on your way to the mail boxes – people have no problem identifying domestic dogs. Most can tell they are not foxes, wolves, or coyotes. There are approximately 400 different domestic dog breeds worldwide – but they all have the same taxonomic classification.

All domestic dogs belong to the same genus and species according to Linnean classification and that is Canis familiarus.  The genus was established in 1758 by Linnaeus to include dogs, wolves (C. rufus, C. lycaon, C. lupus, C. lupaster, C. simnesis) , coyotes (C. latrans), and jackals (C. aureus).  Foxes belong to the genus Vulpes and there are 12 species. This genus forms a clade meaning that they are all descended from a common ancestor.

Domestic dogs can be traced back to 15,000 to 100,000 years ago when they were originally descended from the Gray Wolf in East Asia (1).  Breeding programs have been used to select specific physical and behavioral characteristics of domestic dogs that had led to the observed phenotypic diversity.  The domestication process in general has selected for genetic changes and associated changes at the neurobiological level.  High prevalence illnesses are observed in some dog breeds suggesting that there are heritable loci that could be studied and provide some guidance for human diseases.  Purebred dogs can also have extensive genealogies including family histories and pathology data. 

In terms of comparative genomics (1) there are 4 clades of placental mammals  Afrotheria: ( elephants, manatees, and hyraxes), Xenartha: (sloths, anteaters, and armadillos),  Euarchontoglires: Euarchonta (primates, tree shrews, colugos) + Glires (rodents and lagomorphs), and Laurasiatheria: (shrews, hedgehogs, bats, and other carnivores including dogs).  The most extensively studied mammals at the genetic level all belong to Euarchontoglires (human, chimpanzee, mouse, rat). More detailed information on the dog genome allows for analysis for sections of conserved human DNA, reconstruction of the genetics of a common ancestor between clades, and investigations into the nature of polygenically determined illnesses.

One of the most interesting aspects of reference 1 is the phylogenic tree of the family Canidae showing the relationships between different phyla. This tree was constructed looking at 12 exons (8,080 base pairs (bp) and 4 introns (3029 bp). They were sequences in 30 of the 34 Canid species.  Note where domestic dogs are on the diagram. The boxer photo is used because the boxer genome was the prototypical analysis in this paper because it has some of the longest stretches of homozygosity (62%).  In the diagram clades are color coded (see legend). Each cladogram is constructed with Bayesian analysis generating the respective bootstrap values from Markov chain analysis and posterior probabilities (see legend for location). Indels are insertions-deletions.  Divergence times are in millions of years and are applied to the wolf-like clade discussed in the paper (color coded blue).   

The authors constructed a map of 2,559,519 SNPs (single nucleotide polymorphisms).  They were able to determine the SNP rate for domestic dog breeds and other Canids (wolves and coyotes) and determined it was essentially 1 SNP per 900 (bp) base pairs for all the dog breeds studied except the Alaskan malemute (~1/790 bp).  Wolves and coyotes had greater variation than dogs suggesting a bottleneck during dog domestication.   The authors also demonstrated limited haplotype diversity within dog breeds.  The boxer genome was shown to have homozygosity over 62% of the genome with long blocks having the same haplotype on both chromosomes. The authors looked at the haplotype structure and linkage disequilibrium (LD) across 224 dogs – 10 each from ten breeds and one each from an additional 24 breeds. They used this analysis to construct a population genetics picture of dogs. Among the conclusions is that the dog genome is older (9,000 generations) than the human genome (4,000 generations).   

This is probably a good spot to briefly discuss homozygosity and why that is important.  In terms of experiments. It reduces interindividual variation based on genetics.  Laboratory rats for example have nearly identical genomes after 20 crosses (sib-sib, parent-offspring).  There is a previous post on this blog that discusses stochastics based on behavioral variation in rats with nearly identical genotypes. Dog breeding is a variation on that theme. Dogs do not have the same high degree of homozygosity but they are in the intermediate range.  The majority of dogs in the US are not pure bred but are of mixed heritage.  They can still inherit morphological and behavioral traits as well as genetically based diseases.   The human genome has a lower level of homozygosity due to widespread migration from a common ancestor about 150,000 years ago, a longer life span, as well as cultural constraints such as limits on consanguinity or marriage or a reproductive relationship between two closely related individuals. In the case of marriage by first cousins there is data on consanguinity rates between countries. The medical concern with this practice is that as homozygosity increased the risk of genetically determined autosomal recessive illness increases. Autosomal dominant conditions remain problematic but are not contingent on inheriting identical genes from both parents.   

Species	Homozygosity - same alleles inherited from each biological parent
Norwegian Rat Rattus norvegicus	1: Considered genetically identical at 20 generations of crossbreeding but some heterozygous alleles can be found out to 40 generations. (7) 2:  Rat breeds (phenotypes) are analogous to dog breeds – as an example the albino lab rat is still Rattus norvegicus. 3:  Experimental results on one inbred colony cannot be generalized to the next.
Domestic dogs Canis familiarus	1:  Degree of homozygosity varies with breed and specifics of breeding procedure for pure bred dogs.  Pure bred dogs – 63% homozygosity (10) Mixed breed dogs – 53% homozygosity (10)
Humans Homo sapiens	1: 11% homozygosity in individuals who parents were first cousins (consanguineous) compared with the expected value of 1 out of 16 or 6% (8) applying basic models 2:   Range of homozygosity in humans is wide based on evolutionary factors (bottlenecks, founder effects, inbreeding, outbreeding, background relatedness).  Runs of homozygosity (ROH) are studied more often than whole genome comparisons.

 

In summary, the genetics of domestic dogs is interesting just considering the phenotypic diversity of Canis familiarus.  It highlights issues of classification and that have been discussed in many places on this blog. Students of biology are familiar with these issues from practically every course they have ever taken.  That does not appear to be the case for people who never studied these problems.  Medicine and psychiatry as branches of biology have similar degrees of freedom on an individual basis and for classification purposes.  Any physician knows that no two persons with the same diagnosis are identical and yet there are scores of critics, administrators, politicians, and healthcare companies operating under that illusion. There are similar illusions about social constructs describing some subpopulations.  All humans are still Homo sapiens.  Further subclassification at the genomic or molecular level may be possible but it does not negate the meaning of the Linnean classification.  

In terms of temperament, personality, and behavioral characteristics correlations exist at the genetic level.  Since most of the behavioral traits are polygenic in nature – they have to be considered very early results.   

 There are probably as many advocates that claim a diagnosis has a simplified meaning that they are either advocating for or against.  Socially constructed classifications like race are more problematic.  The basic observation that hundreds of obviously different looking dogs belonging to the same genus and species may drive the phenotypic diversity point home.  The fact that these dogs breeds are also morphologically and behaviorally diverse as well as the fact that that develop unique diseases – provides a potential opportunity for studying morphology and disease mechanisms in humans. Despite suggestions about dog being potential models for human neuropsychiatric disorders that may be too strong of an association.  The research I did for this post was interesting from an evolutionary and genomic standpoint.  It highlights potential genetic and neurobiological effects of domestication as a selective breeding process.

Considering the application of a similar phenotypical diversity concept to complex diseases – why would we not expect hundreds of phenotypes?  Current analyses seem to suggest very simple phenotyping.  In the case of major depression – a single item from a rating scale – emotional blunting or anhedonia and genetic correlates. Other complex diseases like asthma, systemic lupus erythematosus, and diabetes mellitus have similar problems.  On the other hand, we can look at the combinatorics of the verbal descriptions of depression and how many of those combination exist in a clinical population and find 126 subtypes of depression. The question for me is why a handful of rating scale phenotypes of depression would exist and not 126 or more? The same is true for any psychiatric disorder. And of those 126 or more types – what is happening at the genetic and molecular levels?  The idea of a better classification based on some verbal hierarchy or rearranging the verbal descriptions does not seem promising to me.  The dilemma of trying to classify natural phenomena by words is always a limitation. There is no better example than biological classification.       

 

George Dawson, MD, DFAPA

 

 

Graphics Credit:  From reference 1 with permission - Copyright Clearance Center License Number 6004620929064

 

References:

1:  Lindblad-Toh K, Wade CM, Mikkelsen TS, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005 Dec 8;438(7069):803-19. doi: 10.1038/nature04338.

2:  Bergström A, Stanton DWG, Taron UH, et al. Grey wolf genomic history reveals a dual ancestry of dogs. Nature. 2022 Jul;607(7918):313-320. doi: 10.1038/s41586-022-04824-9. Epub 2022 Jun 29. PMID: 35768506; PMCID: PMC9279150.

3:  Spady TC, Ostrander EA. Canine behavioral genetics: pointing out the phenotypes and herding up the genes. Am J Hum Genet. 2008 Jan;82(1):10-8. doi: 10.1016/j.ajhg.2007.12.001.

4:  Parker HG. Genomic analyses of modern dog breeds. Mamm Genome. 2012 Feb;23(1-2):19-27. doi: 10.1007/s00335-011-9387-6. Epub 2012 Jan 10. PMID: 22231497; PMCID: PMC3559126.

5:  Hecht EE, Kukekova AV, Gutman DA, Acland GM, Preuss TM, Trut LN. Neuromorphological Changes following Selection for Tameness and Aggression in the Russian Farm-Fox experiment. J Neurosci. 2021 Jul 14;41(28):6144-6156. doi: 10.1523/JNEUROSCI.3114-20.2021.

6:  Rahim NG, Harismendy O, Topol EJ, Frazer KA. Genetic determinants of phenotypic diversity in humans. Genome Biol. 2008 Apr 24;9(4):215. doi: 10.1186/gb-2008-9-4-215. PMID: 18439327; PMCID: PMC2643926.

7:  National Research Council (US) International Committee of the Institute for Laboratory Animal Research. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington (DC): National Academies Press (US); 1999. Genetic and Phenotypic Definition of Laboratory Mice and Rats / What Constitutes an Acceptable Genetic-Phenotypic Definition. Available from: https://www.ncbi.nlm.nih.gov/books/NBK224550/

8:  Woods CG, Cox J, Springell K, Hampshire DJ, Mohamed MD, McKibbin M, Stern R, Raymond FL, Sandford R, Malik Sharif S, Karbani G, Ahmed M, Bond J, Clayton D, Inglehearn CF. Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet. 2006 May;78(5):889-896. doi: 10.1086/503875. Epub 2006 Mar 21. PMID: 16642444; PMCID: PMC1474039.

9:  Bell JS.  Genetic diversity.  Accessed on March 24, 2025 https://www.akcchf.org/assets/files/Genetic-Diversity_Bell-2021.pdf

10:  Pemberton TJ, Absher D, Feldman MW, Myers RM, Rosenberg NA, Li JZ. Genomic patterns of homozygosity in worldwide human populations. Am J Hum Genet. 2012 Aug 10;91(2):275-92. doi: 10.1016/j.ajhg.2012.06.014. PMID: 22883143; PMCID: PMC3415543.

11:  Shearin AL, Ostrander EA. Leading the way: canine models of genomics and disease. Dis Model Mech. 2010 Jan-Feb;3(1-2):27-34. doi: 10.1242/dmm.004358. PMID: 20075379; PMCID: PMC4068608.

12:  Amfim A, Bercea LC, Cucu N. Canine Genetics and Epidemiology of Behavior in Dogs. Epizootics-Outbreaks of Animal Disease: Outbreaks of Animal Disease. 2025 Feb 5:105.

13:  Ilska J, Haskell MJ, Blott SC, Sánchez-Molano E, Polgar Z, Lofgren SE, Clements DN, Wiener P. Genetic Characterization of Dog Personality Traits. Genetics. 2017 Jun;206(2):1101-1111. doi: 10.1534/genetics.116.192674. Epub 2017 Apr 10. PMID: 28396505; PMCID: PMC5487251.

14:  Friedrich J, Strandberg E, Arvelius P, Sánchez-Molano E, Pong-Wong R, Hickey JM, Haskell MJ, Wiener P. Genetic dissection of complex behaviour traits in German Shepherd dogs. Heredity (Edinb). 2019 Dec;123(6):746-758. doi: 10.1038/s41437-019-0275-2. Epub 2019 Oct 14. PMID: 31611599; PMCID: PMC6834583.

15:  Handegård KW, Storengen LM, Joergensen D, Lingaas F. Genomic analysis of firework fear and noise reactivity in standard poodles. Canine Med Genet. 2023 Mar 8;10(1):2. doi: 10.1186/s40575-023-00125-0. PMID: 36890545; PMCID: PMC9996964.

16: Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, Lohmueller KE, Zhao K, Brisbin A, Parker HG, Vonholdt BM, Cargill M. A simple genetic architecture underlies morphological variation in dogs. PLoS biology. 2010 Aug 10;8(8):e1000451.

17:  Morrill K, Chen F, Karlsson E. Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics. Human Genetics. 2023 Aug;142(8):1231-46.

18. H. J. Noh et al., Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nat. Commun. 8, 774 (2017). doi: 10.1038/s41467-017-00831-x; pmid: 29042551

19. N. H. Dodman et al., A canine chromosome 7 locus confers compulsive disorder susceptibility. Mol. Psychiatry 15, 8–10(2010). doi: 10.1038/mp.2009.111; pmid: 2002940820

20. K. L. Overall, Natural animal models of human psychiatric conditions: Assessment of mechanism and validity. Prog. Neuropsychopharmacol. Biol. Psychiatry 24, 727–776 (2000). doi: 10.1016/S0278-5846(00)00104-4; pmid: 11191711

Preventing Dementia and Blood Pressure Control

 

A paper came out last week (1) that showed blood pressure control was an effective way to prevent dementia.  One of the most effective ways to prevent stroke is to control blood pressure.  Elevated blood pressure also causes blood vessel damage that can lead to dementia – even in the absence of a clearcut stroke. In one of my clinics, we assessed people with various forms of dementia and it was striking how many people had these kinds of changes on their CT or MRI scans and were unaware of them. In some cases, there was a history of uncontrolled blood pressure like eclampsia during pregnancy that probably resulted in brain changes seen decades later that was not investigated at the time.  Substance use problems, undiagnosed forms of transient hypertension, and substance use problems with intoxication and withdrawal associated hypertension are other possibilities.

The study in question was an interventional study across 163 villages in China and a total of 33,995 research subjects. Inclusion criteria into the study was ≥40 years of age with a mean untreated SBP ≥140 mm Hg and/or a DBP ≥90 mm Hg (or ≥130 mm Hg and/or ≥80 mm Hg among those with clinical CVD, diabetes or chronic kidney disease) or a mean treated SBP ≥130 mm Hg and/or a DBP ≥80 mm Hg, based on six measurements taken on two different days. Additional details are available in the paper on online supplementary information.  Patients were treated across the study by physician supervised non-physician community healthcare providers (NPCHPs).  Research subjects were randomized into treatment as usual (TAU) or non-protocol-based treatment for hypertension and protocol-based care. In the protocol-based care patients received first line antihypertensives like angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretic or diuretic-like medications. The treatment group also got free blood pressure medication, lifestyle coaching, and home blood pressure monitors but the TAU group did not.

The primary outcome measures for this intervention study were the presence of dementia and cognitive impairment no dementia (CIND).  Both diagnoses were made by expert panels of neurologists using standardized criteria.  Screening tests were administered at clinic visits to assess cognition, instrumental activities of daily living, and symptoms of dementia in a standard way. 

On the main outcome measures the blood pressure intervention group had a 15% lower risk of dementia and a 16% lower risk of CIND compared with the TAU group.  Those numbers are consistent with an additional meta-analysis done by the authors of similar trials and a previous meta-analysis of blood pressure interventions to prevent dementia.

Strokes are the usual obvious consequences of blood pressure problems and they come in two forms – hemorrhagic and ischemic. Hemorrhagic strokes generally occur through a ruptured blood vessel in the substance of the brain or the subarachnoid space.  Because blood is under very high pressure in the brain that jet can cause additional damage.  In many cases clots form and they can be associated with edema and pressure in the brain. Symptoms can vary from an intense headache to signs of cerebral edema or coma and death.  Ischemic strokes consist of blood vessel occlusion or reduced blood flow to the point that there is inadequate blood supply to neurons. This can occur as the result of ruptured plaques, emboli, or mechanical disruption of the blood vessel.  The emboli can be the result of plaque formation in blood vessels as well as blood clots due to other diseases like atrial fibrillation.  Atrial fibrillation can also be caused by hypertension.

During my teaching seminars on dementia and vascular subtypes – I generally taught about vascular subtypes as cortical or parenchymal infarctions due to major blood vessels (yellow areas on the above diagram), lacunar infarctions due to damage to long perforating arteries to the striatum (pink area), and small vessel ischemic disease or Binswanger’s Disease (BD) due to deep arterioles supplying the subcortical white matter (blue area).  Although BD was described in 1895 it has been a controversial diagnosis that has not been clarified by modern brain imaging and the presence of white matter changes ofet referred to as “white matter ischemic changes” by radiologists.  The diagnosis is also complicated by the fact that many patients has features of both Alzheimer's Disease (AD) and BD and in some cases AD, BD, and small infarctions at autopsy.  If there is any confusion about the diagnosis, a history of hypertension, previous treatment for hypertension, a review of all previous brain imaging, and the clinical pattern of changes in cognition and functional capacity should all be described.   

I am restricting my comments in this post to how hypertension results in dementia so I will not comment on the differential diagnosis of stroke.  Elevated blood pressure can also cause blood vessel damage that is not due to a rupture or embolism.  Prolonged hypertension can cause inflammation in long blood vessels supplying the striatum and periventricular white matter in the brain.  The specifics of that process are being actively studied at this point but damaged is hypothesized to occur because of endothelial cel dysfunction as well as compromise of elastin a connective tissue protein in blood vessels leading to inflammation and narrowing or expansion of blood vessels.  The inflammatory process can lead to further changes and result in a compromised blood-brain barrier and progressive narrowing of those blood vessels.  Eventually the circulation is compromised resulting in the death of neurons visualized as volume loss and white matter changes on imaging studies.   

There seems to be very little work done on the actual pressure signaling at the level of the blood vessel.  Many physiological studies and reviews are focused on overall blood pressure effects and the effect of pressure waves within the vascular system. There are other determinants of endothelial dysfunction including the effects of aging, toxins like tobacco smoke, intercurrent diseases, and metabolic/nutritional factors like blood glucose, lipids, and uric acid.  Epidemiological data supports resting blood pressure and pulse pressure as being significant factors leading to endothelial dysfunction and atherosclerosis.

The modern approach to treating the problem of endothelial dysfunction leading to cardiovascular and cerebrovascular disease is to address all the risk factors.  Hypertension, smoking, diabetes mellitus, metabolic syndrome and obesity, dyslipidemia, and substance use including alcohol all need to be addressed. Many psychiatrists might see this as a primary care problem – but given the way health care is rationed these days a psychiatrist may be the only physician that the patient is seeing on a regular basis.    

That provides the opportunity to collect data like weight, blood pressure and pulse, as well as metabolic parameters if needed. One of my previous posts discusses the issue of blood pressure parameters and white coat effect, and white coat hypertension. The previous thinking was that a lot of people get hypertensive just from the stress of being in a physician’s office.  Some research backed that up showing no difference in outcomes. That research had the same design problems as research about the safety of alcohol.  The control group contained people with cardiovascular diseases and treatment for hypertension. The practical way to address this issue is to advise the patient to check their blood pressure at home with an approved device. Many of these devices can download data into a smartphone app for easy storage.  Home blood pressure monitoring is also useful to detect Transient blood pressure increases due to physical or emotional stress. Although it has not been well studied – this kind of blood pressure reactivity probably needs to be addressed since acute and chronic increases irrespective of etiology are a problem.  

Age is one of the most significant risk factors for dementia. As the incidence of dementia increases with more survivors into old age – there are early interventions that can prevent it from happening.  Good blood pressure control happens to be one of them. 

George Dawson, MD, DFAPA

Supplementary on Binswanger:

Otto Binswanger (1852-1929) was a Swiss physician.  Like many brain specialists of the day he was variously described as a psychiatrist, neurologist, and neuropathologist. He identified as being a psychiatrist primarily but in those days before board certification psychiatry was a much broader field. Both Freud and Meyer had similar qualifications. He is sometimes confused with his nephew Ludwig Binswanger (1881-1966) who was one of the leading researchers of the existential psychiatry movement.  He described “encephalitis subcorticalis chronica progressive” while attempting to differentiate types of dementia from dementia caused by tertiary syphilis that was called general paresis of the insane or GPI at the time.  GPI was a very common reason for institutionalization at the time accounting for 20% of admission and 34% of the death in asylums in the 19^th and early 20^th century before the advent of antibiotics.

Binswanger’s description was controversial up to modern times and I will try to capture that in the graphic below.  The original description was published in 3 issues of a trade paper rather than a medical journal.  It is often critiqued as being long, rambling, and not publishable by today’s standards.  I think that criticism has the benefit of the retroscope since most papers at the time would have similar difficulties.  

Supplemental references on the Binswanger graphic according to those dates:

1894:  Blass JP, Hoyer S, Nitsch R. A translation of Otto Binswanger's article, 'The delineation of the generalized progressive paralyses'. 1894. Arch Neurol. 1991 Sep;48(9):961-72. doi: 10.1001/archneur.1991.00530210089029. PMID: 1953422.

1910:  Dening TR.  Stroke and other Vascular Disorders – Clinical Section.  In: A History of Clinical Psychiatry. Berrios G, Porter R (eds). New Brunswick.  The Athlone Press. 1995: 72-85.

1910:  Nicolson M.  Stroke and other Vascular Disorders – Social Secition. In: A History of Clinical Psychiatry. Berrios G, Porter R (eds). New Brunswick.  The Athlone Press. 1995: 86-94

1986:  Esiri MM, Oppenheimer DR.  Diagnostic Neuropathology. Blackwell Scientific Publications, London, 1896.

1994:  Hansen LA. Pathology of Other Dementias.  In:  Alzheimer Disease.  Terry RD, Katzman R, Bick KL (eds). New York. Raven Press. 1994: 167-196.

The discussion of neuropathology in this text and the subsequent edition is superior to what is seen in general pathology texts and some neuropathology texts.

Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993 Feb;43(2):250-60. doi: 10.1212/wnl.43.2.250. PMID: 8094895. 

2025:  Bir SC, Khan MW, Javalkar V, Toledo EG, Kelley RE. Emerging Concepts in Vascular Dementia: A Review. J Stroke Cerebrovasc Dis. 2021 Aug;30(8):105864. doi: 10.1016/j.jstrokecerebrovasdis.2021.105864. Epub 2021 May 29. PMID: 34062312.

 

References:

1:  He J, Zhao C, Zhong S, Ouyang N, Sun G, Qiao L, Yang R, Zhao C, Liu H, Teng W, Liu X, Wang C, Liu S, Chen CS, Williamson JD, Sun Y. Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial. Nat Med. 2025 Apr 21. doi: 10.1038/s41591-025-03616-8. Epub ahead of print. PMID: 40258956.

2:  Supplementary Information for Reference 1 (see Supplementary Table 7. Meta-Analysis of Randomized Controlled Trials of Antihypertensive Treatment on Dementia) for results of 5 additional RCTs of hypertension treatment in dementia.  https://www.nature.com/articles/s41591-025-03616-8#Sec23

3:  Franklin SS, Thijs L, Hansen TW, O'Brien E, Staessen JA. White-coat hypertension: new insights from recent studies. Hypertension. 2013 Dec;62(6):982-7. doi: 10.1161/HYPERTENSIONAHA.113.01275. Epub 2013 Sep 16. PMID: 24041952.

4:  Lockhart SN, Schaich CL, Craft Set al. Associations among vascular risk factors, neuroimaging biomarkers, and cognition: Preliminary analyses from the Multi-Ethnic Study of Atherosclerosis (MESA). Alzheimers Dement. 2022 Apr;18(4):551-560. doi: 10.1002/alz.12429. Epub 2021 Sep 5. PMID: 34482601; PMCID: PMC8897510.

Listening with the Third Ear….

 

I joined a group co-teaching a resident seminar in psychotherapy a few weeks ago.  It is an interesting exercise blending didactics and experience.  The format is an hour of psychodynamic focused didactics followed by an hour-long discussion of a transcript by everyone in attendance including residents and 4 faculty. That is an interesting discussion of the technical aspects of therapy as well as individual differences in interpretation and intervention.

Today’s session was about listening and how listening in therapy may be different from what people consider to be typically focused or unfocused listening.  There was some discussion of how you listen to friends as opposed to strangers.  There was a secondary discussion of the depth of listening with a focus on unconscious determinants.  It led me to reflect on a couple of things during the session.

The first was focus.  Very early in my discussion with patients I was focused on what they were saying.  My focus was the same focus I would have with friends or family even though none of my patients would ever enter that sphere. People knew that I was serious and took them seriously.  As I thought about the way I interacted with people over the years – it was apparent that even though patients are technically not friends within a very short period, I would know more about them than I knew about most of my friends.  In some cases, I was more worried about them and spent more time worrying about them than I ever worried about most of my friends. The difference was in the relationship.  With friends there is a mutual affiliation and expectation of support.  In the case of patients – the relationship is for the benefit of the patient. Apart from payment, the gratification of doing good work,  and the occasional thank you -  the therapist should expect nothing back from the patient. 

The focus in both diagnostic interviews and psychotherapy was meditative to me.  I felt extremely comfortable in that setting.  I looked forward to seeing people.  It was the place in life where I felt the most comfortable. I was not particularly interested in one problem compared with another – just hearing every unique story.  When you get to a certain point in your career you are full of confidence.  You no longer have to worry about running into an issue that you don’t know how to address. You know that most people will leave your office feeling better than when they entered – even if it is an initial evaluation. 

Focus in a psychiatric interview is multifaceted.  It involves hearing both the content of what is being said and whether it makes any sense.  Do all the elements hang together in a cohesive picture or not?  If not, the job is to immediately clarify what is happening.  That always leads me back to think of an Otto Kernberg seminar that I attended 30 years ago.  Kernberg described the process of confrontation as exactly that – an indirect inquiry that would facilitate bringing these seemingly disparate elements together.  An extreme example that I frequently use is from acute care settings.  In those settings, my first task of the day was to interview people who had been admitted on involuntary holds.  They were often very angry to be hospitalized and demanded to be released. Their first words were typically: “I want you to discharge me.  You have no right to hold me in this hospital and I want to be discharged.”  The reality is that I had never seen the patient before.  I had nothing to do with how they came into the hospital or the fact that they were on an involuntary hold. Restating those facts to the patient was the type of confrontation Kernberg discussed and it most frequently led to a more productive reality-based conversation.

The focus for me always has the elements of attention, testing what is being said against my internal knowledge of reality and doing the same with any emotional content, and thinking about underlying theories for what I am seeing. At times I will explicitly ask the patient for their theories about what is happening to them to see if they have any and if they do whether they are plausible.  It is generally important to try to figure out the meaning of certain patterns of thought and behavior including dreams fantasies, and other potential unconscious content.

There is also a focus of kindness toward the patient.  The relationship is one of beneficence.  It always reminds me of Jerry Wiener’s comments about the essence of psychotherapy “Be kind and say something useful to the patient.” When I bring that up – many therapists bristle at the apparent oversimplification.  Kindness does get directly to the point that the therapeutic relationship is different from the patient’s perspective in that they should experience the therapist as unique relative to the common experiences in their life. Some therapists I have encountered over the years have talked about “reality therapy” to mean that the therapist should be reacting to what the patient does just like everybody else.  This misses one of the main advantages of psychotherapy as an opportunity to examine what is really going on in those other relationships and correct it if necessary.        

I addition to attending to the primary problem in sessions the therapist must also have a focus on the relationship and empathic responses to communicate to the patient that he had an adequate understanding of the mental problem that the patient is describing and what all the elements may be.  The relationship aspect may include the stimulus value of the therapist and how that varies with age, sex, physical appearance, and communication style.  To cite age as an example – it is common for early career psychiatrists just out of residency to be greeted with: “You are too young to be a psychiatrist.  I have never seen a psychiatrist as young as you are”. Those statements come with varying degrees of enthusiasm and carry several implications that can be explored.  On the other end of the spectrum I have not had anyone comment on my advanced age directly – but have heard comments that some doctors are so old “they did not know I was in the room.” 

Transference and countertransference are obviously relevant here but I want to stay with the focus in interviews and sessions.  In the seminar today, a paleontology metaphor was described about mining the different layers of the unconscious and how to get there.  That suggests a lot of heavy lifting to me. I see it as a much more dynamic situation.  After all – here I am extremely comfortable and interested listening to people and editing their comments for plausibility, cognitive and emotional content, defensive patterns, and their own theories about what may be happening to them.  Together we are defining what brought them in to see me along with all the relevant cultural, social, biological, and developmental factors.  This is all unfolding in the context of a specially defined relationship.  Throughout that session I am switching between listening mode and an interventional mode that involves supportive, clarificatory, and interpretive remarks.  That switching needs to be dynamic, context based, and is not the same for any two patients.  There is also the practical or real relationship including payment arrangements, appointment times, call instructions, and emergency contact instructions.

There is a check that must happen during or between sessions. Every therapist has to ask if they really understand what this patient is saying and if the patient is being helped.  That check can occur as early as the first interview.  In some cases, the therapist may consider the patient’s problem to be outside of their field of expertise. This can also happen after prolonged therapy where the benefit to the patient is uncertain – but they want to continue the therapy.

The title of this blog post refers to a famous book called Listening with the Third Ear by psychoanalyst Theodor Reik. I purchased the book in 1986 on the recommendation of one of my psychotherapy supervisors.  The subtitle of the book says it all: “the inner experience of the psychoanalyst.”  Reik was one of Freud’s first students.  In the chapter “The Third Ear” he describes attending to various cues of the unconscious life of the patient as well as what may prevent the analyst from perceiving them. He illustrates how the subjective reaction of the analyst to the patient can be one of those clues.

Reflecting on this essay so far – the one dimension that needs additional commentary is the non-linear nature of listening and the interview process. It is easy to think of the process as a matrix dependent on focused attention and a long sequence of questions.  That is the format of a structured interview. In many cases these interviews are algorithmic based on hierarchies and inclusion and exclusion criteria.  In a clinical and psychotherapy setting the focus is more on all aspects of the presenting problem. What the patient brings in to the session and the continuity over multiple sessions is more of a priority. Reik describes a patient who caused him to feel annoyed, two different patients walking by a mirror outside his office and how they react to the mirror, and the way a patient looked at him as well and what that meant for their unconscious life. 

In a subsequent chapter he goes on to describe how the analyst must avoid selective attention to what they might want to hear and how they must attend to everything.  He points out that Freud used the term gleichschweben  that has the connotation of equal distribution and revolving or circling (p. 157).  He suggests the terms freely floating and poised attention.  He adds Freud’s rationale for this type of attention as being two-fold.  First, it avoids exhaustion since it is impossible to attend to anything for an hour.  Secondly, it avoids biasing the interview or session toward a particular aim or goal.  The session after all is directed at what the patient is deciding is relevant.

As I revisited my technique, this captures what I tend to do in interviews and sessions. Since I read this book nearly 40 years ago – I cannot claim to have invented it.  I can add a little to what Reik and Freud have to say especially in diagnostic interviews.  It is possible to incorporate free-floating attention and transition to a more structured interview as necessary. Most psychiatric practices these days require that psychiatrists seen anywhere from 2 to 5 new patients per day.  Most of those patients will not be seen in either psychoanalysis or psychodynamic psychotherapy. But most of those patients will benefit from the listening techniques and interventions that can be attributed to the early analysts. It is also possible to add a psychotherapy component to practically every patient seen by a psychiatrist over time – even in relatively brief appointments.  

 

George Dawson, MD

 

References:

Reik T.  Listening with the Third Ear. Farrar, Strauss, and Giroux. Toronto. 1948: 144-172.

 

Supplementary 1:  Both Drs. Otto Kernberg and Jerry Wiener in the above essay are psychoanalysts with extensive teaching and publication experience. They are both medical doctors.  I left the qualifications out for the sake of brevity. I heard Dr. Wiener’s remarks at one of the Aspen Psychotherapy Conferences organized by Jerald Kay, MD.   

Supplementary 2: According to Reik, The metaphor listening with the third ear was borrowed from Nietzsche -  Beyond Good and Evil, part VIII, p.246.  A partial excerpt follows:

"What a torture are books written in German to a reader who has a THIRD ear! How indignantly he stands beside the slowly turning swamp of sounds without tune and rhythms without dance, which Germans call a "book"! And even the German who READS books! How lazily, how reluctantly, how badly he reads! How many Germans know, and consider it obligatory to know, that there is ART in every good sentence--art which must be divined, if the sentence is to be understood! If there is a misunderstanding about its TEMPO, for instance, the sentence itself is misunderstood!..."