Are there potential problems in the latest study on antipsychotic medication reduction and discontinuation?

 

A study on antipsychotic medication reduction and discontinuation came out yesterday with fanfare.  The fanfare was basically because the principal investigator is a self-proclaimed critical psychiatrist with many criticisms of psychiatric medication and the results of her trial contradicted the primary hypothesis of the study and that was:

“Our hypothesis was that antipsychotic reduction would improve social functioning with only a small increase in relapse rate.”

Relapse rate in this case was defined as rehospitalization and the authors subsequently state that they thought a 10% rate of relapse would be “acceptable.”  The irony of this situation (ideology versus real world treatment) was not lost on anyone. Several people seemed to congratulate the authors on publishing results inconsistent with their ideology although the study was so embedded in the UK research infrastructure – I doubt that not publishing it would have been an option.

As a clinical trialist myself – the research seems to present several problems and creates several questions that could suggest that it was designed to optimize the likelihood that antipsychotic medication could be reduced and possibly discontinued. Before I get into those scenarios let me briefly summarize the results.  The paper is open access and can be downloaded as well as another paper that describes the research protocol.

In the study there were two arms an antipsychotic maintenance arm (N=127) and a reduction arm (N= 126). Diagnoses were taken from clinical information and the clinical staff had treatment responsibility for the patients.  In those patients who were randomized to dose reduction, a tapering protocol was suggested to the clinical staff and if it went well at some point the option for a more rapid taper or discontinuation was offered.  The research staff monitored the protocol. Baseline and outcome measure included a number of checklists to assess side effects, sexual side effects, positive and negative symptoms, quality of life, and social outcomes at the reassessment points.  Raters were blinded but the measures are essentially self report.  The ultimate result was that the risk of adverse outcomes was worse in the reduction arm with no associated improvement in social functioning.   

He are some potential issues that I noticed based on my experience in clinical trial design and on research review boards.

1.  Recruitment – described in the following:

“Participants were recruited from 19 National Health Service Trust mental health organisations across England. Potential participants were identified initially by clinical staff or recruited through advertisements placed in clinical settings and social media; those patients who expressed an interest in participating were sent further information”.

Not enough information. What did the advertisements say? Were subjects aware of who was running this trial and what the goal of the research was? Were the patients asked why they were interested in participating in this trial?  Were they asked what they think about taking a medication? Did the subjects have any exposure to the considerable press that the critical psychiatry group and the principal investigator generate?  Descriptions in the lay press have been demonstrated to have significant effects on perceived side effects – even to the point of creating a nocebo effect (6) – is there any reason to think that a group emphasizing side effects and minimizing any therapeutic effects might have a similar impact? If that is the case – how would it affect this trial?  

2.  Inclusion/Exclusion criteria –

“Exclusion criteria included being considered by a clinician to pose a serious risk of harm to self or others were the individual to reduce their antipsychotic medication, being mandated to take antipsychotic medication under a section of the Mental Health Act, having been admitted to hospital or treated by a crisis service for a mental disorder within the last month, lacking capacity to consent, having insufficient spoken English, pregnancy, breastfeeding, and being involved in another trial of an investigational medical product; eligibility was assessed by researchers and confirmed by the Principal Investigator for the site.”

Practically all the exclusion criteria result in a population that may be more likely to discontinue antipsychotic medications with less difficulty. Consistent with this is the antipsychotic doses of both the reduction and maintenance arm of 300 mg chlorpromazine equivalents (on average).  According to the Maudsley Prescribing Guidelines (4) 300 mg chlorpromazine is considered the minimally effective dose of medication for relapsing schizophrenia. Whether this was a representative sample of the 4109 patients put forward for research by clinicians a comparison of the demographics and medication doses would have been of interest.  

Selection bias may also be evident in the Consort diagram (page 4).  After subjects consented to be contacted by the research team (N= 958) – a total of 562 declined participation. Was that because they did not want to take the chance of randomization to a medication reduction?

3.  Diagnoses – the diagnosis required was schizophrenia or non-affective psychoses with recurrent episodes. The diagnoses were taken from clinical records.  Considerable heterogeneity is introduced with the non-specific category of psychoses with an unpredictable course for which the concept of maintenance medication was not intended.  

4.  The Dose Reduction - 

The description of the dose reductions in the paper is confusing.  It starts out describing individualized reductions every 2 months based on starting doses but at some point states the patient is allowed to discontinue the medication if the dose reduction has been going well or reduce at a rate of the equivalent of 2 mg haloperidol/day.  2 mg/day of haloperidol is not a slow reduction and it is a departure from reduction every 2 months. Some of the authors here have written about antipsychotic withdrawal reactions – how is the more rapid dose reduction or optional abrupt discontinuation justified? 

4.  Safety Monitoring/Informed Consent: 

The more clinical trials I read (and I have read thousands) – the more I want to see the consent form that each patient signs. Some of the authors here continuously talk about medication side effects.  In fact – the principle investigator (PI) has stated that in her opinion that modern psychiatric medications work in a "drug centered" rather than a disease centered model by producing side effects like sedation, cognitive impairment, dysphoria, and loss of libido (5).  In that model, symptoms of mental illness are muted by side effects rather than effectively treated. The model essentially denies the possibility of effective treatment without medication side effects.  Of course, there are medication side effects but consent forms also must contain a discussion of the risks of the intervention. How are they listed when the investigators do not believe they can be directly addressed?  Were the subjects told about the risk from medication discontinuation of recurrent psychosis, suicidal thinking, and death?  That seems especially relevant in a study where the intervention arm had twice as many deaths as the maintenance arm (see Table 4).

Along those same lines – the protocol paper for the study (2) states that a Data Safety and Monitoring Board (DSMB) assessed the ongoing safety of the protocol and made recommendation to a Programme Steering Committee providing independent oversight – even to the point of stopping the protocol if there was a substantial increase in adverse events related to the intervention. Was there a threshold? In this case why was that threshold not met?  In the trials I have been involved with the PI and the physician responsible for monitoring safety (typically me) had to clearly delineate a safety plan if any of the research subjects developed medical or psychiatric complications from the intervention.  In this case that responsibility seems to have been delegated to the clinicians originally treating the patient.

In the reported causes of death of the trial participants – how is the death of a research subject in the reduction arm attributed to antipsychotic medication when they have been on a low dose, were being followed clinically in an outpatient clinic, and their dose was presumably being reduced?  One patient in each arm died of an “accidental overdose”. What medication was implicated in the accidental overdoses?

This protocol is also a case of shifting risk for the research to the clinicians.  Here the research staff designs an intervention that likely will lead to worsening clinic status and the subjects are followed in a treatment as usual manner. Were any additional safeguards in place for that eventuality?  For example – were the subjects informed that they could contact the principal investigator or research coordinator if things were not going well?

These all seem like significant safety questions to me.

5.  Social Functioning Scale (SFS) to measure the primary outcome - 

The measured results with this scale are in the top line of Table 2 at 6, 12, and 24 months.  The scale has 79 items that are assigned to assess social functioning.  Is there a problem with taking a cross sectional sample of people stabilized on medications and hypothesizing they will function better being tapered off antipsychotic medication? There is an obvious problem and that is there is no accounting for the improvement in social functioning due to the medication in the first place. In other words - what would the subjects have scored leading up to and during the episode of acute or recurrent psychosis - the reason they are taking the medication in the first place. What would the trajectory of these scores be over time? Stabilization of psychosis involves a lot more than treating hallucinations, delusions, and thought disorder symptoms.  With stabilization there is an improvement in social behavior.  The design of the trial suggests that the problem began with medications rather than a significant psychiatric disorder. 

There is a concept in clinical psychiatry and that is trying to get the patient as close as possible to their baseline level of functioning. That requires a knowledge of what they were like before the onset of illness and restoring as much functional and social capacity as possible. That also typically means minimal to no medication side effects if possible.

6.  What is supported reduction of antipsychotic medication?

Is there a protocol that I missed?  I could not find what this means anywhere in either the protocol or final paper or in the supplementaries.  If I was tapering an antipsychotic medication I would meet more frequently with the patient, inform them of what we need to watch for, have additional caregiver and family involvement, and encourage them to call me at specific signs of early problems due to the dosage reduction. In a research protocol, research staff would call and check on how the subject was doing. I would call all of that treatment as usual (TAU) when it comes to antipsychotic medication reduction. Is supported reduction more than that?  Even TAU has been implicated as a potential placebo enhancing effect. Did it have that effect on the intervention in this case?

7.  The overstated conclusion:

“Our findings provide information for people with schizophrenia and related conditions about the probable medium-term impact of reducing the dose of their antipsychotic medication, and they highlight the need for collaborative decision making based on the sharing and careful consideration of all the evidence.”

Actually, it doesn’t.  This is what clinical psychiatrists do and more specifically it is what I did for 35 years of practice. I can still recall community psychiatry seminars with Len Stein, talking about dosage reductions of antipsychotic medications and the implication of a WHO international study looking at that problem in schizophrenia.  That seminar was in 1986. Collaborative decision making seems to be the latest term for informed consent and therapeutic alliance. Informed consent means that the patient is given enough information and discussion so that they can make a decision about the direction of their care including any medications, tests, or other interventions used. The therapeutic alliance is the affiliative relationship between the patient and physician aligned to address the patient's problems and diagnoses.  It is by longstanding definition a collaboration.

What the authors did encounter but did not discuss was the tendency of people on antipsychotics to just discontinue them (several in the maintenance group did this), how much withdrawal was encountered, and why there were no group categorical differences in side effects with the taper.  According to the Glasgow Antipsychotic Side-effect Scale (GASS) guidelines all subjects remained in the moderate side effect range. And if medications work through side effects as the critical psychiatrists say why did the subjects in the dose reduction group worsen?   

Those are a few of the problems that jumped out at me as I read this paper and the associated backgrounder. As can be seen from the above discussion many of these design factors potentially optimize the intervention group in the direction of proving the authors’ hypothesis. It also limits generalizability to other clinical settings.  That makes the result of the trial even more significant.  It also raises some issues that seem more prominent in recent years as pharmaceutical conflict of interest seems to ring hollow.  Is there an ideological conflict of interest and how is it determined?  How does it affect research design, results, and the discussion of research findings?  

 

George Dawson, MD, DFAPA

 

References:

1:  Moncrieff J, Crellin N, Stansfeld J, Cooper R, Marston L, Freemantle N, Lewis G, Hunter R, Johnson S, Barnes T, Morant N, Pinfold V, Smith R, Kent L,  Darton K,  Long M, Horowitz M, Horne R, Vickerstaff V, Jha M, Priebe S.  Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial. Lancet Psychiatry September 28, 2023DOI:https://doi.org/10.1016/S2215-0366(23)00258-4.

2:  Moncrieff J, Lewis G, Freemantle N, Johnson S, Barnes TR, Morant N, Pinfold V, Hunter R, Kent LJ, Smith R, Darton K. Randomised controlled trial of gradual antipsychotic reduction and discontinuation in people with schizophrenia and related disorders: the RADAR trial (Research into Antipsychotic Discontinuation and Reduction). BMJ open. 2019 Nov 1;9(11):e030912.

3:  Danivas V, Venkatasubramanian G. Current perspectives on chlorpromazine equivalents: Comparing apples and oranges! Indian J Psychiatry. 2013 Apr;55(2):207-8. doi: 10.4103/0019-5545.111475. PMID: 23825865; PMCID: PMC3696254.

4:  Taylor D, Paton C. The Maudsley prescribing guidelines. CRC press; 2009 Oct 30.

5:  Middleton H, Moncrieff J.  Critical psychiatry: a brief overview. BJPsych Advances (2019), vol 25, 45-54.

6:  Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med. 2020 Feb 6;382(6):554-561. doi: 10.1056/NEJMra1907805. PMID: 32023375.

Photo Credit:

Many thanks to my colleague Eduardo A. Colon, MD for the photograph at the top of this blog.

Mechanism Of Action Of Lithium - A Brief History

As a chemistry major and a psychiatrist Lithium has a special place in my consciousness.  During the years that I took organic chemistry lithium aluminum hydride was a favorite reducing agent when creating certain organic syntheses.  Most chemistry majors remember metallic lithium as one of those highly reactive metals that was packed under oil to prevent contact with water or even moisture in the air.  Lithium's reactivity is why the free metal does not exist in nature.  The most common form used as a medication is lithium carbonate in various preparations.

There has been a lot of speculation about the mechanism of action of lithium since its discovery.  Early in my career the definitive source of information for all things lithium-related was the Lithium Information Center at the University of Wisconsin Department of Psychiatry.  It was possible to call them and ask them anything about lithium and get the relevant references sent to you.  They also produced the Lithium Encyclopedia for Clinical Practice.  The mechanism of action was described as unknown at the time but ongoing research was cited (p. 7) in "ion substitution with subsequent effects on amine metabolism, membrane transport, glucose metabolism, and neurotransmitter synthesis and degradation."  An entire chapter was dedicated to mechanism of action.  In that chapter, the review of what was known about the mechanism of action at the time is interesting.  The major neurotransmitter systems being studied at the time were catecholamines, serotonin, and acetylcholine.  Animal studies showed acute changes on norepinephrine turnover that was only slight to non-existent with chronic use.  Results on serotonin turnover were conflicting, but it prevented hyperaggressive behavior resulting from a serotonin depleting compound that blocked tryptophan hydroxylase (parachlorophenylalanine).  Acute administration did not alter dopamine turnover.  Chronic administration resulted in increased turnover in mesolimbic and striatal areas but not the cortex.  These observations led to theories that lithium worked by altering post synaptic receptor sensitivity including decreased beta adrenoreceptor effects, stabilized opioid receptors, and preventing dopamine receptor hypersensitivity.

There was some speculation about endocrine mechanisms since it was known that lithium blocks release of thyroid hormone (T4).  It was also believed to reduce testosterone levels as a possible role in the anti-aggressive properties of the medication.  Studies at the time showed that in patients treated for aggression and closely followed, they had increased levels of luteinizing hormone but normal testosterone levels.  A significant theory at the time was that lithium worked by reducing T4 levels and this reduced beta-adrenoreceptor potentiation in mood disorders.  Lithium was also thought  to possibly work by the effect it had on the intracellular concentration of other ions like sodium, calcium, potassium, and magnesium in neurons. The 1980s was a decade when research interest on cell signalling was becoming more widespread after Sutherland's Nobel Prize for the discovery of cyclic AMP (cAMP).  Lithium was noted to inhibit adenylate cyclase the enzyme that produces cAMP.  Specific forms linked to beta-adrenoreceptors and prostaglandin-E1 were noted to be blocked leading to speculation that these mechanisms were related to mania.  

Another definitive source of drug mechanisms over the same era was The Biochemical Basis of Neuropharmacology.  My collection of these texts starts in 1984 with the fourth edition of that text.  There was a single paragraph on the action of lithium and its effect on catecholamines.  They used the term facilitated recapture mechanism (2) suggesting that the overall block  of stimulus related norepinephrine (NE) release may be due to facilitated uptake of NE.  They also point out the difference in acute and chronic effects with supersensitive NE responses with chronic administration.  By the fifth edition of this text (3), the speculative mechanisms had expanded to include inhibiting inositol-1-phosphatase in the phosphoinositide pathway (p. 114), the same NE mechanism as the previous edition (p. 306), and a new observation that lithium facilitates tryptophan uptake initially but with chronic administration tryptophan production normalizes despite increased uptake due to decreased enzymatic conversion to serotonin (5HT).  Shifting the balance between synthesis and uptake was suggested as a more stable mechanism.  By the seventh edition, lithium was back to being mentioned on single page  as part of the larger discussion of deficits in the catecholamine hypothesis of mood disorders - a theme the authors started in the fourth edition.  By the eighth and final version of this text there was no mention of lithium at all.  Two of the authors were involved in a successive text called Introduction to Neuropsychopharmacology (5).  That text describes lithium as "one of the major achievements of psychopharmacology of the past 50 years (p. 321).  The authors acknowledge that the mechanism of action remained unclear but the theories included inhibition of inositol monophosphatase, inhibition of glycogen synthase kinase-β, and modulating g protein function (p. 321).

Another excellent source of the evolution of lithium theory was the American College of Neuropsychopharmacology's (ACNP) Generation of Progress series.  The series has been discontinued.  I have the third to the fifth editions and the most substantial section on lithium action was in the Fifth Generation of Progress (6).  This chapter begins with an overview of the time course of mood stabilizer action and how the focus had changed over the previous 20 years from changes in neurotransmitter release and regulation to changes in cell signalling and morphological changes consistent with "altered signalling in critical regions of the brain."  The chapter is an overview of the complex effects of lithium on ion transport, neurotransmitter release, signal transduction, circadian rhythm, gene expression, and neuroplasticity.  The data showing that lithium and in some cases valproate and carbamazepine can regulate gene expression via transcription factors is reviewed.  Some of the changes produced a neuroprotective effect against a number of factors and at about that time neuroprotection was considered a potential positive effect form both mood stabilizer and antidepressants.  It was very interesting to reread the section on neuroplasticity.  Lithium was known to be an inhibitor of glycogen synthase kinase-3 beta (GSK-3β).  This molecule is a component of the wnt signalling pathway (see diagram).  This inhibition results in reduced phosphorylation of tau protein and the overall effect of  increased microtubule assembly.  Phosphorylation of MAP-1β is also inhibited by lithium and this results in increased axonal spreading and increased growth cone area and perimeter.  Long term down regulation of protein kinase C (PKC) substrate myrisolated alanine-rich c-kinase substrate (MARCKS) via phosphoinositide signalling was also shown to MARCKS expression is high in developmentally important structures like neuronal growth cones necessary for brain development.  It is also high in limbic structures in the human brain that retain the potential for plasticity - like learning and memory.  The authors conclude that section by pointing out that by its action on PI/PKC and GSK-3β signalling cascades, lithium "may alter presynaptic and post-synaptic structure to stabilize aberrant neuronal activity in critical areas of the brain involved in the regulation of mood."  In the space of just a few years, lithium was suddenly implicated in neuroplasticity and neuroprotection.  Maybe the Decade of the Brain did produce some benefits?  

That brings me to the latest piece of the puzzle.  A paper from Molecular Psychiatry (7) this October further examines the role of these signalling systems and how everything comes together.  The authors propose that one common biochemical pathway that may confer susceptibility to psychiatric disorders is the Wnt/ β-catenin pathway.  This is a pathway that is critical in all multicellular organisms for cell differentiation, growth, proliferation and morphology across a number of organ systems.  At least part of the pathway has a direct influence on the cytoskeleton.  It has been implicated in human diseases especially tumors and the metabolism of tumors.  The pathway was discovered about 34 years ago.  The  authors also looked at DIX domain containing-1 (DIXDC1) as a cytoplasmic transducer of the Wnt/ β-catenin pathway.  DIXDC1 interacts with disrupted in schizophrenia-1 (DISC-1) gene that has been implicated in the genetics of schizophrenia, bipolar disorder, and autism spectrum disorder.  DIXDC1 also has a restricted distribution in the nervous system depending on developmental stages.

Like most modern papers this article has an intense experimental section.  The authors prepared a DIXDC1 knockout mouse model and looked at several experimental manipulations.  They used several behavioral pharmacology approaches to model anxiety, depression, and social interaction among the mice.  On these models the Dixdc1KO (knock out) mice showed increased depression, increased anxiety, and less socialization than the Dixdc1WT (wild type) mice.  These behavioral phenotypes correlated with histological changes and the Dixdc1KO mice had reduced spine density and an increased number of filopodial or immature spines on pyramidal cell dendrites.  The authors confirmed that these reduced spine neurons functioned in an electrophysiologically expected manner.  They analyzed the reduced spines in the Dixdc1KO mutants and found that there was a decreased density of glutamatergic synapses along the dendrites of pyramidal neurons.  In order to determine if the Dixdc1KO Wnt/ β-catenin pathway would be impaired by the loss of cytoplasmic signal transduction proteins.  They found that treating the KO and WT neurons with and activator (Wnt3a) - the  level of β-catenin rose as expected in the WT neurons.  Wnt3a also failed to effect spine maturity or glutamatergic synapse density on the KO type neurons.

Most importantly for psychiatrists, the authors hypothesized that lithium would correct both the behavioral phenotype and structural defects in the Dixdc1KO type mice by inhibition of GSK3.  Injection of lithium or the specific GSK inhibitor GSK3i corrected the behavioral phenotypes and spine density, spine morphology, and glutamatergic synapse density in the pyramidal neurons of Dixdc1KO mice.                        

In a separate experiment the authors looked at a large database of patients with psychiatric disorders.  The first database contained 6000 cases of autism spectrum disorder (ASD) and 7000 controls.  The ASD cases had a greater number of sequence disrupting single-nucleotide variants (SNVs) that were judged to be likely to disrupt DIXDC1 function.  They showed the same pattern in patients with bipolar disorder (BD) and schizophrenia (Scz) versus controls.  In the end they had 4 patient data sets totaling 9000 cases (versus 11000 controls) with significantly more rare sequence disrupting SNVs.

The authors also used a cell based Wnt/ β-catenin signalling assay (compared to WT) to test specific missense SNVs from both psychiatric patients (BD, Scz) and ASD patients.  They found that rare missense SNV from ASD patients either increased or decreased Wnt/ β-catenin pathway activation.  Rare missense SNVs from psychiatric patients did not rescue spine density and synaptic deficits but the WT did.  A number of Wnt/ β-catenin pathway hyperactivating SNVs cased the expected decreased spine density, decreased glutamatergic synapse density and increased immature spine density.

The authors conclude that there may be other mechanisms in play that they could have missed.  They cite a downstream mechanism that is independent of the Wnt/ β-catenin pathway that leads to the structural changes they monitored in this study.  There are also different isoforms of DIXDC1 - some more active than others.  They do a great job of summarizing 20 years of research in the following lines:

"Several different biochemical mechanisms have been proposed to underlie the anxiolytic, antidepressant and mood stabilizing properties of lithium, a drug whose systemic use in modern psychiatry began in the first half of the last century.  Lithium's best validated mechanisms of action are inhibitory on IMP and INPP1, central phosphatases in the phosphoinositide pathway and on GSK3, the central kinase in the Wnt/ β-catenin pathway and AKT pathways."  (p. 8).  

 The story of lithium is similar to a lot of stories in biomedicine.  Research on lithium reflects a lot of popular theories of the day rather than any particular unique theory by one scientist.  That says a lot about the difference between physical sciences and biological sciences.  The technique of applying the most popular theories and lab techniques at the time is still common in medicine and neuroscience.  Like most neuroscience there needs to be further testing, replication, and debate about this mechanism but it does seem to be a lot clearer now than at any time in the past.  If the mechanism does check out there may be more than the few applications that currently involve lithium.  A lithium like effect from safer medications is potentially a very interesting one.  Applications may be as diverse as treating addiction - where glutamatergic innervation is thought to be an important component of top down control from the frontal cortex to neurodegenerative disorders and neuroprotection of synaptic complexity.

George Dawson, MD, DFAPA



References:

1:  James W. Jefferson, John H. Griest, Deborah L. Ackerman.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press,  Washington, DC; 1983.

2:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  4th ed. Oxford, England: Oxford University Press, 1982: 214.

3:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology. 5th ed.  Oxford, England: Oxford University Press, 1985: 115, 306, 319.

4:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  7th ed. Oxford, England: Oxford University Press, 1996: 490.

5:  Leslie L. Iverson, Susan D. Iverson, Floyd E. Bloom, Robert H. Roth.  Introduction to Neuropsychopharamcology.  New York, New York: Oxford University Press, 2009: 321-322.

6:  Robert H. Lenox, Alan Frazer.  Mechanism of action of antidepressants and mood stabilizers. In:  Davis KL, Charney D, Coyle JT, Nemeroff C, eds.  Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, Pennsylvania: Lippincott, Williams, and Wilkins, 2002: 1139-1163.

7:   Martin PM, Stanley RE, Ross AP, Freitas AE, Moyer CE, Brumback AC, Iafrati J, Stapornwongkul KS, Dominguez S, Kivimäe S, Mulligan KA, Pirooznia M, McCombie WR, Potash JB, Zandi PP, Purcell SM, Sanders SJ, Zuo Y, Sohal VS, Cheyette BN.  DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.  Mol Psychiatry. 2016 Oct 18. doi: 10.1038/mp.2016.184. [Epub ahead of print] PubMed PMID: 27752079.

8:  Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E. The way Wnt works: components and mechanism. Growth Factors. 2013 Feb;31(1):1-31. doi: 10.3109/08977194.2012.752737. Review. PubMed PMID: 23256519

Attribution:

Wnt signalling pathway is from VisiScience and their ScienceSlides 2016 slide set.

Use Of "Medical Model" As A Pejorative Term

Hearing “medical model” being used used pejoratively is quite tiresome.  I have heard it used that way for the past thirty years, usually to take a shot at psychiatrists.  I thought I would illustrate how this goes and what I disagree with by responding to a recent article authored by the British Psychological Society on how the system of care for psychotic disorders should be changed.  My interest is not in provoking an argument since I think that these errors are obvious.  The target audience is also relevant here and it is described as “service users, their friends and families, journalists, policymakers, mental health workers and the public.”  As such this is really a political document very similar in nature to the documents generated in the US by SAMHSA or treatment guidelines generated by other special interest groups like managed care companies.  That being the case, I will not spend any time on the technical aspects of psychosis alluded to in this paper.  As a political document it requires active refutation or the suggestions might be adapted as wholesale measures.  I don’t know if British psychiatry is any more successful in doing that than the American counterparts, but judging from what I have read in editorials – I doubt it.  Let me start out with a couple of the authors’ statements about the “medical model”.

"At least in the UK, most mental health services are currently based on the ‘medical model’ – the assumption that experiences such as hearing voices indicate illness and result from some sort of problem with the brain. (p. 103). This idea is also enshrined in mental health law and is the basis for compulsion. In the past many professionals have also believed that people experiencing distressing voices or paranoia are unlikely to recover without treatment (usually medication). This belief has led to a perceived ‘duty of care’ to provide treatment, and a tendency to view someone who does not want the treatment being offered as lacking in insight. As this report has shown, both of these assumptions are unfounded." (p. 103 from Reference 2)

And:

"In the past services have been based on what might be called a ‘paternalistic’ approach – the idea that professionals know best and that their job is to give advice. The ‘patient’s’ role is to obey the advice (‘compliance’). This now needs to change. Rather than giving advice, those of us who work in services should think of ourselves as collaborators with the people we are trying to help." (p. 104 from Reference 2) 

The authors definition of a “medical model” looks at three dimensions.  The first is the assumption that psychotic experiences are due to a brain problem.  That is partially true.  They limit themselves to what they describe as “idiopathic” causes of psychosis and ignore specific psychotic states and etiological factors.  They also exclude medical illnesses that are clearly associated with psychotic symptoms.  That happens to be the area that psychiatrists are trained to recognize and treat.  Trivializing psychiatric diagnosis as a list of symptoms that most clinicians do not refer to anyway is certainly consistent with the authors’ main points of contention, but fortunately that is not reality.  Finally, the diagnostic manual that they criticize has numerous categories that have been researched strictly as psychotic disorders (and anxiety and mood disorders) caused by social etiologies rather than brain problems per se.  Early in my career, I reviewed the predominately Scandinavian literature on brief psychoses or brief reactive psychoses so that I could provide necessary prognostic information to patients and their families.  More clear evidence that significant psychotic symptoms can spontaneously remit without any medical intervention.  That information is a critical part of any medical approach to a spontaneously remitting illness.

Secondly, they go on to say that this also means that “professionals” believe that people are unable to recover without treatment.  I don’t know about other professionals but psychiatrists since the time of Kraepelin have known that people recover without treatment, although in Kraepelin’s day they considered asylum care alone to be treatment.  Like many illnesses people can recover without treatment and the literature on brief psychosis is further evidence.  Psychiatrists have also known that specific types of psychosis (catatonia for example) have very grim prognoses without treatment. Some of the earliest studies showed that malignant catatonia had an 80% mortality rate at the turn of the 19th century.  By the turn of the 20th century the mortality rate approaches 1% or less with modern treatment. So the second part of the definition is clearly wrong.

Finally, the authors use “paternalism” to characterize the role of physicians.  This is a charge that frequently accompanies the so-called medical model often amidst the associated charge of authoritarianism.  It is also incorrect.  Medicine is based on the informed consent model of care.  Any psychiatrist is more aware of this than most other physicians.  Informed consent is based on the idea that the patient is provided with adequate information to make a risk-benefit decision and the patient and physician collaborate on the patient’s decision.  I have these conversations every day and many times a day.   Doing nothing, being referred somewhere else, and being denied the agreed upon care by a managed care company are all additional possibilities.  These conversations can occur with patients who are actively bleeding out on the floor and refuse to allow a trauma surgeon to intervene due to impaired judgment from psychosis.  In that particular situation surgeons are likely to remind anyone involved in the care that they would be assaulting the patient if they intervened and did not have informed consent.  Similar situations occur with people who have various forms of treatable but life threatening illnesses (operable cancer, impending paralysis, uncontrolled diabetes mellitus, etc) who were unable to make decisions in their best interest due to the effects of psychosis.

So - the authors’ definition of a medical model is wrong in 2 ½ of 3 dimensions. That is not a good starting point for a proposal to go beyond the “outmoded medical model”.  It is always good to know what the model really is before declaring it outmoded.  I think a lack of scholarship and experience in these matters in a common characteristic of people who criticize the “medical model” in psychiatry.  Of course it is generally not a scholarly endeavor.  For anyone interested in educating themselves in what a real medical model might look like I would suggest reading Systematic Psychiatric Evaluation (Reference 1) or any other guide to psychiatric evaluation.   Take a look at Appendix A and B for the quick story.   The fact that models like this one are widely emulated by nonphysicians may speak to their utility in understanding and treating psychosis and other mental disorders.

How do the authors do on their characterization of psychosis?   They seem to touch on the high spots. Mention of hallucinations, delusions, and formal thought disorder are all there.  They are obviously heavy on phenomena that would not typically come to the attention of psychiatrists, people who experience hallucinations and delusions or some grey zone phenomena that are not quite psychotic symptoms.  But what about the central feature of psychosis that generally comes to the attention of psychiatrists (the ones within the “medical model”)?  It turns out the authors have little to say about judgment or insight.  They have nothing to say about the conscious state of the individual.  These are the distressing and often life threatening aspects of the illness.  This is the aspect of psychotic illness that causes friends and family to state that they no longer recognize the person due to the disruption of their personality characteristics.  Are we really to believe that psychiatrists are having casual conversations with people intellectually curious and not bothered by hallucinations and delusions? Are we really to believe the affected person may not have experienced a profound change in their conscious state that makes them unrecognizable to their friends and family and unable to work or perform their basic life activities? Are we really to believe that change in conscious state may not possibly represent an acute danger to the person affected or their loved ones? Only people who have not been seriously affected by psychotic states and people who are not responsible for assessing and treating those states can make those statements.  Those people generally do not need to see psychiatrists.

The authors claim that a “lack of insight” can result in a person being detained for mental illness. That does not happen where I practice. I have to document “behavioral evidence” rather than a lack of insight and treatment refusal can also not be used as a basis for detaining someone.  In the USA, there is a strong financial incentive to discharge people from hospitals as soon as possible.  The businesses and governments who manage these facilities welcome treatment refusals.  The patient can be discharged immediately with no follow up demands.  From a business perspective that is "cost-effective care".  If any paternalism exists, it is at a societal level.  Society is the proper arbiter of how its most vulnerable citizens should be treated.  Should they be forced into treatment or allowed to die with their rights on?  Psychiatrists have no choice but to follow society's lead.  If psychiatrists have no vested interest in forced treatment, one of the critical questions is why it exists in the first place?  The obvious answer is that it is a far from perfect approach to help families get their loved ones treated and even then families are routinely disappointed.  Hospitals and courts can still have their own interpretations of these laws that will save them money but not provide necessary treatment.  In the end there is still no medical paternalism.

There are two other sections in this paper that merit commentary – dangerousness and etiologies of psychosis.  After their selective and inaccurate characterization of psychiatric assessment the authors drop this bomb:

"Some psychologists are reaching the conclusion that psychosis is often no more and no less than a natural reaction to traumatic events. For example one recent paper suggested that ‘there is growing evidence that the experiences service users report … are, in many cases, a natural reaction to the abuses they have been subjected to. There is abuse and there are the effects of abuse. There is no additional ‘psychosis’ that needs explaining’." (p 42 from Reference 2)


That is a very interesting observation to psychiatrists who screen all of their new evaluations for trauma history and post-traumatic stress disorder (PTSD).  Instead of a “recent paper” what if I am a psychiatrist seeing 500 new cases per year and I screen everybody I see for psychosis, PTSD, childhood adversity and other forms of psychological trauma.  What if over the space of 4 years and 2,000 new evaluations I observe that about 30% of my patients have significant childhood adversity or psychological trauma, about 5-10% have PTSD related to that trauma and about 5% have psychotic symptoms totally unrelated to previous trauma.  I pose that hypothetical because it would be the common experience of most psychiatrists.  The issue of trauma being a cause for symptoms should also lead to the examinations of previous errors postulating trauma as an etiology for symptoms most notably the Multiple Personality Disorder (MPD) fiasco and the associated phenomenon of Satanic Ritualistic Abuse (SRA).  I would recommend against even using highly qualified statements about this as a possible etiology for psychosis without ample evidence.  Although research bias is a frequent accusation in the area of psychopharmacology research, there is no reason to suspect that favorite theories in psychosocial research are less bias producing.

The authors fall back on the statement about mental illnesses not implying dangerousness.  In the vast majority of cases that is true.  It is also true that the population with the most significant illnesses need to be evaluated for suicidal and aggressive behavior.  Tragedies that occur as a result of impaired judgment and altered conscious states from psychotic disorders are commonplace.  People with these problems can be successfully treated and violence and suicide can be prevented.  It is not enough to suggest that people with mental illnesses may be stigmatized by any connection with violence.  People with psychotic disorders and aggression are among the most stigmatized people in our society.  The solution is not to deny that this problem exists but to identify this as a treatable problem and develop an appropriate public health response.  There is also a very strong bias in the American legal system to punish rather than treat anyone with a psychosis who commits a crime.  Escaping punishment as a result of the not guilty by reason of insanity defense (NGRI) is one of the most consistent urban legends in America.  This defense is hardly ever a success and even then it is likely that the patient involved will spend more time in a forensic prison/hospital than they would have if they were criminally sentenced without the NGRI defense.

The authors are certainly wrong about any “medical model” of psychosis or mental disorders that I am used to seeing.  My medical model is the model of Engel and Chisholm and Lyketsos informed by Kandel and others.  There are very few places it can be practiced in the United States because business interests run the field of psychiatry and medicine.  American managed care companies and governments can certainly reduce psychiatric assessment to a series of checkmarks in the electronic health record and documentation that may be unreadable.

A business model of rationing is not a medical model by any stretch of the imagination.  That business model is also not one that will prove to be receptive to any enlightened model of community care.  The best evidence of that is that the ACT (Assertive Community Treatment) Model invented by Stein, Test and others in 1974.  This model consists of active outreach, crisis intervention and housing, medical and psychiatric care, vocational rehabilitation, and peer counseling with a focus on helping individuals maintain stable housing in the community.  There is no insurance company that I know of that supports this level of care.  The ACT Model is cost shifted to state governments and they strictly ration who gets that level of care.  With regard to Cognitive Behavioral Therapy there is no insurance company that I know of that consistently supports research recommended course of therapy for the conditions that have long standing indications – the anxiety and depressive disorders.  What is the likelihood that it will be supported for the treatment of psychotic disorders and grey zone conditions?

I will hold my remaining remarks on the treatment implications of this paper.  This blog contains extensive commentary on that issue and the real limitations on comprehensive assessment and treatment.

None of those limitations are due to a “medical model.”

George Dawson, MD, DFAPA


References:

1. Margaret S. Chisholm, Constantine G. Lyketsos. Systematic Psychiatric Evaluation. A Step-by Step Guide to Applying The Perspectives of Psychiatry. 2012 The Johns Hopkins University Press. 243 pp.

2. The British Psychological Society. Understanding Psychosis and Schizophrenia. Edited by Anne Cook. Available on the web site of the British Psychological Society.

Persecutory Delusions, Psychiatric Treatment, and Violence Prevention

For 23 years I ran an acute care inpatient service where the main focus was preventing violence and suicide.  That is the default function of inpatient units these days and it has been decided  by businesses and governments rather than organized psychiatry.  Organized psychiatry used to take an interest in quality care in hospitals but it has largely been abandoned to the hospitals and organizations that run them.  The regulatory bodies for inpatient care tend to focus on a number of parameters that are irrelevant to quality care.  With such a fragmented regulatory and administrative approach, the focus on quality of care depends solely on the personnel on each unit and how well they work together as a team.  The majority of patients are admitted these days because of concerns about aggressive behavior and suicide.  In my experience, good inpatient teams are highly successful in assessing and treating those problems.

One of the key treatment interventions is determining the people with the highest risk potential for the most intensive treatment interventions.  The treatment outcomes in terms of averting aggressive and suicidal behaviors are generally good.  Given the relatively rare occurrence of aggression or suicide post discharge the actual power of the treatment intervention is unknown.  The potential severity of outcomes precludes any placebo controlled clinical trials.  No human subjects committee would authorize a placebo arm and since many patients are on involuntary status or court holds.  No probate court judge would go along with it either.

The March 2014 edition of the American Journal of Psychiatry has some the most most extraordinary content I have ever noticed in that publication.  Among the articles is a paper called "Association of Violence With Emergence of Persecutory Delusions in Untreated Schizophrenia".  It adds significantly to the literature on psychosis and violence.  The study focuses on the United Kingdom Prisoner Cohort Study and it looked at risk factors for future violence in prisoners who were incarcerated for a violent crime after they were released.  It is a study that could be done on patients who were acutely hospitalized and released because of the naturalistic design and use of nonviolent participants as a comparison group.  That authors were interested in looking at whether the presence of psychosis predicted future violence and if there was any specific pattern of symptoms.  They were also interested in looking at the issue of whether or not treatment was helpful.

The sample consisted of 1,717 prisoner screened at baseline and 967 followed up (787 men and 180 women).  Selection was based on incarceration for at least 2 years for a violent crime and release date within 12 months of the start of the study.  All participants were given a number of structured research assessments to establish diagnosis.  At follow up, the diagnoses of the patients in the study included 94 meeting diagnostic criteria for schizophrenia, 102 for drug induced psychosis, and 29 for delusional disorder.  Only the subgroup with schizophrenia scored higher on psychopathy scores.  Violent behavior at follow up was established by self-report and a national computer police database that classified violence against persons.  According to that database 22.9% of participants were violent between release and follow up (mean 39.2 weeks).

 In terms of the relevant results, the delusional disorder and drug induced psychosis subgroups were no more likely than the the participants without psychosis to be violent at follow up.  Persons with untreated schizophrenia were more than three times as likely to be violent that the non-psychotic participants at follow up.  In that group those with persecutory delusions were more likely to be violent than those with other symptoms of psychosis.  The authors briefly review the indirect evidence supporting their findings including treatment non-adherence and risk of violence, risk of violence at first presentation of treatment rather than subsequent episodes, and psychosis as a risk factor for violence.  They point out that to their knowledge this is the only study of violent recidivism in prisoners that looks at the issue of psychosis as a risk factor.

The actual treatment provided in this case was critical.  In terms of violence prevention any treatment provided in prison only or in prison and on release was effective in preventing violence.  They point out that identification of more people needing treatment by their study methodology may have led to more active treatment of study participants.  They quote data on that fact that in prisons in the UK only about 1/4 of prisoners with severe mental illnesses are identified by mental health teams with that specific function and that of those identified only 13% are accepted into case management.  Overall in the UK less than 1/4 of prisoners who screen positive for psychosis are given a mental health appointment at the time of discharge.

The accompanying editorial by Large is interesting in reviewing the issue of screening versus not screening populations for psychosis and whether that prevent violence.  Several studies have concluded that "risk assessment is insufficiently sensitive to provide a basis for protection of the public."    Without looking at all of the references (I would expect to find significant flaws) the issue is really not a screening issue.  This study happens to appear like it is a screening, but the diagnostic approach is probably much more vigorous than most assessments in correctional settings.  The issue is that you have a person sitting in front of you telling you that they have persecutory delusions and are at risk for continued violence secondary to those delusions.  There is also a significant subgroup who are at personal risk for self harm related to these delusions that the authors either did not find or they did not comment on.  The Large commentary also focuses on antipsychotic medication as the treatment for psychosis and in the UK psychotherapy is also a treatment modality.  He makes the observation that treatment across the entire spectrum is important in that less treatment in the currently treat group will also result in more violence.

This study is useful in the US for several reasons.  County jails have become the largest psychiatric hospitals in the United States largely as a result of government and business policy.  Inpatient units may be useful for acute violence but there is an uneasy relationship with county jails.  Hospital policy may result in suicidal and acutely aggressive psychotic patient being treated in jail settings and using methods that would be seen as completely inappropriate in a medical or psychiatric setting.  Psychiatric follow up in jail settings is often fragmented and it is not uncommon to see medical treatment started and stopped based on the availability of medical staff or prescription medications.  I would consider the UK to be much more enlightened with regard to mental health policy than the US and to have more medically based resources for anyone with a psychosis diagnosis.  I can't imagine follow up numbers from American jails being any better than they are in the UK.

All of this creates a problem for the person with psychosis, persecutory delusions, and violent behavior.  The focus of much of the literature seems to be protecting the public from them but when you are their treating psychiatrist the arguments you are making to them is to protect them from their delusional thoughts.  That will not happen in a rationed, carved out environment that has shifted progressively more care for the severely mentally ill to correctional settings.  The other interesting  cultural phenomenon is that there is no coverage of this study or similar studies in the press.  Their bias seems to be to look at the sensational results of psychosis associated violent crime,  suggest that more treatment might be needed, attribute causation to being in the wrong place at the wrong time, and suggest that we all need to move on (lurch forward?) toward the next catastrophe.

This study provides a platform for a better approach to public policy and a more patient centric approach to violence prevention.

George Dawson, MD, DFAPA    


1: Keers R, Ullrich S, Destavola BL, Coid JW. Association of violence with emergence of persecutory delusions in untreated schizophrenia. Am J Psychiatry. 2014 Mar 1;171(3):332-9. doi: 10.1176/appi.ajp.2013.13010134. PubMed PMID: 24220644.

2:  Large MM. Treatment of psychosis and risk assessment for violence. Am J Psychiatry. 2014 Mar 1;171(3):256-8. doi: 10.1176/appi.ajp.2013.13111479. PubMed PMID: 24585326.




 



    

Straight Talk About the Government Dismantling Care for Serious Mental Illness

The ShrinkRap blog posted a link to an E. Fuller Torrey and D.J. Jaffe editorial in the National Review about how the government has dismantled mental health care for serious mental illnesses and some of the repercussions.   Since I have been saying the exact same thing for the past 20 years, they will get no argument from me.  Only in the theatre of the absurd that passes for press coverage of mental illness and psychiatry in this country can this subject be ignored and silenced for so long.  It was obviously much more important to see an endless stream of articles trying to make the DSM-5 seem relevant for every man.  The stunning part about the Newtown article is the commentary about what government officials responsible for policy have actually been saying about it.

The authors waste very little time examining the sequence of events in the Obama administration following the Newtown, Connecticut mass shooting.  President Obama initially stated he would "make access to mental health care as easy as access to guns." and set up a Task Force under Vice President Biden to make recommendations.  The authors argue that the agency that was consulted, the Substance Abuse and Mental Health Services Administration (SAMHSA) promotes a model of treating mental illness that has no proven efficacy, does not discuss serious mental illnesses in its planning document, ignores effective treatments for serious mental illnesses and actually goes so far as to fund programs that block the implementation of effective treatment programs.  In an example of the obstruction of effective programming by SAMHSA funded programs following the Newtown mass shooting:

"But, alas, the situation is even worse. SAMHSA does not merely ignore effective treatments for individuals with severe mental illness. It also funds programs that attempt to undermine the implementation of such treatments at the state and county level. One such program is the Protection and Advocacy program, a $34 million SAMHSA program that was originally implemented to protect patients in mental hospitals from abuse. It was kidnapped by civil-liberties zealots and has been used to block the implementation of assisted outpatient treatment, funding efforts to undermine it in at least 13 states. For example in Connecticut, following the Newtown massacre of schoolchildren, the federally funded Connecticut Office of Protection and Advocacy for Persons with Disabilities testified before a state-legislature working group in opposition to the proposed implementation of a proposed law permitting court-ordered outpatient treatment for individuals with severe mental illness who have been proven dangerous. The law did not pass."  (page 3, par 2.)

In other words, a SAMHSA funded program was opposed to a law in Connecticut that could potentially reduce violence from persons with severe mental illness.

SAMHSA administrators are quoted at times in the article. Any quote can be taken out of context but the characterizations of severe mental illness as "severe emotional distress", "a spiritual experience" and "a coping mechanism and not a disease" reflect a serious lack of knowledge about these disorders.  The idea that "the  covert mission of the mental health system ...is social control" is standard antipsychiatry philosophy from the 1960s.  How is it that after the Decade of the Brain and the new Obama Brain Initiative  we can have a lead federal agency that apparently knows nothing about the treatment of serious mental illnesses?  How is it that apart from  some fairly obscure testimony, no professional organizations have pointed this out?  How is it in an era where governments at all levels seem to demand evidence based care, that a lead agency on mental health promotes treatment that has no evidence basis and ignores the treatment that is evidence based?

Having been a long time advocate for the prevention of violence by the treatment of severe mental illnesses my comments parallel those of the authors.  Inpatient bed capacity in psychiatry has been decimated.  They point out that there are only 5% of the public psychiatry beds available that there were 50 years ago.  It is well known that people with mental illnesses are being incarcerated in record numbers and some of the nation's county jails have become the largest psychiatric institutions.  Where are all of the civil liberties advocates trying to get the mentally ill out of jail?

Only a small portion of the beds available can be used for potentially violent or aggressive patients and that number gets much smaller if a violent act has actually been committed. Most of the bed capacity in this country is under the purview of some type of managed care organization and that reduces the likelihood of adequate assessment or treatment.  The discharge plan in some cases is to just put the patient on a bus to another state.

Community psychiatry is a valuable unmentioned resource in this area.  In most of the individual cases mentioned in this article, the lack of insight into mental illness or anosognosia is prominent.  It is not reasonable to expect that a person with anosognosia will follow up with outpatient appointments or even continue to take a medication that treats their symptoms into remission.  Active treatment in the community by a psychiatrists and a team who knows the patient and their family is the best way to proceed.  All of this active treatment has been cost shifted out of insurance coverage and is subject to budget cuts at the county and state level.

Civil commitment laws and proceedings are probably the weakest link in treatment.  Further cost shifting occurs and violent patients often end up aggregating in the counties with the most resources.  Even while they are there, many courts hear (from a budgetary perspective) that they are committing too many people and the interpretation of the commitment law becomes more liberal until there is an incident that leads to the interpretation tightening up again.  Bureaucrats involved often become libertarians and suggest that commitment can occur only if an actual violent incident has happened rather than the threat of violence.

Although Torrey and Jaffe are using the extreme situation of violence in the seriously mentally ill to make their point, the majority of the seriously mentally ill are not violent.  They need the same resources.  It has been thirty years of systematic discrimination against these people, their families and the doctors trying to treat them that has led to these problems.  I pointed out earlier on this blog the problem I have with SAMHSA and the use of the term "behavioral health".  The problems with SAMHSA and current federal policy are covered in this article and I encourage anyone with an interest to read it.  If history is any indication, I don't expect anything serious to come of the criticism.  I anticipate a lot of rhetorical blow back at Dr. Torrey.  But as a psychiatrist who has worked in these environments for most of my career, his analysis of the problem is right on the mark.

George Dawson, MD, DFAPA

E. Fuller Torrey & D.J. Jaffe.  After Newtown.  National Review Online.

White House.  Now Is The Time.  The President's plan to protect our children and our communities by reducing gun violence.  January 16, 2013.

Asthma Endophenotypes? Their Implications for Psychiatry

Asthma is an annoying and sometimes fatal disease.  I have first hand experience with it because I have had asthma for at least 40 years.  Like many of my personal medical afflictions that I have posted about on this blog it was initially missed and not treated.  According to recent studies, that is still a common experience.  When I was a teenager, wheezing when mowing the lawn was apparently considered a normal reaction.  When I developed a more systemic reaction right in a physician's office, my parents were taken into an adjacent room and advised that it was apparently all "in my head" and it was some sort of psychosomatic reaction.  The psychosomatic reaction responded well to epinephrine injections and diphenhydramine.  Even when I was in medical school the treatment of asthma was shaky.  I was taking theophylline pills twice a day for several years and the patients I began treating for exacerbations of chronic obstructive pulmonary disease were all on aminophylline drips and corticosteroids.  We all had to memorize those protocols and of course know the mechanism of action (now invalidated) that was based on Sutherland's Nobel Prize winning work on cyclic AMP.  Today theophylline is considered a tertiary option for uncontrolled asthma rather than a first line treatment.

 As a fourth year medical student, I presented a very well received seminar on "slow reacting substance of anaphylaxis" or SRS-A now known to be a mixture of leukotrienes.  Eventually the treatment of asthma changed and glucocorticoid inhalers became the treatment of choice for a while.  As any primary care physician or asthmatic patient knows - no two asthmatic patients are the same.  As an example, peak flow meters are routinely used to measure asthmatic control.  No matter how badly I am wheezing, I can always max out that peak flow meter.  Asthma is a complex disease with varied presentations and the current treatment algorithms are complex with varied medications.

The diagnostic criteria of asthma seem relatively straightforward and are listed in the table below:

Diagnosis of Asthma (see additional details in National Heart, Lung and Blood Institute reference) and reference 8 below:

1.  Recurrent symptoms of airflow obstruction or airway hyperresponsiveness (eg. wheezing, chest tightness, cough, shortness of breath.) 2.  Objective assessment as evidenced by:      A.   Airflow obstruction as least partially reversible by inhaled short acting beta2 agonists as demonstrated by any of the following: -        Increase in FEV1 of ≥ 12% from baseline -        Increase in predicted FEV1 of ≥ 10% from baseline -        Increase in PEF (liters/minute) of ≥ 20% from baseline                   B.   Diurnal variation in PEF of more than 10%      C.   No other causes of obstruction

FEV1 = forced expiratory volume in 1 second (liters) PEF = peak expiratory flow

Medicine texts have traditionally used breakpoints in the above parameters to distinguish mild, moderate and severe asthma.  Despite what seem to be clear diagnostic criteria a recent review (8) in the New England Journal of Medicine states:  "Most patients with asthma have mild persistent disease which tends to be underdiagnosed, undertreated, and inadequately controlled."  The reference cited in that review points out that only 1 in 7 patients achieved good control of their asthma.  

There has been a sudden surge in research on asthma phenotypes, endotypes, and endophenotypes.  Endophenotypes are subtypes of a particular phenotype that are thought to have a common pathophysiological mechanism or in the case of psychiatry a biochemical, neurophysiological, neuropsychological maker that allows for the subclassification.  If you have attended any serious psychiatric genetics course in the past decade you have probably heard about endophenotypes.  Gottesman and Gould published a widely cited paper in the American Journal of Psychiatry in 2003 discussed the concept and its application in psychiatry.  There have been 132 references to papers on endophenotype in the Schizophrenia Bulletin alone, including a special theme issue.

A group of 5 asthma endotypes have been suggested by Corren (7).  He uses the definition of endotype as "a subtype of a condition defined by a distinct pathophysiological mechanism."  The classification was a consensus of experts looking at clinical characteristics, biomarkers, lung physiology, genetics, histopathology, and treatment response.  The following 5 endotypes were identified.

Asthma Endotypes
Allergic Asthma	Childhood onset, hypersensitivity to airborne allergens, Th2 mediated inflammatory process, eosinophilia of blood and airways, inhaled corticosteroids less effective, IgE antagonists are more effective.
Aspirin exacerbated respiratory disease (AERD)	Chronic rhinosinusitis with nasal polyps, severe bronchospasm if NSAIDs are ingested, marked blood and airway eosinophilia, increased expression of leukotriene C4 synthetase, response to cysteinyl leukotriene receptor antagonists and 5-lipoxyenase inhibitors
Allergic bronchopulmonary mycosis (ABPM)	Colonization of airways by Aspergillus fumigatus, increased fungal specific IgE and IgG, elevated blood eosinophil and total IgE levels, elevated airway eosinophils and neutrophils, requires oral corticosteroids and antifungals
Late Onset Asthma	Pulmonary function testing is more impaired than allergic asthma, marked eosinophilia in blood and airways, need oral corticosteroids.  May be mediated by IL-5.
Cross country skiing induced asthma (CCSA)	Triggered by exposure to cold dry air and intense exercise, not usually due to allergies, inflammatory infiltrate consists of lymphocytes, macrophages, and neutrophils rather than eosinophils,  airway remodeling with thickened basement membrane, not usually responsive to inhaled corticosteroids.

The tables on diagnosis and endophenotype are remarkable for their parallels with psychiatric diagnosis and research.  The available endotypes do probably not capture all of the clinical scenarios of asthma because patient behavior is a significant factor.  The endotype classification of asthma by experts is interesting in that it includes a treatment response dimension and this has been avoided in psychiatry at the diagnostic level.

Like mental illnesses, asthma is a complex polygenic disease with considerable clinical heterogeneity.  Using endophenotype approaches very similar to the approaches that have been applied to the study of schizophrenia offers the hope that classification and treatments of subtypes will be more effective and the connection between the genetics of the illness, pathophysiological mechanisms, and subtype will become more apparent.  Although the parallels with mental illness are clear, asthma researchers and clinicians treating asthma have the advantage in that they can proceed without the stigmatization that only accompanies psychiatric disorders and psychiatrists.

George Dawson, MD, DFAPA




1: Barranco P, Pérez-Francés C, Quirce S, Gómez-Torrijos E, Cárdenas R, Sánchez-García S, Rodríguez-Fernández F, Campo P, Olaguibel JM, Delgado J; Severe Asthma Working Group of the SEAIC Asthma Committee. Consensus document on the diagnosis of severe uncontrolled asthma. J Investig Allergol Clin Immunol. 2012;22(7):460-75; quiz 2 p following 475. PubMed PMID: 23397668.

2: Simon T, Semsei AF, Ungvári I, Hadadi E, Virág V, Nagy A, Vangor MS, László V, Szalai C, Falus A. Asthma endophenotypes and polymorphisms in the histamine receptor HRH4 gene. Int Arch Allergy Immunol. 2012;159(2):109-20. doi: 10.1159/000335919. Epub 2012 May 30. PubMed PMID: 22653292.

3: Matteini AM, Fallin MD, Kammerer CM, Schupf N, Yashin AI, Christensen K, Arbeev KG, Barr G, Mayeux R, Newman AB, Walston JD. Heritability estimates of endophenotypes of long and health life: the Long Life Family Study. J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1375-9. doi: 10.1093/gerona/glq154. Epub 2010 Sep 2. PubMed PMID: 20813793; PubMed Central PMCID: PMC2990267. 

 4: Bisgaard H, Bønnelykke K. Long-term studies of the natural history of asthma in childhood. J Allergy Clin Immunol. 2010 Aug;126(2):187-97; quiz 198-9.  doi: 10.1016/j.jaci.2010.07.011. Review. PubMed PMID: 20688204. 

5: Chan IH, Tang NL, Leung TF, Huang W, Lam YY, Li CY, Wong CK, Wong GW, Lam CW. 

Study of gene-gene interactions for endophenotypic quantitative traits in Chinese asthmatic children. Allergy. 2008 Aug;63(8):1031-9.
doi: 10.1111/j.1398-9995.2008.01639.x. PubMed PMID: 18691306. 

6: Thompson MD, Takasaki J, Capra V, Rovati GE, Siminovitch KA, Burnham WM, Hudson TJ, Bossé Y, Cole DE. G-protein-coupled receptors and asthma endophenotypes: the cysteinyl leukotriene system in perspective. Mol Diagn Ther. 2006;10(6):353-66. Review. PubMed PMID: 17154652.

7. Corren J. Asthma phenotypes and endotypes: an evolving paradigm for classification.
Discov Med. 2013 Apr;15(83):243-9. PubMed PMID: 23636141.

8. Bel EH. Clinical Practice. Mild asthma. N Engl J Med. 2013 Aug 8;369(6):549-57.
doi: 10.1056/NEJMcp1214826. PubMed PMID: 23924005