Nocebo - Part 2

I have been waiting for this paper (1) to come out for the past 6 months.  I posted on the very interesting nocebo effect in antidepressant trials and why it was so interesting and in the process learned that the lead author - Seetal Dodd had a paper being reviewed on the nocebo effect in bipolar trials.  That paper finally came out and I had the pleasure of reading it and presenting it here.

As a brief refresher, the nocebo effect is an adverse drug experience or worsening based on taking placebo or inactive medication in a clinical trial.  At the clinical level, it can also be an unrealistic reaction to a medication based on  similar response.  Any researcher who has participated in clinical trials that all breaking the protocol and allow the subject to be informed about whether they were taking active drug or placebo has probably observed this effect.  Clinicians commonly see it as an improbable reaction to a medication or in some cases multiple medications.  It is an important phenomenon because it blurs the results of clinical trials by making it seem that there is less difference between placebo and the active drug being studied.  It also may lead to the rate of actual adverse events due to the study drug being underestimated.

For the purpose of this study the nocebo response is defined as any a treatment emergent adverse events (TEAE) or clinical worsening in people treated with a placebo. That involves collecting data on both TEAEs and rating mania and depression.

The data used in this study was from a randomized placebo controlled clinical trial of olanzapine monotherapy for bipolar disorder versus placebo and several comparators (haloperidol, valproate, olanzapine-fluoxetine combination [OFC]).  The trials occurred between 1996 and 2007.  There were a total of 9 studies and 7 were published.

Only data for the patients randomized to placebo (N = 1185/4680) were used for the purpose of this study and meta-analysis.  866/1185 or 68% experienced  (TEAE) and 4.6% discontinued the study due to a TEAE.  Typical rating scales for mania and depression were used to rate symptoms. TEAEs were significant ranging from 3% to 11.8% of the placebo treated group.  Headache, insomnia , somnolence, anxiety, nausea, diarrhea, irritability, and agitation all occurred in over 5% of the placebo treated patients.  Median time to report the TEAE was 16 days with the longest time of 37 days.

Apart from the TEAEs, a significant number of the placebo treated patients experienced clinical worsening as noted on the rating scales for depression (321 or 27%), mania (585 or 49%), or global function (278 or 23%).

The 806 patients reporting TEAEs reported a total of 1,119 nocebo events.

TEAEs were associated with not being treatment naive, being obese, being located in the US, and participating in an earlier study.  There were no significant difference based on gender or smoking status.

A major limitation of the study is that it is not possible to detect if clinical worsening is a nocebo effect or and the effect of worsening illness.

In their discussion the authors point out that the evidence is that the nocebo effect is significant in clinical trials.  Of all of the possible correlates they studied they di not find any that were useful to predict who might be a nocebo responder.   They discussed some psychological theories and in a couple of additional papers discuss the putative neurobiological underpinnings of both the placebo and nocebo effect.  Certainly any effect that leads to 4.5% or placebo treated patients discontinuing the study is significant.  Until the nocebo effect is better characterized we probably do not have an adequate estimate of the side effect profiles.  The authors describe is as similar to the placebo response as "an expected consequence of exposure to therapy."

The nocebo response may be less clear in looking at the therapeutic effects of medication.  I think it is good to remember that true nocebo/placebo effects are estimated on the placebo response.  In other words a 20% placebo response rate means that 20% of the actively treated group also responded to placebo.  Hence, if 68% of the placebo treated group experience TEAEs and 4.5% discontinue the study on that basis - what happened when those number are applied to the actively treated group?  It would generally mean less subject carried forward in an intent-to-treat analysis and and a more favorable side effect profile if the nocebo responders could be accurately identified. A good place to start to look for more accurate numbers and methods of identification may be in large scale medicine studies looking at an identifiable quantitative endpoint like blood pressure.  The nocebo effect is easier to sort out with a medication that has a clear effect on a more easily measured parameter.

Clinicians are left with estimating the likelihood of a TEAE or nocebo response based on the likelihood of a patient exhibiting a particular side effect.  A low likelihood of a particular presentation is fairly frequent in clinical practice and continuing the medication in those circumstances often comes down to clinical necessity.  As an example, the patient has a vague TEAE, but learns from the physician that there are no other medications that can be prescribed for the problem.

Nocebo responses are certainly out there.  Clinically we can be more specific until there is better research guidance on what to do about it.  I have had conversations with many people who were interested in the placebo response or why a particular pattern of responding to a therapeutic intervention may have been established.     



George Dawson, MD, DFAPA


References:

1: Dodd S, Walker AJ, Brnabic AJM, Hong N, Burns A, Berk M. Incidence and characteristics of the nocebo response from meta-analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder. Bipolar Disord. 2018 Jun 21. doi: 10.1111/bdi.12662. [Epub ahead of print] PubMed PMID: 29926533.

Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927 conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)

If Your Patient Really Needs Lithium.......

I had the good fortune to work in an intense medical setting for about 22 years where I was responsible for the medical care of my patients.  In that setting I had access to excellent specialists, in fact some of the finest physicians I have seen anywhere.  They were typically involved when I had identified a medical problem that potentially complicated the psychiatric care of my patients.  In those cases - no matter what the problem was it usually came down to the question: "If your patient really needs this medication we need to continue it."  One of the most significant complications was renal failure of varying degrees while taking lithium.  Some patients on my unit were hospitalized because they had been stable on lithium but were developing renal failure and needed to be tried on another agent.  In some cases they experienced severe associated complications including delirium either from the bipolar disorder or medications used in the transition.  In some cases, they needed dialysis and renal medicine consultants would advise me on the lithium dose to try while they were receiving hemodialysis.  All of this experience led me to have a very low threshold for recognizing and acting on potential adverse effects of lithium as early as possible. 

At various points in my career, there was a question of renal failure occurred in cohorts on lithium or it was due to a different cause.  As an example, the Lithium Encyclopedia from 1983 (1) stated concisely: "There have been a growing number of reports of morphological and functional kidney damage associated with lithium use.  The actual incidence of lithium nephrotoxicity is not known.  Most researchers believe that irreversible damage is not widespread but that risk increases with length of treatment and serum lithium level."

At the time there were opinions that up to 20% of patients on long term lithium maintenance had morphological changes and functional changes primarily with water absorption but no reduced glomerular filtration rate (GFR) or renal insufficiency.  My favorite renal and electrolyte disorders text cited lithium as a compound that caused vasopressin resistant nephrogenic diabetes insipidus (NDI) (2).  More recent evidence suggests that 15-20% of patients on lithium develop a progressive decrease in GFR typically does not progress to end stage renal disease (ESRD) and dialysis but in some cases it clearly does.  These generalizations are usually based on low numbers of patients who have been identified as having a specific creatinine or GFR.  A creatinine of 2.5 mg/dl predicted progression to ESRD in most patients.  A larger study in Sweden of 3369 patients, suggested a lower threshold. In that study,  13 patients had been off lithium for 2 years before starting dialysis and 11 had a creatinine of > 1.4.  Some were lower but there had been a progressive increase from baseline suggesting the rate of change is important.  Additional factors such as the use of NSAIDS and ACE inhibitors like lisinopril as well as other intrinsic kidney diseases can be a factor.

There have been a recent increase in studies that look at the side effects of lithium and in one case (6) compare lithium side effects to other typical mood stabilizers (valproate, olanzapine, questiapine).  One of the studies uses descriptive statistics and the other two involve calculations of hazard ratios for specific risks.  The results are fairly uniform in their conclusions and have been known in most psychiatry training programs for the past 10-20 years.  The articles here use the Kidney Disease Outcomes Quality Initiative (KDOQI) staging of chronic kidney disease published in 2002.   The range is from stage 1 (eGFR ≥ 90 ml/min/1.73 m² ) to stage 5 (eGFR < 15 ml/min/1.73 m² or dialysis).  For the purpose of these papers Stage 2 is an eGFR of 60-89 and Stage 3 is 30-59. As previously noted progression can occur in some cases even years after the lithium has been stopped.

The most interesting of the three papers is probably from Hayes, et al because of their strategy to look at lithium toxicity but in the context of other commonly used mood stabilizers (valproate, olanzapine, quetiapine) and the associated toxicities of these other mood stabilizers.  As a result they have a table entitled Table 2. Adverse effects during maintenance treatment that looks at these mood stabilizers and CKD (stage 3 and 4), hypothyroidism, hyperthyroidism, hypercalcemia, Type 2 diabetes mellitus, cardiovascular disease, hypertension, hepatotoxicity, and weight gain (greater than 7% and greater than 15%).  Hazard ratios care calculated for all of these adverse effects using lithium as the reference.  The number of events in each category is relatively low compared with the total events in a large clinical sample.  The adverse events described were expected.  They estimated the rate of severe CKD (stage 4 or 5) as 1 in 100 person years at risk.  The estimated rates of stage 3 and stage 4 CKD were 9 in 100 per years at risk.  Hepatotoxicity was rare in the sample and was elevated in the quetiapine group.  Weight gain was most significant for olanzapine, quetiapine, and valproate relative to lithium.  Olanzapine also had the highest rate of new onset hypertension.

None of this information deters me from offering lithium to people who I think are good candidates.  The rationale is that lithium can be a life changing medication, especially for people who have generally never achieved mood stabilization with all of the typical medications prescribed for mood disorders these days.  Informed consent should include this potential complication.  I generally advise people that there is a 40% risk of NDI of varying severity, the need for ongoing testing, the need to avoid additional medications that may complicate the use of lithium, and finally close self monitoring of both side effects and any situation that can complicate lithium therapy like conditions leading to dehydration.  I will add the risk of mild CKD and explain to the patient what that means.

One of the interesting aspects of these articles is that ongoing screening for patients on lithium therapy varies considerably from setting to setting.  National guidelines seem to help.  In these large scale studies there is not enough discussion of work at the clinical level incorporating the red flags from the research.  For example it is obviously important to know about new medications, especially ACEIs, NSAIDs, and serotonergic medications.  Medications that may complicate interpretation of lab finding like Vitamin D and Calcium supplementation in the case of hypercalcemia are also important.  The review of systems is also important anywhere along the spectrum of side effects including neurological, cognitive, gastrointestinal, and renal symptoms.  I generally advise patients that increasing nocturia, polyuria, and polydipsia with associated laboratory finding increases the risk of irreversible renal changes including a low risk of progression to ESRD.  The presence of edema may indicate the rare onset of a nephrotic syndrome that can occur is some people with acute treatment.

The good news is that even now there is an accumulating literature on the potential complications of lithium therapy and some general ideas about what psychiatrists should do about it.  Although the methodology of these studies varies significantly they generally come to similar conclusions about the effect of lithium on renal function, thyroid function, and calcium metabolism.  All of these systems require close monitoring by assessing the patients clinical status and lab testing.  Numerous changes in clinical status should result in departures from any monitoring routine.  The critical elements is communication with the patient and education about when the psychiatrist should be contacted.
   

George Dawson, MD, DFAPA 


References:

1:  Jefferson JW, Greist JH, Ackerman DL.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press, Inc. 1983: p151.  

2:  Schrier RW (ed).  Renal and Electrolyte Disorders, 2nd Ed.  Little, Brown and Company, Inc.  Boston 1980: p. 31.

3:  Lerma VE.  Renal toxicity of lithium. In UpToDate.  Sterns RH, Sheridan AM (eds) (Accessed on January 2, 2018).

4: Bendz H, Schön S, Attman PO, Aurell M. Renal failure occurs in chronic lithiumtreatment but is uncommon. Kidney Int. 2010 Feb;77(3):219-24. doi: 10.1038/ki.2009.433. Epub 2009 Nov 25. PubMed PMID: 19940841. (see open access text).

5:  Dineen R,  Bogdanet D,  Thompson D, Thompson CJ,  Behan LA,  McKay AP, Boran G,  Wall C, Gibney J, O’Keane VO, Sherlock M.   Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.  QJM: An International Journal of Medicine, Volume 110, Issue 12, 1 December 2017, Pages 821–827, https://doi.org/10.1093/qjmed/hcx171

6: Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study. PLoS Med. 2016 Aug 2;13(8):e1002058. doi: 10.1371/journal.pmed.1002058. eCollection 2016 Aug. PubMed PMID: 27483368.

7: Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 Aug 1;386(9992):461-8. doi: 10.1016/S0140-6736(14)61842-0. Epub 2015 May 20. PubMed PMID: 26003379.
    

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.

A Neanderthal - Further Confirmation And Much More On Personal DNA

I like the idea of getting my own DNA analyzed and studying the results.  In an earlier post, I described some results of an analysis through a National Geographic project, and the finding that 2.5% of my DNA was from Neanderthals.  The ability to sequence ancient DNA is a relatively new capability and in the few years that it has been done, it has yielded a number of significant findings.  The applicability to the field of psychiatry is limited at this time to 2 references (1,2).  An additional search on ancient DNA and psychiatry yields 4 additional references (4-6) looking at the early origins of mutation and how the associated disrupted regulatory mechanisms could lead to psychopathology.  One of the susceptibility markers for schizophrenia dates back to the last glacial maximum or 24,500 years BCE.  

After trying out the National Geographic site,  I decided to see if the 23andMe site had anything more to offer.  I pulled up their web site, paid the fee and they sent me a sampling kit.  Their sampling technology if different in that they use a tube of saliva as the sample rather than a scraping from the buccal mucosa.  They send you a number of e-mail updates and finally a notification that your DNA has been processed and the necessary reports have been generated.  There are 67 reports in all that focus on ancestry, carrier status, wellness, and traits.  Some reports are more useful than others.  For example it is interesting that a 4th digit on the hand longer than the second digit or a second toe longer than the great toe are inherited characteristics with certain probabilities.  Unless there are some additional health implications involved I don't really care about my longest toe or finger.  The data I am looking for is precisely the data that the FDA told 23andMe that it should not market in the first place.  That initial FDA warning looks at the testing that the company was offering.  In this document the abbreviation PGS is used for "Personal Genome Service":

"Some of the uses for which PGS is intended are particularly concerning, such as assessments for BRCA-related genetic risk and drug responses (e.g., warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) because of the potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these. For instance, if the BRCA-related risk assessment for breast or ovarian cancer reports a false positive, it could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions, while a false negative could result in a failure to recognize an actual risk that may exist......."

I am sure there are plenty of posts around the Internet on the regulatory aspects of DNA testing and what the FDA is doing to protect the American public.  23andMe does have consistent qualifying statements saying that none of the data is for medical purposes, only for research and education.  My interest is purely personal research and education.  What more can I learn about DNA, genetics, molecular biology and human diseases.  As noted in my original, what more can I learn about my ancestry and the fascinating subject of Paleogenetics and the associated big questions like why is Homo sapiens - the genus and species of all current human beings the only surviving Homo genus.  Why are all of the others extinct?  I also think that it is quite instructive to remind ourselves that as members of that species we all started out in East Africa and migrated all over the world.

Looking at the test results from the 23and Me analysis, there are four major categories and some are more useful than others.  Those categories include ancestry, traits,  carrier status, and wellness.  Since ancestry was the focus of the National Geographic experiment I took a look at that report first.  In terms of methodology the 23and Me technology looks at overlapping regions of DNA and homology with comparison regions of known ethnic groups.  I prepared the following table to look at the predictive value of the 23andMe approach compared with the National Geographic technique looking at the purported ancestries of my grandparents. (click on any graphic to enlarge)  

As noted in the above table, there is more coverage of ethnicities, using the 23andMe approach with  the best example being that it picks up Norwegian, Swedish, and Dutch markers that were not present in the NatGeo analysis.  There are a few problems that might not be obvious at first.  The test subject does complete information about ethnicities and populations of origin that may be incorporated into the algorithm that assigns probabilities of certain ancestry.  These questions reminded me of the clinical data required for quantitative electroencephalogram machines in the 1990s.  The algorithms were supposed to predict psychiatric diagnoses, but the clinical data that was required with every test, frequently interfered with what the machine was going to select.  I take a very dim view of what appear to be scientific decisions being made on the basis of added speculative data.   The ancestry interpretations also depend the level of confidence assigned to the analysis.  As an example, take a look at the following genealogy assessments - the top a conservative estimate and the bottom much more speculation.  Significant changes in the analysis occur just based on how speculative the analysis is.  All things considered, I am quite interested in the range of the analysis and all correlations at this point rather than precision, but is some cases precision is apparently available.         

All together there are 3 ancestry reports and the most interesting report for me was the Neanderthal analysis.  The test looks at 1,436 traits across the genome and generates a report based on a map of all 23 chromosomes and a table that takes a more detailed look several markers.

The traits report was significantly less interesting to me.  It answered the question about whether or not a genetic markers for a trait existed.  For example, the length of the second toe on the foot and the length of the fourth finger on the hand.  The testing predicts that I have a 96% chance of lighter skin and very little chance of freckling.  That is true.

Carrier status was similarly not very interesting.  There was a major focus on congenital illness rather than risk of chronic illness.  Some of the carrier states mentioned include: ARSACS, Agenesis of the Corpus Callosum With Peripheral neuropathy(ACCPN),  Autosomal Recessive Polycystic Kidney Disease (ARPKD) and 33 others.  My carrier status for these relatively rare conditions was negative.  That was really no surprise considering my age, family history, and the fact that most of these are illnesses of infancy or childhood.

The wellness section contained 6 reports and a few were moderately interesting.  Caffeine consumption is regulated by variants near the CYP1A2 and AHR genes and I have those variants.  The prevalence of these variants in various populations are also estimated and it seem that these variants are high.  I do tend to consume significant amounts of caffeine and it is hardly noticeable.  It seems like I am drinking decaffeinated beverages.  I have the rs73598374 variant in the ADA gene that is associated with deep sleep.  I do sleep for short periods of time, but my activity monitor suggests that my sleep may be deeper than people who sleep more hours.  I also have the rs3923809 variant in the BTBD9 gene that predicts more movement in sleep.  The R577X variant in the ACTN3 gene is present and that is associated with a greater portion of fast twitch muscle fibers or what the site refers to as sprinter/power muscle type.  The final two wellness traits were lactose intolerance and the alcohol flushing reaction.  I knew that I had neither trait prior to the genetic testing.

Apart from the Neanderthal testing, the most interesting aspect of the this service is that ability to search your genome looking for points of interest.  I think that this will eventually be the most interesting aspect of these services as long as the users keep in mind that having a genotype, especially of a complex polygenic illness is a probability statement rather than a guarantee.  I am testing out two ways to do these searches.  The first strategy is based on protein analysis and I used a recent paper on bipolar disorder (I have a strong family history) to see if I could find any of these markers.  The original paper suggests that there are higher plasma concentrations of 6 proteins in bipolar disorder including GDF-15, HPX, HPN, MMP-7, RBP-4, and TTR.  A direct search yields a significant number of hits for HPX (5), HPN (14), and TTR (89) genes with specific information on markers, genomic position, possible variants and genotype.  In this case the original paper was a protein analysis and as far as I can tell there is no genetic analysis of the subgroup with higher levels of the identified proteins.  I have sent an e-mail to the lead author to see if I missed any papers on that issue.  An example of the data available searching on these proteins for the HPX protein is shown below:

The second option would be to search for known genotypes.  It is no secret from previous posts that I have asthma that was quiescent for most of my life that was reactivated about 3 years ago by a upper respiratory infection.  Asthma is an interesting disorder because the genetics are very complex just like psychiatric disorders.  For the critics who suggest that there are no tests of any sort for psychiatric disorders, these two sentences are from the latest chapter on the genetics of asthma from UpToDate (9) are instructive:

"Exploration of the genetics of asthma has also been hampered by the fact that there is no "gold standard" diagnostic test for asthma, and the clinical diagnosis is inconsistently applied.  To circumvent these issues, investigators have studied the distribution of asthma-related traits, including bronchial hyperresponsiveness and measures of atopy (eg, total serum IgE levels, skin test reactivity) in addition to the presence of an asthma diagnosis."

This same author reviews the genetic research on asthma to date and points out that prior to the retirement of the Genetic Association Database in 2014 there were over 500 genetic association studies on asthma that identified hundreds of candidate genes for asthma.  From those candidate gene studies, she gives the most replicated genes as filaggrin (FLG) - an epithelial barrier gene also important in atopic dermatitis,  ORMDL3 - a transmembrane protein, Beta-2 adrenergic receptor gene, and Interleukin-4 receptor gene.  Genome-wide association studies (GWAS) have supplanted candidate gene studies and over 50 GWAS have been done in asthma.  These studies have identified other candidate genes and generally shown that GWAS done in populations with European ancestry seem to have little applicability in more ethnically diverse populations.  ORMDL3 was identified in both types of studies so I searched for that in my own DNA and came up with the following:

            
In order to look at specific markers and asthma risk, I searched on one of the genotyped markers (rs8076131) in PubMed and came up with 7 papers on asthma susceptibility.  Searching more broadly on ORMDL3 showed 132 references that were less specific.

This ends my preliminary review on the availability of personal genomics for education and research purposes by individuals.  I hope to come up with more effective strategies to look at several additional disease phenotypes that I either personally possess or that were present in my first degree relatives.  For me, the paleogenetics and personal genome browsing were the most interesting aspects of this data.  For educational purposes, it highlights the difficulties of correlating genetics with disease phenotypes due in part to the fact that multiple genes and polygenes can produce the same phenotype and that makes the activity of specific genes difficult to determine in a DNA sample.



George Dawson, MD, DLFAPA

      



References:

1:  Srinivasan S, Bettella F, Mattingsdal M, Wang Y, Witoelar A, Schork AJ, Thompson WK, Zuber V; Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium, Winsvold BS, Zwart JA, Collier DA, Desikan RS, Melle I, Werge T, Dale AM, Djurovic S, Andreassen OA. Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biol Psychiatry. 2015 Oct 21. pii: S0006-3223(15)00855-0. doi: 10.1016/j.biopsych.2015.10.009. [Epub ahead of print] PubMed PMID: 26681495.

2:  Mariotti M, Smith TF, Sudmant PH, Goldberger G. Pseudogenization of testis-specific Lfg5 predates human/Neanderthal divergence. J Hum Genet. 2014 May;59(5):288-91. doi: 10.1038/jhg.2014.6. Epub 2014 Mar 6. PubMed PMID: 24599118.

3:  Sipahi L, Uddin M, Hou ZC, Aiello AE, Koenen KC, Galea S, Wildman DE. Ancient evolutionary origins of epigenetic regulation associated with posttraumatic stress disorder. Front Hum Neurosci. 2014 May 13;8:284. doi: 10.3389/fnhum.2014.00284. eCollection 2014. PubMed PMID: 24860472; PubMed Central PMCID: PMC4026723.

 4:  Zhang W, Tang J, Zhang AM, Peng MS, Xie HB, Tan L, Xu L, Zhang YP, Chen X, Yao YG. A matrilineal genetic legacy from the last glacial maximum confers susceptibility to schizophrenia in Han Chinese. J Genet Genomics. 2014 Jul 20;41(7):397-407. doi: 10.1016/j.jgg.2014.05.004. Epub 2014 Jun 2. PubMed PMID: 25064678. 

 5:  Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun. 2015 Mar 10;6:6404. doi: 10.1038/ncomms7404. PubMed PMID: 25752243; PubMed Central PMCID: PMC4355952. 

 6:  Toyota T, Yoshitsugu K, Ebihara M, Yamada K, Ohba H, Fukasawa M, Minabe Y, Nakamura K, Sekine Y, Takei N, Suzuki K, Itokawa M, Meerabux JM, Iwayama-Shigeno Y, Tomaru Y, Shimizu H, Hattori E, Mori N, Yoshikawa T. Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet. 2004 Mar 1;13(5):551-61. Epub 2004 Jan 6. PubMed PMID: 14709596.

7:  FDA Warning Letter to 23andMe

8:  Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. 2015 Dec 8;5:e689. doi: 10.1038/tp.2015.185. PubMed PMID: 26645624.

9:  Barnes KC.  Genetics of Asthma. In: UpToDate, Barnes PJ, Raby BA, Hollingsworth H (Ed), UpToDate, Waltham, MA. (Accessed on April 8, 2016)


Attributions:

All of the above graphics and tables with the sole exception the the ancestry table were generated with on site software at 23andMe based on my personal DNA sample.

A Real Case Of Psychosis And What Can Happen

Public radio continues to be a rich source of information when it comes to real life psychiatric problems.  In this case the NY Times was also involved.  Considering the date the story was filed the usual critics have not chimed in yet.  They may not be able to since no psychiatrist or psychiatric medication was involved in the care of this patient - and it shows.  There is no more compelling story that psychiatric disorders exist, are severe, and for various reasons can end catastrophically.  I won't  belabor the point that I have treated hundreds of people with very similar problems.  For 22 years, I treated people with severe psychiatric disorders and most of them had psychotic disorders.  The episode of psychosis described in this story is the kind of psychosis that psychiatrists treat, not the vague symptoms described in a recent paper that suggested that some symptoms of psychosis are a normal experience.

Before I get into a brief discussion of the scenario, I would like to acknowledge the patient Alan Pean for sharing his story.  I heard his story on This American Life and the host Ira Glass was explicit that Mr. Pean  had signed a release of information so that the hospital records and a 50 page report of the incident could be used to construct what had happened. His family members were also available for the interview.  In this age where health care companies view patient information as proprietary corporate information I applaud Mr. Pean's decision to make this very personal private information public.   There are numerous lessons to be learned from this incident that I hope to make explicit  at the end of this post.

For anyone interested in listening to the audio version of this story go to the This American Life web site and look up episode 579 My Damn Mind.  This amazing story begins after Mr. Pean has been shot in the chest and is bleeding to death on the floor of his hospital room.  There is blood  everywhere on the floor and people entering the room have to put on shoe covers.  Later in the story we learn that he lost about 1/3 of his total blood volume.  A trauma surgeon is demanding that the police take the handcuffs of Mr. Pean because even though he is shot and immobile, he is handcuffed lying on the floor.  According to the Centers For Medicaid and Medicare (CMS) report he was trying to get up after he was shot and saying that he was "Superman". From there,  Ira Glass starts to interview Mr.  Pean about the 20 hours prior to this incident.  He describes being anxious and at times panicky.  He was sleeping 4 hours per night and recognized he was manic from his past experiences in 2008 and 2009.  He was diagnosed with possible bipolar disorder treated with medication and had no further episodes in 6 years.  He was trying to unwind by playing a video game online with his friends.  He started to think that the video game controller had been reprogrammed by the enemy and was switching on a processor inside of him.  He could not logon to the game because he knew that drones would triangulate on him if he did and destroy his apartment.  He called his brother for advice.  His brother told him to lay down and put cold water on his face.  He concluded that his circuits were overheating like a robot and his brother knew this.  At one point he knew he had to escape from his third floor apartment balcony because snipers were closing in on him.   As he looked down he thought remember your training - you are trained for this.  At that point Ira Glass jokes with him about that point and they both laugh.  He of course had no training and it was apparent to me that Glass had not talked with many delusional people.  Pean executes a perfect drop to the second floor balcony and grabs the railing.  From there he notices two air conditioning units on the ground swings past then and jumps.  He hits the ground running for his car because he has called in a drone strike in his apartment building using Google Maps.  He jumps in his car and heads out of the parking lot.  When the gate doesn't open he rams it until it opens.  At this point he is thinking that his rendezvous point is the hospital.  In a moment of clarity he also realizes that he needs Geodon, the medication that he takes for psychosis.  He feels like he is a bionic person or a cyborg driving the car at a high rate of speed toward the hospital.  As he approaches, he loses control and hits several autos and the hospital building totaling out his car.  An EMT sees the crash. puts him on a gurney and wheels him into the Emergency Department.

This entire sequence of events was driven by delusions.  In the narrative Pean described an intense fear for his life and the fact that his "adrenaline was pumping" at times.  That combination of emotion, especially high anxiety and delusional thinking can lead to impulsive behavior and a lack of typically rational decision-making.  It is an example of "dangerousness" or the emergency criteria that governs whether a patient with psychiatric problems is offered inpatient treatment or not.  The problem is that Pean's actions are all internally consistent with his delusional state.  He talks with his brother on the phone and does not mention that he thinks he is delusional.  In this state of mind, it is very likely that anyone assessing him for "dangerousness" would seriously underestimate what he was capable of.  A lot of his acts are also environmentally determined.  His delusional biases interpret the information as he sees it.  When he was speeding toward the hospital, he was convinced that some of the buildings he was passing were going to explode at any minute.  Despite the non-psychiatric interview, I think the emotion driving the delusionally based decisions is apparent.  Ira Glass points out that the narrative though irrational is internally consistent like a movie and not what he expected.

Pean is eventually admitted to the trauma surgery service for further observation of injuries from the car crash.  There was ample information that he had a significant psychiatric disorder including direct statements from his father who is a physician.  He is noted to be disoriented and believes that it is 1989.  His speech at time is incoherent, but the staff observe him to be lucid at times.  Immediately prior to the incident, several staff report the patient coming out of his room into the hallway either nude or partially clothed.  He had to be redirected back into his room and asked to put a gown back on.  He was dancing and in some cases danced away from staff trying to help him into the gown.  With his history (and assuming that brain trauma has been ruled out) these can all be features of a severe psychosis.  His parents are concerned that they plan to discharge him without psychiatric consultation.  The hospital they are in does not have an acute inpatient psychiatric unit and he has not seen a psychiatric consultant.  They leave at some point to rent a car so that they can drive him to psychiatric facility if necessary.  While they are gone he becomes extremely agitated.  He is tasered several times and ultimately shot in the chest just 40 minutes later.

The New York Times article goes into detail about the issue of armed security in hospitals.  It reviews the number of people with mental illness who were shot or tasered and killed.  I have pointed out some of the problems with firearms in psychiatric hospitals in an article about visitors carrying firearms into Texas state psychiatric hospitals.  The same issues apply in this case.  Firearms are not a deterrent when confronting a person who is agitated and psychotic.  In this case the patient recalls that he was some kind of cyborg secret agent.  In that frame of mind he is likely to interpret any efforts to contain his agitation and aggression as potentially dangerous to him and it would provoke extreme behaviors to counter that aggression.  In every security setting where I have worked, security and law enforcement lock up their weapons and do not take them into patient care areas even if a patient is highly aggressive and out of control.  It takes well trained staff and security to be able to do this and recognize why this is the best approach.  It also involves a contingency plan to physically restrain the patient in a safe manner as quickly as possible if the patient does not respond to verbal deescalation.

The CMS document discloses several important pieces of information that are not in the media.  The first eye opener is that the hospital administration said the security officer was justified in shooting the patient because he had assaulted them.  That statement grates on any inpatient psychiatrist or nurse who recognizes that is not the appropriate frame of reference for this incident.  This is not a street fight.  This is a vulnerable patient in a hospital whose rights and standard of care needs to be recognized.  One of the implicit assumptions in most hospitals is that psychiatrists and psychiatric staff are supposed to view aggression as an occupational hazard.  A unidentified staff member speaks to that in the radio piece and is very explicit about the amount of aggressive behavior that he sees in the hospital and the fact that he gets hit.  That is not the case in other parts of the hospital where aggressive behavior is more frequently seen as criminal behavior.  Early statements from the hospital administration suggested that the law enforcement officers here were justified in shooting Alan Pean, but they were subsequently modifying their position.  He was also charged with 2 counts of aggravated assault on both of the law enforcement officers who entered his room.  Clearly this is a psychiatric problem and the patient needs  protection.  As I read through the 50 page document from CMS, the suggested solution varied from being vague to solutions that many hospitals already have such and an emergency response team for behavioral emergencies.  They suggest that armed law enforcement officers should be only in the ED, not be involved in the behavioral emergencies until all other resources have been exhausted and intervene only in the case of life-threatening or criminal activity.

One of the primary conclusions of the This American Life piece is that is could have been prevented if the patient had received a psychiatric evaluation.  A hospital staff person pointed out that this was standard procedure and also that any number of staff used to encountering aggressive patients could have contained the patient without firearms.  There is apparently an inpatient psychiatric unit at this medical center where he could have been transferred.  Alan Pean responds to Ira Glass's question about how it is that he went to the hospital with mania and psychosis and ended up getting shot in the hospital instead.  One of his conclusions is that he is a young black man and he does not think that it would happen if he was white.  He remains understandably traumatized by his near death experience.

The only logical conclusion here is one that I have already reached many times in many posts on this blog.  Violence and aggression are treatable problems when they are associated with psychiatric illnesses.  There needs to be psychiatric and psychiatric nursing expertise in major hospitals at several levels.  One of the unusual parts of this story was all of the information available suggesting that the patient in this case had a significant mental illness.  That was made even clearer when his physician father made the statement, requested the psychiatric evaluation, and was told that the patient was being discharged instead.  The CMS report does not address staffing levels in the hospital and whether there are adequate staff to address the problem.  In my experience, a nurse and another staff person going to address a situation where there is potential aggression by a young manic patient is not enough staff.  I have personally found myself in many situations when I walked in a room and there were four highly trained nursing assistants out in the hallway, ready to intervene if necessary.  In every case our goal was to protect the patient from injury.

The lesson in this case is that if you go to a hospital with aggressive behavior due to a psychiatric disorder somebody on the receiving end needs to know what to do to keep you safe.  Only a fraction of American hospitals are set up to do this and provide the necessary psychiatric care to resolve the crisis.  Some hospitals will never be equipped to deal with this problem and the practical solution in most communities is to triage violent and aggressive people to more appropriate facilities.  Even though the New York Times article points out that there has been a 40% increase in hospital violence, many of the people with that problem never make it there.  There needs to be enough capacity to treat people so that people with violent and aggressive behavior from a psychiatric illness can go to a hospital knowing that their problem will be diagnosed and treated and that their safety will be assured.  
             
Nobody should ever have to experience what Alan Pean went through.



George Dawson, MD, DLFAPA




References:

1:  This American Life.  579: My Damn Mind.  February 12, 2016.

2:  Elisabeth Rosenthal.  When The Hospital Fired The bullet.  New York Times February 12, 2016.

3:  Department of Health and Human Services Centers for Medicare and Medicaid Services.  Statement of Deficiencies and Plan of Correction.  St. Joseph Medical Center; 1401 St. Joseph Parkway, Houston Texas 77002.


Supplementary 1:

In the report by This American Life, it was apparent that at least some authorities were looking for evidence that the patient had aggressive tendencies outside of the episodes of mania and psychosis.  They did this by asking his family if he had any criminal convictions.  In the original hospitalization he was also noted to have THC in his toxicology.  The fact that there were no other drugs present and that THC can persist a long time was emphasized in the This American Life piece.  In fact, THC is not a trivial compound in this case.  No conclusions can be made based on the existing data and the lack of direct assessment of this patient, but this compound should be avoided by anyone diagnosed with bipolar disorder, especially if there is any doubt about the diagnosis.


Twitter Graphic:

Does Identifying Bipolar I Disorder Come Down To 6 Proteins?

The Mayo Clinic puts on very good conferences in Psychiatry.  Two of the last three that I have attended had a strong biological and genetic emphasis.  I was interested when I saw a reference in my Facebook feed to a study of potential biological markers of Bipolar I Disorder.  It was even better that the article was published in the open access journal Translational Psychiatry.  In the current article the authors looks at the results from the analysis of serum protein levels in controls and adults seeking treatment for depression and bipolar disorder.  The sera of their subjects and controls was analyzed by Myriad RBM in a quantitative immunoassay designed to search for biomarkers through large numbers of proteins.  The actual product and the proteins analyzed are described on the company's web page.  All of the six proteins identified as possibly being discriminating as listed in the above graphic including growth differentiation factor 15 (GDF-15),  hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4), and transthyretin (TTR) can be located on this page and additional information is provided about the specific proteins

The authors emphasize in several places that this is a pilot or exploratory study but also point out that sufficient power to detect odds ratios for pairwise comparisons between mood disorders versus controls, bipolar disorder versus controls, and bipolar I versus controls.  They looked at 272 proteins from 288 samples (141 controls, 52 Unipolar depression, 49 Bipolar II, and 46 Bipolar I).  It was a one time cross sectional sample and no longitudinal sampling was done.  Rigorous patient selection was used to reduce the risk of substance abuse disorders and inflammatory conditions. In a table describing patient characteristics, the cases had significantly greater BMI, greater lifetime illicit drug use,  greater BMI, greater percentage of smokers, and fewer years of education.  Existing symptoms were rated with the following scales IDS-C (depression), PHQ-9 (depression), GAD-7 (anxiety), YMRS (mania), and AUDIT (alcohol use).  The cases were also being actively treated with antipsychotics, AED mood stabilizers, lithium, antidepressants, sedative/hypnotics, and thyroxine supplement.

The graphic from the article labelled figure 2 above shows the differences in protein concentrations for the six proteins that were significantly different after Bonferroni correction by diagnosis.  As can be seen from the figure all six proteins were at the highest levels in Bipolar I disorder.  ROC curves and the ROC-AUC was used to determine which proteins were better predictors of Bipolar I Disorder.  The text contains theoretical and speculative discussions of these particular proteins, what they have been associated with so far, and what importance that has for the issue of why their concentrations may vary in bipolar disorder.

There are a number of relevant considerations when looking at this type of proteomic analysis.  The most obvious is the assumption that the underlying dynamics of the biological substrate can be measured in meaningful ways by knowing the protein signature of those systems.  Although most of us are used to looking at cartoon depictions of neuron and synapses but the reality is much more complex.  Recent work in Science shows that there are 62 proteins associated with synaptic bouton (2) and vesicle trafficking and that the copy number of these proteins varies greatly.  The authors of that paper speculate that the production and number of those proteins may vary because some physical locations within the neuron may allow for an enrichment effect.  One of the implicit assumptions in the Frye, et al paper is that psychiatric disorders may have a unique configuration in terms of synaptic architecture and that it will be reflected in the proteins responsible for that architecture.  A further assumption is these CNS protein changes are all going to be reflected in the periphery and detectable in blood samples.  

Although it is premature to draw many conclusions about the data in this study, the implications may be far reaching.  It will be an interesting day in psychiatry if and when proteins will be used as biomarkers.  It will be an interesting day even if variants can be found and reliably detected.  Until then students of neuroscience and psychiatry will be able to appreciate that information flow in these systems is significant and we are just on the cusp of being able to understand it.  We are just at the stage of moving from cartoon versions of neurons - to the real thing.


George Dawson, MD, DFAPA

References:

1: Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. 2015 Dec 8;5:e689. doi: 10.1038/tp.2015.185. PubMed PMID: 26645624.

2: Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884. PubMed PMID: 24876496.

Attribution:

The figure at the top of this post is from the above reference 1 and is used per the conditions of a Creative Commons Attribution 4.0 International License.

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.

Silver Lining Playbook - Propsychiatry?

I went to see this film today for a couple of reasons.  Several people recommended it to me as a “pro-psychiatry” movie.  And I saw Robert De Niro interviewed about this movie with some of the cast and he was overcome with emotion and attributed it to the main character of the story and what he apparently went through with bipolar disorder.  As a film the structure and pace of this are well done.  It is enjoyable to watch.  The ensemble cast of Bradley Cooper, Jennifer Lawrence, Robert DeNiro and Jackie Weaver are focused at times on how depression and bipolar disorder affect people and their families.  I think it is generally known that the film focuses on Cooper’s character Pat, at the outset.  We learn that he has been court ordered to a psychiatric hospital.  In one of the opening scenes his mother picks him up and drives him to home to Philadelphia where he is supposed to comply with court ordered therapy, medications, and the conditions of a restraining order that prohibits him from contacting his wife or coming within 500 feet of her.  A police officer shows up to encourage compliance with the restraining order.

The first question in evaluating the movie and my friends’ comments is whether this very entertaining and well acted film is psychiatrically plausible.  Could the Cooper character (Pat Solitano) assault someone with the vigor we see in the film and end up being diverted to what appears to be a low security state psychiatric facility.  My understanding is that the film is based on the novel The Silver Linings Playbook by Matthew Quick.   There seems to be a general consensus that the film version is a very loose adaptation so I suppose I would need to read the novel to see the way this part of the plot was framed.  In real life, assaultive behavior in most states is handled as a criminal matter rather than court ordered psychiatric treatment.  It is one of the reasons that county jails have become large psychiatric facilities.  In some cases there is psychiatric care provided in jail.  In more enlightened systems competency evaluations are provided in jail and that may result in diversion to mental health court rather than criminal court.  An insanity plea has a low likelihood of success and defense attorneys are reluctant to consider it because the length of stay in a psychiatric hospital may be longer than in jail.

In this case Pat has been in the hospital for about 8 months.  We are told his mother made some kind of a deal to get him out.  In the process, one of his fellow patients leaves in the same car illustrating that security is not a priority.  While he is in the hospital, Pat spits his medication out after a mouth check by a nurse and when he gets home he proclaims he is not taking the medication because it affects his mental clarity and gives him physical side effects.  He is intense, wakes his parents up in the middle of the night, and creates a high level of tension in their home.  His parents seem at a loss in terms of how they can help him and invariably end up reminding him about the conditions of his release.  His apparent mental illness peaks with a scene where the entire neighborhood is disrupted and he physically injures his parents.  He eventually begins taking the medication.

His relationship with Tiffany (Jennifer Lawrence) begins in parallel with his initial stability and proceeds as he is getting more stable.  She also discloses a significant depression associated with her husband’s death and some sexual promiscuity.  She is portrayed as a very intense and at times angry and agitated women who is aware of the controversial parts of her character and says she has accepted them.  She has several angry confrontations with Pat and a very animated confrontation with his family about whether or not she is good for their home team’s juju.  Her emotional relationship to Pat as he recovers is one of the most compelling parts of the film.

At various moments, Pat is seen with his psychiatrist Dr. Patel (Anupam Kher) who does a good job of engaging a hypomanic Pat in movie psychotherapy.  Dr. Patel did have qualities that most people would like to see in a physician.  He listened, he was engaged, and he was able to relate to Pat.  In the first clinic scene, we learn that Dr. Patel played some music (or said that he did) to see how Pat would react.  Pat trashed the magazine stand in the waiting area.  This is dramatic license rather than actual psychiatry.  I can’t imagine any reasonable psychiatrist who would be eager to provoke a reaction from a person with a history of aggression who has been conditionally released from a state psychiatric facility.  The reality of these appointments for people with severe mental illnesses is that most of the time is not focused on psychotherapy.  In most public or managed care clinics Dr. Patel would have about 20 minutes to see Pat, discuss his symptoms, discuss medication side effects, order and review labs, and do the necessary documentation.  A casual armchair conversation like the one portrayed in the movie can occur only in special circumstances.

After the initial sessions we next meet Dr. Patel tailgating in the parking lot outside of the Philadelphia Eagle’s game.  He embraces Pat and utters a word that I have never heard a psychiatrist say.  There is an ugly scene involving racism and Dr. Patel and his fellow Indians and some of the locals.  Pat is back in the middle of this fighting to protect his brother.  Although he is arrested they all (including Dr. Patel) end up back at Pat’s parents home – a significant boundary problem.

I think that it is pretty obvious that I don’t really see this as a “pro-psychiatry” movie.  Psychiatrists don’t really act like Dr. Patel and many of the scenes highlighting problems with mental illness are more probably affected by dramatic license.  Some of those scenes were well done in terms of the chaos, aggressive behavior, anger and stress associated with mental illness.  Critics have faulted the film for not going far enough diagnostically, being an antipsychiatry film in that it demonstrates the failures of medical psychiatry, and generally seeing it as a random display of neurosis without enough details.  I think the outlines are there, but let’s face it.  This is not a clinical exercise.  This is art.  When I go to the movies, I am looking for compelling characters and good acting.  It is even better if those characters are acting out a fantasy that I can identify with.  Cooper and Lawrence clearly have a level of intensity that you don’t see in many places these days.  So while this film was really not about psychiatry (certainly not “pro-psychiatry”) it was very entertaining and it captured a lot of the reasons why I go to the movies.

I would like to have read what Robert De Niro read that gave him insights into the pain of the main character.  From what I saw today, they only scratched the surface on that issue.

George Dawson, MD, DFAPA