Cannabis and Causation

Cannabis use is highly politicized in the US at this time largely due to legalization rhetoric that has spilled over into scientific research on the topic.  Despite the broad movement to legalize cannabis across the US, only a minority of the population are regular cannabis users.  More widespread use will undoubtedly lead to increased problems associated with wider exposure, especially wider exposure in populations with vulnerabilities to the toxic effects of cannabis.  The toxic effects of interest include addiction and psychosis.  It is common in clinical practice to encounter daily cannabis smokers who stopped using the substance after several years because they started to get panic attacks, paranoia, or both.  The people I see have all moved on to something else, but there are also a substantial number of chronic smokers who are addicted.  That number is about 9% of users, and that is comparable to the amount of people who have problems from drinking alcohol.  Inpatient psychiatrists commonly see people with florid psychotic episodes from smoking significant quantities of cannabis.  They also see repeat admissions from people who are either detoxified or treated for these psychotic episodes, are discharged and smoke more cannabis to the point of a repeat psychotic episode.  The longstanding controversy among people who are not doing the work and just speculating is whether any good observational studies can be done to show that cannabis does cause psychosis or if this is an artifact of observational methodology.  In other words,  could a reverse causality bias exist that makes people who are prone to schizophrenia or psychotic episodes more likely to smoke cannabis.  In my opinion, there have been excellent observational studies showing the association between cannabis use and psychosis, but as long as that is the technology these studies will always contain the old association is not causation qualifier.

A recent paper (1) in Molecular Psychiatry may have just illustrated the causation that psychiatrists have been experiencing firsthand for decades.  The authors use a novel genetic appraoch to look at the issue of causation.  The main assumption of this study is that using specific genotypes as the independent variable rather than observed individuals gets rid of the confounding demographic and environmental variables that could be casual.  They point out that any actual clinical trial looking at the issue of whether cannabis causes psychosis would be unethical, but that a model that looks at whether causation can be established by looking at single nucleotide polymorphisms (SNPs) from a Genome Wide Association Study (GWAS) looking at the any cannabis use phenotype.  They looked at the top 10 SNPs from that data that were used to calculate gene-exposure (SNP-cannabis) estimates.  SNP-risk of schizophrenia exposure estimates were calculated from available data from the Psychiatric Genomics Consortium.  Instrumental variable estimates were made by dividing the risk of schizophrenia/risk of any cannabis use.  The instrument variable analyses were pooled across SNPs and analyzed with fixed effect meta-analysis.  The authors provide a detailed discussion and rationale for their statistical calculation in the full text of the article and supplementary material.  At this point I am going to post their main graphics.  Click on any graphic to enlarge it.

The first graphic looks at prospective observational studies.  The authors were interested in determining whether their genetically based analysis was in the same direction of this meta-analysis. Ever use cannabis use was associated with a 43% increase in schizophrenia or psychosis.

Figure 1. Meta-analysis of prospective observational studies reporting an association between use of cannabis and risk of schizophrenia or related disorders. Meta-analysis uses a random-effects model. Studies are sorted by type of outcome (schizophrenia only vs schizophrenia and related outcomes). Odds ratios (ORs) and 95% confidence intervals (CIs) express the risk of schizophrenia or psychotic symptoms for ever use of cannabis (compared with never use). For additional information on each study, see Supplementary Table S1. Dunedin, Dunedin Multidisciplinary Health & Development Study; ECA, Epidemiologic Catchment Area; EDSP, Early Developmental Stages of Psychopathology Study; NEMESIS, Netherlands Mental Health Survey and Incidence Study; SC, Swedish Cohort.

Figure 2 looks at the Mendelian Randomization analysis of 34,241 cases of schizophrenia and 45,604 cases of ever use cannabis.  This shows a 37% risk of cannabis users versus non-users for schizophrenia/psychosis risk.  The authors did a sensitivity analysis of this same data by removing each SNP from the analysis to calculate a summary causal effect of 1.33 across all 10 SNPs or 1.88 when restricted to 2 functional SNPs.

Figure 4 is included here to illustrate the authors' sensitivity analysis showing a summary casual effect of about 1.37 (red line).

All things considered this may be a compelling story for causation.  I qualify that of course in a couple of domains.  First. there are a lot of statistical models and calculations operating here.  In my experience mapping complex statistical estimates onto the most complex object in the universe has not worked out very well.  My first hand experience was statistical modeling of quantitative EEG and claims that is was predictive of psychiatric diagnosis.  Those compelling calculations published in Science (4) did not pan out at all in the long run.  It will be interesting to see if the authors applications are more widely applied to other SNPs to determine disease causation from other risk factors.  The second potential problem is a slight variation on that theme and that is the overall imprecision of meta-analysis.  The known  approximate prediction/concordance rates of meta-analyses for clinical trials (2.3) suggests that it may not be good predictor of a reproducible result.  The authors themselves suggest that the potential limitations of their study start with the fact that none of the chosen SNPs met conventional genome wide significance thresholds.  The specific dose effect of cannabis could not be investigated in the study.  The age at exposure is may be a developmental variable of interest and that was unknown.  The Mendelian Randomization techniques may have not been powerful enough to detect pleiotropic (one gene affecting more than one trait) effects, but they discuss how an alternate analysis applies in this situation.

The other question I had was about epigenetic effects on this model.  The authors were certainly aware of smoking as a confounding variable.  The known epigenetic effects of nicotine on brain chromatin would seem to cloud SNPs as pure genetic risk factors.  But this is nonetheless one of the more interesting models and concepts I have seen in a while.

They conclude that their study is "the closest approximation to a randomized trial on the effect of ever use of cannabis and risk of schizophrenia" when such a clinical trial is unethical.   That is an interesting take on their method and causation.  Hopefully it will open up the way for other studies of causation using these techniques.  If that is the case, it is a good idea to study this paper and the supplementary material (26 pages) and have a good idea about its difference from observational/association studies.  The supplementary material is also very useful for the calculations used in the study, a Venn diagram of the overlap between the schizophrenia-GWAS group (N=79,845) and the ever-use cannabis GWAS group (N=37,957), and their review methods of the best observational studies of cannabis use and  schizophrenia/psychosis.  



George Dawson, MD, DFAPA



References:

1: Vaucher J, Keating BJ, Lasserre AM, Gan W, Lyall DM, Ward J, Smith DJ, Pell JP, Sattar N, Paré G, Holmes MV. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry. 2017 Jan 24. doi: 10.1038/mp.2016.252. [Epub ahead of print] PubMed PMID: 28115737.

2: LeLorier J, Grégoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997 Aug 21;337(8):536-42. PubMed PMID: 9262498.

3: Ioannidis JPA, Cappelleri JC, Lau J. Issues in Comparisons Between Meta-analyses and Large Trials. JAMA. 1998;279(14):1089-1093. doi:10.1001/jama.279.14.1089

4:  John ER, Prichep LS, Fridman J, Easton P. Neurometrics: computer-assisted differential diagnosis of brain dysfunctions. Science. 1988 Jan 8;239(4836):162-9. PubMed PMID: 3336779.

"The standard for psychiatric diagnosis and categorization in the United States and Canada is now DSM-III and soon will be DSMIIIR. The categories defined therein have often been criticized as nothing more than a compilation of symptoms. The results obtained with neurometrics have shown that at least the categories studied are much more than arbitrary groupings of symptoms. ............. Validity-the great deficiency of psychiatric nosology - is beginning to emerge and, thus far, to reveal an impressive concordance with biology." p. 169

5: Smith GD, Ebrahim S. Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies. In: National Research Council (US) Committee on Advances in Collecting and Utilizing Biological Indicators and Genetic Information in Social Science Surveys; Weinstein M, Vaupel JW, Wachter KW, editors. Biosocial Surveys. Washington (DC): National Academies Press (US); 2008. 16. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62433/

Selected References on Mendelian Randomization

Attributions:  All graphics except my home-made one at the top are from reference 1 per a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.




Supplementary 1:

With today's publicly available genetic technology it is possible for a person to search their own DNA for the SNPs found in this study.  When I do that using a database where my DNA analysis resides I found the following SNPs from this study from chromosomes 15, 4, and 12 respectively.  I have linked them  to the dbSNP database at NLM:

rs4984460

rs7675351

rs2099149

It is interesting to speculate on what it means to have 3/10 genetic markers for schizophrenia/psychosis susceptibility if any cannabis exposure.


Supplementary 2:  Click on my homemade graphic to see how beautiful it is.  Blogger does not do it justice.

Remission Before Discharge? An Un-American Concept

I encountered a paper this week that had me nostalgic for the old days in American psychiatry.  The days when people were treated in hospitals to the point that their symptoms remitted before they were discharged.  That of course depends on a couple of assumptions.  The first is that their symptoms can be treated to that point.  There are a number of people with a disease process that cannot be treated to that point.  Neurodegenerative disorders like Alzheimer's disease or vascular dementia are good examples, but there are also a number of people who have no known brain insult and yet have treatment resistant depression or psychosis.  Their symptoms do not respond or poorly respond to treatment.  The second assumption is that the person with the illness recognizes why they need to be in a hospital or some form of intensive treatment and they agree to stay long enough.  That is one of the more complicated assumptions because psychiatry is almost exclusively the only medical specialty where the treating physician can disagree with the patient's preference for discharge and put them on a hold pending a judge's decision to order them to stay in a hospital longer.  That court decision in most states depends on three standards - danger to self, danger to others, and general ability to care for oneself.  Those three standards have been condensed over the years to a single word dangerousness.  Practically all inpatient treatment units in the United States are impacted by managed care companies who would generally like people discharged in about 3-5 days irrespective of their diagnosis or treatment plan.  Their de facto discharge criteria is dangerousness.

If you are reading this for the first time, it may sound absurd to base a medical decision on an oversimplified legal standard that is designed to not unduly impact the civil liberty of citizens.  It is definitely absurd for any number of reasons.  If you work in inpatient settings you can have the most carefully crafted treatment plan to restore a person to their previous level of functioning and have to tolerate a managed care case manager or physician ask you "Where is the dangerousness?"  If there is no dangerousness the expectation is that the patient will be discharged and if you (as the treating physician) disagree - the insurance company via their own review can just stop paying for the hospitalization.  The practical result of all of that politics is that a partially stabilized patient is discharged.  That would be bad news if that person was dangerous, but what nobody talks about is that it is probably worse if they are not.  First, the vast majority of people that psychiatrists treat in inpatient units are not dangerous but they are having a very difficult time functioning both in terms of symptom management and what they need to manage in life every day.  If they are partially treated, it is very likely that they will not be able to follow up with a detailed treatment plan.  Managed care companies and the usual critics of psychiatry frequently rationalize this process with global statements like "the outcomes are no different" or inpatient treatment especially involuntary inpatients treatment is not necessary.  The problem is that there are very few studies that look at the process.  After all, who has an interest in continuing to discharge partially stabilized patients?  It is certainly not psychiatrists, patients or their families.

The study I encountered was in the Journal of Clinical Psychiatry this month (1).  The investigators are from the Netherlands.  They looked at 78 cases of postpartum psychosis admitted to the Mother-Baby Inpatient Unit (MBU) at the Erasmus Medical Center between August 2005 and June 2011.  The MBU is a specialized unit to treat cases of severe psychopathology during the postpartum period.  Patients with an onset of psychosis or mania within 6 weeks of the delivery were included.  They included the typical DSM functional psychosis categories and mood disorders with psychotic features.  Substance induced psychosis was excluded.  Of the final group 64 patients had only postpartum psychosis and 14 had either a prior episode of psychosis or mania/hypomania.  The authors had previously developed a standardized approach to treating postpartum psychosis that involved using typical medications indicated for acute inpatient stabilization.  The goal was remission of their symptoms for one week prior to discharge with standard recommendations for pharmacotherapy to maintain symptomatic remission.  They were followed for 9 months and by that time 16 patients had discontinued medication with the remainder taking lithium (n=40) or antipsychotic monotherapy (n=8).

The main outcome measure used was the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT).  That research instrument looked at a number of domains including work, interpersonal relationships, global satisfaction, and recreation.  All of these areas have been shown to be adversely impacted in other studies of the problem of postpartum psychosis.  As an example the authors quote a study that noted a divorce rate of 18% in a similar cohort of patients.  In a previous post on this blog, I made the observation that many women seen in inpatient practice who have a chronic psychotic disorders can be traced back to an initial episode of postpartum psychosis.  The authors here note that although they may have had a sample with low premorbid complications their outcomes were generally very good compared to previous retrospective studies and a matched sample of postpartum women.  As an example, 88.5% of the women had resumed full work and household responsibilities.  In comparison to a general postpartum population, the experimental group showed slightly more anxiety and depressive symptoms due to the the portion of the sample that relapsed.  In comparison to a group of patients with first episode bipolar disorder occurring outside of the postpartum period the comparison favored the experimental group.  Despite the usual limitations of these studies like sampling bias and missing data, the authors conclude that there is plenty of optimism in the treatment of postpartum psychosis using their methodology.  In what I consider to be an understatement of the past three decades in American psychiatry the authors write about how a specialized unit may have biased their results: "Unfortunately, many regions of the world do not have MBU care within a reasonable travel distance for the patient."  To my knowledge there are no MBUs at all in the United States.  They are inconsistent with the prevailing managed care rationing model for psychiatric care in this country.

This is a very important article for a number of reasons.  It highlights the importance of specialized care for women with postpartum psychosis through reduced chronicity and better functional outcomes.  The psychopharmacology result with lithium or antipsychotic monotherapy and discontinuing all benzodiazepines prior to discharge is far superior to any result that could be expected in the US.  Short stays result in polypharmacy.  I would be shocked to see any case of postpartum psychosis not discharged on antidepressants, antipsychotics, benzodiazepines, sleep medications and possibly valproate from American inpatient units.  These medications are difficult to manage and the follow up appointments are typically brief and focused primarily on symptoms and medications.

In the trade off between short lengths of stay and unmanageable polypharmacy - it seems like this research group has developed a quality approach.  It is time for American psychiatrists to acknowledge that the way inpatient units are run by businesses is not working because they never adequately stabilize patients.  That leads to a large population of people who are unnecessarily symptomatic and never recover their baseline level of functioning.  That same population may be taking a lot of medication  that they don't really need.


George Dawson, MD, DFAPA                        
 


Supplementary:

I confirmed that there are no MBUs in the USA and that the median length of stay on the unit described in this study was 55 days.


References:

1: Burgerhout KM, Kamperman AM, Roza SJ, Lambregtse-Van den Berg MP, Koorengevel KM, Hoogendijk WJ, Kushner SA, Bergink V. Functional Recovery After Postpartum Psychosis: A Prospective Longitudinal Study. J Clin Psychiatry. 2017 Jan;78(1):122-128. doi: 10.4088/JCP.15m10204. PubMed PMID: 27631144.

2: Bergink V, Burgerhout KM, Koorengevel KM, Kamperman AM, Hoogendijk WJ, Lambregtse-van den Berg MP, Kushner SA. Treatment of psychosis and mania in the postpartum period. Am J Psychiatry. 2015 Feb 1;172(2):115-23. doi: 10.1176/appi.ajp.2014.13121652. PubMed PMID: 25640930.


Attribution:

Photo at the top is Erasmus Medical Centre - the affiliation of the lead author in this article and location of the study.  It was downloaded from Shutterstock on February 8, 2017 per their agreement specifying editorial and noncommercial use.

Editorial credit: Jaroslav Moravcik / Shutterstock, Inc.
ROTTERDAM, NETHERLANDS - APRIL 1: Erasmus medical centre in Rotterdam on April 1, 2014 in Rotterdam

The Recurring Question Of Antidepressants During Pregnancy

Over the course of my career, the question of whether  or not women should take antidepressants while pregnant has been a recurring question.  The point-counterpoint seems to depend on whether you are a psychiatrist treating women with severe forms of depression or not.  A lot of these studies seem to be driven by the fact that there is a registry somewhere for pregnant women who have had exposure to various medications.  Studies like this make headlines and are simplistically interpreted.  That is a much different perspective than a psychiatrist who is talking with a woman who has had severe postpartum depression and does not want to experience that again.  There is also the case of acute care psychiatrists who have assessed many women who had a significant change in their mood and mental state during or after a pregnancy and never recovered from that.  They became chronically mentally ill at that point and sustained all of the expected comorbidity.  The first few times I encountered that situation it was difficult to accept.  Nobody teaches that in medical school or residency training.  It seemed like a well kept secret.  Since then I have seen many women who developed a chronic mental illness that started as a severe mood change in or immediately after pregnancy.

The most recent question arose as a result of the study in reference 1, an analysis of the Quebec Pregnancy Cohort.  These same authors have an additional 9 references in Medline.  Full text is available for the current study.  The conclusion of these authors is that SSRI, SNRI, and TCA type antidepressants are associated with a significant increase in congential malformations - specifically as cardiac, musculoskeletal, craniofacial, digestive and respiratory defects.  The authors have a detailed flow diagram that details patient selection from the original cohort of 289,688 pregnancies between 1998-2009.  The flow diagram is a good illustration of how the original cohort was narrowed down to 18,487 pregnancies with either first trimester exposure to antidepressants (3,640) or no exposure (14, 847).  Subgroups for the antidepressant exposure include SSRIs (2,327), SNRIs (738), TCAs (382), and other (193).  The numbers and percentages of major malformations for each group were no exposure 1650/14,847 (11.1%), SSRI 279/2327 (12%), SNRI 91/738 (12.3%), and TCA 51/382 (13.4%).    Over the ten year course of the study the prevalence of antidepressant use doubled from 21 to 43 women per 1,000 pregnancies.  Doing some quick arithmetic on those numbers we find that 11.6% (421/3,640) of the antidepressant exposed pregnancies resulted in major congenital malformations.  Using the baseline rate of the unexposed pregnancies to calculate the expected number of major malformations results in 404/3,640 or a difference or 17 major malformations in the exposed group of 3,640 pregnancies.

What did the authors consider to be major malformations?  They used definitions of major congenital malformations according to conventions in two databases and they provided ICD-9 and ICD-10 diagnostic codes.  There were very few named diagnoses as far as I could tell.  There is some concern here because the literature on congenital malformations varies a bit in terms of the rate of birth defects and whether they are considered to be major or not.  Some of this was expressed in a NEJM editorial by Greene in 2007(2).  In commenting on two papers (3,4) on the subject of major congenital malformations associated with SSRIs in that edition he notes that  "A survey of the aggregate data now available — positive, negative, and equivocal — makes it clear that neither SSRIs as a group nor individual SSRIs are major teratogens on the order of thalidomide or isotretinoin."  He goes on to elaborate that there is a low risk with SSRIs but it is not zero and it is not clear cut.  That opinion is in contrast to some written since suggesting that the risk is high enough that no women should be exposed to SSRIs. 

One of the strengths of this study is that they used depressed and anxious mothers as the reference group to attempt to remove any confounders due to those conditions.  A variety of diagnostic codes were determined including 33 ICD9/10 codes for episodic mood disorders, 17 ICD9/10 codes for neurotic disorders, 19 ICD9/10 codes for depressed, anxious, and other cognitive disorders, 3 ICD9/10 codes for adjustment disorders, and 2 ICD9/10 codes for depression not otherwise specified.  Data on indications for antidepressant use were not available but the authors sought to limit indication bias by comparing only women selected for diagnoses of depression.  Women were selected with diagnoses of anxiety or depression who were treated with antidepressants one year before their pregnancy and several exclusion criteria such as exposure to more than one antidepressant or multiple births were applied.  Total psychiatric visits were viewed as a proxy measure for severity rather than confirmation of the diagnosis.        

The primary statistic used in this paper was the Odds Ratio (OR) or Adjusted Odds Ratio (aOR).  I have been skeptical of some applications of OR in the past.  There are also theoretical concerns as discussed in reference 2 below.  The authors present an excellent argument that the OR is widely used in epidemiological studies because it characterizes population variations in risk.  The weakness is that it has low accuracy as a classifying marker and it tends to overestimate relative risk when sample size is low.  A number of papers also point out that when large numbers of comparisons are done like calculating the OR and aOR for a large number of antidepressants it is likely that some of the findings will be explained by chance.  In this case they do the calculations by antidepressant, overall major congenital malformations and by individual body systems.  They conclude that only exposure to citalopram  [(aOR) 1.36, 95% CI 1.08 to 1.73]  in the first trimester increases the risk of major malformations but that there was a trend with other antidepressants (ADs) and that some ADs seemed to result in more system specific malformations.  Another methodological problem that can occur and affect comparisons is when the control group has an unexpectedly large number of malformations and this has happened in some of the research studies.

A much larger study of the problem was provided by the NICE consortium in the UK and their 923 page document on the subject (17).  The supplement of Forest plots alone for this document is an additional 313 pages long.  The authors of this document carefully selected studies of prenatal exposure to psychiatric medications and compiled fairly large studies.  They also showed the actual numbers of lesions in the exposed and unexposed groups by rates and the absolute differences in addition to the OR.  The NICE methodology was exhaustive and included very large number of patients across 6 major drug classes - antidepressants, antipsychotics, anticonvulsants, lithium, benzodiazepines, and stimulants.  The antidepressants studies listed sample sizes ranging from 50,257 to 2,548,463.  According to the authors there was no statistically increased risk in major congenital malformations with SSRIs even though the absolute risk difference was 12 more per 1,000.  There were some possible system specific risks with paroxetine and fluoxetine with a range of absolute risk difference of 3-9 more per 1,000.  In their guideline they translated this to a series of prescribing principles that could be applied to prescribing antidepressants in pregnancy (p 813).  These principles amount to a detailed informed consent discussion about potential risk during pregnancy and breastfeeding.  The document also contains the observation that up to 90% of women stop taking medication when they find out they are pregnant.  That often happens without consultation.

Attending meetings where psychiatrists are the presenters and focused on maternal health provides a much different perspective than pregnancy databases focused on congenital malformations.  In the past couple of years I was to attend three conferences, two of which occurred at the University of Wisconsin Annual Updates.  In all three of those conferences the maternal burden of anxiety and depression is the context and is generally presented first.  Katherine Wisner (11) presented in Madison last year.  Here arguments were based on the fact that psychiatric disorders are the most common chronic conditions of women of childbearing age and that the rate of treatment is very low: 25.5% of non-pregnant women and 14.3% of women who were pregnant in the past year.  She pointed out that medication free and disease free pregnancies are a myth.  Pregnant women get sick and sick women get pregnant.  About 14.5% of pregnant women have a new episode of depression and about 14.5% of women have an episode of postpartum depression.  Dr. Wisner is one of several authors who referenced Cohen's work (6) on the recurrence risk of depression in women who discontinued antidepressants  around the time of conception versus those who did not (68% versus 26%).  Click to enlarge this graphic.

JAMA. 2006 Feb 1;295(5):499-507 with permission

The presentation by Zachary Stowe (10) used the Cohen survival curve to illustrate recurrent depression with antidepressant discontinuation in pregnancy.  He also showed survival curves of treated versus untreated bipolar disorder by Viguera (16) showing that 90% of untreated pregnant bipolar patient relapse during the pregnancy out ot 12 weeks post partum compared to 40% of treated bipolar patients.  He also had two excellent slides on the acute maternal and neonatal consequences of a relapse to a mood disorder documenting numerous neonatal complications maternal complications including suicide.

Michelle Wiersgalla (12) expanded the postpartum disorders to include anxiety and psychosis.  She pointed out that suicide accounts for 20% of the post partum deaths and that suicide was the second leading cause of death in post partum women.   Some sources have classified it as the leading cause of maternal death (13, 14).  Infanticide occurs at the rate of about  8/100,000 and is associated with post partum psychosis.

All of those presenters would seem to have made a strong case for treating mood and anxiety disorders in pregnancy.  And of course the sterile research statistics are nothing like stress of clinical practice when a patient suddenly is destabilized and becomes unpredictable to both their family and the treating physician.  There is also the stress of an unplanned pregnancy in a woman who is being treated for a psychiatric disorder and that speaks to one of Dr. Stowe's main point and that is to treat all women of childbearing age in your practice as being potentially pregnant and documenting method of contraception and advice adn planning on pregnancy given the medication that they are taking.

It seems to me that the recurring problem of antidepressant safety during pregnancy is driven by a large body of research with widely discrepant low frequency findings.  We are generally talking about rates that are in the single to low double digits out of a thousand.  I think the conclusions of that research are probably affected by who is doing it.  You can find people who are interested in "proving" that antidepressants are harmful on the one hand.  They are likely to write from that perspective and minimize or completely ignore the severity of the associated women's mental health problems and the fact that they can be clearly treated with antidepressants.  They also never mention the potentially severe outcomes associated with untreated postpartum depression that can be observed in acute care settings.  On the other hand, there is research written from the perspective of treating women's mental health problems that (unexpectedly) will show less harm.  Clinicians - especially psychiatrists on the front lines who are often left advising women with unexpected pregnancies on what to do about their antidepressant treatment are stuck in the middle.  

A reasonable informed consent discussion with women of childbearing age begins by treating all women in this category as though they are potentially pregnancy or will be at some time. That includes a history of pregnancy and any associated changes in mood or anxiety.  It also includes a discussion of going from a no risk state for the fetus of not being pregnant while taking medications  to pregnancy while taking medication.  That includes plans for pregnancy and documenting the method of birth control.  With some high risk drugs - screening for pregnancy can be done.  If there is any concern about absolute minimization of risk pregnancy screening can be done and repeated if necessary.  In the case of planned pregnancies a window of 6-12 months prior to conception allows for a scheduled taper and discontinuation of the antidepressant medication.  The psychiatric evaluation can be valuable to determine the risk of relapse in these situations.  There are many patients who started taking antidepressants in acute situations where the stressor no longer applies.  There are many patients taking antidepressants for anxiety disorders who have never received psychotherapies for anxiety.  After these practical measures have been exhausted the decision comes down to whether or not there is an unplanned pregnancy and exposure or a situation where the discontinuation of the antidepressants would potentially be problematic.  In the cases I have been involved in, the women were also seeing high risk obstetric specialists and their pregnancies were closely monitored.    

As far as the actual drugs go, I do not think that paroxetine should be prescribed.  I am not basing that on anything in the pregnancy or congenital malformation literature.  I am basing it on my experience in psychiatry and the fact that in the first few years of its release - I determined it was a problematic drug in terms of drug interactions and discontinuation symptoms.  Why prescribe a problematic drug when there are plenty of other equivalent drugs?  I do not understand why anyone prescribes paroxetine these days.  That said, you can look at all of the data from the analyses of pregnancy registries and the difference in complication rates between drugs is so narrow and so small that the difference in changing to another drug with a lower odds ratio for congenital malformations probably makes little sense.  That does not mean that nobody will want to change and patient preference in this case requires a thorough and neutral discussion.



George Dawson, MD, DFAPA


References:

 1: Bérard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017 Jan 12;7(1):e013372. doi: 10.1136/bmjopen-2016-013372. PubMed PMID: 28082367

2: Greene MF. Teratogenicity of SSRIs--serious concern or much ado about little? N Engl J Med. 2007 Jun 28;356(26):2732-3. PubMed PMID: 17596609.

3: Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-2692

4: Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-2683

5: Andrade C. Understanding relative risk, odds ratio, and related terms: as simple as it can get. J Clin Psychiatry. 2015 Jul;76(7):e857-61. doi: 10.4088/JCP.15f10150. PubMed PMID: 26231012.

6:  Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P.  Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker.  Am J Epidemiol (2004) 159 (9): 882-890 https://doi.org/10.1093/aje/kwh101

7: Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998 Mar 28;316(7136):989-91. Review. PubMed PMID: 9550961.

8: Deeks J. When can odds ratios mislead? Odds ratios should be used only in case-control studies and logistic regression analyses. BMJ. 1998 Oct 24;317(7166):1155-6; author reply 1156-7. PubMed PMID: 9784470.

9: Bracken MB, Sinclair JC. When can odds ratios mislead? Avoidable systematic error in estimating treatment effects must not be tolerated. BMJ. 1998 Oct 24;317(7166):1156; author reply 1156-7. PubMed PMID: 9841055.

10: Zachary N. Stowe, MD  Treatment of Mood Disorders in Pregnancy and Lactation: Where Are We Now?  Presented at 2nd Annual Update And Advances In Psychiatry.  October 10-11, 2014; Madison, Wisconsin

11: Katherine Wisner, MD, MS.  Treating Depression During Pregnancy: Are We Asking the Right Questions?  Presented at 4th Annual Update And Advances In Psychiatry.  October 14-15, 2016; Madison, Wisconsin

12: Michelle Wiersgalla, MD.  Postpartum Mood and Anxiety Disorders.  Presented at the Minnesota Psychiatric Society.  October 1, 2016.

13: Oates M. Suicide: the leading cause of maternal death. Br J Psychiatry. 2003 Oct;183:279-81. PubMed PMID: 14519602.

14: Knight M, Nair M, Tuffnell D, Kenyon S, Shakespeare J, Brocklehurst P, Kurinczuk JJ (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care - Surveillance of maternal deaths in the UK 2012-14 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-14. Oxford: National Perinatal Epidemiology Unit, University of Oxford 2016.

"Maternal suicides have now been reclassified by the World Health Organisation as a direct cause of maternal death. The rate of maternal death by suicide remains unchanged since 2003 and maternal suicides are now the leading cause of direct maternal deaths occurring within a year after the end of pregnancy" p. 11.

15:  Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R,Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. Erratum in: JAMA. 2006 Jul 12;296(2):170. PubMed PMID: 16449615.

16:  Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A,Zurick A, Cohen LS. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry. 2007 Dec;164(12):1817-24; quiz 1923. PubMed PMID: 18056236.

17.  National Collaborating Centre for Mental Health.  Antenatal and Postnatal Mental Health Clinical Management and Service Guidance (Updated  Edition 2014). National Clinical Guideline Number 192.

Specific guidelines on treating depression in pregnancy for psychiatrists starts on about page 848 and continues.  A full gamut of treatment interventions in the context of clinical history and evaluation, patient preferences, and informed consent is presented.


antidepressants "congenital malformation"

antidepressants congenital malformation 

antidepressants pregnancy



Attribution:

The figure in the above post if from reference 15 - the figure is entitled:  "Figure. Kaplan-Meier Curves Illustrating the Time to Relapse by the 4 Medication Categories and Medication Reintroduction Categories" with permission from the American Medical Association, order number 4043410033700.  Thank you AMA.


Supplementary 1:

I tried to get permission to post survival curves from references 16.  The APA (of which I am a 32 year member) wanted to charge me $150 to repost a single 10 year old graphic that I have seen used in presentations.

Supplementary 2:

The graphics at the top are the actual fliers for the two conferences mentioned.  Other than two years of residency training, I have no affiliation with the University or Wisconsin Department of Psychiatry. 

Concise Documentation of the Assessment and Plan

I asked Cedric Skillon, MD to write this post to elaborate on his method of documenting elements of the treatment plan. Dr. Skillon and I work in the same system of care. Over the years I have been impressed with the high quality of his work and a lot of that is captured in how the treatment plan is documented. I think his documentation is concise and yet it covers a lot of ground in terms of the clinical discussion with the patient and his thought process. What follows a discussion of his approach and a good example.  The remainder of this post was written by Dr. Skillon.   Fell free to add comments on what you find useful as concise documentation.

George Dawson, MD, DFAPA


Assessment and Recommendation/Plan

Throughout my medical education I was reminded over and over again to document everything that occurred during an appointment; because if it was not documented, it did not happen. But just as important, during my psychiatry residency training at Western Psychiatric Institute and Clinic, Dr. Petronilla Vaulx-Smith expressed upon me the fact that with every medical note that I write, any physician should be able to read my note, understand my logic, and be able to pick up taking care of that client from the last note that I wrote. Over the years my notes have evolved to include the following.

Assessment: In this section of the note I have 1-2 sentences to highlight sign/symptom changes that I have documented in greater detail in the History of Present Illness section of my note.

Recommendations/Plan: In this section I document medication and therapies prescribed, as well as the target symptoms for the medication or therapies that I am recommending. I also educate the patient about potential side effects and medication interactions with the prescribed medications. I then numerically list each step of the plan for that appointment, including medications prescribed and discontinued. With each prescription I state how long the prescription will last and if there was a refill included. I list continued therapies, including community support such as attending AA meetings.

Below is a fictitious example of an Assessment and Recommendation/Plan.

Assessment: Patient reports worsening depressive and anxiety symptoms. Patient has maintained his sobriety.


Recommendation/Plan: Plan to discontinue Wellbutrin XL. Plan to continue with current dose of Prozac. Plan to start Effexor XR in combination therapy with Prozac to treat depressive and anxiety symptoms. The patient will continue with individual psychotherapy and continue attending AA meetings. I educated patient about the risk of serotonin syndrome with the combination of Effexor XR and Prozac. I educated the patient about the symptoms of serotonin syndrome.


1. Patient was educated about the above assessment and plan.

2. Patient was educated about the side effects and potential benefits of each prescribed medication.

3. Patient gave verbal informed consent for the prescribed medications.

4. Discontinue Wellbutrin XL

5. Start Effexor XR 75mg take one pill daily. I gave patient a written prescription for a 30 day supply and no refills.

6. Continue with current dose of Prozac. On 12/20/16, I gave patient a written prescription for a 30 day supply and 5 refills)

7. Patient will continue with individual psychotherapy.

8. Patient will continue attending AA meetings.

9. Patient will schedule a follow up appointment to see Dr. Skillon in 2 weeks.

10. Patient agrees to call readily with questions, side effects, or clinical worsening. Patient agrees to call Dr. Skillon, or go to the closest emergency room if he has onset of suicidal ideation or homicidal ideation.

11. Treatment plan was discussed at length including alternative medications and importance of compliance.

Cedric Skillon, MD




Attributions:

Graphic at the top is from Shutterstock per their licensing agreement - "Medical files on a shelf" by Val Lawless.

Can A Philosophy For Living Prevent Addiction?

A couple of years ago, I responded to a New York Times editorial by a philosopher.  It was focused on the release of the DSM-5 and like most pieces in the press, it was highly critical of psychiatry.  The philosopher's argument was basically that the DSM-5 had an implicit agenda.  That agenda was that it was a blueprint for living.  As an acute care psychiatrist for most of my life, that analysis was more than off the mark - it struck me as absurd.  The only advice about living that I gave people was lowest common denominator advice:

1.  Get a stable place to live where you feel safe and you can unwind each day.

2.  Get adequate sleep.

3.  Eat nutritious food.

4.  Get some exercise.

5.  Stop drinking.

6.  Stop using street drugs.

7.  Try to stop smoking.


This is advice where the patient has been unable to secure any of these elements, is also often physically ill, and we could offer active help.  None of that advice is contained in the DSM-5, but when you are treating people with severe psychiatric disorders it is useful and potentially life saving advice.  You can read about the "blueprint for living" argument and several additional arguments in the comments at this link.  One of my main points is that psychiatry and medicine in general are focused on extremes and not normative human conditions.  Medicine generally tries to draw a line (however imprecise) between the pathological and non-pathological.  The only real life lessons there are is how to avoid some pathological states.

The other part of my career in the outpatient setting is trying to convince people to stop using drugs and alcohol at various stages of addiction.  The pathway to addiction and the pathway to recovery back out again are complex.  Not everybody makes it.  The argument for recovery has always been quite basic.  Stop using or end up "crazy, in jail, or dead."  Far too many people are exposed.  As a reductionist, I teach that there is a certain portion of the population that is at high risk for addiction due to neurobiological factors.   There is also a portion of the population at low risk because of dissimilar factors.  With the current push toward universal cannabis legalization, widespread availability of opioids, and the idealization of hallucinogens and psychedelics larger and larger numbers of people at put at risk, just based on their biology.  The backdrop here of cycling between permissiveness and prohibition at the cultural level was noted by Musto a few decades ago.  The problem is that American society deals with that conflict by political arguments.  Those arguments are focused on liberalized drug use or prohibition without any common sense in between.  In the United States that no man's land points directly to a lack of a philosophy for living.

What do I mean by a philosophy for living?  To me it means a way of living that is based on reasoned principles rather than popular culture.  A way of living based on contemplation rather than impulse.  A way of living based on conscious decisions long before the time when the decisions are no longer conscious or reasoned.

The best example I can think of is from the field of addiction.  There is always a lot of confusion over the issue of decision making in psychiatry and addiction.  Patients without addictions are often told that they have choices.  That is a gross oversimplification when it comes to how people with mental illness make decisions.  The same thing is true of addiction.  The main difference is that a moralistic approach to addiction is still acceptable at many levels of society.  That is - if you correct your moral problem -  the addiction will be solved.  That is presently a lot harder to do with severe mental illness in most settings short of a not-guilty-by-reason-of-insanity defense.  Even in the case of severe mental illness that clearly caused the crime, the the NGRI defense is usually not exculpatory.

Given those scenarios a philosophy for living can be considered a preventive measure rather than a primary cure.  As such it is outside the scope of psychiatry.  There have been a few psychiatrists who were philosophers, but the vast majority were not.  Over the years, I have found a first rate philosopher who I have followed on his blogs and in several of his books.  Massimo Pigliucci has written and edited several excellent books including Denying Evolution and Philosophy of Pseudoscience.  He also stopped writing what I consider to have been and outstanding blog about philosophy called Rationally Speaking that is still available to read.

For the purpose of this post he also writes the blog How To Be A Stoic. Most people have a truncated view of Stoicism.  It is really not like the stereotypical Norwegian bachelor farmers of the upper Midwest.  It is not the image that many of us got studying ancient governments and cultures.  It turns out that Stoicism is a philosophical approach to life.  That makes it unique in the field of philosophy, since most philosophies are not about how to live your life.  He recently offered to field some questions and answer them according to his interpretation of Stoicism.

It is against that backdrop that I sent Massimo the following question:


"I am currently an addiction psychiatrist and that means 100% of the people I see have one or more serious addictions.  While I operate from the neurobiological perspective with regard to addiction - phenotypic plasticity is operative.  I would estimate that 40% of the population is at risk for addiction if exposed to a matching intoxicant.  Availability of drugs as seen in the current opioid epidemic is always a significant factor.  

It is hard to ignore the cultural biases that lead to this exposure.  It seems to be part of the American culture that people expose themselves to drugs and alcohol at an early age.  In Middle School and High School as well as college there is peer pressure.  People who abstain from intoxicants are viewed as being square or possibly closet prohibitionists.  The former President of Mexico Vincente Fox suggested the entire reason for the War on Drugs was "America's insatiable appetite for drugs.."  I think that he was right.

I think that an important public health strategy would be to intervene at the "philosophy for living stage" that currently seems based on hedonism before the significant neurobiological effects from the intoxicants takes over. 

Is there any advice that Stoics may have to offer in this situation?  I guess I see the problem as a lack of a reasonable plan for living at the bare minimum when it comes to excessive drug and alcohol consumption.  

There is not much of a window between that and a full blown addiction."

And this is what he said.  Please read his well thought out post that contains some additional references.  His  discussion of the ancient version of the Serenity Prayer was very interesting.

Can Stoicism as a philosophy for living prevent addiction and a lot of other decisions that Americans make that are not in their best interest?  I agree with Massimo and think there are paths in addition to Stoicism.  The point of this post today is here is one example of what might be possible.  Here is an alternative to moral development that does not quite go the way it is taught in psychiatric texts.  Here is an alternative that offers more than a relatively bankrupt culture that emphasizes money, violence and hedonism.  Here is an alternative to prohibition.  After all if you are contemplative and are assessing your life on a daily basis relative to specific virtues - you will not need external controls.

Having a philosophy of life seems much better than not having one.


George Dawson, MD, DFAPA


Supplementary:  I wrote all of this post except for the book titles and the conclusory paragraph before reading Massimo's reply.  I did not want to be biased by his reply and try to seem more knowledgeable about Stoicism than I am.  A philosophy for living is definitely outside the expertise of most psychiatrists.


Attributions:

Photo at the top is  Agora of Smyrna, built during the Hellenistic era at the base of Pagos Hill and totally rebuilt under Marcus Aurelius after the destructive 178 AD earthquake, Izmir, Turkey from Wikimedia Commons By Carole Raddato from FRANKFURT, Germany [CC BY-SA 2.0 (htta significant hsitroical basis of Stop://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons.

Marcus Aurelius was a Roman emperor and also a practitioner of Stoicism.  His surviving writings provides a modern day resource of Stoicism.  From the number of quotations I think it is safe to say that modern day Stoics consider him to be a Stoic philosopher as well as practitioner.

JWH Compounds Make the NEJM

JWH-018

AMB-FUBINACA

Synthetic cannabinoids have been a problem for over a decade.  There have been sensational news reports that typically occur as a result of aggressive and disorganized behavior when users are acutely intoxicated.  When these compounds initially started to appear on the scene, regulators were far behind the curve.  Some of the first forms were sold in head shops, wrapped in paper and labelled "Not For Human Consumption."  They went by names like K2, Spice, and Plant Food.  They are typically applied to shredded plant material so that they can be smoked.   The chemical structures of these compounds do not resemble typical cannabinoids and the synthesis is relatively straightforward.  That has facilitated black market production.  Apart from easy availability the other draw was that users could take these compounds and not have to worry about standard drug testing protocols in the work place.  The word on the street was that the synthetics were undetectable by typical urine toxicology and that was accurate.  Apart from isolated aggressive incidents there were also deaths associated with their use.  There were some epidemics that clustered in communities and eventually (like most drug epidemics) the sale of the compounds was prohibited and some head shop operators were prosecuted.

From the standpoint of addiction practice, many of these compounds create a dangerous situation for the patient and a dilemma for treatment facilities.  They are highly addictive to some people and unless there is some familiarity with the concept of delirium producing drugs causing addiction, it may not be clear why anyone would continue to use them.  Many people are amnestic for what occurred when they were under the influence.  In some cases they develop life threatening conditions as a result of use and crave the drug when they are being acutely treated for the medical complications.  Another abused drug with this kind of dissociative profile is dextromethorphan.  When used in high doses it leads to delirium and hallucinations and can be highly addictive.


The JWH designation represents the organic chemist John W. Huffman who synthesized the series of compounds as cannabinoid receptor agonists.  The goal of the research was to produce pharmacological probes to study cannabinoid receptors.  He is a coauthor on 30 papers in Medline.  There are several articles in the popular press including several that include his opinion about his original research being used to produce compounds for sale as street intoxicants.     JWH compounds have been in the medical literature since about 2005.  PubChem contains structural information on 281 JWH compounds, 367 protein targets, and 706 bioassays.  PubChem also allows the user to generate 2D and 3D structural similarity comparisons and bioactivity analyses - for example activity at the CB-1 and CB-2 receptor.  As the JWH compounds and other synthetics have evolved they follow a familiar pattern of the development of classes of addictive compounds - subsequent syntheses have increasing activity at the target receptor.

There are other classes of synthetic cannabinoids in addition to the JWH compounds including UR-144, AKB4, AB-CHMINACA, AB-FUBINAC and others.  There are also a number of psychedelic phenethylamines 2C-B, 2C-I, 3C-E, 3C-I, and 2C-P that are often sold as equivalent drugs.  There are obviously no guarantees that purchases from non-medical sources results in the desired chemical or effect.  There is a also a class of synthetic cathinines referred to as Bath Salts, that are structurally similar to amphetamines and are often sold as mephedrone, MDPV, or methylone.  The total number of synthetics and the requirement of relatively sophisticated analysis for detection (gas or liquid chromatography-mass spectrometry) frequently leaves the acute care or addiction physician depending on history alone about what was ingested.

The New England Journal of Medicine has a general review of the issue in the January 19, 2017 edition (1).  Full text of the article is available online.  The article details the current number of new psychoactive compounds as 540 with 177 identified synthetic cannabinoids in 2014.  They have an illustrated timeline of the evolution of these compounds from 2010 to 2016.  The most interesting aspect of the timeline is the evolution of a 50 fold increase in drug potency from JWH-018 in about 2010 to AMB-FUBINACA in 2016.

They also provide an analysis of a mini epidemic of AMB-FUBINACA use in Brooklyn that occurred in 2016.  Of the 33 people exposed - 18 required transport to medical facilities.  An index case is described with features of a blank stare and unresponsiveness 13/15 on the Glasgow Coma Scale.  He had episodic groaning and slowed movement of his extremities.  The term "zombielike" was used as a descriptor but in psychiatry that term is used so frequently by patients and untrained observers that it lacks meaning. The patient was sweating and had normal vital signs with the exception of tachypnea with a respiratory rate of 21.  Screening labs, toxicology, and ECG were all normal.  He recovered in about 9 hours and was discharged.  The authors recovered the original herbal product labelled "AK-47 24 Karat Gold"  and sent that as well as biological samples (blood and urine) from 8 other users for analysis.

The samples were analyzed with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS).  AMB-FUBINACA was confirmed as the compound in the original packet of material.  The de-esterified product rather than the parent compound was confirmed in the blood and urine of the patients with serum concentrations from 66 to 636 ng/ml.  

In the discussion the authors point out the potency increase with these synthetic compounds.  They illustrate the attractiveness to drug dealers and users - about $3800 of AMB-FUBINACA can produce about a half million dollars worth of product containing about 64 mg of the original compound sprayed over shredded plant material.  That is strong incentive for getting this drug out on the street.  They also discuss the role of inter-agency collaboration in identifying novel intoxicants during similar mini-epidemics.  In this case the entire timeline from case to molecular identification was 17 days.  In many toxicology cases that I have been involved with, it often takes that long to learn that the lab you are using is not able do the necessary analysis.

Treating patients addicted to these compounds will be a challenge in the foreseeable future.  People who changed to synthetics just to escape drug testing in the workplace have ended up addicted to these compounds.  The psychoactive side effects of the compounds frequently results in a downward spiral of job loss, loss of relationships, and social isolation that goes along with the preoccupation of using the drug.  Explaining to the patient and their family that this is a potentially life-threatening addiction is not necessarily a deterrent to further use and fatal outcomes are possible.  Understanding the motivation for using a drug that has never been tested in humans, can result in the loss of days or an entire weekend, and can result in toxidromes that directly or indirectly lead to fatal outcome may be another sign that this is a neurobiologically mediated process that bypasses rational thought.

Prevention would seem like it is the best approach but American society remains fascinated by intoxicants and Americans have plenty of money to spend on these drugs.  Like most political arguments the common sense approach of a better plan for living is lost between the poles of liberalized drug use and prohibition.  I hope that the people at highest risk for using these drugs can learn to avoid them without exposure.          


George Dawson, MD, DFAPA




References:


1. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. "Zombie"Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017 Jan 19;376(3):235-242. doi: 10.1056/NEJMoa1610300. PubMed PMID:27973993. (free full text online).


Attribution:

Molecular structures at the  top of this post are generated from NLM PubChem interface and are public domain.


Additional Analyses Available from PubChem:

I ran two analyses for 281 and 279 JWH compounds.  Additional information is available if you run the analysis for yourself.

Supplementary:

I encountered some stories on the Internet about the chemists who originally synthesized these compounds in the course of their professional careers.  Some of them have felt badly about the morbidity and mortality associated with their use as street drugs.  Others have pointed out that they were not intended for human use and not tested in humans and therefore nobody should be using them.  Keeping in mind the profit motive suggested by the NEJM article and the incentives for gaming the system by finding compounds that are not on the Schedule of Controlled Substances, I don't think that there should be any question that the sellers and buyers of these drugs are responsible for the outcomes.

Emery Dreifuss Muscular Dystrophy and Lipodystrophy

Public radio is a consistent source of content about medical problems that contain lessons for everyone.  I happened to hear one last weekend.  The program was This American Life and the story was called Do These Genes Make Me Look Fatless.   The story starts out with writer David Epstein describing the public reaction to his latest book The Sports Gene.  As part of the correspondence a 39 year old woman named Jill Viles sent him an illustrated letter and it contained the heading "Olympic Medalist and Muscular Dystrophy Patient with the Same Mutation."  The side by side photos of Jill Viles and Olympic sprinter  Priscilla Lopes-Schliep are side by side on the web page and I encourage anyone reading this to take a look at the comparisons and try to figure our how Ms.  Viles came to this conclusion.  Epstein was interested and replied getting a detailed scientific brief in return.  He got a second opinion from a geneticist that he consulted in the making of his book who concluded that Ms. Viles was probably wrong about the genetics.

From there the story goes into the incredible history of Jill Viles and how she started to research her illness.  After normal early developmental milestones she started tripping and falling at the age of 4.  She was taken to the Mayo Clinic and Jill, her brother and father were all tested and showed evidence of muscle damage.  They concluded that although it looked like muscular dystrophy, girls never got it and therefore she did not have muscular dystrophy.  Over the next 8 years her arms and legs got extremely thin,  she had a burning sensation in the legs, and all of the subcutaneous fat in her extremities disappeared leaving very prominent veins.  Within a few weeks she started to fall again and was no longer able to ride a bike or roller skate.  She regained her ability to walk and then began a very unusual research program to see if she could find out what was wrong.

She started by looking at tales of the supernatural - like poltergeists.  She reasoned that the people in these books she was reading could not explain what was happening to them and she might find an answer.  Then she went to college and started to study medicine on her own.  Her project involved reading textbooks and journal articles on muscle diseases trying to find one that matched her own experience.  She was reading an article on  Emery-Dreifuss  muscular dystrophy when she noticed the description "Popeye arms" and had an immediate association to the appearance of her father's arm.  As she read the description she noticed that she had features of the illness.  She took a number of the books home on break and her father discovered that he had both the muscular and cardiac symptoms with bradycardia into the 30 beat per minute range.  His doctors told him the symptoms were from exposure to a virus.  He was re-evaluated and a pacemaker was placed.

Jill went to a neurology clinic for confirmation of the diagnosis, but the neurologist there just make a diagnosis of Muscular Dystrophy.  She got angry and would change the diagnosis by writing in the chart.  The rationale was that women do not get Emery Dreifuss Muscular Dystophy (EDMD).  She eventually located a group of researchers in Italy specializing in the disorder and sent them blood samples of her entire family.  Four years later she had confirmation that she had the gene - a single base pain mutation on the Lamin gene.  According to the Universal Mutation Database the LMNA gene has 464 known mutations and 283 variants.  Some of the diseases are more well known than others.

At this point before I get into some additional details of the illness, this is clearly an inspirational story.  Jill is clearly a very bright person.  Transitioning from an explanatory paradigm that went from the supernatural to cutting edge DNA and genetic research within a few years while dealing with a significant chronic medical problem for  which there was no clear diagnosis or treatment is astonishing.  It is a testament to her intelligence, character, and mental flexibility.  In the process she her research also made a significant difference in her father's life and the life of Olympic sprinter Lopes-Schliep.  Hearing her speak about these details in the audio file is necessary to bring some of these details to life.

Jill got a job in a lab at Johns Hopkins combing the research for any reference to the lamin gene.  In the process she came across another photo that reminded her of her own appearance.  In this case the prominent feature was a loss of subcutaneous fat called partial lipodystrophy.  She maintained that she also had this rare disorder and was met again with denials - in this case based on the likelihood of having two rare genetically determined illnesses.  This time she believed the deniers.  She also started to get increasingly anxious in reading about  EDMD and the short life expectancy.  She stopped the research completely and started teaching at a local community college.  She got married and gave birth to a son who does not have EDMD.  She had more severe weakness after the pregnancy.  Jill's father died suddenly at age 63.  In the gathering at the familiy home her sister showed her pictures of Priscilla Lopes-Schliep.  She noticed the characteristic pattern of veins and muscle fibers.  Twelve years after she stopped researching EDMD she started to research lipodystrophy.  Eventually Jill arranged a meeting and they both  submitted samples to a world expert on the condition - Dr. Abhimanyu Garg.  He confirmed they both had the same rare type of hereditary lipdystrophy.  It turns out that the partial lypodystrophy mutation and the EDMD mutation are both on the lamin A/C gene LMNA.

Jill also reached out to Etienne Lefai a researcher studying SREBP-1, transcription factors that control muscle mass through protein synthesis.  Overexpression of these same factors can lead to muscle atrophy.  Dr. Lefai credits Jill with changing the path of his research when she reached out to him.  He described her a awesome and the only example of someone outside of the research community coming in and altering his basic path of research.    

I agree completely with Dr. Lefai.  Part of the story here is how much credence you give the theories that your patients have.  For a psychiatrist it is somewhat easier.  Good psychotherapy depends on finding out underlying theories, testing them and suggesting alternate theories at times.  It can be a trying process.  Sometimes your patient really is being followed by the FBI and figuring that out is a major decision in the diagnosis and treatment plan.  I have gone to some elaborate lengths to create an experiment and conferenced in some experts from other fields like electrical engineering to test a person's theory about how the  world  works.  In the addiction field it is very common to encounter people who have never had a chemistry course in their life and now consider themselves to be experts in pharmacology and organic chemistry.  I listen to all of these theories and carefully weigh them and consider their overall meaning.  It was interesting to read why the experts rejected Jill's correct theories and how they gradually came to accept them.          

Another reason for this post is that is also allows me to highlight what I consider to be the best resource on the Internet for musculoskeletal diseases and that is the Washington University Neuromuscular Disease Center. It is essentially a free online text in neuromuscular diseases ranging from the clinical presentation to pathology to molecular biology.  It is an immediate resource for any physician treating someone with a neuromuscular disease.  In the case of Emery Dreifuss MD, there is a comprehensive page with the genetics listed right at the top.  The National Organization of Rare Diseases has a web page on congenital lipodystrophies.

I often think about what research was like when I was in medical school.  My wife and I would head to the Medical Library and I would run around pulling bound journals while she copied the articles that I needed.  That was a lot of heavy lifting that is no longer necessary thanks to the modern flow of information.

I thought about that when the story described Jill lugging heavy books home in a backpack.  That was definitely another measure of her determination.


George Dawson, MD, DFAPA




References:

1: Dessalle K, Euthine V, Chanon S, Delarichaudy J, Fujii I, Rome S, Vidal H,Nemoz G, Simon C, Lefai E. SREBP-1 transcription factors regulate skeletal muscle cell size by controlling protein synthesis through myogenic regulatory factors. PLoS One. 2012;7(11):e50878. doi: 10.1371/journal.pone.0050878. PubMed PMID:23226416.

2: Gnocchi VF, Scharner J, Huang Z, Brady K, Lee JS, White RB, Morgan JE, Sun YB, Ellis JA, Zammit PS. Uncoordinated transcription and compromised muscle function in the lmna-null mouse model of Emery- Emery-Dreyfuss muscular dystrophy. PLoS One. 2011 Feb 22;6(2):e16651. doi: 10.1371/journal.pone.0016651. PubMed PMID: 21364987.

3: Scharner J, Brown CA, Bower M, Iannaccone ST, Khatri IA, Escolar D, Gordon E, Felice K, Crowe CA, Grosmann C, Meriggioli MN, Asamoah A, Gordon O, Gnocchi VF, Ellis JA, Mendell JR, Zammit PS. Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. Hum Mutat. 2011 Feb;32(2):152-67. doi: 10.1002/humu.21361. PubMed PMID: 20848652. 

4: Scharner J, Gnocchi VF, Ellis JA, Zammit PS. Genotype-phenotype correlations in laminopathies: how does fate translate? Biochem Soc Trans. 2010 Feb;38(Pt 1):257-62. doi: 10.1042/BST0380257. Review. PubMed PMID: 20074070.


Attribution:

Figure at the top is from National Library of Medicine Genetics Home Reference page on the LMNA gene.  It is the cytogenetic location of the LMNA gene.  It was generated with the NCBI Genome Decoration Page.  The copyright is Health and Human Services and I assume this is public domain.

https://www.thisamericanlife.org/radio-archives/episode/577/transcript

http://www.emerydreifussmd.org/genetics.html