Patentable Biomarkers of Suicide

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

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

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

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

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

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

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

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


George Dawson, MD, DFAPA


References:

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

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

3:   Collection of references for biomarkers in suicide.

4:  Simplified Affective State Scale (SASS).

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

6:  Laboratory of Neurophenomics Web Site.

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

8.  Translational Psychiatry Web Site.

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

Attribution:

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

Supplementary:

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

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

Advice To Residents - continued

A couple of things to add to the previous list:

17.  Information - One of the most formative documents that I ever read was Shannon and Weaver's paper on communication theory.  My only reason for reading this paper in the first place was cultural.  I was an undergrad during tumultuous times and learned about this paper in the Whole Earth Catalogue.  Since it was a technical and engineering document I was very surprised to find it in my liberal arts campus library.  After becoming a psychiatrist I have been very aware of the information content and exchange between physicians and patients.  Despite the lack of any quantitative analysis, there are no big surprises.  The more information exchanges the more accurate the diagnosis and the better the treatment plan.  That has implications for how you approach clinical work.  Physicians interested in information tend to maximize the data points they put into their assessments.  They also make a point of getting plenty of collateral data.  They pay more attention to high signal to noise information and learn to set limits on sources where there the signal is low.  It takes discipline to focus on information optimized exchanges in this day when physicians are often their own transcriptionists.  It is also difficult when electronic health record systems degenerate into binary checklists that do not allow for the documentation of unique data.  A focus on information leads to consistently high quality care.


18.  Suicide - Any finalized version of this list will give suicide a much higher priority.  It is always with us.  I know for a fact that the unpredictable aspect of suicide prevents many excellent physicians from going in to psychiatry.  Any professional guideline states that suicidal ideation and potential needs to be assessed on a longitudinal basis at every meeting with the patient.  Residents are immersed in the treatment of a combination of people who are at very high risk for suicide and/or chronically suicidal.  They are taught the very blunt instrument of risk factor analysis to make those decisions.  They are expected to perform contentious interventions to hold people against their will based on the assessment of suicidal behavior.  Residents in every class will lose patients to suicide and will experience a great deal of emotional turmoil related to that loss.  It is the most difficult aspect of the field to negotiate.

What is the best approach to the problem of providing the best possible care to people with suicidal ideation and behavior and minimizing the emotional toll on yourself?  There are three basic considerations.  The first is technical aspects of assessment and treatment.  There has been a recent revival of interest in suicide as a problem independent of diagnosis so I would follow that area of research.  As far as I can tell, The Harvard Medical School Guide To Suicide Assessment and Treatment is still a unique source of information.  On the assessment side not missing psychotic depression is critical and it can be a subtle finding.  The second is the countertransference aspects of care for the suicidal person.  People who are chronically or recurrently suicidal elicit strong emotions in people.  Some of these emotions are readily observable in their friends and relatives.  Recognize them in yourself and figure out what to do about them.  Finally the single best piece of advice is to always make sure that you have done everything possible to prevent the suicide of a patient.  Suicide is a rare event but if it occurs making sure that you did not miss anything is the best way to moderate your emotional response.  The last few sentences seem a lot more straightforward than they really are.  There are always a number of obstacles to the best possible care that you will not have control over.  It is still important to discuss the optimal plan with the patient.  An additional safeguard as a resident is to ask your supervisor: "Is there anything else that you would do in this case to address the patient's suicide potential?"  As a supervisor, I think that is a fair question that I should be able to answer.

These two points came to me since the original post.  The point about suicide was an obvious omission suggested by a colleague.  It highlights the fact that even a senior psychiatrist like myself can omit important points that can be corrected by collegial consultation.

Please feel free to send me any additional points or sources that you have found useful.  The Harvard Medical School Guide.. is dated at this point and I don't think that there has been an updated edition  or any source that improves upon this information.  I have my own approach to this problem that I think is useful to consider, but I am reluctant to post it here without any peer review.

My pep talk to residents at times involves reminding them how tough this field is.  It is intellectually and emotionally rigorous and to do a good job you have to stay focused and at times be fairly hard on yourself.  You also have to check out what you are doing with other psychiatrists - supervisors as a resident and colleagues when you are in practice.    



George Dawson, MD, DFAPA   


Reference:

1.  Aleman A, Denys D. Mental health: A road map for suicide research and prevention. Nature. 2014 May 22;509(7501):421-3. PubMed PMID: 24860882.

Supplementary:

1.  The first 16 points of this thread are contained in the previous post.

JAMA Psychiatry Suicide Article, Statistics and AI

Suicide Rates - Selected OECD Countries

Suicide is a very important problem for psychiatrists.  Even though it is a rare event, it seems like most of our time is focused on preventing suicide.  There are many days where many high risk patients and patients with chronic suicidal ideation are seen in clinics and hospitals.  Most of them are treated in outpatient settings and very few are treated on an involuntary basis in hospital settings.  Since suicide is diametrically opposed to self preservation it is assumed that any rational person would want to get help with those thoughts and impulses.  Like most things in psychiatric practice it is almost never than simple.  Psychiatrists encounter a wide range of of reasons for suicidal thinking.  At times, the suicidal thinking was not obvious until it was declared after a suicide attempt.  Many people decide to see psychiatrists after a first suicide attempt.  Even at that point it is common to find a person who is disappointed that they did not succeed.  It is more common to find a person greatly relieved that they survived but even then that does not assure the cooperation necessary to prevent another attempt.

The standard of practice for assessing suicidal thinking or ideation and potential risk is risk factor analysis.  This has been the standard of practice for as long as I have practiced over the past 30 years.  To do this analysis, it requires making a diagnosis or a series of diagnoses and looking at associated factors and how the patient describes his/her mental state at the time.  Major psychiatric diagnoses like major depression, schizophrenia, bipolar disorder, panic disorder, borderline personality disorder and chronic substance use disorders all have significant lifetime prevalences of suicide varying from 3 to 15%.  Psychological autopsies of series of suicides find that nearly all of the patients who have suicided in these studies had a significant psychiatric disorder.  There are also studies done from a social science perspective that emphasize the social risk factors for suicide including sex, martial and relationship status, economic factors and loss.

Suicide is a widely misunderstood problem sometimes even for the patients who are experiencing the thoughts.  It is common for example to encounter people with suicidal thinking who say that their only deterrent to suicide is that they don't "have the guts" to do it.  An associated worry might be that it is "too painful."  They feel a need to explain why they cannot carry out an irrational act.  I take this to mean that at some point in time, the suicidal person's conscious state has changed.  They are no longer a rational person and that is why they must explain away the fact that they cannot carry out an irrational act.  Another common observation that speaks to the conscious state is that many people will say "I never understood how a person could be suicidal until I finally felt that way."  That suggests that the altered conscious state is associated with a mood state of depression or many times a mixture of depression, anger, and anxiety resulting in an agitated state that led to the understanding about suicidal thoughts.  A final observation is one of the most stressful parts of psychiatric practice and that is:  "Can I believe this person when they tell me they are not going to kill themselves?"  Much of acute care psychiatry hinges on that ultimate question.  The risk factor analysis is essentially nullified if the patient is in an emergency department and their diagnosis and past suicide attempts are known.  The only thing left to go on are the standard questions about current state of mind, deterrents, safety plans and whether the person seems reliable and says they will not kill themselves.   It is widely known that people kill themselves after leaving emergency departments and hospitals.  People have killed themselves in hospitals while under direct observation.

Many of these assessments become adversarial.  By the time a psychiatrist sees a patient in a hospital, a lot has already happened. In all of the hospitals where I have practiced, crisis teams, paramedics, and the police have assessed the person in the community and brought them in to the hospital.  Very few people were under psychiatric care at the time of that intervention.  Friends and family members of the patient were the people who called the first responders.  The patient is usually there out of some concern for their welfare that they may not be aware of.  The psychiatrist comes around sometime in the next 24 hours and the interaction unfolds.  Very few people seem interested in the fact that they might kill themselves.  Getting out of the hospital may be the priority.  Their approach might be one of non-disclosure or denial: "I really did not say I was suicidal." or "I did not mean it",  or "I was drunk or high at the time".  Even those responses can vary from very unlikely (as in a patient with a serious self inflicted gunshot wound) to unlikely (a patient with delusional depression stopped in the midst or a suicide attempt) to possible (the intoxication history with no suicidal ideation while sober).  The interview dynamic is also quite variable.  A person may be sullen, irritated, and not wanting to discuss much information.  They may express concerns about self incrimination: "I know what I can and cannot say to psychiatrists.  I know if I say the wrong thing you will lock me up and throw away the key."  They may blame their problems on the psychiatrist: "Look - I know you don't care about me.  The only thing you care about is covering your ass.  You are going to do whatever you want to do."  They may be more hostile and sarcastic: "Look if I was really going to kill myself I wouldn't be sitting here talking to you.  I'd be dead.  I wouldn't be talking about it."

All of these statements ignore the fact that the person is sitting in front of the psychiatrist as the result of the actions of several other people including persons affiliated with them and having their best interests at heart.  That situation is so intense and uncomfortable that it prevents physicians from going into psychiatry.  I  have had many physicians tell me they could not go into psychiatry because:  "Guessing about whether or not a person will kill themselves is too stressful."  There are many ways to reduce the guesswork involved but the point I am trying to make here is that all of these behaviors are consistent with the patient having undergone a change in their conscious state.  They are no longer acting like a person interested in self preservation, but they are now a person who is contemplating self destruction and taking active measures to hide that thought pattern.  That is the main reason why psychiatrists can't predict suicide over long periods of time with any degree of certainty.  When a person's conscious state changes that completely, their actions are less predictable even to the point that they may be potentially self destructive and want to cover it up.

That is also why risk factor analysis is so imperfect.  In the case of the diagnosis, a lot of clinicians are under the impression that if a person satisfies some written criteria for a diagnosis that provides a lot of critical information about the potential for suicide.  Many clinicians seem to miss the point that a patient can have the exact same written criteria for major depression with psychotic features and the same chronic markers on a suicide risk assessment and suddenly be much more likely to attempt suicide.  The only thing that has changed has been the patient's conscious state and their awareness that suicide is an unwanted state.  The evidence that this happens is clinical and ample.  Patients will report back to their psychiatrists that they were in this conscious state and the psychiatrist did or did not miss it.  Either way, there is no clinician in this situation who could make the correct call.  Without any clear markers, there is no way to figure out if this change in conscious state has occurred.  The patient usually recognizes it only in retrospect.

This clinical information on the assessment of suicide is what makes this JAMA Psychiatry article interesting.  In this article the authors attempt to determine predictors of suicide by soldiers in the year following psychiatric hospitalization within the Veteran's Administration hospital system over a 6 year period.  That was a total of 40,820 hospitalizations or 0.9% of the total Army personnel in any 12 month period.  During that time there were a total of 68 deaths by suicide.  That is number is 12% of all US Army suicides.  The authors consider a long list of potential risk factors that are largely demographic in nature to determine concentration of risk of suicide.  That list includes a law enforcement data base that clinicians do not have access to.  Their overall goal was to determine of it was practical identify high risk patients for post hospitalization intervention and whether that might be a cost effective way to prevent suicide.  They were able to identify the highest risk group - the 5% of hospitalizations in which 52.9% of the suicides occurred.  Like many similar studies the authors also comment on  how their "actuarial" methods usually trump clinicians making the same predictions.  I found very limited commentary on that fact that it is generally possible to illustrate what you want with enough variables or as we used to say "a large enough spreadsheet".  In this case they looked at a large number of variables to come up with 421 predictors for further analysis.  I have reviewed hospital records consisting of the printout of the electronic health record where there were scarcely 421 words and it was usually impossible to determine an admission or discharge date.  Any information on even a short term assessment of suicide risk is scant and it frequently says basically that the patient told us he or she was not going to make a suicide attempt.  In some cases a rating scale approach like the Columbia is used.  Clinicians using these scales are often surprised about how few variables change after the initial rating and how the numerical risk does not necessarily reflect an inpatient versus and outpatient population.

As I read through the article, I was also impressed with the amount of alien statistics and fairly esoteric statistical terms.  If JAMA Psychiatry wants to include these methods, I think an example of the calculations and a bibliography of additional reading would be a minimal requirement.  The addition of statistical reviewers' comments or an independent statistical discussion of the pros and cons of these methods would only enhance the quality of the discussion.  One of my concerns is that as the statistical methods get more abstract and vague notions about big data are more accepted, clinical complexity and wisdom are completely diluted down and out.  I saw a headline the other day that Internet sellers know more about your "personality" than your spouse.  It should be fairly obvious from all of the healthcare research done that is based on HEDIS (The Healthcare Effectiveness Data and Information Set) information, that demographic variables and product choices are not the same thing as clinical assessment and treatment.

If the headlines about artificial intelligence replacing doctors ever comes true, it will only happen if the machine can implement the required knowledge.  The performance of computers sifting through text based findings and diagnostic criteria has been know for 20 years (reference 3).   Those data points were generally far superior to demographics.  I owned 2 of those programs and they don't bother to sell them anymore.  In terms of the assessment and treatment of suicide a knowledge base included in the Harvard  Medical School Guide To Suicide Assessment and Intervention might be a step in the right direction.  A lot of that knowledge depends on the skill of a particular clinician and that includes the personality factors of clinicians who continue to do this impossible job day after day.      

Trying to predict suicide and prevent it can't currently be done with an algorithm.  If I see an algorithm I will consider why the high risk people aren't being seen in follow up from the hospital rather than who should get an intervention.   And I would not mind errors on the false positive side.


George Dawson, MD, DFAPA

1:  Kessler RC, Warner CH, Ivany C, Petukhova MV, Rose S, Bromet EJ, Brown M 3rd, Cai T, Colpe LJ, Cox KL, Fullerton CS, Gilman SE, Gruber MJ, Heeringa SG, Lewandowski-Romps L, Li J, Millikan-Bell AM, Naifeh JA, Nock MK, Rosellini AJ, Sampson NA, Schoenbaum M, Stein MB, Wessely S, Zaslavsky AM, Ursano RJ; Army STARRS Collaborators. Predicting Suicides After Psychiatric Hospitalization in US Army Soldiers: The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). JAMA Psychiatry. 2015 Jan 1;72(1):49-57. doi: 10.1001/jamapsychiatry.2014.1754. PubMed PMID: 25390793.

2:  Douglas G. Jacobs, editor.  Harvard  Medical School Guide To Suicide Assessment and Intervention.  Jossey-Bass Inc., San Francisco, CA, 1998.

3:  Berner ES, Webster GD, Shugerman AA, Jackson JR, Algina J, Baker AL, Ball EV,Cobbs CG, Dennis VW, Frenkel EP, et al. Performance of four computer-based diagnostic systems. N Engl J Med. 1994 Jun 23;330(25):1792-6. PubMed PMID: 8190157.