Eric Kandel Comes To Minnesota

Eric Kandel, MD

Nobel Laureates don't come to Minnesota very often but they apparently come at least once a year to Gustavus Adolphus College and the annual Nobel Conference.  This year's conference was particularly interesting to me because it starred the only modern psychiatrist to be a Nobel Laureate - Eric Kandel.  He shared the podium with his wife and research collaborator Denise Kandel.  Eric Kandel is a giant in neuroscience and has continued to extend his research well into the time in life where most people have been retired for years.  In my addiction lectures, I use his well known paper Psychotherapy and the Single Synapse published in 1979 and his recent work on nicotine exposure and the risk of cocaine use entitled A Molecular Basis for Nicotine as a Gateway Drug published in 2014 as lecture references.  Kandel has been a neuroscientist and a psychiatrist longer than I have been a psychiatrist.  The other aspect of Kandel's more accessible work is his ability to integrate basic neuroscience and cognitive neuroscience into a coherent story of possibilities.  The best example is the book The Age of Insight that I briefly reviewed on this blog.  It is clear from reading Kandel that he has a lot on his mind and he is actively seeking answers and organizing his observations.  Another feature that piqued my interest in this case was why he was presenting at an addiction conference in a state where many people believe that addiction treatment was invented.  I did not find out about the conference until it was too late to take time off of work to attend.  I was very pleased to find the presentations and Q&A sessions by Eric Kandel and Denise Kandel available online.  There are a total of 4 videos and they will load and play in succession.  There may be more videos with the Kandels but I only watched these four.

In the first session Kandel discusses some of the early discoveries in brain systems and how the idea of localization of brain function played out.  For most physicians with a passing knowledge of aphasia and strokes it is a bit tedious.  Eventually he gets to a discussion of memory localization and talks about implicit and explicit memory.  That allows him to look at different features, animal models and the molecular biology of these types of memory.  He goes on to look at age-associated memory loss and Alzheimer's Disease and the different brain substrates and mechanisms.  At that point some of his slides illustrate chromatin and transcription sites but he does not get bogged down in the details as he defers the chromatin issue to a later presentation and discusses RbAp48 as a critical transcription factor in the formation of long term memories.  He showed a plausible mechanism for exercise leading to osteocalcin secretion from bones and improvement in memory as one possible humoral factor associated with vigorous exercise.  In terms of style points, he had great graphics especially the diagram of the DNA strand wrapped around histone octamers and how the transcription process is affected by various molecules. He was clearly there to present a lot of information to non-molecular biologists.  He was a little hurried at times.  He makes a few misstatements and gets distracted like all of us do during presentations.   He interjects some humor along the way.  As the presentation continues it is clear that this is important information.

The Q & A session was focused primarily on the question: "Is addiction a brain disease?"  The other panelists and their biographical sketches can be viewed at this page.  I did not realize it until after I had viewed all of the sessions that the lectures were not a good fit in terms of answering that question.  The lectures were focused on the neurobiology of learning and how epigenetic changes due to nicotine exposure lead to other addictions.  They were not lectures on the neurobiology of addiction per se, but there were some partially suggested mechanisms related to Kandel's work on memory.  Addiction being a brain disease was really not the point of the lectures.    It was obvious that the other panelists were at the minimum resistant to the idea but there was also open opposition.  If you read the biographical sketches one of the panelists has written a book on why addiction is not a disease.  If they really wanted to argue that point they could have brought me down for a Neurobiology of Addiction lecture and I could have dissected the arguments about addiction being a disease or not.  A much better idea would be to bring Eric Nestler in for the lecture.

 The panelists seemed of the opinion that plastic changes in the brain were normal and therefore plastic changes in the brain caused by addictive compounds was not a sign of pathology.  Some seemed not to be focused on the brain at all but cultural or social factors that they thought were important.  In at least one case, they seemed to suggest that addiction needs to occur in a certain context - that all addictions are not created equal.  The example given was a wealthy white guy with a cocaine addiction could just jet off to the Caribbean and go swimming as a way to deal with his addiction.  Someone else would not have that opportunity.  Kandel had a singular focus that all human behavior, that everything that we are occurs because of what is happening in the brain.  He kept going back to this idea and pointed out that alterations in brain plasticity certainly occur during addiction but they are negative and not positive changes.  He of course agrees that social and psychological processes are important intervening factors but all of the processing occurs at the level of the brain.  Some of the panelists seemed uncomfortable with this basic idea and he got into it with one of them, but eventually summarized the problem as a lack of a common culture.  He extended that comment to include the idea that the panel is discussing these problems so that younger generations in the audience will not have to start at that contentious point.  To me it came back to the mismatch between the Kandels' lectures on the epidemiology and molecular biology of nicotine as a gateway drug and the other panelists arguing that addiction was not a disease.

Denise Kandel began the third session reviewing the epidemiology of when people start using addictive substances and what the relationship is to nicotine.  In general, nicotine use is a strong predictor of cocaine use and ongoing cocaine use.   She analyzed three databases that are essentially cross sectional surveys of substance use including the NSDUH (National Survey On Drug Use and Health),  MTF (Monitoring the Future) and NESARC (The National Epidemiologic Survey on Alcohol and Related Conditions).  She discussed the concept of Translational Epidemiology or making population wide observations and then looking at models to explain the observations.  She had what I would call a critical observation on the observed drop in cocaine use and cocaine related mortality and cigarette use.  The recent drop in cocaine related mortality seems to correlate with a decrease in smoking.  Eric Kandel stepped in for the basic science section to elaborate on the mechanism of histone acetylation and how that occurs from nicotine exposure.  Denise Kandel returned to talk about the problems with e-cigarettes as potentiating factors for the use of other drugs and also as probably not a good way to stop smoking.  If you had time to watch one of the videos I would recommend this one.

The final Q & A session was an interesting one.  One of the panelists talked about the sociological theories of drug use rather than a gateway involving a biological substance.  For example, the fact that you take a substance that makes you feel good, increases the likelihood that you will take additional compounds that will do the same and that you will associate with people who have common interests and they will encourage further drug use.  Kandel had three comments during this session that I thought were very interesting.  The first involved the scientific rationale of a reductionist approach.  When you hear it explicitly stated rather than being used in a vague and rhetorical manner - it makes a lot more sense.  The second had to do with a painting by Gustav Klimt called Judith beheading Holofernes (Judith I and the head of Holofernes).  He tells the story about this biblical incident and discusses how this is a painting that combines elements of aggression and sensuality and how recent work by Anderson has shown that there is a 20% overlap between areas of the brain that govern aggressive behavior and areas that govern sexuality and reproductive behavior.  At one point Kandel seemed frustrated by some other panel members and made a reference to reproducibility that may have startled a few of them.  Denise Kandel had previously alluded to the bias against reductionism in her discussion with the statement:   "It's a reductionist approach to which some members of this audience are going to object strenuously"

The videos were very affirming for me.  When I think about the lectures I give on Kandel's work and some of the posts on this blog - I am confident that I have come to the same conclusions that he comes to about the brain and about reductionism.  Of course it is easier for me, because he provides the conclusions and I merely teach them.  I don't think that everybody has come to those conclusions either at a scientific or philosophical level.  It is too easy to get hung up on polarizing questions and political debates about science these days, especially using imprecise definitions like the word disease or claiming that reductionism is a fatal flaw rather than a good way to do science.  It is too easy to mistake journalism - in many cases hatchet-job journalism - for science.  The other striking factor is that this is a brain centric view of the world and that seems like the only logical approach to me.  Various critics will attack the brain centric view of neuroscience or psychiatry in ways that seem to miss the point.  Much of the criticism comes down to the definitions of diseases or disorders and the idea that a biomedical approach to the brain means that only biomedical treatments are possible.

I think that it might be easier to reconcile the brain centric view if the ultimate result of that view is considered and that is tremendous computational power that results in billions of people with billions of unique conscious states.  That is the ultimate product of what Dr. Kandel is talking about in terms of human learning - how it affects the conscious state and the associated brain substrate.  That may have something to do with biomedical treatments, but it also applies to every other intervention that can be brought to bear to facilitate recovery.  To make an even more obvious argument - the cure is in your head - not out in the ether somewhere.  The corollary is that it is important to know what those mechanisms are.

If you have time, watch these videos.  It is a rare chance to see one of the brightest guys in psychiatry and neuroscience in action.  I would also encourage reading The Age of Insight.  It left me with the impression that this is a scientist at the top of his game and it is inspirational reading.


George Dawson, MD, DFAPA  


References:

1: Kandel ER. Psychotherapy and the single synapse. The impact of psychiatric thought on neurobiologic research. N Engl J Med. 1979 Nov 8;301(19):1028-37. PubMed PMID: 40128.

2: Kandel DB, Kandel ER. A molecular basis for nicotine as a gateway drug. N Engl J Med. 2014 Nov 20;371(21):2038-9. doi: 10.1056/NEJMc1411785. PubMed PMID: 25409384.

3: Anderson DJ. Optogenetics, sex, and violence in the brain: implications for psychiatry. Biol Psychiatry. 2012 Jun 15;71(12):1081-9. doi: 10.1016/j.biopsych.2011.11.012. Epub 2011 Dec 29. Review. PubMed PMID: 22209636.

Attribution:  The picture of Eric Kandel is By Bengt Oberger (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons.  The file URL is:  https://upload.wikimedia.org/wikipedia/commons/c/ca/Eric_Kandel_01.JPG.



Supplementary 1:  I am fully aware of the fact that Denise Kandel and the other participants in the conference were there and are all scholars.  The title of this post reflects that fact that the Nobel Laureate came to the Noble Conference.

Supplementary 2:  This is a blog and it should be obvious that none of the speakers, institutions, or content producers mentioned in this blog post endorse this work or even know about it.  This statement is for anyone who does not think it is that obvious.  I did not attend this meeting and had no input into its content.

The Beginnings Of True Pharmacosurveillance

From:  Morbidity and Mortality Weekly Report (MMWR)  October 16, 2015/ 64 (9): 1-14.

I am an advocate of real pharmacosurveillance of anyone prescribing medications in the United States.  To some that might seem like a controversial statement and it needs to be argued at a couple of levels.  There will be some privacy advocates who suggest that medication information is protected information.  Sensitive medical information can be extrapolated from prescriptions and all medical diagnoses are not seen as equal in the eyes of employers or average citizens.  In this era, the knowledge that a person has a significant amount of specific medication in their possession may also put them at risk for theft or exploitation.  There are very good reasons for making sure that this information is not leaked to the general public.  The overriding argument is public safety defined as making sure that a person seeking medical help is going to see competent physicians or in this era competent prescribers.  There are many reasons why a prescriber may not be competent and may put patients at risk, but one of the most significant reasons is that they have developed a practice or prescribing that makes them an outlier.  They are prescribing medications or combinations of medications in a manner that is not like the majority of practitioners. That prescribing pattern may be frivolous or unsafe.  In the case of unsafe patterns, the practitioner should receive immediate feedback and where necessary intervention.

Some reviews currently happen at some level in the US.  In hospitals and care systems where there is routine review of physicians, some cases are reviewed prescribing patterns are observed and they are given feedback.  That process is limited by a lack of standardization and objectivity.  Just a few cases may be reviewed when today's information technology (IT) capability allow for reviewing all of a physician's caseload all of the time.  The review is often part of a larger process like an annual review where there may be conflicting agendas like spinning the review to make the person look as good or as bad an an administrator wants them to look.  Physicians can also be contacted by managed care organization (MCOs) or pharmaceutical benefit managers (PBMs) with letters expressing various concerns.  Examples might be patients who have filled only one prescription for antidepressants, patients seeing multiple prescribers, and polypharmacy.  These letters are often poorly thought out, probably don't apply to the physician or patient at the time the letter is sent, and seem to be heavier on public relations than the technical details of prescribing medications.  In some cases these reviews can be totally inappropriate.  To cite an example, a reviewer notifies nursing staff that a patient on lithium needs follow up and immediate blood tests upon discharge because the inpatient physician has not ordered the appropriate tests when they do not have the most recent records, have not spoken to that physician, and don't know that all of the testing has been done.

Another very relevant question for pharmacosurveillance is: "Who owns the data?"  Any managed care company that I am aware of treats patient data as their own proprietary data whether they know what to do with it or not.  I gave the previous example on this blog of asking a managed care executive for permission to use deidentified brain images for teaching purposes and being told: "Why would we want you to use our data?" despite the defined teaching purpose of the institution and a long history in medicine of teaching all of the available abnormal findings for the purpose of developing better diagnosticians.  Prescription and pharmacy data has an even more clandestine history.  Most physicians were not aware until very recently that all of their prescription data was collected from pharmacies everywhere by a company called IMS America and that information was used primarily by pharmaceutical company sales forces to monitor the products being prescribed and whether their detailing people were having an impact on those prescriptions.  The individual physician was not able to see these records or look at the trends in their prescribing data over time.  The data collection was centralized only for the purpose of selling the collected data to pharmaceutical companies or (for the past 15 years or so) buried in clinic or hospital electronic health records.  The best a physician could do would be to request prescribing data on a particular patient from their pharmacy.  That might result in 20 or 30 faxed pages of lines and lines of prescriptions, usually encompassing only the most recent years.

The state may not only claim the data, but set in place mandatory rules about how practitioners collect the data and transmit it to them.  In the state of Minnesota, all practitioners treating depression are mandated to have their patient complete PHQ-9 rating scales for depression and have those results sent to the state.  The state also monitors prescribing data on stimulant prescriptions for children and mandates that any person taking an antipsychotic medication needs to sign a written consent form.   Currently 49 of 50 states participate in Prescription Drug Monitoring Programs (PDMPs) to track drugs classified on the Controlled Substances Act Schedules II - IV.  The PDMP programs were originally set up to help law enforcement identify illegal activities with controlled substances but developed into a resource for physicians who wanted to know if their patient was getting multiple prescriptions or prescriptions that increased the risk of medications that they might be prescribing.  These pre-existing systems led the CDC and the FDA to develop the Prescription Behavior Surveillance System (PBSS) to look at the trends in the prescriptions of controlled substances.   Typically all pharmacies within a state submit data on controlled substances within a week of the prescription being filled.  The PBSS categorizes all of the data into three categories: benzodiazepines, stimulants, and opioid analgesics.  Buprenorphine is classified in the opioid analgesic category even though the primary use is for treating opioid dependent patients.  Tramadol was not included in the database until it was reclassified in 2014.  There is also a miscellaneous category that includes zolpidem and carisoprodol.  I think it probably makes sense to include GABA enhancing sedative hypnotics like zolpidem, zaleplon, and eszopiclone in the benzodiazepine category.

The preliminary data from the PBSS system that was just released in October is very interesting.  In terms of a representative sample, the eight states reported cover 1/4 of the US population and represent all 4 US Census Bureau Regions.  Prescription rates were calculated as the prescription rate per 1,000 residents as given by the most recent Census data.  Perhaps most surprising is that the rate of opioid prescribing approaches nearly one prescription for every state resident in some states in some states and the rate of opioid prescribing is twice as high as the rate of benzodiazepine or stimulant prescribing.  There are two to four fold differences in state-to-state prescribing of controlled substances across the board.   The top 1% of opioid prescribers in Delaware wrote for one out of four opioid prescriptions in the state.   The top decile of prescribers account for 50-60% of opioid prescribing but that decile does not solely account for state-to-state differences.  Specialists in pain clinics (pain medicine, surgery, physical medicine) were more likely to write more prescriptions per day but are thought to account for < 20% of all opioid prescriptions per day.   The authors suggest that most of the prescriptions in that category are written by general practitioners, family medicine, internal medicine, and midlevel practitioners.

Overlapping prescriptions ( benzodiazepines and opioids and long-acting and short acting opioids) were common.  Multiple provider episodes or MPEs defined as a resident filling a controlled substance prescription from 5 or more prescribers at 5  or more pharmacies in any 6 month period varied significantly by state, age, and the number of controlled substance schedules added.  The totals ranged from a low of 4.4/100,000 residents in Louisiana to 66.8/100,000 in Ohio.  An overall first impression of this system is that there are limitation but it clearly provides valuable information on prescribing behavior relevant to controlled substances.

The current epidemic of accidental overdose deaths was the driving force for the PBSS system.  It shows that a pharmacosurveillance system is possible, but that there are some limitations.  Data quality as inputted from the pharmacies needs to have quality control measures to assure consistency.  An ideal system would also include a diagnosis or indication.  Physician speciality would also be a useful marker.  I think that the best use of a system like this would be to allow physicians to mine their own prescription data and see how they compare with other physicians in general and within their own speciality.  Specific strategies could be developed for self correction at the earliest possible stages.  I wrote about a pharmacosurveillance system used in Wales in a previous post.  The top 5 drugs causing complications in that system were opioids, antibiotics, warfarin, heparin, and insulin - in that order.  With a sophisticated system it would be possible to pick up significant adverse drug events and monitor those events as well.    

All of the talk about patient safety these days is really about patient safety being practiced in the silos: health care businesses, hospitals, and clinics.  Places where individual health care data is considered proprietary - at least until there is a complication big enough that the state authorities mandate that it be reported for investigation.  These businesses have an inherent conflict of interest in reporting adverse drugs events and severe complications.  Pharmacosurveillance should be out there across the entire health care landscape.  It should not depend on reports about complications made by businesses that are in effect protected by patient privacy.  Complications can be actively sought out and investigated any time a prescription suddenly stops or changes.  This data also needs to be freely available to physicians so that they can look at their prescribing data relative to their peers and make changes where necessary.

It is time to view the process as as a way to learn about how to provide the safest possible environment for patient care,  rather than a way to "catch" somebody when something goes wrong.        


George Dawson, MD, DFAPA


References:

1:  Paulozzi LJ, Mack, KA, Hockenberry JM.  Vital Signs: Variation Among States in Prescribing of Opioid Pain Relievers and Benzodiazepines — United States.   Morbidity and Mortality Weekly Report (MMWR) July 4, 2014 / 63(26): 563-568.

2: Paulozzi LJ, Strickler GK, Kreiner PW, Koris CM.  Controlled Substance Prescribing Patterns — Prescription Behavior Surveillance System, Eight States, 2013. Morbidity and Mortality Weekly Report (MMWR)  October 16, 2015/ 64 (9): 1-14.

From Morbidity and Mortality Weekly Report (MMWR) October 16, 2015/ 64 (9): 1-14.

Medical Marijuana For Intractable Pain - The Minnesota Update

Minnesota made headlines at least within the state lately by qualifying intractable pain (typically known as chronic noncancer pain) as a condition for Minnesota's Medical Cannabis program.  I find it politically interesting that when you want to take over medical systems of care the strategy is to eliminate the word medical wherever that is possible.  But in this case when there is limited if any medical evidence for a treatment that carries significant risks and the initiative seems like part of a political movement toward the general legalization of marijuana that the word medical is added to seemingly legitimize the entire process.  I don't think that there is anything medical about marijuana or cannabis.  If you want it legalized, make that argument and don't pretend that a compound (or more appropriately compounds)  that has been around for 5,000 years has suddenly become a miracle drug.  

I previously posted about the original statute and will not repeat any of that in this post.  The full details of the intractable pain indication are listed on a separate DHS web site including the definition of intractable pain.  The statutory definition of intractable pain is quite complicated and seems to misunderstand the nature of chronic pain, ignore the addiction cofounder, and address the non-cannabis treatment of chronic pain with Schedule II to V drugs and issue that seems totally unrelated to cannabis use.  To cite a couple of examples:

"§ Subdivision 1.Definition. For purposes of this section, "intractable pain"means a pain state in which the cause of the pain cannot be removed or otherwise treated with the consent of the patient and in which, in the generally accepted course of medical practice, no relief or cure of the cause of the pain is possible, or none has been found after reasonable efforts. Reasonable efforts for relieving or curing the cause of the pain may be determined on the basis of, but are not limited to, the following:

(1) when treating a nonterminally ill patient for intractable pain, evaluation by the attending physician and one or more physicians specializing in pain medicine or the treatment of the area, system, or organ of the body perceived as the source of the pain; or...." 

With chronic noncancer pain is is generally accepted that there is no medical treatment that will eliminate the pain.  There is no medication that will totally alleviate the pain.  That includes high potency opiate medications.  Most of the literature suggests that whether high potency opiates, anticonvulsants, ar antidepressants are used the result is a moderate amount of pain relief at best and additional measures like physical therapy and psychotherapy are needed to produce optimal results.  There is really minimal to no evidence that the addition of cannabis to existing pain medications will add anything.  In this case, the statute also suggests that all of these pain patients will be referred to "one or more physicians specializing in pain medicine" or the part of the body that the pain is associated with.  This statute seems like it could easily set-up a physician or group of physicians who could add cannabis to the medications that they are already prescribing.  In other words the statute is providing a non-medical indication that can be used to alter medical practice on a large scale by the prescription of an addicting drug.  We have seen previous epidemics of use and overprescribing based on similar theories.

Subd 2. from the same statute gets in to existing medical practice for reasons that are not apparent to me.  It includes the following introductory paragraph and goes on to cite the non-applicability of the statute to the issue of treating substance use disorders, use for non-therapeutic purposes, providing a scheduled drug for the purpose of terminating life in a person with intractable pain, and using a non-approved drug.  Based on my experience Schedule II-V drugs are widely used for non-therapeutic purposes if use for any indication outside of analgesia is considered a non-therapeutic purpose.  A few examples include taking extra medication for insomnia, anxiety, depression as well as mixing the medication with alcohol for an added effect.  It seems more than a little naive to me to think that a controlled substance with broad effects on the conscious state that potentially reinforces its own use will be not be used for other purposes.  That includes the use of cannabis and marijuana.        

"§ Subd. 2.Prescription and administration of controlled substances for intractable pain. Notwithstanding any other provision of this chapter, a physician may prescribe or administer a controlled substance in Schedules II to V of section 152.02 to an individual in the course of the physician's treatment of the individual for a diagnosed condition causing intractable pain. No physician shall be subject to disciplinary action by the Board of Medical Practice for appropriately prescribing or administering a controlled substance in Schedules II to V of section 152.02 in the course of treatment of an individual for intractable pain, provided the physician keeps accurate records of the purpose, use, prescription, and disposal of controlled substances, writes accurate prescriptions, and prescribes medications in conformance with chapter 147."

There is some science added to the Intractable Pain page in the form of a review entitled: Medical Cannabis For Non-Cancer Pain-A Systematic Review.  It was prepared in the standard manner of most current literature reviews critiquing the quality of the studies and looking at what the evidence shows.  Most people who are uninterested in the details of these reviews could benefit from reading the executive summary.  Like most of these systematic reviews the authors conclude that the overall evidence is sketchy, that a few studies established a response better than placebo, that the clinical trials are of short duration and patient selection is not likely to reflect who might use the drug in Minnesota, and that most of the trials looked at adjunctive treatment of cannabis and limited forms rather than cannabis monotherapy.  They also conclude that cannabinoids were associated greater risk of any adverse events, serious adverse events, and events associated with withdrawal from the study than placebo.  The authors were aware of a recent review in JAMA provided an interesting analysis of that data in the context of their review on pages 22 and 23.  The authors point out that their review (unlike the JAMA review) did not use data from unpublished studies in the meta-analysis of treatment effects.  Their re-analysis of the JAMA review data generally shows either evidence that does not show superiority over placebo or in the case where it does - the evidence is of low or insufficient strength.

I am not going to include an exhaustive review of the toxicity of cannabis or the developmental concerns of cannabis exposure in utero or in the developing adolescent brain.  I am considering a separate post on that topic.  For the purposes of an intractable pain post,  I will add a couple points about politics and regulation.  The first point is that chronic pain is a complex disorder.  It resembles what is commonly conceptualized as a psychiatric disorder much closer than what is considered a standard medical or surgical disorder.  Chronic pain is multidimensional and is frequently associated with depression, anxiety, and insomnia.  Pain ratings on any given day can reflect the state of those other conditions.  Cannabis can affect all of those other conditions in unpredictable ways.  The best example I can think of is the chronic marijuana smoker who starts in order to treat anxiety and stops years later because the anxiety is worse and he is now experiencing panic attacks or paranoia.  Anything that complicates the other dimensions of chronic pain will not be an acceptable overall treatment.  The second point is that some chronic pain patients end up taking a drug in an addictive manner independent of pain relief.  That is true for marijuana, opioids, and benzodiazepines.  Many patients will openly admit that they are using the drug because they like the effects, but it is not doing a thing for their pain.  The final point is that some people do not discriminate between numbness and analgesia.  The drug they take for pain has to induce a numb state - one where they generally have a difficult time functioning.  I include these points about chronic pain trials because these additional phenomena are usually not examined in the clinical trials.  The trial occurs as if every subject can rate their pain like they can take a blood pressure reading and that loses a lot of important information in the process.  The studies in the reviews listed here for cannabis in non-cancer pain can show weak positive effects and those kinds of studies will eventually be approved by the FDA as evidenced by some FDA actions where the regulatory considerations trump the scientific ones.  With marijuana being described as a fast growing $3 billion dollar a year business with a projected maximum market of $36.8 billion annually, you can bet there will be a large commercial lobby pushing for approval of whatever products they want to bring to market.  

I don't plan on getting too riled up about the Minnesota experiment and the political indications for "medical" marijuana.  It is clearly a response to the current cultural swing to view cannabis as a benign product and use the medical avenue to get total legalization.  When marijuana use gets as widespread as alcohol use, the population toxicity will be more evident.  In the meantime, I hope physicians don't get pulled into the politics - especially psychiatrists.

I don't plan on registering on the Medical Cannabis Registry and certifying patients for the political indications for its use.  I consider that to be a foolish endeavor.  It would be much easier to take physicians out of the loop instead of having them pretend to select patients for a drug with no medical indications.  If anything, the widespread use of marijuana or cannabis for whatever the reason will complicate psychiatric practice and increase the costs of treatment that is already rationed by healthcare businesses and the government.  


George Dawson, MD, DFAPA

Refs:

1:  Butler M, Krebs E, Sunderlin B, Kane RL.  Medical Cannabis for Non-Cancer Pain: A Systematic Review.  Prepared for: Office of Medical Cannabis Minnesota Department of Health, October 2015.

2:  Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA.2015;313(24):2456-2473. doi:10.1001/jama.2015.6358.


Attribution:

Jennifer Martin (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons at: https://commons.wikimedia.org/wiki/File%3AMarijuana_Plant_01.JPG

Does Identifying Bipolar I Disorder Come Down To 6 Proteins?

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

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

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

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

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


George Dawson, MD, DFAPA

References:

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

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

Attribution:

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

Better Living Through Pharmacology

One of the great unspoken biases in psychopharmacology is the belief system about the medication.  What is the medication supposed to do after all?  Is it supposed to be life-changing in terms of positive improvements?  Is it supposed to eradicate all types of depression and anxiety?  Is it supposed to create the perfect cognitive and emotional state?  Is it supposed to turn an average student into an MIT professor?  Is it just supposed to treat a symptom and if so - how many symptoms?  Does it need to address some underlying physiological disturbance or can anyone take it and get the same benefits?  These are all unspoken biases about psychiatric medications that need to be explored with people who are taking the medications.  I don't think that a psychiatrist should even take for granted that a patient knows the difference between depression or anxiety or why thinking that Attention Deficit Hyperactivity Disorder (ADHD)  with essentially no impairment in professional, academic, or social life is not the same as having that diagnosis.

One of the best examples is the myth of the perfect mind.  If ADHD is finally diagnosed and treated, that means the person's mental functioning will either be normalized or be much better than it was in the past.  It should be possible to read entire book chapters and even books for the first time.  That is true isn't it?  It turns out that the effects of most medications for ADHD are modest and rarely life changing.  I have talked with many people who had clear diagnoses of ADHD as children who did not like the side effects of the medication and stopped taking it or even faked taking it in school.  They developed strategies for coping in the world and were able to achieve academic and vocational success.   Even some of the strongest proponents of medical treatment of ADHD will agree that proper care also involves lifestyle and management strategies and in some cases formal therapies in addition to medication.  That does not mean that some people will not do better with medications and worse with lifestyle modification, but it does mean that there is much more latitude in the treatment of this disorder than is commonly assumed.  It is fair to say that in many clinics these days, there are clinicians actively looking fro any treatable psychiatric disorder.  The theory seems to be: "If I treat the social anxiety disorder, bipolar disorder, ADHD, panic attacks, and insomnia this person will be a lot better off."  There is really no evidence that this is true or that there is even a good way to select what disorders should be treated first.

The patient side of this problem seems to be the myth of the perfect mind extended to many conditions.  It is evident in a number of ways.  Some people present with some very basic knowledge of psychopharmacology.  They may suggest that their "serotonin" or "dopamine" is out of whack and that they heard that there are specific medications to correct that.  In some cases they will suggest a medication.  In other cases, a person will not be very stress tolerant and suggest that they need something that will either reduce day to day stress or significant stress from predictable major life stressors like the disruption of a job or relationship.  They seem to think that there is a medication that will both reduce the emotional reaction to this pain but also remove the cognitive elements from their mental life.  Depending on the person's baseline cognitive state, they can become quite demanding if they think that they are not getting adequate relief or it is not happening fast enough.  The risk in these situations is starting to take a number of medications with substantial side effects that frequently precludes them getting back to their baseline conscious state.  There is often a focus on a person's baseline in psychiatry or medicine, but that baseline is almost never adequately characterized.  That is true in the case of blood pressure but more true in the case of mental illnesses.  In the case of severe mental illnesses like bipolar disorder baseline is almost always defined in terms of the presence or absence of a few symptoms.  Wide areas of a person's life like their baseline intellectual functioning, social behavior, and typical stream of consciousness are rarely considered - even in research studies.

Addiction makes everything worse and therefore it also provides the best illustration.  The graphs at the top of the page show two drug response curves with the blue lines showing a good response.  A person who is using an addictive drug and the high risk response to that drug is conditioned to expect the drug response curve on the right - a continued therapeutic response for increasing doses of the medication.  In that case there is no element of safety or toxicity.  True drug responses are represented by the curve on the left - an interval of response followed by toxicity and limited response at the higher levels.  Addictions have a second effect by creating a bias that mental states can be fine tuned within the space of hours by drugs.  Any feeling state can be immediately modified by the addition of benzodiazepines, stimulants, opioids or alcohol.  This is often erroneously referred to as "self-medication" and it is a strong conditioned response that generalizes to the treatment of disorders with non-addicting drugs.

The psychological effects of these patterns are significant.  They can lead to continued addiction and disrupted care.  A person may have the belief: "If this doctor can't give me something that will get rid of the negative way I feel right now - I will take something to get rid of it."  It may lead to disruption of the therapeutic alliance, through anger and open criticism about the lack of immediate effects or minimization of physician concern about side effects and a general lack of concern about toxicity on the part of the patient.  There is often an associated belief: "I have a very high tolerance for drugs and you can give me higher starting doses and higher maintenance doses of drugs than you give most people."  Many people in this situation experience very high levels of anxiety if they are not getting high doses or the physician does not seem to be increasing the medication fast enough.

The thoughts and feelings about medications is one of the most difficult areas in psychiatry.  Contrary to what is written by critics - nobody is complaining about being overmedicated.  Most of the complaints I hear about are about not getting enough medication and not getting to those high doses fast enough.  The solution is rarely to provide the medication and amount requested.  The solution is to spend enough time talking with the patient about these issues.  I generally start with the limitations of the defined treatment and a medication strategy that is risk avoidant.  In that initial conversation I usually tell the person whether or not they have a diagnosis or if I agree with a pre-existing diagnosis.  If I detect signs that unrealistic expectations about the medication are present I move into that area, point out that the medication will not lead to a perfect mind, and what they have to do in addition to taking medication.  If I find that they are really focused on medication issues to the point that they are experiencing anxiety from it - I usually encourage them to think about something else and provide some examples of what else can be done.

There is some literature on psychodynamic issues and medication in the transference that I have not found very useful. I suppose you could say that from what I have written the medication has meaning far beyond its pharmacology.  There is an interpersonal and intrapsychic context.  I think it is addressable in what is usually considered straightforward supportive psychotherapy, but it definitely needs to be addressed.  It is a frequent cause of medication or treatment "failures".


George Dawson, MD, DFAPA        

Never Miss An Opportunity To Harass A Physician

Despite some PR releases to the contrary, pharmacy benefit managers (PBM) continue to harass physicians and waste their time.  My latest inane conversation occurred after a pharmacy left their usual message about prior authorization and an 800 number about a prescription that I had written.  Unless I call the PBM and jump through all of the necessary hoops they will not cover my patient's prescription and it will likely go unfilled.  It was a newer medication and more importantly one that I had not started in the first place.  In other words, the patient had been maintained on this medication before seeing me.  That means the specific prescription had been approved from another physician a few months earlier.  I was writing this prescription because the patient did not have access to the previous pharmacy and I was the physician of record in another treatment facility.  The conversation with the PBM went like this:

PBM:  "Is this a doctor's office or a pharmacy?"
Me:  "Doctor".
PBM:  "Who is the doctor?"
Me:  "George Dawson"
PBM:  "Who are you?"
Me:  "George Dawson"
PBM: "OK - I was just checking.  What is your fax number?  I can fax you the form in 20 minutes"
Me: (fax number given)
PBM: "OK - you will need to complete the form and then fax it back to us and we will have 15 days to make a determination?"
Me:  "Do you understand that the patient needed this medication two days ago and I just got a notification about this today?"
PBM:  "That is the patient's policy.  We can do an expedited review and give you a determination in 3 days if you like?  But that is in the patient's policy.  We have either 15 days or 3 days to make a determination.  Do you have any questions about that?"
Me:  "Well no I do not.  I am only concerned about appropriate medical care and this delay is not appropriate medical care.  I don't care about your policies.  Your policies have nothing to do with appropriate medical care."
PBM:  "Is there anything else that I can do for you today?"
Me:  "No there is not."

I expected to receive the fax in 20 minutes but did not get it until the next day.  The form is designed to waste additional physician time.  It could have been pre-populated with all of my information and the patients information - but it was not and I had to complete the form by hand.  There were two sections on the form that had to do with failed medication trials.  One wanted specific dates.  Since I am a consultant I do not have specific dates and my experience with most patients is that they have a difficult enough time with the names of medications.  I do know that the patient had tried 8 different medications from the same class and stopped them due to lack of efficacy or intolerable side effects.  I added them to the section and wrote "refer to the previous section" on the redundant form.  Total time to complete the form and try to figure out what they wanted was 20 minutes.   I was seeing other patients it took me an additional 2 1/2 hours to complete the form and fax it.  The 72 hour clock started at that point but there was no place on the form to request an "expedited review".  

I have several posts about PBMs on this blog.  They all have the same modus operandi.  PBMs are at the very minimum a significant delaying action.  They are hoping that the physician, the patient, or both just give up and either withdraw the prescription or opt for a much cheaper generic prescription.  There are a couple of significant problems with that theory.  The first is that all generics in the same so-called drug class are not equivalent.  Any physician with a modicum of experience knows that individual patients have highly individualized responses to medications that are broadly similar and that there are generally sound pharmacological reasons for those responses.  Secondly, physicians have been prescribing less expensive generics medications for decades now and if a new unique medication is being prescribed the odds are very high that the person has not responded to that medication.  In the example given here,  I had a list of 8 medications in my record that failed due to intolerable side effects or a lack of efficacy.  They were all inexpensive generics.  I listed them on the form and faxed it back to them.

This behavior does highlight an important difference in ethics between physicians and medical businesses.  In every case where I prescribe a medication for a patient, the medication is carefully selected and monitored for how well it is tolerated and the effectiveness.  The ethical concept here for physicians is to provide continuity of care for the patient.  That is the reason that I am obligated to provide follow up prescriptions to patients who leave one care setting and go to another.  The PBM obviously has no similar constraint.  I would argue that their 15 or even 3 day policy ignores the fact that the patient needs the medication right now.  The telephone conversation makes it explicit - the company cares more about the policy than the patient who needs the medication.

The political process in all of this is frequently ignored.  How is it possible for a private company to waste so much physician time and interfere with patient care?  A long time ago the healthcare industry and its friends in government sold the American public on the idea that businesses should ration health care.  They sold that idea with rhetoric about how physicians were greedy and tended to squander health care dollars on unnecessary tests, surgical procedures and medicines.  They sold that idea in spite of the fact that the largest independent review organization of physicians documented a trivial amount of excessive resource use.  Businesses are now firmly entrenched as middle men whose only job is to ration health care and that includes prescription medications.  They do that in part by having physicians make tens of thousands of calls like the one outlined here every day and essentially leaving that physician and their patient in the lurch.

Health care businesses currently have the best of all possible worlds.  They are funded by mandatory health care insurance that is essentially the second largest tax on all Americans.  The annual health care premiums easily exceed property taxes, state income taxes, and state sales taxes for almost all Americans.  The does not include the amount of physician and patient time that is wasted by these rationing tactics.  In return Americans get a system of corporate management that consistently places the interests of the corporation and corporate profits ahead of them.  They talk like they are competitive businesses - but they are in fact some of the most heavily subsidized businesses in the US and nobody seems to make the connection between the most expensive health care system in the world and this corporate welfare.

It is well past the time for change and the first step should be to return medical decision making to physicians and stop pretending that a for-profit company cares more about patients than the monied interests of the corporation.


George Dawson, MD, DFAPA

Minnesota Psychiatrist Workforce Shortage

It should be well known by now that Minnesota has a shortage of psychiatrists.  Government officials and administrators everywhere think that the solutions are simple - hire more psychiatrists or (even better from the administrators perspective) - hire more non-physicians to prescribe increasing amounts of medications for psychiatric disorders.  Various posts on this blog elaborate what the real problems are and why it is not a straightforward hiring problem.  There are various markers that point to the real problem as rationing and business approaches to psychiatric care.  At the latest Minnesota Psychiatric Society meeting, there was an invitation to participate in an interview project that is being conducted by the Minnesota Department of Health.  I am posting the following description of that project here as a public service announcement.  I think it offers a rare opportunity to provide direct information on the practice environment to government officials.  Please contact Ms. Morgenstern for the interview if you are interested.  She will provide you with a document of the standard interview questions.  I encourage everyone to be very frank about the practice environment here in Minnesota and what is wrong with it.

The Minnesota Department of Health Office of Rural and Primary Care is doing an interview project on the psychiatric workforce shortage. We wish to conduct ethnographic-style interviews of 30 minutes to a half hour in length with practicing and retired psychiatrists to get their perspectives on job satisfaction, location desirability, and difficulties in entering the workforce. This information will be used in conjunction with other workforce data in a report to the Mental Health Workforce Commission, which is charged with making recommendations to the legislature. If you would like to be a part of this project, please email Gabrielle.Morgenstern@state.mn.us



George Dawson, MD, DFAPA




Attribution:

By Alexrk2 (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

Dreaming of the EHR

The Dream:

I am at the APA convention.

It is in a crummy hotel attached to a mall. I am going down to the street level in an elevator and it stops at a level where there is a big cinema complex. An 8 year old boy runs excitedly into the elevator and jams in to my left. The elevator is crowded. He looks at my name badge and says: "What would George Dawson say if the Watson computer said he wasn't doing a good job?"

I glance down at him and say: "George Dawson would not care."

The kid says: "That's not good" and laughs intensely.......


It is all a dream. I had that dream early Saturday morning. It doesn't require detailed analysis. That last thing I did on Friday was try to review a 22-page paper record that was generated by a modern electronic health record (EHR) system. With the exception of a few paragraphs it was largely unintelligible. It contained bits and pieces of information. I was looking for imaging (CT, MRI, ultrasound reports) and ECG data, but instead could find only a few lines that summarized fewer results. There were no dates - no hospital admission or discharge date.  Although the hospitalization was longer than a week - there was no medication administration record or MAR - showing the specific dates when medications were changed.  There were no comprehensive reports that I am used to seeing for the past 30 years from Radiologists. There was no discharge summary. The documentation was basically unacceptable as a source of clinical information and yet it was created by a very high end, enterprise wide EHR system. It brought back a memory of a mandatory meeting I had with a "coding specialist" about 10 years ago. That person let me know that I had "passed" the documentation review in that I had ticked off the necessary "bullet points" so that documentation specialists would approve my EHR note for the day and the associated billing document that had to be submitted with each note.  She showed me how I could do things faster by ticking off a series of check boxes and electronically signing the note.  She was shocked when I told her that I really could not sign my name to that document because there was no sign that an intelligent human being had seen the patient.  For all of these reasons, very poor documentation in the EHR is always on my mind.

My attempt to read the last report may have been enough of a reason for the dream, but I also spent time on Thursday with a colleague who really dislikes the EHR for additional reasons. We regaled our spouses with tales of incomprehensible reports.  In addition, his reports require a synthesis of many imaging, lab, and clinical reports.  He previously used a system where all of the reports showed up in a queue and he could go down that list in chronological order to dictate the report.  In the new system, he has to go to tabs to find all of the reports he is looking for.  Some of these tabs are hyperlinked and the reports don't load very well.  In the end, he and his colleagues end up printing out all of the reports on paper so they can dictate then more efficiently without having to search for what they need in real time in the EHR.  That reminded me of an experiment I did about 8 years ago with the same EHR.  I went in and read all of the clinical notes looking for chronic diagnoses that were not addressed.  I came up with an additional 8 diagnoses from 340 clinical notes buried in the EHR. There is generally no good way for physicians to mine data on their own patients to make sure that they have done the most thorough assessment of their problems.  On the other hand administrators can get detailed numbers of mouse clicks by nurses in primary care clinics and rate their productivity in terms of mouse clicks, screen views, or tasks completed.  My colleague's theory was that the current EHR is selected for the administrative capabilities like monitoring doctors or nurses rather than any inherent advantage for medical staff.  The major evidence for that is that many EHR vendors have permanent staff in the hospital and they are making constant modifications to the EHR.  In many cases there are meetings of all the physicians in a particular department about these modifications.  The hospitals and clinics purchasing these systems are purchasing incomplete products that require what seems like constant revisions.

It has been about 15 years since the blight of the EHR hit physicians.  It was originally called the electronic medical record (EMR) but I suppose some business type decided that they could really solidify the corporate stranglehold on medicine by eliminating the word "medical" from another phrase.  Corporate psychology also dictates that they give the impression that they are maintaining health rather than treating medical problems.  That is another good reason for eliminating the word medical from the corporate lexicon.

The marketing of the EHR has been masterful.  The political hype promised untold savings.  National candidates seemed to suggest that we could actually "save" enough with the EHR that it would cover a substantial part of American health care inflation.  Any physician involved in the implementation phase of enterprise EHRs knew that was a bold faced lie.  There is no way that annual multimillion dollar a year licensing fees as far as the eye can see are going to save anybody any money.  In fact, I am certain that many clinics and hospitals have had to cut staff and services just to bankroll the EHR. Nobody has ever followed the money on the EHR debacle as far as I know.  Congress is well known to invent businesses and turn people into billionaires overnight.  All it takes is a few Congressional mandates about the need to use an EHR and electronic prescribing.  There is no mandate to keep things cost effective of make sure that independent practitioners can afford it.  There are mandates to implement EHRs and electronic prescribing and the White House brags about it.  The following graphic and text are from a White House document on the EHR entitled: More than Half of Doctors Now Use Electronic Health Records Thanks to Administration Policies.

The problem with the White House statement is that despite spending about $3 billion dollars a year and in some cases $44,000 per physician,  the value of the EHR for the reasons already stated remains in question.  It is very handy to be able to pull up lab results and x-rays on a computer screen.  It is also very handy to be able to send electronic prescriptions to any pharmacy in the country.  On the other hand, it is reasonable to expect that a multimillion dollar piece of software will write a report that any hundred dollar database software from the 1990s could write.  That same software should be capable of allowing physicians to search their own patient results for quality and report writing purposes.  In the end we are left with very expensive, high maintenance systems, and massive amounts of information that is either buried in storage because it is not easily accessible or because it is worthless and generated primarily for justifying a billing document.

That is one of the many real costs of having a health care system run by bureaucrats and politicians.  


George Dawson, MD, DFAPA


Attribution:

Photo at the top of this blog is by Paco Burrola on Flickr and is used courtesy of this Creative Commons license.

NEJM Review of Generalized Anxiety Disorder

There was a review of Generalized Anxiety Disorder (GAD) in this week's New England Journal of Medicine by Stein and Sareen (1).  I just did a bit of a critical review of the concept here and thought I would look at what these authors had to say.  

They start the review with a clinical vignette of a 46 year old married woman with insomnia, headaches, back pain, and excessive worry about a number of daily stressors.  She is also drinking alcohol on a daily basis to "self-medicate".  She is described as a person who comes in frequently for appointments.  After reviewing the phenomenology,  comorbidity, and differential diagnosis - the authors come back to this case and apply what is in the review.

Their review of the diagnosis does highlight a few things that are problematic about the diagnosis.  The key diagnostic feature is chronic excessive worry.  The worry has to be there for at least 6 months.  In their review of other psychiatric causes of anxiety they omit diagnoses that can cause short term worry or anxiety - the adjustment disorders.  They point out that GAD is more common in primary care clinics where it usually presents with a chief compliant of somatic problems rather than excessive worry.  They discuss major depression as a common co-occuring condition and suggest that anhedonia may be a distinguishing symptom for depression.  They also describe anxious depression as episodic depression superimposed on chronic anxiety.  There is no mention of the low diagnostic reliability of the disorder and why that might occur.  I think that any psychiatrist who sees GAD over time experiences the same problem that occurred in the DSM-5 field trials, the diagnosis can seem to change between visits from GAD to major depression, even in the absence of any new stressful life events.  Critics of psychiatry frequently cite this as a problem with DSM-5.  I think that DSM-5 does a good job with the symptom descriptors, but we don't know why this change occurs and I have not heard anyone talk about it like it is a real phenomenon.

Alcohol use is described as a common co-morbidity with 35% of people with GAD "self-medicating."  I put that term in quotes because it suggests that alcohol can actually be used for the purpose of medication.  What really occurs is that over time the person becomes more anxious and sleep deprived because of the negative effects of alcohol on sleep, baseline anxiety, and baseline mood.  Practically everyone I talk with who has an alcohol use disorder can recognize this pattern and modify any remarks about self-medication to "feel better for a few hours" or "knock myself out and forget about my problems".  There is also the issue of alcohol use being the cause of an anxiety disorder rather than temporary relief.  While I am on the topic of substance use and GAD, at one point the authors make the statement: "Data are also lacking on the use, usefulness, and safety of medicinal marijuana for generalized anxiety disorder" (p. 2066).  Many if not most anxious people are averse to the use of marijuana for anxiety.  Initial use of marijuana typically causes a drop in blood pressure with a compensatory tachycardia.  Tachycardia especially if there is a noticeable accentuation of heart beats is not tolerated well by patients with anxiety.  Many have had panic attacks.  Others have cardiac awareness and are sensitive to any changes in heart rate or intensity.  Many people tell me they thought that marijuana was effective for anxiety, but over time it seemed to make them more and more anxious, they developed panic attacks, and they had to stop using it.  These features combined with a tendency of patients to stop talking to their primary care physicians about substance use are good reasons to heavily educate them about these problems at the earliest possible time.

The authors take a risk factor analysis approach to looking at historical features that can also be associated with the diagnosis.  They point out that they are nonspecific and amy be associated with other psychiatric diagnoses.  I would encourage a more developmental approach, looking back at the first recollection of anxiety - usually at some point in childhood and how that developed in the childhood environment.  It is fairly common for the patient to describe one or both parents being anxious and how that was transmitted to them  eg. ) "I started to worry about the same things my  mother worried about" or "I started to worry about my mother because she was worried all of the time - I worried that something was going to happen to her."  Those learning patterns associated with adult anxiety are fairly common and may explain the low heritability (15-20%) of the disorder.  The authors do discuss one feature that is important in this context and that is intolerance of uncertainty.  Clinically that translates to excessive and at times catastrophic worry about uncertain situations.  They are unsure about the biological or experiential origins of the symptom.  I think the important part is that with a careful enough history and sometimes collateral information the learning aspects of this bias can be examined and it can be unlearned in therapy.

The authors advocate for a stepped approach to treatment and I certainly agree.  This approach would include an initial medical assessment to look for common medical conditions that can cause anxiety followed by education about anxiety and lifestyle changes to address sleep, exercise, caffeine intake and alcohol use with monitoring response to those interventions.  Those first two phases could be accomplished at the initial visit.  If those initial interventions don't help moving on to "low intensity psychological interventions" like self-help books, computer-assisted psychotherapy, and support groups.  The next step up is more intensive psychological interventions like individualized cognitive behavioral therapy (CBT) or pharmacological management based on the patient's preference.  The highest level of care would include pharmacotherapy and more intensive CBT alone or in combination with other therapies (psychodynamic or acceptance and commitment therapy (ACT)).  The practical issue with this 4 step algorithmic approach to care is that it is generally not available in primary care settings.  In many of those settings, the patient is screened with the Generalized Anxiety Disorder 7-item questionnaire (GAD-7) and the patient is treated with a medication.  This is viewed as "cost-effective" care by managed care systems because an inexpensive prescription and a 20 minute appointment with a physician is apparently much more "cost effective" to the organization than maintaining computerized psychotherapy or educational and monitoring systems.  There is also the largely undetermined effect of the patient taking a completely passive role in their care.  There is a significant difference between a patient who is actively engaged in lifestyle changes and self education and one who expects a complete cure from a pill.  The actively participating patient has better outcomes.   

The authors include a table of 16 medications used to treat GAD.  They point out that the effects of medication are modest at best and no single medication has better efficacy.  They discuss vilazodone as a promising medication in clinical trials and do not include it in the list.  My current prescribing information says that it is FDA approved only for major depression, but only 4 of the 16 drugs on the list are approved for GAD: paroxetine, venlafaxine XR, duloxetine, and buspirone.   The authors comment on the practice of using hydroxyzine for GAD and suggest not to use it.  I am in complete agreement with that recommendation and think that any anti-anxiety effect comes from the non-specific sedating effect of antihistamines.  The side effect profile is also not very favorable.  They point out the benzodiazepine paradox with GAD - they are recommended for short term (3-6 month) use but the condition is chronic.  There is even more subtlety there.  Some early studies of GAD treated with antidepressants suggests that patients needed to take the medication only 30% of the time over ten years of treatment.  I don't think you will see a similar study with benzodiazepines and I think it has to do with the behavioral pharmacology of the drug.  The single-most important issue when it comes to benzodiazepines is the informed consent and letting the patient know that they are taking a potentially addictive drug.  

The  authors are silent about the fact that GAD may be the most heterogenous of all of the DSM-5 categories.  In October and November of this year, I went to three excellent conferences.  One of the central themes was phenotypic diversity in DSM-5 categories and what it implies for biology and genetics.  GAD seems to offer some of the best clinical features for distinguishing intermediate phenotypes and I outline a few in my previous post.  There are problems with a diagnostic category that says "excessive worry" is a discriminating feature and ignores real physiological markers like persistent tachycardia, hypertension, body mass index, and hyperarousal at the time of sleep.   This also points out how basic science can drive clinical diagnoses in psychiatry and hopefully at some point in the near future we will see this kind of research.

    

I think that we have gotten as much as we can out of the GAD diagnosis at this point and it is time to break it down into what can be more reliably observed. 

George Dawson, MD, DFAPA

References:

1: Stein MB, Sareen J. Generalized Anxiety Disorder. N Engl J Med. 2015 Nov 19;373(21):2059-68. doi: 10.1056/NEJMcp1502514. PubMed PMID: 26580998.

Sprituality.....

I was born and raised a Methodist.  My father was a Catholic and had some problem with that church despite the fact that many of his siblings were devout.  To this day, I have a vague notion of what being a Methodist means.  I remember going to a church that looked like a large house from the outside.   It was a very modest building.  There were a hundred or so people on the inside.  They became familiar faces over time.  I was always interested in what the clergy had to say and the message varied considerably.  I did not know it at the time, but being a protestant clergy is a very political position.  People have to like you or they start to talk and that talk can eventually undermine your ministry.  Even as a kid I thought I could figure out how serious the minister was by what he said.  Was it a rote presentation or did he brings things alive.  I don't mean in the entertaining sense.  Could he (we only had male ministers in those days) get a serious lesson across in an inspirational way?  I was always impressed with how little commentary there was about this central feature of the church service.  It seemed routine to go there, listen to the sermon, sing a few songs and leave.  No enduring message or feeling.

It wasn't until I was a teenager that I saw the inside of a Catholic church.  I was there for my father's funeral.  Several of his devout siblings arranged for the funeral service to occur in the Catholic church despite the fact that (to my knowledge) in my 15 years on earth at that time - he never set foot in church.  In assessing what the church looked like, I recall thinking that "this is the big time."  The structure was huge compared to the Methodist church and the architecture was inspiring.  No wood framing.  There were concrete arches, stained glass, symbols, and actual sculptures of Christ on the cross everywhere.  In a Methodist church there is usually one large plain wooden cross.  The stained glass is always basic with the words: "Faith, Hope, Charity".  The acoustics were definitely different.  Words spoken in a Methodist church tend to project out about 15 rows and rapidly drop off in volume.  In the Catholic church the sound carried and echoed all the way back to the last row.  That last row was at least 4 times the distance of the last row in the Methodist church.  Since then I have been in many churches Catholic and Protestant - typically for weddings and funerals.  Even though the church architecture can be an impressive instrument for the speaker - it all really comes down to the clergy.  Are they doing more than dialing it in?  Are they inspirational?  Is there intellect behind the spoken words?  Can they convey the idea that there is something much larger than our individual conscious states out there?  Those were my first lessons in spirituality.

When I was in the Peace Corps in the 1970s, a fellow volunteer introduced me to a book called Zen and the Art of Motorcycle Maintenance by Robert Pirsig.  On the surface, it was a book about a cross country motorcycle trip by the author and his son.  Below the surface there were lessons about philosophical approaches to life - both eastern and western philosophies.  There was also a flashback to a crisis in the author's life when he was in graduate school and developed a psychotic depression while in the midst of an academic interpersonal conflict with one of his professors.  The lessons for me from Pirsig's book was that spirituality is really independent of other contexts.  He summarizes it in this statement:

“The Buddha, the Godhead, resides quite as comfortably in the circuits of a digital computer or the gears of a cycle transmission as he does at the top of the mountain, or in the petals of a flower. To think otherwise is to demean the Buddha - which is to demean oneself.” ― Robert M. Pirsig, Zen and the Art of Motorcycle Maintenance: An Inquiry Into Values.

After reading Pirsig's book five times, I concluded that he had an unprecedented intellectual look at what he described overall as values.  He also had a look at spirituality in a very unique way and could see it it places where it is not commonly seen - like welding or motorcycle mechanics.  Moreover, it was also a view that made immediate sense to me.  I had been doing the same thing for years.

That brings me up to my work as a psychiatrist.  In that work, spirituality ranges all of the way from religious delusions to the higher power concept in Alcoholics Anonymous and all points in between.  I don't know how many people I have talked with who believed they were God or Jesus or Satan or The Antichrist - but I have had hundreds of conversations about those topics.  On the quieter end of the spectrum, I have had even more conversations with people who were anhedonic, hopeless, spiritually bereft and who felt abandoned by God.  Many of these folks felt as though any spirituality they had was gone.  They lost interest in it like everything else and they had doubts about whether they wanted to get it back.  Did it really mean anything when they had it?  Getting it back turned out to be a critical part of their recovery.  I try to figure out a way to describe it in my clinical assessments and it is difficult.  Some have suggested using the term to capture the Gestalt of the person, but I think it is more complex than that.  In many ways it is like describing people who are charismatic and trying to use the appropriate descriptors.

There is an experiential aspect to spirituality that requires concrete examples rather than me just writing about it.  For that I will turn to a couple of examples from the best interview program anywhere - MPR's Fresh Air with Terry Gross.  I consider it a laboratory for the spectrum of human consciousness and it contains a lot about spirituality.  The first example comes from a story about Iris Dement.  She is a folk singer who began singing in the Pentecostal Church.  Until you hear an explanation of someone who is in that church or experience what they are doing - it is very unlikely that you know what is happening.  After carefully developing the context during the interview she summarizes it at this intellectual level (1) :

   "I saw my parents use music to survive.  They had to have that music.  My mom had to sing and my dad had to go to church and he had to hear that music washing over him and through him.  It wasn't a, "Oh, this is nice"; it was a, "I'm not going to make it if I don't have that."  So I've felt that that's my job.  That's how I think of what I do.  I have to give people that lifeline, you know, that I saw my parents reach out for, and that I was taught to reach out for, and so that's what I aim to do.  And I guess I don't feel like I can do that without that connection to the spirit."

When I listened to that interview and heard that quote, I realized that had just experienced one of the best examples of spirituality.  I encourage anyone with an interest to listen to the audio and have that same experience.  I think that you have to look past your taste in music to what motivates this artist.  Too many people get stopped in their tracks by thinking: "I don't like folk music" or "I don't like country music" or some appalling lack of knowledge of the Pentecostal faith.  Listen to the audio from the perspective of what motivates Iris Dement and keeps her going.

The second MPR experience on spirituality just occurred and it was the final push for this post.  I heard Terry Gross interviewing the Iranian born photographer Abbas on his series of photographs about what people do in the name of God.  The process of the interview is again very important.  Gross sees a spiritual element in one of the photographs but Abbas does not.  He comments that his relationship with God is purely professional - he has no stake in religion.  At the same time he describes some experiences that were moving while he was engaged in photography(2) :  

"Of course.  You know, I mean, you can't touch such a subject without being touched and moved.  I remember very vividly, for instance, a mass in France among the Benedictines, you know, it's monks. They're different from priests, you know, monks - very moved by a mass.  Normally when there's a mass, I don't listen, I just take photographs because it's always the same.  But this time, you know, the father who was saying mass was very spiritual.  He was talking about Jesus, not as a distant prophet, but as a personal friend.  So suddenly I start listening, and I became very moved.  In most religions, at least one event made me - well, I wouldn't say a believer but a participant....."

Like the Iris Dement story, I encourage listening to the actual audio and Abbas description of his technique before and after this excerpt.

What is spirituality?  It is not the same thing as religion, but for some people it is very close.  I also think that it is not easily acquired.  I don't think it is as easy as declaring a higher power.  Spirituality might be haunting rather than reassuring - it may not be a good feeling but it probably leads to a sense of calm.  I like Abbas's idea that it can make you a participant.  I can see it as an unconscious emotional force that probably has some obvious and many not so obvious origins that leads to consistency and may be noticeable by observers.  Some very spiritual people are described as serene and others as inscrutable.  It is not listed in the DSM-5 and that is a good thing.  It is another aspect of conscious experience that psychiatry neglects for the most part.   As far as I can tell, it is like an experiment in consciousness.  Like the examples I gave - you know it when you experience it.


George Dawson, MD, DFAPA


References:

1.  Terry Gross.  Fresh Air on National Public Radio.   For Iris DeMent, Music Is The Calling That Forces Her Into The Spotlight.  October 21, 2015.

2.  Terry Gross.  Fresh Air on National Public Radio.  Photographer Abbas Chronicles 'What People Do In The Name Of God'.  November 19, 2015.

3.  Melissa Block.  All Things Considered on National Public Radio.  A Nephew's Quest: Who Was Brother Claude Ely?  July 14, 2011.

Story of the importance of Pentecostals in rock and roll, especially Brother Claude Ely - with parallel comments about the spirituality involved in that music.  If you doubt it - read the last two paragraphs of the written story first.