Dementia Prevention And Substance Use Disorders

Dementia from Addictive Compounds

As a geriatric psychiatrist and an addiction psychiatrist, what I see happening in both professional literature and lay literature is mind boggling.  There is a clear bias advocating for the benign and even therapeutic effects of alcohol and addicting drugs.  What most articles omit is that the health effects of alcohol are limited to no more than two standard drinks per day for men and one drink per day for women.  The drinks cannot be all taken on the same day.  The limits are per day not per week.  Most of the evidence also suggests that the alcoholic beverage should be wine rather than beer or distilled spirits.  Recent studies suggest that of the 70% of Americans who drink - about 1/3 of them are probably drinking in excess of those amounts.  Doing the arithmetic that amounts to about 56 million people.  Even a low percentage of brain injury will result in a significant number of cases od dementia. Moderate to heavy drinking (3-12+ drinks/day) carries the associated risks of high carbohydrate intake and sedentary life style.  It is very common to find that moderate to heavy drinkers stop their usual outdoor activities and exercise and spend a lot of time watching television.  This can lead to obesity, glucose intolerance and dyslipidemia and in the worst case scenario metabolic syndrome.  All of those consequences lead to increased risk of cardiovascular and cerebrovascular disease.  

There are addiction risks with alcohol consumption apart from atherosclerotic heart disease. Alcohol is proarrhythmic and doubles the risk for arrhythmia.  In one large Danish study (11) they noted that alcohol intake and a history of atrial fibrillation was a risk factor for ventricular fibrillation.  Some authors view alcohol use a risk factor in preventable atrial fibrillation.  In clinical practice it is very common to interview patients with atrial fibrillation who notice that during times of heavy alcohol use they can sense that they are in atrial fibrillation and they spontaneously convert to sinus rhythm as their blood alcohol levels drop.  Atrial fibrillation is a causative mechanism for embolic stroke and associated cognitive disorders.

The direct toxic effect of alcohol on the brain has been debated for years. Amnesia from Wernicke-Korsakoff syndrome is a known diagnostic entity related to thiamine deficiency associated with excessive alcohol use.  It is probably underdiagnosed in most populations compared with postmortem diagnoses of the specific lesions consistent with Wernicke-Korsakoff syndrome (WKS).  A large number of people with alcohol use problems have demonstrable cognitive effects on testing as well as structural and functional brain imaging brain imaging studies suggest some effect on brain structure.  The lack of a pathological lesion has led some to suggest that this is a non-specific effect, but it is very likely that there are several variants of cognitive dysfunction related to alcohol use that are not associated with WKS (12).  On a clinical basis it is very common to see patients with subjective cognitive impairment that typically involves working memory, declarative memory, and executive function.  In treatment setting where abstinence from alcohol is assured many of these problems seem to clear up after about 60 days of abstinence.  But there are also populations of people with varying degrees of anterograde and retrograde amnesia that is not as dense as expected with full WKS.  Many of these patients are seen in treatment settings and never referred for comprehensive assessments of their cognitive disorder.  To my knowledge there have been no studies looking at the issue of whether or not partial amnestic states correlate with WKS lesions at autopsy.        

The problems with recognizing and treating cognitive disorders associated with substance use problems are exemplified in the first few paragraphs about alcohol.  They are no less important for other commonly abused substances.  In the case of stimulants, amphetamine analogues are known neurotoxins.  Studies by Volkow and others have shown persistent changes in dopaminergic neurons up to 15 months after the last use.  This may correlate with a persistent attentional deficit that leads patients to conclude that they now have attention deficit disorder.  Additional brain insults from hemorrhagic strokes and cardiovascular problems associated with long term stimulant use are common.  Stimulants are well known precipitants of acute myocardial ischemia and brain complications from hypoperfusion and emboli.  Acute hypertension and tachycardia are part of the acute intoxication syndrome that can lead to hypertension and hemorrhagic stroke.  This recurrent cycle leads to commonly observed complications of cardiomyopathy in the 4th and 5th decades of life and heightened risk of ventricular arrhythmias and cardiac arrest.

The graphic at that top of this post is not exhaustive - but point out some significant acute and chronic complications of drug use that can lead to permanent brain injury.  These mechanisms cannot be overlooked as avoidable causes of dementia.  I will be trying to elaborate on this graphic in the future to look at developing a review in this area.  Any acute acre and addiction psychiatrist is probably more aware of these syndromes and complications because they are encountered in clinical practice.  I have not seen any formal estimates of the fraction of dementia cases are preventable by avoiding these compounds.  The largest fraction of dementia cases would likely be attributable to the most commonly used drugs - tobacco and alcohol.  Drugs that kill more people acutely on a proportional basis like stimulants and opioids probably leave fewer survivors with dementia as a complication.  

Contrary to the conventional wisdom these days - avoiding dementia is another strong argument for a sober life style.


George Dawson, MD, DFAPA


References:

1: de Gaetano G, Costanzo S, Di Castelnuovo A, Badimon L, Bejko D, Alkerwi A,Chiva-Blanch G, Estruch R, La Vecchia C, Panico S, Pounis G, Sofi F, Stranges S, Trevisan M, Ursini F, Cerletti C, Donati MB, Iacoviello L. Effects of moderate beer consumption on health and disease: A consensus document. Nutr Metab Cardiovasc Dis. 2016 Jun;26(6):443-67. doi: 10.1016/j.numecd.2016.03.007. Epub 2016 Mar 31. Review. PubMed PMID: 27118108.

Moderate consumption is defined as 1 drink per day in women and 2 drinks per day  for men in a non-binge drinking pattern. J-shaped dose-response curve

2: Fernández-Solà J. Cardiovascular risks and benefits of moderate and heavy alcohol consumption. Nat Rev Cardiol. 2015 Oct;12(10):576-87. doi: 10.1038/nrcardio.2015.91. Epub 2015 Jun 23. Review. PubMed PMID: 26099843.

U-Shaped dose-response curve

3: Matsumoto C, Miedema MD, Ofman P, Gaziano JM, Sesso HD. An expanding knowledge of the mechanisms and effects of alcohol consumption on cardiovascular disease. J Cardiopulm Rehabil Prev. 2014 May-Jun;34(3):159-71. doi: 10.1097/HCR.0000000000000042. Review. PubMed PMID: 24667667.

4: Graff-Iversen S, Jansen MD, Hoff DA, Høiseth G, Knudsen GP, Magnus P, Mørland J, Normann PT, Næss OE, Tambs K. Divergent associations of drinking frequency and binge consumption of alcohol with mortality within the same cohort. J Epidemiol Community Health. 2013 Apr;67(4):350-7. doi: 10.1136/jech-2012-201564. Epub 2012 Dec 12. PubMed PMID: 23235547.

5: Weyerer S, Schäufele M, Wiese B, Maier W, Tebarth F, van den Bussche H,Pentzek M, Bickel H, Luppa M, Riedel-Heller SG; German AgeCoDe Study group (German Study on Ageing, Cognition and Dementia in Primary Care Patients). Current alcohol consumption and its relationship to incident dementia: results from a 3-year follow-up study among primary care attenders aged 75 years and older. Age Ageing. 2011 Jul;40(4):456-63. doi: 10.1093/ageing/afr007. Epub 2011 Mar 2. PubMed PMID: 21367764.

6: Bathla M, Singh M, Anjum S, Kulhara P, Jangli S IIIrd. Metabolic syndrome indrug naïve patients with substance use disorder. Diabetes Metab Syndr. 2016 Sep 3. pii: S1871-4021(16)30183-7. doi: 10.1016/j.dsx.2016.08.022. [Epub ahead of print] PubMed PMID: 27618517

Alcohol was the main substance used by patients meeting WHO criteria for Metabolic Syndrome.

7: Vancampfort D, Hallgren M, Mugisha J, De Hert M, Probst M, Monsieur D, Stubbs B. The Prevalence of Metabolic Syndrome in Alcohol Use Disorders: A Systematic Review and Meta-analysis. Alcohol Alcohol. 2016 Sep;51(5):515-21. doi: 10.1093/alcalc/agw040. Epub 2016 Jun 23. Review. PubMed PMID: 27337988. 

1 person in 5 with alcohol use disorder has metabolic syndrome.

8: Wakabayashi I. Frequency of heavy alcohol drinking and risk of metabolicsyndrome in middle-aged men. Alcohol Clin Exp Res. 2014 Jun;38(6):1689-96. doi: 10.1111/acer.12425. Epub 2014 May 12. PubMed PMID: 24818654.

Positive correlation between heavy drinking and metabolic syndrome.

9: Yousefzadeh G, Shokoohi M, Najafipour H, Eslami M, Salehi F. Association between opium use and metabolic syndrome among an urban population in Southern Iran: Results of the Kerman Coronary Artery Disease Risk Factor Study (KERCADRS). ARYA Atheroscler. 2015 Jan;11(1):14-20. PubMed PMID: 26089926; PubMed Central PMCID: PMC4460348.

Current opioid users had the highest prevalence of metabolic syndrome (39.6%) but the study was confounded by a high baseline rate in the controls (37.2%).

10:   Brunner S, Herbel R, Drobesch C, Peters A, Massberg S, Kääb S, Sinner MF.Alcohol consumption, sinus tachycardia, and cardiac arrhythmias at the Munich Octoberfest: results from the Munich Beer Related Electrocardiogram Workup Study (MunichBREW). Eur Heart J. 2017 Apr 25. doi: 10.1093/eurheartj/ehx156. [Epub ahead of print] PubMed PMID: 28449090.

11: Jabbari R. Ventricular fibrillation and sudden cardiac death during myocardialinfarction. Dan Med J. 2016 May;63(5). pii: B5246. Review. PubMed PMID: 2712702.

12: Ridley NJ, Draper B, Withall A. Alcohol-related dementia: an update of the evidence. Alzheimers Res Ther. 2013 Jan 25;5(1):3. doi: 10.1186/alzrt157. eCollection 2013. Review. PubMed PMID: 23347747.


Supplementary:

The calculation for the following observation:

Recent studies suggest that of the 70% of Americans who drink - about 1/3 of them are probably drinking in excess of those amounts.  Doing the arithmetic that amounts to about 56 million people.

321M(current US population) - 80M (population less than drinking age) x 0.7 (percentage of population that drinks) x 0.3 percentage of excess drinkers = 56 million people.

 

Admission, Discharge and Readmission Policies - No Better Example Of Business Driven Pseudoscience

One of the recurrent themes of this blog is that the application of science to medicine, especially at the public policy level has plummeted over the past three decades.  That has been directly attributable to the influence of business on all levels of government.  One of the more pervasive themes is that the behavior of health professionals is best accomplished by incentivization.  In other words financially punish physicians to get them to change their behaviors that you don't want or financially reward the behaviors that you want them to produce.  I haven't looked at the scorecard lately, but my guess is that the punishments greatly outweigh the rewards.  Maybe my perspective has been skewed by working for an HMO for many years that considered it a reward if they "held back" part of your salary and then gave it to you if all of the physicians in your group met the desired productivity targets.  I am sure it took the MBAs a while to dream that one up.  The equation seems to be as simple as -  "OK here is what we want the goal to be.  We don't want to pay out any rewards anymore.  Let's just penalize people for not meeting the goal until eventually everyone is compliant with the goal."  There is probably no better example than the Medicare Hospital Readmissions Program.

A recent editorial in JAMA notes that the 2013 readmission rates for Medicare patients is about 18% within 30 days (1).  That is associated with a potential cost of $26 billion.  Since 2010 Congress has levied a 3% of Medicare reimbursement penalty on hospitals who have readmission rates that are considered too high.  The problem is that 80% of hospitals are being penalized are safety-net hospitals or those that have a disproportionate share of low income patients.  Those hospitals are more likely to be penalized all three years since the penalty started  and they are more likely to be the hospitals with the lowest operating margins.  The likelihood of penalty also correlates with the percentage of patients treated who are elderly and live with poverty or disability.  

The authors opine that hospitals should not be penalized "because of the demographic characteristics of their patients."  They point out that the evidence suggests that is exactly what is happening and they conclude:  “Targeting hospitals for penalties, even if indirectly, simply because those hospitals care for more poor people is not good policy”.  They use this as a foundation to build their argument for a proposed policy initiative – The Hospital Readmissions Program Accuracy and Accountability Act of 2014.  It builds in safeguards for hospitals treating patients from a disadvantaged socioeconomic status.   

The obvious problem with the authors’ logic here is that they seem to not realize that discrimination against patients of the lowest socioeconomic status has been institutionalized and occurring for decades.  The people I am referring to are those people with addictions and severe psychiatric problems.  The facts are clear.  For the past 30 years, even though psychiatric disabilities rank as some of the top 10 disabilities by any measure, they get a much smaller fraction of the health care dollar for care.  I have used the example of a middle-aged man or woman being hospitalized through the emergency department for acute chest pain.  I don’t know the fraction of those people who are discharged the next day.  But consider that basic scenario if the evaluation of chest pain turns out to be non-cardiogenic.  In the hospital where I have worked that generally means an evening on telemetry and serial troponins and either a stress echocardiogram the next day or an echocardiogram and a stress test.  Price tag about $25-30,000 for less than 48 hours in the hospital.  On the other hand,  let’s say a person has an exacerbation of an affective psychosis and is not able to function at home or has put themselves at risk.  The will be hospitalized in a very low tech psychiatric unit, the goal of which is to discharge them when they are no longer “dangerous” or to discharge them upon request if they cannot be held involuntarily.  Irrespective of the price tag for this care the best available data I have on the DRG reimbursement for this care is about $4,800 irrespective of length of stay.  The economic incentives all line up to rarely provide them with the discharge resources they require to maintain even a subsistence life style and remain stable enough to stay out of emergency departments or jails.  Furthermore in many cases, states previously charged patients a for a portion of their medication costs per month out of their disability income.  The direct and indirect costs incurred by patients and families with severe mental illness and addictions are a travesty of the highest magnitude.  The rationing mechanisms that have been in place for the past three decades have results in care that is subpar relative to any other medical specialty.  It has created an entire population to patients with chronic illnesses that are discriminated against.  The financing of care for them has set a number of perverse incentives that would seem to be more destabilizing such as an incentive for hospital discharge in order to beat the designated days in the diagnosis related group (DRG) and readmit them if necessary.  If the entire DRG incentivization for admissions and discharges is pseudoscientific sleight-of-hand based on very crude demographic variables - why would we expect readmissions policies to be any different?

The second dimension of this care is just how unscientific care based on demographic factors is in the first place.  I was previously in a practice where “consultants” who had never practiced medicine came in and commented on the “complexity” of our patients.  At the time I was caring for many patients who I knew would never be admitted to other general psychiatric units in any other hospital in the state due to their medical complexity.  The consultants concluded that my patients were no more complex than any other patients in the state even though they could not define the measures they used to make that determination.  Nobody mentioned the inherent conflict of interest when a pro-discharge administration hires consultants that agree with their world view - discharge patients as soon as possible.

In another scenario and on a committee, I asked if the demographic determined characteristics and time lines for treating community acquired pneumonia led to any differences in mortality or complications – and nobody knew.  The original Big Data approach in medicine looked at HEDIS variables.  Any practicing physician knows this is an incredibly crude approach that in many cases is meaningless.  There is no better example than saying that treating acute and chronic psychosis in a few days makes no difference in outcomes, when nobody knows the best treatment approach and practically no hospital screens for functional or cognitive capacity - two well known areas of psychiatric disability.  In the outpatient sphere, it is the equivalent of saying that 10 or 20 minutes three or four times a year with an emphasis on medications that are not likely being taken by the patient can possibly affect their real life outcome.

In the case of patients with addictions the treatment is more dire.  When a person using heroin, alcohol, and excessive amounts of benzodiazepines cannot get admitted for detoxification or they cannot get admitted for residential treatment, society and its representative governments at all levels are saying that this is a situation where we can ignore conditions that are clearly life-threatening and in many cases fatal.  We can ignore them because businesses and governments say that this is a collection of disabling and life-threatening diseases that we can ignore so that they can either make money or divert money to treat more socially acceptable life-threatening and disabling diseases.  

This is all a clear pattern of discrimination that not only affects the elderly but anyone with a psychiatric disability or addiction.  If the authors want to do something about that – I say let’s start by reversing over 30 years of discrimination against those with psychiatric and substance use problems that is clearly based on socioeconomics especially the lack of a vocal political constituency, very poor research based on demographic variables rather than complexity, and a lack of innovative research based on poor resource allocation.

George Dawson, MD, DFAPA

References:

1: Boozary AS, Manchin J 3rd, Wicker RF. The Medicare Hospital Readmissions Reduction Program: Time for Reform. JAMA. 2015 Jul 28;314(4):347-8. doi: 10.1001/jama.2015.6507. PubMed PMID: 26219049.

Attribution:

Photo by Mark Buckawicki (Own work) [CC0], via Wikimedia Commons.

How Should APA Guidelines Work?

The guidelines of the American Psychiatric Association (APA) are an interesting story in how guidelines are important if used correctly by professional organizations.  The whole idea behind a profession is that the practitioners in that area have special expertise and that the expertise is standardized to some degree.  Standardization is useful in the case of physicians to assure the safety of the practitioners and so that people have some idea of what to expect in terms of safe and effective care.  Over a decade ago the APA began producing guidelines for practice in various areas of the field.  I thought it was an exciting development.  The guidelines were initially sent along with the monthly copy of the Journal of the American Psychiatric Association.  All of the guidelines are available publicly on this web site, but hardly anyone knows about them.  I make this statement because one of the many red herrings that the critics of psychiatry use is that psychiatry has no standards of care.  They seem quite shocked to find that these guidelines exist and address their complaints directly.  

I was asked to critique one of the existing guidelines and suggest how these guidelines could be used more effectively.   In looking at the guidelines web site, it is apparent that some of the guidelines have not been updated in quite a while.  Publication dates range from 2000 - 2010.  Given the pace of clinical research 5 years might be somewhat acceptable, but 10 - 15 is probably not.  Another issue that the APA needs to grapple with is the diagnostic manual versus treatment approaches.  There is widespread confusion about whether or not the DSM-5 is a guidebook for treatment as opposed to a guidebook for diagnoses.  The APA actually two approaches to treatment guidance - the guidelines themselves and a text entitled Treatment of Psychiatric Disorders (TPD).  TPD is currently in its 4th edition and it has gone from a series of two volume detailed text to a more basic single volume text.  That text was published in 2007.  Some of the chapters in the previous editions provide some of the most detailed information on the pathophysiology and treatment of certain disorders that could be found anywhere.  At that level of analysis, the APA has gone from providing outstanding information on the pathophysiology and treatment of psychiatric disorders to a relative vacuum over the past 10 years.

For the purpose of a more detailed analysis I will consider the Practice Guidelines on Substance Use Disorders and the associated Quick Reference Guide and Guideline Watch - a 2007 update of the original 2006 guideline.  I looked at the Guideline Watch first because it should reflect the latest literature reviews and treatment guidelines.  The document reviews medication assisted treatment of tobacco and alcohol use disorders with varenicline, naltrexone and acamprosate.  The document was a good summary of the literature at the time but it needs a serious update.  Since then there have been more extensive studies of the genetics, combination therapies, re-analysis of existing studies and side effects of naltrexone, acamprosate, and varenicline including use in specific psychiatric populations.  In at least one case, the current literature supports a course of action that is exactly the opposite of what is recommended in this document.  That course of action is: " Given its high potency and partial agonist activity at central nicotinic acetylcholine receptors, varenicline should not be combined with alternate nicotine replacement therapies."  An inspection of the references for varenicline notes that additional research has been done in this area and should be discussed.      

The Quick Reference Guide contains extensive tables from the original guideline so I will go directly to that document.  At first glance it looks like a significant document more than 200 pages long.  But about 177 of the 276 pages of the document are relevant text.   The rest are references and polls of various expert groups on what they consider necessary for a guideline.  Looking at the Table of Contents, the first thing that is apparent is that only a subset of substance use disorders is being considered.  Although it is likely that nicotine, alcohol, marijuana, cocaine and opioids represent the majority of abused substances psychiatrists treating addiction see a broader array of compounds being abused.  The full gamut of abused compounds should probably be addressed in the guideline whether or not there is a consensus about treatment methods or not.  The safety of users and treatment setting considerations will still need to be considered as well as the need for further assessments.  A good example would be Hallucinogen Persisting Perceptual Disorder and what might be the best assessment and treatment.  If the guidelines are supposed to apply to clinical practice then patterns encountered in clinical practice need to be addressed.  If the APA does not address them - governments and managed care companies will, most frequently to the detriment of patients.

The guideline uses the following conventions for the treatment recommendations.  They are conventions frequently see in professional guidelines:

[I] Recommended with substantial clinical confidence.
[II] Recommended with moderate clinical confidence.
[III] May be recommended on the basis of individual circumstances.

The introductory section does not suggest who the guidelines are written for.   This is a critical aspect of the document.  There is an implication that it is for psychiatrists based on the statement about a comprehensive psychiatric evaluation but I think that needs to be more explicit.  It is not uncommon for managed care companies to send letters that deny care to psychiatrists.  The letter often contains a list of guidelines that an insurance company reviewer used to deny the care.  The APA needs to be explicit that these guidelines are intended for use by the psychiatrist who has personally assessed and is treating the patient and not by an insurance company employee or contractor who is sitting in an office reading through paperwork.  Somewhere along the line professional organizations seem to have lost track of the concept that only direct assessment and treatment of the patient was considered the correct way to do things.  Putting it in all guidelines is a critical first step.

The next thing I would change in terms of guidelines is breaking out the treatment setting recommendations into separate sections in table form.  For example the Hospitalization guidelines are copied into the Supplementary section of this post.  They are all very appropriate and I doubt that there are any reasonable clinicians that would have a problem with them.   The problem is that these services are rationed to the point that it is difficult for any reasonable clinician to implement them.  By that I mean that a psychiatrist cannot get a patient meeting these criteria into an inpatient detox or treatment setting based on these criteria.  As an example, consider the patient who says they are drinking 1 liter to 1.75 liters of vodka per day for 6 months.  They describe uncomplicated symptoms of alcohol withdrawal (shakes, sweats, hangover symptoms and drinking in the morning to suppress these symptoms).  I think the person in this vignette meets criteria 2 for hospitalization and detox at least.  A significant number of patients presenting to emergency departments with this pattern of findings are not hospitalized.  Many are sent out with a supply of benzodiazepines to detoxify themselves.  Many are sent to county detox facilities where there is no medical coverage or so-called social detoxification settings.  None of these non-hospitalization options are realistic approaches to the problem.  Giving a person with an alcohol use disorder a bottle of benzodiazepines for home detox ignores the uncontrolled use and cross addiction aspects of the primary disorder.  It is highly likely that person will ingest the benzodiazepines all at once or use them to treat the morning withdrawal symptoms of the disorder.  Social detoxification is an equally suboptimal approach.  It depends on probabilities.  It is more likely that the person transferred to that setting will leave due to the adverse environment and go back to drinking or undergo withdrawal and not experience delirium tremens or withdrawal seizures.  Over the past 30 years, the managed care industry has refused to consider admissions in practically all of these situations often whether there was psychiatric comorbidity or not resulting in the rationing of care at the initial assessment in the Emergency Department.  There must be an awareness that clinical guidelines don't operate in a vacuum.  Having a guideline in place that nobody can use is not the best approach to providing quality care.   Managed care companies can deny inpatient care on practically any of the 7 inpatient criteria simply by saying that they do not exist.    

On the treatment side there are inconsistencies noted in the recommendations and editing problems.  For example, there are 49 references to "12-step" and 2 references to 12 steps.  One of the first statement one encounters is:  "The efficacy of treatment is related to the amount of psychosocial treatment received. The 12-step programs, hypnosis, and inpatient therapy have not been proven effective."  That characterization of 12-step recovery is inconsistent with just about every other reference in the document.  Where it is suggested it is footnoted with a "I" designation or "substantial clinical confidence."

Rather than critique other sections based on data that was not available at the time that this guideline was posted, I thought I would end with a comment on the process and general philosophy of professional guidelines.  Right at the top of this guideline is a section entitled "Statement of Intent".  The crux of that argument is contained in the paragraph (p. 5):

 "The American Psychiatric Association (APA) Practice Guidelines are not intended to be construed
or to serve as a standard of medical care. Standards of medical care are determined on
the basis of all clinical data available for an individual patient and are subject to change as scientific
knowledge and technology advance and practice patterns evolve. These parameters of
practice should be considered guidelines only. Adherence to them will not ensure a successful
outcome for every individual, nor should they be interpreted as including all proper methods
of care or excluding other acceptable methods of care aimed at the same results........"

I don't really agree with that approach.  The concerns about saying that these are standards of care is a medico-legal one and I have rarely found that to be a sufficient basis to practice medicine.  An example would be litigation against a psychiatrist for not following the stated standards of care in a malpractice suit.  This may seem protective of psychiatrists for varying practice styles but it also has the more insidious effect of basically allowing any standard of care to apply.  A walk down the street to a different hospital results in an admission for medical detoxification when the first hospital discharges the patient with a prescription of lorazepam and a promise to follow up with their primary care MD.  The resulting business incentive practice creep results in a complete lack of detoxification and a lack of any standards of medical care.  The default standard is whatever businesses decide to pay for.  My observation is that results in an unacceptable level of medical care.  And further:

"The ultimate judgment regarding a particular clinical procedure or treatment plan must be made by the psychiatrist in light of the clinical data presented by the patient and the diagnostic and treatment
options available....." 

I agree with the statement but let's face it,  the judgment of the psychiatrist frequently has very little to do with the judgment of the psychiatrist or what options are ultimately considered in the working alliance with the patient.  Practically all inpatient and residential care these days is dictated by managed care companies and insurance companies irrespective of what a psychiatrist would recommend or a patient would accept.  These are standards of care that are forced on psychiatrists and patients rather than the prospective quality based standards.

Stepping back from that fact medical standards play a peripheral role to what businesses want and that unacceptable standard has been present to one degree to another for the past 30 years, I don't think a new approach in guidelines is too much to ask for.  I don't think it is too much to ask that APA guidelines be up to date, internally consistent, inclusive, actually apply as a standard of care as opposed to using business standards as the default, and be used to advocate for the best possible treatment settings for psychiatrists and their patients.  There are a number of specific methods that can be used and I will discuss them when the draft version of the latest  Practice Guidelines for the Psychiatric Evaluation of Adults comes out this year.


George Dawson, MD, DFAPA


References:

Work Group On Substance Use Disorder.  Practice Guideline For TheTreatment of Patients WithSubstance Use Disorders,  Second Edition.  American Psychiatric Association.  This practice guideline was approved in December 2005 and published in August 2006.


Supplementary 1:   These are the hospitalization guidelines from the APA Substance Use Disorders Guideline.

"Hospitalization is appropriate for patients who 

1) have a substance overdose who cannot be safely treated in an outpatient or emergency department setting

2) are at risk for severe or medically complicated withdrawal syndromes (e.g., history of delirium tremens, documented history of very heavy alcohol use and high tolerance); 

3) have co-occurring general medical conditions that make ambulatory detoxification unsafe; 

4) have a documented history of not engaging in or benefiting from treatment in a less intensive setting (e.g., residential, outpatient); 

5) have a level of psychiatric comorbidity that would markedly impair their ability to participate in, adhere to, or benefit from treatment or have a co-occurring disorder that by itself would require hospital level care (e.g., depression with suicidal thoughts, acute psychosis); 

6) manifest substance use or other behaviors that constitute an acute danger to themselves or others; 

or 

7) have not responded to or were unable to adhere to less intensive treatment efforts and have a substance use disorder(s) that endangers others or poses an ongoing threat to their physical and mental health [I]."      (p.  11).

A Molecular Basis for Gateway Drugs

The Gateway Drug hypothesis proposes that using a particular drug increases the likelihood that there will be a progressions to using other drugs of abuse.  The competing hypothesis is that there is a general predisposition to using more than one drug in people susceptible to addiction and that it does not depend on any sequence of exposures.  In this Shattuck Lecture in the New England Journal of Medicine, Eric and Denise Kandel examine the epidemiology and molecular biology of nicotine use and the development of addictions.  Most addiction treatment centers recognize the importance of nicotine cessation in improving abstinence rates from the primary drugs of choice.  Most of that depends on series of cases discharged from treatment centers.  The idea of nicotine also has importance because one of the approaches to nicotine cessation depends on nicotine substitution and it is important to know if that treatment intervention might lead to increased risk for ongoing substance use problems.  It also has implications for electronic cigarettes (e-cigarettes).  There is a general idea that any form of nicotine that does not involve exposure to combustible or chewed tobacco components is preferred because of all of the conditions associated with the physical and combustible products of tobacco.  If nicotine alone places one at risk for using another drug like cocaine, the risk/benefit decision will need to be reconsidered.

The authors briefly reviewed the epidemiology showing of all US adults who had ever used cocaine, the vast majority of them (87.9%) smoked cigarettes before using cocaine.  Only 3.5% used cocaine first.   The rate of cocaine dependence was highest (20.2%) among those who smoked cigarettes before using cocaine.  They proceed to use an animal model to examine the possible priming effects of nicotine and to possible elucidate the mechanism.  The animal models of addiction in mice included locomotor sensitization and  conditioned place preference.  In both of these models, micd primed with nicotine first and then treated with nicotine and cocaine showed the expected addicted response with heightened locomotor sensitization and place preference.  Mice primed with cocaine did not.

They proceed to look at the effect on synaptic plasticity and the model used was long term potentiation (LTP) in the nucleus accumbens (NAcc).   The  predominate neurons in the NAcc are medium spiny neurons (MSNs) and they are innervated by dopaminergic neurons projecting from the ventral tegmental area (VTA) and glutamatergic neurons from the prefrontal cortex and the amygdala.  Reducing excitatory (glutamatergic) input to the NAcc reduces inhibitory output to the VTA leading to more dopaminergic input to the NAcc or greater reward.  Repeated cocaine administration leads to reduced LTP in the excitatory synapses of the NAcc.  A single injection of cocaine in a mouse primed with 7 days of nicotine exposure leads to marked reduction in LTP.  Nicotine alone, or nicotine after cocaine had no effect on LTP.  Priming with nicotine causes a change in neuronal plasticity that increases cocaine associated reward.

The authors turned to known gene expression markers of addiction in the striatum specifically the expression of FosB.  They demonstrated that nicotine alone for seven days increased FosB expression and adding cocaine led to a further 25% expression.  The next step was to examine if nicotine alters the chromatin structure  at FosB promotor of the gene and they looked at the acetylation of histones H3 and H4 at the FosB promotor.  Nicotine alone increased the acetylation of both histones, cocaine alone increased the acetylation of H4 only.  They went on to demonstrate that the acetylation was widespread after nicotine exposure throughout the striatum.  Cocaine alone had no similar effect.  They went on to clarify that increase acetylation was due to inactivation of histone deacetylase activity (HDAC) and not activation of acetylases.  They carried out additional pharmacological studies to confirm that the hypoacetylated state (caused by nicotine) leads to depression of LTP associated with cocaine and that further it cannot be rapidly reversed.  The authors investigated if nicotine enhanced cocaine induced LTP in the amygdala and hippocampus and found that it did.

This fairly intensive research program and series of experiments allowed the authors to conclude that nicotine has a unidirectional priming effect and it works through an acetylation mechanism by affecting HDAC activity.  The mechanism explains what is seen in human populations at the epidemiological level and in mice at the experimental level.   That has obvious implications for treatment as well as drug development.  It  also points out that e-cigarettes are potentially as much of a potential gateway drug as combustible cigarettes.  In clinical practice it is also fairly common to see patients with addiction who are continuing to use nicotine substitutes (gum, lozenge, patch) long after they have stopped smoking.  If the mechanism elucidated by Kandel and Kandel is accurate it will be important to discuss the implications of continued nicotine exposure.

Kandel's work is always compelling because of his broad view of science and psychiatry.  He is as comfortable discussing psychoanalysis and Freud as he is talking about molecular biology.  In this case he combines views on epidemiology and molecular biology in a very compelling story and suggests it might be a broader model for how gateway drugs work.  As he is drawing his conclusions there is still room for the competing hypothesis and he makes this explicit.  His work is always a breath of fresh air compared to the current zeitgeist of political arguments about science and psychiatry often from people who know very little about either subject.  Go to the article at the link below and read this paper and compare it to his 1979 article Psychotherapy and the Single Synapse.  That covers at least 34 years of studying synaptic plasticity and it is a remarkable accomplishment.


George Dawson, MD, DFAPA


1: Kandel ER, Kandel DB. Shattuck Lecture. A molecular basis for nicotine as agateway drug. N Engl J Med. 2014 Sep 4;371(10):932-43. doi: 10.1056/NEJMsa1405092. PubMed PMID: 25184865. (free full text).

Supplementary 1:  Drawing depicts nicotine inhibiting HDAC leading to increased acetylation of histones per the above discussion.  CREB-1 = cyclic AMP response-element-binding protein; CBP = CREB-binding protein (acetylates histone H4);  PKA= protein kinase A; A=acetyl groups, P=phosphate groups; H2a, H2b, H3, H4 = histone proteins in chromatin; Pol II = RNA polymerase II (catalyzes synthesis of DNA to mRNA).