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.

 

How Do So Many People End Up on Stimulants?

There is no question that thousands if not millions of people end up taking stimulants unnecessarily these days.  Addiction psychiatrists,  have a unique perspective on this that I thinks goes beyond a typical approach to the problem.  I like to consider it to be grounded in behavioral pharmacology and neuroscience.   For the sake of this essay I will limit my remarks to all adults who are college aged or older and should not be taking stimulants.  Neuroscientific discoveries in the area of brain maturation suggest that a significant portion of the college-aged individuals might not make the same decisions they make a decade later, but the practical consideration is that there are millions of people in college making decisions about stimulants every day.  There are several ways to look at the problem.  The best approach I can think of is to look at the various ways that patients present for treatment.  The request for stimulant treatment can be subtle or overt.  Unlike some the papers in the current literature, I don't think that the diagnostic questions here are subtle.  During an initial clinical assessment - diagnosis and treatment commonly overlap and in some cases that I will illustrate treatment considerations become primary in the initial minutes of the interview.

The general psychiatric interview has always been a screen of sorts.  My recollection is that it was typically more problem focused in the past.  Over time, that interview started to incorporate more disorders as a focus of inquiry.  On the outpatient side the disorders added been primarily Post Traumatic Stress Disorder and Attention Deficit-Hyperactivity Disorder in non-geriatric populations.  Any time a screening is being done whether it uses a symptoms checklist or a lengthy interview there is always the chance of missing the true diagnosis or adding a diagnosis that is probably not there.  Here are a few examples.

1.  "I have been depressed for the past ten years...."  An inquiry about mood disorders at some point will focus on concentration.   Impaired concentration and attention span occurs in a number of psychiatric disorders.  Combined with some developmental history and a history of chronicity it is easy to see the problem as a missed diagnosis of ADHD and initiate treatment for that disorder in addition to the primary mood disorder.  There are problems with that approach especially when the history of the mood disorder is clear and it has never been adequately treated.

2.  "I have a diagnosis of bipolar disorder - manic and these medications aren't working...."  ADHD in adults rarely presents as hyperactivity so severe that it could be mistaken for mania.  Manic episodes are also phasic disturbances making it very unlikely that there would be many patients in any single practice who were both manic and had ADHD.  In the cases where it does happen stimulant treatment complicates the treatment of bipolar disorder and can lead to worsening mania, delusional thinking and hallucinations.

3.  "My son/daughter has ADHD....."  There are two variations in this interaction.  In the first, the parent is told about the high heritability of ADHD and advised that they also probably have it and can be assessed for it or mention to their primary care physician that they may need treatment for it.  In the second, the parent of a child with an ADHD diagnosis reads the diagnostic materials and comes into an appointment and says: "You know, I have read the symptoms and think that I have them.  Should I be treated for ADHD?"

4.  "I have always had a problem reading and I was  never any good in school..."  A common approach is to view this as ADHD, do the screening and proceed with treatment.  Physicians in general have had very little training in the assessment or treatment of learning disorder and although there is comorbid ADHD and learning disorders there is also a significant population of people with pure learning disorders who do not have ADHD.

5.  "I took my friend's Adderall and felt like I could concentrate and study for the first time in my life.  I did a lot better on that test...."  The population-wide bias is that stimulants are a specific treatment for ADHD rather than a drug that will temporarily improve anyone's energy level and attention span.  There is also the cultural phenomenon of cognitive enhancement or using stimulants as performance enhancing drugs that may be driving this request.  It is known that the availability of stimulants on campuses and in professional schools is widespread.  This is associated with students selling their prescriptions for profit and availability of stimulants illegally obtained for the purpose of cognitive enhancement.  The issue is further confused by position statements in scientific journals that support this practice.  I have not seen it studied, but it would be interesting to see questions and responses about cognitive enhancement asked at student health centers and practices that see a lot of college and professional students.

6.  "I have ADHD and need a prescription refill...."  It may be true that the patient has a clear-cut documented diagnosis prior to the age of 12 (DSM-5 criteria).  But what has happened since that initial diagnosis in childhood and now is critical history.  Has there been continuous treatment since then or has the treatment been disrupted.  Common causes of disruption include stimulant side effects, symptom resolution with age,  and co-occuring substance use problems.  A detailed history of the course of treatment since childhood is needed to make the decision to continue or reinitiate treatment.

7.  "I heard you had a test for ADHD...."  This question often initiates screening at a higher level.  There are any number of places with extended neuropsychological batteries, brain  imaging tests, or EEG tests that they claim will definitively diagnose ADHD.  In fact, there are no tests with that capability.  I have heard one of the top experts in the world on ADHD make that same statement and he was also a neuropsychologist.  I have had several years of experience with quantitative EEG machines and know their limitations.   At this point several hours of extended testing adds nothing to a detailed interview, review of collateral information, and symptom checklists to basically assure that all of the questions have been asked.

8.  "My meds need to be adjusted....."  This could be a question from a person in treatment for another problem or a person already being treated for ADHD.  The unstated issue here is the underlying belief that by adjusting a medication one's mental processes will be closer to perfection.  A child psychiatrist that I work with said it best:   "The goal in treating ADHD is to get them more functional, not to perfect their functioning."  I think the unrealistic goal of perfection drives a lot of prescriptions that exceed the recommended FDA limits.  It also explains a lot of "rescue medications" superimposed on sustained release preparations like Adderall.  Anyone familiar with the pharmacokinetics of sustained release drugs should realize why rescue medications (like immediate release Adderall on top of sustained release Adderall XR) are unnecessary.

9.  "I can't stay sober if I can't get treated for ADHD....."  This can be a complicated and confusing situation.  The child psychiatry literature had suggested initially that children with treated ADHD were less likely to have substance use disorders as adults than children with untreated ADHD.  As the evidence accumulates that is less clear.  Many adult psychiatrists and some addiction psychiatrists have extrapolated those equivocal findings to mean that treating a known or new diagnosis of ADHD in an adult will improve treatment outcomes for ADHD.  There is no evidence that is true.  Some addiction psychiatrists believe that the opposite is true, that there is a cross addiction phenomenon and that treating a person with an addiction makes it more difficult to stay sober from their drug of choice.  If the person is addicted to stimulant medication and has a clear history of accelerating the dose of stimulants or using them in unorthodox ways (intravenously, smoking, snorting, etc) it is very unlikely that person will be able to take a stimulant prescription in a controlled manner.  It is also very possible that the person making this request has a long history of experiencing prescription or street drugs as being necessary to regulate mental functioning.  That can be highly reinforcing even if the effects are sustained for hours or less.

10.  "I have been sober for one month and can't focus or remember anything......" Subjective cognitive problems are frequent during initial sobriety.  The substance used and total amount used over time probably determine the extent that the cognitive changes persist, but it is a difficult problem to study for those same reasons.  Clinicians know that there are cognitive effects but there is no standard approach to the problem.  From my experience, I think that two months sober is the absolute minimum time to consider evaluating subjective cognitive problems.  Even at that time getting collateral history about the person's cognitive and functional capacity and problem solving with them on work arounds would probably be the biggest part of the treatment.

The above scenarios are not exhaustive and I probably could come up with another 5 or 10 but they are illustrative of pathways to questionable stimulant use.  The common thread here is that anyone in these scenarios can endorse all of the symptoms of ADHD.  Figuring out what those symptoms are is fairly obvious on many checklists.  One of these checklists shows the symptoms and checkboxes necessary to make the diagnosis in grayed out panels.  It is easy to fake the symptoms in an interview or on a diagnostic checklist.  It takes a lot of hard work on the part of the physician to figure out not only who might be faking but also who has the symptoms but not the diagnosis.  One of the features of the DSM that was attacked by several critics during the pre-release hysteria was the "generic diagnostic criterion requiring distress or disability" to establish disorder thresholds (DSM-5 p 21).  In the case of ADHD that is Criterion D "There is clear evidence that the symptoms interfere with or reduce the quality of social, academic, or occupational functioning."  (DSM-5 p 60).

The diagnosis of ADHD is generally not the diagnosis of a severe functional disorder.  As a psychiatrist who practiced in a hospital setting most of the people I assessed clearly met the functional criteria by the time I saw them and diagnosed severe mood disorders, psychotic disorders, substance use disorders or dementias.   Many of them were by definition unable to function outside of a hospital setting.  It is an entirely different assessment when faced with a successful professional who has worked at a high degree of competence for 20 years who presents with any one of the above problems because they think they have ADHD.  It takes more than a review of the diagnostic criteria.   It takes an exploration of the patient's motivations for treatment.  What do they hope to accomplish by treatment?

It also takes a conservative prescribing bias on the part of the prescriber.  Stimulants are potent medications that can alter a person's state of consciousness.  They are potentially addicting medications and that can result in craving or wanting to take the medication irrespective of any therapeutic effect.  The wide availability of stimulants led to the first amphetamine epidemic in the United States.   When I first started out in psychiatry, I was still seeing people who became addicted to stimulants when they were widely prescribed for weight loss.   It is well known that the medications were ineffective for weight loss but people continued to take them at high doses in spite of the fact that they had not lost any weight.  In talking with people about what drives this many people feel like they are only competent when taking stimulants.   They believe that their cognitive and functional capacities are improved despite the fact that there is minimal evidence that this is occurring from their descriptions of what they are doing at work or in their family.

There are a number of strategies in clinical practice to avoid some of the problems with excessive stimulant prescriptions that I will address in a separate post.  My main point with this post was to look at some ways that people with mild subjective cognitive concerns, addictions, people seeking cognitive enhancement, people who have been functioning well but believe that they can function better come in to treatment for ADHD and get stimulant prescriptions.


George Dawson, MD, DFAPA

Supplementary 1:  Literature was used to construct these hypothetical scenarios.