Long Term Use of ADHD Medication and Cardiovascular Outcomes

 

 

I have several posts on this blog about prescribing ADHD medications with a goal of minimizing adverse psychiatric and medical side effects.  Like all medical treatments, close follow-up and monitoring is required to assure efficacy while reducing the risk of adverse effects.  To a trained physician it does not take much effort other than being rigorous in examinations and discussions with patients. In the area of ADHD, there is the frequent assumption that patients are young, healthy, and can probably tolerate medications better than older populations. With the increasing diagnosis of adult ADHD, all the comorbidities need to be carefully addressed and a recommendation of no treatment also needs to be considered.

Who have I advised against treatment? Older adults with obvious cardiovascular problems that are inadequately treated or controlled who may or may not have ADHD.  I do not really care if you are 60 years old and I think you really have ADHD, I am not going to start treatment if your blood pressure is not in good control or if you have other unstable conditions like angina, congestive heart failure, cardiomyopathy, or arrhythmias.

The commonest reason for not treating people was hypertension, measured by me in the office.  In some cases, there was an abnormal ECG showing a previously unknown arrhythmia. It can be difficult to tell a patient that you will not treat them because of a medical condition – but that is just the way it is.  Even if treatment is started – blood pressure monitoring needs to occur at every visit.  In some cases, I recommend that the patient purchase a home blood pressure monitor and send me the results.  Referring the patient to their primary care physician or cardiologist is useful to let that physician know that their patient wants stimulant treatment and provide feedback on what your assessment of their cardiac status was.  It is common for physicians prescribing adequate does of antihypertensives to not know that their patient is still hypertensive. It is always clear that the decision to prescribe stimulants is made by me and does not depend on the opinion of another physician.

White coat hypertension (WCH) is not an exception.  WCH is the idea that people get hypertensive related to the stress of being in physician’s office.  Conventional wisdom was that resolved when the patient left the office and therefore this was a being condition. The problem with that assessment is that it depends on knowing that the blood pressure did normalize away from the office.  That lead to a more modern definition that required ambulatory blood pressure measurements away from the office and subsequent more detailed definitions. As an example, the European Society of Hypertension recommends the following:  subjects with office systolic/diastolic blood pressure readings of ≥140/90 mm Hg and a 24-hour blood pressure <130/80 mm Hg.

In the most recent review, the authors do an excellent job pointing out some of the flaws in the early research that led to no significant differences between subjects with WCH and controls.  The control subjects often had cardiovascular disease or were treated with antihypertensives.  They also make the distinction between white coat effect (WCE) and white coat hypertension (WCH). WCE is defined as “an alerting reaction working through reflex activation of the sympathetic nervous system.”  A standard research technique to assess stress effects on blood pressure is to ask subjects to do mental arithmetic and it generally leads to a blood pressure effect like what the authors describe in this paper of 20 mm systolic or 10 mm diastolic.  The authors provide guidance on differentiating the various combinations of white coat hypertension and hypertension as well as providing guidance for future research.  In the office for the purpose of prescribing stimulants the key question is whether there is a white coat effect, white coat hypertension, and whether it occurs in the context of treated or untreated hypertension. Short of ambulatory blood pressure measurements other sources can provide some additional guidance.  Access to the electronic health record can show long term trends.  If indicated - I would not hesitate to suggest that the patient consult with their primary care physicians or hypertension specialist for ambulatory BP measurement.         

Studies have shown that patients who continue to exhibit a reactive blood pressure problem at home have similar cardiovascular risks to hypertensive individuals.  On the flip side, I have assessed many distressed patients in inpatient settings who were normotensive.  Based on this experience, I do not dismiss elevated blood pressure readings in the office especially if I am going to prescribe a medication that may elevate blood pressure.  

That brings me to the paper that led me to write this post (1).  This is a nested case control study of registry data in Sweden that looked at 10,388 cases of ADHD and 51,672 matched controls (aged 6-64 years old).  Exclusion criteria included pre-existing cardiovascular disease, previous use of ADHD medication, and emigration or death before baseline (defined as day of first ADHD medication or diagnosis – whichever came first).  This study design basically looks at the defined illness (in this case ADHD) and then matches the selected cases to controls from the same cohort – in this case up to 5 controls without known cardiovascular disease.  The exposure in this case was ADHD medications including study period, including methylphenidate, amphetamine] dexamphetamine lisdexamfetamine, atomoxetine, and guanfacine.  The last two medications are nonstimulants and guanfacine has also been used as an antihypertensive medication.  The cardiovascular outcomes included: Ischemic heart disease, cerebrovascular disease, hypertension, heart failure, arrhythmias, thromboembolic disease, and arterial disease.  The statistics of interest were adjusted odds rations comparing cases to controls.  The authors also did a brief literature review in both the introduction and discussion sections of the existing literature in this area and what can be described as mixed results.

Their main finding was that only two cardiovascular conditions – arterial disease and hypertension were significantly associated with stimulant medication use but not with atomoxetine or lisdexamfetamine use.  Risk also increased at a level of 1.5 DDD (defined daily doses) of stimulant medication.  Those specific doses except for guanfacine can be found at this link. 

The authors do a good job of interpreting the limitations of their data including the possibilities of under detection of the true rate of cardiovascular disease at baseline, the possibility of mediation nonadherence and underestimating the effects of medication exposure, and confounding by severity could be an issue through the effect for more severe ADHD on lifestyle factors important in the genesis of cardiovascular disease (CVD). Finally, since the study eliminated subjects with existing CVD – stimulant exposure was not measured at all in that population. The authors advise very cautious treatment and monitoring of those individuals.

All things considered, this was a good approach to studying the effects of ADHD medication exposure and the development of cardiovascular disease on a significant sample.  It was a convenience sample from a pre-existing registry.  The authors point out that some treatment groups were very small and advocated for a similar study with a larger N.   Just looking at the trends in their tables, there is clearly significant cardiovascular disease in both the test and control subjects.  The odds ratios for medication exposure were low when they were significant.  Few medical variables were controlled for (obesity, Type 2 diabetes mellitus, dyslipidemia, and sleep disorders) and of those 3 out of 4 are more common in patient with ADHD (3).  More subtle forms of effects from ADHD like whether there are affective changes (typically irritability and anger) leading to hypertension or a white coat effect are unknown currently.

That leads me back to the need for close monitoring for cardiovascular risk factors and conditions before any medication is considered. The group with pre-existing cardiovascular disease is at highest risk and they have not been studied. My speculation is that even using a large health plan database those numbers (patients with cardiovascular disease started on ADHD medication) will be small.  Any real world clinical scenario where this is being considered should be approached as cautiously as possible and monitored the same way.   

 

George Dawson, MD, DFAPA

Photo Credit:  Sgt. 1st Class Shane Klestinski, Public domain, via Wikimedia Commons.  For full details click on the photo to see Wikimedia Commons page.  I chose this photo because several adults that I diagnosed with ADHD told me that they had adapted to work in warehouse management and logistics - in many cases that involved driving fork lifts. 

References:

  1:  Zhang L, Li L, Andell P, Garcia-Argibay M, Quinn PD, D'Onofrio BM, Brikell I, Kuja-Halkola R, Lichtenstein P, Johnell K, Larsson H, Chang Z. Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases. JAMA Psychiatry. 2024 Feb 1;81(2):178-187. doi: 10.1001/jamapsychiatry.2023.4294. PMID: 37991787; PMCID: PMC10851097.

2:  Franklin SS, Thijs L, Hansen TW, O'Brien E, Staessen JA. White-coat hypertension: new insights from recent studies. Hypertension. 2013 Dec;62(6):982-7. doi: 10.1161/HYPERTENSIONAHA.113.01275. Epub 2013 Sep 16. PMID: 24041952.

3:  Chen Q, Hartman CA, Haavik J, Harro J, Klungsøyr K, Hegvik TA, Wanders R, Ottosen C, Dalsgaard S, Faraone SV, Larsson H. Common psychiatric and metabolic comorbidity of adult attention-deficit/hyperactivity disorder: A population-based cross-sectional study. PLoS One. 2018 Sep 26;13(9):e0204516. doi: 10.1371/journal.pone.0204516. PMID: 30256837; PMCID: PMC6157884.

4:  Fuemmeler BF, Østbye T, Yang C, McClernon FJ, Kollins SH. Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study. Int J Obes (Lond). 2011 Jun;35(6):852-62. doi: 10.1038/ijo.2010.214. Epub 2010 Oct 26. PMID: 20975727; PMCID: PMC3391591.

Hypertension - Clinical and Historical Significance for Psychiatry

 

 

I have written about hypertension in the past on this blog. During the treatment and ongoing care of the many patients I have seen over the years it is always present. The prevalence of hypertension increases with age and other comorbidities. The case of the patients I have seen alcohol and other substance use, obesity, smoking, stress, and prescribed medications are all risk factors. As a psychiatrist following blood pressures, I have to be more compulsive than the average physician. I have rarely been in an outpatient clinic where blood pressures were routinely checked. On the inpatient units where I have worked, blood pressure monitoring could also be a problem. I am reminded of teaching in services on blood pressure monitoring. In inpatient settings is also fairly common to see patients admitted who have discontinued antihypertensive therapy and developed dangerously high blood pressures. In many of those cases they continued to refuse the medication. I was put in the uneasy position of having to follow extremely high blood pressures until a probate court judge could convince the patient it was in their best interest to take those medications.

I have also seen the long-term consequences of uncontrolled hypertension in the form of acute hemorrhagic strokes, subarachnoid hemorrhages, aortic aneurysms, hypertensive cardiomyopathy, and the variations of hypertension related dementia. Many of these findings were in the context of an acute emergency. Several were more of an unexpected finding such as the likely long-term consequences of eclampsia and a brain imaging study done 30 years later.

In the day-to-day care of patients, knowing whether or not they may have hypertension is a critical aspect of care. That is true whether you are considering a medication that can elevate or decrease blood pressure, advising the patient on lifestyle changes to improve their health, or discussing their current exercise program. Most people are unaware of the acute effects of exercise on blood pressure and why strenuous exercise may be contraindicated until they have adequate control of blood pressure.

For all of these reasons, I am always interested in when new guidelines come out or blood pressure screening. Over the years that I have been practicing the suggested cutoffs demarcating hypertension and ranged anywhere from 120/80 to [Age + 100]/90. The [Age + 100]/90 cutoff was a guideline we used when I was an intern in the 1980s. That meant that if you are treating a 70-year-old their acceptable blood pressure was a maximum of 170/90. Over the years extensive research has examined blood pressure dependent outcomes and determined that systolic blood pressures that high are problematic. The question is always-where is the cutoff? Specifically at what point are we maximizing the gains and reducing the risks from overtreatment and using excessive diagnostics. 

The question is one that the US Preventive Services Task Force (USPSTF) seeks to answer. They published their comprehensive look at the issue recently (1).  Hypertension prevalence of 45% of all adults in the US is noted as well as the morbidity and mortality associated with untreated hypertension.  The quoted range of cutoffs is from 130/80 to 140/90. The technical considerations of blood pressure determinations are discussed. Suggested sensitivity of 0.8 and specificity 0.55 for office blood pressure measurement (OBPM) and 0.84 and 0.6 for home blood pressure measurement (HBPM).  Review of 13 study showed that the harms of blood pressure screening are minimal. 

The standard online medical text in the US is UpToDate and it defines hypertension as <120 mmHg systolic and <80 mmHg diastolic with Stage 1 hypertension being 130-139 mmHg systolic and 80-89 mmHg diastolic.  Stage 2 hypertension is defined as systolic of 140 mmHg and diastolic of 90 mmHg. UpToDate also defines a category of treated hypertension for any patient taking antihypertensive medication irrespective of their blood pressure reading. 

The USPSTF paper had an interesting section called How Does Evidence Fit with Biological Understanding? This did not involve a discussion of pathophysiology, but the description of subtypes and what the implications might be.  Sustained hypertension was defined as elevated blood pressure determine both in the office and outside of office settings. Whitecoat hypertension was defined as elevated blood pressure in the office but not in ambulatory settings. Masked hypertension was defined as elevated blood pressure outside of the office but not in office settings. For the purposes of the document, sustained hypertension is considered the entity that the recommendations are based on and the overall risk of cardiovascular disease is sustained hypertension > masked hypertension > whitecoat hypertension.  The diagnosis of white coat hypertension is made by comparing OBPM with HBPM or ABPM (ambulatory blood pressure measurement).  No specific biological mechanisms are discussed. The document points out that even though masked hypertension and whitecoat hypertension are associated with adverse cardiovascular outcomes there is no current evidence that treatment improves as outcomes and they consider that to be a knowledge gap.

UpToDate take a more detailed look at primary and secondary hypertension but does not elaborate much more on the pathogenesis and biology of hypertension. For example, it outlines the autonomic nervous system, the renin aldosterone system, and total plasma volume as being the main systems involved in hypertension. Secondary causes and screening for these causes is suggested but there are no confirmatory tests for essential hypertension.  Interestingly atypical antipsychotics and antidepressants are on a list of medications thought to contribute to hypertension but in personal correspondence with a hypertension specialist – he considered even the most likely medications in that category (bupropion and venlafaxine) to be rare causes.  Empirical treatment and how to treat more resistant forms of hypertension are reviewed. The medications typically address a purported mechanism of hypertension but there is no suggestion to determine the underlying physiology and match it with a medication effect.

Monitoring is another role that psychiatrists can fill. I see the same patient ranging from 6 to 24 visits per year and ideally those would all be heart rate and blood pressure data points. With many of those patients I also discuss home monitoring since approved devices are now very affordable and many of them are being treated often intermittently for hypertension. It is also critical that some patients are able to do HBPM if they are treated with medications that can clearly affect blood pressure such as beta-blockers, prazosin, and clonidine. For subgroup of people who have sustained tachycardia who need close monitoring I also recommend HBPM.

Every psychiatrist should be aware of both the USPSTF screening guideline and either the UpToDate chapter or a similar comprehensive book chapter or review.  Making sure that the patients in question get adequate screening, evaluation, and treatment is as critical as the treatment for their psychiatric disorder.  Comorbidities that are the direct result of end organ damage from hypertension also need to be addressed. I have been able to advise patients on dietary changes, exercise programs, and accepting treatment for obstructive sleep apnea when it was ignored from other sources.

Apart from the medical and clinical considerations of hypertension – are there any other lessons for psychiatry?  It turns out there are and they were first noted in 1960 and since forgotten.  Until that year there was a predominance of the view that diseases are caused by discrete pathological lesions. That view was advanced by Virchow and Koch and was the predominant view of the day. A corollary is that there are always qualitative differences between health and disease.  If a person has the required lesion, they have the disease and if not, they are healthy. That theory was disrupted by a paper by Oldham, et al (3) on the nature of essential hypertension. At that time, the dominant theory of hypertension was that it was an autosomal dominant determined disease that “separately sharply” from the normotensive population. The authors looked at collected data on families and showed that the percentage of families in previous generations with hypertension was too low for Mendelian inheritance.  The authors looked at data on the blood pressure ranges of first-degree relatives of their index hypertensives. The graphical data was interpreted as bimodal distribution of blood pressures consistent with a clear demarcation between elevated blood pressure and normotension.  However, re-examination of the data and a further trial showed that the frequency distribution of blood pressures was not consistent with a bimodal distribution or as the author’s state:

 “seems to illustrate once again that it is not hypertension that is inherited but the degree of hypertension.”

The authors use this data to reject a dominant gene and qualitative differences between disease and non-disease state.  They go on to describe the biological implausibility:

“The alternative hypothesis-that arterial pressure is inherited polygenically over the whole range, and that the inheritance is of the same kind and degree in the so-called normal range as in that characteristic of essential hypertension-is in general conformity with biological theory and with the facts of observation. Just as stature, the classical human example of polygenic inheritance, is the sum of a number of separate bones and tissues, so is the arterial pressure the resultant of a number of discrete components of the cardiovascular system. One need only mention the radii of different parts of the vascular system, the lengths of the vessels constituting the resistance, their elasticity, the chemical composition.”  p. 1092.

As I read that passage, I was reminded of current work looking at the tens to hundreds of network genes activated across the genotypes of millions of unique individuals as a basis for the polygene events that occur in polygenic disorders including psychiatric disorders.

Once the polygene quantitative model was accepted over the single dominant gene qualitative model, it led to a broader application including the obvious one to psychiatric disorders.  Psychiatric disorders have been demonstrated to have familial patterns and some have a very high degree of heritability, but they also do not follow single dominant gene inheritance.  To recap, Oldham, et al basically blew the single gene, qualitative difference between disease state and normality, single pathological mechanism out of the water for complex disorders and they did it in 1960! No philosophy or rhetoric – just good old science. At one point the authors point out that “no student of genetics” had explained the dips in the hypertension frequency graphs.

The psychiatric significance of these authors’ work occurs when Kendell (4) highlighted it 15 years later to illustrate why the single pathological mechanism as “proof” of psychiatric disease is a failure.  Hypertension is a complex polygenic disorder that all psychiatrists must concern themselves with if they are actively treating patients.  It is also a useful comparison model for the psychiatric disorders that we treat,

 the body fluids, the action of the heart, and the

 George Dawson, MD, DFAPA

 

References:

1:  US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, Cabana M, Caughey AB, Davis EM, Donahue KE, Doubeni CA, Kubik M, Li L, Ogedegbe G, Pbert L, Silverstein M, Stevermer J, Tseng CW, Wong JB. Screening for Hypertension in Adults: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2021 Apr 27;325(16):1650-1656. doi: 10.1001/jama.2021.4987. PMID: 33904861.

2:  Basile JM, Bloch MJ. (2021) Overview of Hypertension in Adults. In GL Bakris, WG White, GP Forman, L Kunins, UpToDate (Accessed 4/28/2021) from:  https://www.uptodate.com/contents/overview-of-hypertension-in-adults

3:  Oldham PD, Pickering G, Fraser Roberts JA, Sowry GS. The nature of essential hypertension. Lancet. 1960 May 21;1(7134):1085-93. doi: 10.1016/s0140-6736(60)90982-x. PMID: 14428616.

4:  Kendell RE. The concept of disease and its implications for psychiatry. Br J Psychiatry. 1975 Oct;127:305-15. doi: 10.1192/bjp.127.4.305. PMID: 1182384.

5:  Breu AC, Axon RN. Acute Treatment of Hypertensive Urgency. J Hosp Med. 2018 Dec 1;13(12):860-862. doi: 10.12788/jhm.3086. Epub 2018 Oct 31. PMID: 30379139.

6:  Rossi GP, Rossitto G, Maifredini C, Barchitta A, Bettella A, Latella R, Ruzza L, Sabini B, Seccia TM. Management of hypertensive emergencies: a practical approach. Blood Press. 2021 May 8:1-12. doi: 10.1080/08037051.2021.1917983. Epub ahead of print. PMID: 33966560.

 

Graphics Credit:

The image at the top of this blog is for Shutterstock per their standard licensing agreement. I picked it based on the fact that it reminded me of a patient I saw in the emergency department when I was an intern.  He had a large left basal ganglia cerebral hemorrhage that was most likely due to sustained hypertension.

Apologies:

Editing this post was tough. For some reason my Word processer switched to Polish language and stopped automatically checking my grammar and spelling. That was compounded by the fact that I was dictating in Dragon and sound alike words that were spelled correctly were substituted.  I ended up proofing everything on my phone and just finished tonight (4/29).