Hippocrates the Projective Test

 

There is no doubt that the ancient physician Hippocrates was an advanced thinker in terms of medicine and its conceptualization. He is widely credited with advancing nosology and diagnostics as well as professionalism. In the field of medicine, he was studied right up until the turn of the 19^th century by physicians who attended medical schools in Europe.  Like all prominent figures from the past there is a question of whether invoking Hippocrates these days represents idealization or rhetoric more than his accurate historical position. 

I am referring specifically to a blog by Nassir Ghaemi, MD entitled Hippocratic Psychopharmacology.  After correcting the aphorism “First do no harm” to “As to diseases, try to help, or at least not harm.” he elaborates on a few ideas from Hippocrates and the implications for modern medicine. He interprets the preamble of Hippocrates statement to mean that diseases must be identified and if you cannot or will not take the disease concept seriously you cannot help anyone as a doctor. He emphasizes that there should be a focus on not doing any harm and that overall treatment should be conservative. He acknowledges a bias that too many medications are being used in modern times.

Hippocrates additional idea is that diseases are a natural process and they heal naturally and physicians should not get in the way of that process. He discusses self-limited, treatable, and incurable diseases suggesting only the treatable illnesses are a focus for physicians.

Hippocrates was apparently not enough so Holmes Rules and Osler’s rule are added. The explanation of Holmes Rules is inconsistent because initially it described prescribing based on benefits first and harms second, but in the elaboration the assumption is supposed to be that the medication is harmful. If that is your assumption harms would seem to be prioritized.  Here is an excerpt from the post from 1861:

“……I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind, – and all the worse for the fishes.”

In other words, if you wanted to prescribe something – there is nothing useful to prescribe and given the time frame - that is correct.  1861 was before the discovery of germ theory.  Of the estimated 750,000 Civil War (1861-1865) deaths at the time about 2/3 died of diseases that are treatable in modern times. The only effective medical treatments at the time were citrus fruits and vegetables to prevent scurvy, smallpox vaccines, and quinine for malaria. Four types of wound infections were described including tetanus, erysipelas, hospital gangrene, and pyemia or sepsis with mortality rates of 46-90%.  Since there were no antibiotics infected wounds were treated with repeated debridement or amputation with the hope that remaining healthy tissue would generate an inflammatory and healing response. 

In his writings, Hippocrates describes many forms of orthopedic treatment and general medical treatment for infections including gangrene and erysipelas. Those afflictions were not likely to heal without significant medical and surgical interventions. I suppose in keeping with the stated philosophy they could be reclassified as “untreatable.” The question might become were untreatable diseases less treatable in Hippocrates time than during the Civil War? Either way it is likely that Hippocrates watched at least as many of his patients die as Civil War surgeons did and those were very high mortality rates.

Ghaemi uses the example of antidepressants in bipolar disorder as breaking Holmes Rule “egregiously.” Unfortunately, the presentation of bipolar disorder may not be that clear cut.  As a tertiary care psychiatrist, it was common to see people experience manic episodes after years of treatment for unipolar depression with antidepressants or even as an antidepressant is tapered and discontinued. You must have seen a manic episode along the way in order make the diagnosis and stop the antidepressant.  It also helps if the patient is under the care of a psychiatrist and it is likely the vast number of antidepressants in these presentations were prescribed by other specialists or nonphysicians. I have never heard of a psychiatrist needing more evidence to stop antidepressants in bipolar disorder.  It was done routinely by my colleagues in acute care.

Osler is quoted in the discussion of Osler’s Rule:

“A man cannot become a competent surgeon without a full knowledge of human anatomy and physiology, and the physician without physiology and chemistry flounders along in an aimless fashion, never able to gain any accurate conception of disease, practicing a sort of popgun pharmacy, hitting now the malady and again the patient, he himself not knowing which.”

And what exactly was known in Osler’s time about pathophysiology and pharmacotherapy?  Probably not much more than was known at the time of the Civil War.  Paton’s reference (5) contains several additional quotes to illustrate what he describes as Osler’s nihilism including that there were no useful treatments for scarlet fever, pneumonia, and typhoid fever.  Diarrhea and dysentery were common in soldiers leading to both compromised health status and death.  A summary quote from Osler’s time suggests there were only a few useful treatments including iron for anemia, quinine for malaria, mercury and potassium iodide for syphilis and that there were no other drugs supported by experimental evidence.  It turns out that that the evidence for potassium iodide in syphilis was restricted to reducing inflammation in some late-stage lesions since it was not an anti-spirochetal agent (4).

If Osler was aware of a potentially effective drug – he may have pushed it beyond what his colleagues were using as evidenced in this quote:

'At times of crisis Sir W. Osler and others have pressed up the nitrites to huge doses, in persons upon which these drugs had been well tested. Sir William said he had never seen harm come of large doses if cautiously approached. I think he used to speak of 20-30 grains of sodium nitrite per diem. I have administered half as much in a day.' (pp 88-9).” (3)

20-30 grains of sodium nitrite is roughly equivalent to 1,329 to 1,980 mg.  In a 70 kg patient that would be 19-28.3 mg/kg.  The worrisome complication from nitrites is methemoglobinemia. In severe cases it can result in coma, cardiac arrythmias, and death. PubChem suggests that intravenous doses of 2.7 – 8 mg/kg can be problematic. A leading toxicology text suggests that when sodium nitrite is given intravenously to treat cyanide poisoning the dose is 300 mg given at a rate of 75-150 mg/minute intravenously with a repeat dose at half the amount if necessary, monitoring for symptoms of nitrite toxicity. While it is difficult extrapolating oral toxicity from IV administration there are reports of life threatening and fatal oral ingestions resulting from taking 12.5-18 g of sodium nitrite. The EPA recommends limiting exposure to 1.0 mg/kg/day. All of this toxicology information suggests the the doses that Osler was using were pushing the limit, but it also points to another deficiency in suggesting that his parsimony (or nihilism) is a touchstone for modern physicians.  That deficiency is that his outcomes were unknown. The case reports that I have found were generally limited to a case or two. I could not find any outcomes for high dose versus low dose nitrites for angina or congestive heart failure. Modern nitrate preparations such as isosorbide mono and di-nitrates are limited by tolerance to the vasodilating effect. I may be wrong but I speculate the Osler knew very little about the pharmacology of nitrites and the mechanisms of tolerance and toxicity.

A common theme for these conservative historical pharmacologists is that it is easy to be conservative when there are no known effective treatments.  When your category of treatable diseases is small – it is easy to rationalize watching the self-limited and untreatable illnesses run their course.  There was a very long period of slow progress in therapeutics between the time of Hippocrates (460-375 BCE) and Osler (1849-1914). Penicillin was not available to treat syphilis until 1943. Even though there was some basic science research in pharmacology in the mid 19^th century, Paton’s review shows that potentially effective medications, in pill form and in significant numbers did not occur until about 1920.

Apart from limited therapeutic options, the doctrine of informed consent was either nonexistent or much less clear in earlier times.  Gutheil and Applebaum (6) trace the early evolution and consolidation as occurring in the 1950s and 1960s in the US.  The earliest clear application was for surgery and invasive treatments extending to medical treatments.  In psychiatry, that also extended to medication treatment and neuromodulation but at the time of this book whether it was necessary for psychotherapy or not was not clear.  To me one of the clearest reasons for informed consent is the level of uncertainty in medicine. We know probabilities at the population level but are rarely able to predict side effects and adverse reactions at the individual level.  I have written about my approach to this problem on this blog and it is basically a shared decision-making model where the patient is informed of the uncertainty of both efficacy and adverse events as clearly as possible. That information was not available to to earlier physicians. Detailed regulatory information in package inserts is a relatively recent phenomena starting in 1968 in the US with several modifications since then.  

Ghaemi winds down his critique emphasizing diagnoses over symptoms.  He uses the bipolar disorder example again and hedges suggesting that is it acceptable to treat symptoms sometimes but there are no guidelines only the rather extreme criticism that by treating diseases and developing a Hippocratic psychopharmacology we can avoid the “eclectic mish-mash which is contemporary psychiatry.”

It is apparent to me that Hippocrates and Osler have very little to offer present day psychopharmacologists. They both a had very large body of patients who could not be treated. Both had limited evidence-based pharmacopeias and both prescribed toxic compounds with no clear guidelines or suggestion of efficacy. On diseases, syndromes, and symptoms – the issues are much clearer these days but much is still written about how these concepts are confusing. That is especially true in psychiatry where decades of debate has not resulted in any more clarity.  It is not as easy to separate out insomnia, anxiety, and mood disturbance with bipolar disorder as Ghaemi makes it seem, but treating them all at once in a single point of time is probably not the best approach. In clinical practice at least some people have insomnia, anxiety disorders, and depression prior to the onset of any diagnosis of bipolar disorder. Assuming adequate time to make those historical diagnoses, there are no clear guidelines about what should be treated first and no clinical guidelines on when medications should be started and stopped.  It all comes down to the judgement and experience of the physician and patient consent and preference. Evidence based medicine advocates always argue for that approach but it it highly unlikely that there will be clinical trials for every scenario and the trials that do occur are often limited by inclusion and exclusion criteria.   Hippocrates and Osler have no better guidance.

As therapeutics has evolved, polypharmacy has become a part of the clinical environment of all specialists.  It is common to see patients taking multiple medications in order to treat their cumulative diseases, even before a psychiatric medication is prescribed. Despite all of the rhetoric – I am convinced that experts can manage polypharmacy environments if they need to and do it with both therapeutic efficacy and minimal to no side effects.  

For the record, I agree with Ghaemi’s overall message that you need good indications for medical treatments and that the fewer medications used the better. Those decisions need to incorporate, current evidence, informed consent, and frequent detailed follow up visits to reduce the risks of inadequate treatment and adverse events. That is hard work - not helped by guidance from the ancients or modern-day philosophers.

 

George Dawson, MD, DFAPA

 

References:

1:  Ghaemi N. Hippocratic Psychopharmacology.  Jun 16, 2023. https://psychiatryletter.com/hippocratic-psychopharmacology/

2:  Burns SB.  Civil War Disease and Wound Infection https://www.pbslearningmedia.org/resource/ms17.socct.cw.disinf/civil-war-disease-and-wound-infection/  Accessed on 06.20.2023

3:  Paton W. The evolution of therapeutics: Osler's therapeutic nihilism and the changing pharmacopoeia. The Osler oration, 1978. J R Coll Physicians Lond. 1979 Apr;13(2):74-83. PMID: 374726; PMCID: PMC5373168.

4:  Keen P. Potassium iodide in the treatment of syphilis. Br J Vener Dis. 1953 Sep;29(3):168-74. doi: 10.1136/sti.29.3.168. PMID: 13094013; PMCID: PMC1053890.

5:  Howland MA.  Nitrite (amyl and sodium) and sodium thiosulfate.  In:. Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR Hoffman RS (eds). Goldfrank’s Toxicologic Emergencies. McGraw-Hill Education; 2019. P. 1698-1701.

6:  Gutheil TG, Appelbaum PS.  Clinical Handbook of Psychiatry and the Law, 3^rd ed. Lippincott, Williams and Wilkins; 2000; Philadelphia, PA: 154-157.

7:  Writings of Hippocrates. Translated by Francis Adams. Excercere Cerebrum Publications; 2018.

 

 

Graphics Credits:

 

William Osler aged 32: Notman photographic archives, Public domain, via Wikimedia Commons.  https://upload.wikimedia.org/wikipedia/commons/e/e9/William_Osler_1881.jpg

Hippocrates: ESM, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons. https://upload.wikimedia.org/wikipedia/commons/8/82/Facultat_de_Medicina_de_la_Universitat_de_Barcelona_-_Hip%C3%B2crates_de_Kos.jpg

Adding Rather than Subtracting Bias - An Underlying Basis for Polypharmacy?

There was an interesting piece in Nature this week (1,2) about cognitive biases in complex problem solving.  The research psychologists asked subjects to solve problems of varying complexity and structure from the perspective of whether additional structures or steps were necessary or whether an optimal solution could be obtained by subtracting structures or steps. I will briefly describe each of the problems in the table below (pending permission to use one of their graphics).

Task	Description
Abstract grid task	Transform a grid pattern to make it symmetrical
Suggested changes to a large public university	Changes to improve the sense of community, enable student learning, and prepare students for a lifetime of service
Lego block structure	Improve the 8 or 10 block structure
Lego block structures	3 possible structures built from 12 blocks of a pool of 24 blocks on a 6” x 8” base.
Lego block structure	Revision of original structures made from a possible 20 blocks to make a 10 block structure
Lego block structure	Modify a Lego structure so that it can hold a brick over the head of an action figure in the structure
Read and summarize an article	Make a 6-8 sentence summary and then edit it to a shorter version
Read and summarize an article	Edit someone else’s summary and edit it to “omit needless words”
Day trip to Washington DC	Inspect a trip itinerary and suggest changes to improve it
Make a grilled cheese sandwich	Make a grilled cheese from 27 ingredients -
Modify a soup recipe	From 5, 10, and 15 ingredient soup recipes – modify from a list of ingredients and modify to improves the soup.

Inspection shows that the cognitive tasks cover many domains ranging from 2D and 3D visuospatial tasks, language tasks, and more theoretical tasks that involve speculative rather than confirmed outcomes. The authors suggest an all-encompassing definition: “the cognitive science of problem solving describes iterative processes to imagining and evaluating actions and outcomes to determine if they would produce an improved state.”(p. 258).  They define subtractive transformations as fewer components than the original and additive transformations as more components than the original.  The authors noted a bias in anecdotal literature to making conscious subtractive transformations and that suggested to them that strategy may be less common or undervalued. 

Across all experiments, the tendency toward subtractive strategies with the general instruction were lower but probabilistic.  For example, across all experiments, subtractions ranged from 21-41%.  A second set of conditions with subtle subtraction cues increased the rate of subtractive transformations to 43-61% across the same experiments.  At one point the researchers added a cognitive load task that was basically a distractor to use more attentional resources. In these conditions cognitive shortcuts are less accessible. Under those conditions subjects failed to identify a subtractive solution more frequently.  The authors also studied subjects form Germany and Japan suggesting that there is cultural generalizability of the additive over subtractive strategies.

The authors consider that the differences could be accounted for by generating a number of additive and subtractive ideas and selecting the additive or they simply default to the additive.  They elected to look at the default to the additive mode. They describe heuristic memory searches allowing for the timely access of relevant information.  They suggest a number of reasons what additive strategies may be favored including – the processing may be easier, semantic biases such as more being better, cognitive biases may favor the status quo or less change, and it may be more probable that additive rather than subtractive changes offer a better outcome.

This is an interesting paper from a number of perspectives.  First, it presents a cognitive psychology approach with no purported biological mechanisms. There are no functional imaging studies or brain systems described.  The theories and design of experiments depends on a psychological model of cognitive function. Second, the model is probabilistic.  Although the title suggests systematic overlooking of subtractive strategies, it turns out that many don’t and this bias can be modified by experimental conditions such as subtraction cues. Third, the effect of increased cognitive load can be demonstrated to increase the likelihood of additive rather than subtractive biases. Fourth, the biases extend across a number of domains including physical, social, and intellectual. Fifth, the authors suggest that there may be a number of “cognitive, cultural, and socioecological reasons for favoring the additive bias over the subtractive one.  Sixth, although the additive transformation was more likely to occur that does not mean it offers the best solution to the problem.  It may simply be the most commonly used solution. 

Real world experience illustrates how the additive transformations can be reinforced.  Advertising is a common one. The goal of advertising is basically to sell someone something that they don’t need or change their preferences for something that they do need to a different product.  If it works, it is an additive strategy on top of additive behavior.  If the product being sold affects other learning centers in the brain like reward-based learning that can lead to further additive effects. The photo at the top of this post illustrates another example.  This kitchen drawer for spoons and spatulas is a solution to the cooking problem of how many are needed to accomplish what the cook in this case needs to accomplish. The drawer is packed to the point where it barely closes and at that point, the cook is forced to reassess and decide about cleaning the drawer out and starting over.  Homeowners often forced to make similar downsizing or subtractive decisions after 20-30 years of additive ones and being forced with either space constraints or a smaller family.  

What about medical and psychiatric treatment?  I don’t think there is any doubt that additive transformations are operating. Most treatments that involve medication have a step approach with the addition of medications for symptoms that do not respond or partially respond to the initial treatment. This occurs after an explicit subtractive bias or at least a bias to maintain the status quo 20 years ago.  At that time, hospitals and clinics were reviewed based on criteria to limit the amount of polypharmacy defined as more than one drug from the same class. Today, polypharmacy is common.  Reference 3 below gives an example of polypharmacy defined as 5 or more medications taken concomitantly and hyper-polypharmacy was defined as 10 or more medications taken concomitantly in a 3-month sample of 404 geriatric patients with cardiovascular disease admitted to a hospital during 3-month period.  They found the prevalence of polypharmacy was 95%.  The prevalence of hyper-polypharmacy was 60%.  Most patients (77.5%) also had a potential drug-drug interaction.  Their suggestion be vigilant is a strategy discussed as being potentially successful in containing the additive strategies (2).  

From psychiatry, I am including a common problem that I encountered as a tertiary consultant.  That problem is what to do about a person with a depression that has not responded to high dose venlafaxine. There are geographic areas in the US, where very high dose venlafaxine is used with and without pharmacogenomic testing.  From the options listed in the diagram it is apparent that there are 4 additive (black arrows) strategies and 2 subtractive (red arrows). There is a robust literature on the additive strategies and not so much with the subtractive. As a result, it is common these days to encounter patients who have tried numerous combinations right up to and including “California Rocket Fuel” (4) of the combination of an SNRI like venlafaxine with mirtazapine.  The ways to analyze this situation, especially if there has not been any improvement are significant and depend a lot on patient preferences and side effects in addition to the lack of response. I have found that very high dose venlafaxine, can be sedating to a significant number of people and that they feel better when it is tapered.  I have also seen many people far along the augmentation strategies when tapering or discontinuing the venlafaxine was never considered. In some of these cases, the patient reports that venlafaxine is historically the only antidepressant that has worked for them in the past.

That brings up the issue of additive versus subtractive biases on the part of the patient. We have all been bombarded by pharmaceutical commercials suggesting the best way to mood stabilization is adding another medication – typically aripiprazole or brexpiprazole. In fact, those commercials speak directly to additive biases. It is often very difficult to convince a person to discontinue or reduce a medication that they have talked for years – even when careful review suggests it has been ineffective or creates significant side effects. 

Could a discussion of additive versus subtractive transformations be useful in those situations? There is currently no empirical guidance, but these might be additional experiments to consider for both prescribing physicians and the patients they are seeing. Certainly the expectations that they patient has for any given treatment needs to be discussed and whether that expectation is reasonable given their personal experience and the objective evidence. On the side of prescribing physicians, it is fairly easy to flag medication combinations that are problematic either from the perspectives of too many medications being used at once, physical and side effects not being analyzed closely enough, or medications being changed too frequently. Would discussing additive and subtractive strategies be useful in that setting?  Would a discussion of basic rules to address additive biases such as discontinuing a medication when it is replaced be useful?

Remaining vigilant that there are subtractive strategies out there is a useful lesson from this paper. Physicians are aware of the concept of parsimony and how that can be applied to medical care. Given the fact that the additive strategies are probabilistic and modifiable with conscious strategies – that should still prove to useful in containing polypharmacy.  

 

George Dawson, MD, DFAPA

Supplementary:

Another common additive strategy that I have encountered in the past 10 years is performance enhancement.  The patient presents not so much for treatment of a psychiatric problem but because they believe that adding a medication or two or three will improve their overall ability to function. Common examples would include:

1.  Presenting for treatment of ADHD (with a stimulant medication) not because of an attentional problem but because the stimulant creates increased energy and the feeling of enhanced productivity.

2.  Presenting for treatment of insomnia in the context of drinking excessive amounts of caffeine in the daytime and the caffeine is viewed as necessary to enhance energy at work or in the gym.  In some cases, stimulants are taken in the daytime and the idea is that the medication for insomnia would counter the effect of stimulants or caffeine taken late into the day.

3.  Taking anabolic androgenic steroids (AAS) and expecting to treat the side effects of mood disturbances, insomnia, anger, and irritability in order to keep taking the AAS.  Many AAS users also take other medications for this purpose as well as various vitamins, supplements, and stimulants to enhance work outs.

4.  Taking excessive numbers of supplements with no proven value and seeking to use medications for nondescript symptoms associated with the supplement use. In many cases, patients with psychiatric disorders are sold on elaborate mixtures of minerals and supplements with the promise that they address their symptoms.  In many cases it is difficult to determine if the associated vitamins and supplements interact with the indicated medical treatment or not.

All of these are additive strategies with no proven value that I have seen in the outpatient settings.  It is obviously important to know if the patient being treated is using these strategies.  There are often competing considerations – for example does the patient have a substance use disorder and are substance use disorders another predisposing condition to additive biases (I suspect they strongly are).

 

References:

1:  Meyvis T, Yoon H. Adding is favoured over subtracting in problem solving. Nature. 2021 Apr;592(7853):189-190. doi: 10.1038/d41586-021-00592-0. PMID: 33828311.

2:  Adams GS, Converse BA, Hales AH, Klotz LE. People systematically overlook subtractive changes. Nature. 2021 Apr;592(7853):258-261. doi: 10.1038/s41586-021-03380-y. Epub 2021 Apr 7. PMID: 33828317.

3:  Sheikh-Taha M, Asmar M. Polypharmacy and severe potential drug-drug interactions among older adults with cardiovascular disease in the United States. BMC Geriatr. 2021 Apr 7;21(1):233. doi: 10.1186/s12877-021-02183-0. PMID: 33827442; PMCID: PMC8028718.

4:  Stahl, SM . Essential psychopharmacology: neuroscientific basis and practical applications. Cambridge University Press, Cambridge 2000. p. 363.

 

Graphics Credit:

So far they are all mine.  Yes that is one of my kitchen drawers but I am fairly good at avoiding polypharmacy.  Click on any graphic to enlarge.

Deprescribing - Same Job With A New Spin

During my tenure as an acute care psychiatrist, I had to reconcile a lot of medications. I was doing medication reconciliation before the term was invented for the electronic health record (EHR). The process basically involves trying to figure out what medications the patient was really taking before they were admitted to the hospital. It could be very easy if there were no preadmission medications. On the other hand it could be extremely complicated. There were days when I had to sort through two or three shopping bags full of medications, talk with the patient’s pharmacist, talk with several specialists who were prescribing medications, and talk with the patient’s primary care physician. Even after that long process, I often estimated initial dosages based on the patient's recollection of what they had been taking and how much. I also had to make fairly rapid decisions about whether or not large numbers of medications may have been more harmful to the patient than helpful. Some patients had lists of medications containing 10 to 20 unique medications.

Sometime in the past 10 years the concept of deprescribing medication came up. It is fairly unique term as indicated by the bar graphs below that are drawn based on the references per year to the term. It started out the geriatric literature because elderly people are more sensitive to lower doses of medications and polypharmacy relative to younger and healthier populations. There is actually a list of medications called Beer’s list, that highlights medications that may be more problematic in older adults. It is the intellectual property of the American Geriatrics Society and I can’t reproduce it here. It basically contains classes medications that are known to be problematic in older adults such as anticholinergics and sedative hypnotics. Consistent with that concept - the geriatrics literature has focused on rational pharmacology and the need to reduce the medication burden in some cases the specific pharmacodynamic burden of prescribed medications.  Goal of this post is to look at some of the techniques I typically use to identify polypharmacy - related problems and respond.

In determining whether deprescribing should occur or not I think it is useful to look at hierarchy and I have outlined the following points:

1. In the case of the patient on polypharmacy who is tolerating multiple medications well and they appear to be effective strongly consider doing nothing:

Being an expert in psychopharmacology - doing all the reading and listening to the experts often doesn’t translate into the real world setting very well. There’s no better example than the patient on multiple medications who frequently has a history of numerous or prolonged hospitalizations and who appears to be taking “too many medications”. They could be multiple medications from the same class or different classes. It is easy to take a look at that list of medications and imagine how they came about but with our current fragmented medical record system it would only be an imagining.  It is too high of a risk to stop polypharmacy just based on general principles if the patient is doing well. I am familiar with many cases where changes were made and the patient became markedly destabilized and ended up back in long-term hospitalization. These are the cases that never come to light in the literature where populations rather than outliers are studied.

2. Acute medication side effects: 

In the case of acute side effects changes need to be made based on the urgency involved. Worst-case scenarios would include serotonin syndrome or neuroleptic malignant syndrome where the serotonergic or dopaminergic medications need to be stopped abruptly. That would not occur in typical clinical scenarios but in the emergency setting it is necessary. What clinicians typically face is multiple medications from the same class. When that original guideline was made back in the 1990s classes were a lot more general than they are now. For example, in those days antidepressants were a general class instead of SSRIs, SNRIs, and others.  These days combination antidepressant therapies are relatively common and research articles can be found that look at the addition of bupropion to a standard antidepressant or mirtazapine to a standard antidepressant. Beyond that trazodone might be added to those two antidepressants bring the total to three. This can occur commonly in clinical practice and also can be a source of the patient noted in number 1 above.

Numerous side effects can result from polypharmacy like sedation, headaches, nausea, and cognitive problems that probably indicate the total amount medication needs to be decreased or at least one of the medications could be stopped. The medication I frequently encounter that is prescribed at very high doses resulting in sedation is Venlafaxine ER.  There are areas of the country where very high doses of this medication are prescribed in excess of 350 mg per day - 225 mg per day is considered the FDA recommended max dose. Almost uniformly these patients improve with less venlafaxine and there is less confusion about medication side effects versus depression.

3. Chronic medication side effects:  

Some of the most serious long-term medication side effects include weight gain, metabolic changes including metabolic syndrome, diabetes mellitus, nephrogenic diabetes insipidus, hyperlipidemia, and movement disorders. In many cases the medications being used that lead to the side effects have been the only ones that will that work and even gradual changes may result in destabilization the patient. Some of these transitions between atypical antipsychotics or atypical antipsychotics and mood stabilizers result in a significant medication burden and risk for increasing side effects. It is critical that the transition is actually made to the new set medications.

Any medication side effect on a long term basis is obviously serious. Dry mouth one of the most common side effects can lead to dental caries and mouth soreness. Constipation is often considered a nuisance but it can lead to bowel obstruction and serious medical complications. Sexual side effects are a significant quality of life problem that can impact the most significant relationships in a persons life. Surveying for these side effects is a significant but necessary task for any psychiatrist.  

One of my very first experiences with chronic medication side effects was a patient who had been taking an old antidepressant - doxepin for about 5 years.  I started seeing him in that 5th year and he was no longer sure that he was depressed but he did notice he was chronically fatigued.  Because he had been on the medication for 5 years, I suggested that we taper him off of it.  He came back to see me and said he had not felt as well in a long time.  Not only had his fatigue resolved, but he no longer had chronic headaches.  In retrospect, he said he felt like he "had the flu" for the last 5 years. That experience led me to never suggest that people "get used to the medication" if they are having side effects.  I know that does happen in some cases, but I also know that most people just get used to feeling ill.

4. Rare but serious medication side effects: 

Looking at both neuroleptic malignant syndrome and serotonin syndrome, the literature frequently states that these acute life-threatening disorders occur around times of medication transitions. Trying to keep the load on both serotonergic and dopaminergic systems low during these transitions is one of my goals but I can’t really find any scientific literature to back it up. Literature out there tends to be case reports and that includes literature suggesting that medication transitions are associated with the acute disorders.

5. Interrupted medication transitions: 

I frequently see people who are on full doses of two and often three antidepressants. When I take their history there was a plan to add the new antidepressant and then taper and discontinue the old one but for some reason the old medication was not stopped.  This often happens in the outpatient setting and many times it is due to the patient not knowing that the old medication should be stopped or not getting a specific schedule to taper and discontinue it.

6. Polypharmacy: 

Polypharmacy can be highly problematic. It happens in just about every class of psychiatric medications. As an example, Adderall XR is designed to produce a concentration curve that is equivalent to Adderall immediate release dosed twice a day and yet I commonly see people taking Adderall XR either more than once a day or combined with an afternoon dose of Adderall immediate release. There are similar combinations of antidepressants, antipsychotics, mood stabilizers, and benzodiazepines. In a controlled setting where I practice I can make the necessary medication changes and follow-up the patient frequently. If that occurs in the outpatient setting there needs to be a plan in place for frequent follow-ups as well as active collaboration with the patient and the family.

7. Pharmacokinetic problems: 

The most common pharmacokinetic problem I encounter is people who abruptly stop Lamotrigine and resume the full dose.  Since lamotrigine began its psychiatric applications I have been in touch with the manufacturer many times and was advised that if the patient stops the medications for more than three or four days, the standard titration of lamotrigine needs to occur. It is fairly common for me to hear from people that they go off lamotrigine for a week or two and then resume the full 200 or 400 mg dose. I often see them after they have been on that resumed dose for one week.

The prototypical pharmacokinetic polypharmacy problem was SSRIs that were CYP2D6 inhibitors combined with tricyclic antidepressants (CYP2D6 substrates). The original reports of severe arrhythmias in some cases death from tricyclic antidepressant toxicity was the initial impetus for psychiatric interest in pharmacokinetics and drug interactions. I still see people today who are getting amitriptyline or nortriptyline in combination with fluoxetine or paroxetine and there has been no clear concern about those potential interactions.

8. New medical problems that impact prescription patterns:  

Acute renal and hepatic problems can directly impact the patient’s drug metabolism and dosing requirements or ability to take a specific drug.. One of the best examples I can think of is a case of 40 year old man who was taking gabapentin for anxiety and chronic pain. He was seen by an internist and started on a statin for dyslipidemia. Four days later when I saw the patient he was delirious and completely disoriented. He also had the significant ataxia and sedation. He was evaluated immediately and blood tests showed that he had acute renal failure that was believed to be secondary to the statin. The statin and the gabapentin were discontinued and within days he was back to his baseline.  If he had been on any other medications with primary renal clearance those would have been discontinued at same time.

9.  Correcting the medical side of things:

If the psychiatric medications are being taken incorrectly, there is a good chance  that the polypharmacy for heart disease, hypertension, diabetes mellitus, and asthma/COPD are also being taken incorrectly if they have been taken at all. It is problematic when a person has a disabling mental illness and they are left to take several doses of medication at different times of the day by themselves. When I started out in psychiatry, I could make a public health nursing referral at any time by sending in a form to the appropriate agency.  The next day, and RN would be at the patient's apartment setting up their medications, taking their blood pressure and pulse, and assisting them with managing their medications for the psychiatric disorder as well as all of their chronic medical problems.  That service ended with the rationing of all services to people with severe psychiatric disorders, making it much more likely that these medical conditions will not be as stable as they should be when they see their psychiatrists.  The is both a problem for the patient and the psychiatrist but also an opportunity to correct things.  

These are a few examples of the hierarchy of problems that occur with polypharmacy and in some cases standard pharmacy and how they can be approached. There apparently some groups out there at this time were trying to establish a hierarchy of how medications can be discontinued and when they should be discontinued. Like most cases in medicine in the extreme it is obvious but anything less than that is more difficult and it takes a lot of time to figure out. One thing that might be useful would be to consider drug combinations that are commonly prescribed as a baseline and look for polypharmacy being defined as anything beyond that.

One thing is for sure - the old rule about never prescribing two drugs from the same class - no longer applies.

George Dawson, MD, DFAPA

Remission Before Discharge? An Un-American Concept

I encountered a paper this week that had me nostalgic for the old days in American psychiatry.  The days when people were treated in hospitals to the point that their symptoms remitted before they were discharged.  That of course depends on a couple of assumptions.  The first is that their symptoms can be treated to that point.  There are a number of people with a disease process that cannot be treated to that point.  Neurodegenerative disorders like Alzheimer's disease or vascular dementia are good examples, but there are also a number of people who have no known brain insult and yet have treatment resistant depression or psychosis.  Their symptoms do not respond or poorly respond to treatment.  The second assumption is that the person with the illness recognizes why they need to be in a hospital or some form of intensive treatment and they agree to stay long enough.  That is one of the more complicated assumptions because psychiatry is almost exclusively the only medical specialty where the treating physician can disagree with the patient's preference for discharge and put them on a hold pending a judge's decision to order them to stay in a hospital longer.  That court decision in most states depends on three standards - danger to self, danger to others, and general ability to care for oneself.  Those three standards have been condensed over the years to a single word dangerousness.  Practically all inpatient treatment units in the United States are impacted by managed care companies who would generally like people discharged in about 3-5 days irrespective of their diagnosis or treatment plan.  Their de facto discharge criteria is dangerousness.

If you are reading this for the first time, it may sound absurd to base a medical decision on an oversimplified legal standard that is designed to not unduly impact the civil liberty of citizens.  It is definitely absurd for any number of reasons.  If you work in inpatient settings you can have the most carefully crafted treatment plan to restore a person to their previous level of functioning and have to tolerate a managed care case manager or physician ask you "Where is the dangerousness?"  If there is no dangerousness the expectation is that the patient will be discharged and if you (as the treating physician) disagree - the insurance company via their own review can just stop paying for the hospitalization.  The practical result of all of that politics is that a partially stabilized patient is discharged.  That would be bad news if that person was dangerous, but what nobody talks about is that it is probably worse if they are not.  First, the vast majority of people that psychiatrists treat in inpatient units are not dangerous but they are having a very difficult time functioning both in terms of symptom management and what they need to manage in life every day.  If they are partially treated, it is very likely that they will not be able to follow up with a detailed treatment plan.  Managed care companies and the usual critics of psychiatry frequently rationalize this process with global statements like "the outcomes are no different" or inpatient treatment especially involuntary inpatients treatment is not necessary.  The problem is that there are very few studies that look at the process.  After all, who has an interest in continuing to discharge partially stabilized patients?  It is certainly not psychiatrists, patients or their families.

The study I encountered was in the Journal of Clinical Psychiatry this month (1).  The investigators are from the Netherlands.  They looked at 78 cases of postpartum psychosis admitted to the Mother-Baby Inpatient Unit (MBU) at the Erasmus Medical Center between August 2005 and June 2011.  The MBU is a specialized unit to treat cases of severe psychopathology during the postpartum period.  Patients with an onset of psychosis or mania within 6 weeks of the delivery were included.  They included the typical DSM functional psychosis categories and mood disorders with psychotic features.  Substance induced psychosis was excluded.  Of the final group 64 patients had only postpartum psychosis and 14 had either a prior episode of psychosis or mania/hypomania.  The authors had previously developed a standardized approach to treating postpartum psychosis that involved using typical medications indicated for acute inpatient stabilization.  The goal was remission of their symptoms for one week prior to discharge with standard recommendations for pharmacotherapy to maintain symptomatic remission.  They were followed for 9 months and by that time 16 patients had discontinued medication with the remainder taking lithium (n=40) or antipsychotic monotherapy (n=8).

The main outcome measure used was the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT).  That research instrument looked at a number of domains including work, interpersonal relationships, global satisfaction, and recreation.  All of these areas have been shown to be adversely impacted in other studies of the problem of postpartum psychosis.  As an example the authors quote a study that noted a divorce rate of 18% in a similar cohort of patients.  In a previous post on this blog, I made the observation that many women seen in inpatient practice who have a chronic psychotic disorders can be traced back to an initial episode of postpartum psychosis.  The authors here note that although they may have had a sample with low premorbid complications their outcomes were generally very good compared to previous retrospective studies and a matched sample of postpartum women.  As an example, 88.5% of the women had resumed full work and household responsibilities.  In comparison to a general postpartum population, the experimental group showed slightly more anxiety and depressive symptoms due to the the portion of the sample that relapsed.  In comparison to a group of patients with first episode bipolar disorder occurring outside of the postpartum period the comparison favored the experimental group.  Despite the usual limitations of these studies like sampling bias and missing data, the authors conclude that there is plenty of optimism in the treatment of postpartum psychosis using their methodology.  In what I consider to be an understatement of the past three decades in American psychiatry the authors write about how a specialized unit may have biased their results: "Unfortunately, many regions of the world do not have MBU care within a reasonable travel distance for the patient."  To my knowledge there are no MBUs at all in the United States.  They are inconsistent with the prevailing managed care rationing model for psychiatric care in this country.

This is a very important article for a number of reasons.  It highlights the importance of specialized care for women with postpartum psychosis through reduced chronicity and better functional outcomes.  The psychopharmacology result with lithium or antipsychotic monotherapy and discontinuing all benzodiazepines prior to discharge is far superior to any result that could be expected in the US.  Short stays result in polypharmacy.  I would be shocked to see any case of postpartum psychosis not discharged on antidepressants, antipsychotics, benzodiazepines, sleep medications and possibly valproate from American inpatient units.  These medications are difficult to manage and the follow up appointments are typically brief and focused primarily on symptoms and medications.

In the trade off between short lengths of stay and unmanageable polypharmacy - it seems like this research group has developed a quality approach.  It is time for American psychiatrists to acknowledge that the way inpatient units are run by businesses is not working because they never adequately stabilize patients.  That leads to a large population of people who are unnecessarily symptomatic and never recover their baseline level of functioning.  That same population may be taking a lot of medication  that they don't really need.


George Dawson, MD, DFAPA                        
 


Supplementary:

I confirmed that there are no MBUs in the USA and that the median length of stay on the unit described in this study was 55 days.


References:

1: Burgerhout KM, Kamperman AM, Roza SJ, Lambregtse-Van den Berg MP, Koorengevel KM, Hoogendijk WJ, Kushner SA, Bergink V. Functional Recovery After Postpartum Psychosis: A Prospective Longitudinal Study. J Clin Psychiatry. 2017 Jan;78(1):122-128. doi: 10.4088/JCP.15m10204. PubMed PMID: 27631144.

2: Bergink V, Burgerhout KM, Koorengevel KM, Kamperman AM, Hoogendijk WJ, Lambregtse-van den Berg MP, Kushner SA. Treatment of psychosis and mania in the postpartum period. Am J Psychiatry. 2015 Feb 1;172(2):115-23. doi: 10.1176/appi.ajp.2014.13121652. PubMed PMID: 25640930.


Attribution:

Photo at the top is Erasmus Medical Centre - the affiliation of the lead author in this article and location of the study.  It was downloaded from Shutterstock on February 8, 2017 per their agreement specifying editorial and noncommercial use.

Editorial credit: Jaroslav Moravcik / Shutterstock, Inc.
ROTTERDAM, NETHERLANDS - APRIL 1: Erasmus medical centre in Rotterdam on April 1, 2014 in Rotterdam