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.