What do Recommended and Maximum Dosages Really Mean?

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Not What You Think

The Food and Drug Administration (FDA)-recommended and -maximum dosages for medications are determined through tests on large numbers of individuals. Their purpose is to ensure efficacy and safety for the general population. However, these dosage amounts are statistical averages that really only apply to those people who are roughly average in how they respond and metabolize the drug. An approved dose that is safe for one person might not be for another. A safe dose for one person might be many times lower than the average and for another very much higher. An approved dose that is effective for one might not be for another. An effective dose for one person might be very much lower than the average and for another very much higher. 

Furthermore an effective dose for a given person might be unsafe for him, and a safe dose ineffective. In other words, just because someone’s sensitivity with respect to side effects is high (or low) does not necessarily mean that their sensitivity with respect to efficacy also is, even if that kind of match up is more likely than not–on average. 

It is crucial to understand that individuals respond differently to the same medication due to a variety of factors, including age, weight, liver and kidney function, concurrent medications, overall health and the genetics that influence how rapidly and efficiently a drug is broken down and excreted and how well the drug molecule matches the protein receptors that when “unlocked” produce both desired and undesired effects–as well as factors not yet discovered. This variability means that the ideal dosage for one person need not be the same for another, even if they have the same condition. It also means that the maximum dose—the dose above which there is a risk of unacceptable or toxic side effects, even if the medication has been tolerated up to that dose—will vary from person to person. Here is how this works:

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The vertical (left) axis of the above chart shows how many people of 100, in a hypothetical test, respond to a given dose of the (imaginary) antidepressant “Proloft,” which is shown on the horizontal axis (bottom). So for example, if you go to the 100 mg dose you will see that the blue line above matches about 15 people (15%). The most common dose range, with the most people responding, is around 125 to 200 mg a day (about ⅔ OR 67% of people). Note that there are a small number of people at the extreme left who need no more than 40 mg a day to respond, and likewise a small number of people who require 270 mg a day and even more to respond. 

Now suppose that the FDA has determined in a similar way with a different group of people, whether they respond or not, that out of a hundred people 10 have a bad reaction to Proloft at doses above 250 mg. They therefore set the hypothetical “FDA maximum recommended dose” at 250, having chosen a certain allowed frequency (10 out of 100 in this imaginary case) of bad reactions. This cutoff is a choice—a risk/benefit tradeoff not made on a case by case basis but on a pooled basis, smoothing out the individual differences into a single, one-size-fits-all recommendation. It is true that physicians and patients are permitted to carefully color outside these lines, but they are not encouraged to do so thoughtfully in order to fit treatment to the actual individual and not to a hypothetical average. In reality these guidelines are very often perceived as absolute and very often treated as absolute by the existence of computerized safety databases that lend themselves to black and white interpretation, by advice-givers using these databases (or looking things up online) without actual clinical experience, and unfortunately often by “evidence-based practices” implemented without proper nuance.

This means that if the FDA maximum is taken as an absolute prohibition of higher doses, about 12 out of 100 who respond well to “Proloft” at doses from 250-300 mg will not be properly treated. Some pharmacists insist on adhering to the FDA recommendation as though it were an absolute rule and will refuse to fill prescriptions above that dose. Some less-experienced prescribers are likely as well never to cross this line. Algorithmic treatment protocols (in for example research) won’t either.

Of course, most pharmacists recognize the reality that FDA recommendations are statistical averages and are not to be taken as rigid cutoffs. And if they comment on it all to a patient, when a prescription is to be filled above an FDA recommended maximum dosage, they also acknowledge that the physician has and must have the discretion to use higher doses, with caution and careful observation as experienced psychopharmacologists often do. But pharmacists have the legal authority to refuse to fill any prescription. It does happen from time to time that a pharmacist will refuse to fill a prescription simply because it falls outside the guidelines–in other words treating these statistical guidelines as though they are absolute rules. This creates a psychological obstacle which many patients find difficult to overcome, even with their physician’s explanation. This happens most often when people suffer from anxiety, and when that anxiety takes the form of intense fear of the very medications that would alleviate it. 

The converse is also true—that there will always be a certain number of people who have bad, even toxic,  reactions at lower than even the FDA recommended treatment doses, even much lower. These are of course never going to be picked up on by someone simply following dosage guidelines. It would be a bad mistake to assume that simply because the FDA recommends a dose as “safe” it is invariably safe for everyone. It is crucial for physicians to be well-educated in the frequency with which bad reactions occur at unusually low doses, and to be clinically experienced enough to have a sense, if possible, as to which patients are more likely to be at risk, for example, the elderly. It is also the reason that in good psychopharmacology, dosages are almost always started very low and increased slowly. This is the only way of catching early on, when bad reactions will be mild, those people who at recommended doses will have seriously bad reactions.

The process of finding the optimal dosage for an individual is called “titration.” This requires starting with a lower dose and gradually adjusting it based on the patient’s comparative responses–both good and bad–to the medication, from one dose to next. The continued presence of symptoms is to be expected but once identified the goal of the comparison is to assess any change in severity, duration or frequency. The goal is to find the lowest possible dose that effectively manages the condition without causing unacceptable adverse effects. This lowest dose might be unusually low—even below the lowest tablet size—or it might be unusually high, above the FDA recommended maximum dose.

While there are many individual factors that determine the dose at which a given individual will respond, or will have adverse effects, one major factor is the actual amount of the medication—its concentration—in the bloodstream. In fact, a truly scientific analysis of dose-response will look not at the amount of medication ingested (the dose) and the associated response (good or bad) but the concentration in the bloodstream and the associated response to that. A simple reason that some people require unusually high doses to respond, and also do not have adverse reactions to these high doses, is that they break down the medication unusually rapidly. An unusually high oral dose in these people will lead to unusually low concentrations. Conversely, there are some people for whom a small dose will lead to toxic levels because they break the medication down so slowly. This breakdown speed is called the metabolic rate for that person and that medication.

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You can see from the above hypothetical example involving 250 individuals at various oral doses that while there is a general trend for there to be higher concentrations at higher doses, there is a great deal of overlap. There are even some people at 25 mg whose blood levels fall within the range of concentrations for people at 200 mg! It is perhaps difficult to believe, but the FDA approved standard for research into efficacy for all psychiatric medications requires only to match the dose taken to the response, not the concentration to the response as it should require. This artificially deflates response rates. 

Do Gene Tests Help?

Most all genetic tests for psychiatric medications do not actually assess which medications work intrinsically—the sensitivity of a positive response to a given amount of medication in the blood stream. They assess whether a given medication is most likely to be broken down at the average rate, or slower, or faster, leading to typical or higher concentrations for a given dose. As there are many other factors that influence response—both good responses and bad—it is critical to titrate anyway, for everyone, starting at very low doses. Knowing the metabolic breakdown rate is therefore of little or no use in real-world clinical settings.One must proceed as though everyone was possibly a “slow metabolizer.”

Physicians can most accurately tailor medication dosages to individual patients by closely monitoring their response to the treatment, including any side effects, and comparative changes in their condition (or not), as the dose is introduced and slowly increased. This ensures that each patient receives the most appropriate dose for his unique characteristics, without needing to know the details of characteristics that are largely unknowable (genetic susceptibility for example, again good or bad). It is not common practice, but when doses are unusually high, the actual blood concentration of the medication can and should be measured to insure safety. 

Real World Examples

An individual with unusually fast GI tract transit times illustrates some of these principles. Fast transit time may be due to, for example, gastric surgery for obesity, or surgical excisions of the intestine for malignancies, Crohn’s disease, etc. In such cases, a typical oral dose of for instance quetiapine (Seroquel) is likely to produce low and inadequate blood concentrations simply because the medication is excreted before it can all be absorbed. In one actual case, a woman who had GI surgery required 1600 mg of quetiapine daily–twice the FDA maximum of 800 mg and four times the typical upper dose. After many years at this dose without ill effect and with good response, the pharmacy balked at filling it. To insure this would not happen again a blood level at 1600 mg was ordered. It showed concentrations well within FDA guidelines. This result is now reported at every refill with an explanation. In general, anyone with rapid transit times is likely to require higher than average oral doses of medications, though not necessarily every medication.

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Another example illustrates how obvious measures are lacking even in what ought to be high quality research. This 2013 paper reports on an individual who on his own took 2,000 mg of quetiapine nightly. He suffered only very minor ill effects–slightly elevated liver enzymes. However, no blood concentration was ever measured so we really do not know the extent to which this was, for him, an elevated dose, if it was at all.

Pediatric Doses

Most people assume that the reason children require lower doses than adults is because they are smaller. But this is only true for certain medications–short-lived ones where a given dose is pretty much entirely gone before the next dose. Indeed, for such medications, such as stimulants used to treat ADHD, body mass plays a role in dosing for adults as well. All other factors aside, the greater the mass (weight) the larger the dose needed to achieve a given average concentration in the blood as the medication is dispersed throughout the body. 

However there are other medications that are not entirely excreted before the next dose. Instead, each day the next dose adds to what remains from the prior day. One might assume therefore that the blood level would increase without limit. This is not so, however, because the way metabolic breakdown works, the higher the concentration the faster the medication is broken down.

This results in a climbing, sawtooth shaped graph of concentration that eventually reached a balance between in and out. The balance is called equilibrium, and we are looking for the lowest equilibrium level in the blood that produces the desired result and no unacceptable side effects.

The below chart shows the hypothetical daily concentration of a drug taken once a day until it reaches an equilibrium concentration of about 11 at day 20.

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However, the other major reason for age-adjusted dosing is metabolic rate–the rate at which a person’s body breaks down and excretes the medication. Again all other factors being equal, the younger the person, the slower the metabolic breakdown process. Imagine a bucket filled with water. The volume of the bucket represents the body mass–the volume–of the person, the water is the medication, and being filled means the blood concentration is adequate. However, there is a hole in the bottom of the bucket that represents the metabolic breakdown so that water is continuously leaving the bucket. The size of the hole is the metabolic rate. At whatever rate the water is leaving the bucket, the bucket must be refilled with water regularly–the daily dose–to keep the water level near full. 

In general the smaller the bucket the smaller the hole. In other words, as a person grows metabolic processes speed up (they grow more enzymes) and a  medication is excreted more rapidly. In other words, then, age serves as a proxy for mass/volume in which a medication is dispersed but also as a proxy for the rate at which a medication is broken down and excreted. Hence, until adulthood when the rate of metabolism no longer climbs, age serves as a reasonable proxy for both volume and metabolism.

There are two corollaries. First, for medications that are excreted within a day, body mass/volume must be taken into account for dosing whether in children or adults. Second, for medications that are not excreted within a day, body mass/volume does not affect the equilibrium concentration but it does affect how long it will take to reach equilibrium. 

Thus for example, the dose of fast acting stimulants must be adjusted for age and weight in children and for weight in adults. Slow-acting medications such as antidepressants that stay in the body need adjustment for age but not for weight. Weight will affect how long it takes for a therapeutic dose to be reached in both children and adults.

Conclusions

It is essential for patients to communicate openly with their medical professionals about how they are feeling with their medication regimen—both good and bad—comparing how they feel at the current dose versus how they felt at the prior one. In many respects good psychopharmacology is like a child’s game of hot-and-cold. (More formally, it is a gradient search in a high-dimensional landscape.) Adjustments to dosages should only be made under medical guidance, by properly-trained professionals and not by others—and of course patients should never change their dosage without discussing with their physician first. Psychopharmacology properly done is a sophisticated science.

Further reading:

https://www.thecarlatreport.com/articles/3687-antidepressants-when-dosage-matters

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