We have often heard the term “therapeutic index” or “therapeutic window” of some drugs, typically in the sense of noting that some of our medications have a “low therapeutic index” or a “narrow therapeutic window“. Since these terms come up several times in the psychopharmacology literature, let’s take a moment to be clear about what they mean.
The term therapeutic index can be used differently in different settings. For us, as clinicians, the therapeutic index (also called the therapeutic ratio) is a ratio of the toxic dose of the medication to the therapeutic dose of the medication.
For example, a single dose of about 10 g of acetaminophen (paracetamol) is toxic in an adult (James et al., 2011). If we compare this to a typical therapeutic single dose of 500 mg, the ratio of the toxic dose to the therapeutic dose is 10000 mg/ 500 mg = 20. We would say that the therapeutic ratio or index is 20.
From knowing what a therapeutic index is, it would be obvious that a high therapeutic index is good. A high therapeutic index means that there is a greater margin of safety for that medication. The person would have to take a lot more than the therapeutic dose for the medication to be toxic.
Which medications that we may prescribe have a low therapeutic index?
There is no clear agreement as to how exactly a low therapeutic index should be defined and which medications should be considered to have a low therapeutic index. using a combination of the published literature and my personal judgment, I think that for us the list should include (alphabetically): carbamazepine/ oxcarbazepine, clozapine, lithium, thyroid hormones, and tricyclic antidepressants. (This is not intended to be a complete list of psychotropic medications with a low therapeutic index.)
On the other hand, some medications have not been clearly shown to have a low therapeutic index. These include lamotrigine and valproate (Greenberg et al., 2016).
Here are two technical points, which are not essential for clinicians to know. But, since you have come this far, you might as well read the rest of this section.
– The dose of any medication that is either toxic or therapeutic obviously differs from person to person. This is why a pharmacology researcher would more precisely say that the therapeutic index is the ratio between the dose of the medication that is toxic in 50% of persons to whom it is given (TD-50, where TD means “toxic dose”) to the dose that is effective for 50% of persons (ED-50, where ED means “effective dose”).
– “Toxic” and “effective” can be defined in many different ways. For example, “toxic” can mean leading to some side effects, leading to unacceptable side effects, or leading to death. This is why specific numbers for the therapeutic index don’t mean anything to us unless we know exactly how the numerator and denominator were defined. Fortunately, we don’t need to. For us as clinicians, the term therapeutic index is useful for knowing which medications have a low therapeutic index.
What is the “therapeutic window”?
The therapeutic index can also be looked at a slightly different way and then it is called the therapeutic window. What the “window” means is that as the dose is increased, first you get to an effective dose and, if you keep increasing the dose, eventually you get to a toxic dose. The gap between these two—-the effective dose and the toxic dose—is the therapeutic window.
Note: There is a different use of the term “therapeutic window” as it applies to medications like nortriptyline. There, surprisingly, the medication is typically effective within a range of serum levels. It is less likely to be effective either below this window or above it. Not due to more side effects at the higher dose but due to other, largely unknown, reasons. For more on this, please see the following article on our website: How to order and interpret the serum nortriptyline level.
Since the term therapeutic window can mean more than one thing, I recommend that we use the term therapeutic index instead of therapeutic window.
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