What to Do About Drug Tolerance | Bipolar Blogger Natasha Tracy
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What to Do About Drug Tolerance

Not getting the same effect from your medication? You may be developing a tolerance. Natasha Tracy explains how a new study sheds some light into this phenomenon and what can be done about it.

Drug tolerance is a phenomenon wherein the human body compensates for a drug to the degree where the drug no longer has the desired effects. In other words, one cup of coffee no longer gives you a buzz. The result of tolerance is that more of the drug is needed to produce a desired effect.

Drug tolerance occurs with different drugs at different rates, and previously it was not thought to be an issue with drugs like antidepressants. However, we now know that many people suffer from a spontaneous lack of drug efficacy even after successfully being on a drug for years. This is a form of drug tolerance that is known as “antidepressant poop-out” and it’s something we don’t understand. Loss of effectiveness after a period of good responsiveness has been clinically noted in lithium, valproate (Depakote), lamotrigine (Lamictal), and antidepressants.

Discontinuation Tolerance

Drug tolerance is also known to occur upon drug-discontinuation. In other words, someone who has previously responded well to lithium discontinues the drug, symptoms reemerge, the person goes back on lithium but does not find it effective. Again, we don’t know why this occurs but it does appear to in a small percentage of patients. In one study, it occurred in 13.6 percent of people taking lithium.

Clinically Noted Tolerance

When looking at humans, tolerance developed in 30-40 percent of patients between 2.8-0.9 years after successful treatment began with therapies that included carbamazepine (Tegretol). With valproate, about 25 percent of people developed tolerance after about 2-4 years.

Tolerance to the Anticonvulsant Effect of Carbamazepine and Lamotrigine

It’s very difficult to study tolerance in humans as tolerance happens at random intervals over years after initial treatment. In Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders, this effect is studied in animals. This study was able to track the efficacy of the anticonvulsant (anti-seizure) properties of carbamazepine and lamotrigine, both of which are also used to treat bipolar disorder. Seizures are a lot easier to study than bipolar disorder as seizures can be induced.

In the study, animals were given either carbamazepine or lamotrigine priort to a seizure stimulation. These drugs effectively prevented these seizures, however, after some time, tolerance to these drugs developed and the seizures returned.

If the animal was given several days of seizures without the drug, the drug’s efficacy was renewed once reapplied prior to a seizure. More interestingly, the efficacy of the drug could be renewed even if the animal continued to receive the drug after the seizure stimulation (not prior to it). So, the reversal of tolerance appears to be contingent upon the seizures occurring, not upon drug administration (rather when the drug is administered).

Tolerance in Bipolar Disorder

It is through this study that parallels can be drawn to tolerance in bipolar disorder. The underlying mechanisms (neurochemicals, genes, etc.) differ, but theoretically the overall concept remains the same. The idea is that if you’re on a medication but develop many underlying episodes, that will create tolerance but if few episodes develop, then tolerance will not occur. The sicker you are, the more likely you are to develop medication tolerance. From the study:

“We posit it is the ratio of endogenous pathological alterations (the “bad guys”) to endogenous adaptive alteration (the “good guys”) combined with the exogenous effects of drugs that determines whether or not affective episodes are suppressed, occur episodically, or occur regularly as complete tolerance develops.”

What to Do About Medication Tolerance

According to this study, there are areas of research suggested for drug tolerance. To avoid or slow tolerance the authors suggest:

  • maximum effective medication dose
  • stable dosing
  • valproate over lamotrigine or carbamazepine
  • early treatment (after fewer episodes of illness)
  • combination treatment rather than monotherapy
  • prevention of episodes (such as a reduction in stressors)

According to this study, the following may be useful in reversing tolerance:

  • period of time without the tolerant medication and then re-treatment
  • choosing an medication with a different mechanism of action (for example, an antipsychotic instead of an anticonvulsant)


Warning, this is a preclinical study and as such the implications from it may not be fully understood. Please make sure to make any medication changes only with doctor oversight.
For more information please see the study Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders.

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About the Author

Natasha Tracy is an award-winning writer who specializes in writing about bipolar disorder.