An Explanation of the Second-Dose Effect in Pharmacokinetics and Its Meaning for Clinical Psychopharmacology

Most psychopharmacologic agents are administered in multiple dosing regimens. Frequently, the relative intensity and/or duration of action of a second dose of medication appear to differ from the initial dose. A theoretical pharmacokinetic basis exists for this phenomenon. When a second (and equal) dose of a drug is given after cessation of the pharmacologic effect of the initial dose, the relative intensity is more pronounced and the duration of action is greater. However, the third and subsequent doses are equal in intensity and duration to the second. This second-dose effect occurs regardless of the half-life of the drug when dosing is repeated in response to the observed effect. For many commonly used drugs, multiple dosing regimens are begun on a fixed dosage interval. When dosing is repeated before the previous dose has been eliminated from the body, the second and subsequent doses produce a greater effect than the initial dose, but the relative increase in intensity of subsequent doses diminishes. Published literature supports the concept of a “second-dose effect” in clinical psychopharmacology. An appreciation of the assumptions and limitations of the second-dose effect provides a better understanding of the observed effects of many psychoactive drugs after repeated administration.