Editor in Chief
A mythology exists that creates one of the most significant nemeses for the practicing clinician in psychiatry: drug formularies that impose drug dosage and dispensing limitations that quite often result in an unnecessary and burdensome obstacle to our goal of effectively treating patients. Many of us older psychiatric clinicians reminisce back to a time absent of drug formularies when we could dose a medication unencumbered to maximize the benefit to our patient. Sadly, we have surrendered our power to the insurance magnates who pretend to be more knowledgeable than we are about the medication choices and doses that will provide the best treatment—and hence outcome—for our patients.
A medication’s dosage used in phase 3 clinical trials is chosen to create the highest likelihood of clinically significant separation from placebo, while minimizing adverse effects. Additionally, as required by the FDA to create as clean a treatment population as is possible, participants in clinical trials are not illustrative of the patients we treat on a day-to-day basis in our clinical practices. For most phase 3 clinical trials, subjects can have no psychiatric comorbidity, no significant medical problems, no recent or active substance use disorder, and no serious acute symptoms. They cannot be pregnant, must be of a specific age range, and must be competent to understand and consent to the treatment protocol—and this is just the short list. The enrollment requirements would exclude more than 90% of the patients that I have treated at Seacoast Mental Health Center, where I have practiced for the past 12 years.
It is only after a medication is FDA approved, and we prescribe it to hundreds of thousands of patients—all with unique factors that will determine a serum drug level for each individual patient—that we learn the true clinical range of a new drug. Two common examples of this are risperidone, which we initially dosed too high (based on the FDA approved initial product insert), and ziprasidone, which we initially dosed too low (based on the FDA approved initial product insert). In a time when cost savings is the driving force behind insurance company policies, it would seem wise and prudent to allow treating clinicians to choose the medication they deem most appropriate for a specific patient, and dose it as aggressively as is clinically indicated to improve the patient’s symptoms and functioning and minimize toxicity to the brain.
Let us look at the many variables, unique to each patient, that influence a medication’s serum level. In clinical reality, it is the serum level of the drug, and not the dose of the drug, that determines clinical response. So, let us follow the journey of a drug from the pill bottle to the toilet.
Getting the medication into the body
The first step in the process of getting a clinically effective drug level is getting it into the body. The best route of administration is determined by the many pharmacokinetic and pharmacodynamic properties of the drug. The most common delivery system is that of oral administration, where the medication is simply swallowed. Even with this route of administration significant rules may apply to obtain consistent and adequate serum levels. One common example is that of levothyroxine, which needs to be taken on an empty stomach. Other drugs may require the presence of a specific number of calories to maximize absorption, or a specific pH of the stomach.
1. Cozza KL, Armstrong SC, Oesterheld JR. Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Publishing; 2003.
2. Toselli F, Dodd PR, Gillam EMJ. Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs. Drug Metabol Rev. 2016;48:379-404.