In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.
Recommended dosage range
Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.
Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.
Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.
Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.
When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.
So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.
Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.
TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.
Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.
Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.
Summary
Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.
Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups: