Commentary: Why patients may not respond to usual recommended dosages

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.