Clinical Neuroscience

Receptor occupancy and drug response: Understanding the relationship

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Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.1-3 Similarly, despite significant variability in antidepressant response,4 blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline7—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.8

Antagonist agents: The threshold model of receptor occupancy and clinical response

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

Agonist agents: As receptor occupancy increases, so do clinical effects

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Minimal effective dose of second-generation antipsychotics

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 13,9 and Table 25). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 25). The minimal effective doses for antipsychotics are listed in Table 1.3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.10 Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 25). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

Minimal effective dose of serotonin-reuptake inhibiting antidepressants

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.11 Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor15), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.16 Clinically, this still appears as the minimal effective dose achieving maximal response17-19 without significant parkinsonism despite >90% receptor occupancy.12

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