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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
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.
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
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.
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
Continue to: The second caveat is...
The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.20 It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by clozapine23 compared with other second-generation antipsychotics such as risperidone and olanzapine,24,25 although this point remains debatable.26 Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study27). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.
Minimal effective dose achieves maximal response
An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.18,28,29
For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.28 Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.30 When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.29 This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.18
Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.31 Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.34
Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.3 This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.35 Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).36 For both quetiapine and lurasidone, higher doses are generally required to control psychosis.29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.9
Continue to: Clinical implications
Clinical implications
The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.
Related Resource
- Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.
Drug Brand Names
Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon
1. Farde L, Nordström AL, Wiesel FA, et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49(7):538-544.
2. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157(4):514-520.
3. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as antidepressants. Asia Pacific Psychiatry. 2016;8(3):179-188.
4. Quitkin FM, Rabkin JG, Gerald J, et al. Validity of clinical trials of antidepressants. Am J Psychiatry. 2000;157(3):327-337.
5. Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry. 2004;161(5):826-835.
6. Lundberg J, Tiger M, Landén M, et al. Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(8):1167-1172.
7. Takano H, Arakawa R, Nogami T, et al. Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2. Int J Neuropsychopharmacol. 2014;17(4):553-560.
8. Johnson M, Kozielska M, Pilla Reddy V, et al. Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach. Pharm Res. 2014;31(10):2605-2617.
9. Allen MH, Citrome L, Pikalov A, et al. Efficacy of lurasidone in the treatment of agitation: a post hoc analysis of five short-term studies in acutely ill patients with schizophrenia. Gen Hosp Psychiatry. 2017;47:75-82.
10. Sekine M, Maeda J, Shimada H, et al. Central nervous system drug evaluation using positron emission tomography. Clin Psychopharmacol Neurosci. 2011;9(1):9-16.
11. Ma GF, Raivio N, Sabrià J, et al. Agonist and antagonist effects of aripiprazole on D2-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone. Int J Neuropsychopharmacol. 2014;18(4):pii: pyu046. doi: 10.1093/ijnp/pyu046.
12. Yokoi F, Gründer G, Biziere K, et al. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology. 2002;27(2):248-259.
13. Gründer G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974-977.
14. Mamo D, Graff A, Mizrahi R, et al. Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A)receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry. 2007;164(9):1411-1417.
15. Weiden PJ, Preskorn SH, Fahnestock PA, et al. Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a roadmap. J Clin Psychiatry. 2007;68(suppl 7):1-48.
16. Abi-Dargham A, Rodenhiser J, Printz D, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97(14):8104-8109.
17. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63(9):763-771.
18. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60(7):681-690.
19. Cutler AJ, Marcus RN, Hardy SA, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr. 2006;11(9):691-702; quiz 719.
20. Gründer G, Landvogt C, Vernaleken I, et al. The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology. 2006;31(5):1027-1035.
21. Mizuno Y, Bies RR, Remington G, et al. Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(1):182-187.
22. Moriguchi S, Bies RR, Remington G, et al. Estimated dopamine D2 receptor occupancy and remission in schizophrenia: analysis of the CATIE data. J Clin Psychopharmacol. 2013;33(5):682-685.
23. Pilowsky LS, Mulligan RS, Acton PD, et al. Limbic selectivity of clozapine. Lancet. 1997;350(9076):490-491.
24. Ito H, Arakawa R, Takahashi H, et al. No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study. Int J Neuropsychopharmacol. 2009;12(5):667-675.
25. Arakawa R, Ito H, Okumura M, et al. Extrastriatal dopamine D(2) receptor occupancy in olanzapine-treated patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2010;260(4):345-350.
26. Xiberas X, Martinot JL, Mallet L, et al. Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry. 2001;179:503-508.
27. Cutler AJ, Tran-Johnson T, Kalali A, et al. A failed 6-week, randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned. Psychopharmacol Bull. 2010;43(4):37-69.
28. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
29. Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168(9):957-967.
30. Wong DF, Kuwabara H, Brašic JR, et al. Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects. Psychopharmacology (Berl). 2013;229(2):245-252.
31. Potkin SG, Keator DB, Kesler-West ML, et al. D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. CNS Spectr. 2014;19(2):176-181.
32. de Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15-27.
33. de Leon J, Susce MT, Pan RM, et al. A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels. Pharmacopsychiatry. 2007;40(3):93-102.
34. Narahari A, El-Mallakh RS, Kolikonda MK, et al. How coffee and cigarettes can affect the response to psychopharmacotherapy. Current Psychiatry. 2015;14(10):79-80.
35. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360.
36. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
37. Lindenmayer JP, Brown D, Liu S, et al. The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study. Psychopharmacol Bull. 2008;41(3):11-35.
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
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.
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
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.
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
Continue to: The second caveat is...
The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.20 It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by clozapine23 compared with other second-generation antipsychotics such as risperidone and olanzapine,24,25 although this point remains debatable.26 Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study27). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.
Minimal effective dose achieves maximal response
An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.18,28,29
For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.28 Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.30 When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.29 This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.18
Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.31 Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.34
Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.3 This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.35 Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).36 For both quetiapine and lurasidone, higher doses are generally required to control psychosis.29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.9
Continue to: Clinical implications
Clinical implications
The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.
Related Resource
- Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.
Drug Brand Names
Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon
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
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.
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
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.
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
Continue to: The second caveat is...
The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.20 It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by clozapine23 compared with other second-generation antipsychotics such as risperidone and olanzapine,24,25 although this point remains debatable.26 Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study27). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.
Minimal effective dose achieves maximal response
An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.18,28,29
For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.28 Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.30 When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.29 This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.18
Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.31 Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.34
Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.3 This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.35 Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).36 For both quetiapine and lurasidone, higher doses are generally required to control psychosis.29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.9
Continue to: Clinical implications
Clinical implications
The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.
Related Resource
- Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.
Drug Brand Names
Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon
1. Farde L, Nordström AL, Wiesel FA, et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49(7):538-544.
2. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157(4):514-520.
3. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as antidepressants. Asia Pacific Psychiatry. 2016;8(3):179-188.
4. Quitkin FM, Rabkin JG, Gerald J, et al. Validity of clinical trials of antidepressants. Am J Psychiatry. 2000;157(3):327-337.
5. Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry. 2004;161(5):826-835.
6. Lundberg J, Tiger M, Landén M, et al. Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(8):1167-1172.
7. Takano H, Arakawa R, Nogami T, et al. Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2. Int J Neuropsychopharmacol. 2014;17(4):553-560.
8. Johnson M, Kozielska M, Pilla Reddy V, et al. Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach. Pharm Res. 2014;31(10):2605-2617.
9. Allen MH, Citrome L, Pikalov A, et al. Efficacy of lurasidone in the treatment of agitation: a post hoc analysis of five short-term studies in acutely ill patients with schizophrenia. Gen Hosp Psychiatry. 2017;47:75-82.
10. Sekine M, Maeda J, Shimada H, et al. Central nervous system drug evaluation using positron emission tomography. Clin Psychopharmacol Neurosci. 2011;9(1):9-16.
11. Ma GF, Raivio N, Sabrià J, et al. Agonist and antagonist effects of aripiprazole on D2-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone. Int J Neuropsychopharmacol. 2014;18(4):pii: pyu046. doi: 10.1093/ijnp/pyu046.
12. Yokoi F, Gründer G, Biziere K, et al. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology. 2002;27(2):248-259.
13. Gründer G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974-977.
14. Mamo D, Graff A, Mizrahi R, et al. Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A)receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry. 2007;164(9):1411-1417.
15. Weiden PJ, Preskorn SH, Fahnestock PA, et al. Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a roadmap. J Clin Psychiatry. 2007;68(suppl 7):1-48.
16. Abi-Dargham A, Rodenhiser J, Printz D, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97(14):8104-8109.
17. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63(9):763-771.
18. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60(7):681-690.
19. Cutler AJ, Marcus RN, Hardy SA, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr. 2006;11(9):691-702; quiz 719.
20. Gründer G, Landvogt C, Vernaleken I, et al. The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology. 2006;31(5):1027-1035.
21. Mizuno Y, Bies RR, Remington G, et al. Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(1):182-187.
22. Moriguchi S, Bies RR, Remington G, et al. Estimated dopamine D2 receptor occupancy and remission in schizophrenia: analysis of the CATIE data. J Clin Psychopharmacol. 2013;33(5):682-685.
23. Pilowsky LS, Mulligan RS, Acton PD, et al. Limbic selectivity of clozapine. Lancet. 1997;350(9076):490-491.
24. Ito H, Arakawa R, Takahashi H, et al. No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study. Int J Neuropsychopharmacol. 2009;12(5):667-675.
25. Arakawa R, Ito H, Okumura M, et al. Extrastriatal dopamine D(2) receptor occupancy in olanzapine-treated patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2010;260(4):345-350.
26. Xiberas X, Martinot JL, Mallet L, et al. Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry. 2001;179:503-508.
27. Cutler AJ, Tran-Johnson T, Kalali A, et al. A failed 6-week, randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned. Psychopharmacol Bull. 2010;43(4):37-69.
28. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
29. Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168(9):957-967.
30. Wong DF, Kuwabara H, Brašic JR, et al. Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects. Psychopharmacology (Berl). 2013;229(2):245-252.
31. Potkin SG, Keator DB, Kesler-West ML, et al. D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. CNS Spectr. 2014;19(2):176-181.
32. de Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15-27.
33. de Leon J, Susce MT, Pan RM, et al. A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels. Pharmacopsychiatry. 2007;40(3):93-102.
34. Narahari A, El-Mallakh RS, Kolikonda MK, et al. How coffee and cigarettes can affect the response to psychopharmacotherapy. Current Psychiatry. 2015;14(10):79-80.
35. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360.
36. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
37. Lindenmayer JP, Brown D, Liu S, et al. The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study. Psychopharmacol Bull. 2008;41(3):11-35.
1. Farde L, Nordström AL, Wiesel FA, et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49(7):538-544.
2. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157(4):514-520.
3. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as antidepressants. Asia Pacific Psychiatry. 2016;8(3):179-188.
4. Quitkin FM, Rabkin JG, Gerald J, et al. Validity of clinical trials of antidepressants. Am J Psychiatry. 2000;157(3):327-337.
5. Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry. 2004;161(5):826-835.
6. Lundberg J, Tiger M, Landén M, et al. Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(8):1167-1172.
7. Takano H, Arakawa R, Nogami T, et al. Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2. Int J Neuropsychopharmacol. 2014;17(4):553-560.
8. Johnson M, Kozielska M, Pilla Reddy V, et al. Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach. Pharm Res. 2014;31(10):2605-2617.
9. Allen MH, Citrome L, Pikalov A, et al. Efficacy of lurasidone in the treatment of agitation: a post hoc analysis of five short-term studies in acutely ill patients with schizophrenia. Gen Hosp Psychiatry. 2017;47:75-82.
10. Sekine M, Maeda J, Shimada H, et al. Central nervous system drug evaluation using positron emission tomography. Clin Psychopharmacol Neurosci. 2011;9(1):9-16.
11. Ma GF, Raivio N, Sabrià J, et al. Agonist and antagonist effects of aripiprazole on D2-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone. Int J Neuropsychopharmacol. 2014;18(4):pii: pyu046. doi: 10.1093/ijnp/pyu046.
12. Yokoi F, Gründer G, Biziere K, et al. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology. 2002;27(2):248-259.
13. Gründer G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974-977.
14. Mamo D, Graff A, Mizrahi R, et al. Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A)receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry. 2007;164(9):1411-1417.
15. Weiden PJ, Preskorn SH, Fahnestock PA, et al. Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a roadmap. J Clin Psychiatry. 2007;68(suppl 7):1-48.
16. Abi-Dargham A, Rodenhiser J, Printz D, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97(14):8104-8109.
17. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63(9):763-771.
18. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60(7):681-690.
19. Cutler AJ, Marcus RN, Hardy SA, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr. 2006;11(9):691-702; quiz 719.
20. Gründer G, Landvogt C, Vernaleken I, et al. The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology. 2006;31(5):1027-1035.
21. Mizuno Y, Bies RR, Remington G, et al. Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(1):182-187.
22. Moriguchi S, Bies RR, Remington G, et al. Estimated dopamine D2 receptor occupancy and remission in schizophrenia: analysis of the CATIE data. J Clin Psychopharmacol. 2013;33(5):682-685.
23. Pilowsky LS, Mulligan RS, Acton PD, et al. Limbic selectivity of clozapine. Lancet. 1997;350(9076):490-491.
24. Ito H, Arakawa R, Takahashi H, et al. No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study. Int J Neuropsychopharmacol. 2009;12(5):667-675.
25. Arakawa R, Ito H, Okumura M, et al. Extrastriatal dopamine D(2) receptor occupancy in olanzapine-treated patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2010;260(4):345-350.
26. Xiberas X, Martinot JL, Mallet L, et al. Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry. 2001;179:503-508.
27. Cutler AJ, Tran-Johnson T, Kalali A, et al. A failed 6-week, randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned. Psychopharmacol Bull. 2010;43(4):37-69.
28. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
29. Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168(9):957-967.
30. Wong DF, Kuwabara H, Brašic JR, et al. Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects. Psychopharmacology (Berl). 2013;229(2):245-252.
31. Potkin SG, Keator DB, Kesler-West ML, et al. D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. CNS Spectr. 2014;19(2):176-181.
32. de Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15-27.
33. de Leon J, Susce MT, Pan RM, et al. A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels. Pharmacopsychiatry. 2007;40(3):93-102.
34. Narahari A, El-Mallakh RS, Kolikonda MK, et al. How coffee and cigarettes can affect the response to psychopharmacotherapy. Current Psychiatry. 2015;14(10):79-80.
35. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360.
36. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
37. Lindenmayer JP, Brown D, Liu S, et al. The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study. Psychopharmacol Bull. 2008;41(3):11-35.
