Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients

David Pickar, Tung Ping Su, Daniel R. Weinberger, Richard Coppola, Anil K. Malhotra, Michael B. Knable, Kan Sam Lee, Julia Gorey, John J. Bartko, Alan Breier, John Hsiao

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Objective: The objectives of this study were 1) to pursue the question of clozapine's striatal D2 occupancy in relation to its clinical effectiveness; 2) to investigate the relation between schizophrenic symptoms, clozapine blood levels, and estimated D2 occupancy during clinically stable and unstable conditions; and 3) to examine long-term stability in D2 occupancy. Method: Specific binding of the D2 radioligand [123I]benzamide ([123I]IBZM) was studied with single photon emission computed tomography in 13 patients with schizophrenia when they were clinically stable during chronic clozapine treatment, after clozapine dose reduction of ≤50%, and in a subgroup (N=7) after restabilization on clozapine regimens. Clozapine's estimated D2 occupancy was based on comparison with values from drug-free normal subjects. Results: A wide range of estimated D2 occupancies (18% to ≤80%) were associated with sustained, favorable response to clozapine without correlation with residual symptoms. Clozapine blood levels were negatively related to [123I]IBZM specific binding. Acute dose reduction was associated with predicted worsening in positive and negative symptoms and increases in [123I]IBZM specific binding. Independent of clozapine blood level, patients with more symptoms showed lower [123I]IBZM specific binding, consistent with competition of endogenous dopamine for D2 binding sites in patients with greater symptoms. Restabilization on clozapine regimens produced D2 occupancies closely correlated with baseline values. Conclusions: There was no evidence for a critical degree of D2 occupancy required to sustain clozapine's therapeutic effects across subjects. Simple linear regression was the best-fit model for clozapine's D2 occupancy. Longitudinal follow-up suggests stability over time of D2 occupancy in relation to dose and clinical response within individual patients.

Original languageEnglish (US)
Pages (from-to)1571-1578
Number of pages8
JournalAmerican Journal of Psychiatry
Volume153
Issue number12
StatePublished - Dec 1996
Externally publishedYes

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Dopamine D2 Receptors
Clozapine
Corpus Striatum
Therapeutic Uses
Single-Photon Emission-Computed Tomography
Linear Models
Dopamine
Schizophrenia
Binding Sites

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Pickar, D., Su, T. P., Weinberger, D. R., Coppola, R., Malhotra, A. K., Knable, M. B., ... Hsiao, J. (1996). Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients. American Journal of Psychiatry, 153(12), 1571-1578.

Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients. / Pickar, David; Su, Tung Ping; Weinberger, Daniel R.; Coppola, Richard; Malhotra, Anil K.; Knable, Michael B.; Lee, Kan Sam; Gorey, Julia; Bartko, John J.; Breier, Alan; Hsiao, John.

In: American Journal of Psychiatry, Vol. 153, No. 12, 12.1996, p. 1571-1578.

Research output: Contribution to journalArticle

Pickar, D, Su, TP, Weinberger, DR, Coppola, R, Malhotra, AK, Knable, MB, Lee, KS, Gorey, J, Bartko, JJ, Breier, A & Hsiao, J 1996, 'Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients', American Journal of Psychiatry, vol. 153, no. 12, pp. 1571-1578.
Pickar D, Su TP, Weinberger DR, Coppola R, Malhotra AK, Knable MB et al. Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients. American Journal of Psychiatry. 1996 Dec;153(12):1571-1578.
Pickar, David ; Su, Tung Ping ; Weinberger, Daniel R. ; Coppola, Richard ; Malhotra, Anil K. ; Knable, Michael B. ; Lee, Kan Sam ; Gorey, Julia ; Bartko, John J. ; Breier, Alan ; Hsiao, John. / Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients. In: American Journal of Psychiatry. 1996 ; Vol. 153, No. 12. pp. 1571-1578.
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abstract = "Objective: The objectives of this study were 1) to pursue the question of clozapine's striatal D2 occupancy in relation to its clinical effectiveness; 2) to investigate the relation between schizophrenic symptoms, clozapine blood levels, and estimated D2 occupancy during clinically stable and unstable conditions; and 3) to examine long-term stability in D2 occupancy. Method: Specific binding of the D2 radioligand [123I]benzamide ([123I]IBZM) was studied with single photon emission computed tomography in 13 patients with schizophrenia when they were clinically stable during chronic clozapine treatment, after clozapine dose reduction of ≤50{\%}, and in a subgroup (N=7) after restabilization on clozapine regimens. Clozapine's estimated D2 occupancy was based on comparison with values from drug-free normal subjects. Results: A wide range of estimated D2 occupancies (18{\%} to ≤80{\%}) were associated with sustained, favorable response to clozapine without correlation with residual symptoms. Clozapine blood levels were negatively related to [123I]IBZM specific binding. Acute dose reduction was associated with predicted worsening in positive and negative symptoms and increases in [123I]IBZM specific binding. Independent of clozapine blood level, patients with more symptoms showed lower [123I]IBZM specific binding, consistent with competition of endogenous dopamine for D2 binding sites in patients with greater symptoms. Restabilization on clozapine regimens produced D2 occupancies closely correlated with baseline values. Conclusions: There was no evidence for a critical degree of D2 occupancy required to sustain clozapine's therapeutic effects across subjects. Simple linear regression was the best-fit model for clozapine's D2 occupancy. Longitudinal follow-up suggests stability over time of D2 occupancy in relation to dose and clinical response within individual patients.",
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AU - Knable, Michael B.

AU - Lee, Kan Sam

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