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Brief Report   |    
Subjective Experience and Striatal Dopamine D2 Receptor Occupancy in Patients With Schizophrenia Stabilized by Olanzapine or Risperidone
Lieuwe de Haan, M.D.; Jules Lavalaye, M.D.; Don Linszen, M.D., Ph.D.; Peter M.A.J. Dingemans, Ph.D.; Jan Booij, M.D., Ph.D.
Am J Psychiatry 2000;157:1019-1020. doi:10.1176/appi.ajp.157.6.1019

Abstract

OBJECTIVE: The authors’ goal was to study the relationship between subjective experience during treatment with olanzapine or risperidone and dopamine D2 receptor occupancy in stabilized patients with schizophrenia.METHOD: Subjective experience, psychopathology, and extrapyramidal symptoms were assessed, and D2 receptor occupancy was determined with [123I]iodobenzamide single photon emission computed tomography, in 22 patients whose schizophrenia was stabilized by olanzapine or risperidone.RESULTS: Subjective experience, depression, and negative symptoms were related to dopamine D2 receptor occupancy, but extrapyramidal symptoms were not.CONCLUSIONS: These results provide preliminary evidence that negative subjective experience is related to high D2 receptor occupancy. Longitudinal study is required because this relationship may have implications for dosing strategies.

Abstract Teaser
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The subjective experience of patients treated with antipsychotic medication is related to quality of life (1) and predicts medication compliance (13). Subjectively experienced side effects are more distressing than other side effects (4).

Occupancy of dopamine D2 receptors in the striatum by antipsychotic medication is thought to influence patients’ subjective experiences. The influence of cocaine on the dopamine system has a profound effect on subjective experience (5). The striatum is involved in the control of motivation and reward. Extrapyramidal symptoms are related to D2 receptor occupancy (6), and, in particular, akathisia has an important subjective component.

Olanzapine and risperidone may be associated with a better subjective experience than typical antipsychotic drugs (7, 8). However, if the severity of negative subjective experience is related to D2 receptor occupancy of olanzapine or risperidone, then these agents might not demonstrate more benefits for subjective experience than typical antipsychotic drugs in doses that lead to the same range of D2 receptor occupancy (9).

In this study, we evaluated the relationship between subjective experience and striatal D2 receptor occupancy in patients whose schizophrenia was stabilized by olanzapine or risperidone.

Twenty-one patients with schizophrenia and one patient with schizoaffective disorder, diagnosed according to DSM-IV criteria, were included in the study. Four of the patients were female and 18 were male; their mean age was 22 years (SD=4, range=16–28). Exclusion criteria were neurological or endocrine disease and mental retardation. Nine healthy comparison subjects were also included; their mean age was 24. After a complete description of the study to the subjects, written informed consent was obtained from all.

Patients’ subjective experience during the previous 7 days was measured with the Subjective Well-Being Under Neuroleptic Treatment Scale (1) and the Subjective Deficit Syndrome Scale (10).

Patients’ psychopathology was assessed with the Positive and Negative Syndrome Scale and the Montgomery-Åsberg Depression Rating Scale. Extrapyramidal symptoms and akathisia were assessed with the Simpson-Angus Rating Scale (range=0–40) and the Barnes Rating Scale for Drug-Induced Akathisia, respectively.

Single photon emission computed tomography imaging (SPECT) was performed with a brain-dedicated SPECT camera 2 hours after intravenous injection of 110 MBq of iodobenzamide ([123I]]IBZM). Specifications and imaging procedures have been described elsewhere (11). SPECT imaging was performed after a stable dose period of at least 6 weeks of olanzapine (N=15, mean dose=14.7 mg, SD=5.8, range=5–30) or risperidone (N=7, mean dose=4.1 mg, SD=0.9, range=3–6).

Subjective experience, psychopathology, and extrapyramidal symptoms were assessed within 2 days after SPECT imaging. None of the patients used alcohol, cannabis, or other nonprescribed drugs. Patients were blind to the main goal of this study, i.e., assessment of the relationship between medication and subjective experience.

Semiquantification of [123I]IBZM binding was performed by placing a template of fixed regions of interest over the striatum and occipital cortex (12). Specific striatal binding was defined as striatal binding divided by occipital binding (12). All analyses were performed blind to clinical data. The nine healthy comparison subjects had a mean [123I]IBZM binding ratio of 1.92 (SD=0.08), which was used to calculate the percentage of occupancy by medication as (ratio striatum/occipital region) – 1/(1.92 – 1)×(–100) + 100 (11).

We conducted one-tailed analyses because we hypothesized that high D2 receptor occupancy was related to worse subjective experience. Analyses were performed for the total group of patients (N=22) and for the group receiving olanzapine (N=15). Analyses for the subgroup using risperidone were not performed because there was minimal variation of doses in this group.

Both self-control and emotional regulation items on the Subjective Well-Being Under Neuroleptic Treatment Scale correlated with the percentage of D2 receptor occupancy (t1). Positive and Negative Syndrome Scale negative symptom ratings and Montgomery-Åsberg Depression Rating Scale scores also correlated with D2 receptor occupancy (t1). Other Positive and Negative Syndrome Scale subscale ratings were not significantly correlated with D2 receptor occupancy.

Simpson-Angus ratings were zero in most patients, but two patients each had a total score of 3 and two patients each had a total score of 4. Six patients had a score of 2 on the Barnes scale. Extrapyramidal symptoms were not correlated with percentage of D2 receptor occupancy.

In the subgroup of patients using olanzapine, a significant correlation was found between D2 receptor occupancy percentages and the Subjective Well-Being Under Neuroleptic Treatment Scale self-control score (rs=–0.53, N=15, p=0.02) and the Subjective Deficit Syndrome Scale total score (rs=0.45, N=15, p=0.05). Olanzapine dose correlated with D2 receptor occupancy (rs=0.60, N=15, p=0.01).

The average D2 receptor occupancy was 67% in the olanzapine group and 77% in the risperidone group. The correlations found would not have reached statistical significance if they had been corrected for multiple comparisons by the Bonferroni test.

We found a correlation between striatal D2 receptor occupancy by olanzapine and risperidone and subjective experience, negative symptoms, and depression, in the absence of extrapyramidal symptoms. Higher doses of olanzapine were correlated with higher D2 receptor occupancy and worse subjective experience. Negative subjective experience might be more sensitive to D2 receptor occupancy than extrapyramidal symptoms. The substantial D2 receptor occupancy of olanzapine and risperidone we found is in agreement with the recent findings of others (9).

Our study design permitted assessment only of correlations between subjective experience and D2 receptor occupancy. Therefore, a longitudinal study is required to confirm these results, since a relationship between higher D2 receptor occupancy and worse subjective experience may have important implications for dosing strategies and compliance with antipsychotic medication.

 

Received April 26, 1999; revision received Nov. 12, 1999; accepted Nov. 17, 1999. From the Department of Psychiatry, Academic Medical Center, University of Amsterdam. Address reprint requests to Dr. de Haan, Academic Medical Center, University of Amsterdam, Department of Psychiatry, Postbox 22700 1100 DE, Amsterdam, the Netherlands; l.dehaan@amc.uva.nl (e-mail). Supported by grant 28-1241 from the Dutch Health Research and Development Council.

Naber D: A self-rating to measure subjective effects of neuroleptic drugs: relationships to objective psychopathology, quality of life, compliance and other clinical variables. Int Clin Psychopharmacol  1995; 10:133–138
[PubMed]
 
van Putten T, May PRA, Marder SR: Subjective response to antipsychotic drugs. Arch Gen Psychiatry  1981; 38:187–190
[PubMed]
 
Hogan TP, Awad AG, Eastwood R: A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med  1983; 13:177–183
[PubMed]
[CrossRef]
 
Buis W: Patients’ opinions concerning side effects of depot neuroleptics (letter). Am J Psychiatry  1992; 149:844–845
 
Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R, Shea CE: Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature  1997; 386:827–830
[PubMed]
[CrossRef]
 
Farde L, Nordstr�L, Wiesel FA, Pauli S, Halldin C, Sedvall G: Positron emission tomographic analysis of central D2 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry  1992; 49:538–544
[PubMed]
 
Tollefson GD, Sanger TM, Lu Y, Thieme ME: Depressive signs and symptoms in schizophrenia. Arch Gen Psychiatry  1998; 55:250–258
[PubMed]
[CrossRef]
 
Franz M, Lis S, Pl�nn K, Gallhofer B: Conventional versus atypical neuroleptics: subjective quality of life in schizophrenic patients. Br J Psychiatry  1997; 170:422–425
[PubMed]
[CrossRef]
 
Kapur S, Zipursky RB, Remington G: Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry  1999; 156:286–293
[PubMed]
 
Jaeger J, Bitter I, Czobor P, Volavka J: The measurement of subjective experience in schizophrenia: the Subjective Deficit Syndrome Scale. Compr Psychiatry  1990; 31:216–226
[PubMed]
[CrossRef]
 
K�e B, Br�, Topitz-Schratzenberger A, Tauscher J, Gossler R, Vesely C, Asenbaum S, Podreka I, Kasper S: Striatal dopamine-2 receptor occupancy in psychotic patients treated with risperidone. Psychiatry Res  1996; 68:23–30
[PubMed]
[CrossRef]
 
Verhoeff NP, Kapucu O, Sokole-Busemann E, Van Royen EA, Janssen AG: Estimation of dopamine D2 receptor binding potential in striatum with iodine-123-IBZM SPECT: technical and interobserver variability. J Nucl Med 1993; 34:2076–  2084
 
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References

Naber D: A self-rating to measure subjective effects of neuroleptic drugs: relationships to objective psychopathology, quality of life, compliance and other clinical variables. Int Clin Psychopharmacol  1995; 10:133–138
[PubMed]
 
van Putten T, May PRA, Marder SR: Subjective response to antipsychotic drugs. Arch Gen Psychiatry  1981; 38:187–190
[PubMed]
 
Hogan TP, Awad AG, Eastwood R: A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med  1983; 13:177–183
[PubMed]
[CrossRef]
 
Buis W: Patients’ opinions concerning side effects of depot neuroleptics (letter). Am J Psychiatry  1992; 149:844–845
 
Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R, Shea CE: Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature  1997; 386:827–830
[PubMed]
[CrossRef]
 
Farde L, Nordstr�L, Wiesel FA, Pauli S, Halldin C, Sedvall G: Positron emission tomographic analysis of central D2 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry  1992; 49:538–544
[PubMed]
 
Tollefson GD, Sanger TM, Lu Y, Thieme ME: Depressive signs and symptoms in schizophrenia. Arch Gen Psychiatry  1998; 55:250–258
[PubMed]
[CrossRef]
 
Franz M, Lis S, Pl�nn K, Gallhofer B: Conventional versus atypical neuroleptics: subjective quality of life in schizophrenic patients. Br J Psychiatry  1997; 170:422–425
[PubMed]
[CrossRef]
 
Kapur S, Zipursky RB, Remington G: Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry  1999; 156:286–293
[PubMed]
 
Jaeger J, Bitter I, Czobor P, Volavka J: The measurement of subjective experience in schizophrenia: the Subjective Deficit Syndrome Scale. Compr Psychiatry  1990; 31:216–226
[PubMed]
[CrossRef]
 
K�e B, Br�, Topitz-Schratzenberger A, Tauscher J, Gossler R, Vesely C, Asenbaum S, Podreka I, Kasper S: Striatal dopamine-2 receptor occupancy in psychotic patients treated with risperidone. Psychiatry Res  1996; 68:23–30
[PubMed]
[CrossRef]
 
Verhoeff NP, Kapucu O, Sokole-Busemann E, Van Royen EA, Janssen AG: Estimation of dopamine D2 receptor binding potential in striatum with iodine-123-IBZM SPECT: technical and interobserver variability. J Nucl Med 1993; 34:2076–  2084
 
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