Presynaptic Dopamine Capacity in Patients with Treatment-Resistant Schizophrenia Taking Clozapine: An [¹⁸F]DOPA PET Study

Kim, Euitae,Howes, Oliver D,Veronese, Mattia,Beck, Katherine,Seo, Seongho,Park, Jin Woo,Lee, Jae Sung,Lee, Yun-Sang,Kwon, Jun Soo Nature Publishing Group 2017 Neuropsychopharmacology Vol. No.

<P>Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment-resistant schizophrenia The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment-resistant schizophrenia However, in this study, the treatment-resistant patients were highly symptomatic, whereas the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus, we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment-resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls (n = 12), patients treated with clozapine (n = 12) who had not responded to first-line antipsychotics, and patients who had responded to first-line antipsychotics (n = 12) were recruited. Participants were matched for age and sex and symptomatic severity level in patient groups. Participants' dopamine synthesis capacity was measured by using [F-18]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment (Cohen's d=0.9191 (whole striatum), 0.7781 (associative striatum), 1.0344 (limbic striatum), and 1.0189 (sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment-resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.</P>

Calculating Occupancy when One does not have Baseline: A Comparison of Different Options

Kim, Euitae,Howes, Oliver D,Yu, Kyung-Sang,Jeong, Jae Min,Lee, Jae Sung,Jang, In-Jin,Shin, Sang-Goo,Kapur, Shitij,Kwon, Jun Soo SAGE Publications 2011 Journal of cerebral blood flow and metabolism Vol.31 No.8

<P> Dopamine D2 receptor occupancy of antipsychotic drugs is calculated relative to the subject's D2 receptor binding potential (BP) in the drug-free state (baseline BP). Because baseline BP is seldom known in patients with schizophrenia, population means from unrelated control samples are often used to estimate it. However, this is likely to introduce bias and error into the occupancy measure. There is thus a need for a method to reliably estimate baseline BP for patient populations in whom it may be impractical or unethical to get baseline measurements. It has been previously found that the relationship between plasma concentration and dopamine receptor occupancy by antipsychotic drugs follows a sigmoid Emax model. Based on this, we developed a method for calculating dopamine D2 receptor occupancy by antipsychotic drugs using an inhibitory Emax model ( Imax method) that estimates individual baseline BPs. To validate this, we compared the result from the Imax method with actual occupancy and estimated occupancy calculated from the average baseline BP (substitution method). The data for validation were obtained from two different receptor occupancy studies with the antipsychotic medications YKP1358 and aripiprazole. We estimated the reliability between the true measured occupancy and the predicted occupancy using the intraclass correlation coefficient (ICC), and the variability of occupancy was also compared between the Imax and substitution methods. In YKP1358 study, all the ICCs of the Imax method were above 0.8, but those of the substitution method showed values lower than 0.8. In aripiprazole study, the ICCs of the Imax method were higher than those of the substitution method, but all the ICCs showed higher values than 0.8. The variability of Imax method was significantly smaller than that of substitution method in both studies. The Imax method shows better reliability and less variability than the substitution method. The Imax method can be applied for receptor occupancy study, and bring more reliability and accuracy to the occupancy study in patients with schizophrenia. </P>

Predicting Brain Occupancy from Plasma Levels using PET: Superiority of Combining Pharmacokinetics with Pharmacodynamics while Modeling the Relationship

Kim, Euitae,Howes, Oliver D,Kim, Bo-Hyung,Jeong, Jae Min,Lee, Jae Sung,Jang, In-Jin,Shin, Sang-Goo,Turkheimer, Federico E,Kapur, Shitij,Kwon, Jun Soo SAGE Publications 2012 Journal of cerebral blood flow and metabolism Vol.32 No.4

<P> Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic-PD (PK-PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration-occupancy relationship. To determine the effect of time on the concentration-occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [<SUP>11</SUP>C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK-PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration-occupancy relationship and the value of EC50 was different according to the analysis approach ( EC50 derived from PD modeling alone = 11.1 ng/mL (95% confidence interval (CI) = 10.1 to 12.1); while that derived from combined PK-PD modeling = 8.63 ng/mL (95% CI = 7.75 to 9.51)). This finding suggests that PK-PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics. </P>

The Relationship Between Frontostriatal Connectivity and Striatal Dopamine Function in Schizophrenia: An 18F-DOPA PET and Diffusion Tensor Imaging Study in Treatment Responsive and Resistant Patients

신상호,Jung Wi Hoon,Robert McCutcheon,Mattia Veronese,Katherine Beck,Lee Jae Sung,Lee Yun-Sang,Oliver D. Howes,Kim Euitae,Kwon Jun Soo 대한신경정신의학회 2022 PSYCHIATRY INVESTIGATION Vol.19 No.7

Objective Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC).Methods Twenty-four patients with schizophrenia and twelve HC underwent [¹⁸F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant K_i^cer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between K_i^cer and FA in each group were evaluated using Spearman’s rho correlation coefficients.Results Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384).Conclusion Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.