Abstract
Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.
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INTRODUCTION
Clozapine and quetiapine are atypical antipsychotic drugs (APDs) (Meltzer, 1992; Arvanitis and Miller, 1997; Kane et al, 2001; Davis et al, 2003), which have equivalent and sometimes superior antipsychotic effects to those seen with typical APDs. They produce significantly lower levels of striatal dopamine D2 receptor (DA D2r) occupancy compared to typical APDs at comparable clinical doses (Nordstrom et al, 1993; Kapur et al, 1996; Farde et al, 1994; Gefvert et al, 1998). The lesser occupancy of striatal DA D2r is believed to be responsible at least in part for the low incidence of extrapyramidal side effects (EPS) seen with these drugs. Studies of cfos (Robertson et al, 1994; Robertson and Fibiger, 1992), chronic deltafosB induction (Vahid-Ansari et al, 1996), cortical DA D2r (Janowsky et al, 1992; Florijn et al, 1997), cortical DA D2r mRNA (Damask et al, 1996; Lidow and Goldman-Rakic, 1997), and regional DA release (Yamamoto and Cooperman, 1994; Youngren et al, 1999; Kuroki et al, 1999; Ichikawa et al, 2002) suggest that the atypical profile of clozapine and quetiapine may be mediated by preferential effects on mesocortical and mesolimbic vs nigrostriatal dopaminergic projections. Chronic treatment with clozapine and quetiapine produces depolarization inactivation of ventral tegmental dopaminergic neurons, sparing those in the substantia nigra, whereas haloperidol inactivates both (Chiodo and Bunney, 1983; Goldstein et al, 1993). Whereas clozapine and quetiapine bind to multiple cerebral neurotransmitter receptors (Schotte et al, 1996), the above studies suggest that the atypical profile of these drugs may be mediated, at least in part, by preferential effects on DA D2r-mediated neurotransmission in cortex and limbic regions, compared to the dorsal striatum.
Some but not all imaging studies of occupancy of extrastriatal DA D2r by clozapine and quetiapine report preferential occupancy of cortical DA D2r compared to striatal DA D2r, consistent with the hypothesis that the therapeutic effects of these drugs are mediated by cortical and/or limbic DA D2r. There have been four studies comparing the occupancy of extrastriatal DA D2r by clozapine to typical APDs (Pilowsky et al, 1997; Talvik et al, 2001; Xiberas et al, 2000; Grunder et al, 2006) that have produced conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r and a single study of the occupancy of extrastriatal DA D2r by quetiapine that reported preferential occupancy of cortical DA D2r (Stephenson et al, 2000). The studies of clozapine's occupancy of extrastriatal DA D2r from Pilowsky et al, Talvik et al, and Xiberas et al have been criticized on methodological grounds (Kessler and Meltzer, 2002; Olsson and Farde, 2001; Erlandsson et al, 2003). Grunder's recent study utilized normal control subjects to compute regional occupancies in schizophrenic subjects; this may bias the results, as a number of studies have reported decreased DA D2r levels in the thalamus and temporal cortex in schizophrenics (Talvik et al, 2003; Yasuno et al, 2004; Tuppurainen et al, 2003; Buchsbaum et al, 2004). The quetiapine study (Stephenson et al, 2000) used the same methodology criticized by Olsson (Olsson and Farde, 2001). In a study of olanzapine-treated schizophrenic patients, we have reported no preferential occupancy of cortical DA D2r but sparing of nigral DA D2r occupancy using the same methods utilized here (Kessler et al, 2005).
To evaluate whether clozapine and/or quetiapine produce preferential or nonuniform occupancy of DA D2r in extrastriatal regions, we used PET with [18F]fallypride (Kessler et al, 2000; Mukherjee et al, 2002) to measure the levels of DA D2r occupancy in putamen, ventral striatum, thalamus, amygdala, temporal cortex, and substantia nigra in schizophrenic subjects who were treated with either clozapine or quetiapine monotherapy. [18F]Fallypride is a high-affinity radioligand for DA D2 and D3 receptors that can be used to quantitate levels of DA D2/3r in man in both striatal and extrastriatal regions with a single tracer injection. The results of this study have been previously communicated in an abstract (Kessler et al, 2002).
METHODS
Subjects
This study was conducted under protocols approved by the Vanderbilt University and Centerstone Mental Health Center Institutional Review Boards. All subjects provided informed consent for this study. Subjects meeting the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM IV) (American Psychiatric Association, 1994) criteria, and Research Diagnostic Criteria (Andreasen et al, 1977) for the diagnosis of schizophrenia without a history of significant medical illness or trauma between the ages of 18 and 50 were recruited. Subjects were evaluated using the Brief Psychiatric Rating Scale (BPRS). All subjects were judged capable of giving informed consent by a senior research psychiatrist and provided informed consent for this study. The diagnosis of schizophrenia was established by the Structured Clinical Interview for DSM IV Axis I disorders (SCID-I) (First et al, 1996) and checklist; significant medical conditions and substance abuse other than nicotine use were criteria for exclusion. All subjects had a medical history and physical examination, complete blood count with differential, plasma electrolytes, glucose, blood urea nitrogen, creatinine, calcium, total protein, albumin, bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, cholesterol, triglyceride, and uric acid determinations, a urine analysis, and urine drug screen. Subjects participating in this study were either never treated or were off medication for at least 3 weeks (N=10, five male, five female; mean age of 31.8±8.5 (SD) years and age range of 20–45 years), or chronically treated with clozapine monotherapy (N=6, four male, two female; mean age of 31.8±10.2 (SD) years and age range of 18–46 years) or quetiapine monotherapy (N=7, four male, three female; mean age of 37.9±7.5 (SD) years and age range of 22–45 years). Four of the off-medication subjects were never treated with any APD. Treated subjects had their doses determined using open dosing to achieve optimal therapeutic effects and had been treated for a minimum of 6 months at the time of the PET study. EPS were assessed using the AIMS (Fann et al, 1977) and were minimal in both clozapine- and quetiapine-treated subjects (identical mean ratings of 0.40±0.89, range 0–2.0 for each group). Clozapine-treated subjects were studied approximately 14–15 h after their last daily dose, that is, 250 mg (N=1), 450 mg (N=2), 500 mg (N=1), 700 mg (N=1), or 900 mg (N=1). Quetiapine-treated subjects were studied 2 h following the last oral dose, that is, 200 mg (N=3), 350 mg (N=1), 400 mg (N=2), or 700 mg (N=1), owing to transient occupancy of cerebral DA D2r by quetiapine (Kapur et al, 2000).
Data Acquisition and Analysis
An MRI of the brain was performed using a GE 1.5 T Signa LXi echo-speed MRI scanner. Acquisitions included thin section high-resolution T1-weighted gradient echo acquisitions (IR prepared FSPGR, 512 × 224 matrix, TE=1.8, TR=10–13, IR=400) in the sagittal plane (1.3 mm thick slices) and coronal planes (1.4–1.5 mm thick slices); axial spin density weighted (fast spin echo, TE=19, TR=5,000, 3 mm thick slices) and T2-weighted (fast spin echo, TE=102, TR=5000, 3 mm thick slices) acquisitions were obtained as well. PET scans were performed using a GE Advance PET scanner in the 3-D acquisition mode. [18F]Fallypride (4–5 mCi, specific activity >2000 Ci/mmol) was injected intravenously over a 20 s period and serial scans of increasing duration were obtained from 180 to 240 min, depending on the medication status of the subject; unmedicated subjects were scanned for 240 min, whereas medicated subjects were scanned for 180–240 min depending on the residual counts. A measured attenuation correction was utilized for all scans. All female subjects had a plasma beta HCG determination performed within the 24 h preceding the PET study.
Serial PET scans were coregistered to each other using a rigid-body mutual information algorithm (Maes et al, 1997; Wells et al, 1996). Both PET and MRI scans were interpolated to a 256 × 256 × 256 matrix, coregistered using the same rigid-body mutual information algorithm, and reoriented to the ACPC line. Regions of interest were identified on the IR prepared SPGR thin section T1-weighted MRI images, and automatically transferred to the coregistered PET studies. The putamen and thalamus were manually drawn by a neuroradiologist with considerable PET experience (RMK) on multiple axial slices from 2 to 12 mm above the ACPC line. The ventral striatum was defined using the criteria of Mawlawi et al (2001). The substantia nigra can be stereotactically localized in the ventral midbrain 9–14 mm below the ACPC line (Schaltenbrand and Wahren, 1977) and can be easily visualized in the midbrain on PET [18F]fallypride scans (see Figure 2). The amygdala can be easily visualized in the anteromedial temporal lobe on MRI scans just anterior to the tip of the temporal horn of the lateral ventricle and deep to the uncus (Kessler et al, 2005); stereotactically, the amygdala is localized approximately 6–20 mm below the ACPC line, from 12 to 28 mm lateral to the midline, and from 2 to 12 mm behind the plane of the anterior commissure (Schaltenbrand and Wahren, 1977). To decrease partial voluming from the striatum, regions of interest for the amygdala were drawn on the MRI images from 10 to 16 mm below the plane of the ACPC. Regions of interest for the temporal cortex were manually drawn on axial MRI images from 35 to 25 mm below the ACPC. Our previous studies have shown excellent inter-subject reliability for these regions of interest, that is, inter-subject coefficients of variation of 6.8–15.9% (Riccardi et al, 2005). Regional levels of DA D2r were estimated using the reference region method with the cerebellum used as the reference region (Lammertsma et al, 1996). We and others have shown that the cerebellum is an appropriate reference region (Kessler et al, 2000, 2005; Grunder et al, 2006; Siessmeier et al, 2005) and that reference region method estimates of binding potentials are highly correlated with (r>0.99) and not statistically different from those obtained using modeled estimates with a metabolite corrected plasma input function (Kessler et al, 2000, 2005; Siessmeier et al, 2005).
Statistical Analysis
The regional occupancies of DA D2r were calculated using the appropriate regional mean value for off-medication schizophrenic subjects as follows:
where DA D2ri represents the available level of DA D2r in region ‘i’ in the indicated state. To evaluate whether clozapine and/or quetiapine produced selective and/or nonuniform occupancy of DA D2r in extrastriatal brain regions compared to that in the putamen, an analysis of variance for regional DA D2r occupancy with region as a factor and covaried for putamenal occupancy was performed. Bonferroni corrections were used to adjust significance levels for multiple comparisons. Correlations of DA D2r occupancy in the substantia nigra with other brain regions were performed using Pearson product moment correlations.
RESULTS
Individual and mean regional levels of DA D2r occupancy for clozapine and quetiapine are shown in Table 1 and Figure 1. An analysis of variance for DA D2r occupancy with region as a factor and covaried for putamenal occupancy was performed for clozapine-treated subjects to determine whether there was preferential or nonuniform occupancy in extrastriatal regions in comparison to the putamen. DA D2r occupancy for the temporal cortex, 59.8%, was significantly higher than that seen in the putamen, 47.8% (p=0.0033 uncorrected for multiple comparisons, p=0.05 corrected for multiple comparisons). DA D2r occupancy in the substantia nigra was significantly lower than in all other regions sampled (p=0.0001 uncorrected for multiple comparisons, p=0.0015 corrected for all multiple comparisons). Mean DA D2r occupancy was 18.4% in the substantia nigra vs 47.8% in the putamen for clozapine-treated subjects. No other region demonstrated a significantly lower occupancy compared to the putamen. These results are illustrated in Figure 2 as well as in the time activity curves shown in Figure 3, and suggest that at clinically therapeutic doses, clozapine produces preferential occupancy of temporal cortical DA D2r and spares occupancy of substantia nigra receptors in comparison to that seen in the putamen.
An analysis of variance for DA D2r occupancy in quetiapine-treated subjects was performed using region as a factor and covaried for putamenal occupancy. The results demonstrated significantly higher DA D2r occupancy in the temporal cortex, 46.9%, than in the putamen, 33.5% (p=0.002, uncorrected for multiple comparisons, p=0.03 corrected for multiple comparisons). Unlike clozapine, no significant difference in occupancy was found between the substantia nigra and the putamen. Mean DA D2r occupancy in the substantia nigra was 34.3%, whereas that in the putamen was 33.5%. No other regions showed a significant difference with the putamen after correction for multiple comparisons. Quetiapine appeared to produce preferential occupancy of temporal cortical DA D2r in comparison to that in the putamen, as demonstrated in Table 1 and Figure 1.
Given the difference between clozapine and quetiapine in sparing DA D2r occupancy in the substantia nigra, the relationships of DA D2r occupancies in the substantia nigra to other brain regions were examined for each drug using inter-regional correlations (Table 2). Occupancies in the substantia nigra were not significantly correlated with occupancies in other brain regions for clozapine-treated subjects; correlation coefficients ranged from 0.17 to 0.37. For quetiapine-treated subjects, occupancy in the substantia nigra was significantly correlated with occupancy in all other regions except for the temporal cortex; correlation coefficients ranged from 0.81 to 0.95 for the putamen, ventral striatum, thalamus, and amygdala, but fell to 0.52 for the temporal cortex (see Table 2). These findings suggest that clozapine produces occupancy of nigral DA D2r in a manner different from that in other brain regions. In quetiapine-treated subjects, nigral occupancy appears to be regulated similarly to that in most other brain regions.
Comparing mean regional occupancies for quetiapine-treated subjects to those seen in clozapine-treated subjects reveals that, except for the substantia nigra, occupancies were lower in quetiapine-treated subjects. For subjects receiving 200–350 mg single doses of quetiapine, the mean DA D2r occupancies were 22.4 and 40.2% in the putamen and temporal cortex respectively, whereas at doses of 400–700 mg mean occupancies were 48.2 and 55.8%, respectively—similar to the occupancies seen in clozapine-treated subjects, that is, 47.8 and 59.8%, respectively. These data suggest that for quetiapine to achieve occupancies in striatum and cortex comparable to those seen with clozapine, single doses of 400 mg or greater may be required. The total BPRS scores were 11.8±10.9 in clozapine-treated subjects and 16.6±7.9 in quetiapine-treated subjects; this difference was not significant for the groups studied. Subjects treated with higher doses of quetiapine, 400–700 mg, had lower total BPRS scores than subjects treated with lower doses, 200–350 mg, being 13.7 vs 18.8; this difference was not significant in this small sample.
DISCUSSION
The major findings of this study are (1) that both clozapine and quetiapine produce higher, that is, preferential, occupancy of temporal cortical DA D2r in comparison to putamenal DA D2r occupancy; (2) that clozapine but not quetiapine produces significantly lower DA D2r occupancy in the substantia nigra compared to all other regions examined, that is, sparing of nigral DA D2r occupancy; and (3) that both clozapine and quetiapine produce significant therapeutic effects at DA D2r occupancies in all regions examined less than the 65–70% threshold seen with typical APDs (Nordstrom et al, 1993; Kapur et al, 1996). The putamenal occupancies reported in this study for clozapine and quetiapine are similar to those reported for [11C]raclopride PET studies of DA D2r occupancy (Farde et al, 1994; Gefvert et al, 1998; Tauscher-Wisniewski et al, 2002).
Preferential occupancy of temporal cortical vs striatal DA D2r has been suggested as a mechanism by which clozapine achieves an atypical profile of APD effects (Pilowsky et al, 1997; Grunder et al, 2006).
As discussed above, the issue of whether clozapine and/or quetiapine produces preferential occupancy of cortical DA D2r has been an area of disagreement in the literature (Pilowsky et al, 1997; Xiberas et al, 2000; Grunder et al, 2006; Stephenson et al, 2000; Talvik et al, 2001); previous studies may be criticized on methodological grounds (Kessler and Meltzer, 2002; Olsson and Farde, 2001; Erlandsson et al, 2003; Yasuno et al, 2004; Tuppurainen et al, 2003; Buchsbaum et al, 2004). The results of the current study indicate that both clozapine and quetiapine produce preferential occupancy of temporal cortical DA D2r. The one study that did not report preferential occupancy of temporal cortical receptors by clozapine (Talvik et al, 2001) has been criticized because of the use of two different radioligands, that is, [11C]raclopride to estimate striatal and [11C]FLB457 to estimate cortical DA D2r occupancies, and possible effects of low levels of cerebellar DA D2r on estimates of cortical occupancy (Kessler and Meltzer, 2002). Occupancies were calculated using the simplified reference region method (Gunn et al, 1997). The results showed that clozapine produced similar DA D2r occupancies in cortex and striatum, that is, 42.5% in cortex and 43.3% in striatum. Haloperidol produced a mean occupancy of 80.7% in striatum and 61.7% in cortical regions. Although the authors did not report this difference in striatal vs cortical occupancy to be significant for haloperidol, reanalysis of this data shows a significant difference; haloperidol appears to preferentially occupy striatal DA D2r (Kessler and Meltzer, 2002). This is contrary to our previous results using a single radioligand, [18F]fallypride, which reported similar DA D2r occupancies in the putamen and temporal cortex for haloperidol (Kessler et al, 2005). Although both [11C]FLB457 and [11C]raclopride are benzamides, differences in radioligands may result in different apparent levels of receptor occupancy. Estimates of striatal receptor DA D2r occupancy obtained using [11C]raclopride with the simplified reference region method are well validated (Lammertsma et al, 1996; Lammertsma and Hume, 1996). The presence of low levels of DA D2r in the cerebellum (Delforge et al, 2001; Olsson et al, 1999) causes an underestimation of the level of occupancy, particularly in cortical regions, when using [11C]FLB457 with the simplified reference region method (Christian et al, 2004; Olsson et al, 2004); this underestimation is greater at lower occupancies such as are seen with clozapine and quetiapine. An underestimation of cortical DA D2r occupancies could account for both the failure to observe preferential occupancy of cortical DA D2r by clozapine and the unexpected lower occupancy of cortical DA D2r seen with haloperidol. The difference between studies using [18F]fallypride and Talvik et al's study may be related to the use of two different radioligands to estimate striatal and cortical DA D2r occupancies. In the present study, we utilized [18F]fallypride and employed the reference region method (Lammertsma et al, 1996) similar to the study of Talvik et al (2001). The use of a single tracer capable of quantitating receptor occupancies in striatum and extrastriatal regions circumvents the potential confounds associated with the use of two radioligands. Although the use of the reference region method with [18F]fallypride may also be criticized because of the presence of low levels of cerebellar DA D2r (Gunn et al, 1997), the level of specific [18F]fallypride binding in the cerebellar reference region is low enough, about 3%, not to significantly bias the estimates of regional DA D2r occupancy (Kessler et al, 2000, 2005; Siessmeier et al, 2005).
The [123I]epidepride SPECT studies of clozapine and quetiapine (Pilowsky et al, 1997; Stephenson et al, 2000) have been criticized because of the use of a ratio method before the attainment of a transient equilibrium in striatum, which could lead to underestimation of striatal DA D2r receptor occupancy (Olsson and Farde, 2001). This underestimation is greater for regions with higher receptor levels and could spuriously produce an apparent pattern of preferential occupancy of cortical DA D2r owing to underestimation of striatal DA D2r occupancy. Modeling studies of [123I]epidepride have produced conflicting results regarding whether the 3–4 h period used for measurement of temporal cortical–cerebellar ratios by Pilowsky et al (1997) and Stephenson et al (2000) permits accurate estimation of receptor levels in this region (Fujita et al, 1999; Erlandsson et al, 2003). Xiberas et al (2000), using PET with [76Br]FLB457, have reported greater occupancy of temporal cortical than striatal DA D2r by clozapine and olanzapine using a ratio measure. Xiberas et al reported that 10–20 mg doses of olanzapine produced an apparent striatal DA D2r occupancy of 44%; other studies report a 70–80% striatal occupancy and no preferential occupancy of temporal cortical DA D2r with these doses of olanzapine (Kessler et al, 2005; Nordstrom et al, 1998; Kapur et al, 1998). This underestimation of striatal DA D2r occupancy is consistent with the use of a ratio measure before attainment of a transient equilibrium. In the current study, subjects were scanned for at least 3 h, which is sufficient to produce stable estimates of DA D2r binding potentials in all brain regions with [18F]fallypride (Kessler et al, 2000, 2005; Siessmeier et al, 2005).
As noted above, Grunder et al (2006) used normal subjects to calculate temporal cortical DA D2r occupancies in clozapine-treated schizophrenic subjects. Three (Yasuno et al, 2004; Tuppurainen et al, 2003; Buchsbaum et al, 2004) of the four (Talvik et al, 2003; Yasuno et al, 2004; Tuppurainen et al, 2003; Buchsbaum et al, 2004) previously reported studies of extrastriatal DA D2r levels in unmedicated schizophrenic subjects have reported lower levels of DA D2r in the temporal cortex compared to normal subjects and this difference achieved significance in two of these studies (Tuppurainen et al, 2003; Buchsbaum et al, 2004). Lower levels of temporal cortical DA D2r in schizophrenic subjects could artifactually produce the appearance of preferential occupancy of temporal cortical DA D2r by clozapine. To avoid this potential confound, receptor occupancies in this study were calculated using regional levels of DA D2r in off-medication schizophrenic subjects. Using off-medication schizophrenic subjects as controls does raise the issue of treatment effects. Although a comparison of the off-medication schizophrenic subjects used in this study to age-matched normal controls is the subject of a separate manuscript in preparation, the mean putamenal binding potentials were nearly identical for the 10 off-medication schizophrenic and 10 age-matched normal control subjects, that is, 36.08±4.53 vs 37.34±2.53, consistent with previous studies (Farde et al, 1990; Hietala et al, 1994), and showing no medication effects.
There are a number of possible mechanisms by which clozapine and quetiapine may produce preferential occupancy of cortical DA D2r. These include the higher fraction of DA D2sr in cortex than striatum (Khan et al, 1998), the greater release of DA by clozapine in cortex than striatum (Yamamoto and Cooperman, 1994; Youngren et al, 1999; Kuroki et al, 1999), differences in modes and level of cortical vs striatal dopaminergic neurotransmission (Garris and Wightman, 1994), and differential upregulation of cortical vs striatal DA D2r by clozapine (Damask et al, 1996; Lidow and Goldman-Rakic, 1997). Although there is a higher fraction of DA D2sr in cortex than striatum (Khan et al, 1998), the relative affinities of clozapine, olanzapine, and haloperidol for the DA D2s vs D2L receptors are similar (Schotte et al, 1996); as olanzapine and haloperidol do not produce preferential cortical occupancy, it is unlikely that this could explain clozapine's preferential cortical DA D2r occupancy (Kessler et al, 2005). Similarly, it has been shown that [18F]fallypride has similar in vivo affinity for the DA D2r in striatum and extrastriatal regions (Slifstein et al, 2004). In primate studies, acute clozapine administration produces a 225% increase in cortical DA release and a 170% increase in striatal DA release (Youngren et al, 1999; Kuroki et al, 1999). Chronic clozapine administration elevates cortical extracellular DA levels by 74%, but produces no significant change in striatum (Yamamoto and Cooperman, 1994). Given the large increase in striatal DA release, 44%, needed to produce a 1% decrease in striatal [11C]raclopride binding potential (Breier et al, 1997), it is unlikely that clozapine-induced DA release could lead to the preferential occupancy seen with clozapine or quetiapine. As noted above, chronic clozapine administration upregulates DA D2r binding in cortex but not in striatum (Janowsky et al, 1992; Florijn et al, 1997). Higher levels of cortical DA D2r with chronic clozapine therapy would produce spuriously low levels of cortical DA D2r occupancy compared to striatum. Differential upregulation of cerebral DA D2r does not explain the preferential occupancy of cortical DA D2r seen with clozapine.
The difference in modes and levels of dopaminergic neurotransmission in striatum vs cortex is another potential explanation (Garris and Wightman, 1994) for the preferential cortical DA D2r occupancy observed with clozapine and quetiapine. Both of these atypical APDs have a low affinity for the DA D2r (Schotte et al, 1996). Studies of striatal DA D2r indicate that, although a significant fraction are extrasynaptic, the majority of striatal DA D2r are located at synapses (Levey et al, 1993; Descarries et al, 1996). In the cortex, dopaminergic neurotransmission appears to be largely extrasynaptic or a volume mode (Garris and Wightman, 1994; Smiley et al, 1994; Sesack et al, 1998). In striatum, synaptic DA D2r will be exposed to transiently high levels of DA during phasic firing; this has been measured as high as 250 nM in the vicinity of the synapse and estimated to be 1.6 μM within the synapse (Kawagoe et al, 1992; Venton et al, 2003; Garris et al, 1994). Between phasic firing of DA neurons, the level of tonic extracellular DA is 10-fold higher in striatum than cortex (Yamamoto and Cooperman, 1994; Youngren et al, 1999). APDs with high affinity for the DA D2r such as haloperidol will compete more effectively with the high levels of extracellular striatal DA than low-affinity APDs such as clozapine and quetiapine (Schotte et al, 1996). In the cortex where DA D2r are exposed to much lower levels of extracellular DA owing to both the lower extracellular levels of DA and the volume mode of neurotransmission, the affinity of the APD has less effect on occupancy of the DA D2r. This may be one mechanism by which an atypical profile is achieved and is consistent with previous studies relating an atypical profile to low affinity for the DA D2r (Meltzer et al, 1989; Roth et al, 1995; Seeman and Tallerico, 1998).
In regard to the finding of sparing of nigral DA D2r occupancy by clozapine, the results of the current study differ from those reported by Grunder et al (2006). This difference is likely owing to differences in resolution and partial voluming in these two studies. The substantia nigra is a small structure, which is sensitive to partial volume effects (Kessler et al, 1984). Grunder's study utilized stereotactic normalizations of parametric DA D2r images that were smoothed to a resolution of 12 mm. Regions of interest were then located using a template. Images with 12 mm resolution do not allow adequate quantitation of the substantia nigra, as ideally a resolution of 4 mm or higher is needed to completely quantify the substantia nigra (Kessler et al, 1984). In the current study, the resolution at the center of the field of view where the substantia nigra is located was about 5 mm and regions of interest were delineated on individual coregistered high-resolution MRI studies and transferred to coregistered PET studies. As can be seen in Figure 2, there is good visualization of the substantia nigra in the current study. Although some loss of quantitation likely occurs in the current study, a partial volume correction was not used, as the exact borders of the substantia nigra are not well defined on high-resolution T1-weighted MRI scans. The identifiability of DA D2r levels in this structure when using a PET scanner with high resolution is supported by a number of observations, that is, low mean test–retest error of DA D2r levels for this structure–5.2% (Mukherjee et al, 2002) the high inter-subject reliability for the substantia nigra we have reported in normal subjects–an 8% coefficient of variation across subjects (Riccardi et al, 2006), and the high correlation between PET [18F]fallypride binding potentials in extrastriatal regions of human brain, including the substantia nigra, with quantitative autoradiographic measurements of DA D2r levels in post-mortem human brain (Rieck et al, 2004). The sensitivity of DA D2r occupancy measurements for the substantia nigra is demonstrated by the differences in occupancies seen for clozapine and quetiapine in the current study as well as the significant differences in nigral occupancy. which we have previously reported for haloperidol and olanzapine (Kessler et al, 2005).
Clozapine, like olanzapine but unlike quetiapine or haloperidol (Kessler et al, 2005), produces significantly less occupancy of nigral than putamenal DA D2r. The relative sparing of DA D2r occupancy seen in the substantia nigra may be another mechanism by which a low incidence of extrapyramidal motor side effects may be achieved. There are a number of observations indicating that nigral dopaminergic neurotransmission plays an important role in the regulation of motor tone and function. In rats, selective blockade of nigral DA D2r has been shown to produce increased muscle tone that was not reversed by intravenous apomorphine, despite the presence of intact striatal DA D1 and D2 receptors (Double and Crocker, 1995). Age-related motor deficits in rats have been correlated with nigral but not striatal extracellular DA and DA metabolite levels (Gerhardt et al, 2002). Recovery of motor function after 6-hydroxydopamine treatment followed by GDNF administration correlated with increased levels of DA release in the substantia nigra even in the absence of change in striatal DA release (Gerhardt et al, 1999). Antipsychotic-induced EPS may require a critical level of DA D2r blockade in both the striatum and substantia nigra (Crocker and Hemsley, 2001). The lesser blockade of nigral region DA D2r seen with clozapine may be protective against EPS.
The factors mediating the sparing of DA D2r occupancy in the substantia nigra, which is seen with clozapine and olanzapine (Kessler et al, 2005) but not quetiapine, are unclear. Given the known modulation of substantia nigra dopaminergic neuronal function by 5-HT2A-mediated neurotransmission (Sorenson et al, 1993; Cobb and Abercrombie, 2003; Bruggeman et al, 2000), the correlation of a high 5-HT2A : DA D2 affinity ratio with an atypical profile (Meltzer et al, 1989; Roth et al, 1995), and the three- to seven-fold higher 5-HT2A : DA D2r affinity ratio seen with olanzapine and clozapine compared to quetiapine (Schotte et al, 1996), the role of 5-HT2A-mediated serotonergic neurotransmission in sparing of nigral DA D2r occupancy requires further investigation.
In addition to preferential occupancy of cortical and sparing of nigral DA D2r occupancy, non-DA D2r-mediated mechanisms may be involved in the production of an atypical antipsychotic profile. Previous studies have suggested that a threshold of DA D2r occupancy of 65–70% is required for APDs to produce therapeutic effects (Kapur et al, 1996; Nordstrom et al, 1993). Although clozapine and quetiapine have been shown to have lower occupancy in the striatum at therapeutic doses than seen with typical APDs (Farde et al, 1994; Pilowsky et al, 1997; Gefvert et al, 1998), it has been suggested that clozapine and quetiapine produce preferential occupancy of cortical DA D2r, resulting in levels of cortical occupancy similar to those seen with typical APDs (Pilowsky et al, 1997; Stephenson et al, 2000). While quetiapine produces preferential occupancy of temporal cortical DA D2r, all regional DA D2r occupancies seen in quetiapine-treated subjects were significantly lower than those previously reported in haloperidol-treated subjects (p=0.02–0.006, ANOVA with drug and region as factors, corrected for multiple comparisons) (Kessler et al, 2005); there was no significant difference in BPRS total scores for quetiapine- vs haloperidol-treated subjects, that is, scores of 16.6 vs 15.0 (RM Kessler, unpublished data), consistent with previous studies showing similar therapeutic effects for quetiapine and haloperidol (Davis et al, 2003; Arvanitis and Miller, 1997). Clozapine has been shown to be superior to typical APDs in neuroleptic-resistant patients (Kane et al, 2001; Davis et al, 2003). These superior therapeutic effects occur at DA D2r occupancies that are significantly lower than those seen with haloperidol-treated subjects in all regions except the temporal cortex (p=0.02–0.0006, ANOVA with drug and region as factors, corrected for multiple comparisons), which has nonsignificantly lower occupancy compared to haloperidol, that is, 59.8 vs 70.9% (Kessler et al, 2005). These findings suggest that receptor interactions beyond DA D2r blockade are involved, at least in part, in the therapeutic effects of these drugs. Non-DA D2r-mediated mechanisms may include interactions at 5-HT2A, 5-HT2C, NK3, α1 and/or α2 receptors (Meltzer, 1999; Meltzer et al, 2004; Svensson, 2003).
In comparing the levels of DA D2r occupancy seen in quetiapine- and clozapine-treated subjects, the results, although preliminary, suggest that single doses of 400 mg or greater may be needed to produce levels of putamenal and temporal cortical DA D2r occupancy similar to those seen with clozapine. BPRS scores were lower with single doses of quetiapine greater than 400 mg. A recent study of quetiapine, 400 mg/day, in treatment-resistant patients with schizophrenia found it to be no more effective than typical APDs (Conley et al, 2005) although the current results suggest that the dose utilized may not have been high enough.
In conclusion, preferential occupancy of cortical DA D2r, sparing of DA D2r occupancy in the substantia nigra, as well as interactions at sites beyond the DA D2r may all be mechanisms by which clozapine and quetiapine achieve an atypical antipsychotic profile. As previously suggested (Roth et al, 2003; Meltzer et al, 2004), an atypical profile of APD action may be achieved by multiple mechanisms.
References
Andreasen NC, Endicott J, Spitzer RL, Winokur G (1977). The family history method using diagnostic criteria. Reliability and validity. Arch Gen Psychiat 34: 1229–1235.
Arvanitis LA, Miller BG (1997). Multiple fixed doses of ‘seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The seroquel trial 13 study group. Biol Psychiat 42: 233–246.
Breier A, Su T-P, Saunders R, Carson RE, Kolachana BS, De Bartolomeis A et al (1997). Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94: 2569–2574.
Bruggeman RM, Heeringa M, Westerink BHC, Timmerman W (2000). Combined 5-HT2/D2 receptor blockade inhibits the firing rate of SNR neurons in the rat brain. Prog Neuro-Psychopharm Biol Psychiat 24: 579–593.
Buchsbaum MS, Christian BT, Lehrer DS, Mukherjee J, Siu B, Mantil J (2004). D2/D3 dopamine receptor binding in the thalamus of medication-naïve schizophrenics. Int J Neuropsychopharmacol 7: S430.
Chiodo LA, Bunney BS (1983). Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci 3: 1607–1619.
Christian BT, Narayanan T, Shi B, Morris ED, Mantil J, Mukherjee J (2004). Measuring the in vivo binding parameters of [18F]-fallypride in monkeys using a PET multiple-injection protocol. J Cereb Blood Flow Metab 24: 309–322.
Cobb WS, Abercrombie ED (2003). Differential regulation of somatodendritic and nerve terminal dopamine release by serotonergic innervation of substantia nigra. J Neurochem 84: 576–584.
Conley RR, Kelly DL, Nelson MW, Richardson CM, Feldman S, Benham R et al (2005). Risperidone, quetiapine and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Clin Neuropharmacol 28: 163–168.
Crocker AD, Hemsley KM (2001). An animal model of extrapyramidal side effects induced by antipsychotic drugs: relationship with a D2 dopamine receptor occupancy. Prog Neuro-Psychopharm Biol Psychiat 25: 573–590.
Damask SP, Bovenkerk KA, De la Pena G, Hoversten KM, Peters DB, Valentine AM et al (1996). Differential effects of clozapine and haloperidol dopamine receptor mRNA expression in rat striatum and cortex. Brain Res Mol Brain Res 41: 241–249.
Davis JM, Chen N, Glick ID (2003). A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiat 60: 553–564.
Delforge J, Bottlaender M, Loc'h C, Dolle F, Syrota A (2001). Parametric images of the extrastriatal d2 receptor density obtained using a high-affinity ligand (FLB 457) and a double-saturation method. J Cereb Blood Flow Metab 21: 1493–1503.
Descarries L, Watkins KC, Garcia S, Bosler O, Doucet G (1996). Dual character, asynaptic and synaptic, of the dopamine innervation in adult rat neostriatum: a quantitative autoradiographic and immunocytochemical analysis. J Comp Neurol 375: 167–186.
American Psychiatric Association 1994. Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM-IV). American Psychiatric Association: Washington, DC.
Double KL, Crocker AS (1995). Dopamine receptors in the substantia nigra are involved in the regulation of muscle tone. Proc Natl Acad Sci USA 92: 1669–1673.
Erlandsson K, Bressan RA, Mulligan RS, Ell PJ, Cunningham VJ, Pilowsky LS (2003). Analysis of D2 dopamine receptor occupancy with quantitative SPET using the high-affinity ligand [123I]epidepride: resolving conflicting findings. NeuroImage 19: 1205–1214.
Fann WE, Stafford JR, Malone RL, Frost Jr JD, Richman BW (1977). Clinical research techniques in tardive dyskinesia. Am J Psychiat 134: 759–762.
Farde L, Nordstrom NS, Halldin C, Sedvall G (1994). D1-, D2- and 5-HT2-receptor occupancy in clozapine-treated patents. J Clin Psychiat 9 (Suppl BJ): 67–69.
Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordstrom AL, Hall H et al (1990). D2 dopamine receptors in neuroleptics-naïve schizophrenic patients: a positron emission tomography study with [11C] raclopride. Arch Gen Psychiat 47: 213–219.
First MB, Spitzer RL, Gibbon M, Williams JBW 1996. Structured Clinical Interview for Axis I DSM-IV Disorders—Patient Edition (with Psychotic Screen) (SCID-I/P) (Version 2.0). Biometrics Research Department, New York State Psychiatric Institute: New York.
Florijn WJ, Tarazi FI, Creese I (1997). Dopamine receptor subtypes: differential regulation after 8 months treatment with antipsychotic drugs. J Pharm Exp Ther 280: 561–569.
Fujita M, Selbyl JP, Verhoeff PILG, Ichise M, Baldwin RM, Zoghbi SS et al (1999). Kinetic and equilibrium analyses of [123I]epidepride binding to striatal and extrastriatal dopamine D2 receptors. Synapse 34: 290–304.
Garris PA, Ciolkowski EL, Pastore P, Wightman RM (1994). Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain. J Neurosci 14: 6084–6093.
Garris PA, Wightman RM (1994). Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J Neurosci 14: 442–450.
Gefvert O, Bergström M, Långström, Lundberg T, Lindström L, Yates R (1998). Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel®) in patients with schizophrenia. Psychopharmacology 135: 119–126.
Gerhardt GA, Cass WA, Huettl P, Brock S, Zhang ZM, Gash DM (1999). GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys. Brain Res 817: 163–171.
Gerhardt GA, Cass WA, Yi A, Zhang Z, Gash DM (2002). Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J Neurochem 80: 168–177.
Goldstein JM, Litwin LC, Sutton EB, Malick JB (1993). Seroquel: electrophysiological profile of a potential atypical antipsychotic. Psychopharmacology (Berl) 112: 293–298.
Grunder G, Landvogt C, Vernaleken, Buchholz H-G, Ondracek J, Siessmeier (2006). The striatal and extrastriatal D2/3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology 31: 1027–1035.
Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ (1997). Parametric imaging of ligand–receptor binding in PET using a simplified reference region model. NeuroImage 6: 279–287.
Hietala J, Syvalahti E, Vuorio K, Nagren K, Lehikoinen P, Ruotsalainen U et al (1994). Striatal D2 dopamine receptor characteristics in neuroleptics- naïve schizophrenic patients studied with positron emission tomography. Arch Gen Psychiat 51: 116–123.
Ichikawa J, Dai J, Meltzer HY (2002). Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5HT1A receptor agonism. Brain Res 956: 349–357.
Janowsky A, Neve KA, Kinzie JM, Taylor B, dePaulis T, Belknap JK (1992). Extrastriatal dopamine D2 receptors: distribution pharmacological characterization and region-specific regulation by clozapine. J Pharm Exp Ther 261: 1282–1290.
Kane JM, Marder SR, Schooler NR, Wirshing WC, Umbricht D, Baker RW (2001). Clozapine and haloperidol in moderately refractory schizophrenia. Arch Gen Psychiat 58: 965–972.
Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S et al (1996). High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiat 153: 948–950.
Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000). A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiat 57: 553–559.
Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA et al (1998). 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiat 155: 921–928.
Kawagoe KT, Garris PA, Wiedmann DJ, Wightman RM (1992). Regulation of transient dopamine concentration gradients in the microenvironment surrounding nerve terminals in the rat striatum. Neuroscience 51: 55–64.
Kessler R, Ansari MS, Li R, Lee M, Schmidt D, Dawant B et al (2002). Occupancy of cortical and substantia nigra DA D2 receptors by typical and atypical antipsychotic drugs. NeuroImage 16: S9.
Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B et al (2005). Occupancy of striatal and extrastriatal DA D2/3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30: 2283–2289.
Kessler RM, Ellis Jr JR, Eden M (1984). Analysis of emission tomographic scan data: limitations imposed by resolution and background. J Comput Assist Tomogr 8: 514–522.
Kessler RM, Mason NS, Jones C, Ansari MS, Manning RF, Price RR (2000). [18F]N-allyl-5-fluoropropylepidepride (fallypride): radiation dosimetry, quantification of striatal and extrastriatal dopamine receptors in man. NeuroImage 11: S32.
Kessler RM, Meltzer HY (2002). Regional selectivity in clozapine treatment. Am J Psy 159: 1064–1065.
Khan ZU, Mrzljak L, Gutierrez A, DeLa Calle A, Goldman-Rakic PS (1998). Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Scad Sci Neurobiol 95: 7731–7736.
Kuroki T, Meltzer HY, Ichikawa J (1999). Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharm Exp Ther 288: 774–781.
Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ et al (1996). Comparison of methods of analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 16: 42–52.
Lammertsma AA, Hume SP (1996). Simplified reference tissue model for PET receptor studies. NeuroImage 4 (3 Part 1): 153–158.
Levey AI, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA et al (1993). Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci USA 90: 8861–8865.
Lidow MS, Goldman-Rakic PS (1997). Differential regulation of D2 and D4 dopamine receptor mRNAs in the primate cerebral cortex vs neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs. J Pharmacol Exp Therapeut 283: 939–946.
Maes F, Collignon A, Vandermuele D, Marchal G, Suetens P (1997). Multimodality image registration by maximization of mutual information. IEEE Trans Med Imag 16: 187–198.
Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR et al (2001). Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Acurracy and precision of D (2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21: 1034–1057.
Meltzer HY, Matsubara S, Lee J-C (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Therapeut 251: 238–246.
Meltzer HY (1992). The mechanism of action of clozapine in relation to its clinical advantage. In: Meltzer HY (ed). Novel Antipsychotic Drugs. Raven Press: New York. pp 1–13.
Meltzer HY. (1999). The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21: 106S–115S.
Meltzer HY, Arvanitis L, Bauer D, Rein W (2004). Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiat 161: 975–984.
Mukherjee J, Christian BT, Dunigan KA, Shi B, Narayanan TK, Satter M et al (2002). Brain images of 18F-fallypride in normal volunteers: blood analysis, distribution, test–retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D-2/D-3 receptors. Synapse 46: 170–188.
Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C et al (1993). Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects—a double-blind PET study of schizophrenic patients. Biol Psychiat 33: 227–235.
Nordstrom AL, Nyberg S, Olsson H, Farde L (1998). Positron emission tomography finding of a high striatal D2 receptor occupancy in olanzapine-treated patients. Arch Gen Psychiat 55: 283–284.
Olsson H, Farde L (2001). Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy—a simulation study based on experimental data. NeuroImage 14: 945–946.
Olsson H, Halldin C, Farde L (2004). Differentiation of extrastiatal dopamine D2 receptor density and affinity in the human brain using PET. NeuroImage 22: 794–803.
Olsson H, Halldin C, Swahn CG, Farde L (1999). Quantification of [11C] FLB 457 binding to extrastriatal dopamine receptors in the human brain. J Cereb Blood Flow Metab 10: 1164–1173.
Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa D, Kerwin RW (1997). Limbic selectivity of clozapine. Lancet 350: 490–491.
Riccardi P, Li R, Ansari MS, Zald D, Park S, Dawant B et al (2006). Amphetamine induced displacement of [18F] fallypride in striatum and extrastriatal regions in humans. Neuropsychopharmacology 31: 1016–1026.
Rieck RW, Ansari MS, Whetsell Jr WO, Deutch AY, Kessler RM (2004). Distribution of dopamine D2-like receptors in the human thalamus: autoradiographic and PET studies. Neuropsychopharmacology 29: 362–372.
Robertson GS, Fibiger HC (1992). Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 46: 315–328.
Robertson GS, Matsumura H, Fibiger HC (1994). Induction patterns of fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity. J Pharmacol Exp Ther 271: 1058–1066.
Roth BL, Sheffler D, Potkin SG (2003). Atypical antipsychotic drug actions: unitary or multiple mechanisms for ‘atypicality’? Clin Neurosci Res 3: 108–117.
Roth BL, Tandra S, Burgess LH, Siblry DR, Meltzer HY (1995). D4 dopamine receptor binding affinity does not distinquish between typical and atypical antipsychotic drugs. Psychopharmacology 120: 365–368.
Schaltenbrand G, Wahren W (1977). Atlas for Stereotaxy of the Human Brain. Yearbook Medical Publisher Inc.: Chicago.
Schotte A, Janssen PFM, Gommeren WM, Lyuten WHML, Van Gompel P, Lesage AS et al (1996). Risperidone compared with new and reference antipsychotic drugs: in vigor and in vivo receptor binding. Psychopharmacology 124: 57–73.
Seeman P, Tallerico T (1998). Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiat 3: 123–134.
Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI (1998). Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci 18: 2697–2708.
Siessmeier T, Zhou Y, Buchholz HG, Landvogt C, Vernaleken I, Piel M et al (2005). Parametric mapping of binding in human brain of D2 receptor ligands of different affinities. J Nucl Med 46: 964–972.
Slifstein M, Hwang D-R, Huang Y, Guo NN, Sudo Y, Narendran R et al (2004). In vivo affinity of [18F]fallypride for striatal and extrastriatal dopamine D2 receptors in nonhuman primates. Psychopharmacology 175: 274–286.
Smiley JF, Levey AI, Ciliax BJ, Goldman-Rakic PS (1994). D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines. Proc Natl Acad Sci USA Neurobiol 91: 5720–5724.
Sorenson SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK et al (1993). Characterization of the 5-HT2 receptor antagonist MLD 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies. J Pharm Exp Ther 266: 684–691.
Stephenson CME, Bigliani V, Jones HM, Mulligan RS, Acton PD, Visvikis D et al (2000). Striatal and extra-striatal D2/D3 dopamine receptor occupancy by quetiapine in vivo. Br J Psychiat 177: 408–415.
Svensson TH (2003). Adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuro-Psychopharmacol Biol Psychiat 27: 1145–1158.
Talvik M, Nordstrom AL, Olsson H, Halldin C, Farde L (2003). Decreased thalamic D2/D3 receptor binding in drug-naïve patients with schizophrenia: a PET study with [11C]FLB 457. Int J Neuropsychopharmacol 6: 361–370.
Talvik M, Nordström AL, Nyberg S, Olsson H, Halldin C, Lars F (2001). No support for regional selectivity in clozapine-treated patients: a PET study with [11C]raclopride and [11C] FLB 457. Am J Psychiat 158: 926–930.
Tauscher-Wisniewski S, Kapur S, Tauscher J, Jones C, Daskalakis ZJ, Papatheodorou G et al (2002). Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade. J Clin Psychiat 63: 992–997.
Tuppurainen H, Kuikka J, Viinamaki H, Husso-Saastamoinen M, Bergstrom K, Tiihonen J (2003). Extrastriatal dopamine D 2/3 receptor density and distribution in drug-naïve schizophrenic patients. Mol Psychiat 8: 453–455.
Vahid-Ansari F, Nakabeppu Y, Robertson GS (1996). Contrasting effects of chronic clozapine, Seroquel (TM) (ICI 204,636) and haloperidol administration of delta FosB-like immunoreactivity in the rodent forebrain. Eur J Neurosci 8: 927–936.
Venton BJ, Zhang H, Garris PA, Phillips PEM, Sulzer D, Wightman RM (2003). Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing. J Neurochem 87: 1284–1295.
Wells III WM, Viola P, Atsumi H, Nakajima S, Kikinis R (1996). Multimodal volume registration by maximization of mutual information. Med Imag Anal 1: 35–51.
Xiberas X, Marinot JL, Mallet L, Artiges E, Loc'h C, Mazière B et al (2000). Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiat 179: 503–508.
Yamamoto BK, Cooperman MA (1994). Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14: 4159–4166.
Yasuno F, Suhara T, Okubo Y, Sudo Y, Inoue M, Ichimiya T et al (2004). Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia. Am J Psychiat 161: 1016–1022.
Youngren KD, Inglis FM, Pivirotto PH, Jedema HP, Bradberry CW, Goldman-Rakic PS et al (1999). Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20: 403–412.
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This work was supported by NIMH Grant number 1R01MH60898, by funding from Astra Zeneca, from the William K Warren Medical Research Foundation, the Ritter Foundation, and Centerstone Mental Health Center.
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Kessler, R., Ansari, M., Riccardi, P. et al. Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine. Neuropsychopharmacol 31, 1991–2001 (2006). https://doi.org/10.1038/sj.npp.1301108
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DOI: https://doi.org/10.1038/sj.npp.1301108
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