Antipsychotics, dopamine D2 receptor occupancy and clinical improvement in schizophrenia: A meta-analysis

Schizophrenia Research 140 (2012) 214–220

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Antipsychotics, dopamine D2 receptor occupancy and clinical improvement in schizophrenia: A meta-analysis Zeynep Yilmaz a, c, d, Clement C. Zai b, d, Rudi Hwang a, d, Steve Mann e, Tamara Arenovich c, Gary Remington a, b, e,⁎, Zafiris J. Daskalakis a, b, e,⁎ a

Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Clinical Research Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada d Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada e Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada b c

a r t i c l e

i n f o

Article history: Received 30 April 2012 Received in revised form 14 June 2012 Accepted 15 June 2012 Available online 12 July 2012 Keywords: Schizophrenia Dopamine D2 receptor occupancy Antipsychotic medication response Clinical improvement Meta-analysis Neuroimaging

a b s t r a c t Objective: Treatment of schizophrenia (SCZ) was revolutionized with the development of the antipsychotic medications. Although imaging studies have linked antipsychotic D2 receptor occupancy and clinical response in SCZ, heterogeneity between cohorts and methods has made it challenging to generalize findings across studies. The main objective of this meta-analysis was to analyze the relationship between in vivo estimation of typical and atypical antipsychotic D2 receptor occupancy and treatment response in SCZ. Methods: Using the keywords “dopamine D2 receptor occupancy,” “schizophrenia,” “PET/SPECT” and “antipsychotics,” and further refining our search to journal articles with information on % striatal D2 occupancy and % change in clinical symptoms as indexed by either the BPRS or the PANSS, our final analysis consisted of 16 imaging studies (20 cohorts; N = 206). Results: The first step of the meta-analysis confirmed the positive relationship between antipsychotic medication and clinical improvement in SCZ (ES = 1.36; 95% CI: 1.13–1.60). The second step of our analysis revealed that when D2 occupancy was limited to less than 80% in order to control for the appearance of extrapyramidal symptoms, high D2 occupancy was correlated with reduction in clinical scores (r = 0.4, p b 0.001) for medications other than clozapine or quetiapine. Conclusions: Our results suggest that D2 occupancy is a contributing factor for the mechanism of antipsychotic effect in SCZ for some but not all antipsychotic medications. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia (SCZ) is a serious and often chronic psychiatric syndrome with a lifetime prevalence rate of 1%–3.2% (Perala et al., 2007). Discovery of antipsychotic medications such as haloperidol, thiothixene and chlorpromazine (now referred to as first generation or typical antipsychotics) played a crucial role in the deinstitutionalization of SCZ patients; however, these agents are often associated with the risk of extrapyramidal symptoms (EPS; van Os and Kapur, 2009). More recently, second generation antipsychotics (e.g., clozapine, olanzapine, risperidone, quetiapine) have largely supplanted their first generation counterparts in part related to their diminished prevalence of EPS (Kapur and Remington, 2001; Kapur and Seeman, 2001). Although it was initially thought that the atypical antipsychotics were more effective than typical antipsychotics in terms of targeting negative and cognitive ⁎ Corresponding authors at: Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8. Tel.: +1 416 535 8501x4319; fax: +1 416 979 6936. E-mail address: [email protected] (Z.J. Daskalakis). 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2012.06.027

symptoms, the magnitude and impact of these changes has been challenged (Lieberman et al., 2005; Jones et al., 2006; Kahn et al., 2008). The fact that antipsychotic medications were quickly identified as dopamine D2 receptor antagonists led to the dopamine hypothesis of SCZ (Carlsson and Lindqvist, 1963; van Rossum, 1966; Matthysse, 1973; Seeman et al., 1976). Several lines of research have been cited as indirect evidence (Carlsson and Lindqvist, 1963; Abi-Dargham et al., 2000), and it has been demonstrated in vitro that D2 occupancy closely correlates with the antipsychotic potencies of the different agents (Seeman et al., 1976). However, two important observations have challenged the validity of the dopamine hypothesis. First, imaging studies have demonstrated that while D2 occupancy greater than 60–65% optimizes chance of antipsychotic response (Kapur et al., 2000a), blockade of more than 80% of the D2 receptors markedly increases the risk of EPS (Tort et al., 2006), which does not agree with the implied linear relationship between D2 blockade and clinical improvement. Based on this evidence, it has been postulated that there is a therapeutic window for the D2 receptor occupancy of antipsychotics, between 65% and 80% (Kapur et al., 2000a; Kapur and Seeman, 2001; Tort et al., 2006), which has been recently confirmed

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by a systematic pooled analysis of imaging studies (Uchida et al., 2011). The second criticism has to do with the low D2 affinity of clozapine, which occupies less than 50% of D2 receptors 2 hours following administration (Kapur and Seeman, 2001). Considering that clozapine is the treatment of choice for refractory SCZ, its low D2 blockade does not fit well with the dopamine hypothesis. At a molecular level, it has been demonstrated that clozapine has a more transient effect on the D2 receptors (Kapur and Seeman, 2001), with data indicating that clozapine binds to and releases from the receptor 100 times that of haloperidol (Scatton et al., 1997). Furthermore, this rapid dissociation phenomenon has been reported for quetiapine as well (Gefvert et al., 2001; Kapur and Remington, 2001). Taken together, evidence suggests that for these drugs will differ from other antipsychotics in terms of their relationship between D2 receptor occupancy and clinical response. Since neuroimaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have become widely available, there have been numerous studies designed to test the D2 hypothesis of SCZ and antipsychotic medications. Through the detection of pairs of gamma rays emitted indirectly by a receptor-specific radiotracer, both PET and SPECT imaging can provide researchers with an estimate for the percentage of receptor occupancy in different brain regions, and this has led to several studies measuring D2 receptor occupancy in striatum following the administration of antipsychotic medications. However, due to heterogeneity in sampling and methodology, findings resulting from these studies have not been entirely consistent. A recent meta-analysis of dopaminergic function in SCZ patients compared to healthy controls reported elevated presynaptic dopaminergic function (Howes et al., 2012), but there has not been a rigorous review of the literature to evaluate the imaging findings pertaining to clinical outcome following treatment with an antipsychotic medication in an objective and standardized fashion. The present meta-analysis was meant to address this conundrum, and set as its objective two goals: (1) to empirically establish the relationship between antipsychotic medications and clinical improvement in SCZ; and (2) to assess the role of striatal D2 occupancy and clinical improvement.

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multiple medication use was reported, each medication group was treated as a separate cohort (N= 20, 206 participants in total; see Table 1 for details). 2.2. Statistical analysis The following variables were extracted from each publication: (1) number of participants (per cohort if multiple medications were used); (2) scan type; (3) ligand information; (4) treatment duration in days; (5) antipsychotic medication used; (6) means and standard deviations for pre- and post-scan clinical scores; and (7) mean posttreatment D2 % striatal occupancy. The standardized mean difference in clinical response was estimated using the “meta” command in STATA version 8 (StataCorp LP, College Station, TX, USA). The pooled odds ratio was calculated using the inverse variance method under the fixed-effects model, as well as the DerSimonian and Laird method under the random-effects model within STATA. Heterogeneity was assessed using the chi-squared test. Subsequently, the relationship between clinical response and % striatal D2 occupancy was determined using linear regression analysis, with mean % D2 occupancy as the independent variable and the standardized mean difference in clinical response as the dependent variable (SPSS version 15). The mean for each cohort was weighted for the number of patients included in the cohort. We also carried out secondary analyses to determine the possible confounding effect of treatment duration on clinical response by hierarchical linear regression (SPSS). We repeated the regression analysis to investigate: 1) all antipsychotics included; 2) all antipsychotics, excluding clozapine; 3) all antipsychotics, excluding clozapine and quetiapine (Gefvert et al., 2001); and 4) all antipsychotics, excluding clozapine, quetiapine, and cohorts where the D2 occupancy is more than 80% (to control for the presence of EPS due to high D2 blockade, which interferes with clinical improvement; Tort et al., 2006). When sample sizes allowed, we repeated the analyses including cohorts where striatal % D2 occupancy was determined solely by PET or SPECT, and where clinical response was measured by PANSS or BPRS. 3. Results

2. Methods 3.1. Antipsychotic medication and clinical response 2.1. Literature search We performed a literature search on PubMed using the search terms “D2 occupancy”, “antipsychotic”, “schizophrenia”, and “PET or SPECT” for papers published up to June 30, 2011. Our search returned 178 articles. Inclusion criteria for the meta-analysis were: (1) administration of a typical or atypical antipsychotic medication to SCZ patients; (2) % striatal D2 receptor occupancy obtained by either PET or SPECT following the administration of the medication for at least a two-week period; and (3) inclusion of pre-treatment and post-scan Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS)scores (means and standard deviations). In the end, we identified 16 papers as suitable for the meta-analysis (Farde et al., 1988; Kapur et al., 1998; Nordstrom et al., 1998; Nyberg et al., 1999; Kapur et al., 2000a, 2000b; Barnas et al., 2001; Bernardo et al., 2001; Tauscher-Wisniewski et al., 2002; Bressan et al., 2003; Moresco et al., 2004; Corripio et al., 2005; Agid et al., 2007; Mamo et al., 2007, 2008; Meisenzahl et al., 2008; Uchida et al., 2008). D2 receptor binding potential was calculated either as a ratio of average striatal ligand uptake over time divided by average (considered non-specific) ligand uptake in the cerebellum, occipital cortex (Corripio et al., 2005), or frontal cortex (Barnas et al., 2001; Bernardo et al., 2001), or it was calculated by the simplified reference tissue model (e.g., Bressan et al., 2003). D2 receptor occupancy was then estimated from the percentage reduction in D2 receptor binding potential after drug treatment from baseline, which was derived from D2 binding potential in the same subjects before drug treatment, in healthy controls, or in drug-naïve/free schizophrenia patients. When

Our preliminary analyses did not show a publication bias. We weighted each study for PANSS under the fixed effects model because we did not detect significant heterogeneity in our meta-analysis of PANSS change during antipsychotic medication. However, BPRS was weighted under the random effects model due to significant heterogeneity. The first step of the meta-analysis consisted of exploring the relationship between antipsychotics medication and clinical improvement, as assessed by PANSS. As summarized in Fig. 1, the effect size of antipsychotic medication on PANSS score improvement, as assessed by the 17 cohorts included in the analysis, was 1.36 (95% CI: 1.13–1.60), thus demonstrating that administration of antipsychotics is associated with improvement in symptoms. When studies that used BPRS scores for clinical improvement were assessed, the effect size obtained from the 7 cohorts included in the analysis was 1.25 (95% CI: 0.61–1.89). 3.2. Striatal D2 receptor occupancy and clinical response 3.2.1. PANSS total Based on the entire sample (n = 17 cohorts; Fig. 2), we did not find D2 receptor occupancy predicted antipsychotic response, as measured by change in total PANSS scores (r = − 0.067, p = 0.511; Table 2). The results remained nonsignificant with the removal of one cohort treated with clozapine (n = 16 cohorts, r = 0.147, p = 0.148), as well as removal of cohorts treated with clozapine or quetiapine (n = 14 cohorts, r = 0.123, p = 0.271). When we further excluded one cohort with D2 occupancy of over 80% though, we did find a significant positive

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Table 1 Studies included in the meta-analysis of clinical response and D2 receptor occupancy of antipsychotic medication (20 cohorts, 206 participants).a Study

N

Medicationb

Scan

Ligand

Tx history

Tx duration (days)c

% D2 occupancy

Clinical measure

Agid et al. (2007) Barnas et al. (2001) Bernardo et al. (2001) (cohort 1) Bernardo et al. (2001) (cohort 2) Bressan et al. (2003) Corripio et al. (2005) (cohort 1) Corripio et al. (2005) (cohort 2) Farde et al. (1988) Kapur et al. (1998) Kapur et al. 2000b) Mamo et al. (2007) Mamo et al. (2008) Meisenzahl et al. (2008) Moresco et al. (2004) (cohort 1) Moresco et al. (2004) (cohort 2) Nordstrom et al. (1998) Nyberg et al. (1999) Tauscher-Wisniewski et al. (2002) Uchida et al. (2008) (cohort 1) Uchida et al. (2008) (cohort 2)

14 12 13 14 6 10 10 2 12 12 12 14 29 9 6 3 7 14 5 2

OLZ/RISP ZOT HDL OLZ RISP HDL ZIP RAC OLZ QUET ARIP OLZ AMIS OLZ CLZ OLZ RISP QUET RISP RISP

PET SPECT SPECT SPECT SPECT SPECT SPECT PET PET PET PET PET SPECT PET PET PET PET PET PET PET

Raclopride IBZM IBZM IBZM Epidepride IBZM IBZM Raclopride Raclopride Raclopride Raclopride Raclopride IBZM FESP FESP Raclopride Raclopride Raclopride Raclopride Raclopride

Mixed Chronic Tx-naïve Tx-naïve Chronic Chronic Chronic Chronic Tx-naive Tx-naive Chronic Chronic Chronic Chronic Chronic Mixed Tx-naive Mixed Chronic Chronic

15 28 28 28 162.6 18.5 15.4 30 14 14 28 168 14 56 56 – 42 84 312 312

71.9 71.8 64 49 43.8 74.7 60.2 70 70 61 90 57.9 73.3 42.7 10.8 75.3 72 62 46.6 79

PANSS PANSS PANSS PANSS PANSS, PANSS PANSS BPRS BPRS PANSS PANSS BPRS PANSS, PANSS, PANSS, PANSS PANSS PANSS PANSS PANSS

BPRSd

BPRS BPRS BPRS

a

For studies that used more than one medication, each medication group was treated as a separate cohort. OLZ= olanzapine; RISP = risperidone; ZOT= zotepine; HLD = haloperidol; ZIP = ziprasidone; RAC = raclopride; QUET = quetiapine; ARIP = aripiprazole; AMIS = amisulpride; CLZ = clozapine. c For studies in which treatment length varies between patients, average treatment length was used. There was no information on treatment duration for the Nordstrom et al. (1998) publication. d Endpoint standard deviation assumed to be same as baseline for all clinical measures. b

correlation between D2 occupancy and antipsychotic response (n = 13 cohorts, r = 0.400, p b 0.001). The final model for PANSS total showed that D2 occupancy accounted for about 15% of the total variance in PANSS total improvement. Removal of individual cohorts one by one from the analysis did not change results, demonstrating robustness of the results. When we added treatment duration to the model, results remained similar for response measured by change in total PANSS scores (p b 0.001; Table 3). 3.2.2. BPRS Analysis of those cohorts where antipsychotic response was measured by change in BPRS scores did not establish a correlation between D2 occupancy and antipsychotic response (n = 7 cohorts, r = 0.169, p = 0.092; Table 2); the nonsignificance of results did not change when we removed one cohort treated with clozapine (n = 6 cohorts, r = 0.183, p = 0.091). When we added treatment duration to the model, we observed a statistically significant positive correlation with change in total PANSS scores (p = 0.002; Table 3). However, BPRS findings did not pass the sensitivity analysis. Of note, BPRS studies did not include quetiapine or D2 occupancy >80%. 3.2.3. SPECT only For PANSS cohorts where D2 occupancy was measured using SPECT, a significant positive correlation between D2 occupancy and response was found (n = 7 cohorts, r = 0.593, p b 0.001; Table 2). The SPECT studies did not include clozapine, quetiapine, or D2 occupancy > 80%. There was not a sufficient number of SPECT studies reporting BRPS scores to analyze separately.

3.2.4. PET only None of the analysis of PANSS cohorts where D2 occupancy was measured using PET yielded a correlation between D2 occupancy and response (Table 2). The PET studies did not include D2 occupancy > 80%, and in the case of PET studies that reported BPRS scores, we also did not find a correlation between D2 occupancy and clinical improvement.

4. Discussion In this meta-analysis, we examined the association between antipsychotic medications and clinical improvement, in addition to critically evaluating the relationship between striatal D2 receptor occupancy and clinical improvement in patients with SCZ. While the dopamine hypothesis of SCZ has played a central role in our conceptualization of this illness for decades, it has been difficult to examine its validity through individual imaging studies due to the many sources of heterogeneity in sampling and methodology. In addition to objectively summarizing the literature and the positive association of antipsychotic medications with clinical response, this meta-analysis also revealed a positive correlation between % D2 receptor occupancy and clinical response in SCZ, thus providing at least partial evidence for the dopamine hypothesis of SCZ. These findings held true when studies were stratified by scan or clinical measure. However, both the r and r 2 values for statistically significant correlations were modest at best, and the highest effect size observed accounted for less than 20% of the total variance in clinical improvement, indicating that D2 receptor occupancy is only part of the story regarding antipsychotic medication response. Reflective of its transient D2 binding (Seeman and Tallerico, 1998; Kapur and Remington, 2001; Kapur and Seeman, 2001), clozapine was an outlier in our analysis and its inclusion significantly weakened the correlation between D2 occupancy and clinical response. Similarly, quetiapine shares this same pharmacological profile (Kane, 1996) and, as such, also was found to weaken such a correlation, as was also established here (Kapur et al., 2000b). Our results also affirm that 80% D2 occupancy seems to be a critical cutoff for the positive effects of antipsychotic medications, thus confirming the presence of a ceiling effect. This finding is also in line with a recent review of PET studies that concluded 77–78% D2 occupancy represented the most specific and sensitive threshold for risk of EPS (Uchida et al., 2011). D2 occupancy over 80% is associated with increased liability for EPS but little likelihood of improved clinical response (Kapur et al., 2000a), in line with our finding of a positive association between D2 and clinical improvement only with the exclusion of D2 occupancy over 80%.

Z. Yilmaz et al. / Schizophrenia Research 140 (2012) 214–220

A

Standardised Mean diff. % Weight (95% CI)

Study

1.23 (0.42,2.04) 1.26 (0.38,2.15) 1.44 (0.57,2.31) 1.50 (0.66,2.35) 1.23 (-0.02,2.49) 1.72 (0.68,2.76) 0.95 (0.02,1.88) 0.49 (-0.33,1.30) 0.87 (0.03,1.71) 1.62 (1.02,2.21) 1.71 (0.61,2.80) 2.61 (1.00,4.22) 2.82 (0.29,5.34) 3.30 (1.61,4.99) 1.61 (0.75,2.47) 0.45 (-0.81,1.71) 2.97 (-0.54,6.48)

Agid et al. 2007 Barnas et al. 2001 Bernardo et al. 2001 (cohort 1) Bernardo et al. 2001 (cohort 2) Bressan et al. 2003 Corripio et al. 2005 (cohort 1) Corripio et al. 2005 (cohort 2) Kapur et al. 2000 Mamo et al. 2007 Meisenzahl et al. 2008 Moresco et al. 2004 (cohort 1) Moresco et al. 2004 (cohort 2) Nordstrom et al. 1998 Nyberg et al. 1999 Tauscher-Wisniewski et al. 2002 Uchida et al. 2008 (cohort 1) Uchida et al. 2008 (cohort 2)

8.5 7.2 7.4 7.9 3.6 5.2 6.5 8.5 8.0 15.9 4.7 2.2 0.9 2.0 7.6 3.6 0.5

1.36 (1.13,1.60)

Overall (95% CI)

0

-6.47868

B

217

6.47868 Standardised Mean diff. Standardised Mean diff.

Study

(95% CI)

% Weight

Bressan et al. 2003

2.00 (0.57,3.43)

Farde et al. 1988

5.98 (-0.20,12.15)

1.0

Kapur et al.1998

1.00 (0.15,1.85)

17.9

Mamo et al. 2008

0.27 (-0.47,1.02)

19.4

Meisenzahl et al. 2008

1.98 (1.35,2.62)

20.9

Moresco et al. 2004 (cohort 1)

1.05 (0.06,2.04)

16.1

Moresco et al. 2004 (cohort 2)

1.09 (-0.14,2.32)

13.3

Overall (95% CI)

1.25 (0.61,1.89)

0

-12.1504

11.3

12.1504 Standardised Mean diff.

Fig. 1. A. Results of the meta-analysis exploring the relationship between antipsychotic medication and clinical improvement as assessed by PANSS total (under fixed effects model). B. Results of the meta‐analysis exploring the relationship between antipsychotics medication and clinical improvement as assessed by BPRS (under random effects model).

Standardized mean difference for each cohort, obtained form STATA

5.00

Excluding Clozapine/Quetiapine/D2 occupancy > 80% Clozapine Quetiapine

4.00

D2 occupancy >80%

3.00

2.00

1.00

0.00 0

20

40

60

80

100

Mean % D2 occupancy Fig. 2. Graph resulting from the linear regression, with standardized mean difference in symptom severity as the dependent variable and D2 receptor occupancy as the independent variable. Standardized mean difference for each cohort on the y-axis was obtained from the meta-analysis and is based on sample size and clinical improvement.

This meta-analysis has a number of limitations that merit consideration. First, the analysis included various antipsychotic medications (typical and atypical); however, this strategy which is in line with the D2 blockade has been identified as the sine qua non of antipsychotic activity and an inherent component of all currently available antipsychotics (Kapur and Remington, 2001). A second limitation is the lack of standard dosage among different cohorts and even patients in each study. At the same time though, we would expect medication dose to be positively correlated with D2 occupancy, with higher doses leading to higher D2 occupancy. As much as we have controlled for treatment duration (see Table 3), its potential role as a confounding variable also warrants consideration. Length of treatment duration may suggest chronicity and limited response, though our findings did not indicate a significant effect of treatment duration on the relationship between D2 occupancy and clinical outcome. To boost the power of the meta-analysis, we included both PET and SPECT studies and although we separated cohorts by methods where numbers allowed, it is important to acknowledge the differences between these two imaging techniques. Indeed, striatal D2 receptor binding may differ

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Z. Yilmaz et al. / Schizophrenia Research 140 (2012) 214–220

Table 2 Results from linear regression with standardized mean difference in symptom severity as the dependent variable, and D2 receptor occupancy as the independent variable (shown for all studies, stratified by PET or SPECT studies, with the removal of studies with clozapine, quetiapine, and studies where D2 occupancy exceeded 80%). Scan PANSSa

All

SPECT

PET

BPRSb,c

All

PET

No. of studies r (adjusted r2) p No. of studies R (adjusted r2) p No. of studies r (adjusted r2) p No. of studies r (adjusted r2) p No. of studies r (adjusted r2) p

All

No Cloz

No Cloz/Quet

No Cloz/Quet >80% Occ

17 −0.07 (−0.01) 0.51 –

16 0.15 (0.01) 0.15 –

14 0.12 (0.002) 0.27 –

10 −0.25 (0.04) 0.10 7 0.283 (0.068) 0.01 5 0.097 (−0.015) 0.54

9 0.003 (−0.02) 0.98 6 0.321 (0.090) 0.006 4 0.235 (0.028) 0.16

7 −0.08 (−0.03) 0.71 –

13 0.40 (0.16) b0.001 7 0.59 (0.34) b0.001 6 0.34 (0.07) 0.14 –

–

–

Statistically significant p-values in bold. a None of the SPECT studies that reported PANSS scores used clozapine or quetiapine, or reported D2 occupancy over 80%. b None of the studies that reported BPRS scores used quetiapine or reported D2 occupancy over 80%. c The number for SPECT studies that reported BPRS scores was not adequate to be analyzed separately (N = 2).

as much as 13% between [123]IBZM and [11C]Raclopride (Catafau et al., 2009), and additional scatter correction may be needed for SPECT images (Bullich et al., 2010). These differences in scan type and ligands could decrease the signal to noise ratio in our meta-analysis, though other recent studies have also combined PET and SPECT (e.g., Howes et al., 2012). Additionally, use of a variety of ligands could also be deemed a limitation, as the sensitivity and specificity of ligands can differ. Another considerable limitation is the use of different formulae and strategies for measuring and estimating D2 occupancy. For example, while some studies provided baseline scans for the same subjects before antipsychotic medication (Bernardo et al., 2001), others relied on separate healthy subjects or drug-free SCZ patients as controls in the calculation of D2 occupancy. It is important to consider the presence of a number of assumptions in the calculation of receptor occupancy and binding potential: the PET or SPECT radioligands only occupy a negligible percentage of the receptor of interest, and that neither the radioligand nor the drug of interest interacts with the endogenous ligand for the receptor. Despite these limitations, the occupancy data appears to be reliable and replicable in schizophrenia studies; however, these heterogeneous procedures for determining D2 occupancy could have introduced noise in our meta-analysis results. The analyses pertaining to BPRS may have been influenced by insufficient

power due to small sample size, as there were only seven cohorts included in this meta-analysis. Last but not least, and as shown in Table 1, the vast majority of studies evaluating D2 occupancy have been conducted in chronic cohorts as opposed to patients who are treatment naïve or experiencing a first psychotic episode. The meta-analysis lacked sufficient power to analyze these two cohorts separately, but it is important to consider the qualitative differences between these two samples, as well as the possible effects of chronic antipsychotic medication use and treatment resistance in efforts to establish a relationship between D2 occupancy and clinical response. Despite these limitations, this meta-analysis accomplished the goal of summarizing the findings from 20 separate cohorts in a standardized fashion, allowing collective comparison of the individual results and assessing heterogeneity. Our findings very much align with the current state of the art regarding development of new compounds for the treatment of SCZ. The rapid expansion of a new generation of antipsychotics in the 1990s, premised on mechanisms of action that extended beyond dopamine, raised awareness regarding the possibility of establishing antipsychotic efficacy through alternate pharmacological pathways (Agid et al., 2008). Efforts continue in the search for other pharmacological mechanisms that may translate to stand alone antipsychotic

Table 3 Results for linear regression with standardized mean difference in symptom severity as dependent variable, and D2 receptor occupancy and treatment duration as independent variables. Significance values from ANOVA as well as those from t-tests of each independent variable (with standardized beta coefficients within parentheses) are shown. Scan PANSS

a

All

SPECT

PET

BPRSb,c

All

PET

pANOVA (Std. b) pD2occ (Std. b) pduration pANOVA (Std. b) pD2occ (Std. b) pduration pANOVA (Std. b) pD2occ (Std. b) pduration pANOVA (Std. b) pD2occ (Std. b) pduration pANOVA (Std. b) pD2occ (Std. b) pduration

All

No Cloz

No Cloz/Quet

No Cloz/Quet >80% Occ

0.033 (−0.192) 0.075 (−0.269) 0.014 –

0.098 (0.044) 0.696 (−0.196) 0.085 –

0.003 (−0.083) 0.484 (−0.408) 0.001 –

0.096 (−0.338) 0.034 (−0.161) 0.301 0.001 (0.087) 0.373 (−0.336) 0.001 0.009 (0.048) 0.650 (−0.531) b 0.001

0.898 (−0.059) 0.737 (−0.076) 0.667 0.002 (−0.048) 0.703 (−0.397) 0.002 b0.001 (−0.021) 0.867 (−0.528) b 0.001

0.163 (−0.317)0.162 (−0.418)0.069 –

b0.001 (0.231) 0.066 (−0.301) 0.017 b0.001 (0.274) 0.035 (−0.506) b 0.001 0.213 (0.128) 0.626 (−0.342) 0.203 –

–

–

Statistically significant p-values in bold. a None of the SPECT studies that reported PANSS scores used clozapine or quetiapine, or reported D2 occupancy > 80%. b None of the studies that reported BPRS scores used quetiapine or reported D2 occupancy > 80%. c The number for SPECT studies that reported BPRS scores was not adequate to be analyzed separately (n = 2).

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efficacy; the recent work with LY2140023 is a good example of this (Mezler et al., 2010). At the same time, further lines of investigation take us in at least two other directions. The first is one of building upon D2 antagonism to augment efficacy, still though with the focus on psychosis per se (Emsley, 2009; Barnes and Paton, 2011). The second builds upon the broader conceptualization of SCZ that presently exists, an approach that acknowledges various symptom domains beyond psychosis and, in addition, the importance of these domains with respect to functional outcome measures in SCZ (Agid et al., 2008; Zink et al., 2010; Marder et al., 2011). Whatever the line of investigation, we are reminded that, at best, dopamine represents only part of a very complex story. Going forward, there is no doubt though that lines of research will broaden to reflect changes that have taken place in conceptualizing SCZ, as well as continued efforts to find treatments for psychosis that are not responsive to D2 blockade. Role of funding source The authors have no funding sources to report for this meta-analysis. ZY is funded by a Canadian Institutes of Health Research (CIHR) Doctoral Research Award. CCZ is the recipient of a research fellowship from the American Foundation for Suicide Prevention. GR is funded by grants from the CIHR, Canadian Diabetes Association, and Schizophrenia Society of Ontario. ZJD holds operating grants from the Ontario Mental Health Foundation (OMHF), CIHR, the Brain and Behaviour Research Foundation and the Grant Family through the Centre for Addiction and Mental Health (CAMH) Foundation. Contributors ZY, RH, SM, GR and ZJD conceptualized the study. ZY, CCZ, RH and SM conducted the literature search and selected the studies suitable for the meta-analysis and extracted data. ZY, CCZ and TA performed the statistical analyses. ZY prepared the manuscript with the assistance of CCZ, GR and ZJD. Conflict of interest CCZ holds a research fellowship from Eli Lilly. GR is funded by Roche (consultant fees), Laboratorios Farmacéuticos ROVI (consultant fees), Novartis (speaker fees), Medicure (research support), and Neurocrine Biosciences (research support). ZJD receives external funding through Neuronetics and Brainsway Inc, Aspect Medical and a travel allowance through Pfizer and Merck. ZJD has also received speaker funding through Sepracor Inc and served on the advisory board for Hoffmann-La Roche Limited. These companies neither were involved in nor influenced the results of this study. ZY, RH, SM and TA have no interests to disclose. Acknowledgements None.

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