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Striatal dopamine release in schizophrenia comorbid with substance dependence.

Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR, Beckerman Y, Harkavy-Friedman JM, Gil R, Abi-Dargham A - Mol. Psychiatry (2012)

Bottom Line: There were no significant group differences in baseline BPND.Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST.Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05).

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

ABSTRACT
Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal DA release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore, we aimed to measure striatal DA release in patients with comorbid schizophrenia and substance dependence. We used [(11)C]raclopride positron emission tomography and an amphetamine challenge to measure baseline DA D2-receptor availability (BPND) and its percent change post-amphetamine (ΔBPND, to index amphetamine-induced DA release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence, and 15 healthy controls. There were no significant group differences in baseline BPND. Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal DA release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, DA release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic DA release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal postsynaptic D2 function.

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Related in: MedlinePlus

a. ∆BPND for DD (n=11) and control (n=15) groups. *p<.05 per between-group planned comparisons of the estimated marginal means derived from linear mixed modeling (see text) with the exception of STR, which was assessed with an independent-samples t-test.b. Effect sizes (Cohen’s d) for group differences between DD (n=11) and controls (n=15) in ∆BPND.DD=dual-diagnosis; see Table 2 for other abbreviations.
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Figure 1: a. ∆BPND for DD (n=11) and control (n=15) groups. *p<.05 per between-group planned comparisons of the estimated marginal means derived from linear mixed modeling (see text) with the exception of STR, which was assessed with an independent-samples t-test.b. Effect sizes (Cohen’s d) for group differences between DD (n=11) and controls (n=15) in ∆BPND.DD=dual-diagnosis; see Table 2 for other abbreviations.

Mentions: Linear mixed modeling using ∆BPND as the dependent variable and striatal ROI as a repeated measure indicated significant main effects of diagnosis [F(1, 24)=8.38, p=.008; Table 2 and Figure 1a] and ROI [F(4, 24]=46.51, p<.001]; however, the diagnosis×ROI interaction was not significant [F(4, 24)=0.67, p=.618]. Between-group planned comparisons of the estimated marginal means indicated that DD patients had significantly smaller amphetamine-induced ∆BPND in all striatal subregions except for VST (Table 2 and Figure 1a). The effect sizes (Cohen’s d) for group differences in ∆BPND were large for putamen (preDPU=1.15, postPU=1.42) and caudate (preDCA=0.82, postCA=0.85), and moderate for the VST (0.55); Figure 1b.


Striatal dopamine release in schizophrenia comorbid with substance dependence.

Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR, Beckerman Y, Harkavy-Friedman JM, Gil R, Abi-Dargham A - Mol. Psychiatry (2012)

a. ∆BPND for DD (n=11) and control (n=15) groups. *p<.05 per between-group planned comparisons of the estimated marginal means derived from linear mixed modeling (see text) with the exception of STR, which was assessed with an independent-samples t-test.b. Effect sizes (Cohen’s d) for group differences between DD (n=11) and controls (n=15) in ∆BPND.DD=dual-diagnosis; see Table 2 for other abbreviations.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4128915&req=5

Figure 1: a. ∆BPND for DD (n=11) and control (n=15) groups. *p<.05 per between-group planned comparisons of the estimated marginal means derived from linear mixed modeling (see text) with the exception of STR, which was assessed with an independent-samples t-test.b. Effect sizes (Cohen’s d) for group differences between DD (n=11) and controls (n=15) in ∆BPND.DD=dual-diagnosis; see Table 2 for other abbreviations.
Mentions: Linear mixed modeling using ∆BPND as the dependent variable and striatal ROI as a repeated measure indicated significant main effects of diagnosis [F(1, 24)=8.38, p=.008; Table 2 and Figure 1a] and ROI [F(4, 24]=46.51, p<.001]; however, the diagnosis×ROI interaction was not significant [F(4, 24)=0.67, p=.618]. Between-group planned comparisons of the estimated marginal means indicated that DD patients had significantly smaller amphetamine-induced ∆BPND in all striatal subregions except for VST (Table 2 and Figure 1a). The effect sizes (Cohen’s d) for group differences in ∆BPND were large for putamen (preDPU=1.15, postPU=1.42) and caudate (preDCA=0.82, postCA=0.85), and moderate for the VST (0.55); Figure 1b.

Bottom Line: There were no significant group differences in baseline BPND.Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST.Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05).

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

ABSTRACT
Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal DA release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore, we aimed to measure striatal DA release in patients with comorbid schizophrenia and substance dependence. We used [(11)C]raclopride positron emission tomography and an amphetamine challenge to measure baseline DA D2-receptor availability (BPND) and its percent change post-amphetamine (ΔBPND, to index amphetamine-induced DA release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence, and 15 healthy controls. There were no significant group differences in baseline BPND. Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal DA release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, DA release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic DA release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal postsynaptic D2 function.

Show MeSH
Related in: MedlinePlus