Limits...
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.

Show MeSH

Related in: MedlinePlus

a. The association between ∆BPND and ∆PTOT (i.e. amphetamine-induced change in PANSS positive symptoms) for DD (n=10, data from current study; ∆BPND for preDCA) and schizophrenia (n=34, data from Laruelle et al.;4 ∆BPND for whole striatum). The lines result from a regression with a common slope and study-specific intercepts: ∆BPND = 1.34 × ∆PTOT + 13.13 (schizophrenia, dashed) or ∆BPND = 1.34 × ∆PTOT + 1.73 (DD, solid). The fit demonstrates that the same change in symptoms is associated with a smaller change in tracer binding in DD compared to schizophrenia.b. The same fits, transformed to the increase in D2 receptor occupancy by DA following amphetamine. Baseline occupancy in DD is assumed to be similar to that previously reported for substance-dependent patients.33 The main qualitative result is that a given increase in symptoms (5 on the Positive-Symptom subscale of the PANSS in this example) results from a smaller increase in the number of receptors being stimulated in DD than in schizophrenia.Amph.=amphetamine; Base.=baseline; DA=dopamine; DD=dual-diagnosis; Occ.=occupancy; PANSS=Positive and Negative Syndrome Scale; preDCA=precommissural dorsal caudate; SCZ=schizophrenia.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4128915&req=5

Figure 3: a. The association between ∆BPND and ∆PTOT (i.e. amphetamine-induced change in PANSS positive symptoms) for DD (n=10, data from current study; ∆BPND for preDCA) and schizophrenia (n=34, data from Laruelle et al.;4 ∆BPND for whole striatum). The lines result from a regression with a common slope and study-specific intercepts: ∆BPND = 1.34 × ∆PTOT + 13.13 (schizophrenia, dashed) or ∆BPND = 1.34 × ∆PTOT + 1.73 (DD, solid). The fit demonstrates that the same change in symptoms is associated with a smaller change in tracer binding in DD compared to schizophrenia.b. The same fits, transformed to the increase in D2 receptor occupancy by DA following amphetamine. Baseline occupancy in DD is assumed to be similar to that previously reported for substance-dependent patients.33 The main qualitative result is that a given increase in symptoms (5 on the Positive-Symptom subscale of the PANSS in this example) results from a smaller increase in the number of receptors being stimulated in DD than in schizophrenia.Amph.=amphetamine; Base.=baseline; DA=dopamine; DD=dual-diagnosis; Occ.=occupancy; PANSS=Positive and Negative Syndrome Scale; preDCA=precommissural dorsal caudate; SCZ=schizophrenia.

Mentions: This is the first description of a group of patients with schizophrenia who display low presynaptic dopamine release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal post-synaptic D2 function. In this small group of patients with comorbid schizophrenia and substance dependence, we observed a generalized blunting of DA release in all striatal subregions, to varying degrees, with putamen most affected and VST least affected. Despite the low range of DA release displayed by DD patients compared to controls and to previously published reports in schizophrenia, DA release was significantly associated with the amphetamine-induced change in positive symptoms, as previously observed in schizophrenia.4 Amphetamine-induced changes in positive symptoms were most strongly associated with ∆BPND in the precommissural caudate and VST, adding to the data linking psychosis more specifically with the associative striatum, as well as the limbic striatum, and confirming a prominent role for these two areas in the neurobiology of psychosis. Quantitatively, the relationship between ∆BPND and change in positive symptoms following amphetamine (∆PTOT) observed in this study is strikingly similar to that observed in patients with schizophrenia.4 When data from the two studies are pooled, analysis of model order suggests that linear regression with a shared slope is more parsimonious than fitting the two studies separately with two different slopes, F(1, 40)=1.15, p=0.71 (∆BPND=1.34 × ∆PTOT + intercept, where the fitted intercept is 13.13 for schizophrenia and 1.73 for DD; Figure 3). That is, a unit difference in ∆PTOT results from 1.34 units of difference in ∆BPND in both studies.


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. The association between ∆BPND and ∆PTOT (i.e. amphetamine-induced change in PANSS positive symptoms) for DD (n=10, data from current study; ∆BPND for preDCA) and schizophrenia (n=34, data from Laruelle et al.;4 ∆BPND for whole striatum). The lines result from a regression with a common slope and study-specific intercepts: ∆BPND = 1.34 × ∆PTOT + 13.13 (schizophrenia, dashed) or ∆BPND = 1.34 × ∆PTOT + 1.73 (DD, solid). The fit demonstrates that the same change in symptoms is associated with a smaller change in tracer binding in DD compared to schizophrenia.b. The same fits, transformed to the increase in D2 receptor occupancy by DA following amphetamine. Baseline occupancy in DD is assumed to be similar to that previously reported for substance-dependent patients.33 The main qualitative result is that a given increase in symptoms (5 on the Positive-Symptom subscale of the PANSS in this example) results from a smaller increase in the number of receptors being stimulated in DD than in schizophrenia.Amph.=amphetamine; Base.=baseline; DA=dopamine; DD=dual-diagnosis; Occ.=occupancy; PANSS=Positive and Negative Syndrome Scale; preDCA=precommissural dorsal caudate; SCZ=schizophrenia.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: a. The association between ∆BPND and ∆PTOT (i.e. amphetamine-induced change in PANSS positive symptoms) for DD (n=10, data from current study; ∆BPND for preDCA) and schizophrenia (n=34, data from Laruelle et al.;4 ∆BPND for whole striatum). The lines result from a regression with a common slope and study-specific intercepts: ∆BPND = 1.34 × ∆PTOT + 13.13 (schizophrenia, dashed) or ∆BPND = 1.34 × ∆PTOT + 1.73 (DD, solid). The fit demonstrates that the same change in symptoms is associated with a smaller change in tracer binding in DD compared to schizophrenia.b. The same fits, transformed to the increase in D2 receptor occupancy by DA following amphetamine. Baseline occupancy in DD is assumed to be similar to that previously reported for substance-dependent patients.33 The main qualitative result is that a given increase in symptoms (5 on the Positive-Symptom subscale of the PANSS in this example) results from a smaller increase in the number of receptors being stimulated in DD than in schizophrenia.Amph.=amphetamine; Base.=baseline; DA=dopamine; DD=dual-diagnosis; Occ.=occupancy; PANSS=Positive and Negative Syndrome Scale; preDCA=precommissural dorsal caudate; SCZ=schizophrenia.
Mentions: This is the first description of a group of patients with schizophrenia who display low presynaptic dopamine release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal post-synaptic D2 function. In this small group of patients with comorbid schizophrenia and substance dependence, we observed a generalized blunting of DA release in all striatal subregions, to varying degrees, with putamen most affected and VST least affected. Despite the low range of DA release displayed by DD patients compared to controls and to previously published reports in schizophrenia, DA release was significantly associated with the amphetamine-induced change in positive symptoms, as previously observed in schizophrenia.4 Amphetamine-induced changes in positive symptoms were most strongly associated with ∆BPND in the precommissural caudate and VST, adding to the data linking psychosis more specifically with the associative striatum, as well as the limbic striatum, and confirming a prominent role for these two areas in the neurobiology of psychosis. Quantitatively, the relationship between ∆BPND and change in positive symptoms following amphetamine (∆PTOT) observed in this study is strikingly similar to that observed in patients with schizophrenia.4 When data from the two studies are pooled, analysis of model order suggests that linear regression with a shared slope is more parsimonious than fitting the two studies separately with two different slopes, F(1, 40)=1.15, p=0.71 (∆BPND=1.34 × ∆PTOT + intercept, where the fitted intercept is 13.13 for schizophrenia and 1.73 for DD; Figure 3). That is, a unit difference in ∆PTOT results from 1.34 units of difference in ∆BPND in both studies.

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