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 [11C]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.
Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) with D2/3 radiotracers and the amphetamine-challenge paradigm measure the change in D2/3 radiotracer binding related to changes in synaptic DA concentration induced by amphetamine, thus providing an indirect measure of stimulated DA release. These studies have shown that, compared with healthy controls, DA release is higher in the striatum in patients with schizophrenia1, 2, 3, 4 and is blunted in those with addiction.5, 6, 7 With better topographical characterization from use of higher-resolution scanners and better data analysis methods allowing reliable measurements within the striatal subdivisions,8 more recent studies have suggested that in schizophrenia, DA transmission is increased in the precommissural caudate (preDCA) of the associative striatum (AST) in particular,9 whereas in addiction, the ventral striatum (VST) appears to be especially affected.6 In summary, DA transmission is altered in opposite directions in schizophrenia and addiction, apparently within discrete striatal subdivisions.
Epidemiological studies have shown that patients with schizophrenia are at a greater risk for developing substance-use disorders than the general population. The Epidemiological Catchment Area Study reported a 4.6-fold increase in the prevalence of any substance abuse in patients with schizophrenia, compared with the general population.10 Alcohol is most commonly used, with a lifetime prevalence of abuse or dependence of 33.7% compared with 27.5% for all other drugs. The CATIE trial reported substance use in 60% of patients with schizophrenia,11, 12 and higher rates of homelessness, depression and severity of psychosis among substance-using patients. In the 544 patients with a substance-use disorder, 87% used alcohol, 44% marijuana and 36% cocaine. A study examining the temporal relationship between use and symptoms in patients recorded in real time with electronic ambulatory monitoring found that sad mood and psychotic symptoms were associated with later substance use, and that substance use was associated with increased risk of subsequent anxiety and psychotic-symptom onset; these results suggest that while the intent may be to self medicate, the consequences are that substances may exacerbate symptoms.13 Comorbidity occurs early, as substance-use disorders are prevalent in first-episode psychosis patients (up to 50%).14, 15, 16 These patients are more likely to show non-adherence to treatment, poor remission rates17 and higher frequency of suicidal behavior.18
In summary, patients with schizophrenia are often addicted to substances, from early on, and the effects of both factors, the psychotic illness and addiction, are intertwined throughout the stages of the disorders and difficult to disentangle. Few studies have attempted to address how the neurobiology of each disorder may be changed in cases where they co-exist in the same patients. Structural imaging studies have reported inconsistent findings, with some indicating smaller brain volumes in this population when compared with schizophrenia without comorbid substance-use disorders,19, 20, 21 and others finding no change.22 No studies have assessed parameters of neurotransmission in such patients. Therefore, we undertook a study to assess striatal DA dysregulation in patients with both disorders, that is, schizophrenia and substance dependence. On the basis of available findings, our working hypothesis was that the striatal DA alterations that have been associated with each disorder, that is, higher release in the preDCA with schizophrenia and lower release in the VST with addiction, coexist in these comorbid patients. Such a set of alterations could set up a vicious cycle of using drugs to self medicate due to low ventrostriatal DA transmission, which in turn may further dysregulate DA functioning in the AST, causing or worsening psychosis. We also hypothesized that DA release in the VST would be negatively related to measures of dependence severity, whereas DA release in the preDCA would be positively associated with severity of psychosis.
This study was approved by the Institutional Review Board of New York State Psychiatric Institute (NYSPI) of Columbia University Medical Center (CUMC). All participants provided written informed consent after the procedures were fully explained to them, and all patient participants were independently assessed for capacity to provide consent by a psychiatrist who was not a member of the research team. Dual-diagnosis (DD) patients were recruited through advertisements, clinician referral, the inpatient and outpatient programs at NYSPI and the emergency department of CUMC. Healthy controls were recruited through advertisements. Medical screening procedures included a physical examination and history, blood and urine tests, an electrocardiogram and a structural magnetic resonance imaging scan of the brain. Participants were free of significant medical and neurological illnesses and were not pregnant or nursing.
Inclusion criteria for DD patients were: (1) lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) diagnosis of schizophrenia, schizoaffective or schizophreniform disorder, with the requirement of follow-up assessments of patients with schizophreniform disorder to confirm the diagnosis of schizophrenia; (2) lifetime DSM-IV diagnosis of alcohol, cannabis, and/or cocaine dependence; (3) no history of violent behavior; (4) no antipsychotic treatment for 3 weeks before PET scan participation; and (5) a negative urine drug screen prior to PET. Nicotine dependence was permitted for DD patients. Inclusion criteria for healthy controls were: (1) absence of any current or past DSM-IV Axis-I diagnosis, including substance abuse (past but not current nicotine dependence was permitted); and (2) no family history (first-degree) of psychotic illness. Current smokers were excluded from the control group with the aim of having a ‘clean’ comparison group with regard to any kind of substance dependence. Diagnostic status was determined with the Psychiatric Research Interview for Substance and Mental Disorders for DSM-IV 23 for DD patients, and with either the Diagnostic Interview for Genetic Studies24 or an abbreviated version of the Structured Clinical Interview for DSM-IV Axis I disorders25 for healthy controls. Participant and parental socioeconomic status were calculated according to Hollingshead.26 Additionally, within 1 week before participating in PET, DD patients were assessed with the Positive and Negative Syndrome Scale (PANSS).27 Clinical assessments were administered by trained interviewers.
DD patients with current drug use upon study enrollment were offered inpatient admission to assist in fulfilling the abstinence requirements for PET participation. Patients who were psychiatrically stable were permitted to undergo detoxification as outpatients, underwent weekly urine toxicology tests (at minimum), and were scheduled for PET once they tested negative. A urine toxicology test was repeated on PET days to confirm abstinence.
All participants underwent two PET scans with an ECAT EXACT HR+ scanner (Siemens/CTI, Knoxville, TN, USA) on the same day: at baseline and after receiving amphetamine. [11C]raclopride was administered as bolus plus constant infusion for 80 min, as previously described.28 Emission scan data were collected in 3-dimensional mode 40–80 min after [11C]raclopride injection as eight frames of 5 min each. The second [11C]raclopride injection was initiated 2 min after i.v. administration of 0.3 mg/kg of dextro-amphetamine. Venous blood samples were collected 40 min after amphetamine administration to measure plasma amphetamine levels.
All participants received a high-resolution structural magnetic resonance imaging scan for coregistration. Image analysis was performed using MEDx (Medical Numerics, MD, USA). The striatum was divided into five anatomical regions of interest (ROIs): VST, preDCA, precommissural dorsal putamen (preDPU), postcommissural caudate (postCA) and postcommissural putamen (postPU).29 Based on the input each of these regions receives, they have been classified into three functional subdivisions: the limbic striatum (comprising the VST), the AST (comprising the preDCA, preDPU and postCA), and the sensorimotor striatum (comprising the postPU). ROIs were manually drawn on each subject's magnetic resonance image and transferred to co-registered PET data. Cerebellum (CER) was used as a reference region to estimate the concentration of free and non-specifically bound [11C]raclopride. Our analyses included the five striatal subregions and a composite ‘whole striatum’ region.
Equilibrium analysis was used to derive the outcome measure BPND (binding potential relative to the nondisplaceable compartment in the brain):
BPND reflects DA D2/3 receptor availability, as measured by [11C]raclopride. The primary outcome measure for this study was the percent change in BPND from baseline to post-amphetamine scan (ΔBPND); this measure reflects the relative reduction in D2/3 receptor availability for [11C]raclopride binding after amphetamine-induced DA release, and thus is used to index amphetamine-induced DA release.
Cardiovascular and behavioral responses to amphetamine
Blood pressure and heart rate of participants were measured at baseline and at regular intervals after amphetamine administration (approximately every 2.5 min for the first 20 min, every 5 min from 20–40 min and every 10 min from 40–80 min). Subjective responses to amphetamine were measured using a simplified version of the Amphetamine Interview Rating Scale (AIRS);30, 31 Supplementary Table S1. The area under the curve (AUC) was calculated, relative to baseline, for each cardiovascular measure and AIRS item. The PANSS was used to evaluate behavioral responses to amphetamine. Change scores from pre- to post-amphetamine were calculated for the PANSS (Positive-symptom and Negative-symptom subscales); Supplementary Table S2.
Group comparisons on demographic features were performed with independent-samples t-tests or χ2-tests. Within-subject comparisons on scan parameters across scan conditions were performed with paired t-tests, and between-group comparisons on scan parameters, striatal volumes and AUC values (cardiovascular and AIRS) were performed with independent-samples t-tests. In the case of non-normally distributed data, comparisons were repeated with non-parametric tests (Wilcoxon for paired tests, Mann−Whitney U-test for independent-samples tests); non-parametric test results are included here only if they differed from parametric test results. Group comparisons on our primary PET outcome measures, baseline BPND and ΔBPND, were performed using linear mixed modeling for which diagnosis (DD versus control) and region of interest (ROI; five striatal subregions) were treated as fixed effects, and ROI was treated as a repeated-measures variable; between-group planned comparisons were also conducted for each striatal subregion. Cohen's d was used as an index of effect size; the s.d. pooled across the two groups was used for this calculation. Correlational analyses were performed using Spearman's rank correlations, because of non-normal distributions (skew and/or kurtosis) observed for several variables. For exploratory analyses, we used Bonferroni correction for comparisons across six ROIs (five striatal subregions and whole striatum), which resulted in an adjusted P value of 0.008. All statistical tests were two-tailed.
Demographic and clinical characteristics
Twenty-one patients were enrolled to participate in this study; however, because of technical difficulties or participant withdrawal, only 13 of these 21 patients completed the scanning procedures. Data from two of these patients were excluded from analyses (one because of excessive movement in the scanner, and the other because additional diagnostic information on follow-up suggested that her initial presentation of schizoaffective disorder was due to Lyme disease), resulting in a final patient group of 11. Fifteen healthy adults matched to the patient group for age, sex, ethnicity and parental socioeconomic status were included as a comparison group (Table 1). DD patients had significantly lower participant socioeconomic status compared with controls, t(17.91)=−2.97, P=0.008; Table 1.
Six of the eleven DD patients met the criteria for schizophrenia, four for schizoaffective disorder and one for schizophreniform disorder (with a later confirmed diagnosis of schizophrenia). Their mean age of psychosis onset was 18.09±4.16, and duration of psychotic illness averaged to 11.0±8.73 years (Table 1). Two patients were antipsychotic-naive. DD patients met the criteria for current or past cannabis dependence (n=10) or abuse (n=1), alcohol dependence (n=8), and/or cocaine dependence (n=3); Supplementary Table S3. Eight DD patients reported current regular tobacco use (all controls were nonsmokers). Patients began using drugs on a regular basis at a mean age of 16.45±2.46, which was, on average, 12.90±7.68 years before study participation.
Striatal subregion volumes
There were no significant group differences in any of the ROI volumes. Across the total sample, age was negatively associated with volumes of the preDCA (rs=−0.49, P=0.011) and whole striatum (rs=−0.47, P=0.016); however, these associations were not significant after Bonferroni correction.
There were no significant differences between conditions (baseline and post-amphetamine) or between groups in injected dose, injected mass or specific activity of [11C]raclopride (Table 1). Likewise, the groups did not differ significantly in their plasma amphetamine levels.
Group comparisons on baseline BPND and ΔBPND
Baseline D2/3 receptor availability
Linear mixed modeling using baseline BPND as the dependent variable and striatal ROI (the five subregions) as a repeated measure showed no significant effect of diagnosis (F(1, 24)=1.12, P=0.301; Table 2). There was a significant main effect of ROI (F(4, 24)=317.69, P<0.001), and the diagnosis × ROI interaction was also significant (F(4, 24)=2.78, P=0.050). However, as indicated by planned pairwise comparisons of the estimated marginal means derived from the linear mixed model, there were no significant group differences in baseline BPND in any of the striatal subregions (Table 2).
Amphetamine-induced reduction in D2/3 receptor availability
Linear mixed modeling using ΔBPND as the dependent variable and striatal ROI as a repeated measure indicated significant main effects of diagnosis (F(1, 24)=8.38, P=0.008; Table 2 and Figure 1a) and ROI (F(4, 24)=46.51, P<0.001); however, the diagnosis × ROI interaction was not significant (F(4, 24)=0.67, P=0.618). Between-group planned comparisons of the estimated marginal means indicated that DD patients had significantly smaller amphetamine-induced ΔBPND in all striatal subregions except for VST (Table 2 and Figure 1a). The effect sizes (Cohen's d) for group differences in ΔBPND 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.
Cardiovascular and behavioral responses to amphetamine
The groups did not differ significantly in their mean change (AUC) in systolic or diastolic blood pressure or heart rate following amphetamine administration. As compared with controls, DD patients reported experiencing a greater increase in happiness (t(22)=2.68, P=0.014) and energy (t(22)=2.03, P=0.054; Mann−Whitney U-test, P=0.032) after amphetamine administration (mean AUC of self-report AIRS ratings; n=9 for patients because of missing data); these differences were not considered significant after Bonferroni correction. Groups did not differ significantly in their amphetamine-related restlessness or anxiety ratings (Supplementary Table S1). Among controls but not patients, changes in ratings of energy were positively associated with ΔBPND in the preDPU (rs=0.72, P=0.002), preDCA (rs=0.76, P=0.001), VST (rs=0.69, P=0.005), and whole striatum (rs=0.74, P=0.002).
Supplementary Table S2 provides the pre-amphetamine and amphetamine-related change scores for the PANSS (Positive-symptom and Negative-symptom subscales) by group. There was a large degree of inter-subject variability in positive-symptom change scores (ΔPTOT) among patients, in contrast to controls (DD range=−6.0 to 10.0; control range=0.0 to 6.0; Figure 2). For controls, the mean increase in positive symptoms after amphetamine (1.36±1.87, n=14; Supplementary Table S2) was primarily driven by the excitement item of the Positive-Symptom subscale. As predicted, among DD patients, ΔPTOT (n=10; Figure 2) was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.029; Figure 2). This relationship was also observed in the VST (rs=0.64, P=0.048), although it was not considered significant after multiple-comparisons correction. ΔPTOT was not significantly related to ΔBPND at the level of the whole striatum (rs=0.36, P=0.306).
Correlations with baseline symptoms and other clinical features
Among the DD patients, there was a significant negative association between the age of psychosis onset and ΔBPND in the preDPU (rs=−0.77, P=0.005), indicating that DD patients who developed psychotic symptoms at an earlier age had greater ΔBPND in the preDPU (or conversely that those with a later age of onset had lower preDPU ΔBPND). There were no other significant associations between psychosis age of onset, duration of psychotic illness, or weeks since antipsychotic medication exposure and baseline BPND or ΔBPND across the striatal subregions. There were also no significant associations between age of onset of regular drug use, years since regular drug use was initiated, or weeks since last drug use and BPND or ΔBPND across the striatal subregions. Baseline symptom severity as measured by the PANSS (using the standard 7-day assessment time frame) was not significantly associated with baseline BPND or ΔBPND in any striatal subregion.
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. 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 with controls and with 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 ΔBPND in the preDCA and VST, adding to the data linking psychosis more specifically with the AST, as well as the limbic striatum, and confirming a prominent role for these two areas in the neurobiology of psychosis. Quantitatively, the relationship between ΔBPND and change in positive symptoms following amphetamine (ΔPTOT) 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 (ΔBPND=1.34 × ΔPTOT+intercept, where the fitted intercept is 13.13 for schizophrenia and 1.73 for DD; Figure 3). That is, a unit difference in ΔPTOT results from 1.34 units of difference in ΔBPND in both studies.
To explore this further, we reframed this correlation in terms of D2 receptor occupancy by DA rather than ΔBPND, assuming that the main effect in ΔBPND is due to competition with DA and using existing information regarding baseline receptor occupancy by DA:
DA depletion studies have suggested that average baseline D2 receptor occupancy by DA is ∼20% in schizophrenia32 and ∼7% in substance dependence.33 It is not known which of these might be more reflective of baseline occupancy in DD, but any baseline occupancy in the range of 7−20% results in the relationship between amphetamine-induced change in occupancy and ΔPTOT being nearly parallel for both groups, with DD biased downward compared with schizophrenia (Figure 3b). The lower intercept observed for DD compared with schizophrenia suggests that, assuming similar levels of receptor availability, a smaller increase in D2 receptor occupancy by DA in DD compared with schizophrenia leads to a similar magnitude of symptom change. These results suggest that D2 receptors are more sensitive to DA in terms of psychosis exacerbation in DD compared with schizophrenia. Thus, our findings suggest that D2 function may be abnormal in this group of patients, such that small variations in agonist stimulation have amplified effects. These may be due to abnormal intracellular signaling events, or alternatively, could be an indirect effect of D2 stimulation on other non-dopaminergic components of the network that may be abnormal in schizophrenia. The exact mechanism of this D2-mediated effect is unclear.
Prior research suggests that the blunted DA release observed among the DD patients is related to their comorbid drug use. The primary drugs of dependence included alcohol and cannabis, and the majority also reported current tobacco use. Previous studies have shown that alcohol dependence is associated with blunted DA release,6, 34 whereas cannabis dependence, at least of moderate severity, is not.35 With regard to tobacco use, there are reports of both decreased D2 receptor availability36 and reduced amphetamine-induced DA release in the striatum of nicotine-dependent subjects.37 A limitation of this study is that we cannot distinguish the respective contributions of any one of these drugs to the overall decrease in DA transmission. For example, most of the DD patients reported current regular cigarette smoking, and this tobacco use may have contributed to our results. However, given that all of the patients used more than one drug and the sample is too small to examine the effect of each drug separately, this study cannot address such questions.
There are no clear mechanisms at this point to explain the decrease in presynaptic DA either in this study or in prior studies reporting a similar decrease in substance-use disorders. One view is that the decrease may precede drug use and predispose patients to develop addictions, whereas another is that the decrease is a result of chronic substance use (for discussion, see Volkow and colleagues38, 39, 40).
In contrast to the findings in addiction,6, 34, 36 we did not observe a downregulation of D2 receptors. This may be because of the small sample size and/or the confounding effect of previous antipsychotic exposure, which is known to induce an upregulation of D2.
Our sample size is relatively small because of the difficulty in recruiting this group of patients. Nevertheless, our results are clear and compelling regarding the magnitude of DA blunting detected in these patients. However, the small sample size limited our ability to confidently characterize some of the clinical correlates of this blunted DA release.
In summary, we observed that patients with comorbid schizophrenia and mixed substance dependence displayed significant blunting of striatal DA release. Despite this blunting, DA release was associated with acute and transient increases in positive symptoms. Overall, these findings suggest that in substance-dependent patients with schizophrenia, hypersensitivity of D2 receptors to dopaminergic stimulation is the predominant dopaminergic alteration, as opposed to excess presynaptic release.41 This hypersensitivity may be related to intrinsic factors within the D2 signaling cascade42 and/or from the effects of excess D2 signaling on the rest of the circuitry. Translational studies of altered pre- and postsynaptic mechanisms are needed to clarify this issue.
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235–9240.
Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–767.
Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997; 94: 2569–2574.
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R . Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999; 46: 56–72.
Martinez D, Narendran R, Foltin RW, Slifstein M, Hwang DR, Broft A et al. Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry 2007; 164: 622–629.
Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A et al. Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 2005; 58: 779–786.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 1997; 386: 830–833.
Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR et al. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D2 receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 2001; 21: 1034–1057.
Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010; 67: 231–239.
Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990; 264: 2511–2518.
Swartz MS, Wagner HR, Swanson JW, Stroup TS, McEvoy JP, McGee M et al. Substance use and psychosocial functioning in schizophrenia among new enrollees in the NIMH CATIE study. Psychiatr Serv 2006; 57: 1110–1116.
Swartz MS, Wagner HR, Swanson JW, Stroup TS, McEvoy JP, Canive JM et al. Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study. J Nerv Ment Dis 2006; 194: 164–172.
Swendsen J, Ben-Zeev D, Granholm E . Real-time electronic ambulatory monitoring of substance use and symptom expression in schizophrenia. Am J Psychiatry 2011; 168: 202–209.
Cantwell R, Brewin J, Glazebrook C, Dalkin T, Fox R, Medley I et al. Prevalence of substance misuse in first-episode psychosis. Br J Psychiatry 1999; 174: 150–153.
Van Mastrigt S, Addington J, Addington D . Substance misuse at presentation to an early psychosis program. Soc Psychiatry Psychiatr Epidemiol 2004; 39: 69–72.
Barnett JH, Werners U, Secher SM, Hill KE, Brazil R, Masson K et al. Substance use in a population-based clinic sample of people with first-episode psychosis. Br J Psychiatry 2007; 190: 515–520.
Lambert M, Conus P, Lubman DI, Wade D, Yuen H, Moritz S et al. The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis. Acta Psychiatr Scand 2005; 112: 141–148.
Verdoux H, Liraud F, Gonzales B, Assens F, Abalan F, van Os J . Suicidality and substance misuse in first-admitted subjects with psychotic disorder. Acta Psychiatr Scand 1999; 100: 389–395.
Schiffer B, Muller BW, Scherbaum N, Forsting M, Wiltfang J, Leygraf N et al. Impulsivity-related brain volume deficits in schizophrenia-addiction comorbidity. Brain 2010; 133: 3093–3103.
Ebdrup BH, Glenthoj B, Rasmussen H, Aggernaes B, Langkilde AR, Paulson OB et al. Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia. J Psychiatry Neurosci 2010; 35: 95–104.
Mathalon DH, Pfefferbaum A, Lim KO, Rosenbloom MJ, Sullivan EV . Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Arch Gen Psychiatry 2003; 60: 245–252.
Wobrock T, Sittinger H, Behrendt B, D’Amelio R, Falkai P . Comorbid substance abuse and brain morphology in recent-onset psychosis. Eur Arch Psychiatry Clin Neurosci 2009; 259: 28–36.
Hasin D, Samet S, Nunes E, Meydan J, Matseoane K, Waxman R . Diagnosis of comorbid psychiatric disorders in substance users assessed with the psychiatric research interview for substance and mental disorders for DSM-IV. Am J Psychiatry 2006; 163: 689–696.
Nurnberger Jr JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH genetics initiative. Arch Gen Psychiatry 1994; 51: 849–859.
First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders - Non-Patient Edition. New York Biometrics Research: New York State Psychiatric Institute, New York, NY, USA, 1996.
Hollingshead AB . Four Factor Index of Social Status, Working paper Connecticut, 1975 (Unpublished Working Paper, Department of Sociology, Yale University, New Haven, CT, USA).
Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.
Watabe H, Endres CJ, Breier A, Schmall B, Eckelman WC, Carson RE . Measurement of dopamine release with continuous infusion of [11C]raclopride: Optimization and signal-to-noise considerations. J Nucl Med 2000; 41: 522–530.
Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y et al. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 2003; 23: 285–300.
van Kammen DP, Murphy DL . Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment. Psychopharmacologia 1975; 44: 215–224.
Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea-Ponce Y, Zoghbi SS et al. SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med 1995; 36: 1182–1190.
Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000; 97: 8104–8109.
Martinez D, Greene K, Broft A, Kumar D, Liu F, Narendran R et al. Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion. Am J Psychiatry 2009; 166: 1170–1177.
Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M et al. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci 2007; 27: 12700–12706.
Urban NB, Slifstein M, Thompson JL, Xu X, Girgis RR, Raheja S et al. Dopamine release in chronic cannabis users: A [(11)C]raclopride positron emission tomography study. Biol Psychiatry 2012; 71: 677–683.
Fehr C, Yakushev I, Hohmann N, Buchholz HG, Landvogt C, Deckers H et al. Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse. Am J Psychiatry 2008; 165: 507–514.
Busto UE, Redden L, Mayberg H, Kapur S, Houle S, Zawertailo LA . Dopaminergic activity in depressed smokers: a positron emission tomography study. Synapse 2009; 63: 681–689.
Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F . Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol 2007; 64: 1575–1579.
Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F . Imaging dopamine's role in drug abuse and addiction. Neuropharmacology 2009; 56 (Suppl 1): 3–8.
Michaelides M, Thanos PK, Kim R, Cho J, Ananth M, Wang GJ et al. PET imaging predicts future body weight and cocaine preference. Neuroimage 2012; 59: 1508–1513.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment: Meta-analysis of imaging studies. Arch Gen Psychiatry 2012: doi:10.1001/archgenpsychiatry.2012.1169.
Schubert KO, Focking M, Prehn JH, Cotter DR . Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder? Mol Psychiatry 2011; 0: 1–13.
We thank the research participants of this study and express gratitude for the expert assistance of Beatriz Alvarez, Rawad Ayoub, Jennifer Bae, Felipe Castillo, John Castrillon, Ray Goetz, Elizabeth Hackett, Deborah Hasin, Olga Kambalov, Olga Medina, Elizabeth Raggi and Sharon Samet. This work was supported by a grant from the National Institute on Drug Abuse [R21 DA023039-01] to Anissa Abi-Dargham.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
About this article
Cite this article
Thompson, J., Urban, N., Slifstein, M. et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry 18, 909–915 (2013). https://doi.org/10.1038/mp.2012.109
- drug dependence
Schizophrenia Bulletin (2020)
Schizophrenia Research (2020)
Biological Psychiatry (2020)
JAMA Psychiatry (2020)