Regional striatal volume abnormalities in schizophrenia: Effects of comorbidity for alcoholism, recency of alcoholic drinking, and antipsychotic medication type

Schizophrenia Research 79 (2005) 189 – 200 www.elsevier.com/locate/schres

Regional striatal volume abnormalities in schizophrenia: Effects of comorbidity for alcoholism, recency of alcoholic drinking, and antipsychotic medication type Anjali Deshmukha, Margaret J. Rosenblooma,b, Eve De Rosac, Edith V. Sullivanb,*, Adolf Pfefferbauma,b b

a Neuroscience Program, SRI International, Menlo Park, California Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Stanford University School of Medicine, Stanford, CA 94305-5723 c Department of Psychology, University of Toronto, Toronto, Ontario, Canada

Received 9 February 2005; received in revised form 18 April 2005; accepted 26 April 2005 Available online 15 June 2005

Abstract Striatal structures form critical nodes of multiple circuits that are implicated in the pathophysiology of schizophrenia and alcoholism. Here, we examined the separate and combined effects of schizophrenia and alcoholism and effects of medication type and drinking recency on striatal volumes. Accordingly, we measured caudate nucleus, putamen, and nucleus accumbens in 27 schizophrenic, 25 alcohol-dependent, 19 comorbid (schizophrenia and alcohol dependence or abuse), and 51 age-matched control men. Schizophrenics were classified by antipsychotic medication (typical or atypical), and alcoholics were classified by recency of sobriety. All measured structures were smaller in the patient groups than the control group. The caudate deficit was comparable across groups, whereas putamen and nucleus accumbens deficits were greater in schizophrenia than alcoholism; comorbids fell between these groups. Schizophrenic patients treated with atypical medication showed greater volume deficits in the putamen than those treated with typical medication. Recently sober (b 3 weeks) alcoholics had greater deficits in nucleus accumbens than longer sober drinkers. In conclusion, caudate, putamen, and nucleus accumbens exhibited different patterns of volume deficit in patients with alcoholism and schizophrenia alone, with no evidence for compounded deficits in comorbid patients. Further, these cross-sectional data provide indirect support for at least partial recovery of nucleus accumbens volume with sobriety in alcoholics, regardless of schizophrenia comorbidity. D 2005 Elsevier B.V. All rights reserved. Keywords: Striatum; Nucleus accumbens; Caudate nucleus; Putamen; Alcoholism; Schizophrenia; Comorbidity

* Corresponding author. Tel.: +1 650 498 7328; fax: +1 650 859 2743. E-mail address: [email protected] (E.V. Sullivan). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.04.025

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1. Introduction Alcohol comorbidity has a high prevalence in schizophrenia (Cuffel, 1992; Fowler et al., 1998; Regier et al., 1990) and an adverse impact on its clinical course (for reviews, see Buckley, 1998; Dixon, 1999). Comorbidity with alcoholism also compounds or accounts for brain volume abnormalities of schizophrenia in cortical (Mathalon et al., 2003), cerebellar (Sullivan et al., 2000), pontine and thalamic (Sullivan et al., 2003) sites. Striatal structures are of considerable relevance to the study of alcoholism and its comorbidity with schizophrenia because they have been shown in studies of alcoholics to be the site of preferential alcohol-related dopamine release (Boileau et al., 2003) and lower dopamine D2 receptor levels (Heinz et al., 2004; Volkow et al., 2002) and also demonstrate activation specifically associated with alcohol-related cues (Braus et al., 2001; George et al., 2001; Heinz et al., 2004; Myrick et al., 2004). In particular, the nucleus accumbens, a component of the extended amygdala, has been identified as critically involved in the reinforcing effects of alcohol and other drugs of abuse (Koob, 2000). Furthermore, it has been hypothesized that abnormalities of the reward-related neural circuitry found in schizophrenia may render patients vulnerable to addictive behavior (Chambers et al., 2001). Until recently, however, there has been limited evidence that alcoholism on its own has a measurable impact on the volume of any striatal structure. Indeed, neuropathological studies of alcoholic brains have reported no volume loss in various basal ganglia structures including caudate, putamen, and globus pallidus (for review, see Harper, 1998). However, one MRI study reported volume deficits of the caudate nucleus in children with fetal alcohol syndrome compared with control children (Archibald et al., 2001). Another, based on the same alcoholic and comparison subjects as in the current report, showed volume deficits in caudate and putamen in alcoholic men as well as reduction in nucleus accumbens, most marked in those recently drinking (Sullivan et al., 2005). Dysmorphology of striatal brain structures in chronically treated schizophrenia is attributable both to intrinsic pathology and to the effects of antipsychotic medication. First episode, neuroleptic naı¨ve patients show small or normal volumes (Gunduz et al., 2002;

Gur et al., 1998; Keshavan et al., 1998; Levitt et al., 2002), whereas postmortem (Heckers et al., 1991) and in vivo (Gur et al., 1998; Hokama et al., 1995; Jernigan et al., 1991) studies of schizophrenia patients on btypicalQ medication showed enlarged striatal structures. Longitudinal studies comparing patients before and after treatment with typical antipsychotics have shown caudate volume enlargement (Chakos et al., 1994; Corson et al., 1999; Keshavan et al., 1994), whereas those following patients treated exclusively or predominantly with atypical antipsychotics have shown reduction in various striatal structure volumes (Chakos et al., 1995; Corson et al., 1999; Scheepers et al., 2001). The effect of typical antipsychotic medication on nucleus accumbens volumes in schizophrenia has not been widely reported, but this structure, along with the caudate and putamen, is a site for the D2 receptor blockade by typical antipsychotic medication. Such a blockade leads to changes in synaptic plasticity, including possible increase in number of neurons as well as of synapses that may contribute to observed volume increases (for reviews see Kapur and Mamo, 2003; Konradi and Heckers, 2001). The current analysis addressed three questions: does comorbidity for alcoholism exacerbate striatal volume abnormalities in schizophrenia as it exacerbates abnormalities in other brain structures; does antipsychotic medication type affect volume abnormalities in patients with schizophrenia, regardless of their comorbidity for alcoholism; and does the nucleus accumbens show the same pattern of sensitivity to recent alcohol consumption in comorbid patients as was found in non-comorbid alcoholics? To answer these questions, we compared volumes of the putamen, caudate nucleus, and nucleus accumbens in patients with alcoholism alone, schizophrenia alone, schizophrenia with alcoholism, and healthy comparison subjects, classifying both groups of patients with schizophrenia by medication type and both groups of patients with alcoholism by recency of sobriety.

2. Methods 2.1. Subjects All four groups of participants were included in earlier reports on the cerebellum (Sullivan et al.,

717.7 696.1 7.66 11.9

10.1 8.1 2.9 784.4 47.4 107.5 14.0 838.9 – – 10.9 6.3 2.8 923.2 42.8 104.2 13.4 1014.7 – –

–

8.1 5.8 2.1 143.0 9.6 7.4 41.5 110.5 14.3 104.5 39.3 17.0

c

b

a

– 560.9 771.7 – 503.48 648.14 –

4-Group: F = 4.20, df = 3, 95, p b 0.008. Comparison N alcohol, schizophrenia, comorbid. 4-Group: F = 9.07, df = 3, 118, p b 0.0001. Comparison N alcohol, schizophrenia, comorbid. 4-Group: F = 59.25, df = 3, 103, p b 0.0001. Alcohol N comorbid, schizophrenia, comparison.

7.9 7.0 1.9 192.4 7.7 7.9 41 7.5 43.6 106.4 6.6 105.5 13.7 1.6 13.9 218.6 214.7 106.5 42.8 8.4 43.5 18.2 6.8 21.4 45.2 13.9 49.4 10.9 44.7 112.5 7.0 106.7 8.3 108.6 16.3 2.4 13.9 3.4 14 56.1 80.3 1263.6 790.1 22.4 – – 41.9 – – 21.4

Age (years) Premorbid IQ (NART)a Years of educatiuonb Lifetime alcohol intake (kg)c BPRS total score Length ill with schizophrenia (years) Length sober (days)

Mean

SD Mean SD

8.6 7.8 2.4 25.4 9.1 8.3

SD Mean SD Mean SD Mean SD Mean Mean SD SD

On typical antipsychotics (n = 13)

Measures

Mean

Sober b 3 weeks brecently soberQ (n = 11) On typical antipsychotics (n = 29)

Sober N 3 weeks blonger soberQ (n = 31)

Patients with alcohol dependence alone and alcohol dependence with schizophrenia Patients with schizophrenia alone and schizophrenia with alcohol dependence

Patients with alcohol dependence (n = 25) Healthy comparison subjects (n = 51)

Patients with Patients with schizophrenia schizophrenia (n = 27) and alcohol dependence (n = 19)

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Group

2000), cortex (Mathalon et al., 2003), and thalamus and pons (Sullivan et al., 2003); only the alcoholics and controls were included in an earlier report on striatal structures (Sullivan et al., 2005). All subjects were men and gave written informed consent to participate in neuroimaging research after reading a detailed description of the study and having any questions answered. The protocol was approved by the Stanford University and the Veterans Affairs Institutional Review Boards; data analysis was approved by SRI International and Stanford University. Patients were recruited from a Veterans Administration medical center and included 27 with a DSM-III-R Axis I diagnosis of schizophrenia only, 19 comorbid for DSM-III-R-defined schizophrenia and alcohol dependence or abuse, and 25 with DSM-III-R-defined alcohol dependence only. Patients with a lifetime diagnosis of non-alcohol substance dependence or current diagnosis of non-alcohol substance abuse or any other Axis I disorder were excluded. Most of the schizophrenic patients were scanned while inpatients. Patients with alcoholism were scanned when returning for follow-up studies (Pfefferbaum et al., 1995, 1998). Lifetime alcohol consumption was assessed with a semi-structured interview (Pfefferbaum et al., 1992; Skinner, 1982; Skinner and Sheu, 1982) in all patients with alcoholism and healthy comparison subjects, 14 of the 19 comorbid patients, and 19 of the 27 patients with schizophrenia only. Length of sobriety at time of MRI varied considerably for both comorbid (14 to 2382 days, median = 150) and alcoholic (1 to 1994 days, median = 204) patients but did not differ between groups (Mann Whitney U = 86, df = 32, p = 0.30). Patients scanned within 3 weeks of their last drink (6 alcoholics and 5 comorbids) were classified as brecently sober.Q They did not differ from the blonger soberQ alcoholics in age, years of education, or lifetime alcohol use. All schizophrenia and comorbid patients were being treated pharmacologically when tested, with the majority (17 schizophrenia, 12 comorbid) on typical antipsychotic medication. Patients on typical medication did not differ in age, years of education, or lifetime alcohol use from those on atypical medication. Current symptom severity was evaluated in patients with schizophrenia using the Brief Psychiatric Rating Scale (BPRS), administered by two raters with

Table 1 Demographic characteristics of 4 study groups, combined schizophrenia group divided by medication type, and combined alcoholism group divided by sobriety length

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established reliability. BPRS scores (total, positive symptoms, negative symptoms) did not significantly differ between comorbid and schizophrenia patients, or between patients on typical and those on atypical medications. The healthy comparison group (N = 51) was recruited from the local community and screened to exclude any Axis I disorder, substance abuse in the year before the study, and alcohol consumption of more than four drinks a day for over a month. One-way analyses of variance (ANOVAs) of demographic variables (Table 1) across the four groups yielded significant differences in education ( F = 9.07, df = 3, 118, pb0.0001), premorbid intelligence (estimated with the National Adult Reading Test (NART) (Nelson, 1982) ( F = 4.20, df = 3, 95, pb0.008), and total lifetime consumption of alcohol ( F = 59.25, df = 3, 103, pb0.0001) but not age ( F = 1.99, df = 3, 118, p = 0.12). Follow-up t-tests revealed that the group with alcoholism only consumed more alcohol than any other group ( p = .0001 for each comparison) and that the comorbid group consumed ten times more alcohol in their lifetime than the schizophrenic group (t(30) = 4.113, p = .0003) and four times more than the control group (t(61) = 4.611, p = .0001). Differences

among the comorbid, schizophrenia, and healthy comparison groups were not significant. The three patient groups had equivalent years of education and NART IQs. 2.2. Image acquisition and analysis MRI scans were acquired on a 1.5T General Electric Signa using a 3D SPoiled Gradient Recalled (SPGR) sequence (TR = 24 ms; TE = 5 ms; flip angle 408; 124 slices; 24 cm field of view; 256  196 matrix, reconstructed resolution = 0.9  0.9  1.5 mm, acquired resolution = 0.9  1.2  1.5 mm). Image data were reformatted to 1 mm isotropic voxels and aligned along the anterior–posterior commissural plane and interhemispheric fissure. All images were coded to allow processing to be performed blind to all aspects of subject identity. The borders for each region of interest were traced by placing points following anatomical landmarks on successive 1.0 mm thick coronal slices using in-house software developed and run on a Unix platform with IDL (Boulder, CO) (Fig. 1). Volumes for each structure were estimated by summing designated pixels across all slices on which that structure appeared.

Fig. 1. Example of manual outlining of caudate, putamen, and nucleus accumbens on 16 consecutive coronal slices, for a 37-year old comorbid man. Color-coded outlines from manual scoring are presented for the putamen, caudate and nucleus accumbens on each slice where they appear.

0.3 0.3 0.97 0.48 0.2 0.5 0.77 1.35 0.2 0.8 0.76 1.41 0.2 0.9 0.85 1.04 0.3 1.0 0.86 1.00 0.2 0.8 0.79 1.24 0.3 1.2 0.96 0.48 0.2 0.9 1.10 0.00

1.01 to 1.19 0.37 to 0.37

1.2 1.1 5.73 0.73 0.7 0.7 5.26 1.22 0.8 0.9 4.89 1.66 0.8 0.7 5.38 1.12 0.8 0.7 5.41 1.12 1.0 1.0 5.21 1.29 1.2 1.2 5.75 0.68 0.9 0.9 6.47 0.00

6.11 to 6.80 0.37 to 0.37

0.9 1.2 5.12 0.79 0.8 1.1 5.06 0.87 0.6 0.8 5.00 0.99 0.8 1.0 5.30 0.55 0.6 0.7 5.10 0.84 0.8 1.1 5.29 0.57 1.0 1.4 5.12 0.78 5.43 to 5.95 0.37 to 0.37 0.7 1.0 5.69 0.00

Caudate Volume (cm3) Z-score Putamen Volume (cm3) Z-score Nucleus accumbens Volume (cm3) Z-score

SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean 99% Cl SD Mean

Sober N 3 weeks blonger soberQ (n = 31) Sober b 3 weeks brecently soberQ (n = 11) On typical antipsychotics (n = 13) On typical antipsychotics (n = 29)

Patients with alcohol dependence alone and alcohol dependence with schizophrenia (n = 42) Patients with schizophrenia alone and schizophrenia with alcohol dependence (n = 42)

Patients with schizophrenia and alcohol dependence (n = 19)

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Brain region and measure

To standardize measurements of these structures, particularly the nucleus accumbens, which is considerably smaller than caudate and putamen, and adjust for variance observed in controls attributable to intracranial volume (ICV) and age, we derived Z-scores using a two-step regression analysis previously described (Pfefferbaum et al., 1992, 1994). Z-scores were derived by first regressing the volume of each structure against an estimate of ICV based on a three dimensional volume of the cerebrum (Sullivan et al., 2000, 2001). The resulting regression coefficients were used to calculate ICV-residualized scores that were then regressed on age. Values from individual subjects were converted to standardized Z-scores with an expected mean for the comparison subjects of Z = 0 F 1 S.D. Data were also analyzed as absolute volumes. Group differences in structures were assessed with four-group, one-way ANOVAs with follow-up t-tests (alpha = .05, one-tailed Scheffe test for comparisons between patient and comparison groups). Two-group repeated measures ANOVAs for caudate, putamen, and nucleus accumbens were also performed for each patient group relative to compari-

Patients with schizophrenia (n = 27)

2.4. Statistical analysis

Patients with alcohol dependence (n = 25)

A detailed description of structure boundaries and reliability assessments is provided in a separate report (Sullivan et al., 2005). In brief, the caudate and putamen were traced on 18 to 20 slices from the most anterior slice on which each were visualized bilaterally to the last on which the internal capsule extended to cerebral peduncle. The nucleus accumbens was measured on 6 to 8 slices starting with the slice on which bilateral putamen was present and ending where the globus pallidus, anterior commissure, and optic chiasm appeared bilaterally. Inter-rater reliability for 14 cases drawn quasi-randomly from this dataset ranged from 0.85 to 0.97 for all structures except the left caudate region, which was only 0.72. To compensate for low intra-class correlations, both raters (AD and EDR) measured the left and right caudate regions in all subjects, and the unilateral volumes were expressed as the mean of the measurements made by the two scorers.

Healthy comparison subjects (n = 51)

2.3. Regions of interest measurement and reliability

Table 2 Unadjusted volumes (cc) and Z-scores for bilateral caudate, putamen, and nucleus accumbens for 4 study groups, combined schizophrenia group divided by medication type, and combined alcoholism group divided by sobriety length

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son subjects, and schizophrenic patients relative to alcoholic patients, to test for group by structure interactions that would signify a structurally specific pattern of deficit. The contribution of antipsychotic medication type to volume of each striatal structure in schizophrenia patients (with or without alcohol comorbidity) was assessed by a two-by-two group ANOVA for diagnosis (schizophrenic vs. comorbid) and medication type (typical vs. atypical) with follow-up t-tests. A similar analysis was performed for contribution of drinking recency among alcoholics and comorbid patients. Associations between brain variables and subject descriptors were assessed with Pearson or Spearman correlations, as appropriate.

3. Results Among healthy comparison subjects, the correlations between absolute regional volume and age or ICV were not significant for any structure. Furthermore, the four groups did not differ in ICV [ F = .41, df = 3,118, p = 0.75]. 3.1. Four-group analysis Means and standard deviations for bilateral unadjusted volumes and Z-scores of three structures for four groups are listed in Table 2 and plotted (means and standard error) in Fig. 2. ANOVA of Z-scores for each structure revealed group effects for caudate ( F = 4.87, df = 3,118, p = 0.003), putamen ( F = 13.15, df = 3,118, p b .0001), and nucleus accumbens ( F = 11.32, df = 3118, p b .0001). Follow-up

Fig. 2. Mean and standard error (SE) volume measures, expressed both as cc (upper panel) and as age and intracranial volume corrected Zscores (lower panel) for bilateral volumes of caudate, putamen, and nucleus accumbens for healthy control subjects, patients with alcoholism only, patients with schizophrenia only, and patients comorbid for both disorders.

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(one-tailed) t-tests indicated that for all three patient groups the caudate (alcoholism, t = 2.869, p b .003; schizophrenia t = 2.41, p b .009; comorbid, t = 3.444, p b .0005)), putamen (alcoholism, t = 2.78, p b .004; schizophrenia t = 5.76, p b .0001; comorbid, t = 4.867, p b .0001), and nucleus accumbens (alcoholism, t = 1.9, p = .03; schizophrenia t = 5.96, p b .0001; comorbid, t = 3.9, p b .0001) were significantly smaller in patients than in comparison subjects. Relative to alcoholics, schizophrenics had smaller volumes putamen (t = 2.01, p b .03) and nucleus accumbens (t = 2.716, p b .005). The comorbid group fell between the schizophrenic and alcoholic group but did not differ significantly from either. This pattern of findings was similar for unadjusted volume measures. We conducted a series of two group by three structure ANOVAs to test for interactions indicative of disproportionate deficits in selective structure volumes. Interactions were significant for schizophrenic vs. control group

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( F = 6.58, df = 2152, p = .002) and schizophrenic vs. alcoholic group ( F = 8.19, df = 2,100, p = .0005) comparisons. Follow-up t-tests comparing pairs of structures in the schizophrenic group alone showed significant difference between the caudate and both putamen (t = 4.168, df = 26, p = .0003) and nucleus accumbens (t = 3.375, df = 26, p V .003) but not between putamen and nucleus accumbens (t = 0.37, df = 26, p = .71). By contrast, none of the pairwise comparisons in the alcoholic group were significant (Fig. 2). 3.2. Effect of medication type (schizophrenic and comorbid patients) Equivalent proportions of patients with schizophrenia alone (29%) and of those with schizophrenia and alcohol dependence (33%) were on atypical medication (v 2 = .08, p = .77). Patients with schizophrenia alone and schizophrenia with alcohol dependence were entered into a two-by-two

Fig. 3. Upper panel: Mean and standard error (SE) striatal structure volumes (Z-scores) for all patients with schizophrenia, with or without alcoholism, categorized according to antipsychotic medication type. Lower panel: Mean and standard error (SE) striatal structure volumes (Zscores) separately for patients with schizophrenia only and schizophrenia comorbid with alcoholism categorized according to antipsychotic medication type.

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group ANOVA, separately calculated for each striatal structure. There were no significant group effects for caudate or nucleus accumbens. The putamen analysis yielded a medication type effect ( F = 4.178, df = 1,38, p V .05), in which patients on atypical medication showed greater volume deficits than those on typical medication. Fig. 3 (upper) plots Z-scores for each structure for patients on typical and atypical medication; Fig. 3 (lower) plots the same data separately for patients with schizophrenia alone and combined with alcoholism. 3.3. Effect of drinking recency (alcoholic and comorbid patients) Equivalent proportions of patients with alcoholism alone (25%) and of those with schizophrenia and alcohol dependence (29%) were recent drinkers (v 2 = .153, p = .69). Patients with alcohol dependence alone and schizophrenia with alcohol dependence were entered into a two-by-two group ANOVA, separately calculated for each striatal structure. There was no significant effect for putamen or caudate

but the nucleus accumbens showed a recency effect ( F = 4.45, df = 1,38, p = .04) where recently sober alcoholics had greater volume deficits than longer sober ones. Fig. 4 (upper) plots Z-scores for each structure for recently sober and longer sober patients; Fig. 4 (lower) presents the same data separately for patients with alcoholism alone and combined with schizophrenia. 3.4. Other clinical and demographic variables Psychotic symptom severity measured by the BPRS (total score, positive subscale, negative subscale) in the two schizophrenia groups combined did not correlate with volume measures of any of the striatal structures examined. Likewise, neither lifetime alcohol consumption nor days of sobriety in the two alcoholism groups combined correlated with volume measures in any of the striatal structures examined. In addition, neither years of education nor NART IQ were associated with any striatal volume among the controls or among all the patient groups combined. Despite an overall absence of group difference in age, the alcoholic

Fig. 4. Upper panel: Mean and standard error (SE) striatal structure volumes (Z-scores) for all patients with alcoholism with or without schizophrenia, categorized according to recency of sobriety. Lower panel: Mean and standard error (SE) striatal structure volumes (Z-scores) separately for patients with alcoholism only and alcoholism comorbid with schizophrenia, categorized according to recency of sobriety.

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men were significantly older than the comorbid men (t = 2.9, df = 42, p b .01). Among all alcoholics, whether comorbid or not, the recently sober did not differ in age from the longer sober; nor was there any interaction between diagnosis and drinking recency.

4. Discussion This study examined the effects of disease comorbidity, medication type, and drinking recency on structures of the striatum in patients with schizophrenia, alcoholism, and those comorbid for both disorders. Previous studies, based on this cohort of patients, have identified different effects of alcohol comorbidity in schizophrenia patients for different brain regions. An exacerbation was seen for prefrontal and anterior temporal gray matter regions (Mathalon et al., 2003) both of which are adversely affected in schizophrenia (Sullivan et al., 1998) and alcoholism (Fein et al., 2002; Pfefferbaum et al., 1997). We thus hypothesized that the pathology imposed by schizophrenia rendered these regions particularly vulnerable to well established toxicity from alcoholism. Given the lower lifetime alcohol consumption in the comorbid compared to alcoholic patients, the extent of deficit seen at the prefrontal lobes represented an exacerbated rather than a merely additive effect (Mathalon et al., 2003). An alcohol toxicity effect was seen for the anterior superior cerebellar vermis (Sullivan et al., 2000) and pons (Sullivan et al., 2003). Neither of these structures showed a deficit in patients with schizophrenia alone, but both showed alcohol effects in schizophrenic patients comorbid for alcoholism. A third pattern, a medication effect, appeared for the thalamus, a structure affected by D2 receptor blockade occurring with typical neuroleptic treatment (e.g., Xiberas et al., 2001). The thalamus did not show a significant deficit, relative to controls, in schizophrenic patients and though it showed a deficit in the alcoholic patients, differed from the pons, in not showing a significant deficit in schizophrenia patients comorbid for alcoholism (Sullivan et al., 2003). The three structures examined in the current report – caudate, putamen, and nucleus accumbens – are all candidates for a medication mitigation effect. However, unlike the thalamus, which did not show a significant deficit in these schizophrenic patients,

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these striatal structures all showed deficits. Indeed, patients with schizophrenia alone generally showed more severe deficits in caudate, putamen, and nucleus accumbens than those with alcoholism alone, while comorbid patients fell in between. The absence of exacerbated or even additive deficits for any of these structures in the comorbid patients, may reflect an effect of medication, especially for those on typical neuroleptics. The D2 receptor blockade associated with typical neuroleptics has been hypothesized to lead to observed volume increases in striatal structures possibly due to changes in synaptic plasticity, including possible increase in number of neurons as well as of synapses (for reviews see Kapur and Mamo, 2003; Konradi and Heckers, 2001). Contrary to the findings of others (Chakos et al., 1994; Corson et al., 1999; Gur et al., 1998; Heckers et al., 1991; Hokama et al., 1995; Jernigan et al., 1991; Keshavan et al., 1994), patients on typical neuroleptics in our study did not have larger volume caudate or putamen than controls or patients not on such medication. They did tend to have larger volumes structures than patients on atypical medications, an effect that was significant only for the putamen. Lack of adequate medication histories for conversion to chlorpromazine equivalents preclude a more detailed evaluation of the relationship between drug dosage and structure volume or a satisfactory resolution of inconsistencies with other reports. This study showed that a bimodal classification of alcoholic drinking recency rather than chronic exposure to alcohol, as measured by lifetime alcohol consumption, appears to be a critical factor accounting for significant volume deficits in the nucleus accumbens, regardless of schizophrenia comorbidity. Scans from alcoholic and comorbid patients had been acquired after lengths of sobriety ranging from two weeks to over six years, with a substantial minority (n = 11) still within three weeks of their last drink. This permitted a comparison between those who were still in early abstinence with those sober for longer periods. Increase in dopaminergic responsivity during even earlier stages of withdrawal from alcohol was suggested by a study measuring growth hormone secretion to apomorphine challenge in alcoholics at 1 and 8 days after their last drink (Dettling et al., 1995). In that study, dopaminergic responsivity remained depressed only in the subjects who subsequently relapsed. More recently, the same research

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group has used positron emission tomography and the D2 radioligand [18F] desmethoxyfallypride to demonstrate reduced D2 receptor availability in the ventral striatum in alcoholics, scanned within 2 to 4 weeks of their last drink than controls, with association between D2 receptor levels and craving. Using [11C] raclopride Volkow et al (Volkow et al., 2002) also showed reduced D2 receptor levels, relative to controls, in caudate at 6 weeks after detoxification that persisted 1 to 4 months later. Reduced D2 receptor levels observed in putamen, however, had normalized by follow-up. Our finding that patients who had been drinking within the past 3 weeks had greater volume deficits in the nucleus accumbens relative to controls than those sober for longer periods needs to be replicated in a longitudinal design— ideally one that can also assess changes in dopaminergic activity at different stages of abstinence. We have already reported the recency of drinking effect on nucleus accumbens volume in this sample of non-comorbid alcoholics examined alone (Sullivan et al., 2005). The appearance of the same effect in patients with schizophrenia who also have alcoholism strengthens our interpretation that the nucleus accumbens, part of the extended amygdala and critically involved in the reinforcing effects of alcohol and other drugs of abuse (Koob, 2000), is particularly susceptible to the recent effects of drinking but may show recovery with sobriety, whereas the caudate and putamen show volume deficits that persist even after more extended sobriety. In conclusion, in these subjects alcoholism comorbidity in patients with schizophrenia neither exacerbates striatal volume deficits associated with schizophrenia alone nor alters the regional striatal profile of deficits that differentiates patients with alcoholism alone from those with schizophrenia alone. Further, patients with chronic schizophrenia have more marked deficits in putamen and nucleus accumbens than caudate, and those on typical medications show more modest deficits in the putamen than those on atypical medications. Finally, deficits associated with chronic alcohol use, with or without schizophrenia comorbidity, are more likely to resolve with sobriety for the nucleus accumbens than for the caudate or the putamen. That recent excessive drinking exerted such a significant adverse effect on volumes of the nucleus accumbens in two separate samples of

individuals with alcoholism underscores the relevance of the nucleus accumbens in human alcohol dependence. The morphological plasticity of this structure in response to heavy alcohol exposure may also serve as a marker for those at risk for developing the alcohol dependence syndrome.

Acknowledgments This project was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA05965, AA 12388, and AA10723) and the National Institute on Mental Health (MH58007 and MH30854). A partial report of these data was presented at the annual meeting of the Society of Biological Psychiatry, April 29 to May 1, 2004, New York, NY.

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