Dopamine transporter availability and depressive symptoms during alcohol withdrawal

Psychiatry Research: Neuroimaging Section 90 Ž1999. 153]157

Dopamine transporter availability and depressive symptoms during alcohol withdrawal T. Pekka J. Laine a,U , Aapo Ahonenb, Pirkko Rasanen ¨ ¨ a , Jari Tiihonen c a Department of Psychiatry, Uni¨ ersity of Oulu, FIN-90220 Oulu, Finland Department of Nuclear Medicine, Uni¨ ersity of Oulu, FIN-90220 Oulu, Finland c Department of Forensic Psychiatry, Uni¨ ersity of Kuopio, FIN-70210 Kuopio, Finland b

Received 23 September 1998; received in revised form 29 April 1999; accepted 12 May 1999

Abstract Alcohol-related temporary depressive symptoms are hypothesized to be related to dopaminergic dysfunction. The aim of this study was to investigate whether or not depressive symptoms correlate with reduced dopamine transporter ŽDAT. availability. We studied the DAT availability in 28 alcoholic subjects with b-CIT Žw123-iodiumx-2-bcarbomethoxy-3-b-Ž4-iodophenyl.-tropane. single photon emission tomography ŽSPET. and found a reduction in DAT availability during withdrawal that subsequently showed a significant increase during sobriety. The relationship ˚ between DAT availability and Montgomery-Asberg Depression Rating scale scores, both during withdrawal and after sobriety, was assessed. The main finding was a statistically significant correlation between DAT variances and depressive symptom scores during both states. The findings indicate a possible dopaminergic etiology for depressive symptoms in alcohol withdrawal, which suggests that dopaminergic antidepressants might be beneficial in the treatment of alcohol withdrawal. Q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: SPET; Tropanes; Monoamines; b-CIT; Alcoholism

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Corresponding author. Tel.: q358-40-5144163; fax: q358-8-539855. E-mail address: [email protected] ŽT.P.J. Laine.

0925-4927r99r$ - see front matter Q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 5 - 4 9 2 7 Ž 9 9 . 0 0 0 1 9 - 0

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1. Introduction Alcohol abuse can cause secondary depressive symptoms lasting up to 6 weeks after withdrawal ŽAmerican Psychiatric Association, 1993; Schuckit et al., 1997.. Depression is considered to be associated with decreased monoaminergic activity, particularly for dopamine, serotonin and norepinephrine Žvan Praag et al., 1990; Stahl, 1998.. We hypothesized that the depressive symptoms observed during alcohol withdrawal could be associated with a down-regulation of net dopaminergic activity ŽRoy et al., 1991., and we postulated that decreased dopamine release and re-uptake reflect striatal dopamine transporter ŽDAT. availability. The aim of this study was to test the above hypothesis using the DAT-specific ligand b-CIT Žw 1 2 3 -I x -2 b -carbomethoxy-3 b - Ž 4-iodophenyl . tropane. and single photon emission tomography ŽSPET..

2. Methods In this study we recruited a group of 28 Caucasian alcoholics fulfilling DSM III-R criteria for alcoholism, consisting of 23 men and five women, ranging from 24 to 69 years of age, who were previously admitted to an inpatient detoxification clinic after a 2 week Žminimum. drinking spree: mean s 3.5 ŽS.D.s 1.4. grkg per day for men; mean s 3.5 ŽS.D.s 1.2. grkg per day for women. Most patients were detoxified with benzodiazepines. Use of antidepressant or neuroleptic medication or illegal drugs Žcontrolled by urine tests. and central nervous system diseases were exclusion criteria for the study. Brain MRI examinations were performed to exclude any structural brain pathology. Liver function tests and laboratory markers of alcohol abuse Ž CDT s carbohydrate deficient transferrin, GGT s gglutamyltranspherase ., weekly meetings with the author ŽTPJL. to monitor sobriety, and other parameters indicated true abstinence during follow-up. The variables considered were age, sex, duration of the last drinking bout, daily amount of alcohol consumed during the last drinking bout, number of days of abstinence preceding the first

SPET imaging, withdrawal symptom score in the Selected Severity Scale ŽSSA, Gross et al., 1973., ˚ the Montgomery-Asberg Depression Rating Scale ŽMADRS. scores during withdrawal and after 4 ˚ weeks of abstinence ŽMontgomery and Asberg, . 1979 , and the total amount of benzodiazepines Žas diazepam-equivalents. administered to the patient preceding the first imaging. After a comprehensive description of the study, patients gave their written informed consent to participate. The protocol was approved by the Ethical Committee of the Oulu University Hospital. SPET studies were performed using a dual head gamma camera ŽADAC Vertex. equipped with high resolution fan beam collimators. The b-CIT binding in striatum was examined for the first time during the acute withdrawal symptoms 1]4 days after cessation of alcohol intake and then after 4 weeks of abstinence, which we refer to as the ‘sobriety state’. Transaxial slices, oriented in an orbito-meatal line, were reconstructed and the regions of interest were drawn over the striatum ŽSTR. and the white matter of the frontal lobes ŽFWM. using MRI. The ratio ŽSTR-FMWrFWM. at 24 h after injection of the radioligand was calculated to obtain DAT availability. The difference between DAT values during withdrawal and after 4 weeks of abstinence, the percental DAT variance, DDATs ŽDAT2y DAT1. = DAT1r100%, was selected to represent the individual change in DAT activity for each individual. The DDAT was compared with MADRS scores at the beginning and after 4 weeks of sobriety. The SSA score, which represented withdrawal symptoms, patient-reported alcohol consumption ŽDDA, daily dose of alcohol, grkg per day. and the amount of benzodiazepines administered during detoxification, were compared with the DDAT. All ratings were done by the author ŽTPJL.. Spearman’s two-tailed correlation coefficients were used to compare the means, and a paired sample t-test was used to test differences between measurements.

3. Results The decreased DAT availability initially

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observed ŽDAT 1. was found to recover significantly Ž P- 0.0001, paired samples t-test. during sobriety from a mean of 6.5 ŽS.D.s 1.2, range s 4.6]8.9. to 7.3 ŽS.D.s 1.2, range s 4.9]10.9., as we reported earlier ŽLaine et al., 1999.. MADRS scores decreased significantly Ž P- 0.0001, paired samples t-test; Table 1.. The association between DDAT and the depressive symptoms score was statistically significant during both withdrawal Ž r s 0.43, Ps 0.03, n s 25. ŽFig. 1. and sobriety measurements Ž r s 0.55, Ps 0.006, n s 23. ŽFig. 2.. However, DDAT failed to correlate with differences between MADRS scores Ž r s 0.1564, P s 0.466, n s 24., even when use of benzodiazepines was parsed out Ž r s 0.087, Ps 0.69, n s 21.. There were no statistically significant correlations between DAT densities and depressive symptoms during withdrawal Ž r s 0.25, Ps 0.224, n s 26. or during sobriety Ž r s y0.23, Ps 0.29, n s 24.. The DDAT did not correlate with DDA Ž r s 0.02, Ps 0.9, n s 27. or SSA scores Ž r s 0.30, Ps 0.123, n s 27., even when age was parsed out ŽDDA vs. DAT: r s 0.063, Ps 0.78, n s 20., although DDA correlated with SSA Ž r s 0.420, Ps 0.029, n s 27.. The use of benzodiazepines did not correlate significantly with DDAT or MADRS score during withdrawal, or in the later measurement, but did

Table 1 Mean scores of studied subjects ŽLaine et al., 1999. Variable

Mean ŽS.D..

Range

D-DAT Ž%. DAT-1 DAT-2 D-MADRS MADRS-1 MADRS-2 Age Žyears. Diazepam eq. Žmg. DDA Žgrkg. DDA Žg. SSA GGT-1 GGT-2 CDT-1 CDT-2

y11.2 Ž10.8. 7.53 Ž1.19. 8.31 Ž1.2. 14.0 Ž12.1. 21.8 Ž12.9. 8.6 Ž12.6. 42.2 Ž10.1. 107 Ž81. 3.4 Ž1.3. 250 Ž94. 11.0 Ž5.5. 346 Ž605. 101 Ž134. 31.2 Ž15.9. 14.6 Ž5.1.

y26.4]20.4 5.6]9.9 5.9]11.9 y12]35 0]49 0]41 24]70 0]240 1.7]5.9 140]444 2]22 18]2706 23]457 8]70 6]28

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correlate with DDA Ž r s 0.42, Ps 0.029, n s 27. and SSA Ž r s 0.27, Ps 0.18, n s 27..

4. Discussion The main finding of this study was in the correlation between DDAT and MADRS scores during withdrawal. This may reflect a down-regulation of dopaminergic activity during the apparent ethanol-withdrawal depressive state. The correlation between DDAT and MADRS scores after 4 weeks of sobriety may indicate fragility in the dopaminergic system among seriously depressed patients. As we have reported earlier, DAT availability in alcoholics did not differ from that in a non-alcoholic population after 4 weeks of abstinence ŽLaine et al., 1999.. It is likely that those patients who had been the heaviest drinkers also had longer-lasting depressive symptoms. The lack of correlation between MADRS scores and DAT densities may be due to the large inter-individual variation in dopaminergic activity ŽSeibyl et al., 1996.. The lack of correlation between the change in MADRS scores and DDAT is unclear. This may be due to different time curves for DAT functionality and depressive symptoms, as we found DAT to recover in only a few days ŽLaine et al., 1999. while recovery from alcohol-related depression takes several weeks ŽSchuckit et al., 1997.. b-CIT is a radioligand with very high affinity to dopamine and serotonin re-uptake sites. It has been used as a radioligand in investigating changes of DAT availability with SPET ŽBrucke et al., ¨ 1993.. Previously, an inverse correlation between DAT level and Hamilton Depression Rating Scale scores was reported in cases of acute cocaine abstinence, as measured by b-CIT SPECT ŽMalison et al., 1998a.. The use of benzodiazepines reflects the severity of intoxication and withdrawal, but it did not bear any relation to the difference in DAT availability. Six subjects were not administered any benzodiazepines and, as we have reported earlier, they had similar results to those of the other subjects in our study ŽLaine et al., 1999.. Some depressive symptoms are com-

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Fig. 1. The correlation between MADRS scores during withdrawal and percental DAT variance in SPECT examinations during early withdrawal and after 4 weeks of sobriety Ž DDAT..

mon to both alcohol withdrawal and major depression. Furthermore they might have the same etiology, i.e. decreased net dopaminergic activity. The dopamine transporter is the main mecha-

nism that eliminates synaptic dopamine, but causality between dopaminergic activity and dopamine transporter availability needs further clarification. b-CIT has been used previously to mea-

Fig. 2. The correlation between MADRS scores after 4 weeks of sobriety and DDAT.

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sure patient groups in comparison to control subjects. To our knowledge, this is the first study to use patients as their own controls for two different states. As a high affinity ligand, b-CIT is not affected by endogenous dopamine ŽMalison et al., 1998b.. While the monoamines serotonin and norepinephrine have been targets for the development of novel antidepressants, some researchers have found that the antidepressant effect of SSRIs is mediated via the dopaminergic system ŽTiihonen et al., 1996; Smith et al. 1997.. Dopaminergic antidepressant drugs, such as the specific dopamine reuptake inhibitor amineptine, the presynaptic dopamine antagonist amisulpride, and the D2rD3 agonists roxindole and pramipexole, all cause a rapid relief of depressive symptoms ŽWillner, 1997.. On the basis of our results, these could be useful supplements to benzodiazepine therapy in the treatment of transient depressive symptoms typically encountered during alcohol withdrawal. A rapid-acting medication could be beneficial, because even a few weeks of depression can predispose to an early drinking relapse or perhaps relapsing depressive episodes ŽJudd, 1997..

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