1 Department of Psychiatry and Psychotherapy, University of Luebeck,
2 Gilead IV, Psychiatric Hospital, Bielefeld,
3 Clinic Holstein, Luebeck,
4 Department of Psychiatry and Psychotherapy, University of Frankfurt/Main and
5 Institute of Immunology, University of Aachen, Germany
Received 1 October 2002; in revised form 14 November 2002; accepted 18 November 2002
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ABSTRACT |
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INTRODUCTION |
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Two to 6 weeks after cessation of drinking, baseline plasma, salivary and urinary cortisol values return to normal, but the cortisol response to stress remains blunted (Errico et al., 1993; Bernardy et al., 1996
; Lovallo et al., 2000
), with a gradual, but incomplete, normalization of HPA parameters within 12 weeks (Ehrenreich et al., 1997
).
As yet, no study has investigated the relationship between the HPA axis stress response and relapse. Along with a gradual normalization of ACTH and cortisol responses, the risk of relapse also decreases with sustained abstention (Whitworth et al., 1996; Project Research Group MATCH, 1997
). On the assumption that these two phenomena are related, we hypothesized that alcoholics with a particularly blunted HPA axis response during early abstention have an increased risk of relapse, since their stress responsivity is especially disturbed. As comorbid anxiety disorder was shown to be associated with an increased risk of relapse (Driessen et al., 2001
), and as the effect of comorbid anxiety disorder on HPA axis responsivity was unclear, early abstinent alcohol-dependent patients with and without comorbid anxiety disorder were included in the study.
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PATIENTS AND METHODS |
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Altogether, 36 male alcohol-dependent patients were recruited after cessation of drinking for at least 2 weeks (Table 1): 18 of them had no additional psychiatric disorder (group A), whereas the other 18 had a current comorbid anxiety disorder as the only comorbidity (group A + A). Of the latter, 13 had a panic disorder with or without agoraphobia, four had a comorbid social phobia and two received both comorbid diagnoses. Two patients of the non-comorbid group and three patients with a comorbid anxiety disorder dropped out for follow-up, as they entered a long-term treatment within the follow-up period. They were included in the evaluation of stress response, but were not considered for the calculations on early relapse. The healthy controls (group C) were recruited by advertisements. They underwent the same diagnostic procedures and were unmedicated. The three study groups were matched with regard to age.
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The experiments always started with the insertion of an intravenous cannula into an antecubital vein at 12.00. The baseline values for serum cortisol, pulse, systolic and diastolic blood pressure were assessed at 13.00 (T1), after which the TSST was performed. The response parameters were investigated again immediately after the stress test (T2), and then after 20 (T3), 40 (T4) and 60 min (T5). The collected blood was transferred to serum tubes, centrifuged, and serum was isolated and frozen at -20°C until the assay was performed. Cortisol levels were measured by specific radio-immunoassay techniques (Cortisol Assay Kit, cat. # 1841; Coulter-Immunotech Diagnostics). The lower limit of detection was 10 nmol. The intra- and interassay coefficients of variation were 3.9 and 6.6%, respectively.
Six weeks after discharge from the hospital, the patients were interviewed face to face about relapse, the alcohol level was controlled via a breathalyser and blood samples for the assessment of -glutamyl transferase, mean corpuscular volume of the erythrocytes and carbohydrate-deficient transferrin were taken. The interviewer was blind with regard to the results of the TSST. Relapse was defined as consumption of at least one alcoholic beverage since discharge from the hospital. Confirmation of the interview data through a third person was collected. No patient denied a relapse when faced with the laboratory or third person reports indicating relapse. The day of first drink was calculated with the time-line follow-back strategy.
The data on serum cortisol were analysed applying analyses of variance (ANOVAs) for area under the curve (AUC) for the five time points. AUC was calculated according to the trapezium rule (Matthews et al., 1990). With respect to blood pressure, ANOVAs with repeated measurements for three-group analyses were performed. Significant group differences were evaluated with post hoc Bonferroni tests. T-tests for independent samples and
2 tests were applied where appropriate. For the calculations, the statistical program SPSS version 10 was used with a two-sided alpha of 0.05.
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RESULTS |
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There was a significant time effect for pulse, diastolic and systolic blood pressure (ANOVA: F = 2.68, P < 0.05 for pulse; F = 4.9, P < 0.01 for diastolic and F = 11.8, P < 0.01 for systolic pressure), but no interaction effect (time x group) for these parameters during testing (Fig. 1).
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Concerning the cortisol stress response, the relapsers had a significantly lower AUC of serum cortisol than the healthy controls, while the abstainers did not differ significantly from the controls (relapse: 16 447.7 ± 2869.0; controls: 26 253.5 ± 2566.1; abstainers: 18 115.0 ± 2280.1; ANOVA: F = 2.052, P < 0.05; post hoc test: relapsers vs controls: P < 0.05; abstainers vs controls and relapsers vs abstainers: P > 0.05).
This difference between relapsers and abstainers in comparison with the healthy controls could be further substantiated by the results of the immediate cortisol response as calculated by the difference between the cortisol baseline value (T1) and the value at T2 (delta-cortisol) (Fig. 3). While the relapsers showed almost no response, the abstainers again did not differ significantly from the healthy controls (ANOVA: F = 3.21, P = 0.05; post hoc: relapsers vs controls: P < 0.05; relapsers vs abstainers and abstainers vs controls: P > 0.05). Delta-cortisol values above 30 nmol/l were produced only by 25% of the relapsers, as compared with 46.7% of the abstainers and 66.7% of the controls (
2: 6.76, P < 0.05). In accordance with our hypothesis, there was a positive correlation between the days of abstention after discharge and delta-cortisol (r = 0.39, P < 0.05).
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DISCUSSION |
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In contrast to the blunted HPA axis response, all groups showed an equal and significant stress reaction to the TSST with respect to blood pressure and pulse rate. In the light of other results (Ehrenreich et al., 1997), this can tentatively be interpreted as a normal noradrenergic stress responsiveness during early abstention.
There is an analogy of the study results on a psychosocial stress response in alcoholics with some studies on the HPA axis response to alcoholic beverages. Thus, Schuckit et al.(1987, 1988)
found an attenuated ACTH and cortisol response to alcohol in non-alcoholic children of alcoholics and, in two other studies, a blunted response of ACTH and cortisol in drinking alcoholics could be demonstrated (Berman et al., 1990
; Wand and Dobs, 1991
). This could mean that a diminished cortisol response during early abstention is not a result of a disturbed HPA axis function due to heavy alcohol consumption, but, rather, a marker for a stronger predisposition to a dependent drinking pattern with a higher risk of relapse as a consequence. This is supported by a recently published animal study demonstrating that the increased ethanol self-administration of early abstinent male Wistar rats can be attenuated by central injection of corticotropin-releasing factor (Valdez et al., 2002
). As our data seem to point in the same direction, it appears important to explore further a connection between HPA axis (dys-)regulation and relapse. For further studies, a larger sample size with assessment of more neurobiological parameters of the HPA axis and inclusion of female probands are recommended to increase the impact of the results.
While the present data on this small sample do not support an association of the attenuated response with the duration of alcohol dependence or with a positive family history of alcoholism, factors which usually contribute to the severity of alcoholism, it remains to be elucidated in further studies with a larger sample size, whether such an impaired HPA axis response is connected to the drinking pattern before abstention.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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