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Gabapentin's acute effect on mood profile — A controlled study on patients with alcohol withdrawal
Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 434 – 438 www.elsevier.com/locate/pnpbp
Gabapentin's acute effect on mood profile — A controlled study on patients with alcohol withdrawal Udo Bonnet a,⁎, Michael Specka a , F. Markus Leweke b , Peter Nyhuis a , Markus Banger a a
Rheinische Kliniken Essen, Klinik für Psychiatrie und Psychotherapie und Klinik für abhängiges Verhalten und Suchtmedizin, Universität Duisburg-Essen, Virchowstr. 174, D-45147 Essen, Germany b Rheinische Kliniken Düsseldorf, Klinik für Psychiatrie und Psychotherapie der Heinrich-Heine Universität Düsseldorf, Bergische Landstr. 2, D-40629 Düsseldorf, Germany Received 12 August 2006; received in revised form 20 October 2006; accepted 4 November 2006 Available online 18 December 2006
Abstract Rationale: Delayed beneficial effects of gabapentin on mood were frequently reported in various patient populations. This is the first controlled study which addressed acute effects of gabapentin on mood. Methods: Analysis of the German version of Profile of Mood States (POMS) throughout a randomised placebo-controlled, double-blinded study of gabapentin on acute alcohol withdrawal [Bonnet, U., Banger, M., Leweke, F.M., Specka, M., Müller, B.W., Hashemi, T., Nyhuis, P.W., Kutscher, S., Burtscheidt, W., Gastpar, M. 2003. Treatment of acute alcohol withdrawal with gabapentin — results from a controlled two-center trial. J Clin Psychopharmacol 23, 514–519]. In addition, subjective severity of alcohol withdrawal was determined by the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) to control effects of concurrent withdrawal on POMS. Ratings were performed at intake (baseline), day 1 (study medication 400 mg q.i.d.), day 2 (study medication 400 mg q.i.d.) and day 7 (no study medication). Results: Analyses could be performed on 46 out of 59 randomised subjects. Within the first two days of the study, a significant stronger increase in the POMS-vigour subscore occurred in the gabapentin group. A subgroup analysis suggests that gabapentin's effect on vigour largely results from a stronger improvement of vigour in a small group of 11 patients with co-morbid mild depression (according to ICD-10: dysthymia or depressive adjustment disorder). There were no significant differences between the treatment groups regarding the other POMS-subscores (dejection, fatigue, anger) ruling out an overall fast effect on mood. Moreover, ESA-measures were not significantly altered indicating a missing effect of 400 mg gabapentin q.i.d. on acute alcohol withdrawal itself. After tapering off study medication, no more significant differences between gabapentin and placebo group were observed on vigour, strongly suggesting that the initial effect results from a pharmacological gabapentin action. Conclusion: Gabapentin selectively accelerated the improvement of the vigour-subscore of patients with acute alcohol withdrawal within 48 h. This effect was independent from the subjective severity of withdrawal and especially marked in patients with co-morbid mild depression. © 2006 Elsevier Inc. All rights reserved. Keywords: Alcohol withdrawal; Depression; ESA; Mood; POMS; Vigour
1. Introduction In epilepsy patients many investigators found delayed beneficial effects on mood with gabapentin (e.g. Harden et al., 1999). This observation was confirmed by a couple of open Abbreviations: BDI, Beck Depression Inventory; ESA, Essen SelfAssessment of Alcohol Withdrawal Scale; GABA, γ-aminobutyric acid; MAO-A, monoamine oxidase, type A; MAWS, Mainz Alcohol Withdrawal Scale; POMS, Profile of Mood States. ⁎ Corresponding author. Fax: +49 201 7227 303. E-mail address: [email protected] (U. Bonnet). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.11.006
studies on patients with affective disorders (Maidment, 2001; Yasmin et al., 2001; Perugi et al., 2002; Wang et al., 2002). However, two placebo-controlled trials did not find gabapentin superior to placebo if administered as an adjunct to patients with bipolar depression (Frye et al., 2000; Pande et al., 2000a). Considering the open study of Wang et al. (Wang et al., 2002) and our own unpublished experiences with patients in alcohol withdrawal gabapentin's beneficial effect on mood may start rapidly within the first days of treatment. To test this impression we evaluated the Profile of Mood States (POMS)-subscores (McNair et al., 1981; Biehl et al., 1986; Bullinger et al., 1990)
U. Bonnet et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 434–438
from our placebo-controlled trial on gabapentin's efficacy and tolerability in acute alcohol withdrawal (Bonnet et al., 2003). The POMS-subscores rely on self-report comprising a well-understood factoral structure (Buros, 1978; Bullinger et al., 1990). 2. Materials and methods 2.1. Design and participants Data were gathered within a controlled study on the efficacy and tolerability of gabapentin (400 mg q.i.d.) in the treatment of acute alcohol withdrawal syndrome (Bonnet et al., 2003). The study was conducted at 2 psychiatric hospitals in Essen and Düsseldorf (Germany). Inpatients were included if they suffered from alcohol dependence (ICD-10) and displayed a moderate or severe alcohol withdrawal syndrome, according to the Mainz Alcohol Withdrawal Scale (MAWS; Banger et al., 1992). Patients were not included if they had a psychiatric disorder requiring medication or a relevant medical condition or other substance abuse with the exception of dependence on tobacco (c.f. Bonnet et al., 2003). Subjects were randomised to get either gabapentin or placebo and received their first dose of study medication (placebo or 400 mg gabapentin, double-blind) immediately after inclusion (rescue medication was clomethiazole). Subsequently, a capsule of study medication was given every 6 h during the next 48 h. After the third day of detoxification the study medication was reduced by one capsule every day (c.f. Fig. 1). As reported elsewhere (Bonnet et al., 2003), the objective severity of the alcohol withdrawal syndrome, which was assessed by the
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MAWS, was very similar between groups and no statistically significant differences emerged throughout the study. Also, the amount of the rescue-clomethiazole (Majumdar, 1990) was not significantly different between the groups (Bonnet et al., 2003). During the study, mood was measured by the German POMS-version, a self-assessment questionnaire containing 35 adjectives (Biehl et al., 1986; Bullinger et al., 1990). On each item subjects had to estimate on a 0–6 scale the intensity of their feelings during the last 24 h. The German POMS-version comprises 4 subscales, “dejection” (e.g. feeling sad, helpless, miserable), “fatigue” (e.g. tired, exhausted, listless), “vigour” (e.g. energetic, lively, active), and “anger” (e.g. angry, irritated, bad-tempered). Each subscale consists of 7 items, except “dejection” (14 items). Measures were taken at intake (baseline), and in the late morning of day 1, 2 and 7. In addition, subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) comprising 21 physical and psychological symptoms, to be rated on a 0–3 scale (Banger et al., 2001). 2.2. Data analysis Analyses were performed on those subjects who had completed POMS-measurements at baseline, day 1 and day 2. Tests of statistical significance were performed using repeated measures analysis of variance, with multivariate criteria (ANOVA). Group comparisons with respect to follow-up data (day 7) were made using t-tests. In an additional follow-up analysis, missing values at day 7 were replaced by an estimated value derived from regressing scores at day 7 on scores on day 2. Statistical software was SPSS Vers. 11.0.1. Significance level for all tests was 5%. 3. Results 3.1. Subjects
Fig. 1. Study design. Study medication (gabapentin or placebo 400 mg q.i.d.) started at baseline. After a 3 days-lasting plateau of 400 mg gabapentin or placebo q.i.d. the study medication was tapered by 400 mg each day. POMS, ESA and MAWS were carried out at baseline, after the first 24 h (day 1), the second 24 h (day 2) and at day 7 of alcohol withdrawal. Day 3 was taken to adapt the treatment to normal daily rhythm. Baseline: Mainz Alcohol Withdrawal Score (MAWS) ≥ 4, Breath Alcohol Concentration (BAC) ≤ 0.15%. X = number of rescue capsules clomethiazole required to treat acute AWS within the first 24 h (X ≥ 0). If required this rescue medication was started when the first dose of study medication was given at least 1 h before. For details see Bonnet et al., 2003.
Analyses could be performed on 46 out of 59 randomised subjects. Five subjects dropped out of the study during the first 2 days, 8 subjects had incomplete or missing data. Rates of patients analysable were 76% (n = 22) in the placebo group and 80% (n = 24) in the gabapentin group. Thirteen patients included in the analysis were female (28%), 33 were male (72%). Age was between 31 and 59 years, median 45 years. In the placebo group, 2 patients (9%) had an additional diagnosis of dysthymia (F34.1 according to ICD-10) and 3 patients (14%) were diagnosed to have a depressive adjustment disorder (F43.21). In the gabapentin group, 6 patients (25%) suffered from dysthymia. Both depressive conditions were mild, did not require medication. The history of the patients did not show any hint at a uni- or bipolar affective disorder, anxiety disorder or psychosis. 3.2. POMS The courses of the POMS-subscores over time are given in Fig. 2. At baseline group means differed only slightly. At days 1
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U. Bonnet et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 434–438
Fig. 2. Course of POMS-subscores (A–D, F) and ESA (E) throughout the study. Gabapentin significantly (⁎p b 0.05) and reversibly increased the improvement of the vigour-score (C) There were no significant differences between the treatment groups in the resting POMS-subscores (A, B, D) ruling out an overall fast action on mood. The significant difference in vigour was particularly apparent in the small group of patients with mild depression (⁎⁎p b 0.05) (F, right panel). For patients without mild depression no differential effect of medication on vigour was found (F, left panel). In contrast to C (⁎p = 0.035) and F, right panel (⁎⁎p = 0.022) there was no significant group × time interaction (estimated for days 0–2) in A ( p = 0.58), B (0.16), D (0.43), E (0.63) and F, left panel (0.065). Abbreviations: Profile of Mood States (POMS), Essen Self-Assessment of Alcohol Withdrawal Scale (ESA).
and 2 (gabapentin 400 q.i.d.), the gabapentin group displayed less dejection, fatigue and anger, and more vigour than the placebo group. Repeated measures ANOVAs revealed significant overall changes over time on all four scales (all p b 0.001). A significant (F = 3.62, d.f. 2;43, p = 0.035) group × time interaction resulted exclusively with respect to the vigour-subscore. That means, the increase of vigour from baseline to day 2 was significantly stronger in the gabapentin group than in the placebo group (Fig. 2C). Non-significant interactions were found for dejection ( p = 0.58), fatigue ( p = 0.16), and anger ( p = 0.43) (Fig. 2A,B,D). To test the robustness of the significant interaction effect for vigour, analysis was repeated using rank-transformed data. Again, a significant ( p = 0.046) interaction effect was found. After gabapentin had been tapered off at day 7 (c.f. Fig. 1), dejection, fatigue and anger had further declined in both groups, and vigour had increased (Fig. 2). Group comparisons using t-tests
did not reveal any significant differences between the groups at follow-up (day 7), the smallest p-value being 0.42. An additional analysis with missing data replaced by an estimated value did show nearly identical results, the smallest p-value being 0.53. Thus, the significant increase in vigour within the first days on gabapentin was not apparent after tapering off the drug which obviously points to a reversible gabapentin-effect on vigour. 3.3. ESA Simultaneously, there was a significant ( p b 0.001) overall decline of subjective complaints about withdrawal symptoms (ESA, Fig. 2E), but no group × time interaction ( p = 0.62). As reported elsewhere, objective improvement of acute alcohol withdrawal (measured by MAWS) was also not significantly different between the treatment groups (Bonnet et al., 2003).
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3.4. Subgroup analysis An analysis of those 11 patients, who had a co-morbid mild depression (F 34.1, F43.21), revealed no significant time × group interaction for dejection, fatigue, anger or subjective withdrawal (all p N 0.05). According to vigour, the group × time interaction resulted in p = 0.022. As demonstrated in Fig. 2F, mild depressive patients had lower initial vigour scores than patients without mood disorder, although this difference is not statistically significant (t-test, p = 0.29). Throughout the treatment, vigour scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without mood disorder, while depressive patients treated with placebo did not change much from baseline. In patients without mood disorder the superiority of gabapentin to placebo in the improvement of vigour came close to significance ( p = 0.065). 4. Discussion This study shows an acceleration in the improvement of vigour within the first two days of gapapentin-treatment in patients with alcohol withdrawal. Because there was no significant difference between the groups in rescue-clomethiazole as well as in objective withdrawal measures (Bonnet et al., 2003) and in ESA, this effect on vigour could not be attributed to a beneficial gabapentin action on alcohol withdrawal itself. Importantly, the significant effect on vigour disappeared along with the taper of gabapentin, strongly suggesting a reversible pharmacological action rather than a type I-error. The dejection- and anger-scales of POMS were not significantly impinged with gabapentin suggesting no general effect on mood (Buros, 1978) within the short-lasting administration. Regarding the studies on patients with affective or circumscripted anxiety disorders, beneficial gapapentin effects were found somewhat later in the treatment (Harden et al., 1999; Pande et al., 1999; Pande et al., 2000a,b; Maidment, 2001; Yasmin et al., 2001; Perugi et al., 2002). The vigour-scale in POMS (feeling e.g. energetic, lively, active) may represent the patients’ level of energy and drive (Buros, 1978; Biehl et al., 1986; Bullinger et al., 1990) which splashes over in hyperactive and manic patients. Indeed, there are a few case reports about hypomanic or manic symptoms in epilepsy patients (Short and Cooke, 1995; Lee et al., 1996; Wolf et al., 1996; Leweke et al., 1999; Trinka et al., 2000), which occurred with gabapentin. A tendency to develop hypomanic activity and hyperactive behaviour would be reflected by the courses of the fatigue and dejection subscores of POMS which still did not differ between our treatment groups. Gabapentin was markedly more efficacious on the improvement of vigour in the small subgroup of patients with mild depression. Although the history of these patients did not reveal signs of uni- or bipolar depression so far, such future courses are absolutely possible — all the more, because the diagnoses of dysthymia and depressive adjustment disorder were found to be very unstable in longitudinal studies (Clayton, 1998). In this context, it was recently reported that gabapentin might be particularly effective in depressive patients with co-morbid
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alcohol abuse (Perugi et al., 2002). An improvement of depression, however, would require an additional impingement of other POMS-subscores, e.g. dejection and anger (Buros, 1978). Searching for a pharmacological explanation for the fast increase in vigour, it might be relevant that the GABA-level was found to grow in human brain within the first hours after oral gabapentin administration (Petroff et al., 2000). An unspecific stimulation of the central GABA-system, however, is not very likely to be decisive for the vigour-increase because diazepam was on the opposite found to decrease vigour one hour after administration (Johanson and Uhlenkuth, 1980). A rapid increase in vigour was demonstrated for amphetamine, which (in contrast to gabapentin) reduced also the fatigue POMSsubscore (Johanson and Uhlenkuth, 1980). Interestingly, gabapentin increased cerebrospinal fluid levels of the serotonin metabolite 5-hydroxy-indoleacetic acid measured within three days of administration to epilepsy patients (Ben-Menachem et al., 1992) suggesting an effect on the central serotonin system consistent with many known antidepressive drugs (Nathan et al., 1995). In literature, a selective increase in vigour comparable to that found with gabapentin could be only found with the reversible MAO-A-inhibitor moclobemide in patients with chronic fatigue syndrome. But this aspect similar to the one by gabapentin found in the present study was measured not before two weeks after onset of the treatment (Hickie et al., 2000). It should be mentioned that we found no significant difference between the groups in objective MAWS and in subjective ESA. These finding stands in contrast in respect to data showing gabapentin efficacy in reducing objective withdrawal measures (Myrick et al., 1998; Bozikas et al., 2002; Johnson et al., 2005; Mariani et al., 2006). However, only the present study comprises a placebo condition and a subjective withdrawal measure. The study is limited by the lack of correlates of mood by other rating scales, such as the Beck Depression Inventory (BDI) or the Hamilton Depression Scale. Nonetheless, the POMS is a widely used valid instrument to assess the emotional state (Albani et al., 2005) and there are strong correlations between the dejection POMS-subscale and the BDI (Jacobs and Boze, 1993; Malouff, 1985; Nyenhuis et al., 1999). In conclusion, gabapentin significantly and reversibly increased the vigour-score without changing the resting POMS-subscores in patients with alcohol withdrawal. This was found within 48 h especially in patients with mild depression and appeared independent from withdrawal-severity. The fast increase in vigour might support the compliance for adjunctive treatments. Acknowledgement The study was supported by Gödecke/Parke-Davis. References Albani C, Blaser G, Geyer M, Schmutzer G, Brähler E, Bailer H, et al. The German short version of profile of mood states (POMS): psychometric evaluation in a representative sample. Psychother Psych Med 2005;55:324–30.
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Banger M, Philipp M, Herth T, Hebenstreit M, Aldenhoff J. Development of a rating scale for quantitative measurement of the alcohol withdrawal syndrome. Eur Arch Psychiatry Clin Neurosci 1992;241:241–6. Banger M, Specka M, Lodemann E, Finkbeiner T, Rösinger C, Kutscher S-U. Development of a self-assessment scale for the alcohol withdrawal syndrome (ESA, Essen self-assessment—alcohol withdrawal). Sucht 2001;47:404–13. Ben-Menachem E, Persson LI, Hedner T. Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin. Epilepsy Res 1992;11:45–9. Biehl B, Dangel S, Reiser A. Profile of mood states. CIPS – Internationale Skalen für Psychiatrie. Weinheim: Beltz; 1986. Bonnet U, Banger M, Leweke FM, Specka M, Müller BW, Hashemi T, et al. Treatment of acute alcohol-withdrawal with gabapentin — results from a controlled two-center trial. J Clin Psychopharmacol 2003;23:514–9. Bozikas V, Petrikis P, Gamvrula K, Savvidou I, Karavatos A. Treatment of alcohol withdrawal with gabapentin. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:197–9. Bullinger M, Heinisch M, Ludwig M, Geier S. Studien zur Erfassung des Wohlbefindens: psychometrische Analysen zum profile of mood states (POMS) und zum psychological general wellbeing index (PGWI). Z Differ Diagn Psychol 1990;11:53–61. Clayton PJ. Depression subtyping: treatment implications. J Clin Psychiatry 1998;59(suppl 16):5-12. Buros OK. Profiles of mood states. In: Buros OK, editor. Mental measurements yearbook. 8th ed. Highland Park, New York: Gryphon Press; 1978. p. 1015–9. Frye MA, Kettler TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA. A placebocontrolled study of lamotigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000;20:607–14. Harden CL, Lazar LM, Pick LH, Nikolov B, Goldstein MA, Carson D, et al. A beneficial effect on mood in partial epilepsy patients treated with gabapentin. Epilepsia 1999;40:1129–34. Hickie IB, Wilson AJ, Wright M, Bennett BK, Wakefield D, Lloyd AR. A randomized, double blind, placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. J Clin Psychiatry 2000;61:643–8. Jacobs KW, Boze MM. Correlations among scales of the Beck Depression Inventory and the profile of mood states. Psychol Rep 1993;73:431–4. Johanson CE, Uhlenkuth EH. Drug preference and mood in humans: diazepam. Psychopharmacology 1980;71:269–73. Johnson BA, Swift RM, Addolorato G, Ciraulo DA, Myrick H. Safety and efficacy of GABAergic medications for treating alcoholism. Alcohol Clin Exp Res 2005;29:248–54. Lee DO, Steingard RJ, Cesena M, Helmers SL, Riviello JJ, Mikati MA. Behavioral side effects of gabapentin in children. Epilepsia 1996;37:87–90. Leweke FM, Bauer J, Elger CE. Manic episode due to gabapentin treatment. Br J Psychiatry 1999;175:291. Maidment ID. Gabapentin treatment for bipolar disorders. Ann Psychopharmacother 2001;35:1264–9.
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Gabapentin's acute effect on mood profile — A controlled study on patients with alcohol withdrawal Udo Bonnet a,⁎, Michael Specka a , F. Markus Leweke b , Peter Nyhuis a , Markus Banger a a
Rheinische Kliniken Essen, Klinik für Psychiatrie und Psychotherapie und Klinik für abhängiges Verhalten und Suchtmedizin, Universität Duisburg-Essen, Virchowstr. 174, D-45147 Essen, Germany b Rheinische Kliniken Düsseldorf, Klinik für Psychiatrie und Psychotherapie der Heinrich-Heine Universität Düsseldorf, Bergische Landstr. 2, D-40629 Düsseldorf, Germany Received 12 August 2006; received in revised form 20 October 2006; accepted 4 November 2006 Available online 18 December 2006
Abstract Rationale: Delayed beneficial effects of gabapentin on mood were frequently reported in various patient populations. This is the first controlled study which addressed acute effects of gabapentin on mood. Methods: Analysis of the German version of Profile of Mood States (POMS) throughout a randomised placebo-controlled, double-blinded study of gabapentin on acute alcohol withdrawal [Bonnet, U., Banger, M., Leweke, F.M., Specka, M., Müller, B.W., Hashemi, T., Nyhuis, P.W., Kutscher, S., Burtscheidt, W., Gastpar, M. 2003. Treatment of acute alcohol withdrawal with gabapentin — results from a controlled two-center trial. J Clin Psychopharmacol 23, 514–519]. In addition, subjective severity of alcohol withdrawal was determined by the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) to control effects of concurrent withdrawal on POMS. Ratings were performed at intake (baseline), day 1 (study medication 400 mg q.i.d.), day 2 (study medication 400 mg q.i.d.) and day 7 (no study medication). Results: Analyses could be performed on 46 out of 59 randomised subjects. Within the first two days of the study, a significant stronger increase in the POMS-vigour subscore occurred in the gabapentin group. A subgroup analysis suggests that gabapentin's effect on vigour largely results from a stronger improvement of vigour in a small group of 11 patients with co-morbid mild depression (according to ICD-10: dysthymia or depressive adjustment disorder). There were no significant differences between the treatment groups regarding the other POMS-subscores (dejection, fatigue, anger) ruling out an overall fast effect on mood. Moreover, ESA-measures were not significantly altered indicating a missing effect of 400 mg gabapentin q.i.d. on acute alcohol withdrawal itself. After tapering off study medication, no more significant differences between gabapentin and placebo group were observed on vigour, strongly suggesting that the initial effect results from a pharmacological gabapentin action. Conclusion: Gabapentin selectively accelerated the improvement of the vigour-subscore of patients with acute alcohol withdrawal within 48 h. This effect was independent from the subjective severity of withdrawal and especially marked in patients with co-morbid mild depression. © 2006 Elsevier Inc. All rights reserved. Keywords: Alcohol withdrawal; Depression; ESA; Mood; POMS; Vigour
1. Introduction In epilepsy patients many investigators found delayed beneficial effects on mood with gabapentin (e.g. Harden et al., 1999). This observation was confirmed by a couple of open Abbreviations: BDI, Beck Depression Inventory; ESA, Essen SelfAssessment of Alcohol Withdrawal Scale; GABA, γ-aminobutyric acid; MAO-A, monoamine oxidase, type A; MAWS, Mainz Alcohol Withdrawal Scale; POMS, Profile of Mood States. ⁎ Corresponding author. Fax: +49 201 7227 303. E-mail address: [email protected] (U. Bonnet). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.11.006
studies on patients with affective disorders (Maidment, 2001; Yasmin et al., 2001; Perugi et al., 2002; Wang et al., 2002). However, two placebo-controlled trials did not find gabapentin superior to placebo if administered as an adjunct to patients with bipolar depression (Frye et al., 2000; Pande et al., 2000a). Considering the open study of Wang et al. (Wang et al., 2002) and our own unpublished experiences with patients in alcohol withdrawal gabapentin's beneficial effect on mood may start rapidly within the first days of treatment. To test this impression we evaluated the Profile of Mood States (POMS)-subscores (McNair et al., 1981; Biehl et al., 1986; Bullinger et al., 1990)
U. Bonnet et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 434–438
from our placebo-controlled trial on gabapentin's efficacy and tolerability in acute alcohol withdrawal (Bonnet et al., 2003). The POMS-subscores rely on self-report comprising a well-understood factoral structure (Buros, 1978; Bullinger et al., 1990). 2. Materials and methods 2.1. Design and participants Data were gathered within a controlled study on the efficacy and tolerability of gabapentin (400 mg q.i.d.) in the treatment of acute alcohol withdrawal syndrome (Bonnet et al., 2003). The study was conducted at 2 psychiatric hospitals in Essen and Düsseldorf (Germany). Inpatients were included if they suffered from alcohol dependence (ICD-10) and displayed a moderate or severe alcohol withdrawal syndrome, according to the Mainz Alcohol Withdrawal Scale (MAWS; Banger et al., 1992). Patients were not included if they had a psychiatric disorder requiring medication or a relevant medical condition or other substance abuse with the exception of dependence on tobacco (c.f. Bonnet et al., 2003). Subjects were randomised to get either gabapentin or placebo and received their first dose of study medication (placebo or 400 mg gabapentin, double-blind) immediately after inclusion (rescue medication was clomethiazole). Subsequently, a capsule of study medication was given every 6 h during the next 48 h. After the third day of detoxification the study medication was reduced by one capsule every day (c.f. Fig. 1). As reported elsewhere (Bonnet et al., 2003), the objective severity of the alcohol withdrawal syndrome, which was assessed by the
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MAWS, was very similar between groups and no statistically significant differences emerged throughout the study. Also, the amount of the rescue-clomethiazole (Majumdar, 1990) was not significantly different between the groups (Bonnet et al., 2003). During the study, mood was measured by the German POMS-version, a self-assessment questionnaire containing 35 adjectives (Biehl et al., 1986; Bullinger et al., 1990). On each item subjects had to estimate on a 0–6 scale the intensity of their feelings during the last 24 h. The German POMS-version comprises 4 subscales, “dejection” (e.g. feeling sad, helpless, miserable), “fatigue” (e.g. tired, exhausted, listless), “vigour” (e.g. energetic, lively, active), and “anger” (e.g. angry, irritated, bad-tempered). Each subscale consists of 7 items, except “dejection” (14 items). Measures were taken at intake (baseline), and in the late morning of day 1, 2 and 7. In addition, subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) comprising 21 physical and psychological symptoms, to be rated on a 0–3 scale (Banger et al., 2001). 2.2. Data analysis Analyses were performed on those subjects who had completed POMS-measurements at baseline, day 1 and day 2. Tests of statistical significance were performed using repeated measures analysis of variance, with multivariate criteria (ANOVA). Group comparisons with respect to follow-up data (day 7) were made using t-tests. In an additional follow-up analysis, missing values at day 7 were replaced by an estimated value derived from regressing scores at day 7 on scores on day 2. Statistical software was SPSS Vers. 11.0.1. Significance level for all tests was 5%. 3. Results 3.1. Subjects
Fig. 1. Study design. Study medication (gabapentin or placebo 400 mg q.i.d.) started at baseline. After a 3 days-lasting plateau of 400 mg gabapentin or placebo q.i.d. the study medication was tapered by 400 mg each day. POMS, ESA and MAWS were carried out at baseline, after the first 24 h (day 1), the second 24 h (day 2) and at day 7 of alcohol withdrawal. Day 3 was taken to adapt the treatment to normal daily rhythm. Baseline: Mainz Alcohol Withdrawal Score (MAWS) ≥ 4, Breath Alcohol Concentration (BAC) ≤ 0.15%. X = number of rescue capsules clomethiazole required to treat acute AWS within the first 24 h (X ≥ 0). If required this rescue medication was started when the first dose of study medication was given at least 1 h before. For details see Bonnet et al., 2003.
Analyses could be performed on 46 out of 59 randomised subjects. Five subjects dropped out of the study during the first 2 days, 8 subjects had incomplete or missing data. Rates of patients analysable were 76% (n = 22) in the placebo group and 80% (n = 24) in the gabapentin group. Thirteen patients included in the analysis were female (28%), 33 were male (72%). Age was between 31 and 59 years, median 45 years. In the placebo group, 2 patients (9%) had an additional diagnosis of dysthymia (F34.1 according to ICD-10) and 3 patients (14%) were diagnosed to have a depressive adjustment disorder (F43.21). In the gabapentin group, 6 patients (25%) suffered from dysthymia. Both depressive conditions were mild, did not require medication. The history of the patients did not show any hint at a uni- or bipolar affective disorder, anxiety disorder or psychosis. 3.2. POMS The courses of the POMS-subscores over time are given in Fig. 2. At baseline group means differed only slightly. At days 1
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Fig. 2. Course of POMS-subscores (A–D, F) and ESA (E) throughout the study. Gabapentin significantly (⁎p b 0.05) and reversibly increased the improvement of the vigour-score (C) There were no significant differences between the treatment groups in the resting POMS-subscores (A, B, D) ruling out an overall fast action on mood. The significant difference in vigour was particularly apparent in the small group of patients with mild depression (⁎⁎p b 0.05) (F, right panel). For patients without mild depression no differential effect of medication on vigour was found (F, left panel). In contrast to C (⁎p = 0.035) and F, right panel (⁎⁎p = 0.022) there was no significant group × time interaction (estimated for days 0–2) in A ( p = 0.58), B (0.16), D (0.43), E (0.63) and F, left panel (0.065). Abbreviations: Profile of Mood States (POMS), Essen Self-Assessment of Alcohol Withdrawal Scale (ESA).
and 2 (gabapentin 400 q.i.d.), the gabapentin group displayed less dejection, fatigue and anger, and more vigour than the placebo group. Repeated measures ANOVAs revealed significant overall changes over time on all four scales (all p b 0.001). A significant (F = 3.62, d.f. 2;43, p = 0.035) group × time interaction resulted exclusively with respect to the vigour-subscore. That means, the increase of vigour from baseline to day 2 was significantly stronger in the gabapentin group than in the placebo group (Fig. 2C). Non-significant interactions were found for dejection ( p = 0.58), fatigue ( p = 0.16), and anger ( p = 0.43) (Fig. 2A,B,D). To test the robustness of the significant interaction effect for vigour, analysis was repeated using rank-transformed data. Again, a significant ( p = 0.046) interaction effect was found. After gabapentin had been tapered off at day 7 (c.f. Fig. 1), dejection, fatigue and anger had further declined in both groups, and vigour had increased (Fig. 2). Group comparisons using t-tests
did not reveal any significant differences between the groups at follow-up (day 7), the smallest p-value being 0.42. An additional analysis with missing data replaced by an estimated value did show nearly identical results, the smallest p-value being 0.53. Thus, the significant increase in vigour within the first days on gabapentin was not apparent after tapering off the drug which obviously points to a reversible gabapentin-effect on vigour. 3.3. ESA Simultaneously, there was a significant ( p b 0.001) overall decline of subjective complaints about withdrawal symptoms (ESA, Fig. 2E), but no group × time interaction ( p = 0.62). As reported elsewhere, objective improvement of acute alcohol withdrawal (measured by MAWS) was also not significantly different between the treatment groups (Bonnet et al., 2003).
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3.4. Subgroup analysis An analysis of those 11 patients, who had a co-morbid mild depression (F 34.1, F43.21), revealed no significant time × group interaction for dejection, fatigue, anger or subjective withdrawal (all p N 0.05). According to vigour, the group × time interaction resulted in p = 0.022. As demonstrated in Fig. 2F, mild depressive patients had lower initial vigour scores than patients without mood disorder, although this difference is not statistically significant (t-test, p = 0.29). Throughout the treatment, vigour scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without mood disorder, while depressive patients treated with placebo did not change much from baseline. In patients without mood disorder the superiority of gabapentin to placebo in the improvement of vigour came close to significance ( p = 0.065). 4. Discussion This study shows an acceleration in the improvement of vigour within the first two days of gapapentin-treatment in patients with alcohol withdrawal. Because there was no significant difference between the groups in rescue-clomethiazole as well as in objective withdrawal measures (Bonnet et al., 2003) and in ESA, this effect on vigour could not be attributed to a beneficial gabapentin action on alcohol withdrawal itself. Importantly, the significant effect on vigour disappeared along with the taper of gabapentin, strongly suggesting a reversible pharmacological action rather than a type I-error. The dejection- and anger-scales of POMS were not significantly impinged with gabapentin suggesting no general effect on mood (Buros, 1978) within the short-lasting administration. Regarding the studies on patients with affective or circumscripted anxiety disorders, beneficial gapapentin effects were found somewhat later in the treatment (Harden et al., 1999; Pande et al., 1999; Pande et al., 2000a,b; Maidment, 2001; Yasmin et al., 2001; Perugi et al., 2002). The vigour-scale in POMS (feeling e.g. energetic, lively, active) may represent the patients’ level of energy and drive (Buros, 1978; Biehl et al., 1986; Bullinger et al., 1990) which splashes over in hyperactive and manic patients. Indeed, there are a few case reports about hypomanic or manic symptoms in epilepsy patients (Short and Cooke, 1995; Lee et al., 1996; Wolf et al., 1996; Leweke et al., 1999; Trinka et al., 2000), which occurred with gabapentin. A tendency to develop hypomanic activity and hyperactive behaviour would be reflected by the courses of the fatigue and dejection subscores of POMS which still did not differ between our treatment groups. Gabapentin was markedly more efficacious on the improvement of vigour in the small subgroup of patients with mild depression. Although the history of these patients did not reveal signs of uni- or bipolar depression so far, such future courses are absolutely possible — all the more, because the diagnoses of dysthymia and depressive adjustment disorder were found to be very unstable in longitudinal studies (Clayton, 1998). In this context, it was recently reported that gabapentin might be particularly effective in depressive patients with co-morbid
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alcohol abuse (Perugi et al., 2002). An improvement of depression, however, would require an additional impingement of other POMS-subscores, e.g. dejection and anger (Buros, 1978). Searching for a pharmacological explanation for the fast increase in vigour, it might be relevant that the GABA-level was found to grow in human brain within the first hours after oral gabapentin administration (Petroff et al., 2000). An unspecific stimulation of the central GABA-system, however, is not very likely to be decisive for the vigour-increase because diazepam was on the opposite found to decrease vigour one hour after administration (Johanson and Uhlenkuth, 1980). A rapid increase in vigour was demonstrated for amphetamine, which (in contrast to gabapentin) reduced also the fatigue POMSsubscore (Johanson and Uhlenkuth, 1980). Interestingly, gabapentin increased cerebrospinal fluid levels of the serotonin metabolite 5-hydroxy-indoleacetic acid measured within three days of administration to epilepsy patients (Ben-Menachem et al., 1992) suggesting an effect on the central serotonin system consistent with many known antidepressive drugs (Nathan et al., 1995). In literature, a selective increase in vigour comparable to that found with gabapentin could be only found with the reversible MAO-A-inhibitor moclobemide in patients with chronic fatigue syndrome. But this aspect similar to the one by gabapentin found in the present study was measured not before two weeks after onset of the treatment (Hickie et al., 2000). It should be mentioned that we found no significant difference between the groups in objective MAWS and in subjective ESA. These finding stands in contrast in respect to data showing gabapentin efficacy in reducing objective withdrawal measures (Myrick et al., 1998; Bozikas et al., 2002; Johnson et al., 2005; Mariani et al., 2006). However, only the present study comprises a placebo condition and a subjective withdrawal measure. The study is limited by the lack of correlates of mood by other rating scales, such as the Beck Depression Inventory (BDI) or the Hamilton Depression Scale. Nonetheless, the POMS is a widely used valid instrument to assess the emotional state (Albani et al., 2005) and there are strong correlations between the dejection POMS-subscale and the BDI (Jacobs and Boze, 1993; Malouff, 1985; Nyenhuis et al., 1999). In conclusion, gabapentin significantly and reversibly increased the vigour-score without changing the resting POMS-subscores in patients with alcohol withdrawal. This was found within 48 h especially in patients with mild depression and appeared independent from withdrawal-severity. The fast increase in vigour might support the compliance for adjunctive treatments. Acknowledgement The study was supported by Gödecke/Parke-Davis. References Albani C, Blaser G, Geyer M, Schmutzer G, Brähler E, Bailer H, et al. The German short version of profile of mood states (POMS): psychometric evaluation in a representative sample. Psychother Psych Med 2005;55:324–30.
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