Mood improvements by VNS in epilepsy patients

Reports from the early randomized controlled trials on VNS for epilepsy treatment (EO3, EO5) suggested improved quality of life in a majority of patients (Ben-Menachem et al., 1994; Handforth et al., 1998): At the 14-weeks follow-up, about 50-60% of the patients stated that their quality of life has improved since implantation. From a psychometric point of view, reliability and validity of these data were questionable and these reports had to be considered as preliminary. But they initiated some studies of this phenomenon which will be reviewed in the following section.

Harden et al. (2000) recently published a study on VNS and mood in which 20 epilepsy patients under VNS and 20 control patients were enrolled (a nonrandomized, nonblinded, controlled clinical trial). Mood outcome measures were scores from standard psychiatric rating scales (Cornell Dysthymia Rating Scale; Mason et al., 1993; Hamilton Depression Rating Scale/Hamilton Anxiety Rating Scale; Hamilton, 1960) and from the Beck Depression Inventory (Beck, 1967), an estab lished self-report questionnaire. Significant improvements of depression scores from baseline to follow-up were observed only in the VNS treatment group. A slight decrement in the score of the Hamilton Anxiety Rating Scale was not significant. No significant mood changes were observed within the control group. No between-group differences were obtained at baseline or follow-up and the authors failed to demonstrate a significant interaction effect (group x time) to confirm their hypothesis; only for the BDI score did the interaction effect approach significance (P = 0.07). From the within-group changes which were limited to the VNS group, Harden et al. (2000) concluded that their findings, for the first time, showed improvements of depressed mood in epilepsy patients during VNS treatment by means of psychometrically evaluated measures.

Elger et al. (2000) completed the EO3 study on seizure outcome of VNS, in which their unit participated with some patients in 1993, with a comprehensive psychiatric evaluation. This international multisite outcome study included 14 weeks of a randomized control trial (RCT). Patients were randomly assigned to a low or high stimulation condition (dose-effect study). In order to give patients from both groups the feeling of participating in an optimal treatment condition, patients from the low stimulation group were told that VNS has optimal effects when subjects are just able to recognize the signal. In contrast, patients from the high stimulation group were informed that VNS should be maximized according to subjective tolerability of adverse effects (with 1.75 mA as the predefined maximum). Seizure and psychiatric data were recorded 4 weeks before implantation (baseline) and at the 3- and 6-month follow-ups. Medication was unchanged during the entire duration of the study. From our unit, 11 patients with severe drug-resistant epileptic seizures enrolled in the EO3 study and agreed to participate in the psychiatric study as well. An experienced psychiatrist, to whom the stimulation conditions were masked, completed several standard rating scales, such as the Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery and Asberg, 1979) and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1981). Figure 19.1 depicts improvements of depressive mood states during VNS treatment as revealed by the MADRS.

Despite the small sample size, and consequently small statistical power, MADRS changes from baseline to the 6-month follow-up were significant in the total sample (nonparametrical ANOVA, Friedman tests: P< 0.05; post hocpairwise analysis by Wilcoxon test: P < 0.05). Interestingly, patients from the high and low stimulation group tended to experience different courses of mood improvements: in the high stimulation group mood improvements appeared earlier and were already seen at the 3-month follow-up and sustained until the 6-month follow-up. Patients from the low stimulation group experienced significant mood improvements, particularly after finishing the RCT, that is, after output currencies were increased and

Figure 19.1. Improvement of depressed mood during VNS treatment: high (n = 6) vs. low stimulation (n = 5).

3 months post

6 months post

Figure 19.1. Improvement of depressed mood during VNS treatment: high (n = 6) vs. low stimulation (n = 5).

adapted to the other patients during the second ramp-up period. At the 3-month follow-up, group differences between the MADRS scores approached significance (Mann-Whitney test: P<0.10). This finding is consistent with the notion of a (partial) VNS dose-response relationship which may indicate specificity of the observed effects. In addition, data revealed a (partial) independence of mood improvements and the antiseizure effect of VNS: 9 of 11 patients presented mood responses whereas only 3 of 11 patients had about 50% reductions in seizure frequency, that is, mood improvements in 6 of 9 patients could not be attributed to improved seizure control.

Both studies have to be regarded as preliminary and the most critical methodological aspects, such as a possible rater bias due to missing attempts of masking the experimental conditions in the Harden et al. (2000) study and the missing control group in the Elger et al. (2000) study, are carefully discussed in both papers. From a rigorous methodological point of view, both studies fail to definitely prove the specificity of the observed effect and to exclude a mere placebo effect. However, it is questionable whether this issue can be taken further: blinding is difficult in surgical treatments such as VNS; arranging an appropriate group of control patients is very questionable; masking VNS patients to their stimulation condition appears almost impossible; and it is unclear whether a placebo condition needs to include surgery as well. Furthermore, even a controlled dose-response study may be difficult to perform since today's patients are probably well informed about the effects of low and high stimulation, due to comprehensive patient information.

In an on-going study we are trying to circumvent these problems by using self-report questionnaires: here patients are asked to evaluate their present mood states (e.g. last 4 weeks). At the follow-up, 6 months after implantation, they are presumed to be unable to remember their former answers to single items. Mood score changes can be compared to normative data as recorded during construction of the questionnaire, e.g. to exclude a mere regression to the mean effect.

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