Pharmacotherapy in Dementia with Lewy Bodies

Fig. 16.1

Mean changes from baseline in the (a) Mini-Mental State Examination and (b) Neuropsychiatric Inventory (NPI-10) in the exploratory RCT of donepezil in DLB [23]

16.2.2.3 Recently, we conducted a phase 3 study, integrating an RCT [25] and an open-label long-term extension study [26] (Fig. 16.2a, b). Patients with DLB (n = 142) were randomly assigned to placebo or 5 mg or 10 mg donepezil that was administered once daily for 12 weeks. Co-primary endpoints were changes in cognitive function assessed using MMSE and behavioral and neuropsychiatric symptoms using the NPI-2. The predefined superiority of donepezil to the placebo was not confirmed in either active group in the primary analysis. MMSE significantly improved compared to placebo in the 10-mg group, whereas the change in MMSE in the 5-mg group was not significant. This result may be due to a relatively higher number of earlier discontinuations. Thirty-one patients discontinued treatment, with more discontinuations in the 5-mg group than in the 10-mg group. In the 5-mg group, eight patients (17.0 %) discontinued by week 4 when the blood concentrations of 5 mg donepezil reached the steady state, whereas only one (3.0 %) had discontinued in the previous study [23]. Although NPI-2 improved compared to baseline in active groups, the differences from placebo were not significant. The placebo group also showed improvement. Evaluation of psychiatric symptoms may be affected by advanced education and instructions for caregivers. Although the incidence of parkinsonism was slightly higher in the 10-mg group, the change in the UPDRS III score was minimal without a significant difference from the placebo group.

Fig. 16.2

(a) Study flow and (b) mean changes from baseline in the Mini-Mental State Examination in the phase 3 RCT of donepezil in DLB [25]

16.2.2.4 A double-blind, randomized, placebo-controlled, crossover study was designed to examine the safety and efficacy of donepezil [27]. Fourteen patients with PD and cognitive impairment received donepezil (5 or 10 mg/day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the MMSE score, the CIBIC-plus score, and the motor subscale of the UPDRS. After 10 weeks of treatment, the mean MMSE score was increased by 2.1 (SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC-plus score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE ( p = 0.013) and CIBIC-plus ( p = 0.034). Parkinsonism did not increase during donepezil treatment.

16.2.2.5 An RCT was designed to examine the safety and efficacy of donepezil [28]. Nine PD patients with dementia or cognitive impairment received placebo, and seven patients received donepezil (2.5–10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary outcome measures were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. The study was completed by 10 out of 16 (62.5 %) subjects. Patients on donepezil showed selective and significant improvement on the memory subscale of the Dementia Rating Scale (DRS). A trend toward improvement in a measure of psychomotor speed and attention was also observed. No group differences were seen in the MMSE score, DRS total score, psychiatric status, motor function, or ADL as measured at baseline or the end-point.

16.2.2.6 Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of PD were randomly assigned to receive placebo or 3–12 mg rivastigmine per day for 24 weeks [29]. A total of 541 patients with PDD were randomly assigned to treatment with rivastigmine or placebo in a ratio of 2:1. The primary outcome measures were the scores for the ADAS-cog and Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC). The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for AD. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score on the 70-point ADAS-cog from a baseline score of 23.8, compared with a 0.7-point worsening in the placebo group from a baseline score of 24.3 ( p < 0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 % of patients in the rivastigmine group and 14.5 % of those in the placebo group, and clinically meaningful worsening was observed in 13.0 % and 23.1 %, respectively (mean scores at 24 weeks, 3.8 and 4.3, respectively; p = 0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary outcome measures such as ADCS-ADL, NPI-10, MMSE, the Clinical Dementia Scale (CDR), power of attention tests, etc. Deterioration was not noted in the UPDRS III score in any active groups at the final evaluation.

16.2.2.7 A double-blind, randomized, placebo-controlled, crossover study was designed to examine the safety and efficacy of donepezil [30]. Twenty-two patients with PDD were randomized to receive either donepezil (5 or 10 mg/day) (during 10 weeks) followed by identical placebo (during 10 weeks) or placebo followed by donepezil, with an open-label washout period of 6 weeks between the two periods. The primary outcome measure was the ADAS-cog. A 1.9-point trend toward better scores on the ADAS-cog on treatment was observed compared with placebo, but the difference was not statistically significant. The secondary cognitive measures showed a statistically significant 2-point benefit on the MMSE and no change on the Mattis Dementia Rating Scale. The CGIC showed a significant 0.37-point improvement with donepezil. No improvement was observed on the Brief Psychiatric Rating Scale (BPRS). No worsening of PD symptoms was observed as measured by the total or motor sections of the UPDRS.

16.2.2.8 A 24-week, multinational RCT was designed to examine the efficacy and safety of donepezil given once daily in patients with PDD [31]. Five hundred fifty patients with PDD were randomized to donepezil (5 or 10 mg) or placebo and were evaluated at baseline and at weeks 12 and 24. Co-outcome measures were the ADAS-cog and the CIBIC-plus. ADAS-cog mean changes from baseline to week 24 (end-point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model. Alternative ADAS-cog analysis in which the treatment-by-country interaction term was removed from the model revealed a significant, dose-dependent benefit with donepezil. The 10-mg group, but not the 5-mg group, had significantly better CIBIC-plus scores compared with placebo. Secondary outcome measures—MMSE, Delis–Kaplan Executive Function System, and Brief Test of Attention that represents cognitive functions particularly relevant to PDD—showed a significant benefit for both donepezil doses. No significant differences in ADL or behavior were observed. Adverse events (AEs) were more common with donepezil but mostly mild/moderate in severity.

16.2.3 Long-Term Safety Studies in DLB

16.2.3.1 Twenty-nine patients with DLB were recruited from a placebo-controlled trial of rivastigmine [22] and treated for up to 96 weeks [32]. All patients were recruited after a 3-week open-label washout phase. Of the 29 patients, nine discontinued treatment during the course of the trial: four discontinued because of side effects, four were nonresponders, and one died from an unrelated cause. Improvement from baseline was seen in cognitive function as measured by the MMSE and neuropsychiatric symptoms as measured by the NPI over the first 24 weeks of treatment. By 96 weeks, neither the MMSE scores nor the NPI scores were significantly worse than at baseline. UPDRS total and subscale scores were not significantly increased from baseline in weeks 36–96, showing no detectable deterioration in parkinsonism over the treatment period.

16.2.3.2 A 52-week, multicenter, open-label extension study was designed to investigate the safety and efficacy of long-term administration of donepezil in patients with DLB (Fig. 16.3) [24]. Up to 8 weeks after the completion of the preceding RCT [23], 108 patients started treatment with 3 mg donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Ninety patients (83.3 %) completed 24 weeks of treatment, and 81 patients (75 %) completed 52 weeks. The overall discontinuation rate of this study was 25 % (n = 27), and 18 patients discontinued treatment due to AEs. Three patients underwent a dose reduction from 5 to 3 mg/day due to occurrence of AEs. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the MMSE, the NPI, Cognitive Fluctuation Inventory, and the ZBI, respectively. Cognitive function and dementia-related behavioral symptoms including cognitive fluctuations improved after the start of donepezil treatment, and improvement was maintained for 52 weeks, although a relationship between the washout period and attenuation of the treatment effect was suggested. Reduction in caregiver burden that was observed in the preceding RCT returned to the baseline level at 52 weeks. However, of note, burden on caregivers did not increase throughout the cumulative observational period. Delayed AE onset induced by long-term administration of donepezil was unlikely to appear. The long-term study showed that donepezil at 5 mg/day was well tolerated and sustained improvement in cognitive impairment and psychiatric symptoms over 52 weeks, or up to 64 weeks if the preceding treatment period is included.

Fig. 16.3

Mean change in MMSE score [24]. (a) Overall mean change during the treatment period (n = 103). (b) Mean change in the placebo group of the preceding RCT (n = 27). (c) Mean cumulative changes by treatment group in the preceding RCT throughout both the preceding RCT and this extension study. Notes: * indicates P < 0.05. P values were calculated compared to baseline using paired t-tests in (a) and (b). No statistical test was performed in (c). Vertical bars indicate standard deviations. LOCF last observation carried forward

16.2.3.3 The long-term efficacy and safety of 10 mg donepezil in patients with dementia with DLB were investigated in a 52-week phase 3 trial. This study consisted of a 16-week RCT [25] and a 36-week open-label extension phase [26]. Of 142 DLB patients enrolled in the RCT phase, 110 entered the extension phase. The placebo group of the RCT phase initiated active treatment at week 16. After week 24, all patients received 10 mg. Dose reduction to 5 mg for safety concerns was allowed. Efficacy measures included MMSE for cognitive function and NPI for behavioral symptoms. Safety evaluations included AEs and the UPDRS III. In total, 100 subjects completed the study. During the extension phase, ten patients discontinued treatment because of AEs (six patients) and the patient’s request (four patients). Cognitive function improvement was sustained for 52 weeks (Fig. 16.4). Patients who received placebo in the RCT phase showed an improvement after starting active treatment. NPI improved in all the groups throughout the study, including the placebo period. In the subgroup of the 5-mg group without remarkable cognitive or behavioral improvement at week 24, further improvement was observed after a dose increase to 10 mg. After week 24, 21 patients underwent dose reduction. Because MMSE scores remained above the baseline at all times, the effects can be maintained, even with a reduction to 5 mg. The incidence of any AEs did not increase over time. Thus, the possibility of delayed onset of AEs with long-term treatment seems low. Most of the treatment-related AEs were mild or moderate, and only parkinsonism had an incidence of 5 % or more.

Fig. 16.4

Mean changes in the Mini-Mental State Examination by treatment group throughout both the placebo-controlled phase and open-label extension phase [26]. Placebo → 10 mg (PLA-DON10) started treatment with 3 mg at week 16, and the dose was increased to 5 mg at week 18. Placebo → 10 mg (PLA-DON10) and donepezil 5 mg → 10 mg (DON5-DON10) started treatment with 10 mg at week 24 (dose decreased to 5 mg was allowed)

16.2.4 Comments

Case studies and open trials of ChEIs in DLB or PDD have consistently shown improvements in neuropsychiatric symptoms. Donepezil [16, 17 19, 21], rivastigmine [18], and galantamine [20] reduced various psychotic symptoms such as hallucinations, delusions, apathy, etc.

No head-to-head trials have been performed to compare the efficacy of ChEIs in DLB and PDD, but donepezil and rivastigmine have a wide evidence base. As mentioned above, six RCTs for donepezil, two for DLB [23, 25], and four for PDD [27, 28, 30, 31] have been performed, and two RCTs for rivastigmine, one for DLB [22], and one for PDD [29] have also been performed. A recent meta-analysis [33] indicated beneficial effects of donepezil and rivastigmine for cognitive and psychiatric symptoms. Rivastigmine, but not donepezil, was associated with a greater risk of AEs.

Results from our two long-term studies suggest that improvement in cognitive impairment by donepezil at 5 and 10 mg is sustainable for at least 1 year in patients with DLB. In an open-label long-term study of donepezil in patients with mild-to-moderate AD, the improvement in MMSE was maintained until 24 weeks after administration started and then gradually waned and deteriorated [34]. Considering this result in the context of a similar or faster progression in cognitive impairment in DLB than in AD [35, 36], the duration during which the cognitive improvement induced by donepezil persists in patients with DLB may surpass that in patients with AD. Rivastigmine is also effective in improving cognition and reducing neurobehavioral disturbances over 96 weeks [32]. The major limitation of these three long-term studies is their open-label, single-arm design. However, due to the progressive nature of DLB in which mortality is accelerated, allocating patients to a placebo is not appropriate for long periods of time.

Theoretically, ChEIs can exacerbate parkinsonism. However, this was rare and rarely bothersome enough to warrant the discontinuation of medication. Although severe autonomic dysfunctions such as symptomatic bradycardia and QT prolongation were not remarkable, such fragile patients were usually excluded from these trials. We should confirm the AEs induced by ChEIs in DLB or PDD in a real clinical setting.

16.3 Previous Studies Using Memantine in DLB and PDD

Memantine, which is a selective, noncompetitive blocker of NMDA receptors, has been used to treat AD and vascular dementia. The mechanism of action is related to the modulation of glutamatergic transmission, which mediates cortico-cortical and cortico-subcortical interactions in the brain. Changes in markers of glutamatergic activity have been identified in patients with DLB [37]. Evidence for striatal glutamatergic overactivity has been reported in animal models of parkinsonism [38]. Given that Alzheimer-type pathology such as amyloid deposits and neurofibrillary tangles is common in DLB and PDD, the observation that therapy with memantine is effective in these patients is not surprising.

16.3.1 Case Series and Open-Label Studies

16.3.1.1 Three patients with DLB experienced worsening delusions and visual hallucinations as a result of memantine therapy [39]. Significant resolution occurred once treatment was discontinued.

16.3.1.2 To determine the effect of memantine for the treatment of DLB, the authors reviewed the charts of 11 subjects with DLB that were prospectively evaluated and treated with memantine (with or without ChEIs) for varying lengths of time [40]. Nine of eleven DLB subjects on memantine were also on ChEIs. Seven of 11 were stable or improved with memantine, and the remaining four worsened or responded adversely when exposed to the drug. AEs included increased hallucinations and sedation. No adverse effects on motor function were observed.

16.3.1.3 An open, controlled, 16-week study was performed to evaluate the efficacy and safety of memantine in patients with DLB or PDD [41]. The study included 23 patients who were divided into two groups: 14 patients received memantine at a dose of 20 mg/day, and nine patients constituted the control group. Patients did not receive ChEIs for at least 2 months prior to inclusion in the study. Efficacy was evaluated using a battery of quantitative neuropsychological tests (MMSE, Mattis Dementia Scale, clock-drawing test), clinical scales for assessment of fluctuations in mental states (the clinician assessment of fluctuation (CAF) scale, the one-day fluctuation assessment scale (ODFAS)), scales for assessment of behavioral and psychotic disorders, and the general clinical impression scale. Motor impairments were evaluated using UPDRS III. The results demonstrated that memantine had positive effects on the patients’ general status and cognitive functions (increases on the MMSE by 1.5 points), mainly because of improvements in attention and control functions. Reductions in the severity of fluctuations in mental state, aggressiveness, lack of spontaneity, and disinhibition were also observed. The severity of psychotic and motor disorders did not change significantly. Tolerance of memantine was good, and only two patients withdrew from the study because of episodes of confusion during the dose titration period.

16.3.2 Randomized Placebo-Controlled Studies

16.3.2.1 A 22-week RCT was designed to examine the safety and tolerability of memantine (20 mg/day), in 25 patients suffering from PDD [42]. Global, cognitive, and behavioral outcome measures were administered at baseline, at end of study drug treatment (week 16), and at drug termination (week 22). The primary outcome measure was global cognitive impairment with emphasis on subcortical functions as assessed by the DRS. Secondary outcome measures were the NPI, MMSE, and CIBIC-Plus to assess global change by an independent assessor. Memantine was well tolerated by participants at 20 mg/day dosing. No participant withdrew due to memantine-related AEs. Statistically significant differences between groups on the DRS total and the NPI total as well as the MMSE were not observed. At week 16, a trend toward improvement in global functioning in mean CIBIC-Plus scores in the memantine (60 %) versus the placebo group (43 %) was observed. Six weeks after drug withdrawal, a significantly greater proportion (70 %) of memantine-treated participants deteriorated globally compared with those treated with placebo (29 %). These findings suggest that continued treatment with memantine may be needed to maintain a global level of functioning over time. No worsening of motor symptoms as measured by the motor sections of the UPDRS III was seen.

16.3.2.2 A 24-week, multinational RCT was designed to examine the efficacy and safety of memantine (20 mg/day) in patients with PDD or DLB [43]. Stable treatment with ChEIs was allowed before (at least 6 months before enrollment) and during the trial. The primary outcome measure was CGIC, which ranged from 1 to 7 points; a low score indicates a better outcome. Analysis was performed by intention to treat based on the LOCF. Seventy-two patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo; 56 (78 %) completed the study. All withdrawals were due to AEs, but the proportion of withdrawals was similar in both groups. At week 24, the patients in the memantine group had better CGIC scores than those taking placebo. No differences were observed in the mean CGIC LOCF between the memantine- and placebo-treated patients with DLB. The mean score in the PDD group was 4.3 in the placebo group and 2.9 in the memantine group, suggesting a more pronounced global response in patients with PDD. With the exception of improved speed on attentional tasks in the memantine group, no significant differences were found between the groups in secondary outcome measures. Patients with DLB or PDD may benefit from treatment with memantine, which was well tolerated.

16.3.2.3 A 24-week, multinational RCT was designed to examine the efficacy and safety of memantine (20 mg/day) in patients with mild-to-moderate PDD or DLB [44]. Patients were randomly assigned to placebo or memantine (20 mg per day) and did not receive ChEIs for at least 6 weeks prior to enrolling in the study. No primary outcome measure was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid post-baseline assessment. Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo; 159 (80 %) patients completed the study: 80 in the memantine group and 79 in the placebo group. At week 24, patients with DLB who received memantine showed greater improvement according to ADCS-CGIC scores compared to those who received placebo. No significant differences were noted between the two treatments in patients with PDD or in the total population. NPI scores showed significantly greater improvement in the memantine group than in the placebo group in patients with DLB, but not in those with PDD or in the total patient population. No significant differences were found between the two treatment groups in any of the study populations in most of the cognitive test scores, ADCS-ADL scores, and the ZBI scores. The incidence of AEs and number of discontinuations due to AEs were similar in the two groups. Memantine seems to improve global clinical status and behavioral symptoms of patients with mild-to-moderate DLB.

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