main topic Wien Med Wochenschr DOI 10.1007/s10354-015-0360-y
Phytopharmaceutical treatment of anxiety, depression, and dementia in the elderly: evidence from randomized, controlled clinical trials Siegfried Kasper
Received: 6 March 2015 / Accepted: 10 May 2015 © Springer-Verlag Wien 2015
Summary Based on subgroup analyses of randomized, controlled clinical trials, we review the efficacy of three phytopharmaceutical drugs, respectively of the corresponding active substances silexan® (WS® 1265, lavender oil) in anxiety disorders, WS® 5570 (Hypericum extract) in major depression, and EGb 761® (Ginkgo biloba extract) in Alzheimer, vascular, or mixed type dementia, in elderly patients aged ≥ 60 years. Four trials were eligible in each indication. Metaanalyses and analyses based on pooled raw data showed that the three drugs were significantly superior to placebo in the elderly subset, and that their treatment effects reflected in the main outcome measures (Hamilton Anxiety scale, Hamilton Depression scale, Neuropsychiatric Inventory) were comparable with those observed in the original trials without age restrictions. The results confirm the efficacy of the three herbal active substances in elderly patients of ≥ 60 years of age. In anxiety, depression, and dementia, they thus represent efficacious and well-tolerated alternatives to synthetic drugs. Keywords Evidence-based phytotherapy · Elderly · Anxiety/depression/dementia · Randomized controlled trials
Herrn Prof. Hippius zum 90. Geburtstag gewidmet. O. Univ. Prof. Dr. h.c.mult. Dr.med. S. Kasper () Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria e-mail: [email protected]
13
Phytopharmaka bei der Behandlung von Angststörungen, Depressionen und Demenz bei älteren Patienten – Evidenz aus randomisierten, klinischenStudien Zusammenfassung Auf der Grundlage randomisierter, kontrollierter Studien untersuchten wir die Wirksamkeit dreier Phytopharmaka mit den Wirkstoffen Silexan® (WS® 1265, Lavendelöl) bei Angststörungen, WS® 5570 (Hypericum-Extrakt) bei Depressionen und EGb 761® (Ginkgo-biloba-Extrakt) bei Alzheimer- oder vaskulärer Demenz und bei Mischformen, bei Patienten im Alter ab 60 Jahren. In jeder der drei Indikationen genügten vier Studien unseren Auswahlkriterien. Metaanalysen und Analysen auf der Grundlage der gepoolten Rohdaten wiesen auch im Kollektiv der Patienten ab 60 Jahren die Überlegenheit der drei Phytopharmaka gegenüber Plazebo nach. Dabei waren die Behandlungseffekte ähnlich jenen, die in den Ausgangsstudien für die nicht nach Alter ausgelesenen Wirksamkeitskollektive beobachtet worden waren. Das galt für die Hauptzielvariablen Hamilton Angstskala, Hamilton Depressionsskala und Neuropsychiatrisches Inventar. Die Ergebnisse bestätigen die Wirksamkeit der drei pflanzlichen Wirkstoffe auch für ältere Patienten ab 60 Jahre. Die Präparate bieten sich damit als wirksame und gut verträgliche Alternative zu synthetischen Therapeutika bei Angststörungen, Depressionen oder Demenz an. Schlüsselwörter Evidenz-basierte Phytotherapie · Ältere Menschen · Angst/Depression/Demenz · Randomisierte kontrollierte klinische Studie
Phytopharmaceutical treatment of anxiety, depression, and dementia in the elderly
1
main topic Introduction According to the 2015 Ageing Report of the EuropeanCommission [1], the proportion of people aged 65 years and over among the general population of the European Union (EU) is projected to increase from 18 % in 2013 to 28 % by 2060, and the share of those aged 80 or above is expected to increase from 5 to 12 %. Demographic change is attributable to a combination of decreased fertility rates and increased life expectancy: between 1960 and 2012, the average life expectancy in the EU member states increased by approximately 9.5 years, and an increase by another 6–7 years is anticipated until 2060, due to improved healthcare education, prophylactic measures, and therapeutic opportunities. On the other hand, the total fertility rate decreased from 2.67 in 1960 to 1.56 in 2012 and is expected to remain stable during the coming decades. As a result of demographic change, the medical profession is faced with challenges not only arising from an increase in typical age-related diseases, such as dementia, diabetes mellitus, gout, circulatory, cardiovascular or rheumatic disorders, and osteoporosis, but also from the need for providing appropriate care to an ageing, increasingly multimorbid patient population in general. Elderly individuals often suffer from chronic diseases whose sequels, the resulting functional impairments, and the drugs prescribed for their treatment show a complex interaction [2]. Moreover, advancing age is associated with deteriorating regulation of the processes that provide functional integration between cells and organs, which in turn lead to pharmacokinetic and pharmacodynamic changes such as a reduction in renal and hepatic clearance and an increase in volume of distribution of lipophilic drugs as well as altered sensitivity to several classes of drugs [3]. It has been shown that polypharmacy caused by multimorbidity in the elderly is associated with an exponential increase of the risk of adverse effects [4, 5]. For example, it increases the risk of falls [6, 7], delirium [8], bleeding complications [9], dizziness, and cognitive impairment [10], and may ultimately lead to an increased risk of mortality [11, 12]. The use of drugs that have a favorable safety profile and a low potential for drug interactions is therefore essential in this particularly vulnerable patient population [13]. Phytopharmaceutical drugs are also referred to as Herbal Medicinal Products (HMPs) in the European legislation (according to the European Medicines Agency [EMA] and the Committee on Herbal Medicinal Products [HMPC] guidelines). Herbal active substances are complex multicomponent mixtures that contain several pharmacologically active ingredients and act on multiple targets [14]. Thus, they possess a broader therapeutic profile than most synthetic drugs and cause fewer side effects related to their mechanisms of action. In particular, severe or serious adverse effects are rare or even unknown, and many phytopharmaceutical drugs have a low potential for drug interactions. This makes them an interesting therapeutic option in the elderly population
where multiple chronic complaints and polypharmacy are common [15]. Based on data from randomized, controlled trials, we review the efficacy of phytopharmaceutical drugs in elderly patients in selected neuropsychiatric indications. Evidence is presented for three patented herbal active substances: lavender oil preparation silexan in anxiety disorders, Hypericum extract WS 5570 in depression, and Ginkgo biloba extract EGb 761 in neuropsychiatric symptoms of dementia.
General methods The criteria for the selection of the trials included into our analyses are described in the sections below. The analyses of treatment efficacy were performed in subsets of patients aged 60 years or older and derived from the full analysis set that had been prespecified as the primary analysis population in the protocols of the included trials. Efficacy was assessed based on validated psychiatric scales that assessed disease-specific symptoms or global clinical outcome. In the indications of anxiety disorders and dementia only placebo-controlled trials were selected. For the subsets of elderly patients, analyses of variance (with treatment as a fixed factor) or covariance (with treatment as a fixed factor and the baseline value of the outcome measure as a covariate) were performed within each study, and the results were then combined using meta-analyses based on fixed-effect models. For depression, two of the identified trials did not include a placebo control group. Rather than using meta-analyses, subgroup analyses for elderly patients were therefore carried out after pooling the raw data of the primary trials. Missing data for efficacy outcomes were imputed in the same manner as in the original protocols of the included trials, by carrying forward the last valid observation. Two-sided p values ≤ 0.05 are considered descriptively significant. Meta-analyses were performed using the R software package “meta”. All other analyses were performed using SAS data analysis software version 9.2.
Lavender oil preparation silexan for anxiety disorders Background Anxiety disorders are a prevalent mental health problem in older age with a considerable impact on quality of life. Longitudinal studies indicate that elderly suffering from anxiety disorders have a high risk of relapse and persistence alongside the progression to depression and mixed anxiety depression states [16]. Drug treatment of anxiety is predominantly carried out using antidepressant drugs (notably selective serotonin reuptake inhibitors, SSRIs), benzodiazepines, and neuroleptics [17].
2 Phytopharmaceutical treatment of anxiety, depression, and dementia in the elderly
13
main topic
Table 1 Silexan in anxiety disorders—characteristics of included trials Trial
Trial A
Trial B
Trial C
Trial D
Kasper et al. 2010 [26]
Kasper et al. 2010 [22]
Kasper et al. 2014 [23]
(unpublished)
Design characteristics
Double-blind, randomized, placebo-controlled multicenter trial
Diagnosis for inclusion
Restlessness and agitation (ICD-10 R45.1)
Anxiety disorder not otherwise specified (DSM-IV 300.00; ICD-10 F41.9)
Generalized anxiety disorder (DSM-5 300.02)
Generalized anxiety disorder (DSM-5 300.02)
Hamilton Anxiety Scale scores (points) for inclusion
Total score ≥ 18, Tension ≥ 2, Insomnia ≥ 2
Total score ≥ 18, Anxious mood ≥ 2, Insomnia ≥ 2
Total score ≥ 18, Anxious mood ≥ 2, Tension ≥ 2
Total score ≥ 18, Anxious mood ≥ 2, Tension ≥ 2
Interventions
80 mg/day silexan or placebo, 10 weeks
Number of patients ≥ 60 years/total
Silexan 18/86 Placebo 17/84
Silexan 14/135 Placebo 13/135
Silexan 10/103 Placebo 11/102
Main efficacy outcome measures
Hamilton Anxiety Scale (HAMA), Clinical Global Impressions (CGI)
Silexan 13/104 Placebo 16/107
Silexan1 is a patented active substance consisting of an essential oil produced from Lavandula angustifolia flowers by steam distillation and complies with the monograph Lavender oil of the European Pharmacopoeia (Ph. Eur.) [18]. It exceeds the quality definition of the Ph. Eur. with respect to items important for efficacy and tolerability. The HMP is approved as a drug in Germany for the treatment of restlessness related to anxious mood, with a recommended dose of 1 × 80 mg/day. The anxiolytic effect of silexan can be explained by a potent inhibition of voltage-dependent calcium channels (VOCCs), however, without binding to the gabapentin binding site at the 2-1 and -2 subunits of the presynaptic VOCCs of the P/Q-type [19] as well as by a significant reduction the serotonin-1 A receptor (5-HT1A) binding potential in several brain clusters [20]. In adult patient populations, the drug has been demonstrated to be superior to placebo in subsyndromal anxiety disorder and generalized anxiety disorder (GAD) as well as comparably efficacious as paroxetine and lorazepam in GAD [21–24]. Known side effects of silexan are limited to gastrointestinal complaints (mainly eructation) and allergic skin reactions. Sedation, abuse liability, or drug interactions have not been reported.
Studies and participants Our analysis included all randomized, placebo controlled trials with silexan initiated by the manufacturer in which the anxiety level of the participants was assessed using the Hamilton Anxiety Scale (HAMA [25]). We identified and included four trials (Kasper et al. 2010 [26]; Kasper et al. 2010 [22], Kasper et al. 2014 [23], and one unpublished trial) performed in the indications of GAD and subsyndromal anxiety disorders whose basic characteristics are shown in Table 1. All trials had a double-blind treatment phase of 10 weeks during which the participants received 1 × 80 mg/ day silexan or placebo. The study reported by Kasper et Silexan® (WS® 1265) is the active substance of Lasea® (Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany).
1
13
al. [23] and the unpublished trial also investigated other daily doses of the active substance silexan; however, only the marketed dose of 1 × 80 mg/day was considered in our analyses.
Outcomes Meta-analyses were performed for absolute HAMA total score change between baseline and the end of the 10-week acute treatment phase as well as for Items 1 (“Severity if Illness”) and 2 (“Global Improvement” compared with baseline) of the Clinical Global Impressions (CGI [27]) scale.
Results Out of a total of 857 trial participants, 112 (silexan 55, placebo 57) were at least 60-year-old and were included into our meta-analyses (see Table 1 for details). Across the four trials, 80.0 % of the elderly participants in the silexan group and 75.4 % in the placebo group were female individuals, with a notable deviation in Trial D where 90.0 % of the ≤ 60-year-old participants in the silexan group and 54.6 % in the placebo group were female individuals. In the pooled data set of the elderly subset of the included trials, the HAMA total score decreased from a baseline mean value (± standard deviation) of 25.1 ± 5.7 points to 11.6 ± 7.4 points at week 10 for silexan and from 25.2 ± 5.8 points to 15.7 ± 7.6 points for placebo. In the meta-analysis of the four trials, silexan was superior to placebo by a median difference of − 4.26 points (95 % confidence interval [CI]: − 1.28; − 7.25 points) for change between baseline and week 10 (p
Phytopharmaceutical treatment of anxiety, depression, and dementia in the elderly: evidence from randomized, controlled clinical trials Siegfried Kasper
Received: 6 March 2015 / Accepted: 10 May 2015 © Springer-Verlag Wien 2015
Summary Based on subgroup analyses of randomized, controlled clinical trials, we review the efficacy of three phytopharmaceutical drugs, respectively of the corresponding active substances silexan® (WS® 1265, lavender oil) in anxiety disorders, WS® 5570 (Hypericum extract) in major depression, and EGb 761® (Ginkgo biloba extract) in Alzheimer, vascular, or mixed type dementia, in elderly patients aged ≥ 60 years. Four trials were eligible in each indication. Metaanalyses and analyses based on pooled raw data showed that the three drugs were significantly superior to placebo in the elderly subset, and that their treatment effects reflected in the main outcome measures (Hamilton Anxiety scale, Hamilton Depression scale, Neuropsychiatric Inventory) were comparable with those observed in the original trials without age restrictions. The results confirm the efficacy of the three herbal active substances in elderly patients of ≥ 60 years of age. In anxiety, depression, and dementia, they thus represent efficacious and well-tolerated alternatives to synthetic drugs. Keywords Evidence-based phytotherapy · Elderly · Anxiety/depression/dementia · Randomized controlled trials
Herrn Prof. Hippius zum 90. Geburtstag gewidmet. O. Univ. Prof. Dr. h.c.mult. Dr.med. S. Kasper () Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria e-mail: [email protected]
13
Phytopharmaka bei der Behandlung von Angststörungen, Depressionen und Demenz bei älteren Patienten – Evidenz aus randomisierten, klinischenStudien Zusammenfassung Auf der Grundlage randomisierter, kontrollierter Studien untersuchten wir die Wirksamkeit dreier Phytopharmaka mit den Wirkstoffen Silexan® (WS® 1265, Lavendelöl) bei Angststörungen, WS® 5570 (Hypericum-Extrakt) bei Depressionen und EGb 761® (Ginkgo-biloba-Extrakt) bei Alzheimer- oder vaskulärer Demenz und bei Mischformen, bei Patienten im Alter ab 60 Jahren. In jeder der drei Indikationen genügten vier Studien unseren Auswahlkriterien. Metaanalysen und Analysen auf der Grundlage der gepoolten Rohdaten wiesen auch im Kollektiv der Patienten ab 60 Jahren die Überlegenheit der drei Phytopharmaka gegenüber Plazebo nach. Dabei waren die Behandlungseffekte ähnlich jenen, die in den Ausgangsstudien für die nicht nach Alter ausgelesenen Wirksamkeitskollektive beobachtet worden waren. Das galt für die Hauptzielvariablen Hamilton Angstskala, Hamilton Depressionsskala und Neuropsychiatrisches Inventar. Die Ergebnisse bestätigen die Wirksamkeit der drei pflanzlichen Wirkstoffe auch für ältere Patienten ab 60 Jahre. Die Präparate bieten sich damit als wirksame und gut verträgliche Alternative zu synthetischen Therapeutika bei Angststörungen, Depressionen oder Demenz an. Schlüsselwörter Evidenz-basierte Phytotherapie · Ältere Menschen · Angst/Depression/Demenz · Randomisierte kontrollierte klinische Studie
Phytopharmaceutical treatment of anxiety, depression, and dementia in the elderly
1
main topic Introduction According to the 2015 Ageing Report of the EuropeanCommission [1], the proportion of people aged 65 years and over among the general population of the European Union (EU) is projected to increase from 18 % in 2013 to 28 % by 2060, and the share of those aged 80 or above is expected to increase from 5 to 12 %. Demographic change is attributable to a combination of decreased fertility rates and increased life expectancy: between 1960 and 2012, the average life expectancy in the EU member states increased by approximately 9.5 years, and an increase by another 6–7 years is anticipated until 2060, due to improved healthcare education, prophylactic measures, and therapeutic opportunities. On the other hand, the total fertility rate decreased from 2.67 in 1960 to 1.56 in 2012 and is expected to remain stable during the coming decades. As a result of demographic change, the medical profession is faced with challenges not only arising from an increase in typical age-related diseases, such as dementia, diabetes mellitus, gout, circulatory, cardiovascular or rheumatic disorders, and osteoporosis, but also from the need for providing appropriate care to an ageing, increasingly multimorbid patient population in general. Elderly individuals often suffer from chronic diseases whose sequels, the resulting functional impairments, and the drugs prescribed for their treatment show a complex interaction [2]. Moreover, advancing age is associated with deteriorating regulation of the processes that provide functional integration between cells and organs, which in turn lead to pharmacokinetic and pharmacodynamic changes such as a reduction in renal and hepatic clearance and an increase in volume of distribution of lipophilic drugs as well as altered sensitivity to several classes of drugs [3]. It has been shown that polypharmacy caused by multimorbidity in the elderly is associated with an exponential increase of the risk of adverse effects [4, 5]. For example, it increases the risk of falls [6, 7], delirium [8], bleeding complications [9], dizziness, and cognitive impairment [10], and may ultimately lead to an increased risk of mortality [11, 12]. The use of drugs that have a favorable safety profile and a low potential for drug interactions is therefore essential in this particularly vulnerable patient population [13]. Phytopharmaceutical drugs are also referred to as Herbal Medicinal Products (HMPs) in the European legislation (according to the European Medicines Agency [EMA] and the Committee on Herbal Medicinal Products [HMPC] guidelines). Herbal active substances are complex multicomponent mixtures that contain several pharmacologically active ingredients and act on multiple targets [14]. Thus, they possess a broader therapeutic profile than most synthetic drugs and cause fewer side effects related to their mechanisms of action. In particular, severe or serious adverse effects are rare or even unknown, and many phytopharmaceutical drugs have a low potential for drug interactions. This makes them an interesting therapeutic option in the elderly population
where multiple chronic complaints and polypharmacy are common [15]. Based on data from randomized, controlled trials, we review the efficacy of phytopharmaceutical drugs in elderly patients in selected neuropsychiatric indications. Evidence is presented for three patented herbal active substances: lavender oil preparation silexan in anxiety disorders, Hypericum extract WS 5570 in depression, and Ginkgo biloba extract EGb 761 in neuropsychiatric symptoms of dementia.
General methods The criteria for the selection of the trials included into our analyses are described in the sections below. The analyses of treatment efficacy were performed in subsets of patients aged 60 years or older and derived from the full analysis set that had been prespecified as the primary analysis population in the protocols of the included trials. Efficacy was assessed based on validated psychiatric scales that assessed disease-specific symptoms or global clinical outcome. In the indications of anxiety disorders and dementia only placebo-controlled trials were selected. For the subsets of elderly patients, analyses of variance (with treatment as a fixed factor) or covariance (with treatment as a fixed factor and the baseline value of the outcome measure as a covariate) were performed within each study, and the results were then combined using meta-analyses based on fixed-effect models. For depression, two of the identified trials did not include a placebo control group. Rather than using meta-analyses, subgroup analyses for elderly patients were therefore carried out after pooling the raw data of the primary trials. Missing data for efficacy outcomes were imputed in the same manner as in the original protocols of the included trials, by carrying forward the last valid observation. Two-sided p values ≤ 0.05 are considered descriptively significant. Meta-analyses were performed using the R software package “meta”. All other analyses were performed using SAS data analysis software version 9.2.
Lavender oil preparation silexan for anxiety disorders Background Anxiety disorders are a prevalent mental health problem in older age with a considerable impact on quality of life. Longitudinal studies indicate that elderly suffering from anxiety disorders have a high risk of relapse and persistence alongside the progression to depression and mixed anxiety depression states [16]. Drug treatment of anxiety is predominantly carried out using antidepressant drugs (notably selective serotonin reuptake inhibitors, SSRIs), benzodiazepines, and neuroleptics [17].
2 Phytopharmaceutical treatment of anxiety, depression, and dementia in the elderly
13
main topic
Table 1 Silexan in anxiety disorders—characteristics of included trials Trial
Trial A
Trial B
Trial C
Trial D
Kasper et al. 2010 [26]
Kasper et al. 2010 [22]
Kasper et al. 2014 [23]
(unpublished)
Design characteristics
Double-blind, randomized, placebo-controlled multicenter trial
Diagnosis for inclusion
Restlessness and agitation (ICD-10 R45.1)
Anxiety disorder not otherwise specified (DSM-IV 300.00; ICD-10 F41.9)
Generalized anxiety disorder (DSM-5 300.02)
Generalized anxiety disorder (DSM-5 300.02)
Hamilton Anxiety Scale scores (points) for inclusion
Total score ≥ 18, Tension ≥ 2, Insomnia ≥ 2
Total score ≥ 18, Anxious mood ≥ 2, Insomnia ≥ 2
Total score ≥ 18, Anxious mood ≥ 2, Tension ≥ 2
Total score ≥ 18, Anxious mood ≥ 2, Tension ≥ 2
Interventions
80 mg/day silexan or placebo, 10 weeks
Number of patients ≥ 60 years/total
Silexan 18/86 Placebo 17/84
Silexan 14/135 Placebo 13/135
Silexan 10/103 Placebo 11/102
Main efficacy outcome measures
Hamilton Anxiety Scale (HAMA), Clinical Global Impressions (CGI)
Silexan 13/104 Placebo 16/107
Silexan1 is a patented active substance consisting of an essential oil produced from Lavandula angustifolia flowers by steam distillation and complies with the monograph Lavender oil of the European Pharmacopoeia (Ph. Eur.) [18]. It exceeds the quality definition of the Ph. Eur. with respect to items important for efficacy and tolerability. The HMP is approved as a drug in Germany for the treatment of restlessness related to anxious mood, with a recommended dose of 1 × 80 mg/day. The anxiolytic effect of silexan can be explained by a potent inhibition of voltage-dependent calcium channels (VOCCs), however, without binding to the gabapentin binding site at the 2-1 and -2 subunits of the presynaptic VOCCs of the P/Q-type [19] as well as by a significant reduction the serotonin-1 A receptor (5-HT1A) binding potential in several brain clusters [20]. In adult patient populations, the drug has been demonstrated to be superior to placebo in subsyndromal anxiety disorder and generalized anxiety disorder (GAD) as well as comparably efficacious as paroxetine and lorazepam in GAD [21–24]. Known side effects of silexan are limited to gastrointestinal complaints (mainly eructation) and allergic skin reactions. Sedation, abuse liability, or drug interactions have not been reported.
Studies and participants Our analysis included all randomized, placebo controlled trials with silexan initiated by the manufacturer in which the anxiety level of the participants was assessed using the Hamilton Anxiety Scale (HAMA [25]). We identified and included four trials (Kasper et al. 2010 [26]; Kasper et al. 2010 [22], Kasper et al. 2014 [23], and one unpublished trial) performed in the indications of GAD and subsyndromal anxiety disorders whose basic characteristics are shown in Table 1. All trials had a double-blind treatment phase of 10 weeks during which the participants received 1 × 80 mg/ day silexan or placebo. The study reported by Kasper et Silexan® (WS® 1265) is the active substance of Lasea® (Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany).
1
13
al. [23] and the unpublished trial also investigated other daily doses of the active substance silexan; however, only the marketed dose of 1 × 80 mg/day was considered in our analyses.
Outcomes Meta-analyses were performed for absolute HAMA total score change between baseline and the end of the 10-week acute treatment phase as well as for Items 1 (“Severity if Illness”) and 2 (“Global Improvement” compared with baseline) of the Clinical Global Impressions (CGI [27]) scale.
Results Out of a total of 857 trial participants, 112 (silexan 55, placebo 57) were at least 60-year-old and were included into our meta-analyses (see Table 1 for details). Across the four trials, 80.0 % of the elderly participants in the silexan group and 75.4 % in the placebo group were female individuals, with a notable deviation in Trial D where 90.0 % of the ≤ 60-year-old participants in the silexan group and 54.6 % in the placebo group were female individuals. In the pooled data set of the elderly subset of the included trials, the HAMA total score decreased from a baseline mean value (± standard deviation) of 25.1 ± 5.7 points to 11.6 ± 7.4 points at week 10 for silexan and from 25.2 ± 5.8 points to 15.7 ± 7.6 points for placebo. In the meta-analysis of the four trials, silexan was superior to placebo by a median difference of − 4.26 points (95 % confidence interval [CI]: − 1.28; − 7.25 points) for change between baseline and week 10 (p
