Velnacrine for the treatment of Alzheimer's disease: A double-blind,placebo-controlled trial

Summary The present study examines the safety and efficacy of the centrally acting cholinesterase inhibitor, velnacrine, in treating the cognitive symptoms of Alzheimer's disease. Seven hundred thirty-five patients with mild-to-severe Alzheimer's disease were treated in a double-blind, placebo-controlled study. Following the screen visit, patients were treated with velnacrine (10, 25, 50 and 75 mg t.i.d.) or placebo in a double-blind dose-ranging study to identify velnacrine-responsive patients and their best dose. Following placebo washout velnacrine responsive patients were randomly assigned to their best dose of velnacrine (N=153) or placebo (N=156) in a six week double-blind dosereplication study. Primary efficacy measures were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS) and the Physician's Clinical Global Impression of Change.Statistically significant improvement was observed in both primary efficacy measures in velnacrine-treated patients during the dose-replication study. Velnacrine patients scored better on the cognitive subscale of the ADAS than placebo patients (P < 0.001), with patients receiving the highest velnacrine dose averaging a 4.1-point improvement with respect to screen values. Clinical Global Impression of Change scores of velnacrine-treated patients were significantly improved at the end of the 6 weeks of treatment when compared to those of placebo patients (P < 0.05). The most common side effect was asymptomatic elevation in liver transaminase levels, which occurred among 29% of patients. These data suggest that velnacrine produces modest clinical improvement in a subset of patients with mild-to-severe Alzheimer's disease.     

Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial

BACKGROUND: Antidepressant treatments that achieve a higher remission rate than those currently available are urgently needed. The thyroid hormone triiodothyronine may potentiate antidepressant effects. OBJECTIVE: To determine the antidepressant efficacy and safety of liothyronine sodium (triiodothyronine) when administered concurrently with the selective serotonin reuptake inhibitor sertraline hydrochloride to patients with major depressive disorder. DESIGN: Double-blind, randomized, 8-week, placebo-controlled trial. SETTING: Outpatient referral centers. PATIENTS: A total of 124 adult outpatients meeting unmodified DSM-IV criteria for major depressive disorder without psychotic features. INTERVENTIONS: Patients were randomized to receive sertraline hydrochloride (50 mg/d for 1 week; 100 mg/d thereafter) plus liothyronine sodium (20-25 microg/d for 1 week; 40-50 microg/d thereafter) or sertraline plus placebo for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was categorical response to treatment (> or =50% decrease in scores on the 21-item Hamilton Rating Scale for Depression from baseline to study end point). Remission rate (final Hamilton Rating Scale for Depression score, < or =6) was a secondary outcome measure. RESULTS: Intent-to-treat Hamilton Rating Scale for Depression response rates were 70% and 50% in the sertraline-liothyronine and sertraline-placebo groups, respectively (P = .02; odds ratio, 2.93; 95% confidence interval, 1.23-7.35); remission rates were 58% with sertraline-liothyronine and 38% with sertraline-placebo (P = .02; odds ratio, 2.69; 95% confidence interval, 1.16-6.49). Baseline T(3) values were lower in patients treated with sertraline-liothyronine who had remissions than in those without remissions (t(48) = 3.36; P<.002). Among patients treated with sertraline-liothyronine, remission was associated with a significant decrease in serum thyrotropin values (F(1,73) = 4.00; P<.05). There were no significant effects of liothyronine supplementation on frequency of adverse effects. CONCLUSIONS: These results demonstrate enhancement of the antidepressant effect of sertraline by concurrent treatment with liothyronine without a significant increase in adverse effects. The antidepressant effect of liothyronine may be directly linked to thyroid function.     

Depression during treatment with beta-blockers: results from a double-blind placebo-controlled study.

Depressive symptoms were rated during a double-blind placebo-controlled trial of nadolol for chronic aggression. Depressive symptoms were not significantly different in nadolol and placebo groups during any phase of the drug trial.     

Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial

BACKGROUND: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. METHODS: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. RESULTS: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. CONCLUSION: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.     

Randomized, placebo-controlled, double-blind pilot trial of ramipril in McArdle's disease

McArdle's disease causes limitation in exercise capacity as well as disability, the severity of which has been associated with the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) haplotype-patients with the genotype associated with higher ACE activity show the most severe phenotype. Modulation of ACE activity through the use of inhibitors may thus positively affect disease expression. In a double-blind, randomized, placebo-controlled trial, we assessed the efficacy of an ACE inhibitor (2.5 mg ramipril) in 8 patients with McArdle's disease. End-points were changes in parameters of exercise physiology (cycloergometer and muscle 31P-magnetic resonance spectroscopy), quality of life (QoL) according to the Short Form 36 (SF-36), and disability according to the World Health Organization-Disability Assessment Scale II (WHO-DAS II). Patients had lower QoL and higher disability than controls. Measures of exercise physiology were not changed by ramipril in the whole group, but treatment induced higher peak VO2 (P = 0.017) in ACE D/D patients, yet not in I/D patients. Treatment significantly improved disability (P < 0.05). McArdle's disease is a disabling condition affecting patients' QoL. Treatment with ramipril improves disability and modifies exercise physiology only in D/D patients, raising the possibility of a differential haplotype-linked sensitivity to the treatment.     

Treatment of dysthymia with sertraline: a double-blind, placebo-controlled trial in dysthymic patients without major depression

BACKGROUND: The selective serotonin reuptake inhibitor sertraline has been shown to be efficacious and well tolerated for the treatment of major depressive disorder. Relatively few trials, however, have examined the role of pharmacotherapy in dysthymia without concurrent major depression. The current investigation focuses on the use of sertraline for the treatment of dysthymia. METHOD: In this 12-week, multicenter, double-blind study, 310 patients with a DSM-III-R diagnosis of dysthymic disorder without concurrent major depression were randomly assigned to receive either sertraline (N = 158) or placebo (N = 152). Sertraline was initiated at a dose of 50 mg daily, with titration permitted to a maximum of 200 mg daily. The primary evaluation criteria were the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. RESULTS: Mean percentage reductions for the intent-to-treat population in SIGH-SAD scores were 44.6% for the sertraline-treated group and 33.2% for the placebo-treated group (p = .03); MADRS scores, 43.6% and 33.0% (p = .02); and CGI-S scores, 32.8% and 22.8% (p = .02). A significantly greater proportion of the sertraline-treated group was classified as responders (defined for HAM-D and MADRS scores as a 50% score reduction and for CGI-I as a score of 1 or 2 by the final visit) and remitters (SIGH-SAD score < or = 8) relative to the placebo-treated group by the final visit. In addition, sertraline-treated patients experienced greater improvements in all 9 domains of the Battelle Quality of Life Questionnaire than placebo-treated patients did, with a significant difference observed in favor of sertraline in 8 of the 9 domains. The life satisfaction and social interaction quality of life domains showed significantly greater response in sertraline responders compared with placebo SIGH-SAD responders. Sertraline was well tolerated. Thirteen percent of the sertraline-treated group versus 8% of the placebo-treated group withdrew from therapy owing to adverse events (p = .14). CONCLUSION: Sertraline is efficacious and well tolerated in the short-term treatment of dysthymia without concurrent major depression.     

Risperidone for psychosis of Alzheimer's disease and mixed dementia: results of a double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of low-dose risperidone in treating psychosis of Alzheimer's disease (AD) and mixed dementia (MD) in a subset of nursing-home residents who had dementia and aggression and who were participating in a randomized placebo-controlled trial of risperidone for aggression. METHOD: This post-hoc analysis included only patients diagnosed with AD or MD with psychosis, defined by a score of >or= 2 on any item of the Behavioral Pathology of Alzheimer's Disease (BEHAVE-AD) psychosis subscale at both screening and baseline. Co-primary efficacy endpoints were changes in scores on BEHAVE-AD psychosis subscale and Clinical Global Impression of Change (CGI-C). RESULTS: Overall, 93 patients (46 risperidone and 47 placebo) fulfilled the psychosis of AD criteria. Mean change at endpoint in BEHAVE-AD psychosis subscale with risperidone was superior to placebo (-5.2 vs -3.3; p = 0.039). Distribution of CGI-C at endpoint also favoured risperidone (p < 0.001). The superior improvement with risperidone compared with placebo occurred as early as the first two weeks and persisted to the end of the treatment period. At endpoint, 59% of risperidone-treated patients were responders (i.e. were 'very much' or 'much' improved) compared with 26% of patients receiving placebo. The mean risperidone dose was 1.03 +/- 0.61 mg/day. Twelve weeks of treatment were completed by 37 patients treated with risperidone (80%) and 35 with placebo (74%). A total of 46 (98%) placebo- and 44 (96%) risperidone-treated patients experienced at least one adverse event, with only somnolence occurring more frequently in the risperidone group. CONCLUSION: Risperidone effectively reduces psychosis and improves global functioning in elderly patients with moderate-to-severe psychosis of AD and MD.     

Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials

OBJECTIVES: The efficacy of lamotrigine as maintenance treatment for bipolar disorder (BD), particularly for delaying depressive episodes, is well established, but its efficacy in the acute treatment of bipolar depression is less clear. This paper reports the results of five randomized, double-blind, placebo-controlled trials of lamotrigine monotherapy for the acute treatment of bipolar depression. METHODS: Adult subjects with bipolar I or II disorder experiencing a depressive episode were randomized to placebo or lamotrigine monotherapy (after titration, at a fixed dose of 50 mg or 200 mg daily in Study 1; a flexible dose of 100-400 mg daily in Study 2; or a fixed dose of 200 mg daily in Studies 3, 4 and 5) for 7-10 weeks. RESULTS: Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [17-item Hamilton Depression Rating Scale in Studies 1 and 2; Montgomery-Asberg Depression Rating Scale (MADRS) in Studies 3, 4 and 5]. In Study 1, lamotrigine significantly separated from placebo on some secondary measures of efficacy, including the MADRS, the Clinical Global Impressions-Severity (CGI-S) and the CGI-Improvement (CGI-I), but seldom differed on secondary efficacy endpoints for the other studies. CONCLUSIONS: Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies. Lamotrigine was well tolerated in the acute treatment of bipolar depression.     

Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial

BACKGROUND: High-frequency left-sided repetitive transcranial magnetic stimulation (HFL-TMS) has been shown to have antidepressant effects in double-blind trials. Low-frequency stimulation to the right prefrontal cortex (LFR-TMS) has also shown promise, although it has not been assessed in treatment-resistant depression and its effects have not been compared with those of HFL-TMS. OBJECTIVE: To prospectively evaluate the efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression and compared with a sham-treated control group. DESIGN: A double-blind, randomized, sham-controlled trial. SETTING: Two general psychiatric services. PARTICIPANTS: Sixty patients with treatment-resistant depression who had failed to respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that did not differ in age, sex, or any clinical variables. All patients completed the double-blind phase of the study. INTERVENTIONS: Twenty 5-second HFL-TMS trains at 10 Hz and five 60-second LFR-TMS trains at 1 Hz were applied daily. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil.Main Outcome Measure Score on the Montgomery-Asberg Depression Rating Scale. RESULTS: There was a significant difference in response among the 3 groups (F56,2 = 6.2), with a significant difference between the HFL-TMS and sham groups and between the LFR-TMS and sham groups (P<.005 for all) but not between the 2 treatment groups. Baseline psychomotor agitation predicted successful response to treatment. CONCLUSIONS: Both HFL-TMS and LFR-TMS have treatment efficacy in patients with medication-resistant major depression. Treatment for at least 4 weeks is necessary for clinically meaningful benefits to be achieved. Treatment with LFR-TMS may prove to be an appropriate initial repetitive TMS strategy in depression taking into account safety, tolerability, and efficacy considerations.     

A 6-month, double-blind, placebo-controlled trial of eptastigmine in Alzheimer's disease

OBJECTIVES: To evaluate the efficacy and safety of eptastigmine as a treatment for patients with mild-to-moderate Alzheimer's disease (AD). PATIENTS AND METHODS: The study was designed as a randomized, double-blind, placebo-controlled, parallel-group study. It was performed in 26 Italian and American geriatric and neurological centers. The study group comprised 349 outpatients with a diagnosis of probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association. Patients were assigned to one of the three study groups: placebo (n = 119), eptastigmine 10 mg t.i.d. (n = 115) or eptastigmine 12 mg t.i.d. (n = 115) for 25 weeks. The AD Assessment Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB) were the primary outcome measures for efficacy. RESULTS: The two doses of eptastigmine produced similar results and are presented together. Percentages of patients completing double-blind treatment were 82 and 87% in the placebo and eptastigmine groups, respectively. At the end of treatment, the intent to-treat analysis on 342 patients showed a statistically significant effect of eptastigmine compared to placebo on both ADAS-Cog (p = 0.047) and CDR-SB (p = 0.010). Patients on eptastigmine performed significantly better than placebo-treated patients also on the Mini-Mental State Examination (p < 0.001). The drug was well tolerated with 5% of patients withdrawing due to adverse events versus 3% on placebo. Adverse events were recorded in 46% of the patients on placebo compared to 52% of the patients taking eptastigmine. Cholinergic side effects (nausea, vomiting, diarrhea and abdominal pain) were reported with similar frequency in the eptastigmine and placebo-treated patients. CONCLUSION: Eptastigmine doses up to 12 mg t.i.d. for 25 weeks are well tolerated. The drug positively affects cognitive performance and global function of patients with mild-to-moderate AD.     

A controlled clinical trial of sertraline in the treatment of depression in nursing home patients with late-stage Alzheimer's disease.

A sample of 31 female nursing home patients with late-stage Alzheimer's disease participated in a double-blind clinical trial of the antidepressant medication sertraline. Measures of depression included various objective scales and two measures of facial expressions of emotion coded during a semistructured interview using a facial affect coding system. Repeated-measures ANOVAs at baseline and at the 8-week endpoint indicated that on all measures, both the treatment and placebo groups improved over time, with three of six measures showing a significant time effect. The "knit-brow" facial measure approached significance for a Treatment x Time effect. Thus, sertraline had no significant benefits over placebo. However, if, as we hypothesize, the knit-brow response is more sensitive to signs of depression in advanced dementia, our study justifies the further investigation of the use of sertraline in this population.     

Antidepressant efficacy and safety of low-dose sertraline and standard-dose imipramine for the treatment of depression in older adults: results from a double-blind, randomized, controlled clinical trial

This study compared the efficacy and tolerability of 150 mg/day imipramine and 50 mg/day sertraline for the treatment of a major depressive episode (DSM-IV) in older adults (N = 55) in an 8-week, randomized, double-blind, controlled clinical trial. Intention-to-treat analysis (last observation carried forwards) showed a reduction of 50% or more on the baseline scores of the Montgomery-Asberg Rating Scale (MADRS) in 60.7% and 55.6% of patients receiving imipramine and sertraline, respectively (p = .698). Full remission of symptoms (MADRS < 9) was observed in 50.0% and 51.8% of patients, respectively (p = .891). Side effects were more frequent among patients treated with imipramine (86.7%) than among patients treated with sertraline (42.1%) (p = .008). Dropout rates were high in both groups (46.4% and 29.6% respectively, p =.200). These results indicate that imipramine and sertraline are equally effective for the treatment of major depression in later life, although adverse reactions are more frequent among subjects treated with imipramine than with sertraline.     

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial.

BACKGROUND: Preliminary reports have suggested that concomitant institution of pindolol and serotonin reuptake inhibitors robustly hastens clinical response; however, contradictory evidence from a randomized double-blind, controlled trial was recently reported by this group in a population of depressed patients who were prescribed fluoxetine and pindolol. Herein, we report final results from an extended sample size. METHODS: Drug-free outpatients with a major depressive episode were randomized in a double-blind manner to one of two treatment conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for 3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol. RESULTS: Eighty-six patients completed at least 1 or more weeks on protocol, with 45 and 41 patients randomized to the pindolol and placebo groups respectively. After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in depression rating scores from baseline) rates for pindolol (16%) and placebo (19%) groups were comparable. By the study's end, a partial remission was achieved, at least transiently, for 67% of the pindolol group and 80% of the placebo group. Pindolol treatment was associated with statistically significant reduction in blood pressure and pulse as compared to the control group. The two groups did not have overall differences in rates of attrition, time to response, and side effects. CONCLUSIONS: In accord with our previously published findings, these extended results do not support the efficacy of pindolol in hastening clinical response to fluoxetine in a patient population with predominantly chronic and recurrent depression.     

A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease.

BACKGROUND: Previous studies suggest a potential benefit from nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD). Prescribing NSAIDs, however, carries the risk of significant gastrointestinal adverse events. OBJECTIVES: To study whether treatment with an NSAID prevents expected decline in AD patients and evaluate whether co-administration of the gastro-protective agent, misoprostol, with an NSAID is safe in AD. METHODS: The efficacy and safety of diclofenac in combination with misoprostol (D/M) was evaluated in 41 patients with mild-moderate AD in a prospective 25-week, randomized, double-blind placebo-controlled trial. Efficacy measures comprised the Alzheimer's Disease Assessment Scale cognitive and noncognitive subsections, Global Deterioration Scale, Clinical Global Impression of Change, Mini-Mental State Examination, Instrumental Activities of Daily Living, Physical Self-Maintenance Scale, and a caregiver-rated Global Impression of Change. RESULTS: There were no group differences with any of the outcome measures in an intent-to-treat analysis. There were some nonsignificant trends for the placebo group to have deteriorated more than the D/M-treated patients. Withdrawal rates were 12 of 24 in the D/M group and 2 of 17 in the placebo group. There were no serious drug-related adverse events. CONCLUSIONS: This pilot study, with small treatment numbers, did not demonstrate a significant effect of NSAID treatment in AD, but the trends observed justify further investigations with a larger number of participants. D/M is safe in AD patients, but its tolerability is not optimal.     

Viqualine in resistant depression: a double-blind, placebo-controlled trial

Viqualine dihydrochloride is a new molecule, which possesses strong serotonin reuptake inhibition properties and, at the same time, diazepam-like actions, such as [3H]-diazepam-binding inhibition and antipunishment effect. The drug was administered double-blindly to 10 patients suffering from major depression resistant to previous treatments with tricyclics. The comparison group (10 patients) received placebo. Lorazepam (10 mg/day) was also given to both groups. Viqualine proved to be significantly superior to placebo in the 4th week of treatment on all the three rating scales which were used. Tolerability of viqualine was good both objectively and on subjective grounds.     

Zishenpingchan granules for the treatment of Parkinson's disease:a randomized,double-blind,placebo-controlled clinical trial

Levodopa preparations remain the preferred drug for Parkinson's disease.However,long-term use of levodopa may lead to a series of motor complications.Previous studies have shown that the combination of levodopa and Zishenpingchan granules(consisting of Radix Rehmanniae preparata,Lycium barbarum,Herba Taxilli,Rhizoma Gastrodiae,Stiff Silkorm,Curcuma phaeocaulis,Radix Paeoniae Alba,Rhizoma Arisaematis,Scorpio and Centipede) can markedly improve dyskinesia and delay the progression of Parkinson's disease,with especially dramatic improvements of non-motor symptoms.However,the efficacy of this combination has not been confirmed by randomized controlled trials.The current study was approved by the Hospital Ethics Committee and was registered in the Chinese Clinical Trial Register(registration number:Chi CTR-INR-1701194).From December 2014 to December 2016,128 patients(72 males and 56 females,mean age of 65.78 ± 6.34 years) with Parkinson's disease were recruited from the Department of Neurology of Longhua Hospital and Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine in China.Patients were equally allocated into treatment and control groups.In addition to treatment with dopamine,patients in treatment and control groups were given Zishenpingchan granules or placebo,respectively,for 24 weeks.Therapeutic efficacy was assessed using the Unified Parkinson's Disease Rating Scale,on-off phenomenon,Hoehn-Yahr grade,Scales for Outcomes in Parkinson's disease–Autonomic,Parkinson's disease sleep scale,Hamilton Anxiety Scale,Hamilton Depression Scale,Mini-Mental State Examination,and the Parkinson's Disease Quality of Life Questionnaire.Artificial neural networks were used to determine weights at which to scale these parameters.Our results demonstrated that Zishenpingchan granules significantly reduced the occurrence of motor complications,and were useful for mitigating dyskinesia and non-motor symptoms of Parkinson's disease.This combination of Chinese and Western medicine has the potential to reduce levodopa dosages,and no obvious side effects were found.These findings indicate that Zishenpingchan granules can mitigate symptoms of Parkinson's disease,reduce toxic side effects of dopaminergic agents,and exert synergistic and detoxifying effects.