Evaluation of cycloserine in the treatment of Alzheimer's disease. Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. A preliminary study of D-cycloserine treatment in Alzheimer's disease. D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. Double-blind placebo-controlled study of velnacrine in Alzheimer's disease. A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group. Double-blind, placebo-controlled, crossover trial of D-cycloserine adjuvant therapy for treatment-resistant schizophrenia. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results.
This multicenter study evaluated the efficacy and safety of cycloserine and measured its effects on explicit and implicit memory tests in patients with Alzheimer's disease (AD). Four hundred ten patients with AD, aged 50 years or older, were enrolled in this parallel-group, double-blind, placebo-controlled, randomized trial of 5, 15, or 50 mg cycloserine or placebo twice daily, and 403 entered the double-blind treatment phase. Two hundred sixty-five patients completed the entire 26-week treatment phase. There were no baseline differences among the four treatment groups. Cognitive Drug Research (CDR) efficacy assessments showed no differences between active treatments and placebo from baseline to study weeks 2, 6, 14, or 26. Patients receiving 15 mg of cycloserine improved significantly on one section of an implicit memory test. No differences among treatments were observed for any other assessment scales evaluated. The incidence and severity of adverse events were similar across treatment groups. Cycloserine was well tolerated but did not demonstrate consistent evidence of efficacy during the course of therapy. Higher doses may be necessary to achieve efficacy in the AD population and do not appear to be precluded by the adverse event profile seen in this study. Glutamatergic neurotransmission is important for memory and cognition and is severely affected in Alzheimer's disease. D-Cycloserine exhibits partial agonist activity at the glycine site of N-methyl-D-aspartate subtype glutamate receptor, facilitating activation of the receptor and improving cognition and memory.
                Seventeen patients with Alzheimer's disease received a three-phase, double-blind, placebo-controlled trial of 50 mg and 100 mg/day of D-cycloserine.
                D-Cycloserine was associated with significant improvement in scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (improvement of 3.0 points) when given at a dose of 100 mg/day.
                D-Cycloserine has cognitive benefits for patients with Alzheimer's disease. In a preliminary dose-finding study, D-cycloserine, a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, improved negative symptoms and cognitive function when added to conventional neuroleptics at a dose of 50 mg/d.
                Forty-seven patients with schizophrenia meeting criteria for deficit syndrome were randomized to D-cycloserine, 50 mg/d (n=23) or placebo (n=24) added to their conventional neuroleptic for an 8-week, double-blind trial. Clinical assessments were performed at baseline and at weeks 1, 2, 4, 6, and 8. Serum concentrations of D-cycloserine, relevant amino acids, and homovanillic acid were assayed at baseline and at weeks 4 and 8. A cognitive battery was performed at baseline and at week 8.
                Thirty-nine patients completed the 8-week trial. Seven dropouts occurred in the D-cycloserine group and 1 in the placebo group. The mean reduction in negative symptoms with D-cycloserine (23%) was significantly greater than with placebo (7%) as calculated by slopes representing Scale for the Assessment of Negative Symptoms (SANS) total scores. Improvement of negative symptoms was predicted by low neuroleptic dose and low baseline SANS total score. No differences were found in performance on any cognitive test between groups or in changes in any other clinical measure. Clinical response did not correlate significantly with serum amino acid concentrations at baseline or with concentrations of D-cycloserine at weeks 4 and 8.
                These results support the hypothesis that agents acting at the glycine modulatory site of the NMDA receptor improve primary negative symptoms. D-cycloserine is a partial agonist on the glycine site of the N-methyl-D-aspartate glutamate receptor. This double-blind crossover study of 15 mg D-cycloserine in Alzheimer's disease patients did not demonstrate clinical benefit. Higher medication dosage or long-term treatment may be required. A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia. The present study assessed the safety and efficacy of the cholinesterase inhibitor, velnacrine, for treating the cognitive symptoms of Alzheimer's disease. Patients (N = 236) meeting NINCDS-ADRDA criteria for Alzheimer's disease entered a double-blind, placebo-controlled dose-ranging protocol (30, 75, 150, 225 mg/day each for one week) to identify velnacrine responders (> or = four point improvement on the cognitive subscale of the Alzheimer's Disease Assessment Scale [ADAScog]). After a two week drug washout, velnacrine responders were randomly assigned to their best velnacrine dose or placebo in a six week dose-replication protocol employing the ADAScog and the Clinical Global Improvement scale as primary outcome measures. During dose-replication, intent-to-treat analysis revealed that velnacrine patients scored significantly better than placebo patients on the ADAScog after two (p < 0.004), four (p < 0.025) and six (p < 0.001) weeks of treatment. No significant treatment effect on Clinical Global Improvement scores was observed. The primary adverse event was an asymptomatic elevation of liver transaminases found among 28% of the 236 treated patients. Cholinergic side effects including diarrhea (14%), nausea (11%) and vomiting (5%) were observed and 8% of patients experienced skin rash. The present study identified a subgroup of Alzheimer's patients who demonstrated a significant, but modest, improvement during velnacrine treatment on structured cognitive testing. A multicenter trial to evaluate the efficacy of controlled-release physostigmine salicylate, a cholinesterase inhibitor, was conducted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects.
                During dose titration, subjects received 18, 24, or 30 mg of physostigmine or placebo daily. After a 2-week washout period, 366 subjects with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. Nonresponding patients (439) were randomized to receive in a separate double-blind trial either placebo or their highest tolerated dose of physostigmine. The primary efficacy measures included the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Global Impression of Change (CGIC). Secondary measures included the Mini-Mental State Examination and two activities-of-daily-living scales.
                At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to physostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. Common adverse events included nausea, vomiting, diarrhea, and anorexia. There were no significant changes in liver function tests.
                This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patients who responded in the initial dose titration study period. Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment. Dysfunction of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may be relevant to the pathogenesis of negative symptoms in schizophrenia. The tuberculostatic compound D-cycloserine (DCS) acts as a partial agonist at the strychnine-insensitive glycine regulatory site on the NMDA receptor complex. Dose-finding trials suggest that DCS doses of 50-100 mg/d may be beneficial in the treatment of negative symptoms in schizophrenia. Nine treatment-resistant chronic schizophrenic patients participated in a double-blind, placebo-controlled, adjuvant treatment trial with 50 mg/d DCS. Between treatment-groups differences in symptom changes were not significant. However, a significant (p<0.05) reduction in negative symptoms was registered during treatment with DCS but not placebo. Greater reductions were registered in patients with lower baseline serum glycine levels (p<0.008). No side effects were registered. These preliminary findings indicate a potential role of DCS in the treatment of negative symptoms in schizophrenia. However, the degree of symptom reduction may be modest, at least among treatment-resistant inpatients. Laboratory evidence of cholesterol-induced production of amyloid beta as a putative neurotoxin precipitating Alzheimer disease, along with epidemiological evidence, suggests that cholesterol-lowering statin drugs may favorably influence the progression of the disorder.
                To determine if treatment with atorvastatin calcium affects the cognitive and/or behavioral decline in patients with mild to moderate Alzheimer disease.
                Pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40-mg tablets) or placebo using last observation carried forward analysis of covariance as the primary method of statistical assessment.
                Individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination score of 12-28) were recruited. Of the 98 participants providing informed consent, 71 were eligible for randomization, 67 were randomized, and 63 subjects completed the 3-month visit and were considered evaluable.
                The primary outcome measures were change in Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Global Impression of Change Scale scores. The secondary outcome measures included scores on the Mini-Mental State Examination, Geriatric Depression Scale, the Neuropsychiatric Inventory Scale, and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. The tertiary outcome measures included total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels.
                Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared with placebo. This beneficial effect reached significance for the Geriatric Depression Scale and the Alzheimer's Disease Assessment Scale-cognitive subscale at 6 months and was significant at the level of a trend for the Alzheimer's Disease Assessment Scale-cognitive subscale, Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale at 12 months assessed by analysis of covariance with last observation carried forward.
                Atorvastatin treatment may be of some clinical benefit and could be established as an effective therapy for Alzheimer disease if the current findings are substantiated by a much larger multicenter trial.
The lack of a positive effect of D-cycloserine on cognitive outcomes in controlled clinical trials with statistical power high enough to detect a clinically meaningful effect means that D-cycloserine has no place in the treatment of patients with Alzheimer's disease.