Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia.

OBJECTIVE: The pharmacokinetic profile of a drug often gives little indication of its potential therapeutic application, with many therapeutic uses of drugs being discovered serendipitously while being studied for different indications. As hypothesis-driven, quantitative research methodology is exclusively used in early-phase trials, unexpected but important phenomena may escape detection. In this context, this study aimed to examine the potential for integrating qualitative research methods with quantitative methods in early-phase drug trials. To our knowledge, this mixed methodology has not previously been applied to blinded psychopharmacologic trials. METHOD: We undertook qualitative data analysis of clinical observations on the dataset of a randomized, double-blind, placebo-controlled trial of N-acetylcysteine (NAC) in patients with DSM-IV-TR-diagnosed schizophrenia (N = 140). Textual data on all participants, deliberately collected for this purpose, were coded using NVivo 2, and emergent themes were analyzed in a blinded manner in the NAC and placebo groups. The trial was conducted from November 2002 to July 2005. RESULTS: The principal findings of the published trial could be replicated using a qualitative methodology. In addition, significant differences between NAC- and placebo-treated participants emerged for positive and affective symptoms, which had not been captured by the rating scales utilized in the quantitative trial. Qualitative data in this study subsequently led to a positive trial of NAC in bipolar disorder. CONCLUSIONS: The use of qualitative methods may yield broader data and has the potential to complement traditional quantitative methods and detect unexpected efficacy and safety signals, thereby maximizing the findings of early-phase clinical trial research. TRIAL REGISTRATION: www.anzctr.org.au Identifier: ACTRN12605000363684.

N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period. METHODS: A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment. RESULTS: Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [-5.97 (-10.44, -1.51), p = .009], PANSS negative [mean difference -1.83 (95% confidence interval: -3.33, -.32), p = .018], and PANSS general [-2.79 (-5.38, -.20), p = .035], CGI-Severity (CGI-S) [-.26 (-.44, -.08), p = .004], and CGI-Improvement (CGI-I) [-.22 (-.41, -.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits. CONCLUSIONS: These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.