Prospective, head-to-head comparison of quantitative coronary angiography, quantitative computed tomography angiography, and intravascular ultrasound for the prediction of hemodynamic significance in intermediate and severe lesions, using fractional flow reserve as reference standard (from the ATLANTA I and II Study).

The objective of this study was to compare the diagnostic accuracy of quantitative coronary angiography (QCA), coronary computed tomography angiography (CTA), and intravascular ultrasound (IVUS) with fractional flow reserve (FFR) measurements. Eighty-five lesions (40% to 99% diameter stenosis) in 85 patients were prospectively interrogated by QCA, CTA, IVUS, and FFR. Minimal lumen diameter (MLD), percent diameter stenosis (%DS), minimal lumen area (MLA), and percent area stenosis (%AS) were measured. Correlation, receiver operating characteristic analysis, kappa statistics, and multivariable logistic regression was used to assess relation between anatomic measurements and FFR. Average age was 61.3 ± 7.8; 62% were men. QCA-derived mean %DS was 55.3% ± 19.5%; mean FFR 0.81 ± 0.17; 27% had FFR ≤0.75. QCA had the strongest correlation, followed by CTA and then IVUS for MLD (r = 0.67, 0.47, and 0.29, respectively) and for %DS (r = -0.63, -0.52, and -0.22, respectively); QCA-derived MLD had area under the curve of 0.96, with 95% sensitivity and 82% specificity. Cut-point, area under the curve, sensitivity, and specificity for CTA-MLA and IVUS-MLA were 3.11 mm(2), 0.86, 81%, and 81% and 2.68 mm(2), 0.75, 70%, and 80%. In multivariable analysis for each modality, MLD on QCA (odds ratio [OR]: 0.002), %AS on CTA (OR: 1.09) and MLA on IVUS (OR: 0.28) remained independent predictors. In conclusion, in intermediate-to-severe lesions, QCA-, CTA-, and IVUS-derived quantitative anatomic measurements correlated with FFR. CTA-derived cut-points were similar to respective measurements on QCA and IVUS and had similar or better diagnostic performance compared with IVUS.

Apoprotein B, small-dense LDL and impaired HDL remodeling is associated with larger plaque burden and more noncalcified plaque as assessed by coronary CT angiography and intravascular ultrasound with radiofrequency backscatter: results from the ATLANTA I study.

BACKGROUND: Apoprotein B-containing lipoproteins are atherogenic, but atheroprotective functions of apoprotein A-containing high-density lipoprotein (HDL) particles are poorly understood. The association between lipoproteins and plaque components by coronary computed tomography angiography (CTA) and intravascular ultrasound with radiofrequency backscatter (IVUS/VH) has not been evaluated. METHODS AND RESULTS: Quantitative, 3-dimensional plaque measurements were performed in 60 patients with CTA and IVUS/VH. Apoproteins, lipids, and HDL subpopulations were measured with 2-dimensional (2D) gel electrophoresis, and correlation was assessed with univariate and multivariable models. ApoB particles were associated with a higher proportion of noncalcified plaque (NCP) and a lower proportion of calcified plaque (small, dense low-density lipoprotein cholesterol and high-density NCP: r=0.3, P=0.03; triglycerides and low-density NCP: r=0.34, P=0.01). Smaller, dense, lipid-poor HDL particles were associated with a shift from calcified plaque to NCP on CTA (α3-HDL% and low-density NCP: r=0.32, P=0.02) and with larger plaque volume on IVUS/VH (α4-HDL%: r=0.41, P=0.01; α3-HDL%: r=0.37, P=0.03), because of larger dense calcium (α4-HDL%: r=0.37, P=0.03), larger fibrous tissue (α4-HDL%: r=0.34, P=0.04), and larger necrotic core (α4-HDL%: r=0.46, P<0.01; α3-HDL%: r=0.37, P=0.03). Larger lipid-rich HDL particles were associated with less low-density NCP on CTA (α2-HDL%: r=-0.34, P=0.02; α1-HDL%: r=-0.28, P=0.05), with smaller plaque volume on IVUS/VH (pre-α2-HDL: r=-0.33, P=0.05; α1-HDL%: r=-0.41, P=0.01; pre-α2-HDL: r=-0.33, P=0.05) and with less necrotic core (α1-HDL: r=-0.42, P<0.01; pre-α2-HDL: r=-0.38, P=0.02; α2-HDL: r=-0.35, P=0.03; pre-α1-HDL: r=-0.34, P=0.04). Pre-ß2-HDL was associated with less calcification and less stenosis by both modalities. CONCLUSIONS: ApoB and small HDL particles are associated with larger plaque burden and more noncalcified plaque, whereas larger HDL and pre-ß2-HDL particles are associated with plaque burden and less noncalcified plaque by both CTA and IVUS/VH.

A peripheral blood gene expression score is associated with plaque volume and phenotype by intravascular ultrasound with radiofrequency backscatter analysis: results from the ATLANTA study.

BACKGROUND: A composite, peripheral gene expression score based on quantitative RNA-measurements has been validated for detecting stenosis against invasive coronary X-ray angiography. IVUS/VH has been validated for quantitative measurements of coronary plaque volume and composition and has been shown to be predictive of outcomes and treatment effects. The correlation between peripheral gene expression and coronary plaque composition by intravascular ultrasound with radiofrequency backscatter (IVUS/VH) is unknown. METHODS: Peripheral blood gene expression score (GES) was prospectively measured in 18 patients undergoing IVUS/VH. Plaque volume and composition [fibrous tissue (FI), fibro-fatty tissue (FF), necrotic core (NC) and dense calcium (DC)] were quantified in 3 dimensions in all plaques within the entire pullback. The relationship to GES was assessed by Spearman rank correlation. RESULTS: Mean age was 61.1±8.6 years; 67% were male. 1,158 mm of coronary anatomy was imaged by IVUS/VH. Using a validated scale of 1-40, mean GES was 21.6±9.4. GES was associated with plaque volume (R(2)=0.55; P=0.018), NC volume (R(2)=0.56; P=0.015), DC volume (R(2)=0.60; P=0.007), and non-calcified plaque volume (R(2)=0.50; P=0.036) by Spearman rank correlation. CONCLUSIONS: In this preliminary report, increased GES was associated with higher plaque volume and a more vulnerable plaque phenotype as evidenced by NC and DC. This composite GES is not only associated with obstructive coronary disease, but also with higher plaque volume and vulnerable phenotype.

Prospective validation that vulnerable plaque associated with major adverse outcomes have larger plaque volume, less dense calcium, and more non-calcified plaque by quantitative, three-dimensional measurements using intravascular ultrasound with radiofrequency backscatter analysis : results from the ATLANTA I Study.

Whether quantitative, two-dimensional, and three-dimensional plaque measurements by intravascular ultrasound with radiofrequency backscatter (IVUS/VH) are different between intermediate lesions with or without major adverse cardiovascular events (MACE) is unknown. IVUS/VH-derived parameters were compared in 60 patients with an intermediate coronary lesion (40-70 %) between lesions that did or did not result in MACE over 12 months. IVUS/VH measurements were done at the site of the minimal lumen area (MLA) and on a per-plaque basis, defined by 40 % plaque burden. Pre-specified, adjudicated MACE events occurred in 5 of 60 patients (8.3 %). MACE lesions had larger plaque burden (65 % vs. 53 %, p = 0.004), less dense calcium (6.6 % vs. 14.7 %, p = 0.05), and more non-calcified plaque, mostly fibrofatty kind (17.6 % vs. 10 %, p = 0.02). Intermediate coronary lesions associated with MACE at 12 months have more plaque, less dense calcium, and more non-calcified plaque, particularly fibrofatty tissue by IVUS/VH.

A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania.

OBJECTIVE: Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC). METHODS: This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period. RESULTS: Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint. CONCLUSIONS: Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.

Effects of N-acetyl cysteine on cognitive function in bipolar disorder.

AIMS: Bipolar disorder is characterized by progressive changes in cognition with declines in executive functioning, memory and sustained attention. Current pharmacotherapies for bipolar disorder target mood symptoms but have not addressed these cognitive changes resulting in euthymic individuals who still experience cognitive deficits. N-acetyl cysteine (NAC) has been shown to have effects on antioxidant status, glutamate transmission, inflammation and neurogenesis. Adjunctive treatment with NAC improves the symptoms experienced by those with bipolar disorder, particularly depression, and it was hypothesized that cognition may also be improved following NAC treatment. METHODS: As part of a larger randomized, double-blind, placebo-controlled trial, participants in the current report were tested at baseline and 6 months to assess changes in cognitive function following either 2000 mg of NAC daily or placebo. RESULTS: This study failed to find changes in cognitive function following treatment with NAC compared to placebo. CONCLUSIONS: While an important pilot study, this study had a small sample size and included a limited battery of cognitive tests. Further investigations on the effects of NAC on cognitive performance in bipolar disorder are required.

Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial. METHODS: Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities. RESULTS: Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity. CONCLUSION: Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states--and thus guide antioxidant use--in BD.

N-acetylcysteine for major depressive episodes in bipolar disorder.

OBJECTIVE: In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder. METHOD: Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period. RESULTS: Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo. DISCUSSION: These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.

N-acetylcysteine for major depressive episodes in bipolar disorder / N-acetilcisteína para o tratamento de episódios de depressão maior no transtorno bipolar

OBJECTIVE: In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder. METHOD: Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period. RESULTS: Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo. DISCUSSION: These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.

OBJETIVO: Neste relato, avaliamos o efeito da N-acetilcisteína (NAC) adjuvante em sintomas depressivos e desfechos funcionais no transtorno bipolar. Para isso, conduzimos uma análise secundária de todos os pacientes com critérios diagnósticos para um episódio depressivo em um ensaio clínico randomizado comparando NAC adjuvante com placebo no transtorno bipolar. MÉTODO: Ensaio clínico randomizado comparando NAC adjuvante com placebo para episódios depressivos no transtorno bipolar durante 24 semanas. Desfechos funcionais e sintomáticos foram coletados no período. RESULTADOS: Dezessete participantes estavam disponíveis para esta análise. Tamanhos de efeito grandes foram encontrados para sintomas depressivos e desfechos funcionais. Oito dos dez participantes no grupo da NAC tiveram resposta clínica ao fim do tratamento. O mesmo ocorreu em apenas um dos sete que receberam placebo. DISCUSSÃO: Esses resultados indicam que a NAC adjuvante pode ser útil para episódios de depressão maior no transtorno bipolar. Estudos desenhados para confirmar esta hipótese são necessários.

Prospective validation of standardized, 3-dimensional, quantitative coronary computed tomographic plaque measurements using radiofrequency backscatter intravascular ultrasound as reference standard in intermediate coronary arterial lesions: results from the ATLANTA (assessment of tissue characteristics, lesion morphology, and hemodynamics by angiography with fractional flow reserve, intravascular ultrasound and virtual histology, and noninvasive computed tomography in atherosclerotic plaques) I study.

OBJECTIVES: This study sought to determine the accuracy of 3-dimensional, quantitative measurements of coronary plaque by computed tomography angiography (CTA) against intravascular ultrasound with radiofrequency backscatter analysis (IVUS/VH). BACKGROUND: Quantitative, 3-dimensional coronary CTA plaque measurements have not been validated against IVUS/VH. METHODS: Sixty patients in a prospective study underwent coronary X-ray angiography, IVUS/VH, and coronary CTA. Plaque geometry and composition was quantified after spatial coregistration on segmental and slice-by-slice bases. Correlation, mean difference, and limits of agreement were determined. RESULTS: There was significant correlation for all pre-specified parameters by segmental and slice-by-slice analyses (r = 0.41 to 0.84; all p < 0.001). On a segmental basis, CTA underestimated minimal lumen diameter by 21% and overestimated diameter stenosis by 39%. Minimal lumen area was overestimated on CTA by 27% but area stenosis was only underestimated by 5%. Mean difference in noncalcified plaque volume and percent and calcified plaque volume and percent were 38%, -22%, 104%, and 64%. On a slice-by-slice basis, lumen, vessel, noncalcified-, and calcified-plaque areas were overestimated on CTA by 22%, 19%, 44%, and 88%. There was significant correlation for percentage of atheroma volume (0.52 vs. 0.54; r = 0.51; p < 0.001). Compositional analysis suggested that high-density noncalcified plaque on CTA best correlated with fibrous tissue and low-density noncalcified plaque correlated with necrotic core plus fibrofatty tissue by IVUS/VH. CONCLUSIONS: This is the first validation that standardized, 3-dimensional, quantitative measurements of coronary plaque correlate with IVUS/VH. Mean differences are small, whereas limits of agreement are wide. Low-density noncalcified plaque correlates with necrotic core plus fibrofatty tissue on IVUS/VH.

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 add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial.

BACKGROUND: The evidence base for the pharmacological treatment of bipolar II disorder is limited. In bipolar disorder, there is evidence for glutathione depletion and increased oxidative stress, as well as dysregulation of glutamate; N-acetyl cysteine (NAC) has effects on both of these systems. Add-on NAC has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. In this report, we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial. METHODS: Individuals were randomized to NAC or placebo in addition to treatment as usual, in a double-blind fashion. Mood and functional outcomes were assessed up to 24 weeks of treatment. RESULTS: Fourteen individuals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group; this was true for only two people in the placebo group (χ(2)=4.67, p=0.031). LIMITATIONS: Subgroup analyses in a small subsample of patients. Not all participants had elevated depression scores at baseline. CONCLUSION: Notwithstanding all the limitations that subgroup analysis of trials carry, this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression.

Lesion- and vessel-specific coronary artery calcium scores are superior to whole-heart Agatston and volume scores in the diagnosis of obstructive coronary artery disease.

BACKGROUND: The whole-heart coronary artery calcium (CAC) score has poor predictive value for obstructive coronary artery disease (CAD). We hypothesized that vessel- and lesion-specific CAC scores are more accurate. OBJECTIVES: To evaluate the usefulness of vessel- and lesion-specific CAC in predicting obstructive CAD and to assess the incremental value added by the vessel- and lesion-specific CAC to the conventional whole-heart CAC approach. METHODS: Ninety-one patients with CAC scores and invasive angiography (XRA) data were enrolled. Besides whole-heart CAC, Agatston score (AgSc) and volume score (VolSc) were measured individually for each lesion in the 4 major epicardial coronary arteries. Maximum and average lesion-specific scores in each vessel were also determined. For the primary analysis, obstructive CAD was defined as 50% diameter stenosis by XRA. RESULTS: Whole-heart AgSc and VolSc were not different between patients with and without obstructive CAD (P = .23 and P = .18), whereas vessel- and lesion-specific scores were (maximum lesion specific AgSc, P < .0001). Maximum lesion-specific AgSc had superior diagnostic performance compared with whole-heart AgSc (area under receiver operating characteristics, 0.71 vs 0.58). Overall sensitivity, specificity, and diagnostic accuracy were improved. When specificity was fixed at 80%, sensitivity of maximum lesion-specific AgSc was superior to whole-heart AgSc (56.6% vs 35.1%). Most importantly, with lesion-specific AgSc, fewer patients were classified as "indeterminate" compared with whole-heart AgSc (17.9% vs 50%). CONCLUSIONS: Vessel- and lesion-specific CAC scores are superior to the whole-heart AgSc and VolSc in predicting obstructive CAD. This simple refinement in CAC scoring may significantly improve the clinical predictive role of CAC imaging.

Quantification of left ventricular parameters obtained by automated software for 64-slice multidetector computed tomography and comparison with magnetic resonance imaging.

The dataset obtained with 64-slice multidetector CT (MDCT) for coronary artery evaluation can be used to calculate important left ventricular (LV) volumetric parameters. We compared LV parameters derived by new, commercially available, fully automated software for MDCT (Syngo Circulation, Siemens, Germany) to cardiac magnetic resonance (CMR) as a reference standard. Twenty patients underwent CMR after completing a clinically indicated MDCT. Ejection fraction (EF), end-systolic volume (ESV), end-diastolic volume (EDV), stroke volume (SV), and myocardial mass (MM) for MDCT were obtained using automated software and were compared to CMR measurements, with papillary muscles (PMs) included in, or excluded from, the blood pool. The Pearson correlation coefficient (r) and Bland-Altman method were used to determine agreement between methods. When PMs were included in the blood pool, the correlation was excellent for EF (r=0.92, p\0.001), ESV (r=0.86, p\0.001), and EDV (r=0.80, p\0.001). When PMs were excluded from CMR, correlation was still very good for EF (r=0.89, p\0.001), ESV (r=0.82, p\0.001), and EDV (r=0.82, p\0.001). MDCT values for SV and MM showed a good correlation compared to both CMR methods. When PMs were included, the correlation was good for SV (r=0.70, p\0.001), and MM (r=0.70, p\0.001); when they were excluded, the correlation was less robust but still significant for SV (r=0.71, p\0.001) and MM (r=0.73, p\0.001). In conclusion, EF, ESV, and EDV obtained by MDCT using simple, automated software correlated very well with CMR; SV and MM showed good correlation. Automated analysis of volumetric parameters by MDCT can be reliably utilized for clinical purposes.

Effects of N-acetylcysteine on substance use in bipolar disorder: A randomised placebo-controlled clinical trial.

OBJECTIVE: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU). METHODS: Participants were randomised to a 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using a Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU. RESULTS: Among the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumed caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared to placebo at week 2 of treatment but not at other study visits. CONCLUSIONS: NAC appeared to have little effect on the participants who were using substances. A larger study on a substance-using population will be necessary to determine if NAC may be a useful treatment for substance use.

Effects of N-acetylcysteine on substance use in bipolar disorder: a randomised placebo-controlled clinical trial.

OBJECTIVE: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU). METHODS: Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU. RESULTS: Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits. CONCLUSION: NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.

N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial.

BACKGROUND: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder. METHODS: A randomized, double-blind, multicenter, placebo-controlled study of individuals (n = 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning. RESULTS: NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: -8.05 [-13.16, -2.95], p = .002) and most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p = .968) and no significant between-group differences in adverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts. CONCLUSIONS: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar disorder.

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.

Evaluation of a short scale to assess female sexual functioning.

This article provides information on the external and concurrent validity, test-retest reliability, and sensitivity to change of a short form of the Personal Experiences Questionnaire, which was adapted from the McCoy Female Sexuality Questionnaire. We drew participants from convenience samples of women attending three different clinic settings: family planning clinics, psychiatrists, and sex therapists. We chose the psychiatry and sex therapy clinics as samples likely to show poor sexual functioning in order to assist with external validity assessment and to establish a cut-off score indicating sexual dysfunction. Satisfactory external criterion validity, concurrent validity, reliability on re-test, and validation of the composite score were demonstrated. A cut-off score of 7 or below distinguishes with 79% specificity and sensitivity those with sexual dysfunction.

Oxytocin and female sexuality.

A search of the literature has been prepared to determine how oxytocin may affect sexual and reproductive in women. Many animal studies suggest that oxytocin induces a variety of reproductive behaviors, including grooming, sexual arousal, orgasm, gamete transport, nesting, birthing, and specific maternal behaviors such as breast-feeding and bonding between mother and infant. These actions are apparently facilitated by the 'priming' effect on certain cells by sex and steroid hormones - as the brief case report would also suggest. However, no adequate double-blind trial has confirmed the observations from this report in women. Only animal studies have been performed, albeit over a wide range of species. A variety of other causes and effects of sexual interest and arousal relating to oxytocin are considered, including some of those in males. More research is needed to clarify the role of oxytocin in human reproductive behaviors, including its potential 'aphrodisiac' or prosexual effect in women in the presence of the sex-steroid hormones.