Retrospective chart review of urinary glycosaminoglycan excretion and long-term clinical outcomes of enzyme replacement therapy in patients with mucopolysaccharidoses.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of rare, inherited metabolic diseases that result from a deficiency in one of several lysosomal enzymes essential for stepwise glycosaminoglycan (GAG) degradation, leading to GAG accumulation and widespread cellular pathology and clinical disease. Although disease presentation is heterogeneous, the clinical hallmarks are largely comparable across several MPS subtypes. Extensive data have shown that the level of urinary GAG (uGAG) excretion above normal is strongly correlated with disease severity and clinical outcomes in MPS diseases. Thus, change in uGAG excretion may have significant value as a potential primary endpoint in clinical trials of MPS diseases that are too rare to study using traditional clinical endpoints. METHODS: A retrospective medical chart review was undertaken of patients with MPS I, II, and VI who had been treated long term with enzyme replacement therapy (ERT). The relationship between uGAG reduction and clinical outcomes relevant to the major clinical manifestations of these MPS diseases was evaluated. A multi-domain responder index (MDRI) score was calculated, measuring the following 4 domains: 6-min walk test, pulmonary function, growth rate, and Clinician Global Impression of Change. For each domain, a minimal important difference (MID) was defined based on published information of these outcome measures in MPS and other diseases. RESULTS: Of the 50 patients evaluated, 18 (36%) had MPS I, 23 (46%) had MPS II, and 9 (18%) had MPS VI. Forty-two were clinical practice patients and 8 had participated in clinical trials. Across all MPS subtypes, the mean (± SD) uGAG level at baseline was 66.0 ± 51.5 mg/mmol creatinine (n = 48) and there was a mean reduction of 54.6% following ERT. Analysis of the MDRI score based on the MID defined for each domain showed a greater magnitude of improvement in patients with increased uGAG reduction when compared with those patients with lower uGAG reduction for all assessed uGAG thresholds, and a trend toward a higher likelihood of positive mean MDRI score in patients with a uGAG reduction ≥40%. CONCLUSIONS: In this retrospective study, uGAG reduction was associated with long-term clinical outcomes as assessed by a number of approaches, supporting the use of uGAG reduction as a biomarker primary endpoint.

Open-label phase 1/2 study of vestronidase alfa for mucopolysaccharidosis VII.

Vestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received intravenous vestronidase alfa administered every other week (QOW) for 14 weeks (2 mg/kg), followed by 24-week forced-dose titration (1, 4, and 2 mg/kg QOW; 8 weeks each), 36-week continuation (2 mg/kg), and long-term extension (4 mg/kg). Vestronidase alfa was well tolerated and led to dose-responsive, sustained reductions in urinary glycosaminoglycan excretion.

Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials.

Extended placebo-controlled clinical trials in schizophrenia research pose an ethical challenge. This study examines factors that have implications for the design and duration of placebo-controlled acute efficacy trials: Does early response discriminate active drug (AD) from placebo, and are the early differences sustained over time? A post hoc pooled analysis of 2 randomized 6-week double-blind clinical trials was performed comparing patients with schizophrenia treated with placebo or low-dose olanzapine (1 mg/d; placebo/low dose [PBO] group, n = 170) to patients treated with a 10- to 20-mg/d dose of haloperidol or medium- to high-dose olanzapine (7.5 to 17.5 mg/d; AD group, n = 252). Mixed-model repeated-measure analysis tested for group differences. Power analysis was undertaken to compare study designs with shorter durations. At 2 weeks, the mean reduction in the Brief Psychiatric Rating Scale total score was significantly greater for the AD group (-10.1) compared with the PBO group (-4.1; P < 0.001); this difference was sustained until the study ended (6 weeks). A higher proportion of early treatment responders were observed for the AD group (52%) compared with the PBO group (29%; P < 0.001). Early nonresponse to placebo or drug was predictive of subsequent nonresponse (negative predictive value: PBO = 95%, AD = 84%). Power analysis indicates that the placebo-drug differences are robust at 2 weeks. Treatment responders from the AD and the PBO groups followed a similar response path. Early response to antipsychotic treatment discriminated AD from placebo. Reducing placebo-controlled clinical trials from 6 weeks to 2 to 4 weeks was found to be a viable option for efficacy identification in acutely ill patients.

Impact of race on efficacy and safety during treatment with olanzapine in schizophrenia, schizophreniform or schizoaffective disorder.

BACKGROUND: To examine potential differences in efficacy and safety of treatment with olanzapine in patients with schizophrenia of white and black descent. METHODS: A post-hoc, pooled analysis of 6 randomized, double-blind trials in the treatment of schizophrenia, schizophreniform disorder, or schizoaffective disorder compared white (N = 605) and black (N = 375) patients treated with olanzapine (5 to 20 mg/day) for 24 to 28 weeks. Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) total score; and positive, negative, and general psychopathology scores; and the Clinical Global Impression of Severity (CGI-S) scores at 6 months. Safety measures included differences in the frequencies of adverse events along with measures of extrapyramidal symptoms, weight, glucose, and lipid changes over time. RESULTS: 51% of black patients and 45% of white patients experienced early study discontinuation (P = .133). Of those who discontinued, significantly more white patients experienced psychiatric worsening (P = .002) while significantly more black patients discontinued for reasons other than efficacy or tolerability (P = .014). Discontinuation for intolerability was not different between groups (P = .320). For the estimated change in PANSS total score over 6 months, there was no significant difference in efficacy between white and black patients (P = .928), nor on the estimated PANSS positive (P = .435), negative (P = .756) or general psychopathology (P = .165) scores. Overall, there was no significant difference in the change in CGI-S score between groups from baseline to endpoint (P = .979). Weight change was not significantly different in white and black patients over 6 months (P = .127). However, mean weight change was significantly greater in black versus white patients at Weeks 12 and 20 only (P = .028 and P = .026, respectively). Additionally, a significantly greater percentage of black patients experienced clinically significant weight gain (≥ 7%) at anytime compared to white patients (36.1% vs. 30.4%, P = .021). Changes across metabolic parameters (combined fasting and random lipids and glucose) were also not significantly different between groups, with the exception of a greater categorical change in total cholesterol from borderline to high among white subjects and a categorical change from normal to low in high density lipoprotein (HDL) cholesterol among white males. CONCLUSIONS: The findings did not demonstrate overall substantive differences in efficacy or safety between white and black patients diagnosed with schizophrenia or related disorders treated with olanzapine. However, a significantly greater percentage of black patients (36.1%) experienced clinically significant weight gain compared to white patients (30.4%).

Number needed to treat or harm analyses of olanzapine for maintenance treatment of bipolar disorder.

The number-needed-to-treat (NNT) or the number-needed-to-harm (NNH) analysis was performed on olanzapine and comparators for all known controlled clinical studies of olanzapine for bipolar maintenance treatment or relapse prevention to assess safety and efficacy. Studies compared olanzapine (n = 225) and placebo (n = 136) for 12 months, olanzapine (n = 217) and lithium (n = 214) for 12 months, and olanzapine plus lithium or valproate (n = 72) and placebo plus lithium or valproate (n = 64) for 18 months. For prevention of all-cause treatment discontinuation, the NNT was 7 to 8. For 9 of 11 efficacy and disposition measures examined, beneficial outcomes were more common with olanzapine than placebo. Beneficial outcomes were more common with olanzapine than lithium for 7 measures and more common for olanzapine plus lithium or valproate than placebo plus lithium or valproate for 1 measure. The NNHs of 5 to 8 for a weight gain of 7% or higher and 10 to 11 for the increase in body mass index category to overweight or obese during maintenance treatment indicated that these outcomes were more common for olanzapine or olanzapine plus mood stabilizers than for the comparators. All efficacy and disposition measures showing significant differences between groups for 12 to 18 months have NNTs favoring olanzapine or olanzapine plus lithium or valproate over placebo, lithium, or placebo plus lithium or valproate. However, the NNHs favor these comparators for avoidance of weight gain and of increase in body mass index category to overweight or obese. Clinicians should consider these and other potential benefits and risks in using maintenance treatments for patients with a bipolar disorder.

Predicting response to atypical antipsychotics based on early response in the treatment of schizophrenia.

OBJECTIVE: To test whether early onset of response to antipsychotic medications accurately predicts subsequent response in the treatment of patients with schizophrenia. METHODS: We used data from 5 randomized, double-blind clinical trials comparing olanzapine with other atypical antipsychotic drugs in the treatment of patients with schizophrenia and related disorders, who were at least moderately ill at baseline and who were treated for a minimum of 2 weeks (N=1077). Early response was defined as >or=20% improvement on the PANSS total score at 2 weeks. Conditional probabilities (sensitivity, specificity, positive and negative predictive values) were used to characterize the likelihood of "subsequent response" to treatment (i.e., >or=40% improvement on the PANSS total score with treatment up to 3 months). Subsequent analyses focused on varying thresholds of subsequent response, and at different time points. RESULTS: Most (80%) of subsequent non-responders by 3 months were correctly classified as early non-responders at 2 weeks (high specificity), and 84% of early non-responders at 2 weeks were subsequent non-responders by 3 months (high negative predictive value). For early responders, prediction of subsequent response was substantially lower. A higher threshold (e.g., >or=40% improvement) had greater predictive accuracy at all time points measured. Early non-responders attained less symptom improvement overall, and were more likely to discontinue from treatment. CONCLUSIONS: Early non-response to antipsychotic medications was a robust predictor of subsequent lack of response in the treatment of patients with schizophrenia. Evaluating patients as early as 2 weeks in treatment can help identify non-responders who may benefit from an alternative therapeutic approach.

Olanzapine versus aripiprazole for the treatment of agitation in acutely ill patients with schizophrenia.

Rapid control of agitation is of critical importance in the treatment of acutely ill patients with schizophrenia. Both olanzapine and aripiprazole have been shown to be safe and effective in this setting, with each having somewhat different receptor binding affinity profiles. This 5-day, randomized, double-blind trial evaluated relative improvements in agitation in hospitalized patients who received orally dosed olanzapine (n = 306, 20 mg/d) or aripiprazole (n = 298, 15 mg/d, increasing to 30 mg/d as needed). Lorazepam was also given as needed (total dose, < or =4 mg/d) but not in place of a study drug dose increase. The primary efficacy measure was daily mean change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score. Secondary measures of positive symptoms and safety were also assessed. Significant improvements from baseline in PANSS-EC and secondary efficacy measures were seen for both olanzapine and aripiprazole (P < 0.001),with no between-group differences. A greater proportion of aripiprazole-treated patients received lorazepam at each visit compared with olanzapine-treated patients, but this difference was significant only at visit 5 (41.2% vs 31.0%, P = 0.033). Fasting glucose and triglycerides increased more significantly in olanzapine-treated patients (P = 0.030 and P < 0.001, respectively). Prolactin increased in the olanzapine group and decreased in the aripiprazole group with a significant between-group difference (P < 0.001). During the first 5 days of randomized treatment, olanzapine and aripiprazole displayed similar efficacy profiles for treating agitation associated with schizophrenia. Aripiprazole-treated patients had smaller increases in glucose and lipids, but no difference was observed between treatments in the proportion of patients experiencing categorical shifts in these measures.

Sexual dysfunction in patients with schizophrenia treated with conventional antipsychotics or risperidone.

OBJECTIVE: To better understand sexual dysfunction in patients with schizophrenia and its associations with prolactin and reproductive hormones. METHODS: This was a secondary analysis of an open-label, one-day study (N = 402). The primary objective of the study was to assess the prevalence of hyperprolactinemia in patients with schizophrenia who had been treated with conventional antipsychotics or risperidone. Other atypical antipsychotics available at the time of the study were not included due to a more favorable prolactin profile. RESULTS: The majority of patients (59% of females and 60% of males) reported impairment of sexual function. In postmenopausal females, risk of impaired sexual interest was increased by 31% for every 10 ng/ml increase in prolactin (p = 0.035). In males, lower testosterone was associated with higher prolactin (p < 0.001) and with orgasmic (p = 0.004) and ejaculatory dysfunction (p = 0.028). CONCLUSION: These findings suggest that hyperprolactinemia may be associated with sexual dysfunction. They also provide more information on the relationships between prolactin, reproductive hormones, and sexual dysfunction. Sexual dysfunction is an understudied yet important consideration in the treatment of schizophrenia. More attention is warranted in this area as it may provide opportunities for improved quality of life and adherence to treatment for patients.