Likelihood of response with subsequent dosing for patients with migraine and initial suboptimal response with eptinezumab: A post hoc analysis of two placebo-controlled randomized clinical trials.

OBJECTIVE: To develop a multivariable model assessing factors predicting a second-dose response to eptinezumab treatment over weeks 13-24 in patients with migraine initially reporting a suboptimal response over weeks 1-12. BACKGROUND: Eptinezumab is a monoclonal antibody used for migraine prevention, administered every 12 weeks. In the PROMISE-1 and PROMISE-2 studies, the first-dose response to eptinezumab treatment (≥50% monthly migraine day [MMD] reduction over weeks 1-12) occurred in ~50-60% of patients with episodic (EM) and chronic migraine (CM), respectively. METHODS: This post hoc analysis included patients with suboptimal first-dose response (<50% MMD reduction over weeks 1-12) with EM and CM, with patient-reported outcome data at weeks 12 and 24. Eptinezumab 100 and 300 mg doses were pooled. RESULTS: The analysis included 416/888 patients (46.8%) from PROMISE-1 and 479/1072 patients (44.7%) from PROMISE-2 with suboptimal first-dose response. The proportion of suboptimal first-dose responders who were second-dose responders was 37.0% (71/192; eptinezumab) and 33.9% (42/124; placebo) in PROMISE-1 and 28.8% (79/274) and 18.5% (38/205) in PROMISE-2. Significant first-dose predictors of second-dose response were percent change in MMDs across weeks 1-12 (PROMISE-1, odds ratio [OR]: 0.97, 95% confidence interval [CI]: 0.95, 0.98, p = 0.0001; PROMISE-2, OR: 0.94, CI: 0.92, 0.96, p < 0.0001) and change in 6-item Headache Impact Test (HIT-6) total score (PROMISE-2 only, OR: 0.92; CI: 0.87, 0.98; p = 0.027). In PROMISE-1, the probability of second-dose response ranged from 21.7% in patients with first-dose 0% MMD change to 56.0% in patients with first-dose 45% MMD reduction. In PROMISE-2, depending on HIT-6 total score, probability of second-dose response ranged from 5.9-12.1% in patients with first-dose 0% MMD change to 54.2%-72.3% in patients with first-dose 45.0% MMD reduction. CONCLUSION: Individuals with migraine not experiencing ≥50% MMD response to their first dose of eptinezumab may benefit from a second dose.

Effectiveness of vortioxetine for major depressive disorder in real-world clinical practice: US cohort results from the global RELIEVE study.

Introduction: Effective treatment of major depressive disorder (MDD) involves addressing both depressive and functional symptoms, increasing patients' overall sense of well-being and quality of life (QoL). Methods: RELIEVE was an international observational, prospective study in patients ≥18 years with a current diagnosis of a major depressive episode (MDE) initiating vortioxetine in routine clinical practice; outcomes for the cohort of participants from the United States are presented here. Functioning was assessed at weeks 12 and 24 versus baseline using the Sheehan Disability Scale (SDS). Secondary effectiveness analyses assessed changes from baseline to weeks 12 and 24 in functioning, depression severity, cognitive symptoms, sexual function, and QoL. Results: 244 participants had an average of 8.2 previous MDEs; mean duration of their current MDE at baseline was 93.5 weeks. Vortioxetine was used as second- or later-line treatment for 80.5% of participants. Least-squares mean (SE) SDS total score significantly decreased from baseline by 7.19 (0.52) points at week 12 and 8.19 (0.56) points at week 24 (p < 0.0001 for both). Significant improvements were also reflected across SDS subscores, depression severity, cognitive function, sexual function, and QoL. Healthcare resource utilization and productivity parameters also improved. Adverse events were observed in 21.8% of patients, with nausea being the most common (7.3%). Conclusion: This real-world study demonstrated improvements in functioning, depressive symptoms, and cognitive function in patients with MDD treated with vortioxetine in routine clinical practice in the cohort of patients enrolled in the United States. Outcomes were consistent with the efficacy and safety profile of vortioxetine in randomized controlled trials.

Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials.

BACKGROUND: The humanized anti-CGRP monoclonal antibody eptinezumab has been evaluated in five large-scale clinical trials conducted in patients with migraine. This integrated analysis was conducted to evaluate the comprehensive safety and tolerability of eptinezumab in patients with migraine across these studies. METHODS: Data were pooled from four randomized, double-blind, placebo-controlled studies and the first year of one open-label study. RESULTS: The pooled population comprised 2867 adults with migraine: eptinezumab, n = 2076 (4797 infusions); placebo, n = 791 (1675 infusions). A total of 1137/2076 (54.8%) patients who received eptinezumab and 414/791 (52.3%) patients who received placebo experienced ≥1 treatment-emergent adverse event (TEAE); rates were similar across eptinezumab dose groups (10-1000 mg). For most patients with TEAEs, the events were mild or moderate in severity and considered unrelated to study drug by the investigators. Thirty infusion-site AEs occurred in 27/2076 (1.3%) patients who received eptinezumab and 7 in 7/791 (0.9%) patients who received placebo. Infusion-site AEs led to infusion interruption in 19/2076 (0.9%) and 5/791 (0.6%) patients in the eptinezumab and placebo groups, respectively. Nasopharyngitis occurred in ≥2% of patients in the eptinezumab 300-mg group and with an incidence of at least 2 percentage points greater than in the placebo group; however, in most patients (eptinezumab, 139/140; placebo 40/41), its occurrence was considered not related to study treatment. Adverse events coded to hypersensitivity occurred for 23/2076 (1.1%) patients treated with eptinezumab and no patients in the placebo group. If additional TEAE terms that could indicate hypersensitivity are considered (e.g., urticaria, flushing/hot flush, rash, and pruritus), hypersensitivity reactions in the two pivotal placebo-controlled phase 3 studies occurred in ≥2% of patients in the eptinezumab 100-mg and 300-mg groups, and the incidence was at least 2 percentage points greater in either of these groups than in the placebo group. Most hypersensitivity reactions were not serious and resolved with standard medical treatment or observation without treatment, usually within 1 day. CONCLUSIONS: In adults with migraine, the intravenous administration of eptinezumab every 12 weeks demonstrated a favorable safety and tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov (Identifiers: NCT01772524 , NCT02275117 , NCT02559895 , NCT02974153 , NCT02985398 ).

IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells.

HIV continues to be a major global health issue. In spite of successful prevention interventions and treatment methods, the development of an HIV vaccine remains a major priority for the field and would be the optimal strategy to prevent new infections. We showed previously that a single immunization with a SIV-based integrase-defective lentiviral vector (IDLV) expressing the 1086.C HIV-1-envelope induced durable, high-magnitude immune responses in non-human primates (NHPs). In this study, we have further characterized the humoral responses by assessing antibody affinity maturation and antigen-specific memory B-cell persistence in two vaccinated macaques. These animals were also boosted with IDLV expressing the heterologous 1176.C HIV-1-Env to determine if neutralization breadth could be increased, followed by evaluation of the injection sites to assess IDLV persistence. IDLV-Env immunization was associated with persistence of the vector DNA for up to 6 months post immunization and affinity maturation of antigen-specific memory B cells.

Testis-specific ATP synthase peripheral stalk subunits required for tissue-specific mitochondrial morphogenesis in Drosophila.

BACKGROUND: In Drosophila early post-meiotic spermatids, mitochondria undergo dramatic shaping into the Nebenkern, a spherical body with complex internal structure that contains two interwrapped giant mitochondrial derivatives. The purpose of this study was to elucidate genetic and molecular mechanisms underlying the shaping of this structure. RESULTS: The knotted onions (knon) gene encodes an unconventionally large testis-specific paralog of ATP synthase subunit d and is required for internal structure of the Nebenkern as well as its subsequent disassembly and elongation. Knon localizes to spermatid mitochondria and, when exogenously expressed in flight muscle, alters the ratio of ATP synthase complex dimers to monomers. By RNAi knockdown we uncovered mitochondrial shaping roles for other testis-expressed ATP synthase subunits. CONCLUSIONS: We demonstrate the first known instance of a tissue-specific ATP synthase subunit affecting tissue-specific mitochondrial morphogenesis. Since ATP synthase dimerization is known to affect the degree of inner mitochondrial membrane curvature in other systems, the effect of Knon and other testis-specific paralogs of ATP synthase subunits may be to mediate differential membrane curvature within the Nebenkern.

Ocean Acidification Has Multiple Modes of Action on Bivalve Larvae.

Ocean acidification (OA) is altering the chemistry of the world's oceans at rates unparalleled in the past roughly 1 million years. Understanding the impacts of this rapid change in baseline carbonate chemistry on marine organisms needs a precise, mechanistic understanding of physiological responses to carbonate chemistry. Recent experimental work has shown shell development and growth in some bivalve larvae, have direct sensitivities to calcium carbonate saturation state that is not modulated through organismal acid-base chemistry. To understand different modes of action of OA on bivalve larvae, we experimentally tested how pH, PCO2, and saturation state independently affect shell growth and development, respiration rate, and initiation of feeding in Mytilus californianus embryos and larvae. We found, as documented in other bivalve larvae, that shell development and growth were affected by aragonite saturation state, and not by pH or PCO2. Respiration rate was elevated under very low pH (~7.4) with no change between pH of ~ 8.3 to ~7.8. Initiation of feeding appeared to be most sensitive to PCO2, and possibly minor response to pH under elevated PCO2. Although different components of physiology responded to different carbonate system variables, the inability to normally develop a shell due to lower saturation state precludes pH or PCO2 effects later in the life history. However, saturation state effects during early shell development will carry-over to later stages, where pH or PCO2 effects can compound OA effects on bivalve larvae. Our findings suggest OA may be a multi-stressor unto itself. Shell development and growth of the native mussel, M. californianus, was indistinguishable from the Mediterranean mussel, Mytilus galloprovincialis, collected from the southern U.S. Pacific coast, an area not subjected to seasonal upwelling. The concordance in responses suggests a fundamental OA bottleneck during development of the first shell material affected only by saturation state.

Programmed evolution for optimization of orthogonal metabolic output in bacteria.

Current use of microbes for metabolic engineering suffers from loss of metabolic output due to natural selection. Rather than combat the evolution of bacterial populations, we chose to embrace what makes biological engineering unique among engineering fields - evolving materials. We harnessed bacteria to compute solutions to the biological problem of metabolic pathway optimization. Our approach is called Programmed Evolution to capture two concepts. First, a population of cells is programmed with DNA code to enable it to compute solutions to a chosen optimization problem. As analog computers, bacteria process known and unknown inputs and direct the output of their biochemical hardware. Second, the system employs the evolution of bacteria toward an optimal metabolic solution by imposing fitness defined by metabolic output. The current study is a proof-of-concept for Programmed Evolution applied to the optimization of a metabolic pathway for the conversion of caffeine to theophylline in E. coli. Introduced genotype variations included strength of the promoter and ribosome binding site, plasmid copy number, and chaperone proteins. We constructed 24 strains using all combinations of the genetic variables. We used a theophylline riboswitch and a tetracycline resistance gene to link theophylline production to fitness. After subjecting the mixed population to selection, we measured a change in the distribution of genotypes in the population and an increased conversion of caffeine to theophylline among the most fit strains, demonstrating Programmed Evolution. Programmed Evolution inverts the standard paradigm in metabolic engineering by harnessing evolution instead of fighting it. Our modular system enables researchers to program bacteria and use evolution to determine the combination of genetic control elements that optimizes catabolic or anabolic output and to maintain it in a population of cells. Programmed Evolution could be used for applications in energy, pharmaceuticals, chemical commodities, biomining, and bioremediation.

Efficacy and safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful combination therapy of treatment-resistant major depressive disorder.

This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to ≥ 2 different antidepressants for ≥ 6 weeks within the current MDD episode were acutely treated for 6-8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions-Severity of Depression score of ≥ 4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (≥ 7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs.

Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia.

We compared long-term treatment effectiveness of monthly olanzapine long-acting injection (LAI) with that of oral olanzapine. Outpatients with 2 or more episodes of psychotic worsening in the past 24 months with Positive and Negative Syndrome Scale total score of lower than 70 were randomized to 405 mg/4 weeks of olanzapine LAI (n = 264) or 10 mg/d of oral olanzapine (n = 260) for 2 years of open-label treatment. Dosing thereafter was flexible (150-405 mg/4 weeks of LAI vs 5-20 mg/d of oral). Primary outcome was time to all-cause discontinuation. At baseline, patients were clinically stable (mean Positive and Negative Syndrome Scale total score of 57). Seventeen percent of patients had been psychiatrically hospitalized in the previous 6 months, and 4.6% were rated nonadherent in the month before study entry. The groups did not differ significantly in median time to all-cause discontinuation (645 days for LAI, 678 days for oral; P = 0.61), discontinuation rate (53.8% for LAI, 51.2% for oral; P = 0.60), or relapse rate (20.1% for LAI, 18.5% for oral; P = 0.66). Postbaseline psychiatric hospitalization rate was low for both groups (7.6% for LAI, 9.2% for oral), but mean hospitalization duration was significantly longer for oral patients (1.80 days [20 for those hospitalized] vs 0.43 days [6 for those hospitalized], P = 0.02). There were no clinically significant group differences in adverse events or safety measures. No post-injection delirium/sedation syndrome events occurred. In conclusion, olanzapine LAI and oral olanzapine were similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia. Treatment discontinuation for olanzapine LAI was similar to that of oral olanzapine, despite the 3-hour post-injection observation period and other precautionary procedures related to risk of post-injection delirium/sedation syndrome.

Olanzapine in pregnancy and breastfeeding: a review of data from global safety surveillance.

BACKGROUND: Olanzapine use has been reported during pregnancy and breastfeeding, but there are no controlled clinical trials assessing the safety of olanzapine exposure to infants and fetuses. The purpose of this report was to review and analyze prospective post-marketing cases of pregnancy and breastfeeding with olanzapine, in order to guide clinicians and women on the use of olanzapine therapy during pregnancy and/or breastfeeding. METHODS: A worldwide safety database maintained by Eli Lilly and Company was searched for all spontaneous-reported data regarding olanzapine use during pregnancy and/or breastfeeding. Cases reported prior to pregnancy outcome were considered to be prospective, and follow-up was pursued after the delivery date to assess outcome. RESULTS: Outcome data were available for 610 prospectively identified pregnancies during which olanzapine was used. The majority of women had normal births (66%), although premature births were reported in 9.8% and perinatal conditions in 8% of the pregnancies. A total of 102 pregnancies reported olanzapine treatment during breastfeeding. In these infants, the most commonly reported adverse events were somnolence (3.9%), irritability (2%), tremor (2%), and insomnia (2%), although the majority of pregnancies reported no adverse events (82.3%). CONCLUSIONS: The frequency of fetal outcomes in these prospectively identified pregnancies exposed to olanzapine did not differ from rates of outcomes reported in the general population. These data may be useful to help guide clinicians and women decide to continue, or discontinue, olanzapine therapy during pregnancy and/or breastfeeding, but should be considered within the limitations associated with spontaneously reported data. Women should notify their clinicians if they become pregnant or intend to become pregnant while being treated with olanzapine. Because of limited experience in humans, olanzapine should be used in pregnancy only when potential benefit justifies potential risk to the fetus. Olanzapine should only be considered during breastfeeding when the potential benefit justifies the potential risk to the infant.

Risk of Mortality (including Sudden Cardiac Death) and Major Cardiovascular Events in Users of Olanzapine and Other Antipsychotics: A Study with the General Practice Research Database.

Objective. Assess risk of cardiac events and mortality among users of olanzapine and other antipsychotics relative to nonusers. Methods. The General Practice Research Database was used to identify cohorts of antipsychotic users and nonusers with psychiatric illness. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Results. 183,392 antipsychotic users (including 20,954 olanzapine users) and 193,920 psychiatric nonusers were identified. There was a significantly higher rate of cardiac mortality (adjusted RR [aRR]: 1.53, CI, 1.12-2.09) in olanzapine users relative to psychiatric nonusers, consistent with findings for both atypical and typical antipsychotics. Relative to psychiatric nonusers, no increased risk of all-cause mortality was observed among olanzapine users (aRR: 1.04, CI, 0.93-1.17), but elevated all-cause mortality risk was observed when compared to all antipsychotic users (aRR: 1.75, CI, 1.64-1.87). There was no increased risk of CHD or VA among olanzapine users relative to psychiatric nonusers, consistent with findings for atypical but not typical antipsychotics. SCD cases were uncommon. Conclusions. Use of antipsychotic agents was associated with increased risk of all-cause and cardiac mortality. Patients treated with olanzapine were found to be at increased risk of cardiac mortality versus psychiatric nonusers.

Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database.

Objective. Antipsychotics have been associated with increased cardiac events including mortality. This study assessed cardiac events including mortality among antipsychotic users relative to nonusers. Methods. The General Practice Research Database (GPRD) was used to identify antipsychotic users, matched general population controls, and psychiatric diseased nonusers. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Sensitivity analyses were conducted for age, dose, duration, antipsychotic type, and psychiatric disease. Results. 183,392 antipsychotic users (115,491 typical and 67,901 atypical), 544,726 general population controls, and 193,920 psychiatric nonusers were identified. Nonusers with schizophrenia, dementia, or bipolar disorder had increased risks of all-cause mortality compared to general population controls, while nonusers with major depression had comparable risks. Relative to psychiatric nonusers, the adjusted relative ratios (aRR) of all-cause mortality in antipsychotic users was 1.75 (95% CI: 1.64-1.87); cardiac mortality 1.72 (95% CI: 1.42-2.07); SCD primary definition 5.76 (95% CI: 2.90-11.45); SCD secondary definition 2.15 (95% CI: 1.64-2.81); CHD 1.16 (95% CI: 0.94-1.44); and VA 1.16 (95% CI: 1.02-1.31). aRRs of the various outcomes were lower for atypical versus typical antipsychotics (all-cause mortality 0.83 (95% CI: 0.80-0.85); cardiac mortality 0.89 (95% CI: 0.82-0.97); and SCD secondary definition 0.76 (95% CI: 0.55-1.04). Conclusions. Antipsychotic users had an increased risk of cardiac mortality, all-cause mortality, and SCD compared to a psychiatric nonuser cohort.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases.

BACKGROUND: An advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI. METHODS: Safety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors. RESULTS: Based on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified. CONCLUSIONS: Post-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

A Canadian naturalistic study of a community-based cohort treated for bipolar disorder.

BACKGROUND: Bipolar illness is associated with significant psychosocial morbidity and health resource utilization. Second generation antipsychotics, used alone or in combination with mood stabilizers are effective in treating acute mania in community settings. This study was designed to compare the change in clinical parameters and resource utilization at one month in a group of patients who required treatment intervention for exacerbation of mania. The clinical response at one year was also evaluated. METHODS: 496 patients were enrolled at 75 psychiatric practices across Canada. The Olanzapine cohort (n = 287) included patients who had olanzapine added to their medication regimen or the dose of olanzapine increased. The Other cohort (n = 209) had a medication other than olanzapine added or the dose adjusted. Changes from baseline in the Young Mania Rating Scale (YMRS), Montgomery Asberg Depression Rating Scale, Beck Anxiety Inventory and SF-12 Health Survey were compared at one month using ANCOVA. Categorical variables at one month for health resource utilization, employment status, abuse/dependency, and the number of suicide attempts were compared using Fisher's Exact test. Patients were followed for one year and a subgroup was evaluated. RESULTS: At one month, patients in the Olanzapine cohort recorded a mean reduction in the YMRS of 11.5, significantly greater than the mean reduction in the Other cohort of 9.7 (ANCOVA P = 0.002). The Olanzapine cohort was significantly improved compared to the Other cohort on the scales for depression and anxiety and did not experience the deterioration in physical functioning seen in the Other cohort. No significant differences were detected in health-related quality-of-life measures, employment status, drug abuse/dependency, number of suicide attempts, mental functioning, emergency room visits or inpatient psychiatric hospitalizations. In a subgroup treated for 12 months with a single second generation antipsychotic, improvements in illness severity measures were maintained with no evidence of significant differences among the antipsychotics. CONCLUSIONS: Patients with bipolar disorder requiring treatment intervention for exacerbation of mania in the community setting responded to olanzapine at one month. In a subset analysis, second generation antipsychotic treatment continued to be beneficial in reducing bipolar symptoms at one year.

Outcomes for Latin American versus White patients suffering from acute mania in a randomized, double-blind trial comparing olanzapine and haloperidol.

Data from a published double-blind randomized trial comparing olanzapine versus haloperidol in acute mania were used to address the response and tolerability of Latin American patients. Primary efficacy end point was the remission rate (Young Mania Rating Scale score

Low delta sleep predicted a good clinical response to olanzapine administration in schizophrenic patients.

INTRODUCTION: Schizophrenic patients show sleep abnormalities, consisting mainly of decreased delta sleep time, short rapid eye movement (REM) sleep latency, and a reduction in sleep continuity variables. Olanzapine is a novel antipsychotic drug with an atypical profile. The goals of the present study were to determine if pre-treatment sleep variables and the initial response to olanzapine administration on the sleep variables can predict the clinical improvement after eight weeks of treatment. MATERIAL AND METHODS: Twenty-one schizophrenic (DSM-IV) patients were studied. They were clinically evaluated using the positive and negative syndrome scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Sleep recordings were as follows: one acclimatization nigh, one night of baseline recordings, and two nights in which the patients receives olanzapine 10 mg, one hour before bedtime. For sleep-comparison purposes, a group of normal volunteers were also studied with acclimatization and baseline nights. After the sleep recordings ended patients continued with the administration of 10 mg/d of olanzapine, that was titrated as needed up to 20 mg/d or down to 5 mg/d. Evaluations were conducted weekly. RESULTS: Awakening and sleep latency variables were significantly higher in schizophrenic patients compared to normal volunteers. Delta sleep was lower in patients than in normal subjects, with no detectable values in some of the schizophrenics. There was not correlation at baseline, between psychopathological scores and delta sleep or other sleep variables. The acute administration of olanzapine 10 mg produced an improvement in continuity sleep variables as well as increase in deltas sleep percentage. Having less than 10% of delta sleep at baseline predicted a good clinical outcome. Eleven of 18 patients showed good clinical improvement after eight weeks of treatment with olanzapine, those were the subjects that had an augmentation of delta sleep above 10% with the first two doses of olanzapine, with minimal side effects. CONCLUSIONS: To have low delta sleep at baseline and the effect of the augmentation of this variable in schizophrenic patients seems to predict a good response to olanzapine. Olanzapine was therapeutically useful, well-tolerated medication, with a favorable safety profile.

A cost-effectiveness clinical decision analysis model for treatment of Schizophrenia.

BACKGROUND: Schizophrenia afflicts approximately 0.7% of Mexican citizens during their lifetime. This study explored whether the difference in clinical efficacy and safety between atypical antipsychotics and conventional neuroleptics results in decreases in use and cost of medical services in Mexico, offsetting the higher price of atypical antipsychotics. METHODS: A U.S. decision analytic Markov model was adapted for use in Mexico to determine cost-effectiveness of treatments and outcomes that Mexican patients with schizophrenia may experience over a 5-year period when treated with olanzapine, haloperidol, or risperidone. Model parameter estimates were based on clinical trial data, published medical literature, and where needed, clinician judgment. Direct medical costs were incorporated into the model and outcomes were estimated using lack of relapse and clinical outcomes based on the Brief Psychiatric Rating Scale (BPRS) as effectiveness indicators. All costs are reported in Mexican pesos. RESULTS: Over a 5-year period, the cost of treating schizophrenia ranged from 196,620 pesos per patient initiating therapy with haloperidol to 226,670 pesos per patient beginning therapy with risperidone. Olanzapine was estimated to have slightly better non-relapse and BPRS-based effectiveness outcomes, but comparative total medical costs compared to risperidone. Patients receiving olanzapine experienced 13 and 2% fewer relapses compared with patients on haloperidol and risperidone, respectively. The 5-year incremental cost-effectiveness ratio of olanzapine compared with haloperidol was 52,740 pesos per improved patient, BPRS-based outcome and 212,540 pesos per avoided relapse. Sensitivity analyses indicated the model was sensitive only to changes in drug costs. CONCLUSIONS: Compared with haloperidol, olanzapine therapy results in improved symptoms, fewer relapses, and is cost-effective, even with conservative values for key model parameters. Olanzapine results in slightly improved patient outcomes and comparable costs compared with risperidone.

Olanzapina: un nuevo antipsicótico / Olanzapine: a new antipsychotic drug

La olanzapina es un antipsicótico novedoso perteneciente a la clase de las tienobenzodiazepinas. Una característica importante es su afinidad por los receptores dopaminérgicos que se encuentran en el área A10, el trayecto que comunica a la corteza cerebral con el área mesolímbica. Esta área se ha relacionado con la psicopatología de la esquizofrenia. El mecanismo de acción de la olanzapina (OLZ) no es del todo claro. Se ha propuesto que su acción antipsicótica se relaciona con su actividad antidopaminérgica y antiserotoninérgica tipo 2. Diversos estudios han demostrado la eficacia clínica de OLZ en pacientes esquizofrénicos en comparación con placebo, haloperidol y risperidona. Una serie de ensayos clínicos demostró que OLZ posee un perfil de eficacia y de seguridad superior al placebo, al antipsicótico típico haloperidol y al antipsicótico atípico RPD. Estos resultados deberán de ser replicados mas adelante con otros estudios. El presente trabajo efectúa una revisión de la literatura