Clinical and economic ramifications of switching antipsychotics in the treatment of schizophrenia

<p>Abstract</p> <p>Background</p> <p>Switching between antipsychotic medications is common in the treatment of schizophrenia. However, data on clinical and economic outcomes from antipsychotic switching, in particular acute care service use, is fairly limited. The goal of this research was to assess the clinical and economic ramifications of switching antipsychotics during outpatient management of schizophrenia.</p> <p>Methods</p> <p>Data from a 1-year randomized, open-label cost-effectiveness study involving typical and atypical antipsychotics were assessed. The study protocol permitted switching of antipsychotics when clinically warranted. The risk of crisis-related events, use of acute-care services, and the time to the initial use of such services were determined in outpatients who switched antipsychotics compared with those who continued with their initial medications. Health care resource utilization data were abstracted from medical records and other sources (e.g., patient self-report), and direct costs were estimated using previously published benchmarks.</p> <p>Results</p> <p>Almost one-third of patients (29.3%) underwent a switch from their initial antipsychotic agent, with an average duration of 100 days before such treatment alterations. Compared with their counterparts who remained on their initial therapies, individuals who switched antipsychotics experienced a significantly higher risk of acute-care services, including hospitalization (p = .013) and crisis services (p = .011). Patients undergoing medication switches also used acute-care services significantly sooner (p = .004) and accrued an additional $3,000 (a 25% increase) in annual total health care costs per patient, most of which was due to acute-care expenditures.</p> <p>Conclusion</p> <p>Switching antipsychotic medications was found to be associated with considerably poorer clinical and economic outcomes, as reflected by, more frequent and more rapid use of acute-care services compared with persons remaining on their initial treatments.</p> <p>Trial Registration</p> <p>Trial ID 2325 in LillyTrials.com (also accessible via ClinicalStudyResults.org).</p

The Effect of Chronic Antipsychotic Drug on Hypothalamic Expression of Neural Nitric Oxide Synthase and Dopamine D2 Receptor in the Male Rat

Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect. It has been demonstrated that both neuronal nitric oxide (nNOS) and dopamine D2 receptor (DRD2) in the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus have important roles in the regulation of sexual behaviour. We investigated the influences of 21 days’ antipsychotic drug administration on expression of nNOS and DRD2 in the rat hypothalamus. Haloperidol (0.5 mg/kg/day i.p.) significantly decreased nNOS integrated optical density in a sub-nucleus of the MPOA, medial preoptic nucleus (MPN), and decreased the nNOS integrated optical density and cell density in another sub-nucleus of the MPOA, anterodorsal preoptic nucleus (ADP). Risperidone (0.25 mg/kg) inhibited the nNOS integrated optical density in the ADP. nNOS mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 mRNA and protein expression in both the MPOA and the PVN. Quetiapine (20 mg/kg/day i.p.) did not influence the expression of nNOS and DRD2 in either the MPOA or the PVN. These findings indicate that hypothalamic nNOS and DRD2 are affected to different extents by chronic administration of risperidone and haloperidol, but are unaffected by quetiapine. These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs

Is the PANSS used correctly? a systematic review

<p>Abstract</p> <p>Background</p> <p>The PANSS (Positive and Negative Syndrome Scale) is one of the most important rating instruments for patients with schizophrenia. Nevertheless, there is a long and ongoing debate in the psychiatric community regarding its mathematical properties.</p> <p>All 30 items range from 1 to 7 leading to a minimum total score of 30, implying that the PANSS is an interval scale. For such interval scales straightforward calculation of relative changes is not appropriate. To calculate outcome criteria based on a percent change as, e.g., the widely accepted response criterion, the scale has to be transformed into a ratio scale beforehand. Recent publications have already pointed out the pitfall that ignoring the scale level (interval vs. ratio scale) leads to a set of mathematical problems, potentially resulting in erroneous results concerning the efficacy of the treatment.</p> <p>Methods</p> <p>A Pubmed search based on the PRISMA statement of the highest-ranked psychiatric journals (search terms "PANSS" and "response") was carried out. All articles containing percent changes were included and methods of percent change calculation were analysed.</p> <p>Results</p> <p>This systematic literature research shows that the majority of authors (62%) actually appear to use incorrect calculations. In most instances the method of calculation was not described in the manuscript.</p> <p>Conclusions</p> <p>These alarming results underline the need for standardized procedures for PANSS calculations.</p

Predictors of switching antipsychotic medications in the treatment of schizophrenia

<p>Abstract</p> <p>Background</p> <p>To identify patient characteristics and early changes in patients' clinical status that best predict subsequent switching of antipsychotic agents in the long-term treatment of schizophrenia.</p> <p>Methods</p> <p>This post-hoc analysis used data from a one-year randomized, open-label, multisite study of antipsychotics in the treatment of schizophrenia. The study protocol permitted switching of antipsychotics when clinically warranted after the first eight weeks. Baseline patient characteristics were assessed using standard psychiatric measures and reviews of medical records. The prediction model included baseline sociodemographics, comorbid psychiatric and non-psychiatric conditions, body weight, clinical and functional variables, as well as change scores on standard efficacy and tolerability measures during the first two weeks of treatment. Cox proportional hazards modeling was used to identify the best predictors of switching from the initially assigned antipsychotic medication.</p> <p>Results</p> <p>About one-third of patients (29.5%, 191/648) switched antipsychotics before the end of the one-year study. There were six variables identified as the best predictors of switching: lack of antipsychotic use in the prior year, pre-existing depression, female gender, lack of substance use disorder, worsening of akathisia (as measured by the Barnes Akathisia Scale), and worsening of symptoms of depression/anxiety (subscale score on the Positive and Negative Syndrome Scale) during the first two weeks of antipsychotic therapy.</p> <p>Conclusions</p> <p>Switching antipsychotics appears to be prevalent in the naturalistic treatment of schizophrenia and can be predicted by a small and distinct set of variables. Interestingly, worsening of anxiety and depressive symptoms and of akathisia following two weeks of treatment were among the more robust predictors of subsequent switching of antipsychotics.</p

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia

Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial.

OBJECTIVE: The authors compared the efficacy of olanzapine and lithium in the prevention of mood episode relapse/recurrence. METHOD: Patients with a diagnosis of bipolar disorder (manic/mixed), a history of two or more manic or mixed episodes within 6 years, and a Young Mania Rating Scale total score > or =20 entered the study and received open-label co-treatment with olanzapine and lithium for 6-12 weeks. Those meeting symptomatic remission criteria (Young Mania Rating Scale score < or =12; 21-item Hamilton depression scale score < or =8) were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5-20 mg/day (N=217), or lithium (target blood level: 0.6-1.2 meq/liter) (N=214). RESULTS: Symptomatic relapse/recurrence (score > or =15 on either the Young Mania Rating Scale or Hamilton depression scale) occurred in 30.0% of olanzapine-treated and 38.8% of lithium-treated patients. The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (-0.1% to 17.8%) exceeded the predefined noninferiority margin (-7.3%). Secondary results showed that compared with lithium, olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence. Depression relapse/recurrence occurred in 15.7% of olanzapine-treated and 10.7% of lithium-treated patients. Mean weight gain during open-label co-treatment was 2.7 kg; during double-blind monotherapy, weight gain was significantly greater with olanzapine (1.8 kg) than with lithium (-1.4 kg). CONCLUSIONS: These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment. Both agents were comparable in preventing depression relapse/recurrence

Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population

Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.This study was supported by Fondo de Investigation Sanitaria (FIS) EC07/90393, EC07/90466 and EC07/90604 Grants. Berta Almoguera's work is supported by a Rio Hortega Grant from Instituto de Salud Carlos III. Pedro Dorado is supported by Instituto de Salud Carlos III-FIS and European Union (FEDER) Grant CP06/00030. The contribution from the Extremadura group is coordinated in the frame of the Iberoamerican Network of PharmacogeneticsPeer reviewe

Cell adhesion molecules in context: CAM function depends on the neighborhood

Cell adhesion molecules (CAMs) are now known to mediate much more than adhesion between cells and between cells and the extracellular matrix. Work by many researchers has illuminated their roles in modulating activation of molecules such as receptor tyrosine kinases, with subsequent effects on cell survival, migration and process extension. CAMs are also known to serve as substrates for proteases that can create diffusible fragments capable of signaling independently from the CAM. The diversity of interactions is further modulated by membrane rafts, which can co-localize or separate potential signaling partners to affect the likelihood of a given signaling pathway being activated. Given the ever-growing number of known CAMs and the fact that their heterophilic binding in cis or in trans can affect their interactions with other molecules, including membrane-bound receptors, one would predict a wide range of effects attributable to a particular CAM in a particular cell at a particular stage of development. The function(s) of a given CAM must therefore be considered in the context of the history of the cell expressing it and the repertoire of molecules expressed both by that cell and its neighbors