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Reasons and Outcomes of Olanzapine Dose Adjustments in the Outpatient Treatment of Schizophrenia
Abstract
Antipsychotic treatment dose adjustments may influence treatment outcomes in patients with schizophrenia.
We analysed data from 4,247 outpatients with schizophrenia who started olanzapine monotherapy in the 3-year, prospective, observational SOHO study to determine factors associated with olanzapine dose adjustments and how these impact on treatment effectiveness and tolerability.
Regression analyses showed an association between changes in the Clinical Global Impression (CGI) and olanzapine dose changes: patients with a lack of effectiveness were more likely to have their dose increased, whereas patients with good treatment response were more likely to have a dose decrease. Improvement in tardive dyskinesia was associated with dose increase or no change (p=0.034) and worsening of sexual problems was associated with dose decrease (p=0.001). Conversely, an increase in olanzapine dose was associated with subsequent clinical improvement (CGI), but dose adjustment had no significant effects on tolerability outcomes.
These results indicate that psychiatrists tend to modify olanzapine dose according to treatment response. Dose increases seem to be associated with a better response to treatment and not with a worsening of side-effects.
... However, prescribers may also take into account other factors such as age, gender, race, duration of illness and baseline symptoms, etc. Flexible dose trials and naturalistic studies where clinical status is periodically assessed with standard measures and in which providers are free to choose and change the dose in accordance with their clinical judgment provide the best opportunity study the relationship between measures of clinical status and real-world prescribing practices. A previous effort by Suarez et al. (2009) found that both current general clinical impression of illness severity and change in the clinical impression from previous assessments predicted antipsychotic dose increases while improvement in sexual and extrapyramidal side effects predicted dose decreases (Suarez et al., 2009). A second study found that the baseline severity of symptoms and symptom change predicted dose increase while side effect profiles but not symptom levels predicted dose decreases (Lipkovich et al., 2005). ...
... However, prescribers may also take into account other factors such as age, gender, race, duration of illness and baseline symptoms, etc. Flexible dose trials and naturalistic studies where clinical status is periodically assessed with standard measures and in which providers are free to choose and change the dose in accordance with their clinical judgment provide the best opportunity study the relationship between measures of clinical status and real-world prescribing practices. A previous effort by Suarez et al. (2009) found that both current general clinical impression of illness severity and change in the clinical impression from previous assessments predicted antipsychotic dose increases while improvement in sexual and extrapyramidal side effects predicted dose decreases (Suarez et al., 2009). A second study found that the baseline severity of symptoms and symptom change predicted dose increase while side effect profiles but not symptom levels predicted dose decreases (Lipkovich et al., 2005). ...
... Our finding that global illness severity as measured by the CGI-S was the factor most strongly related to antipsychotic dose increase is similar to that found by Suarez et al. (2009) and Lipkovich et al. (2008) where increasing dose was associated with baseline CGI and PANSS respectively (Lipkovich et al., 2005;Suarez et al., 2009) In addition, both previous studies also demonstrated that a change in illness severity was related to dose increase, a result replicated here. Global illness severity at the time of dosing displayed a stronger association with dose increase compared with change in symptomatology in this study, again similar to the findings of Lipkovich et al. (2008) but contrasting with those of Suarez et al. (2009) where the relationship with both variables had a similar magnitude. ...
Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) was used with the objective of evaluating factors associated with antipsychotic dose changes. CATIE was a randomized, comparative effectiveness trial for patients with schizophrenia in which a clinician prescribed a double-blind, flexible dose of one of five antipsychotic medications. The mean number of capsules prescribed monthly was evaluated to identify the period following up-titration with the least sample attrition in which dose changes were likely in response to clinical factors. Demographic, efficacy and tolerability variables were evaluated in two regression models predicting a one capsule dose decrease or increase. The mean dose increased to 2.7 capsules over the first 3 months. The post-titration plateau was identified as between 3 and 6 months. Factors associated with dose increases included the Clinical Global Impression Scale at 6 months and change in the Positive and Negative Syndrome Scale between 3 and 6 months. Decreased dosing was associated only with lower patient rated at 6 months global impression of health. Neither tolerability measures, nor body weight was significantly associated with dose changes. In conclusion, dose changes were weakly associated with measures of current or changing clinical status and not affected by measures of side effects.
... Previous studies have observed a decrease in weight gain, or weight loss, in patients switching from standard olanzapine tablets (SOT) to orally disintegrating olanzapine (ODO) tablets. In some study, patients treated with ODO experienced a similar mean change in Body Mass Index (BMI) and weight from baseline, to those patients treated with SOT (Karagianis et al., 2009;Suarez et al., 2009). ...
The present work focuses on preparation of olanzapine, orally dispersing tablets by direct compression method. Effect of super disintegrant crospovidone, disintegration time, drug content on in vitro release has been studied. A factorial design was employed in formulating a prompt dispersible tablet. The selected independent variables crospovidone and fmelt showed significant effect on dependent variables i.e. disintegration time and percent drug dissolved. Disintegration time and percent drug dissolved decreased with increase in the level of crospovidone. The similarity factor f_2 was found to be 97.48 for the developed formulation indicating the release was similar to that of the marketed formulation. Pharmacokinetics of olanzapine after single-dose oral administration of orally disintegrating tablet in normal volunteers were evaluated and the results showed that PK parameters (Cmax, Tmax, AUC) of the designed ODT matrix were similar to those of commercial product, Zyprexa Zydis^{(R)} as a reference.
... Furthermore, a number of patients with schizophrenia do not adequately respond to an antipsychotic within the officially approved dose range [7]. As current clinical practices are limited by the empirical evidence available to accurately predict optimal doses, prescribed doses may be adjusted following the observation of extrapyramidal side effects [8,9]. In response, the physician may reduce the dose or switch the antipsychotic altogether. ...
Aim:
In order to administer antipsychotic medication with the most beneficial outcome, the appropriate drug and dose needs to be identified. Though often not considered in pharmacogenetic studies, dosage plays an important role in treatment outcome. This study set out to analyze the association between 109 SNPs and antipsychotic dosage among schizophrenia patients. In a previous study, we tested 134 SNPs in regards to antipsychotic dosage. In the current study, we tested additional markers in the same candidate genes that we investigated in the previous study to confirm our previous findings.
Methods:
We included 263 participants with schizophrenia spectrum disorders between the ages of 18-75. Each participant was assessed cross-sectionally to collect clinical and antipsychotic treatment information through a semi-structured interview. The antipsychotic dosage for each individual was standardized according to chlorpromazine equivalents (CPZe), defined daily dose, and the percentage of maximum dosage (PM%). For each participant, 109 SNPs from 29 candidate genes were imputed or genotyped using a Customized Illumina Chip.
Results:
Polymorphisms in the GABRB1 gene were significantly associated with higher antipsychotic dosage according to CPZe and PM% standardization.
Conclusion:
Our analysis suggests that variation in the GABRB1 gene may be significantly associated with antipsychotic dosage according to CPZe and PM% standardization. Antipsychotic dosage remains an integral measure for treatment response that warrants future pharmacogenetic testing and studies with larger sample sizes.
... Using the same dose and drugs, some patients may eventually go into remission while others show no significant change or potentially a worsening of symptoms. As there is limited empirical evidence to be able to predict the appropriate drug and dose for each individual, medication is adjusted after the patient has undergone the debilitating side effects (Hermes and Rosenheck, 2012;Lipkovich et al., 2005;Suarez et al., 2009). As a result, medication may be switched or a higher dosage may be recommended. ...
... 60 Prior to switching early olanzapine nonresponders to another medication, optimizing the dose may be prudent given that increasing the dose of olanzapine has been shown to improve efficacy. 61 limitations This was a post hoc analysis from an observational study of treatment with olanzapine in the People's Republic of China. Use of concomitant medications, including antipsychotics in usual clinical care, may have improved the longer-term response rate relative to continuing treatment with olanzapine monotherapy. ...
Background
The aims of this analysis were to identify factors associated with early response (at 4 weeks) to olanzapine treatment and to assess whether early response is associated with better longer-term outcomes for patients with schizophrenia in the People’s Republic of China.
Methods
A post hoc analysis of a multi-country, 6-month, prospective, observational study of outpatients with schizophrenia or bipolar mania who initiated or switched to treatment with oral olanzapine was conducted using data from the Chinese schizophrenia subgroup (n=330). Factors associated with early response were identified using a stepwise logistic regression with baseline clinical characteristics, baseline participation in a weight control program, and adherence with antipsychotics during the first 4 weeks of treatment. Mixed models for repeated measures with baseline covariates were used to compare outcomes over time between early responders and early nonresponders to olanzapine.
Results
One hundred and thirty patients (40%) achieved an early response. Early response was independently predicted by higher baseline Clinical Global Impressions-Severity score (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.15–1.97), fewer years since first diagnosis (OR 0.94, CI 0.90–0.98), a greater number of social activities (OR 1.22, CI 1.05–1.40), participation in a weight control program (OR 1.81, CI 1.04–3.15), and high adherence with antipsychotics during the first 4 weeks of treatment (OR 2.98, CI 1.59–5.58). Relative to early nonresponders, early responders were significantly more likely to meet treatment response criteria at endpoint, had significantly greater symptom improvement (Clinical Global Impressions-Severity), and had significantly greater improvement in functional outcomes (all P<0.05).
Conclusion
High levels of adherence to prescribed antipsychotics and participation in a weight control program were associated with early response to olanzapine in Chinese patients with schizophrenia. Early response was associated with greater improvement in symptomatic, functional, and quality of life outcomes at 6 months compared with early nonresponse. Current findings are consistent with previous research outside of the People’s Republic of China.
Antipsychotic dosage is generally adjusted by physicians depending on the stability of the patient and the response to that particular drug. Our hypothesis is that patients with previous suicide attempt are prescribed higher doses of antipsychotics.
We examined the dosage and patterns of antipsychotic use in regard to past suicidal behaviour.
For this study, 304 subjects with schizophrenia spectrum disorders between the ages of 18 and 75 were recruited. A cross-sectional assessment was used for this study, in which data were collected from each patient through an interview and self-report questionnaires. The percentages of the Compendium of Pharmaceuticals and Specialties (CPS) maximum recommended daily dose were applied to standardize antipsychotic dosages across different treatments. We compared the standardized dosage of antipsychotics in schizophrenics with previous suicide attempts and those who have never attempted suicide.
Applying the ANCOVA, our preliminary results show no significant difference (P = 0.467) in antipsychotic dosage in the attempters and non-attempters. The prescribed clozapine dosage fails to show a significant relationship with suicidal history (P >0.05).
In summary, our analysis does not show antipsychotic dosage adjustment based on past suicide attempt, after controlling for the current suicidal ideation and hopelessness.
Communicating potential benefits and harm to patients and payers is essential for high-quality care. However, there are no published guidelines or consensuses on how to communicate potential benefits and harm to patients and payers.
The goal of this review was to identify key elements for communication between clinicians, patients, and payers to achieve maximal benefits and minimal risk.
Literature published from January 1980 to July 2011 and cited on MEDLINE was searched using the terms communication, benefit, harm, effectiveness, cost, cost-effectiveness, psychiatry, bipolar disorder, schizophrenia, and major depressive disorder. Elements related to communicating benefits and/or harm to patients and payers were identified, with only key elements discussed in detail here.
Evidence-based medicine, number needed to treat to benefit (NNTB) or harm (NNTH), and the likelihood of being helped or harmed (LHH) have been advocated as the basis for communication in all specialties of medicine. Phase-dependent communication of benefits and harm is novel, especially in patients with different phases of illness, such as bipolar disorder. Duration-dependent (short-term versus long-term) communication is essential for all psychiatric disorders to reduce the burden of relapse and adverse events with long-term treatment. For drugs with multiple therapeutic indications, a disease-dependent approach is crucial to maximize benefits and minimize harm. The exclusion of comorbid psychiatric disorders in pivotal efficacy trials affects their generalizability. Communicating cost (direct versus indirect) is an essential component in reducing health care expenditures. The results of available cost-effectiveness analyses of psychiatric pharmacotherapy have been inconsistent and/or contradictory.
Evidence-based communication of potential benefits and harm to patients and payers, using NNTB, NNTH, and LHH, should be the key principle that guides decision making. Phase-, duration-, and disease-dependent communication and evidence-based cost-saving principles can maximize benefit and reduce harm.
Infliximab dosing for inflammatory bowel disease (IBD) is based on patient weight and treatment response. Understanding dosing patterns may provide insight into treatment response and predictability of treatment cost. The purpose of this medical record review was to assess dose and dose frequency of infliximab maintenance treatment in patients with IBD using patient chart data.
A retrospective chart review was conducted at 14 community gastroenterology clinics (GI clinics). Patients were aged ≥18 years, diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), and had a first infliximab administration (index date) between January 1, 2005 and September 30, 2007. At least 24 months of continuous data availability were required with dosing data collected for 12 months after initiation of infliximab therapy. Patients with biologic use and/or participation in an IBD clinical trial within 12 months before the index date were excluded.
Charts from 182 CD patients and 86 UC patients were analyzed. About half of the patients were female. Over 90% of patients initiated treatment with infliximab 5 mg/kg. Among CD patients and UC patients, respectively, 79% and 61% continued receiving this dose for maintenance therapy at stable intervals.
This retrospective descriptive study is limited by the type and quantity of information available in patient charts from 14 GI clinics during the first year of infliximab treatment. Further, non-anti-tumor necrosis factor medication data were intermittently collected in some charts and, therefore, did not allow for analysis.
Weight-based dosing and, presumably, patient response enabled providers to find the effective infliximab dose for IBD patients. The maintenance dose and administration frequency remained stable during the initial year.
The number needed to treat (NNT) for all-cause medication discontinuation in large, industry-sponsored, non-randomized, observational studies conducted across world geographies was compared with NNTs from CATIE, an 18-month, NIMH-sponsored, randomized study.
NNTs (with 95% confidence intervals) were calculated using data from 3 large Lilly-sponsored, non-randomized, observational studies (EU-SOHO, IC-SOHO, and US-SCAP, n=20 957). Group differences at medication initiation were adjusted by Cox regression modeling. These NNTs were compared with published NNTs for CATIE (phase 1).
NNTs for olanzapine vs. risperidone and for olanzapine vs. quetiapine were similar across the observational studies and similar to those of CATIE. The NNTs for olanzapine vs. oral typical antipsychotics were similar across the observational studies but demonstrated a somewhat stronger effect size than the NNT reported for olanzapine vs. perphenazine in CATIE.
NNTs for all-cause treatment discontinuation (a proxy measure of a medication's effectiveness from patients' and clinicians' perspectives) appear to be consistent across study designs (non-interventional, observational vs. RCT), study sponsorship (industry vs. independent), and across world geographies, suggesting that antipsychotics differ in this measure.
The authors conducted a review and meta-analysis of studies that compared the efficacy and tolerability of typical and second-generation antipsychotics for patients with treatment-resistant schizophrenia.
A systematic search revealed 12 controlled studies (involving 1,916 independent patients), which were included in the review. For the seven studies that compared clozapine to a typical antipsychotic, a meta-analysis was performed to examine clozapine's effects on overall psychopathology, response rate, extrapyramidal symptoms, and tardive dyskinesia.
The meta-analysis confirmed that treatment-resistant schizophrenic patients have more favorable outcomes when treated with clozapine rather than a typical antipsychotic, as reflected by Brief Psychiatric Rating Scale total score, categorical response rate, Scale for the Assessment of Negative Symptoms score, Simpson-Angus Rating Scale score, and compliance rate. Clozapine also conferred benefits on the sickest treatment-resistant schizophrenic patients. Patients treated with olanzapine also had more favorable outcomes with regard to categorical response and compliance rates.
In the aggregate, the results of a meta-analysis indicated that clozapine exhibits superiority over typical antipsychotics in terms of both efficacy (as measured by improvement in overall psychopathology) and safety (in terms of reduced extrapyramidal side effects). However, the magnitude of the clozapine treatment effect was not consistently robust. Efficacy data for other second-generation antipsychotics in the treatment of patients with refractory schizophrenia were inconclusive. There is, therefore, a growing need to consider new and different treatment strategies, whether they be adjunctive or monotherapeutic, for schizophrenia that continues to be resistant or only partially responsive to treatment.
We characterized prescribing in Connecticut's State public mental health system to assess the feasibility of implementing an evidence-based medication algorithm. Medication records for a random sample of outpatients with diagnoses of schizophrenia spectrum disorders showed prescribing patterns similar to the entire United States. The base rate of changing antipsychotic medications was moderate. Over half of patients received decanoate medications, polypharmacy was nontrivial, and there was variability in prescribing patterns across physicians. Caucasian patients were more likely to receive an atypical antipsychotic and less likely to have a decanoate medication, and Latino patients were less likely to change medications. Because the base rate of changing medications was moderate and a considerable proportion of patients were prescribed newer antipsychotic medications, introducing a research-derived medication algorithm with newer atypical antipsychotics as first line agents may fit well with current practice. Further, implementing such an algorithm may reduce racial and ethnic disparities in prescribing patterns.
The method of generalized estimating equations (GEE) is often used to analyze longitudinal and other correlated response data, particularly if responses are binary. However, few descriptions of the method are accessible to epidemiologists. In this paper, the authors use small worked examples and one real data set, involving both binary and quantitative response data, to help end-users appreciate the essence of the method. The examples are simple enough to see the behind-the-scenes calculations and the essential role of weighted observations, and they allow nonstatisticians to imagine the calculations involved when the GEE method is applied to more complex multivariate data.
Olanzapine, a thienobenzodiazepine, is one of the relatively new atypical antipsychotic drugs. The lowest threshold of effective olanzapine plasma levels in inpatient treatment is assumed to be 9 ng/ml. Very little is known about the plasma concentration in patients at various oral doses of olanzapine or about the clinically relevant interactions with co-medications.
In 71 schizophrenic patients (age 32.6 +/- 12.1, range 18-63 years; 31 women, 40 men), plasma olanzapine levels were assessed in 377 tests by high-performance liquid chromatography (HPLC) with electrochemical detection. Fifty-six of these plasma levels were assessed while patients were receiving olanzapine as monotherapy; otherwise, the plasma levels were assessed with the patients receiving various co-medications.
The mean daily oral dose of olanzapine was 17.5 mg (SD = 7.0, range 5-40 mg), and the mean olanzapine plasma concentration was 54.2 ng/ml (SD 37.8 ng/ml, range 1.2-208 ng/ml). The plasma concentration of olanzapine increased linearly with the daily oral dose (r = 0.64, p < 0.001). A multiple variance analysis considering age and sex as covariables showed a significant difference in the dose-corrected plasma levels of olanzapine among 40 smokers and 31 non-smokers; age and sex did not affect the dose-corrected plasma levels. However, women received a significantly lower daily dose of olanzapine under routine clinical study conditions. No differences could be detected among the dose-corrected plasma concentration of those patients who were taken off olanzapine because they did not respond (n = 14) or because of side effects (n = 5) and those who were discharged while still on olanzapine. Under the co-medication with fluvoxamine, significantly higher dose-corrected olanzapine plasma concentrations were found than with olanzapine monotherapy, whereas significantly lower dose-corrected olanzapine plasma concentrations were detected under lithium and trimipramine co-medication. Under co-medication with amitriptyline, benperidol, carbamazepine, flupentixol, and lorazepam, the dose-corrected olanzapine plasma concentrations were no different than the plasma levels under olanzapine monotherapy.
The relevance of therapeutic drug monitoring is emphasized with respect to the data presented and to the literature. Future studies should examine, in particular, the effects of a wider range of co-medications in a larger patient sample.
The aim of this study was to evaluate clinical outcomes and the tolerability of ziprasidone in relation to its plasma levels.
Thirteen inpatients affected by schizophrenia were included in the study after an acute exacerbation phase. Ziprasidone monotherapy was administered for a period of eight weeks at a mean dose of 123.07+/-30.38 mg/day. Plasma concentrations were measured by high-performance liquid chromatography.
Nine patients completed the study. A significant clinical improvement was observed, especially in negative symptoms ( P<0.05), and there was a significant improvement in extrapyramidal symptoms ( P<0.01). Clinical laboratory tests, such as ECG and weight, did not significantly change from baseline. Plasma ziprasidone levels ranged from 20 ng/mL to 160 ng/mL (mean: 75.8 ng/mL) and were significantly related to the improvement in negative symptoms.
The study showed that ziprasidone was effective and tolerable, that use of ziprasidone was characterized by an absence of extrapyramidal symptoms and weight gain, and that no alterations in clinical laboratory tests occurred. The findings suggest a relationship between plasma levels and the clinical response to negative symptoms of schizophrenia.
The aim of this prospective study was to compare the predictive validity of early improvement of subjective experience and early improvement of rater assessed symptoms on enduring symptomatic remission (ESR) status during 5 years follow.
110 consecutively admitted patients suffering from a first episode of schizophrenia or related disorders were investigated. We defined early improvement of subjective well-being as a delta-score of the total Subjective Well-being under Neuroleptics scale-20 item version (SWN-K) at admission and after 6 weeks treatment. The severity of psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) at admission, 6 weeks, 6 months, 3 and 5 years after admission. Enduring symptomatic remission (ESR) was defined as complying to the symptomatic remission criteria at PANSS assessment at 6 months and 5 years and continuing this state between 6 months and 5 years follow-up. Paired-samples and independent t-test were used to compare means.
Patients with ESR (n=30) had a higher mean improvement of subjective well-being during early treatment as assessed with the SWN-K than those without ESR (n=74) (p=0.004). Early symptomatic improvement as assessed with the PANSS was not related to ESR (p=0.95).
Early improvement of subjective well-being is related to ESR in first episode schizophrenia or related disorders.
The European Schizophrenia Outpatient Health Outcomes (SOHO) study is a 3-year, observational, naturalistic study of the outpatient treatment of schizophrenia. Over 10,000 patients from ten countries who were initiating or changing antipsychotic medication for the treatment of schizophrenia within the normal course of care have been enrolled. The 6-, 12-, 24- and some of the 36-month results have been published so far, and have demonstrated that patients treated with olanzapine and clozapine tended to have somewhat better outcomes than patients treated with other atypical or typical antipsychotics on a wide range of pragmatic treatment effectiveness outcomes: response, relapse, remission and treatment discontinuation. Atypical antipsychotics as a class were associated with a lower frequency of extrapyramidal symptoms and anticholinergic use than typical antipsychotics. Weight gain occurred in all treatment cohorts but was greater in patients treated with olanzapine and clozapine. The results from the SOHO study indicate that differences in effectiveness and tolerability do exist between the antipsychotics.
The authors evaluated the comparative efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular placebo for the treatment of acute agitation in schizophrenia.
Hospitalized patients with schizophrenia received one to three injections of intramuscular olanzapine, 10 mg, intramuscular haloperidol, 7.5 mg, or intramuscular placebo over a 24-hour period. Agitation was measured with the excited component of the Positive and Negative Syndrome Scale and two additional scales.
According to scores on the excited component of the Positive and Negative Syndrome Scale, both intramuscular olanzapine and intramuscular haloperidol reduced agitation significantly more than intramuscular placebo 2 and 24 hours following the first injection. Intramuscular olanzapine reduced agitation significantly more than intramuscular haloperidol 15, 30, and 45 minutes following the first injection. No patients treated with intramuscular olanzapine experienced acute dystonia, compared with 7% of those who were treated with intramuscular haloperidol. No significant QT(c) interval changes were observed in any patients.
Intramuscular olanzapine represents a rapid, effective, and safe treatment for acute agitation in schizophrenia.
This study investigated the association between antipsychotic-induced weight gain and therapeutic response to haloperidol and three commonly used atypical neuroleptic medications in schizophrenia and schizoaffective disorder. The subjects were 151 patients enrolled in a double-blind experiment with a duration of 14 weeks comparing the therapeutic efficacy of haloperidol (n = 36), clozapine (n = 38), olanzapine (n = 38), and risperidone (n = 39). Absolute and relative (%) gain in body weight and body mass index (BMI) was determined for the entire duration of the double-blind treatment period; therapeutic response was assessed by the total score and the individual subscales of the Positive and Negative Symptom Scale. Compared with the pretreatment baseline, results indicated that for olanzapine and clozapine, therapeutic response was closely related to an absolute and relative gain in weight and to a gain in BMI. No association between weight gain and therapeutic response was found for risperidone and haloperidol. These findings suggest that patients who are likely to have the maximal benefits of olanzapine or clozapine treatment for symptom alleviation are at the highest risk of a clinically significant increase in weight gain.
Some, but not all, previous studies have indicated that weight gain is associated with greater improvement in psychopathology during clozapine treatment. Possible reasons for the inconsistent results include failure to adjust for initial body weight and level of psychopathology, differences in trial duration, outcome measures, reliability of assessment, concomitant medications and clozapine dosage. The purpose of this study was to test the hypothesis that clozapine-induced weight gain is related to antipsychotic efficacy at 6 weeks and 6 months after adjusting for initial body weight and severity of illness.
Weight and psychopathology were determined in 74 patients with schizophrenia or schizoaffective disorder at baseline and after 6 weeks and 6 months of open treatment with clozapine monotherapy. The primary measures of psychopathology were the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms subscales, Schedule for Assessment of Negative Symptoms (SANS), Schedule for Assessment of Positive Symptoms (SAPS) and Global Assessment of Function Scale (GAFS).
Significant improvement in the key measures of psychopathology was noted at 6 weeks and 6 months. Mean weight gains at 6 weeks and 6 months were 3.7+/-5.7 S.D. and 7.3+/-7.9 S.D. kg, respectively, with the increase between 6 weeks and 6 months being significant. Age, but not gender, initial body weight, clozapine dosage or plasma levels predicted weight gain at both time points. At 6 weeks and 6 months, after adjustment for age, initial weight and level of psychopathology, the percentage change in weight significantly predicted the improvement in the BPRS Total and Positive symptoms subscale, the SANS Global score, as well as other measures of psychopathology.
Increase in weight with clozapine predicted improvement in psychopathology. This suggests that effects of clozapine on neurotransmitters which influence weight gain, e.g. 5-HT(2C) and 5-HT(1a) antagonism, in association with individual variations in these receptors and others molecules, e.g. peptides and transporters, due to polymorphisms or post-translational editing of mRNAs, may also contribute to the improvement in psychopathology.
The objective of the European Schizophrenia Outpatient Health Outcomes (SOHO) study is to understand the comparative costs and outcomes of antipsychotic drug treatment, with specific focus on olanzapine. The study will also provide a large database for research into the treatment and outcome of schizophrenia. The role of observational studies in the assessment of the effectiveness of antipsychotic agents is reviewed, and the rationale, design and recruitment issues surrounding the SOHO study are presented.
SOHO is a 3-year, prospective, observational study of the health outcomes associated with antipsychotic treatment in Europe.
Over 10 000 patients have been recruited from 10 countries. Baseline evaluation included measures of clinical status, social functioning, quality of life, service use and pharmacological treatment. Patients will be followed for 3 years.
The SOHO study will complement randomized controlled trial findings on the treatment of schizophrenia and will address relevant clinical and policy research questions.
To describe the baseline findings and study population of the Schizophrenia Outpatient Health Outcomes (SOHO) Study.
The SOHO study is an ongoing, large, prospective, long-term observational study of schizophrenia treatment in 10 European countries. The study population consists of out-patients who initiate therapy or change to a new antipsychotic.
A total of 1096 investigators enrolled 10 972 patients. Approximately 60% of patients were men and the mean age was 40 years. Patients treated with clozapine and more than one antipsychotic are more severely ill, patients receiving depot medications have a history of non-compliance, and patients receiving their first antipsychotic for schizophrenia are most likely to receive an atypical agent.
The SOHO study population appears to represent European out-patients with schizophrenia in whom a treatment decision is required. Baseline findings reflect European clinical practice with respect to patients treated with individual antipsychotics.
Patients experiencing an acute decompensation of schizophrenia or bipolar disorder often present in an agitated state. Agitation presents a barrier to therapy, interrupting the typical physician-patient alliance and creating a disruptive, even hazardous, environment. Rapid assessment and effective treatment are necessary to manage agitation and, potentially, to shorten the time to recovery.
One hundred forty-eight acutely agitated patients received either: rapid initial dose escalation (RIDE) in which up to 40 mg of oral olanzapine was allowed on days 1 and 2, up to 30 mg on days 3 and 4, and 5 to 20 mg thereafter; or usual clinical practice (UCP) in which patients received 10 mg/d olanzapine plus up to 4 mg lorazepam on days 1 and 2, up to 2 mg on days 3 and 4, and olanzapine 5 to 20 mg/d thereafter. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC: poor impulse control, tension, hostility, uncooperativeness, and excitement) measured at 24 hours was the primary measure. Secondary assessments of agitation and safety were also performed.
Agitation improved significantly from baseline for both treatment groups; however, improvement with the RIDE strategy was superior to UCP. The RIDE group improvement was superior on the primary efficacy measure (PANSS-Excited) at 24 hours; it was superior on all agitation measures at the end of double-blind treatment. Both treatments were well tolerated, with no clinically significant differences in safety measures. Treatment was not limited by oversedation and attention improved from baseline in both groups.
This study demonstrates the value of olanzapine in the treatment of acutely agitated patients. A new approach to olanzapine dosing that expands the initial dose range up to 40 mg/d may offer superior efficacy in rapidly and effectively controlling the symptoms of agitation.
Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.
The European Schizophrenia Out-patient Health Outcomes study is an observational study investigating treatment in schizophrenia. We report treatment-emergent adverse events during the first 6 months of treatment.
The rate of extrapyramidal symptoms (EPS), anticholinergic use, weight gain and sexual related dysfunctions were assessed in 8,400 out-patients.
Patients typical antipsychotics and risperidone experienced significantly more EPS and anticholinergic use than patients in the clozapine, olanzapine, and quetiapine cohorts. Patients treated with amisulpride, typical antipsychotics and risperidone were significantly more likely to have sexual related dysfunctions and/or amenorrhea. Increases in weight and body mass index occurred in all cohorts, but were significantly greater in the olanzapine and clozapine cohorts.
Patients treated with olanzapine, quetiapine and clozapine had better tolerability outcomes regarding EPS and sexual related dysfunctions compared with patients receiving risperidone, amisulpride and typicals. Patients treated with olanzapine and clozapine had higher weight increases than patients treated with risperidone, quetiapine and typicals.
Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.
In a new approach to the interpretation of data from flexible-dose studies, we examined the safety and efficacy measurements that preceded and followed dose changes, to identify clinical factors that predict dose change as well as subsequent outcome of clinical status with dose change. This was a post hoc analysis of 3 flexible-dosed olanzapine studies: acutely ill bipolar I patients with an index manic episode (N = 452) who received olanzapine (5-20 mg/d) or haloperidol (3-15 mg/d); acutely ill patients with schizophrenia (N = 339) who received olanzapine (10-20 mg/d) or risperidone (4-12 mg/d) for 28 weeks; and remitted bipolar I patients (N = 361) who received olanzapine (5-20 mg/d) or placebo for 48 weeks. The major findings of this analysis were: an increase in dose was predicted by baseline illness severity in the acute studies, and a decrease in dose was predicted by illness symptom improvement or worsening of adverse events. Dose decrease was followed by significantly decreased efficacy for patients with acute mania treated with olanzapine or haloperidol, and olanzapine dose increases were followed by improved efficacy. Treatment-emergent extrapyramidal symptom adverse events and akathisia typically predicted dose decreases. Techniques used in this analysis may prove to be useful in assessing the relationship between dose change and safety and efficacy measures.
Treatment-emergent weight gain may be a general marker of therapeutic improvement, even when improvements occur in the absence of active antipsychotic treatment.
To investigate the association between treatment-emergent weight gain and therapeutic improvement across placebo and active treatments, and to examine the association between reported treatment-emergent weight changes and the treatments’ reported efficacy.
Data from a randomized, double-blind trial comparing treatment of schizophrenia with placebo and olanzapine were used to correlate weight change and change in psychopathology. Additionally, we correlated effect sizes of the efficacy of clozapine, olanzapine, risperidone, haloperidol and placebo (reported in meta-analytical reviews), with their reported weight changes.
Weight gain significantly correlated with clinical improvements for placebo and olanzapine. The correlation between treatments’ efficacy and corresponding weight changes was high (r 0.88, p 0.05).
Treatment-emergent weight gain appears to be an important marker of symptom reduction, and may not be exclusively attributable to pharmacological perturbations.
More than 50 years after the introduction of modern pharmacotherapies for schizophrenia, there remains a tremendous need for therapeutic advances. A second generation of antipsychotic drugs, introduced over the past 15 years, has provided uncertain advantages over the first-generation drugs. This paper reviews the designs of studies that evaluate the effectiveness of putative antipsychotic drugs. Data from the trials needed to achieve regulatory approval do not meet all the needs of clinicians and policy makers. Practical and large, simple trials that evaluate the comparative effectiveness of antipsychotic drugs in real-world settings can help to meet these needs once a drug has reached the market.
Acute psychotic episodes represent critical situations during the course of schizophrenia. Olanzapine (OLZ), a second-generation antipsychotic, is efficacious in acute settings at dosages of 5 to 20 mg/d, and it can be considered a first-line treatment for patients with an acute episode of schizophrenia. The aim of this study was to evaluate the efficacy and tolerability of OLZ at a starting dose of 5 mg versus 20 mg in acute schizophrenic patients and to compare titration versus nontitration.Fifty-one schizophrenic inpatients were randomly assigned to receive OLZ at 5 mg/d (26 patients, group 1) or 20 mg/d (25 patients, group 2) as a starting dosage during an exacerbation phase. In group 1, the OLZ dosage was increased to a mean dosage of 10.55 (+/- 4.00) mg/d. Group 2 received OLZ at a fixed dose of 20 mg throughout the hospitalization period. Olanzapine was significantly and clinically effective on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale, PANSS positive symptoms, and Hamilton Rating Scale for Depression in both groups. There were no significant differences between groups 1 and 2 in the percent improvement in BPRS, Positive and Negative Syndrome Scale, PANSS positive symptoms, PANSS negative symptoms, or Hamilton Rating Scale for Depression; but group 2 was significantly superior in the mean percent improvement in the BPRS items of anxiety (P < 0.001) and suspiciousness (P < 0.05). In conclusion, the higher doses evidence more efficacy on anxiety and suspiciousness, so it seems to be useful to begin therapy with a full dose of the drug to obtain the maximum effect without any significant side effects.
Treatment dissatisfaction and discontinuation continue to limit the long-term treatment of patients with schizophrenia. Schizophrenia comprises a wide spectrum of symptoms, including hallucinations, delusions, hostility, cognitive deficits, and depression and anxiety symptoms. Medication is often effective in the treatment of the positive and hostility symptoms of schizophrenia, but less effective on other symptoms of the disease i.e. negative, affective and cognitive symptoms. However, each one of these symptoms can impinge on the functionality of the patient and decrease their quality of life. For example, negative and affective symptoms may lead to low self-esteem and depression, while cognitive deficits are a major impediment to social and vocational rehabilitation. Even when therapy does address the spectrum of symptoms, often the side effects are severe and may contribute to patient non-compliance or withdrawal of therapy, as patients prefer to experience their disease symptoms rather than drug-induced adverse effects. Optimisation of long-term therapy to overcome these issues is now the challenge for antipsychotic therapy. Recent advances in the development of newer atypical antipsychotics bring us closer to achieving the correct balance between long-term efficacy, tolerability and patient function. Atypical antipsychotics have been shown to be effective for the treatment of positive, negative, affective and cognitive symptoms of schizophrenia. In addition, their advancing mechanisms of action provide advantages over the older agents in terms of long-term tolerability. The use of atypical agents to address the full range of psychotic symptoms with minimal adverse effects should ensure improved functionality and an improved patient quality of life in patients with schizophrenia: both can be regarded as positive reinforcers for long-term compliance.
Patients with schizophrenia and their physicians face a number of challenges, such as long-term control of symptoms, maintaining cognitive function and subjective well-being, and preventing relapse. While randomised, placebo-controlled trials and open-label extensions can provide valuable information about the long-term efficacy and tolerability of newer antipsychotic agents, they cannot address all the variables that may affect treatment outcome. Factors such as cognitive function, antipsychotic side effects, patients' attitudes to medication and subjective well being can all affect the results of treatment in real-life clinical practice. Moreover, the patient cohorts enrolled in clinical trials are often not reflective of the wider population with schizophrenia. For example, patients with conditions such as anxiety and panic disorders or comorbid substance abuse, as well as those with severe illness and patients from certain ethnic or age groups, may often be excluded from clinical trials. In addition, patients themselves may refuse to participate in placebo-controlled studies because of a fear of being under-treated. Naturalistic studies are, therefore, an important means of providing additional data on the safety and effectiveness of antipsychotic agents in 'real-world' settings. Studies such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, the Schizophrenia Outpatient Health Outcomes (SOHO) study and the Broad Effectiveness Trial with Aripiprazole (BETA) studies, together with large-scale database analyses, are now producing results supplementary to those observed in long-term, open-label extension studies. Such naturalistic studies will continue to provide important data on the real-world effectiveness of atypical antipsychotics with respect to key outcomes such as treatment continuation and prolonged recovery.
Antipsychotic discontinuation rates are a powerful indicator of medication effectiveness in schizophrenia. We examined antipsychotic discontinuation in the Schizophrenia Outpatient Health Outcomes (SOHO) study, a 3-year prospective, observational study in outpatients with schizophrenia in 10 European countries. Patients (n=7728) who started antipsychotic monotherapy were analyzed. Medication discontinuation for any cause ranged from 34% and 36% for clozapine and olanzapine, respectively, to 66% for quetiapine. Compared to olanzapine, the risk of treatment discontinuation before 36 months was significantly higher for quetiapine, risperidone, amisulpride, and typical antipsychotics (oral and depot), but similar for clozapine. Longer medication maintenance was associated with being socially active and having a longer time since first treatment contact for schizophrenia, whereas higher symptom severity, treatment with mood stabilizers, substance abuse, having hostile behaviour were associated with lower medication maintenance. Antipsychotic maintenance in SOHO was higher than the results of previous randomized studies.
Sexual dysfunction is a common side effect of antipsychotic medication. Although increased prolactin levels caused by antipsychotic agents are believed to play a major role with regard to sexual side effects, the underlying mechanism of antipsychotic agent-induced sexual dysfunction remains poorly understood.
In a multicentric study 587 psychiatric inpatients were assessed by means of a self-rating sexual questionnaire. Focussing on antipsychotic treatment three subgroups were drawn from the original sample. One group was treated with prolactin-increasing antipsychotics (n=119), the other with prolactin-neutral medication (n=109) and the third patient group was comprised of non-medicated clinical controls (n=105).
The majority of all patients (50-75%) reported at least minor sexual dysfunction. On comparison of the subgroups, only female patients treated with prolactin-increasing medication reported more severe sexual dysfunction. However, multiple regression analysis did not confirm an association between the type of treatment and sexual impairment.
Sexual dysfunction frequently occurs in psychiatric inpatients treated with antipsychotics. Our findings only partly support the assumptions concerning a major role of prolactin-increasing neuroleptics for medication-induced sexual impairment.
The aim of this study was to evaluate the efficacy of a psychoeducational program (PEP) for weight control in patients who had experienced an increase of body weight during treatment with olanzapine.
Eligible patients were randomised to the PEP (Group 1) or to no intervention (Group 2) and continued on olanzapine. After 12 weeks, the PEP was also started in Group 2 and continued in Group 1, up to week 24. Body weight was measured every month. Other measures included quality of life, and change in plasma glucose and lipids levels.
Patients in Group 1 (n=15) had a mean weight loss of 3.6 kg at week 12 and 4.5 kg at week 24 (p<0.01 at both times, p<0.01 between groups at week 12), while those in Group 2 (n=18) had no changes at week 12 and a significant weight loss at week 24 (-3.6 kg from week 12, p<0.01). Changes of BMI paralleled those of body weight. Quality of life (Q-LES-Q-SF categorisation) and functioning (GAF) significantly improved in the total population at endpoint (p<0.01). No significant changes were observed in fasting glucose and lipid profile, while insulin levels significantly decreased from baseline to endpoint in both groups (p<0.05). HOMA index and hepatic insulin sensitivity improved, too.
Patients with increased BMI during treatment with olanzapine experienced significant weight and BMI loss following a structured psychoeducational program.
The objective of this study was to assess the dose-response relationship of standard and higher doses of olanzapine in a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10 (n = 199), 20 (n = 200), and 40 mg/d (n = 200) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment. Patients meeting criteria for antipsychotic treatment resistance were excluded. Dose-response relationship was assessed by linear regression analysis with log-transformed dose (independent variable) and Positive and Negative Syndrome Scale (PANSS) total score (dependent variable). There were no significant dose group differences in patients completing the study (overall, 67.8%). All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship (P = 0.295). Post hoc analysis of response showed significant interaction between baseline PANSS and dose (P = 0.023), indicating better response at higher doses for patients with higher baseline PANSS. There was a significant dose response for mean change in weight (P = 0.003) with significant difference between the 10- and 40-mg-dose groups (P = 0.002; 1.9 [10 mg/d], 2.3 [20 mg/d], and 3.0 kg [40 mg/d]). There was a significant dose response for change in prolactin (P < 0.001) with a significant difference between each group (-10.5 [10 mg/d], -1.7 [20 mg/d], and 4.9 ng/mL [40 mg/d]; P < or = 0.018). Over 8 weeks, non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-response relationship, suggesting that for many patients with schizophrenia or schizoaffective disorder, particularly those who are mildly or moderately ill, 10 mg/d should be the initial dose of choice.