All-cause Treatment Discontinuation Research Articles

Hostility in schizophrenia: An integrated analysis of the combined Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the European First Episode Schizophrenia Trial (EUFEST) studies

Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study enrolled a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) enrolled 498 patients. We have combined these two samples to study the effects of hostility on study discontinuation as well as to examine correlates and predictors of hostility. Individual data from 1154 patients with complete data were used for analyses. Survival analysis demonstrated that higher hostility was associated with earlier all-cause treatment discontinuation. Furthermore, regression analysis indicated that increased hostility was associated with more severe positive symptoms, lower adherence to pharmacological treatment, younger age, impaired insight, and more drug or alcohol consumption. The clinical implications of the results point to the importance of establishing therapeutic alliance while managing patient's symptoms of hostility with antipsychotics such as olanzapine combined with psychosocial interventions to improve insight and reduce substance use.

Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients.

The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood. A systematic review and meta-analysis of RPCCT comparing pharmacological treatment and placebo in adults with ADHD was carried out. The study outcomes were all-cause treatment discontinuation, efficacy on ADHD symptoms, and safety. Patient-, intervention-, and study design-related covariates were collected. Meta-regression methods were applied. Forty-four studies involving 9952 patients were included. All-cause treatment discontinuation was slightly higher with pharmacological treatment than with placebo (odds ratio (OR) = 1.18; 95% confidence interval (CI) 1.02, 1.36; p = 0.003). A better outcome on all-cause treatment discontinuation was observed in studies that provided concomitant psychotherapy when compared to those that did not (rate of OR (ROR) = 0.68, p = 0.048). Pharmacological treatment was efficacious for reducing ADHD symptoms (standardized mean difference (SMD) = 0.45; 95% CI 0.37, 0.52; p < 0.00001), with stronger intervention effects found in studies investigating stimulant drugs (difference of SMD (Diff SMD) = 0.18, p = 0.017), in shorter studies (Diff SMD = -0.01, p = 0.044), and when clinician-rated scales were used (Diff SMD = 0.44, p < 0.0001). Pharmacological treatment was associated with more frequent adverse events (AEs) (OR = 2.29; 95% CI 1.97, 2.66; p = 0.006). Studies with a lead-in phase and with a higher proportion of patients previously treated with stimulants were associated with a better safety outcome (ROR = 0.59, p = 0.017; ROR = 0.98, p = 0.036, respectively). Pharmacological treatment provides mild symptom improvement but is associated with frequent AEs and higher treatment discontinuation than placebo, particularly when no concomitant psychotherapy is administered. Stimulants appear more efficacious than non-stimulant drugs and the former should be preferred over the latter. The efficacy of pharmacological treatment should be monitored over time because it may decrease progressively.

The Effectiveness of Tyrosine Kinase Inhibitors and Molecular Monitoring Patterns in Newly Diagnosed Patients With Chronic Myeloid Leukemia in the Community Setting.

Clinical outcomes of patients with chronic myeloid leukemia (CML) treated in clinical trials, including response to therapy, may not be representative of those treated in a community setting. Thus, we sought to determine the real-world effectiveness of first-line tyrosine kinase inhibitors in CML by evaluating response rates, all-cause discontinuation, and adherence. Response monitoring patterns were also analyzed. This retrospective observational study, using the McKesson Specialty Health/US Oncology Network (MSH/USON) iKnowMed electronic health record database and medical charts, identified newly diagnosed CML patients who received first-line imatinib, dasatinib, or nilotinib from July 2007 to March 2011, and were then followed for ≥ 18 months. Three hundred patients met study criteria (222 imatinib-treated, 34 dasatinib-treated, and 44 nilotinib-treated in the first-line). Molecular and cytogenetic response assessments were conducted less frequently than recommended (40% never had cytogenetic or molecular monitoring at any time). Patients treated with either dasatinib or nilotinib experienced higher response rates by 6, 12, and 18 months, faster time to major molecular response, and a significantly lower rate of all-cause treatment discontinuation within 18 months relative to imatinib-treated patients. Approximately 56% of all patients were adherent to tyrosine kinase inhibitor therapy. Dasatinib and nilotinib were more effective than imatinib as first-line therapy for CML in a community setting, as observed in descriptive and univariate analyses. The frequency of cytogenetic and molecular monitoring was lower than that recommended by current guidelines, including patients with no molecular or cytogenetic assessments during the 18-month follow-up. Therefore, MSH/USON is working toward improving compliance with response monitoring guidelines.

Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents.

Attention deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder of childhood onset, which may persist into adulthood. ADHD has a significant impact on a child's daily life, affecting relationships and academic performance. Its core symptoms include developmentally inappropriate levels of inattention, hyperactivity, and impulsive behaviour. Tricyclic antidepressants (TCAs) are sometimes used as second line of treatment in the reduction of ADHD symptoms in children and adolescents with ADHD. However, their efficacy is not yet known. To assess the efficacy of TCAs in the reduction of ADHD symptoms within the broad categories of hyperactivity, impulsivity, and inattentiveness in young people aged 6 to 18 years with established diagnoses of ADHD. On 26 September 2013, we searched CENTRAL, Ovid MEDLINE, Embase, PsycINFO, CINAHL, seven other databases, and two trials registers. We also searched the reference lists of relevant articles, and contacted manufacturers and known experts in the field to determine if there were any ongoing trials or unpublished studies available. Randomised controlled trials (RCTs), including both parallel group and cross-over study designs, of any dose of TCA compared with placebo or active medication in children or adolescents with ADHD, including those with comorbid conditions. Working in pairs, three review authors independently screened records, extracted data, and assessed trial quality. We calculated the standardised mean differences (SMD) for continuous data, the odds ratio (OR) for dichotomous data, and 95% confidence intervals (CIs) for both. We conducted the meta-analyses using a random-effects model throughout. We used the Cochrane 'Risk of bias' tool to assess the risk of bias of each included trial and the GRADE approach to assess the quality of the body evidence. We included six RCTs with a total of 216 participants. Five of the six trials compared desipramine with placebo; the remaining trial compared nortriptyline with placebo. One trial compared desipramine with clonidine and placebo, and another compared two TCAs (desipramine and clomipramine) with methylphenidate and placebo. Of the six trials, one RCT primarily assessed the efficacy of TCA in children with ADHD and comorbid tic or Tourette disorder, and another one trial was in children with comorbid tic disorder. RCTs that met our inclusion criteria varied both in design and quality, and none were free of bias. The quality of the evidence was low to very low according to our GRADE assessments.TCA outperformed placebo regarding the proportions of patients achieving a predefined improvement of core ADHD symptom severity (OR 18.50, 95% CI 6.29 to 54.39, 3 trials, 125 participants, low quality evidence). In particular, there was evidence that desipramine improved the core symptoms of ADHD in children and adolescents as assessed by parents (SMD -1.42, 95% CI -1.99 to -0.85, 2 trials, 99 participants, low quality evidence), teachers (SMD -0.97, 95% CI -1.66 to -0.28, 2 trials, 89 participants, low quality evidence), and clinicians (OR 26.41, 95% CI 7.41 to 94.18, 2 trials, 103 participants, low quality evidence). Nortriptryline was also efficacious in improving the core symptoms of ADHD in children and adolescents as assessed by clinicians (OR 7.88, 95% CI 1.10 to 56.12). Desipramine and placebo were similar on "all-cause treatment discontinuation" (RD -0.10, 95% CI -0.25 to 0.04, 3 trials, 134 participants, very low quality evidence). Desipramine appeared more efficacious than clonidine in reducing ADHD symptoms as rated by parents (SMD -0.90, 95% CI -1.40 to -0.40, 1 trial, 68 participants, very low quality evidence) in participants with ADHD and comorbid tics or Tourette syndrome.Although this Cochrane Review did not identify serious adverse effects in patients taking TCAs, it did identify mild increases in diastolic blood pressure and pulse rates. Also, patients treated with desipramine had significantly higher rates of appetite suppression compared to placebo whilst nortriptyline resulted in weight gain. Other reported adverse effects included headache, confusion, sedation, tiredness, blurred vision, diaphoresis, dry mouth, abdominal discomfort, constipation, and urinary retention. Most evidence on TCAs relates to desipramine. Findings suggest that, in the short term, desipramine improves the core symptoms of ADHD, but its effect on the cardiovascular system remains an important clinical concern. Thus, evidence supporting the clinical use of desipramine for the treatment of children with ADHD is low.

Pharmacological treatment of attention deficit hyperactivity disorder with co-morbid drug dependence.

Drug dependence is frequent in patients with attention deficit hyperactivity disorder (ADHD). Nevertheless, the efficacy and safety of pharmacological treatments in this population are unclear. A systematic review with meta-analysis was performed. Randomised placebo-controlled clinical trials investigating the efficacy of pharmacological treatment in patients with co-occurring ADHD and substance use disorder (SUD) were included. ADHD symptom severity, drug abstinence and all-cause treatment discontinuation were the primary study endpoints. The effects of patient-, intervention- and study-related covariates over the primary outcomes were investigated by means of meta-regression. Thirteen studies were included, enrolling a total of 1,271 patients. A small to moderate reduction of ADHD symptoms was found. Meta-regression analysis identified the presence of a lead-in period as a covariate associated with reduced efficacy. Conversely, no beneficial effect was observed either on drug abstinence or treatment discontinuation. The efficacy on ADHD symptoms was smaller in studies with a lead-in period. A positive correlation between the efficacy for ADHD and that for SUD was found. The efficacy of pharmacological interventions for co-occurring ADHD and SUD has been little investigated. Mixed results were obtained: while pharmacological interventions improved ADHD symptoms, no beneficial effect on drug abstinence or on treatment discontinuation was noted. The strength of the recommendation of pharmacological treatment for co-occurring ADHD and SUD is therefore modest. The study was registered with the international prospective register of systematic reviews (PROSPERO): CRD 4212003414.

EPA-1421 – Progress in the selection and delivery of pharmacological treatments in psychiatry

Improvements in study designs, in statistical methods and the use of ’real world’ data as well as better safety monitoring helped in better defining efficacy, effectiveness and safety of drugs. New formulations of available drugs have been developed. Better information on efficacy, effectiveness and safety and larger variety of formulations help to improve the selection of the right drug for different patient groups and for individual patients. The aims of this study are to examine 1/. How different formulations of antipsychotic drugs may impact on treatment? 2/. How recent comparative analyses of treatment efficacy/effectiveness and safety may help clinicians and patients in making better selection from the available pool of antipsychotic drugs? Selected review of the literature on antipsychotic treatment. Variables: all-cause treatment discontinuation and patients’ preference. Small but robust, in some cases significant differences exist between the efficacy/effectiveness of antipsychotics and their different formulations (1,2). Patients may prefer one formulation over the other and a high proportion of patients prefer to continue taking their prescribed drug, rather than switching to another one (3). Clinically relevant differences exist between antipsychotic drugs and between different formulations of the same drug. Treatment patterns may influence treatment efficacy.

Real-world effectiveness of antipsychotic monotherapy vs. polypharmacy in schizophrenia: To switch or to combine? A nationwide study in Hungary

BackgroundLeading guidelines recommend antipsychotic (AP) monotherapy for schizophrenia, nonetheless the combination of antipsychotics (polypharmacy) is common practice worldwide. We conducted a nationwide population-based study to investigate the comparative effectiveness of monotherapy versus polypharmacy in schizophrenia and other psychotic disorders. MethodsData was collected from the Hungarian National Health Insurance Fund's database and a non-interventional retrospective–prospective parallel arm study was designed with a monotherapy arm (MA, switch to a new antipsychotic after >60days of monotherapy, N=5480) and a polypharmacy arm with two APs (PA, addition of a second antipsychotic after >60days of monotherapy, N=7901). The analyses focused on therapy changers, who started a new monotherapy or added a new AP to the existing one. Polypharmacy combinations with more than two APs were not investigated. Fourteen APs were investigated representing the majority of marketed antipsychotics of Hungary in the period of 1/2007–12/2009. The principal endpoint was the time to all-cause treatment discontinuation during a one-year observation period. Kaplan–Meier survival analysis and Cox proportional hazards model were applied with propensity score adjustment. ResultsThe principal outcome measure time to all-cause discontinuation indicated superiority for monotherapy over polypharmacy for the majority of (oral and depot) second generation APs (SGAs). For first generation APs (FGAs), oral formulations did not show a difference between monotherapy and polypharmacy, while depot formulations exhibited polypharmacy advantage. For the four most frequently used oral SGAs, the median times to all-cause discontinuation for monotherapy and polypharmacy, respectively, were 192 and 100days for aripiprazole; 222 and 86days for olanzapine; 176 and 91days for quetiapine; and 157 and 93days for risperidone. For mortality and hospitalization, a significant overall advantage of polypharmacy was detected. ConclusionsOur study provides evidence for the superiority of monotherapy over polypharmacy for SGAs in terms of all-cause treatment discontinuation in schizophrenia. Polypharmacy, however, was associated with a lower likelihood of mortality and hospitalizations. The finding that MA is superior to PA for long-term sustained treatment whereas polypharmacy has advantage in mortality and psychiatric hospitalizations suggests that combination treatments may be more efficacious during exacerbation of psychotic symptoms.

Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta‐analysis and meta‐regression

Atomoxetine is a non-stimulant drug that could be an alternative to methylphenidate, whose benefit : risk balance for the treatment of adults with attention deficit hyperactivity disorder (ADHD) has recently been shown to be unclear. This study aimed to compare all-cause discontinuation rate between atomoxetine and placebo in adults with ADHD. Secondarily, efficacy and safety were investigated. Systematic review and meta-analysis of randomized controlled trials comparing atomoxetine with placebo in adults with ADHD were performed. All-cause treatment discontinuation was the primary endpoint. Efficacy in reducing ADHD symptoms and safety were the secondary endpoints. Odds ratio (OR) and the standardized mean difference (SMD) were calculated for dichotomous and continuous outcomes, respectively. Data were pooled using the fixed and random effects model. The influence of study design-related, intervention-related and patient-related co-variables over the primary endpoint was investigated by means of meta-regression. This study is registered with the international prospective register of systematic reviews (PROSPERO): CRD 42012002042. Twelve studies (3375 patients) were included. Treatment discontinuation was larger with atomoxetine than with placebo (OR = 1.39). No co-variable was found to modify the effect of atomoxetine over treatment discontinuation. Atomoxetine showed modest efficacy in reducing ADHD symptoms irrespective of the assessor: patient (SMD = -0.33); clinician (SMD = -0.40). The rate of adverse events-induced discontinuation was higher with atomoxetine than with placebo (OR = 2.57). This study suggests that atomoxetine has a poor benefit-risk balance for the treatment of adults with ADHD. The recommendation of atomoxetine use in this population is weak.

E.05.03 The unmet needs in the treatment of alcohol dependence

Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study enrolled a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) enrolled 498 patients. We have combined these two samples to study the effects of hostility on study discontinuation as well as to examine correlates and predictors of hostility. Individual data from 1154 patients with complete data were used for analyses. Survival analysis demonstrated that higher hostility was associated with earlier all-cause treatment discontinuation. Furthermore, regression analysis indicated that increased hostility was associated with more severe positive symptoms, lower adherence to pharmacological treatment, younger age, impaired insight, and more drug or alcohol consumption. The clinical implications of the results point to the importance of establishing therapeutic alliance while managing patient's symptoms of hostility with antipsychotics such as olanzapine combined with psychosocial interventions to improve insight and reduce substance use.

Treatment discontinuation with methylphenidate in adults with attention deficit hyperactivity disorder: a meta-analysis of randomized clinical trials

Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line pharmacological treatment. The aim of our study was to compare all-cause discontinuation rate of methylphenidate and its pharmaceutical presentations with placebo in adults with ADHD. This was a systematic review and meta-analysis of randomized controlled trials comparing methylphenidate with placebo in adults with ADHD. All-cause treatment discontinuation was the primary endpoint. The efficacy in reducing ADHD symptoms and safety were the secondary endpoints. Twelve studies (2,496 patients) met the inclusion criteria. Four racemic methylphenidate and one dexmethylphenidate presentations were investigated. The rate of all-cause treatment discontinuation was greater with methylphenidate than with placebo, but this difference was not statistically significant [odds ratio (OR) 1.19, 95 % confidence interval (95 % CI) 0.82-1.74, P = 0.37, I(2) = 64 %] This finding reached the conventional threshold of statistical significance after one outlier study was excluded (OR 1.44, 95 % CI 1.14-1.82, P = 0.002, I(2) = 0). Methylphenidate was more efficacious than placebo for reducing ADHD symptoms and it was associated with a higher proportion of patients dropping out due to adverse effects. Despite reducing ADHD symptoms, methylphenidate showed no advantage over placebo in terms of treatment discontinuation. More attention should be given in the future to the endpoint "all-cause treatment discontinuation" when making regulatory decisions and developing clinical guidelines involving the treatment of ADHD in adulthood.

Time to all-cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis

Objective: This comprehensive review and meta-analysis compared the effectiveness of olanzapine and other antipsychotics in schizophrenia treatment, defining effectiveness as time to all-cause medication discontinuation (primary) and as all-cause treatment discontinuation rates. This study examined randomized clinical trials (RCTs) and observational non-interventional studies. Experimental procedures: Schizophrenia studies that compared olanzapine with individual first- (FGAs) and/or second-generation antipsychotics (SGAs) were included in the meta-analyses. Hazard ratios (HR), risk ratios (RR), and their associated 95% confidence intervals were extracted for RCTs and observational studies. Sensitivity analyses assessed the impact of sources of funding, dose of olanzapine, and allocation concealment method on final results. Results: There were 60 RCTs (N=33,360) and 27 observational studies (N=202,591) included. On time to all-cause medication discontinuation, olanzapine was significantly better than aripiprazole, quetiapine, risperidone, ziprasidone and perphenazine for RCTs and better than amisulpride, risperidone, haloperidol, and perphenazine for observational studies. There were no significant differences between olanzapine and clozapine in RCTs or observational studies. All-cause discontinuation rates in RCTs were significantly lower for olanzapine compared to all comparators except amisulpride and clozapine. In observational studies, olanzapine was less effective than clozapine. Industry-sponsored studies favored olanzapine when compared to haloperidol and perphenazine; higher dose of olanzapine favored quetiapine and perphenazine when compared to olanzapine; method of allocation concealment did not generally affect the results. Conclusion: Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective – in both RCTs and observational studies – than most SGAs and FGAs, except for clozapine.

Aripiprazole

Oral aripiprazole (Abilify®) is an atypical antipsychotic agent that is approved worldwide for use in adult patients with schizophrenia. It is a quinolinone derivative that has a unique receptor binding profile as it exhibits both partial agonist activity at dopamine D(2) receptors and serotonin 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors. In several well designed, randomized, clinical trials of 4-6 weeks duration, aripiprazole provided symptomatic control for patients with acute, relapsing schizophrenia or schizoaffective disorder. Furthermore, following 26 weeks' treatment, the time to relapse was significantly longer for patients with chronic, stabilized schizophrenia receiving aripiprazole compared with those receiving placebo. Using a variety of efficacy outcomes, aripiprazole showed a mixed response when evaluated against other antipsychotic agents in randomized clinical trials. Longer-term data showed that improvements in remission rates and response rates favoured aripiprazole over haloperidol, although, the time to failure to maintain a response was not significantly different between the treatment arms. On the other hand, improvements in positive and negative symptom scores mostly favoured olanzapine over aripiprazole, although, the time to all-cause treatment discontinuation was not significantly different between the two treatments. Several open-label, switching trials showed that aripiprazole provided continued control of symptoms in patients with schizophrenia or schizoaffective disorder. Using a variety of efficacy outcomes or quality-of-life scores, longer-term treatment generally favoured patients switched to receive aripiprazole compared with standard-of-care oral antipsychotics. Aripiprazole was generally well tolerated in patients with schizophrenia. In particular, its use seems to be associated with a lower incidence of extrapyramidal symptoms than haloperidol and fewer weight-gain issues than olanzapine. Aripiprazole also showed a favourable cardiovascular tolerability profile and its use was associated with a reduced risk of metabolic syndrome than placebo or olanzapine. As a consequence, aripiprazole may provide a more cost-effective treatment option compared with other atypical antipsychotics. In conclusion, oral aripiprazole provides an effective and well tolerated treatment alternative for the acute and long-term management of patients with schizophrenia.

The NIMH-CATIE Schizophrenia Study: What Did We Learn?

It has been over 10 years since the initiation of the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and 5 years since the first publication of its primary results (1). In this period, the initial report has been cited in the literature over 1,600 times (2) while more than 80 articles from the study’s extensive database (Table 1), as well as a book serving as an archive of the study’s results and implications (3), have been published. In the meantime, several more randomized trials comparing the effectiveness of antipsychotics have been completed (4–6), meta-analyses that bear on the findings of the CATIE study have been performed (7, 8), and commentaries on CATIE’s findings and critiques of its methodology have been published (9–11). All of these help us to view the CATIE study in a broader context and enable us to determine what we really learned from it. When the CATIE study was designed in 1999– 2000, the prevailing opinion of researchers and clinicians alike was that the newer (second-generation) antipsychotic drugs were vastly superior to the older (first-generation) antipsychotic drugs in efficacy and safety. This largely reflected the results of studies sponsored by the manufacturers of the new drugs (12, 13), marketing messages of pharmaceutical companies and the hopes of many who wanted better treatments. Indeed, the hypothesis and expectation of the CATIE study investigators was that the firstgeneration antipsychotic perphenazine would be inferior to the newer agents. Consequently, the finding that perphenazine was similar in effectiveness to most other medications had a profound effect that extended beyond the scientific and psychiatric communities to the lay public and various stakeholder groups. Somewhat sensational news reports decried the preferential use and greater cost of the newer medications and the marketing practices that led to them. For example, the September 21, 2005, editorial page of The New York Times opined, “A government-financed study has provided the strongest evidence yet that the system for approving and promoting drugs is badly out of whack. The study compared five drugs used to treat schizophrenia and found that most of the newest, most heavily prescribed drugs were no better than an older drug that is far cheaper. The nation is wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors” (14). But what did we really learn from the CATIE study? In this commentary, we summarize its major implications and their relevance to clinical practice. We will also address some of the study’s most relevant critiques.

Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy

This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

Monotherapy After Polypharmacy Effective for Some Patients

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessMonotherapy After Polypharmacy Effective for Some PatientsMark MoranMark MoranSearch for more papers by this authorPublished Online:3 Jun 2011https://doi.org/10.1176/pn.46.11.psychnews_46_11_15_2AbstractTwo-thirds of people who were being treated for psychosis with more than one antipsychotic and who were switched to monotherapy did so successfully, without discontinuing therapy and with no difference in symptom control compared with those who stayed on polypharmacy. Moreover, switching to monotherapy was associated with weight loss, according to a report in the May American Journal of Psychiatry. The study did find that treatment discontinuation was more common in the group that switched to monotherapy than in the polypharmacy group, but the symptom control and weight loss associated with the switch to monotherapy suggests that monotherapy may be an option worth trying for patients who are relatively stable. ("Discontinuation" in the study was defined as dropping out of the assigned group, not stopping treatment altogether; patients who switched to monotherapy but then "discontinued," for instance, returned to polypharmacy or another form of treatment.) "I don't think our results say that polypharmacy should not be a part of treatment guidelines, but rather that the guidelines should encourage a trial of monotherapy if it seems reasonable and the patient has a chance to go back to polypharmacy if necessary," said senior author Nancy Covell, Ph.D., an assistant professor of clinical psychology in the Department of Psychiatry at Columbia University. In the study, adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuingone antipsychotic. The trial lasted six months, with a six-month naturalistic follow-up. The analysis did not examine the relative effects of switching to or from different kinds of antipsychotics.Results showed that patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86 percent of those assigned to stay on polypharmacy were still taking both medications, whereas 69 percent of those assigned to switch to monotherapy were still taking the same medication. However, the two groups did not differ with respect to psychiatric symptoms or hospitalizations. And on average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. Among those assigned to switch to monotherapy, 18 discontinued their assigned treatment. Of those, 11 reported an increase in symptoms, six expressed a preference to discontinue, and one experienced hyper-lipidemia. Of the 18 monotherapy-switch patients who discontinued, 12 returned to their baseline polypharmacy combination, three began a different polypharmacy combination, one began monotherapy with an agent other than one of the two baseline medications, one began monotherapy with one of the baseline agents and changed to monotherapy with the second baseline agent after 90 days, and one began to taper one of the two agents but did not complete the taper after symptom levels increased. Covell said that psychosis has a natural variability—some days are better than others—and some of the monotherapy-switch patients who discontinued may have attributed natural variation of the disease to the switch. "While this study suggests some people taking antipsychotic polypharmacy might benefit from a switch to monotherapy, it does not address the risks and benefits associated with adding a second antipsychotic to monotherapy. Studies addressing the risks and benefits of going from antipsychotic monotherapy to polypharmacy are sorely needed." "Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy" is posted at <http://ajp.psychiatryonline.org/cgi/content/abstract/appi.ajp.2011.10060908v1>. ISSUES NewArchived

Time to All-Cause Treatment Discontinuation as the Primary Outcome in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study

Time until all-cause treatment discontinuation was the primary outcome of the CATIE trial. We discuss the advantages and disadvantages of this outcome, and evaluate its association with clinical correlates through graphical response profiles. We investigate the characteristics of patients who discontinued for patient decision, including a reclassification of patient decision into other reasons. All-cause discontinuation is compared to a related outcome, time until treatment failure. Patients who discontinued had lower quality of life scores than other patients. Patients discontinuing for lack of efficacy had worsened efficacy scores compared with an improvement for other patients. Those who discontinued for patient decision had lower compliance. Blinded reclassification of discontinuation for patient decision identified 5% of cases as lack of efficacy and 21% as intolerable side effects. Reclassified patients participated in the next study phase at a higher rate than those remaining as patient decision (67% vs. 10%). Treatment group differences for time to discontinuation due to patient decision were attenuated after censoring the reclassified patients, but were still suggestive. Treatment comparisons for time to treatment failure were consistent with all-cause discontinuation, although somewhat smaller. All-cause discontinuation is recommended as a simple and comprehensive outcome for pharmaceutical Phase II-IV clinical trials.

PMH2 EARLY RESPONSE PREDICTS SUBSEQUENT RESPONSE TO OLANZAPINE LONG-ACTING INJECTIONS IN THE TREATMENT OF SCHIZOPHRENIA

Objective: Early non-response to oral antipsychotics was previously shown to be a robust predictor of subsequent non-response to continued treatment with the same oral antipsychotic medication in the treatment of schizophrenia. This study assessed whether early response or early non-response to treatment can serve as a clinical marker in the treatment of schizophrenia with an atypical antipsychotic in long-acting injection formulation (depot). Methods: This post-hoc analysis used data (n=233) from an 8-week randomized, double-blind, placebocontrolled study of olanzapine long-acting injection (olanzapine LAI) in the treatment of inpatients with schizophrenia. Early response to olanzapine LAI was defined as a ≥30% improvement on the PANSS total score (items scored 0-6) from baseline to 4 weeks of treatment. Subsequent response was defined as a ≥40% improvement on the PANSS total score from baseline to endpoint. Predictive accuracy was assessed by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall predictive accuracy. Early responders and early nonresponders to olanzapine LAI were also compared on change in clinical and functional outcome measures. Results: Early response/non-response to olanzapine LAI, assessed following 4 weeks of treatment, predicted subsequent response/nonresponse with a high level of overall accuracy (79%), sensitivity (85%), specificity (72%), PPV (78%), and NPV (80%). Compared to early nonresponders, early responders had significantly longer time to all-cause treatment discontinuation, greater symptom improvement at all time points (per PANSS total and subscale scores), and greater improvement in quality of life and level of social functioning (all at p≤.01). Conclusions: In this study of inpatients with schizophrenia, early response to olanzapine LAI was found to be a robust predictor of subsequent response to the medication. Early responders experienced significantly better clinical and functional outcomes compared to early nonresponders and had longer treatment duration. Current findings are consistent with previous research on oral antipsychotics and will require replication in future studies.

Antipsychotic‐associated all‐cause and cardiac mortality: what should we worry about and how should the risk be assessed?

Antipsychotic‐associated all‐cause and cardiac mortality: what should we worry about and how should the risk be assessed?

Treatment Outcomes of Patients With Tardive Dyskinesia and Chronic Schizophrenia

We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. clinicaltrials.gov Identifier: NCT00014001.

Number Needed to Treat or Harm Analyses of Olanzapine for Maintenance Treatment of Bipolar Disorder

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