The burden of schizophrenia includes direct costs, indirect costs, and intangible costs. Direct costs are estimated by the amount of services used and the price of treatment. Indirect costs are estimated by the averaged reduced future earnings of both patients and caregivers. Intangible costs are those that may be associated with the illness, such as trauma and depression. This topic presents evidence on direct pharmaceutical costs, including cost of drug treatments and related mental health care services.

What is the evidence for the costs of treating schizophrenia?

Moderate or moderate to low quality evidence suggests the cost of olanzapine is lower than haloperidol, but higher than risperidone. The cost of risperidone is also lower than fluphenazine, haloperidol, or other first generation antipsychotics. The cost of clozapine is lower than first generation antipsychotics including haloperidol and chlorpromazine, and mental healthcare and total healthcare costs of clozapine may be higher than risperidone. The cost of trifluoperazine alone, or in addition to individual psychotherapy, is lower than electroshock or milieu treatments.

October 2020

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Antipsychotic dose comparison determines the lowest dose range that is sufficient to produce a satisfactory clinical response, while avoiding unnecessary side effects. Near-maximal effective dose is the highest dose just before efficacy plateaus and minimum effective dose is the lowest dose that is significantly more effective than placebo.

What is the evidence for antipsychotic dose?

Moderate quality evidence finds a small to medium-sized effect of fewer relapses in people receiving standard dose antipsychotics compared to those receiving very low dose antipsychotics (< 50% of daily defined dose), although very low dose antipsychotics produced fewer side effects. No differences were reported in relapses or side effects when low dose (50 to < 100% of daily defined dose) was compared to standard dose.

Moderate to low quality evidence finds no differences in clinical improvement between low dose (≤400 mg/day) and medium dose (401 mg/day to 800 mg/day) chlorpromazine, but there were higher rates of extrapyramidal symptoms with medium-dose chlorpromazine in the short-term only (up to 12 weeks). Moderate quality evidence finds a small effect of greater clinical improvement and a medium-sized effect of fewer relapses with high-dose chlorpromazine (>800 mg/day) compared to low dose (≤400 mg/day) chlorpromazine. There were more extrapyramidal symptoms and more people leaving the study early for any reason in the high-dose group, although more people in the low-dose group left the study due to deterioration in behaviour.

Moderate to high quality evidence finds intermittent antipsychotic therapy used only during periods of symptom exacerbation or imminent relapse is less effective for preventing relapse than ongoing maintenance therapy. There were small effects showing rapid initiation/titration of antipsychotic therapy was significantly superior to slow initiation for improving symptoms in acute patients. There were no differences in symptom severity between rapid or slow initiation in stable patients switching from one antipsychotic to another, and no benefit for symptoms by increasing antipsychotic dose when patients do not respond initially to standard doses.

Moderate to high quality evidence finds a large effect of lower clozapine concentration to dose ratio and a medium-sized effect of lower olanzapine concentration to dose ratio in smokers versus non-smokers with schizophrenia.

Moderate to low quality evidence finds different minimum and near-maximal effective doses for individual antipsychotic medications (for details, see the technical table).

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Studies have shown that about 80% of patients relapse to psychosis within 5 years of initial treatment. This is often due to lack of adherence to antipsychotic medications. Long-acting injectable antipsychotics are a treatment option for patients who are not adhering to treatment or who do not remember to take their oral preparations.

What is the evidence for mode of administration?

Moderate to high quality evidence shows long-acting injectable second-generation antipsychotics are more effective than placebo injections for symptom improvement and functioning. There were small effects of better functioning, fewer relapses, longer time to relapse, and fewer hospital days with long-acting injectable second-generation antipsychotics compared to oral second-generation antipsychotics. There was also a large effect of lower hospitalisation rates with long-acting injectables.

High quality evidence finds no differences in rates of at least one adverse event between long-acting injectable and oral antipsychotics, although there were more extrapyramidal symptoms and low-density lipoprotein cholesterol change with injectables. Moderate to high quality evidence also finds more anxiety, and moderate to low quality evidence finds more akinesia with long-acting injectable antipsychotics.

For individual antipsychotics, moderate to low quality evidence finds fewer relapses with long-acting injectable fluphenazine compared to oral fluphenazine. Moderate to high quality evidence found no differences in response or relapse rates between injectable and oral risperidone, olanzapine, or aripiprazole. Moderate quality evidence finds no differences in response or relapse rates between injectable and oral haloperidol. There were no differences between injectable or oral  formulations in adverse effects, apart from a small effect of less hyperprolactinemia with long-acting injectable risperidone and more dropouts due to inefficacy with long-acting injectable olanzapine.

October 2020

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Placebo effects in pharmaceutical trials vary widely, with response rates varying from 20% to 70%. The placebo response can include improvement in symptoms and even adverse reactions that have been associated with the antipsychotic being tested. Placebo effects can substantially influence conclusions about the efficacy of antipsychotic medications as they reduce any differences in response to the antipsychotic and the placebo.

What is the evidence for placebo response?

Moderate to high quality evidence found a small to medium-sized improvement in overall symptoms with placebo, however the response to antipsychotics was greater than the response to placebo. The placebo response was greatest in studies with more efficacious drugs, younger samples, shorter illness duration, more severe baseline symptoms, shorter study duration, increased number of study sites, and non-university or non-Veteran Affairs settings.

For people with stable schizophrenia and predominant negative symptoms, there was a small placebo response for negative symptoms which was most apparent in studies with larger numbers of arms in the trials, larger numbers of study sites, and trials with industry sponsorship rather than academic grants.

Around 66% of people receiving placebo also report an adverse event, with the type of event corresponding to the type of antipsychotic. 27% of people receiving placebo reported nervous system disorders, 13% reported gastrointestinal disorders, and 30% reported psychiatric disorders (anxiety, depression, agitation etc). A higher level of schizophrenia symptoms at baseline was associated with more adverse events with placebo.

There was increased placebo response over time, and decreased treatment response over time (1960 to 2014). This may be explained by enrolment of less severely ill patients in newer studies and higher expectations that medications will improve symptoms.

There was greater improvement in symptoms in the placebo arm of studies using last observation carried forward (LOCF) methods than in studies using mixed-effect models for repeated measures (MMRM). Studies involving more countries and studies in outpatient settings had greater placebo response in the analysis of MMRM methods, while studies with shorter study duration showed greater placebo response in the analysis of LOCF methods.

Overall, there was less variability in response to antipsychotics than in response to placebo, with older studies, those with younger patients, higher dose treatments, and greater mean-difference in symptom-change being associated with less variability.

October 2020

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Medication combination treatment, also called polypharmacy, has been utilised in clinical practice for patients who are unresponsive or partially responsive to antipsychotic monotherapies.

What is the evidence for polypharmacy?

Moderate to high quality evidence finds a medium-sized improvement in overall symptoms, and a small improvement in clinical response, with antipsychotic polypharmacy vs. monotherapy. There is also less study discontinuation for any reason with antipsychotic polypharmacy. However, studies assessing rates of relapse after switching from polypharmacy to monotherapies found no differences in relapse rates and more study discontinuation with polypharmacy.

Moderate quality evidence finds antipsychotic polypharmacy is most often associated with the use of first-generation antipsychotics and with inpatient status and is higher in Asia and Europe than in North America and Oceania. Augmenting any antipsychotic with aripiprazole can improve symptoms, particularly negative symptoms, when compared to antipsychotic monotherapy in open-label trials, but not when compared to adjunctive placebo in blinded trials.

For people with inadequate response to clozapine, moderate to high quality evidence finds augmenting clozapine with other second-generation antipsychotics may improve negative and depressive symptoms, but not necessarily positive symptoms. Adjunctive sulpiride and adjunctive ziprasidone were particularly effective for negative symptoms, and adjunctive aripiprazole and adjunctive ziprasidone were particularly effective for depressive symptoms. Moderate to low quality evidence finds improved total symptoms with clozapine augmentation of antidepressants fluoxetine, paroxetine and duloxetine. Adding topiramate, sodium valproate or lithium to clozapine may also improve total symptoms, while adding memantine may improve negative symptoms.

October 2020

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Achieving an optimum pharmacological response may require switching medications. Reasons for switching include individual differences in response, sensitivity to side effects, and peculiaraties of schizophrenia such as changes in symptoms over time.

What is the evidence for switching medications?

Moderate to high quality evidence from mirror-image studies finds fewer hospitalisations after switching from oral to long-acting injectable antipsychotics.

Moderate to high quality evidence finds no differences in symptoms between rapid or slow initiation while switching from one antipsychotic to another in stable patients. However, rapid initiation resulted in more all-cause discontinuation and more nausea.

High quality evidence finds no differences in symptoms between immediate, gradual or delaying discontinuation while switching antipsychotic medications. When switching to olanzapine, there was less insomnia with gradual discontinuation. When switching to ziprasidone, there were less parkinsonism symptoms with gradual discontinuation, but more somnolence.

October 2019

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