A review of olanzapine pamoate

INTRODUCTION: Olanzapine long-acting injection (OLAI), or olanzapine pamoate , is one of three second generation (SGA) antipsychotics now available in a long-acting formulation. OLAI is a microcrystalline salt of pamoic acid and olanzapine suspended in an aqueous solution that slowly dissociates into the separate components once injected intramuscularly (im) into gluteal muscle. AREAS COVERED: A systematic search of databases including PubMed, PsychInfo, and Embase was conducted using the keywords. Relevant articles were then hand searched and relevant websites (FDA, EMA, Eli Lilly, and NIH) were also reviewed. EXPERT OPINION: Efficacy has been demonstrated in the short term and maintenance treatment of schizophrenia with OLAI at doses of 150 - 300 mg every two weeks or 405 mg every four weeks. The overall side effect profile is similar to oral olanzapine. While injection site complications are mild, there is an incidence rate per injection of 0.07 % (incidence rate per patient of 1.4%) of post-injection delirium sedation syndrome (PDSS). This manifests as overdose-like symptoms which necessitates mandatory administration and continuous monitoring of OLAI by health care professionals for the first three hours in a suitable clinical facility. As a consequence, final regulatory approval was delayed and market release and clinical use have been limited.     

Olanzapine pamoate for the treatment of schizophrenia

Introduction: Nonadherence is still a major problem in the long-term treatment of schizophrenia. Long-acting injectable or depot atypical antipsychotics are associated with better maintenance. Olanzapine pamoate, available since 2010, is the second depot atypical antipsychotic. Areas covered: This review covers data on the efficacy and tolerability/safety of olanzapine pamoate, the long-acting formulation of the atypical antipsychotic olanzapine. Administered as a pamoate salt, it has an elimination half-life of 30 days, allowing a 2- or 4-week injection interval. Antipsychotic efficacy was documented in an 8-week trial in 404 acutely ill schizophrenia patients with maintenance therapy in a 24-week trial in 1065 chronic patients. The side-effect profile is comparable to that of oral olanzapine. The most relevant adverse event is the post-injection delirium/sedation syndrome, occurring at a rate of 0.07% of injections or 1.4% of patients. It requires administration by qualified personnel in settings where a post-injection observation period for 3 h by medical personnel is available. Expert opinion: Olanzapine pamoate is an efficacious formulation, particularly for patients with a history of good response to oral olanzapine and doubtful adherence. Psychiatrists should reconsider their negative attitudes toward long-acting or depot antipsychotics and should offer this administration to the majority of patients, not only to a negatively selected population.     

A review of olanzapine pamoate

Introduction: Olanzapine long-acting injection (OLAI), or olanzapine pamoate, is one of three second generation (SGA) antipsychotics now available in a long-acting formulation. OLAI is a microcrystalline salt of pamoic acid and olanzapine suspended in an aqueous solution that slowly dissociates into the separate components once injected intramuscularly (im) into gluteal muscle.

Areas covered: A systematic search of databases including PubMed, PsychInfo, and Embase was conducted using the keywords. Relevant articles were then hand searched and relevant websites (FDA, EMA, Eli Lilly, and NIH) were also reviewed.

Expert opinion: Efficacy has been demonstrated in the short term and maintenance treatment of schizophrenia with OLAI at doses of 150 – 300 mg every two weeks or 405 mg every four weeks. The overall side effect profile is similar to oral olanzapine. While injection site complications are mild, there is an incidence rate per injection of 0.07 % (incidence rate per patient of 1.4%) of post-injection delirium sedation syndrome (PDSS). This manifests as overdose-like symptoms which necessitates mandatory administration and continuous monitoring of OLAI by health care professionals for the first three hours in a suitable clinical facility. As a consequence, final regulatory approval was delayed and market release and clinical use have been limited.     

Aripiprazole: a review of its use in the management of schizophrenia in adults

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.     

Intramuscular olanzapine: a review of its use in the management of acute agitation

Intramuscular olanzapine (Zyprexa) is a rapid-acting atypical antipsychotic drug that is also indicated for use in patients with agitation associated with schizophrenia or bipolar mania, the focus of this review. Evidence from three well designed trials indicates that this formulation of olanzapine is at least as effective as intramuscular haloperidol or lorazepam in the treatment of patients with acute agitation associated with schizophrenia or bipolar mania, and has a faster onset of action. Although transient reductions in blood pressure and heart rate may occur in some patients administered intramuscular olanzapine, preliminary evidence of a general lack of clinical effect on the corrected QT (QTc) interval and a low incidence of extrapyramidal symptoms (EPS) is promising. The parenteral formulation of olanzapine appears to offer an effective, fast-acting and generally well tolerated alternative in the treatment of this significant behavioural problem.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

Long-acting risperidone: a review of its use in schizophrenia

Long-acting risperidone (Risperdal Consta) is a novel, intramuscular formulation of the atypical antipsychotic risperidone, which has shown efficacy in the treatment of patients with schizophrenia.Long-acting risperidone is pharmacokinetically equivalent to and causes less plasma drug concentration fluctuation than the oral formulation. This novel formulation is an aqueous suspension of microspheres comprising risperidone and a biodegradable copolymer. Significant release of risperidone from the microspheres begins 3 weeks after the first injection: thus, administration of another antipsychotic is necessary during this period only. Steady-state plasma concentrations are reached after the fourth injection. Elimination is complete 7-8 weeks after the last injection.Long-acting risperidone 25 or 50mg every 2 weeks demonstrated significantly greater antipsychotic efficacy than placebo and equivalent efficacy to oral risperidone 2-6 mg/day in two randomised, double-blind, double-dummy, 12-week trials of patients with schizophrenia. Additionally, in one of these trials, improvements in health-related quality of life (HRQOL) were superior with long-acting risperidone than placebo. Compared with baseline, improvements in the symptoms of schizophrenia in stable patients were significant with long-acting risperidone 25 or 50mg (12-month trial) and 25, 37.5 or 50mg (12-week trial) every 2 weeks, in two noncomparative, multicentre trials. Patient satisfaction with their medication and patient HRQOL mental health scores improved significantly in the 12-month trial.Long-acting risperidone is generally well tolerated, with a low incidence of injection site pain and an otherwise similar profile of adverse effects to the oral formulation. The overall incidence of extrapyramidal disorders in clinical trials was low (< or= 10%) with similar, yet minimal, changes in extrapyramidal symptom severity between patients treated with long-acting risperidone, oral risperidone or placebo. Tardive dyskinesia was reported in the 12-month trial, in 0.7% of patients. CONCLUSIONS: Long-acting risperidone is effective and generally well tolerated in patients with schizophrenia, including those patients with stable symptoms. Long-acting risperidone is the first atypical antipsychotic available in a formulation which offers a sustained, steady release of drug and is thus an attractive, new option in the treatment of patients with schizophrenia.     

Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Pharmacological management of acute agitation

Acute agitation occurs in a variety of medical and psychiatric conditions, and when severe can result in behavioural dyscontrol. Rapid tranquillisation is the assertive use of medication to calm severely agitated patients quickly, decrease dangerous behaviour and allow treatment of the underlying condition. Intramuscular injections of typical antipsychotics and benzodiazepines, given alone or in combination, have been the treatment of choice over the past few decades.Haloperidol and lorazepam are the most widely used agents for acute agitation, are effective in a wide diagnostic arena and can be used in medically compromised patients. Haloperidol can cause significant extrapyramidal symptoms, and has rarely been associated with cardiac arrhythmia and sudden death. Lorazepam can cause ataxia, sedation and has additive effects with other CNS depressant drugs.Recently, two fast-acting preparations of atypical antipsychotics, intramuscular ziprasidone and intramuscular olanzapine, have been developed for treatment of acute agitation. Intramuscular ziprasidone has shown significant calming effects emerging 30 minutes after administration for acutely agitated patients with schizophrenia and other nonspecific psychotic conditions. Intramuscular ziprasidone is well tolerated and has gained widespread use in psychiatric emergency services since its introduction in 2002. In comparison with other atypical antipsychotics, ziprasidone has a relatively greater propensity to increase the corrected QT (QTc) interval and, therefore, should not be used in patients with known QTc interval-associated conditions. Intramuscular olanzapine has shown faster onset of action, greater efficacy and fewer adverse effects than haloperidol or lorazepam in the treatment of acute agitation associated with schizophrenia, schizoaffective disorder, bipolar mania and dementia. Intramuscular olanzapine has been shown to have distinct calming versus nonspecific sedative effects. The recent reports of adverse events (including eight fatalities) associated with intramuscular olanzapine underscores the need to follow strict prescribing guidelines and avoid simultaneous use with other CNS depressants. Both intramuscular ziprasidone and intramuscular olanzapine have shown ease of transition to same-agent oral therapy once the episode of acute agitation has diminished. No randomised, controlled studies have examined either agent in patients with severe agitation, drug-induced states or significant medical comorbidity. Current clinical experience and one naturalistic study with intramuscular ziprasidone suggest that it is efficacious and can be safely used in such populations. These intramuscular atypical antipsychotics may represent a historical advance in the treatment of acute agitation.     

Effectiveness and cost of risperidone and olanzapine for schizophrenia: a systematic review

Risperidone and olanzapine are novel antipsychotic medications that compete as first-line agents in treating patients with schizophrenia. The objective of this paper is to review the available evidence regarding the effectiveness and cost of risperidone versus olanzapine. We reviewed both randomised and peer-reviewed non-randomised head-to-head (olanzapine versus risperidone) studies in populations with schizophrenia. The studies were selected through a MEDLINE search. Risperidone and olanzapine provide control of positive, negative and global symptoms of schizophrenia. Each drug has a distinct adverse effect profile. Five randomised trials comparing risperidone with olanzapine suggested grossly similar efficacy in the first 2 months of treatment, with some results indicating advantages for olanzapine over the longer term. Only two of the trials included measures of service utilisation. One had 28-week follow-up, and the other followed patients for 12 months but had small sample sizes. Both experimental and naturalistic studies indicated that the acquisition cost of olanzapine is about 50% greater than for risperidone at dose levels commonly used for the treatment of schizophrenia. The only experiment with 12-month total treatment cost data found essentially equivalent costs for patients assigned to olanzapine or risperidone, showing that there are circumstances where total cost is similar in spite of the higher drug acquisition cost of olanzapine. Most retrospective studies also reported comparable total cost. Few studies gave enough information to evaluate cost effectiveness. The clear difference in acquisition cost of these two medications was rarely reflected in overall treatment cost in the studies we reviewed. Overall, our review of the literature highlights that there is inadequate evidence to distinguish the relative total cost of care associated with risperidone versus olanzapine, although accumulating evidence suggests the difference is small. This population-based conclusion does not indicate which medication is more costly or more cost effective for a particular patient; this depends on each patient's response to each medication.     

Spotlight on long-acting risperidone in schizophrenia

Long-acting risperidone (Risperdal Consta?) is a novel, intramuscular formulation of the atypical antipsychotic risperidone, which has shown efficacy in the treatment of patients with schizophrenia. Long-acting risperidone is pharmacokinetically equivalent to and causes less plasma drug concentration fluctuation than the oral formulation. This novel formulation is an aqueous suspension of microspheres comprising risperidone and a biodegradable copolymer. Significant release of risperidone from the microspheres begins 3 weeks after the first injection; thus, administration of another antipsychotic is necessary during this period only. Steady-state plasma concentrations are reached after the fourth injection. Elimination is complete 7–8 weeks after the last injection. Long-acting risperidone 25 or 50mg every 2 weeks demonstrated significantly greater antipsychotic efficacy than placebo and equivalent efficacy to oral risperidone 2–6 mg/day in two randomized, double-blind, double-dummy, 12-week trials of patients with schizophrenia. Additionally, in one of these trials, improvements in health-related quality of life (HRQOL) were superior with long-acting risperidone than placebo. Compared with baseline, improvements in the symptoms of schizophrenia in stable patients were significant with long-acting risperidone 25 or 50mg (12-month trial) and 25, 37.5 or 50mg (12-week trial) every 2 weeks, in two noncomparative, multicenter trials. Patient satisfaction with their medication and patient HRQOL mental health scores improved significantly in the 12-month trial. Long-acting risperidone is generally well tolerated, with a low incidence of injection site pain and an otherwise similar profile of adverse effects to the oral formulation. The overall incidence of extrapyramidal disorders in clinical trials was low (≤10%) with similar, yet minimal, changes in extrapyramidal symptom severity between patients treated with long-acting risperidone, oral risperidone or placebo. Tardive dyskinesia was reported in the 12-month trial, in 0.7% of patients. Conclusion: Long-acting risperidone is effective and generally well tolerated in patients with schizophrenia, including those patients with stable symptoms. Long-acting risperidone is the first atypical antipsychotic vailable in a formulation which offers a sustained, steady release of drug and is thus an attractive, new option in the treatment of patients with schizophrenia.     

Comparing tolerability of olanzapine in schizophrenia and affective disorders: a meta-analysis

Background: Olanzapine is prescribed for a number of psychiatric disorders, including schizophrenia, bipolar mania, and unipolar and bipolar depression. Olanzapine treatment is associated with tolerability issues such as metabolic adverse effects (e.g. weight gain, increase in blood glucose, triglycerides and total cholesterol levels), extrapyramidal symptoms [EPS] (e.g. parkinsonism, akathisia, tardive dyskinesia) and sedative adverse effects. Metabolic issues lead to some long-term consequences, which include cardiovascular diseases (CVD) and type 2 diabetes mellitus, and these complications cause high rates of mortality and morbidity among patients with severe mental illnesses. The expanded indications of olanzapine in psychiatry suggest a need to investigate whether there is a difference in the incidence and severity of adverse effects related to category diagnosis. Are the adverse effects expressed differently according to phenotype? Unfortunately, there are no reported studies that investigated these differences in adverse effects associated with olanzapine treatment in psychiatric patients with different phenotypes. Objective: The aim of the present meta-analysis is to separately examine olanzapine-induced cardiometabolic adverse effects and EPS in patients with schizophrenia and affective disorders. Data Sources: A search of computerized literature databases PsycINFO (1967-2010), PubMed (MEDLINE), EMBASE (1980-2010) and the clinicaltrials.gov website for randomized clinical trials was conducted. A manual search of reference lists of published review articles was carried out to gather further data. Study Selection: Randomized controlled trials were included in our study if (i) they assessed olanzapine adverse effects (metabolic or extrapyramidal) in adult patients with schizophrenia or affective disorders; and (ii) they administered oral olanzapine as monotherapy during study. Data Extraction: Two reviewers independently screened abstracts for choosing articles and one reviewer extracted relevant data on the basis of predetermined exclusion and inclusion criteria. It should be mentioned that for the affective disorders group we could only find articles related to bipolar disorder. Data Synthesis: Thirty-three studies (4831 patients) that address olanzapine monotherapy treatment of adults with schizophrenia or bipolar disorder were included in the analysis. The primary outcomes were metabolic adverse effects (changes in weight, blood glucose, low-density lipoprotein, total cholesterol and triglyceride levels). The secondary outcomes of our study were assessing the incidence of some EPS (parkinsonism, akathisia and use of antiparkinson medication). The tolerability outcomes were calculated separately for the schizophrenia and bipolar disorder groups and were combined in a meta-analysis. Tolerability outcomes show that olanzapine contributes to weight gain and elevates blood triglycerides, glucose and total cholesterol levels in both schizophrenia and bipolar disorder patients. However, olanzapine treatment produced significantly more weight gain in schizophrenia patients than in bipolar disorder patients. In addition, increases in blood glucose, total cholesterol and triglyceride levels were higher in the schizophrenia group compared with the bipolar disorder group, even though these differences were not statistically significant. Based on our results, the incidence of parkinsonism was significantly higher in the schizophrenia group than in the bipolar disorder group. Subgroup analysis and logistic regression were used to assess the influence of treatment duration, dose, industry sponsorship, age and sex ratio on tolerability outcome. Conclusions: Our results suggest that schizophrenia patients may be more vulnerable to olanzapine-induced weight gain. The findings may be explained by considering the fact that in addition to genetic disposition for metabolic syndrome in schizophrenia patients, they have an especially high incidence of lifestyle risk factors for CVD, such as poor diet, lack of exercise, stress and smoking. It might be that an antipsychotic induces severity of adverse effect according to the phenotype.     

Extended-release intramuscular paliperidone palmitate: a review of its use in the treatment of schizophrenia

Extended-release intramuscular paliperidone palmitate (Xeplion?; Invega? Sustenna?) [henceforth referred to as intramuscular paliperidone palmitate] is a long-acting injectable (LAI) formulation of the well established atypical antipsychotic agent paliperidone (9-hydroxyrisperidone), which is the major active metabolite of risperidone. This article reviews, from an EU perspective, the therapeutic efficacy and tolerability of intramuscular paliperidone palmitate in the treatment of adults with schizophrenia, and the pharmacology of paliperidone that is relevant to the intramuscular formulation. Intramuscular paliperidone palmitate 25-150 mg equivalents (mg eq.) effectively reduced symptoms of schizophrenia in most short-term (9-13 weeks) placebo-controlled trials, as demonstrated by improvements in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint that were significantly greater in intramuscular paliperidone palmitate than placebo recipients. The onset of clinical response was 8 days in patients who received the recommended initial 150 mg eq. dose of intramuscular paliperidone palmitate into the deltoid muscle on day 1. In a longer-term (24-week maintenance phase and variable length double-blind phase) placebo-controlled trial, intramuscular paliperidone palmitate was associated with a significantly longer time to relapse than placebo in patients with schizophrenia at a preplanned interim analysis conducted after 68 relapse events. Because of these favourable results, the study was terminated early. In two 13-week trials, one of which was conducted in Chinese patients, intramuscular paliperidone palmitate administered using the recommended initiation dosage regimen was noninferior to LAI-risperidone in patients with schizophrenia in terms of the between-group treatment difference (intramuscular paliperidone palmitate vs LAI-risperidone) for the mean change from baseline to endpoint in PANSS total score. The tolerability of intramuscular paliperidone palmitate was generally acceptable in clinical trials of schizophrenia. No new safety concerns were revealed compared with oral paliperidone, except for injection site-related reactions. In conclusion, intramuscular paliperidone palmitate is a useful option for the treatment of patients with schizophrenia.     

Olanzapine: an updated review of its use in the management of schizophrenia

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Sulpiride augmentation of olanzapine in the management of treatment-resistant chronic schizophrenia: evidence for improvement of mood symptomatology

Several recent studies, albeit limited in sample number, design and generalizability, have suggested that augmentation of atypical antipsychotic medication (such as clozapine and olanzapine) with sulpiride, a substituted benzamide antipsychotic medication, may play a role in the management of treatment-resistant psychotic conditions. The objective of this study was to investigate any change in clinical symptomatology or side-effect profile in treatment-resistant schizophrenia patients receiving sulpiride in addition to olanzapine. Seventeen patients with treatment-resistant chronic schizophrenia, who were receiving olanzapine monotherapy for at least 6 months before study commencement, were randomized in a 1:1 fashion to receive either adjunctive treatment with sulpiride (study group) or to continue their pre-study treatment with olanzapine with no medication augmentation (control group), each for a period of 8 weeks. Changes in measures of positive and negative symptoms, anxiety, depression and extrapyramidal symptoms were assessed at baseline and at 8 weeks. Study observations indicated no significant differences in the changes in positive or negative symptomatology between patients receiving a combined regimen of olanzapine with sulpiride (600 mg/ day) augmentation and controls. However, a significantly greater improvement of depressive symptomatology (P < 0.05; as assessed by the Hamilton Scale for Depression) was noted in the sulpiride augmentation group. These data indicate improvement in depressive symptomatology with sulpiride augmentation of olanzapine in treatment-resistant chronic schizophrenia patients.     

Ziprasidone: a review of its use in schizophrenia and schizoaffective disorder

Ziprasidone (Geodon, Zeldox) is an atypical antipsychotic agent with a unique neurotransmitter receptor-binding profile. The oral formulation is indicated for the treatment of adult patients with schizophrenia and the intramuscular formulation for the control of acute agitation in these patients. In adult patients with schizophrenia or schizoaffective disorder, oral ziprasidone was effective at a dosage of 40-80 mg twice daily in patients experiencing a phase of acute illness, and at a dosage of 20-80 mg twice daily in those with chronic schizophrenia or schizoaffective disorder, including those who were symptomatically stable. Ziprasidone offers the advantage over most other atypical antipsychotic agents of being available in a fast-acting intramuscular formulation for control of acute agitation, thus providing clinicians with the option to safely and effectively transition to longer-term treatment with the oral formulation. Although careful consideration should be given to the propensity for ziprasidone to cause corrected QT (QTc) interval prolongation, albeit at a relatively low incidence, the drug generally has a favourable tolerability profile of low extrapyramidal syndrome (EPS) liability, neutral bodyweight gain, and potentially low propensity for metabolic complications. Thus, ziprasidone is an effective option for the management of patients with schizophrenia or schizoaffective disorder, with the intramuscular formulation providing a useful option for the treatment of acute agitation in these patients.     

Efficacy and safety of novel antipsychotics: a critical review

Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.     

Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study

SOHO is a 3-year, prospective, observational study of schizophrenia patients who started a new antipsychotic in 10 European countries. Cohorts of patients were defined according to the antipsychotic started at baseline: olanzapine, risperidone, quetiapine, amisulpride, clozapine, oral typical and depot typical antipsychotics. Tolerability in terms of rates of extrapyramidal symptoms (EPS), tardive dyskinesia (TD), anticholinergic use, loss of libido/impotence, amenorrhoea/galactorrhoea/gynaecomastia, and weight change was assessed in 4939 patients who started monotherapy. Logistic regression models related medication initiated at study entry to adverse events over follow-up, adjusting by baseline differences among treatment cohorts. Patients taking typical antipsychotics or risperidone were more likely to experience EPS and TD during follow-up than patients taking olanzapine. Patients taking olanzapine were less likely to have loss of libido/impotence during follow-up than patients in the risperidone, amisulpride, clozapine, oral typical and depot typical cohorts. Weight gain occurred in all groups, but was greater with olanzapine. In conclusion, antipsychotics have different tolerability profiles in terms of the adverse events we monitored. Results should be interpreted conservatively due to the observational study design.     

Intramuscular aripiprazole : a review of its use in the management of agitation in schizophrenia and bipolar I disorder

An intramuscular formulation of the atypical antipsychotic aripiprazole (Abilify) has been developed and is approved in the EU for use in agitation and disturbed behaviour associated with schizophrenia. In the US, it is approved for the treatment of agitation associated with schizophrenia or bipolar I disorder (manic or mixed). In large, well designed trials, intramuscular aripiprazole was an effective and generally well tolerated treatment for agitation associated with schizophrenia, schizoaffective disorder, schizophreniform disorder or bipolar I disorder. Intramuscular aripiprazole was more effective than placebo in these patient populations and was noninferior to intramuscular haloperidol in those with agitation associated with schizophrenia and its related disorders. Aripiprazole is associated with a low risk for extrapyramidal symptoms (EPS), cardiac effects, hyperprolactinaemia, weight gain and other metabolic disturbances. Head-to-head trials comparing intramuscular aripiprazole with other intramuscular atypical antipsychotics are required before the relative position of each of these agents can be fully determined. In the meantime, intramuscular aripiprazole, with its favourable tolerability profile, is a valuable treatment option for agitation in patients with schizophrenia, schizoaffective disorder, schizophreniform disorder or bipolar I disorder.