Negative Symptom Response Research Articles

Serotonin transporter polymorphisms and early response to antipsychotic treatment in first episode of psychosis

There is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Variations in several serotonin transporter ( 5-HTT) gene polymorphisms have been associated with antipsychotic response among chronic patients with schizophrenia, although their implication in early response among first-episode patients remains unclear. Two polymorphisms in the 5-HTT gene (a 44 bp insertion/deletion in the promoter region and the functional polymorphism rs25531) were genotyped in a sample of 147 drug-naïve patients experiencing a first episode of a non-affective psychosis. Early (6 weeks) response to antipsychotic treatment with haloperidol, olanzapine or risperidone was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. No clear association was found between the rs25531 variant and treatment response. However, significant associations were observed between 5-HTT-LPR variants and early negative symptom response among first-episode patients with psychosis. Our results suggest a minor contribution to antipsychotic drug response of genetic alterations in the 5-HTT gene.

S35-02 - Pharmacogenetic studies of treatment response in first-episode psychosis

IntroductionAntipsychotic drugs are limited in their efficacy by the relatively poor response of negative and cognitive symptoms of schizophrenia as well as by the substantial variability in response between patients. Although there is a substantial number of pharmacogenetic studies of antipsychotic drug response, relatively few have studied response in first-episode patients. Still fewer have separated effects on positive and negative symptoms, despite the established differences in response to drug treatment between these syndromes.ObjectivesTo identify genetic polymorphisms contributing to individual variability in the response of different symptoms to antipsychotic drug treatment of first-episode psychosis.MethodsFunctional polymorphisms in several candidate genes implicated in antipsychotic drug mechanisms have been investigated in first-episode psychosis patients and assessed for their association with response of different symptom subgroups.ResultsWe have identified the importance of a common functional polymorphism in the 5-HT1A receptor gene on response of negative and depressive symptoms in initially drug-naive psychotic patients; a longer term (one year) study of first-episode subjects demonstrated an association of the 5-HT transporter gene on negative symptom outcome. Despite the discrepancy between these and other reports, most findings are consistent with the conclusion that dopamine D2 and D3 receptor polymorphisms appear to relate to positive symptom response, while negative symptom improvement relates to polymorphisms of genes influencing 5-HT neurotransmission.ConclusionsIdentifying the genetic factors influencing initial symptom response to antipsychotic drugs may provide both an understanding of the underlying neurotransmitter mechanisms and an indication of the clinical utility of genetic testing.

NPs Should Develop Greater Skills in Dealing with the Mentally Ill

I recently sat at the bedside of a young man who was lost in the black corridors of deep depression. His recalcitrant depression failed to respond to any therapy and made it impossible to work and distanced him from friends and family. He felt alienated and isolated and abandoned from all forms of support, including a cumbersome health care system and providers whose compassion could not be accessed because it was curbed by bureaucracy. Nurse practitioners (NPs) working in primary care have seen glimpses of these conditions in many of their patients. A serious mental illness is reported to affect 6.3% of all U.S. adults. According to the 1999 World Health Organization global burden of disease study, severe mental illnesses (bipolar disorder, schizophrenia, severe major depression, and others) collectively account for more than 15% of the overall burden of disease from all causes. This same report finds that major depression is the leading cause of disability worldwide among persons 5 years and older. These serious mental health problems take a significant toll on individuals, families, and society. Depression and other mental illnesses also negatively impact the economy due to diminished productivity and increased use of health care resources. Society and government have failed to adequately address these problems and these vulnerable patients remain suffering and at risk, many times on the extreme margins of the health care system itself. Both psychotherapy and pharmacotherapy are critical to the treatment of serious mental illness. Pharmacotherapy in some patients shows efficacy in treating positive psychotic symptoms (delusions, hallucinations, disorganized thinking, and catatonic behavior). Drugs may also improve, to a limited extent, negative symptoms (alogia, affective blunting, anhedonia, amotivation, and attentional impairment) and reduce the risk of relapses and hospitalizations. But there are limitations to drug treatment, and there are no perfect drugs. Adverse effects are associated with a poor treatment response of negative and cognitive symptoms, with high nonadherence rates and inadequate functional improvement. Partial adherence and nonadherence are very common in serious mental illness and are associated with relapses and hospitalizations. Medication nonadherence rates may be as high as 60%. Even with adequate drug therapy, roughly 30% of individuals with positive psychotic symptoms respond partially or not at all, and negative symptoms and cognitive symptoms often do not adequately respond to pharmacotherapy. Additionally, symptomatic improvement may not mean functional improvement. Even worse, patients with serious mental illness have a lowered life expectancy and often die about 9 years earlier compared to the general population because of higher medical comorbidity, increased risk of suicide, toxicity from psychotropic medications, and other factors. Vagaries in our reimbursement system make it difficult for patients who have urgent mental health problems to see primary care providers and mental health providers on the same day. Thus, integration of more mental health diagnosis and treatment skills into primary care services is essential. To this end, we hope that this issue of JNP, with its focus on mental health issues, will stimulate NPs to develop greater knowledge and skills to help meet these desperate challenges.

Antipsychotics in the early stage of development

In this article, we will summarize some of the most recent pharmacological approaches by briefly reviewing the latest research results related to different neurotransmitter receptor systems but also alternative approaches that do not affect central nervous system receptors directly. Although the field still struggles with the lack of major breakthroughs, some novel pharmacological leads have provided encouraging findings in proof of concept or early phase II clinical trials. Although some of these approaches are based on the modified dopamine/glutamate hypothesis of schizophrenia, others appear to have been driven by more serendipitous observations. Apart from this, more traditional routes such as compounds targeting D2/HT2 receptors are also still being pursued. Attempts to advance treatment response of negative symptoms and cognitive impairment, two areas of considerable unmet need have been an overriding theme in many studies. Clinical psychopharmacologists increasingly realize that it is highly unlikely that we have a magic bullet to treat adequately all aspects of this complex disorder in the foreseeable future. Rational polypharmacy may be the trend for the next decade.

Table of Contents

AbstractEquivalent Clinical Response to Mirtazapine and SSRIs for DepressionQuestions Remain About Use of Newer Antipsychotics in Pediatric PopulationEffect of Variance in Drug Transporter on Risperidone ConcentrationN‐Acetyl Cysteine for Depressive Symptoms in Bipolar DisorderQuetiapine Addition to SRI not Effective for OCDThe 5‐HT1A Receptor Gene and Negative Symptom Response to RisperidoneAripiprazole‐Induced Hypersexuality in Schizoaffective DisorderRecall: Dextroamphetamine Sulfate 5 mg TabletsNew Injection Site for Risperdal ConstaFDA Warning Letters

SEROTONIN TRANSPORTER POLYMORPHISMS AND EARLY RESPONSE TO ANTIPSYCHOTIC TREATMENT IN FIRST-EPISODE OF PSYCHOSIS

article i nfo There is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Variations in several serotonin transporter (5-HTT) gene polymorphisms have been associated with antipsychotic response among chronic patients with schizophrenia, although their implication in early response among first-episode patients remains unclear. Two polymorphisms in the 5- HTTgene (a 44 bp insertion/deletion in the promoter region and the functional polymorphism rs25531) were genotyped in a sample of 147 drug-naive patients experiencing a first episode of a non-affective psychosis. Early (6 weeks) response to antipsychotic treatment with haloperidol, olanzapine or risperidone was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. No clear association was found between the rs25531 variant and treatment response. However, significant associations were observed between 5-HTT-LPR variants and early negative symptom response among first-episode patients with psychosis. Our results suggest a minor contribution to antipsychotic drug response of genetic alterations in the 5-HTT gene.

The —1019 C/G polymorphism of the 5-HT1A receptor gene is associated with negative symptom response to risperidone treatment in schizophrenia patients

The application of pharmacogenetics is currently one of the most promising developments in anti-psychotic treatment and is attracting more and more attention. Although risperidone belongs to the first-line atypical anti-psychotics, there have been relatively few risperidone pharmacogenetic studies, especially in Asian populations. We investigated the relationship between the C825T polymorphism of GBN3 (rs5443) and the -1019 C/G polymorphism of 5-HT(1)A (rs6295) and response to risperidone treatment. One-hundred and thirty schizophrenia patients were recruited. They were treated with risperidone monotherapy for eight weeks. Clinical response was assessed on the Positive and Negative Syndrome Scale (PANSS) on the day of admission and was subsequently assessed after eight weeks following the treatment. Patients were genotyped for two functional polymorphisms: C825T of GBN3 (rs5443) and -1019 C/G of HT(1)A (rs6295). Association tests between genotypes and percentage improvement in total PANSS scores, as well as positive symptom scores and negative symptom scores, were performed using analyses of variance (ANOVA). The -1019 C/G polymorphism of HT(1)A (rs6295) was associated with negative symptom response to treatment. Patients with the CC genotype showed substantial improvement as regards negative symptom response (F = 4.177, df = 2, P = 0.019), compared with the patients with the CG and GG genotypes. No association was observed between C825T of GBN3 (rs5443) and changes in PANSS scores. The results suggest that the -1019 C/G polymorphism (rs6295) in the 5-HT(1)A gene may be a useful predictor of reduction in negative symptoms in schizophrenic patients treated with risperidone.

Homer 1 and metabotropic glutamate-receptor 5 polymorphisms are associated with response to treatment in schizophrenic patients

A hypofunction of glutamatergic NMDA-currents is discussed as pathophysiologic correlative of symptoms in schizophrenia. Polymorphisms within metabotropic glutamate receptors (mGluRs) were found to be associated with schizophrenia. The Homer proteins are part of the postsynaptic density in glutamatergic neurons and bind to mGluR 5 receptors. We investigated ten SNPs in the mGlu5 receptor and five SNPs in the Homer gene and their relationships to response in therapy. We genotyped 212 schizophrenic patients, who were treated with atypical antipsychotics. Psychopathology was measured weekly using the PANSS for a minimum of six weeks. 412 healthy subjects served as controls for allele distribution. The homocygote TT-allele carriers of the SNP rs979763 (T/C) of the mGlu5 receptor showed a statistically significant reduction in PANSS-negative and –global scales in comparison to the combined TC/CC-allele carriers. The combined GG/GT allele carriers of the SNP rs1993842 (G/T)of the mGlu5 receptor displayed almost no reduction in PANSS-negative scores compared to the TT homozygotes which was statistically significant. The homozygote AA allele carriers of SNP rs10039490 of the Homer-1 gene had a significantly more pronounced reduction in PANSS-positive and -global scores. This is the first study which shows an association between therapy response of negative symptoms in schizophrenia and the mGlu5 receptor gene and positive symptoms and the Homer-1 gene.

Effect of 5-HT 1A Receptor Gene Polymorphism on Negative and Depressive Symptom Response to Antipsychotic Treatment of Drug-Naive Psychotic Patients

The serotonin 5-HT(1A) receptor may modulate some of the negative, cognitive, and affective symptoms of schizophrenia and is a potential target of action of some antipsychotic drugs. A functional polymorphism in the promoter region of the 5-HT(1A) receptor gene is associated with depression and suicidal behavior. The authors sought to determine whether this polymorphism influences symptom response to antipsychotic drug treatment. Sixty-three drug-naive patients with first-episode psychosis who were genotyped for the -1019C/G polymorphism were recruited for this study and received standard care. The Positive and Negative Syndrome Scale and the Calgary Depression Scale were used to monitor symptom changes over 3 months. The polymorphism was associated with, and accounted for much of the variance in, changes in negative and depressive symptoms but not positive symptoms. These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.

Dopamine D2 receptor gene variants and quantitative measures of positive and negative symptom response following clozapine treatment

Objective: Explore relationships between 12 dopamine D2 gene variants and quantitative measures of positive and negative symptom response following clozapine treatment in two treatment refractory or intolerant populations (Caucasian and African-American). Experimental procedures: Subjects included 97 Caucasian and 35 African-American DSM-III-R or DSM-IV schizophrenics and were genotyped by 5′-exonuclease fluorescence assays. Genotype, allele +/− and haplotype groups were compared on Brief Psychiatric Rating Scale (BPRS) overall, positive (BPOS) and negative symptom subscales (BNEG) using analysis of variance. Results: In Caucasians, no significant associations were found for any individual polymorphisms or haplotypes. In African-Americans, the TaqIB B2 (T) allele and rs1125394 allele 1 (A), and a two-marker haplotype containing these two alleles were associated with improvement in overall BPRS and BPOS response. Conclusions: Variability in clozapine response is still not fully understood and likely involves multiple factors. This study suggests that D2 receptor gene variants may be among such factors.

A six-month, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients

D-Cycloserine, a partial agonist at the glycine site of the N-methyl-D-aspartate receptor, has demonstrated inconsistent efficacy for negative and cognitive symptoms of schizophrenia. The strongest evidence for efficacy has come from studies using D-cycloserine at a dose of 50 mg/day added to conventional antipsychotics in trials of 8 weeks duration or less. To assess the efficacy for negative symptoms and cognitive impairment of D-cycloserine augmentation of conventional antipsychotics in a 6-month trial. Fifty-five schizophrenia patients with prominent negative symptoms, treated with conventional antipsychotics, were randomly assigned to treatment with D-cycloserine 50 mg/day or placebo for 6 months in a double-blind, parallel group design. Twenty-six subjects completed the 6-month trial; drop-out rates did not differ between treatment groups. D-Cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks, including response of negative symptoms and performance on a cognitive battery. Serum D-cycloserine concentrations did not correlate with response of negative symptoms. D-Cycloserine did not exhibit therapeutic effects in this trial, possibly reflecting the high drop-out rate, a narrow range of therapeutic serum concentrations, a modest magnitude of therapeutic effect for the selected outcome measures, or loss of efficacy over time. Because D-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and D-serine.

Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response

We have been studying the pharmacogenetic correlates of side effects and early response to antipsychotic treatment in a series of Chinese Han first-episode drug-naïve patients with schizophrenia. Here, we report the association of three functional polymorphisms of receptor genes on initial symptom severity and outcome in these patients. We studied the dopamine D3 receptor ser9gly, the dopamine D2 receptor Taq IA and the 5-HT2C receptor promoter −759C/T polymorphisms in 117 patients who had symptoms assessed by Positive and Negative Syndrome Scale (PANSS) on admission and following 10-week antipsychotic treatment, primarily with risperidone or chlorpromazine. The D2 polymorphism was found not to be significantly associated with baseline levels or changes in total PANSS in these patients. The D3 genotype is associated with the change in total PANSS ( p<0.01), an effect reflecting positive and general (each p<0.01) but not negative symptom improvement. However, symptom improvement at 10 weeks strongly correlates with total PANSS score on admission, in which the greater improvement is seen with the more severe initial symptom score. The D3 genotype is also related to severity on admission, i.e. to total baseline PANSS ( p<0.05), including baseline PANSS score as a covariate, the association of the genotype to change over 10 weeks remains significant for total PANSS ( p<0.05) and for positive and general, but not negative, symptom scores. The 5-HT2C promoter polymorphism was also associated with improvement in PANSS ( p<0.05), but reflecting effects on negative and general, but not positive, symptom scores. This polymorphism was not associated with PANSS score on admission, although after controlling for the effect of this parameter on 10-week outcome, a stronger association with change in total PANSS ( p<0.01) was apparent, again reflecting improvements in negative and general symptoms but not changes in positive symptoms.

Receptor mechanisms in the treatment of schizophrenia.

There remain many limitations to the treatment of schizophrenia. In addition to the poor response of negative and cognitive symptoms to antipsychotics, and the substantial proportion of poor- or non-responders, there are a variety of unpleasant and restricting side-effects of these drugs. The introduction of several 'atypical' drugs, with diminished propensity to cause extrapyramidal motor effects (EPS), has greatly improved the tolerability of antipsychotic treatments. The pharmacology of atypical antipsychotics is varied and, although dopamine D2 receptor antagonism is common to all antipsychotics, the mechanisms of a typicality are complex and not fully understood. Thus, antagonism at 5-HT2 and/or other receptors, weak dopamine receptor affinity and, most recently, partial agonism at dopamine D2 receptors, have been variously implicated. However, because EPS have diminished with improvements in drug treatment, drug-induced weight gain has emerged as a major concern, and the pharmacological basis of this problem, involving effects at 5-HT2c and perhaps other receptors, is yielding to investigation. Some drugs, notably the D2 partial agonists, can provide antipsychotic effects without the emergence of several of the seproblematic side-effects, which bodes well for future treatment.

Negative symptom and cognitive deficit treatment response in schizophrenia. Richard S. E. Keefe and Joseph P. McEvoy. American Psychiatric Press, Inc., Washington, DC, 2001. Pages: 201. Price: $42.50

<i>Negative symptom and cognitive deficit treatment response in schizophrenia</i>. Richard S. E. Keefe and Joseph P. McEvoy. American Psychiatric Press, Inc., Washington, DC, 2001. Pages: 201. Price: $42.50

The onset and time course of response of negative symptoms to add-on fluvoxamine treatment

Not enough is known about the propensity of individual negative symptoms to respond to treatment and the dynamics of this change. We have previously shown that adding the selective serotonin reuptake inhibitor fluvoxamine to antipsychotics can improve negative symptoms, and now provide data on the response of individual negative symptoms to such treatment. We examined items on the Schedule for the Assessment of Negative Symptoms for patients participating in two published controlled studies comparing the effect of add-on fluvoxamine and placebo on negative symptoms. Using a mixed regression model, we analysed item scores at each week of the study to identify the first signs of a treatment effect. Potential confounding effects of depressive extrapyramidal and positive symptoms were statistically controlled. Eleven of 16 items tested showed improvement, five within 2 weeks and a further four within 3 weeks of starting treatment. The most rapidly responding items included core negative symptoms such as alogia. The propensity for and rate of improvement with fluvoxamine treatment differs for the various negative symptoms. Many symptoms, including those generally agreed to be core features of the illness such as alogia, improved within 2-3 weeks of treatment initiation.

Add-on fluvoxamine improves primary negative symptoms: evidence for specificity from response analysis of individual symptoms.

Establishing that treatment for negative symptoms improves primary features of schizophrenia rather than similar symptoms of other etiology is an important clinical issue. Primary negative symptoms may also differ among themselves in the propensity to respond to a given treatment. In this study, we examined the response of negative symptoms to add-on fluvoxamine by analyzing discrete symptoms independently and controlling for potential confounding variables. Data from two published controlled studies comparing fluvoxamine to placebo were pooled for the analysis. Eleven of sixteen Scale for the Assessment of Negative Symptoms items tested, including key negative symptoms such as affective flattening and alogia, improved. The improvement was not related to baseline levels of depressive, extrapyramidal, and positive symptoms or to changes in the symptom scores during the study. The findings support the view that fluvoxamine augmentation can improve primary negative symptoms in chronic schizophrenia patients.

Fluvoxamine Augmentation of Olanzapine in Chronic Schizophrenia: Pharmacokinetic Interactions and Clinical Effects

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.

Negative Symptom and Cognitive Deficit Treatment Response in Schizophrenia

Back to table of contents Previous article Next article Book Forum: The Schizophrenia SpectrumFull AccessNegative Symptom and Cognitive Deficit Treatment Response in SchizophreniaMARC-ANDRÉ ROY, M.D., M.SC., F.R.C.P., MARC-ANDRÉ ROYSearch for more papers by this author, M.D., M.SC., F.R.C.P., Beauport, Que., CanadaPublished Online:1 Apr 2002https://doi.org/10.1176/appi.ajp.159.4.683AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail This is a timely collection of review papers by some of the leading researchers in the field of negative symptoms and cognitive impairments, who summarize this literature as it applies to treatment trials. Although the papers were written independently, they reflect a sometimes controversial ongoing dialogue, which makes this book lively reading. Rather than simply reviewing available evidence on the treatment of negative symptoms and cognitive impairment, the chapter authors focus on core methodological and conceptual issues that have been addressed incompletely so far, not only providing the reader with a good grasp of current knowledge but also pointing correctly toward limitations in current evidence.This book clearly emphasizes negative symptoms. Several points of consensus emerge regarding the need for additional studies specifically designed to address their treatment response, given the traditional emphasis on positive symptoms in therapeutic trials. Indeed, convincing arguments are made for the need for longer duration of trials, longer washout duration, and sampling specific populations with predominantly negative symptoms. This book also reflects the disagreements on how direct effects on negative symptoms should be differentiated from indirect improvements of negative symptoms mediated by reduction in psychoses, improvement in extrapyramidal symptoms, or other indirect mechanisms. Indeed, although Buchanan and Carpenter call for studies including patients with deficit/primary negative symptoms, others point toward difficulties in distinguishing primary and secondary negative symptoms and in recruiting a sufficient number of such patients. The latter argue for the use of statistical techniques to disentangle direct versus indirect effects. The authors on both sides, who are probably the best suited to defend these opinions, present their positions very thoroughly, which provides an interesting debate that calls for the readers’ critical sense.Other very pertinent original contributions in this book include a chapter devoted to the perspective of the family, which is often overlooked. Another, coauthored by Limpert and Amador, provides a very insightful review of the literature on the subjective experience of negative symptoms. Hence, this book provides an in-depth overview of research on negative symptoms and its clinical implications. However, it would have been even more complete had it included a chapter providing clinical guidelines on the distinction between primary and secondary negative symptoms and had the literature on psychosocial treatment for negative symptoms been reviewed.Concerning cognitive deficits, I would say that the title of the book is a little misleading, since this issue is provided much less emphasis than are negative symptoms. However, the chapter by Keefe on the assessment of neurocognitive treatment response is particularly interesting and provides, for example, a much-needed discussion on dosing issues, which tend to be somewhat overlooked when interpreting evidence on the impact of neuroleptics on cognition.Overall, this book provides a thorough overview on the research regarding the treatment of negative symptoms (and, to a lesser extent, cognitive performance), making this complex literature much more understandable. The book should appeal to a broad readership, ranging from clinicians treating people suffering from schizophrenia to researchers in the field of negative symptoms and cognitive impairments.Edited by Richard S.E. Keefe, Ph.D., and Joseph P. McEvoy, M.D. Washington, D.C., American Psychiatric Press, 2001, 216 pp., $37.00. FiguresReferencesCited byDetailsCited ByNone Volume 159Issue 4 April 2002Pages 683-683 Metrics PDF download History Published online 1 April 2002 Published in print 1 April 2002

Spotlight on ziprasidone in schizophrenia and schizoaffective disorder.

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin levels. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.

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

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily, at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin concentrations. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.