Atypical Antipsychotic Olanzapine Research Articles

P.3.127 A randomised, double-blind clinical trial comparing treatment with amisulpride or risperidone for six weeks in elderly patients with schizophrenia

Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); ≥10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); ≥20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.

Generalization testing with atypical and typical antipsychotic drugs in rats trained to discriminate 5.0 mg/kg clozapine from vehicle in a two‐choice drug discrimination task

AbstractClozapine (CLZ) drug discrimination is used as a preclinical model to evaluate compounds for putative atypical antipsychotic properties. In rats, a 1.25 mg/kg CLZ training dose appears to have greater pharmacological specificity for atypical antipsychotic drugs than the traditional 5.0 mg/kg CLZ training dose; however, methodological differences among studies have precluded a direct comparison between these training doses. In the present study, rats were trained to discriminate a 5.0 mg/kg CLZ dose from vehicle in a two‐choice drug discrimination task using methods similar to those in a previous study from our laboratory that used a 1.25 mg/kg CLZ training dose. Clozapine produced full substitution (≥80% CLZ‐lever responding) for itself at the training dose (5.0 mg/kg). The atypical antipsychotics olanzapine, quetiapine, and ziprasidone also produced full substitution for 5.0 mg/kg CLZ, whereas the atypical antipsychotics risperidone and sertindole produced partial substitution (≥60% CLZ‐lever responding). The typical antipsychotic, thioridazine, produced full substitution for the 5.0 mg/kg CLZ training dose, but the typical antipsychotics chlorpromazine, fluphenazine, and haloperidol failed to substitute for clozapine. In a subgroup of 1.25 mg/kg CLZ‐trained rats, ziprasidone produced strong partial substitution (73.0 % CLZ‐lever responding) for the 1.25 mg/kg CLZ training dose. Based on these findings, some atypical antipsychotic drugs (i.e., quetiapine and ziprasidone) produce full substitution only for the 5.0 mg/kg CLZ training dose, whereas other atypical antipsychotic drugs (i.e., sertindole and risperidone) produce full substitution only for the 1.25 mg/kg CLZ training dose. Thus, both of these training doses are important for the screening of putative atypical antipsychotic drugs with the clozapine drug discrimination assay. Drug Dev. Res. 64:55–65, 2005. © 2005 Wiley‐Liss, Inc.

P.3.129 Aripiprazole for relapse prevention in bipolar disorder: a 26-week placebo-controlled study

Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); ≥10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); ≥20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.

The atypical antipsychotic agents zisprasidone, risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an unremitting, advancing disease of central nervous system white matter. PML is caused by infection of the JC polyoma virus, most always in patients with immunosupression due to, for example, cancer, anti-rejection transplant medications or HIV. There is no specific treatment or cure for PML, and untreated it has a median life expectancy is less than four months. Highly active antiretroviral treatment (HAART) has greatly reduced the incidence and prevalence of PML in HIV+ patients likely, however, even in the best case scenario of an HIV+ patient with PML and taking HAART, a significant mortality remains. Novel treatments for PML are needed. Recently Atwood and colleagues have found that the cellular receptor for JC virus is the serotonin 5HT2A receptor. In vitro they used the older antipsychotic medications chlorpromazine and clozapine to block the serotonin 5HT2A receptor and block JC virus cell entry. Unfortunately, however, chlorpromazine and clozapine have such significant side effects and toxicities, e.g., extrapyramidal symptoms and the possibility of bone marrow dyscrasias - that they may be problematic to use clinically. Here, we point out that some newer atypical antipsychotics such as zisprasidone, risperidone and olanzapine--medicines with much better side effect and toxicity profiles than the older antipsychotics--in vitro are significantly more potent 5HT2A receptor antagonists than chlorpromazine or clozapine by in some cases more than a factor of 10, and thus may be useful as treatment for or prophylaxis against PML.

Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats

Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model. The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug. Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED50 for suppression of jaw movements divided by the ED50 for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1-14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing. On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.

Selective prescribing of atypical antipsychotics

The aim of the study was to investigate whether the most recent introduced atypical antipsychotics olanzapine and risperidone were preferentially prescribed to patients susceptible to develop extrapyramidal side effects (EPS) and those not responding adequately to typical antipsychotics. Data were obtained from the Dutch PHARMO system that includes complete medication and hospital admission records of 675 000 residents of 14 Dutch cities. A total number of 129 new users of olanzapine and 142 new users of risperidone as well as 507 new users of typical antipsychotic drugs were identified from our database in the period of 1996-1998. The prevalence of markers of EPS, therapy resistance and therapy non-compliance were assessed in the period of 1 year prior to a new start of an antipsychotic. New use of olanzapine and risperidone was significantly associated with previous use of other antipsychotics (odds ratio 4.0, 95%CI: 2.5-6.7 and odds ratio 3.0, 95%CI: 2.0-4.7, respectively). New use of olanzapine and risperidone was also associated with previous use of anticholinergic drugs compared to users of typical antipsychotics (over three and two times more, respectively). This effect diminished when adjusted for previous use of antipsychotics. In particular olanzapine and also risperidone were selectively prescribed to patients formerly treated with other antipsychotics and to those susceptible for EPS. If not recognised or controlled for, observational studies comparing different antipsychotic drugs may produce biased results on efficacy or frequency of side effects for the different types of antipsychotics.

Effects of Changing From Typical to Atypical Antipsychotic Drugs on Subjective Sleep Quality in Patients With Schizophrenia in a Japanese Population

To investigate the effects of the atypical antipsychotic drugs risperidone, olanzapine, quetiapine, and perospirone on the subjective quality of sleep in patients with schizophrenia. Subjects were 92 inpatients (mean age = 59.9 years) who had been receiving treatment with conventional antipsychotic drugs and who met the DSM-IV criteria for schizophrenia. Subjects were randomly assigned to receive 1 of 4 atypical antipsychotic drugs (olanzapine, perospirone, quetiapine, and risperidone). Subjective sleep quality and psychopathology were assessed twice: at baseline and 8 weeks after switching. Data were collected from June 2001 to December 2001. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI), and psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS). Subjective sleep quality as assessed by the PSQI was significantly improved with administration of olanzapine, risperidone, or quetiapine, but not with perospirone, in comparison with conventional antipsychotic drugs. Multiple regression analysis revealed that the improvement of sleep quality with administration of atypical antipsychotic drugs was predicted by poor sleep quality at baseline. In addition, improvement of sleep quality was significantly correlated with improvement of negative symptoms as assessed by the PANSS. These results demonstrated that atypical antipsychotic drugs improved subjective quality of sleep in patients with schizophrenia compared with conventional antipsychotic drugs, suggesting that the marked potency of serotonin-2 receptor blockade in atypical antipsychotic drugs may be involved in the mechanism of this improvement. These improvements were correlated with improvement of negative symptoms.

EEG Abnormalities Under Treatment with Atypical Antipsychotics: Effects of Olanzapine and Amisulpride as Compared to Haloperidol

Abnormal EEG patterns are well known electrophysiological effects of treatment with antipsychotic drugs. To estimate the risk of EEG alterations including epileptiform activity under recently developed antipsychotics, we have analysed EEG recordings of all inpatients with schizophrenia medicated with atypical antipsychotics olanzapine or amisulpride in monotherapy, in comparison to a control group under haloperidol within a two-year period.

Olanzapine versus Flupenthixol in the Treatment of Inpatients with Schizophrenia: A Randomized Double-Blind Trial

The atypical antipsychotic olanzapine has extensively been compared with haloperidol, whereas studies vs. other (conventional) neuroleptics are scarce. This exploratory double-blind 4-week study was designed to compare the efficacy and the safety of olanzapine (OLA) and flupenthixol (FLU) which have recently been considered as a "partially atypical" antipsychotics. Twenty-eight inpatients with schizophrenia (DSM-IV) were randomly assigned for treatment with OLA (N = 15, 5-20 mg/d) or FLU (N = 13, 5-20 mg/d). The Brief Psychiatric Rating Scale (BPRS) and the Negative Symptoms Rating Scale (NSRS), plus the Patient Global Impression (PGI) and Clinical Global Impression (CGI) scales, were used to assess the efficacy of both compounds; safety was determined by using the Simpson Angus Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS) and by assessing treatment-emergent adverse events. Non-parametric statistics were applied. BPRS and NSRS scores improved in both groups (exploratory tests; all p < or = 0.02). Similar results were observed for CGI-Severity, CGI- and PGI-Improvement. There were no significant group differences. Responder rates (at least 40 % decrease in BPRS total) were 9/13 OLA patients (69 %) and 9/12 FLU patients (75 %). EPS events were reported only in the FLU group (p < 0.01); FLU patients needed significantly more anticholinergic medication. Weight gain was higher in OLA patients (p < 0.01). Overall, fewer patients with adverse events were observed in the OLA group (p = 0.04). No significant changes were noted on SAS and AIMS scores. Findings from this study suggest that overall and negative symptomatology improved in both treatment groups, while the safety and tolerability profiles differed for both substances.

Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat

There has been increasing evidence that atypical antipsychotics are effective in the treatment of mood disorders or for augmenting 5-hydroxytryptamine selective reuptake inhibitors for treatment-resistant depression. Upregulation of neurogenesis in the adult hippocampus is a marker of antidepressant activity, and the present study investigated the influence of the atypical antipsychotic drug olanzapine on cell proliferation in the hippocampus of adult rat. The regulation of cell proliferation in the prelimbic cortex of adult rat was also examined. Chronic (21 days) olanzapine administration increased the number of newborn cells in the dentate gyrus of the hippocampus to the same extent as fluoxetine. Olanzapine or fluoxetine treatment also increased the number of proliferating cells in the prelimbic cortex. In contrast, there was no effect of either drug in the subventricular zone or primary motor cortex, and there was a trend for an increase in the striatum. Subchronic (7 days) administration of olanzapine had no effect on cell proliferation in hippocampus or prelimbic cortex, consistent with the time course for the effect of fluoxetine and the therapeutic actions of antidepressant treatment. The combination of olanzapine plus fluoxetine did not result in a greater induction of cell proliferation in either brain region. Analysis of the cell phenotype demonstrated that approximately 20% of the newborn cells in the prelimbic cortex differentiated into endothelial cells but not neurons, in contrast to the dentate gyrus, where most newborn cells differentiated into neurons. The results demonstrate that antidepressant or atypical antipsychotic medications can increase the proliferation of glia in limbic brain structures, an effect that could reverse the loss of glia that has been observed in depressed patients.

Atypical antipsychotic medications for borderline personality disorder: What’s the story?

Atypical antipsychotic medications have been approved for treatment of schizophrenia and broad efficacy has led to trials for other illnesses. For borderline personality disorder (BPD), traditional antipsychotics had been demonstrated to reduce symptoms, but were not well tolerated. This paper reviews the new data emerging from trials assessing safety and efficacy of the atypical antipsychotic medications risperidone, olanzapine, and quetiapine (studies of ziprasidone and aripiprazole have not been published). To date, the results of studies with atypical antipsychotics have shown reduction of symptoms from across a broad number of domains. Also, early placebo-controlled trials show an advantage for these agents. Taken together, these new studies are pointing to a positive direction and offer hope for the treatment of BPD.

Understanding and Treating Schizophrenia: Contemporary Research, Theory, and Practice

Back to table of contents Previous article Next article Book ReviewsFull AccessUnderstanding and Treating Schizophrenia: Contemporary Research, Theory, and PracticeAnn Hackman, M.D.Ann HackmanSearch for more papers by this author, M.D.Published Online:1 Aug 2004https://doi.org/10.1176/appi.ps.55.8.952AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Understanding and Treating Schizophrenia: Contemporary Research, Theory, and Practice is described in its first paragraph as an effort to present a balanced critical overview of current research and theoretical perspectives on schizophrenia. In the preface, author Glenn D. Shean, Ph.D., compares the effort to describe schizophrenia by using a single modality of analysis to the attempts of the five proverbial blind men who encounter an elephant. Each man gives a description of only part of the elephant, which is correct but quite different from the description given by the others, and none are comprehensive. Dr. Shean, an extensively published research psychologist and professor of psychology at the College of William and Mary in Williamsburg, Virginia, holds that researchers often look at very different portions of the picture of schizophrenia and may describe only small pieces, sometimes providing information that is simply inaccurate. Dr. Shean goes on to say that this book is an effort to summarize the work and ideas of each group involved in the study and treatment of schizophrenia.Perhaps the topic is simply too big or the goal too lofty, or perhaps part of the problem is that I as a clinical psychiatrist see a somewhat different part of the picture. However, it seemed to me in reading this text that Dr. Shean has fallen into the very trap he describes in his preface. In my reading of the text I found that large areas were covered inadequately or almost not at all. The most significant of these is the pharmacologic treatment of schizophrenia. In a text of more than 300 pages, a scant dozen pages are devoted to antipsychotic medication and neurochemical theories—compared with more than 30 pages on cognitive and behavioral approaches and therapies. The atypical antipsychotics olanzapine, ziprasidone, and quetiapine are mentioned only in a single sentence, where they are described only as having been approved by the Food and Drug Administration. I saw nothing in the text about adjunctive medications or about issues surrounding medication adherence. Clearly Dr. Shean does not see medication as the primary treatment modality for schizophrenia; for example, he cites literature indicating that medications do not facilitate social recovery among persons with schizophrenia. He also notes repeatedly that there is a great deal more to the treatment of schizophrenia than medication. Although this is certainly a valid point, it still seems that pharmacologic treatment of this illness is a mainstay of our approach to schizophrenia and merits more than cursory mention in a text titled Understanding and Treating Schizophrenia. For example, discussion of the recommendations of the Schizophrenia Patient Outcomes Research Team (PORT) might have been helpful.Other areas that I felt were somewhat neglected include people with schizophrenia who have dual diagnoses, the consumer movement, and the recovery model. (Recovery is mentioned but not thoroughly discussed.) I thought the chapter called "Schizophrenia and the Family" seemed oddly skewed, with its focus on literature addressing the role of the family in the development of schizophrenia.Despite these criticisms, there is much to recommend about this book. It is well organized and contains useful summaries of each chapter. The first section, on "The development, evolution, epidemiology, and subsyndromes of schizophrenia," provides a very nice historical overview and an excellent discussion of the changes in diagnostic criteria over time; it also addresses the question of exactly what schizophrenia is and whether we are looking at one disorder or more than one. I found the section on psychodynamic theories to be interesting and informative from a historical perspective. Furthermore, Dr. Shean does a wonderful job of describing some of the nonpharmacologic approaches to schizophrenia, with an especially comprehensive chapter on cognitive-behavioral approaches and therapies.I recommend the book to mental health care providers of various disciplines who are interested in the history of our thinking on schizophrenia and in nonpharmacologic approaches to treatment of the illness. I would not recommend it for most individuals with schizophrenia or their families.Dr. Hackman is assistant professor of psychiatry, medical director of assertive community treatment, and associate director of psychiatry residency training at the University of Maryland in Baltimore.by Glenn D. Shean, Ph.D.; New York, Haworth Clinical Practice Press, 2004, 336 pages, $44.95 softcover FiguresReferencesCited byDetailsCited ByNone Volume 55Issue 8 August 2004Pages 952-953 Metrics PDF download History Published online 1 August 2004 Published in print 1 August 2004

Lower Mortality in Geriatric Patients Receiving Risperidone and Olanzapine Versus Haloperidol: Preliminary Analysis of Retrospective Data

<h3>Objective</h3> The authors examined the mortality rate in geriatric patients receiving either haloperidol or atypical antipsychotics. <h3>Methods</h3> Authors tracked mortality over a 2-year period in patients age 65 years or older receiving haloperidol (N=299) or the atypical antipsychotics risperidone or olanzapine (N= 1,254). <h3>Results</h3> Sixty-four patients in the haloperidol group (21.4%) and 61 patients in the atypical group (4.75%) died during the 2-year study period. The difference was statistically significant. <h3>Conclusions</h3> The findings suggest that mortality in elderly patients receiving haloperidol is significantly higher than in those receiving the atypical antipsychotics risperidone or olanzapine. Authors discuss possible causal mechanisms.

Advances in Therapeutic Drug Monitoring of Atypical Antipsychotic Drugs

The introduction in clinical practice of new antipsychotic drugs neurologically safer and with a broader spectrum of efficacy than “classical” neuroleptics has brought about significant improvement in the therapy of schizophrenic patients. These second-generation antipsychotics usually called “atypical” antipsychotics, have several therapeutical features in common, such as their effectiveness against the negative symptoms of schizophrenia and the advantage of not causing severe extrapyramidal symptoms and hyperprolactinemia. The therapeutic drug monitoring of patients treated with atypical antipsychotics is however, still advisable. In many cases, it can avoid the onset of side and toxic effects due to high plasma levels of the drug caused by overdose or interactions with other drugs. Furthermore, monitoring can significantly improve the patients compliance, thus leading to higher treatment efficacy. The pharmacological properties of the most widely used atypical antipsychotics (clozapine, olanzapine, risperidone and quetiapine) will be treated herein with particular attention paid to metabolism, side effects and pharmacokinetics. The analytical methods suitable for the therapeutical drug monitoring of these drugs will also be discussed, in terms of sensitivity, selectivity and usefulness in clinical settings. Other recent atypical agents (ziprasidone, aripiprazole, iloperidone, sertindole and zotepine) will be described as well.

Management of the atypical antipsychotic olanzapine (Zyprexa) in a clinical environment with particular regard to therapeutic drug monitoring (TDM) in a German state hospital

Management of the atypical antipsychotic olanzapine (Zyprexa) in a clinical environment with particular regard to therapeutic drug monitoring (TDM) in a German state hospital

Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain

Background The combination of the antidepressant fluoxetine (FLX) and the atypical antipsychotic olanzapine (OLA) appears to be more effective for the treatment of resistant depression than single drugs. We hypothesize that such combination may determine a specific modulation of neuroplastic genes, which could contribute to therapeutic activity. Methods We investigated the expression of the neurotrophic molecule basic fibroblast growth factor 2 (FGF-2) after acute or chronic administration of FLX and OLA, alone or in combination. Ribonuclease (RNase) protection assay and Western blot analysis were employed to determine FGF-2 expression in different brain structures and to identify the intracellular pathways possibly involved in FGF-2 modulation. Results After single injection, we found that FGF-2 mRNA levels were selectively upregulated in the prefrontal cortex only when the two drugs were coadministered, an effect paralleled by a significant increase of phosphorylated protein kinase B (P-Akt) levels. Conversely, chronic treatment with a combination of FLX and OLA (FLX+OLA) increased FGF-2 mRNA levels in prefrontal cortex, as well as in hippocampus and striatum. Conclusions Based on these data, we hypothesize a role of endogenously synthesized FGF-2 in the effects of FLX/OLA combination on brain function and plasticity, which could contribute to its superior efficacy for the treatment of resistant depression.

Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats.

Sexual dysfunction is a major, although poorly understood, side-effect of treatment with antipsychotic drugs. We have recently show marked disruption of reproductive function and weight gain in female rats treated subchronically with risperidone and haloperidol. The aim of the present study was to examine further the potential relationship between reproductive dysfunction and weight gain in female rats treated with olanzapine. The effects of olanzapine on weight gain, food and water intake, intra-abdominal fat, the oestrous cycle and uterine weight were assessed in group-housed adult female hooded-Lister rats. Olanzapine (0.5-4.0 mg/kg i.p.) or vehicle was administered once daily for 21 days and body weight, food and water intake measured, with histological examination of vaginal lavage to determine the stage of the oestrous cycle. On day 22, animals were sacrificed and intra-abdominal fat, wet and dry uterine weights measured. Olanzapine induced significant weight gain with concomitant increases in food and water intake and intra-abdominal fat without an effect on the oestrous cycle, wet and dry uterine weights or plasma prolactin levels. These results confirm the ability of olanzapine to induce weight gain in female rats on unrestricted normal diet with a concomitant increase in food and water intake and increased intra-abdominal fat. These effects of olanzapine were produced in the absence of any apparent impairment in reproductive function, in contrast to the substantial disruption of oestrous and uterine atrophy previously shown in rats treated with risperidone and haloperidol.

Effect of switching to atypical antipsychotics on memory in patients with chronic schizophrenia

While the usefulness of atypical antipsychotics for improving cognitive function has been proven, the specific effects of these drugs are still unknown. The objective of this study was to investigate changes of the immediate memory and verbal working memory in patients with chronic schizophrenia after switching to one of four atypical antipsychotic agents and cessation of anticholinergic therapy. The subjects included 77 schizophrenic patients who were treated primarily with typical antipsychotics. Treatment was randomly switched to one of four atypical antipsychotics (olanzapine, perospirone, quetiapine, or risperidone) over a 4-week period, and then the drug was continued for another 4 weeks while the patient was taken off anticholinergics. The immediate memory, verbal working memory, and symptoms were evaluated. Significant improvement of immediate memory was only seen with olanzapine and risperidone. Improvement was also seen after switching to perospirone, but immediate memory worsened after treatment with this anticholinergic drug was discontinued. Deterioration was seen after switching to quetiapine, but immediate memory improved and reached the previous level after treatment with anticholinergic drugs was discontinued. Significant improvement of the verbal working memory was only seen during risperidone administration. The findings suggested that switching chronic schizophrenic patients to atypical antipsychotics can improve both the immediate memory and the verbal working memory when risperidone is used, while improvement of immediate memory can be expected with olanzapine. From the viewpoint of improving the memory, quetiapine should not be administered concomitantly with anticholinergic drugs, and caution should be exercised when discontinuing anticholinergic drugs during treatment with perospirone.

Cognitive function and depression in symptom resolution in schizophrenia patients treated with an atypical antipsychotic

Objective. To investigate which cognitive and affective features contribute most to responder/non-responder group separation during a switching trial with atypical antipsychotic. Design. A prospective open trial with an atypical antipsychotic (olanzapine). Patients. One hundred and thirty-four patients meeting diagnostic criteria for schizophrenia, schizophreniform or schizoaffective disorder began an 8-week open-label olanzapine treatment at a dose of 5 mg/day which was increased to 10 mg/day after one week. Interventions. Olanzapine during 8 weeks. Patients were considered as responders if their BPRS score decreased of at least 20% ( n=96) and non-responders if it did not ( n=38). Neuropsychological assessments were carried out at baseline, at four and at eight weeks. Results. Neurocognitive measures were analyzed for discriminate factors between responder and non-responder groups. A regression analysis was applied to explain the effects of depression on each cognitive variable. Depression was found to be a weak discriminant factor, however this finding could not firmly establish that depression is a potential factor in explaining deficits and improvements in cognition.

Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain

Background The combination of the antidepressant fluoxetine (FLX) and the atypical antipsychotic olanzapine (OLA) appears to be more effective for the treatment of resistant depression than single drugs. We hypothesize that such combination may determine a specific modulation of neuroplastic genes, which could contribute to therapeutic activity. Methods We investigated the expression of the neurotrophic molecule basic fibroblast growth factor 2 (FGF-2) after acute or chronic administration of FLX and OLA, alone or in combination. Ribonuclease (RNase) protection assay and Western blot analysis were employed to determine FGF-2 expression in different brain structures and to identify the intracellular pathways possibly involved in FGF-2 modulation. Results After single injection, we found that FGF-2 mRNA levels were selectively upregulated in the prefrontal cortex only when the two drugs were coadministered, an effect paralleled by a significant increase of phosphorylated protein kinase B (P-Akt) levels. Conversely, chronic treatment with a combination of FLX and OLA (FLX+OLA) increased FGF-2 mRNA levels in prefrontal cortex, as well as in hippocampus and striatum. Conclusions Based on these data, we hypothesize a role of endogenously synthesized FGF-2 in the effects of FLX/OLA combination on brain function and plasticity, which could contribute to its superior efficacy for the treatment of resistant depression.