Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice.

RATIONALE: The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice. OBJECTIVES: We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice. METHODS: Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured. RESULTS: Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors. CONCLUSIONS: Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.

An in vivo zebrafish screen identifies organophosphate antidotes with diverse mechanisms of action.

Organophosphates are a class of highly toxic chemicals that includes many pesticides and chemical weapons. Exposure to organophosphates, either through accidents or acts of terrorism, poses a significant risk to human health and safety. Existing antidotes, in use for over 50 years, have modest efficacy and undesirable toxicities. Therefore, discovering new organophosphate antidotes is a high priority. Early life stage zebrafish exposed to organophosphates exhibit several phenotypes that parallel the human response to organophosphates, including behavioral deficits, paralysis, and eventual death. Here, we have developed a high-throughput zebrafish screen in a 96-well plate format to find new antidotes that counteract organophosphate-induced lethality. In a pilot screen of 1200 known drugs, we identified 16 compounds that suppress organophosphate toxicity in zebrafish. Several in vitro assays coupled with liquid chromatography/tandem mass spectrometry-based metabolite profiling enabled determination of mechanisms of action for several of the antidotes, including reversible acetylcholinesterase inhibition, cholinergic receptor antagonism, and inhibition of bioactivation. Therefore, the in vivo screen is capable of discovering organophosphate antidotes that intervene in distinct pathways. These findings suggest that zebrafish screens might be a broadly applicable approach for discovering compounds that counteract the toxic effects of accidental or malicious poisonous exposures.

Galantamine improves apomorphine-induced deficits in prepulse inhibition via muscarinic ACh receptors in mice.

BACKGROUND AND PURPOSE: Galantamine, a weak acetylcholine esterase (AChE) inhibitor and allosteric potentiator of nicotinic ACh receptors (nAChRs), improves apomorphine-induced deficits in prepulse inhibition (PPI), sensory information-processing deficits, via a nAChR-independent mechanism. The present study examined the role of muscarinic ACh receptors (mAChRs) in the effect of galantamine, and studied the mechanism of galantamine-induced increases in prefrontal ACh levels in mice. EXPERIMENTAL APPROACH: Apomorphine (1 mg kg(-1)) was administered to male ddY mice (9-10 weeks old) to create a PPI deficit model. Extracellular ACh concentrations in the prefrontal cortex were measured by in vivo microdialysis. KEY RESULTS: Galantamine- and donepezil-mediated improvements in apomorphine-induced PPI deficits were blocked by the preferential M(1) mAChR antagonist telenzepine. The mAChR agonist oxotremorine also improved apomorphine-induced PPI deficits. Galantamine, like donepezil, increased extracellular ACh concentrations in the prefrontal cortex. Galantamine-induced increases in prefrontal ACh levels were partially blocked by the dopamine D(1) receptor antagonist SCH23390, but not by antagonists of mAChRs (telenzepine) and nAChRs (mecamylamine). Galantamine increased dopamine, but not 5-HT, release in the prefrontal cortex. CONCLUSIONS AND IMPLICATIONS: Galantamine improves apomorphine-induced PPI deficits by stimulating mAChRs through increasing brain ACh levels via a dopamine D(1) receptor-dependent mechanism and AChE inhibition.

High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia.

BACKGROUND: Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine. In this study, we assessed whether high-dose glycine may also be therapeutically beneficial when added to olanzapine and risperidone treatment. METHODS: Seventeen olanzapine- or risperidone-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover treatment trial with.8 g/kg/day glycine added to their ongoing antipsychotic medication. Clinical assessments were performed biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. RESULTS: Glycine treatment was well tolerated and resulted in a significant (p <.0001) 23% +/- 8% reduction in negative symptoms. Significant improvements were also registered in cognitive and positive symptoms. The negative symptoms improvement remained significant even following covariation for changes in other symptom clusters and extrapyramidal side effects. High posttreatment glycine serum levels significantly predicted (r =.60) clinical response. CONCLUSIONS: These findings indicate that the efficacy of olanzapine and risperidone may be augmented using high-dose adjuvant glycine treatment and suggest that these atypical antipsychotics may affect NMDA receptor-mediated neurotransmission differently than clozapine.

Schizophrenia and Parkinson's disease lead to equal motor-related changes in cortical and subcortical brain activation: an fMRI fingertapping study.

In schizophrenia and Parkinson's disease, cortical and subcortical motor organization is influenced by primary disease conditions and neuroleptic treatment. Using functional magnetic resonance imaging patients with schizophrenia were compared, according to Diagnostic and Statistical Manual of Mental Disorders (4th edn), under stable treatment with olanzapine (n = 7; OL) or haloperidol (n = 7; HA) to healthy controls (n = 7; HC), patients with schizophrenia without any neuroleptic treatment (n = 7; UN) and to patients with left (n = 7; LHP)- and right (n = 7; RHP)-sided hemiparkinsonism. All subjects performed a unilateral left-handed fingertapping task. All groups had significant activation in the contralateral motor cortex and the putamen (P < 0.001). Different activation patterns between groups within cortical and subcortical regions of interest were revealed. In particular, different subcortical activation patterns were found between OL- and HA-treated patients with schizophrenia. Activation of the contralateral putamen was increased in right-sided hemiparkinsonism. Significant thalamus activation was found in patients under neuroleptic treatment as well as in hemiparkinsonism, whereas the thalamus was not activated in untreated patients with schizophrenia and in healthy controls. Comparing dopaminergic depletion in hemiparkinsonism and dopaminergic blockade in HA-treated patients, an increase in activation was found within the contralateral primary motorcortex, in the ipsilateral putamen and the contralateral thalamus in hemiparkinsonism. In contrast, activation of the contralateral putamen differed between OL and HA, LHP and RHP. These findings confirm that cortical and subcortical motor-related brain loop functions are influenced by both primary neuropsychiatric conditions as well as by treatment effects. It is hypothesized that dopaminergic depletion in hemiparkinsonism and dopaminergic blockade under neuroleptic agents influence basal ganglia activity in a different way; in particular regarding functional connectivity. Basal ganglia and thalamic interaction seems to have a key role in cortical-subcortical interaction.

Olanzapine effects on auditory sensory gating in schizophrenia.

OBJECTIVE: New-generation antipsychotics have been proposed to normalize the P50 sensory gating index in patients with schizophrenia. In the context of a double-blind comparison of olanzapine and haloperidol, the authors examined the effect of olanzapine on P50 suppression. METHOD: P50 measurements were obtained at baseline while patients were being treated with fluphenazine and after 12 weeks of double-blind treatment with either olanzapine (N=12) or haloperidol (N=12). RESULTS: There were no treatment group differences in P50 amplitude, latency, or sensory gating ratio. CONCLUSIONS: These results suggest that there is not a significant differential effect of olanzapine and haloperidol on the P50 sensory gating index in schizophrenia.

A Canadian multicenter trial assessing memory and executive functions in patients with schizophrenia spectrum disorders treated with olanzapine.

Serial verbal learning task (explicit long-term memory) and verbal fluency (generation of a response) are tests that are usually severely impaired in schizophrenia. Despite the growing literature supporting the clinical efficacy of olanzapine, psychiatrists still question its cognitive consequences. This study assessed the efficacy of olanzapine on neurocognitive functioning. Patients (N = 134) meeting diagnostic criteria for schizophrenia, schizophreniform, or schizoaffective disorders began an 8-week, open-label olanzapine treatment at a dose of 5 mg/d, which was increased to 10 mg/d after 1 week. Daily dosage was subsequently adjusted between 5 and 20 mg/d based on individual clinical status. All previous antipsychotics were tapered and discontinued during the first 2 weeks of the study. Neuropsychologic assessments were carried out at baseline and at 4 and 8 weeks. Explicit long-term memory was assessed with the Rey Auditory-Verbal Learning Test: the average immediate recall score significantly improved (P < 0.001), as did the delayed recall score (P < 0.001). The average total score on category fluency improved from 34.6 words at baseline to 37.6 words at end point (P < 0.0001). Time on both Trail A and B making tasks significantly decreased (P < 0.0001). Lack of a control arm makes it impossible to exclude a practice effect as an explanation for the enhanced cognitive performance, although the Word List Recall test represents one of the better resources to avoid a practice effect. After switching to olanzapine, there was a statistically significant improvement of cognitive function in the 3 main domains tested and no significant worsening of any memory or executive function measure.

Olanzapine vs risperidone in the management of schizophrenia: a randomized double-blind trial in Australia and New Zealand.

Improved drug therapy for schizophrenia may represent the best strategy for reducing the costs of schizophrenia and the recurrent chronic course of the disease. Olanzapine and risperidone are atypical antipsychotic agents developed to meet this need. We report a multicenter, double-blind, parallel, 30-week study designed to compare the efficacy, safety, and associated resource use for olanzapine and risperidone in Australia and New Zealand. The study sample consisted of 65 patients who met DSM-IV criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder. Olanzapine-treated patients showed a significantly greater reduction in Positive and Negative Syndrome Scale (PANSS) total, Brief Psychiatric Rating Scale (BPRS) total, and PANSS General Psychopathology scores at endpoint compared to the risperidone-treated patients. Response rates through 30 weeks showed a significantly greater proportion of olanzapine-treated patients had achieved a 20% or greater improvement in their PANSS total score compared to risperidone-treated patients. Olanzapine and risperidone were equivalent in their improvement of PANSS positive and negative scores and Clinical Global Impression-Severity of Illness scale (CGI-S) at endpoint. Using generic and disease-specific measures of quality of life, olanzapine-treated patients showed significant within-group improvement in most measures, and significant differences were observed in favor of olanzapine over risperidone in Quality of Life Scale (QLS) Intrapsychic Foundation and Medical Outcomes Study Short Form 36-item instrument (SF-36) Role Functioning Limitations-Emotional subscale scores. Despite the relatively small sample size, our study suggests that olanzapine has a superior risk:benefit profile compared to risperidone.

Treatment of bipolar I rapid cycling patients during dysphoric mania with olanzapine.

The simultaneous presentation of manic and depressive symptoms in the same patient is fairly common. The terms and have been used as equivalents to mixed states. Pharmacotherapy is less effective in this group of patients. The aim of this study is to determine the effectiveness and safety of olanzapine as an add-on therapy in patients with bipolar disorder with a rapid cycling course during a dysphoric mania episode. Thirteen patients treated with mood stabilizers for at least 1 year and diagnosed with a mixed episode were included in an open trial. All had at least 4 episodes in the last year. Patients with organic diseases, including altered thyroid function, were excluded from the research. Patients were evaluated at inclusion and at day 28. Response was defined as a decrease of 50% in the Young Mania Rating Scale and the Hamilton Rating Scale for Depression concomitant with a Clinical Global Impression improvement of 1 or 2. All patients completed the study. The doses of olanzapine were 16.15 +/- 5.82 mg/day. There was a reduction in the manic and depressive symptoms in all patients. Ten of the 13 patients were considered to have responded to the treatment according to the response definition. Adverse effects included somnolence (23.08%) and weight gain (0.81 +/- 1.96 kg in women, 2.20 +/- 2.28 kg in men). Our results suggest that olanzapine combined with mood stabilizers is safe and effective in the treatment of the manic and the depressive symptoms of dysphoric mania with a rapid cycling course.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Effects of acute versus chronic treatment with typical or atypical antipsychotics on d-amphetamine-induced sensorimotor gating deficits in rats.

RATIONALE: Dopamine (DA) receptor agonists disrupt the prepulse inhibition (PPI) in rats which is considered to model PPI deficits observed in schizophrenic patients. Many laboratories have demonstrated that both "typical" and "atypical" antipsychotics reverse the disruptive effect of DA agonists on PPI in rats. These results are based on acute treatment with antipsychotics, which is different from clinical observations since humans receive treatment for months and the effects of antipsychotics only emerge after weeks of treatment. OBJECTIVES: We aimed to investigate the effect of chronic treatment with "typical" and "atypical" antipsychotics on the PPI model in rats. METHODS: We investigated the effect of acute versus sub-chronic (3 days) and chronic (21 days) treatment with haloperidol or two "atypical" antipsychotics (olanzapine; sertindole) on d-amphetamine-disrupted PPI in rats. RESULTS: We observed that all three antipsychotics dose-dependently reversed the disruptive effect of d-amphetamine after acute or sub-chronic treatment, but that this reversal effect disappeared after chronic treatment. We confirmed this effect in the same model using oral administration instead of mini-pumps, and in an additional model predictive of antipsychotic action, i.e. d-amphetamine-induced hyperactivity in rats. CONCLUSIONS: The d-amphetamine-disrupted PPI model highlighted a modification in the effects of antipsychotics after chronic treatment when compared to their acute effects, but only the acute treatment can be considered predictive of antipsychotic action in clinic.

Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats.

RATIONALE: Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. However, recent studies have questioned the robustness of this paradigm. OBJECTIVE: The existence of a substantial dataset generated over 4 years in our laboratory has allowed the investigation of the robustness and reliability of the procedure under a variety of environmental conditions. The effects of atypical antipsychotics (clozapine, olanzapine and risperidone) under different experimental conditions are also reported. METHOD: At weaning, Hooded Lister pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, the startle and PPI response of isolates and grouped rats was investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse=80 dB/30 ms; ISI=100 ms) or variable

Maternal obesity and risk of neural tube defects.

QUESTION: One of my patients is taking olanzapine for schizophrenia. She has gained a lot of weight, which, I understand, often happens with some of the new atypical antipsychotics. Due to her weight gain, she failed to notice she had become pregnant. Is she at risk? ANSWER: Experience with olanzapine is relatively slight, but available prospective data do not show increased teratogenic risk. Adiposity, on the other hand, is associated with increased risk of neural tube defects. Only some of this risk can be reduced by folate supplementation.

Olanzapine as alternative therapy for patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter, collaborative trial in Latin America.

Conventional antipsychotic agents can induce extrapyramidal symptoms (EPS) that may be alleviated by switching patients to novel agents such as olanzapine. Patients with schizophrenia and related disorders (ICD-10) who were taking haloperidol (N = 94; mean dose = 12.7 mg/day) and had EPS (Simpson-Angus Scale [SAS] > 3) were directly switched to 6 weeks of open-label olanzapine treatment (mean dose = 11.4 mg/day). There were significant mean improvements (p <0.001 for all measurements) from baseline to endpoint on the SAS (-9.69+/-5.33; percentage change, 87.2%), the Barnes Akathisia Scale (-1.00+/-1.19; percentage change, 82.5%), and the Abnormal Involuntary Movement Scale (-1.48+/-2.89; percentage change, 81.1%), and anticholinergic use decreased from 47.9% to 12.8% (mean baseline to endpoint change: -1.52+/-1.91-mg equivalents of benztropine; p < 0.001). Significant mean baseline to endpoint improvements (p < 0.001 for all measurements) were observed on the Positive and Negative Syndrome Scale (PANSS; -25.28+/-18.67; percentage change, 30.3%), the PANSS-extracted Brief Psychiatric Rating Scale (0-6 scale, -13.41+/-10.16; percentage change, 54.4%), and the Clinical Global Impressions Severity scale (-1.16+/-1.19; percentage change, 26.4%). Spontaneously reported treatment- emergent adverse events with a greater than 5% incidence were somnolence (16.0%), increased appetite (14.9%), weight gain (11.7%), headache (8.5%), anxiety (7.4%), dizziness (6.4%), and insomnia (5.3%). Criteria for a successful switch were met by 90.5% of patients. Psychotic symptom exacerbation was experienced by 30.9% of patients at any time during the study and by 11.7% of patients at endpoint. Results suggest that a direct switch to olanzapine is a therapeutic option when patients with haloperidol-induced EPS are unable to tolerate a more gradual switch.

Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways.

The effects of three chronically administered antipsychotic drugs on selected neurochemical markers of dopaminergic and GABAergic transmission were compared within the cerebral regions making up the basal ganglia-thalamocortical parallel processing neuronal pathways. All three drugs reduce psychosis in humans, whereas only haloperidol, but not olanzapine or sertindole, induce purposeless oral chewing movements (CMs) in rats or cause high rates of parkinsonism or tardive dyskinesia in humans. Male Sprague Dawley rats were treated with haloperidol, sertindole, or olanzapine delivered in drinking water for 6 months at doses which produce drug plasma levels in rat in the human therapeutic range. Results show the expected dopamine D2 receptor upregulation in striatum predominantly with haloperidol, although mild D2 upregulation was apparent in striatum after olanzapine. GAD67 mRNA was increased in striatum and decreased in globus pallidus by haloperidol and sertindole, but not by olanzapine. In the substantia nigra pars reticulata (SNR), both olanzapine and sertindole failed to induce GABA(A) receptor upregulation or D1 receptor downregulation, but haloperidol did both, confirming a previous report. In thalamus, all three drugs increased GAD expression in the reticular nucleus, whereas only haloperidol decreased GABA(A) binding in the mediodorsal nucleus, actions consistent with a reduction in nigrothalamic, GABA-mediated neural transmission. These results are consistent with the idea that the two new antipsychotics tested have mild and regionally restricted actions within the basal ganglia nuclei and a common action on increasing GAD expression in the reticular nucleus of the thalamus (RtN). Haloperidol, in contrast, has a broad and potent action in basal ganglia, causing changes in SNR and in the mediodorsal nucleus, while also altering GAD mRNA in RtN, potentially reflective of its dyskinetic and antipsychotic actions.

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications.

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.

Summary from the 153rd meeting of the American Psychiatric Association. 13-18 May 2000, Chicago, Illinois, USA.

The annual meeting of the American Psychiatric Association focuses on a variety of topics, including those on psychopharmacology. The latest developments are typically those found in the New Research sections, which is where this summary will focus.

A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial.

Little controlled data exist on the treatment of substance induced psychotic disorders. In this study, 30 patients meeting DSM-IV criteria for cannabis induced psychotic disorder were randomly allocated to receive either olanzapine or haloperidol in a 4-week double-blind clinical trial. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (haloperidol 25.7; olanzapine 27.1; P = 0.70); Clinical Global Impression (CGI) severity scale (haloperidol 1.8, olanzapine 2.3; P = 0.21) or the CGI improvement scale (haloperidol 1.3, olanzapine 1.7; P = 0.16). The haloperidol group however, developed significantly more extrapyramidal side-effects as measured by the Simpson Angus Scale (haloperidol 11.4, olanzapine 2.5; P = 0.014). Significantly (P = 0.027) more biperidin was used for extrapyramidal side-effects in the haloperidol (7.143 mg) than in the olanzapine (0.357 mg) group. Olanzapine appears to be as effective as haloperidol in the treatment of cannabis induced psychotic disorder, but is associated with a lower rate of extrapyramidal side-effects.