Chronic nicotine and dizocilpine effects on nicotinic and NMDA glutamatergic receptor regulation: interactions with clozapine actions and attentional performance in rats

Blockade of NMDA glutamate receptors with dizocilpine (MK-801) has been shown to cause substantial cognitive deficits and has been used to model symptoms of schizophrenia. Nicotine or nicotinic agonists, in contrast, may enhance cognitive or attentional functions and be of therapeutic potential in schizophrenia. Nicotinic–glutamatergic interactions, therefore, may have important implications in cognitive functions and antipsychotic treatments. Clozapine, a widely used antipsychotic drug, has been shown in some studies to be effective in ameliorating the cognitive deficits associated with schizophrenia. However, there is some evidence to suggest that clozapine similar to haloperidol may impair sustained attention in rats. In this study, we sought to determine whether chronic nicotine or dizocilpine may modify the effects of acute clozapine on attentional parameters and whether the behavioral effects would correlate with nicotinic or NMDA receptor densities in discrete brain regions. Adult female rats trained on an operant visual signal detection task were given 4 weeks of nicotine (5 mg/kg/day), dizocilpine (0.15 mg/kg/day), the same doses of both nicotine and dizocilpine as a mixture, or saline by osmotic minipump. While on chronic treatment, rats received acute injections of various doses of clozapine (0, 0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on attentional tasks. The pumps were removed on day 28 and 24 h later the animals were sacrificed for measurements of receptor densities in specific brain regions. The percent correct hit as a measure of sustained attention was significantly impaired by clozapine in a dose-related manner. Neither chronic nicotine nor dizocilpine affected this measure on their own or modified the effects of clozapine. Both nicotine and dizocilpine affected the receptor bindings in a region specific manner and their combination further modified the effects of each other in selective regions. Attentional performance was inversely correlated with alpha-bungarotoxin binding in the frontal cortex only. In conclusion, the data suggest attentional impairments with clozapine alone and no modification of this effect with nicotine or dizocilpine. Moreover, cortical low affinity nicotinic receptors may have a role in attentional functions.     

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

RATIONALE: The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. OBJECTIVE: The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. METHODS: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. RESULTS: PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). CONCLUSIONS: These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.     

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.     

The effect of chronic atypical antipsychotic drugs and haloperidol on amphetamine-induced dopamine release in vivo.

The effect of chronic administration of antipsychotic drugs (21 days in drinking water followed by 3 days drug washout) on the D-amphetamine (1.0 mg/kg, s.c.)-induced increase in dopamine (DA) release in the striatum and the nucleus accumbens of awake, freely-moving rats was investigated with microdialysis. Chronic administration of haloperidol, a typical antipsychotic, (0.5 mg/kg/day), decreased basal extracellular DA release in the striatum and the nucleus accumbens but did not affect D-amphetamine-induced DA release in either region. In marked contrast, chronic administration of three atypical antipsychotic drugs: amperozide (2 mg/kg/day), clozapine (10 mg/kg/day) and melperone (2 mg/kg/day) increased basal extracellular DA and enhanced D-amphetamine-induced DA release in the striatum. In the nucleus accumbens, basal extracellular DA was decreased by chronic amperozide, unchanged by chronic clozapine and increased by chronic melperone. Most significantly, D-amphetamine-induced DA release was inhibited by chronic amperozide or clozapine, but unaffected by chronic melperone in this region. These results suggest that atypical antipsychotic drugs can alter DA release in a region specific manner. In particular, attenuation of amphetamine-like stimulation of DA release with reduced basal DA release in the nucleus accumbens could contribute to the antipsychotic action of amperozide which has a very weak affinity for D2 DA receptors.     

Role of GABAergic antagonism in the neuroprotective effects of bilobalide

Many studies suggest that the 5-HT6 receptors are involved, along with other 5-HT receptors, in the pathophysiology and pharmacotherapy of schizophrenia. It is a putative therapeutic target of atypical antipsychotic drugs, notably clozapine, as well as some other psychotropic agents. Preferential potentiation of dopamine (DA) efflux in the medial prefrontal cortex (mPFC) and hippocampus (HIP) has been suggested to contribute to the ability of atypical antipsychotic drugs (APDs), e.g. clozapine, risperidone, olanzapine and ziprasidone, to improve cognitive function in schizophrenia. The present study demonstrated that SB-399885, a selective 5-HT6 receptor antagonist, at doses of 3 and 10 mg/kg, had no effect on cortical DA release in freely moving rats. However, both doses of SB-399885 slightly but significantly increased DA release in the HIP. Of particular interest, SB-399885, 3 mg/kg, significantly potentiated the ability of a typical antipsychotic drug haloperidol, a D2 receptor antagonist, at a dose of 0.1 mg/kg, to increase DA release in the HIP but not the mPFC. The atypical antipsychotic drug risperidone, a multireceptor antagonist, which lacks 5-HT6 receptor antagonist properties, at doses of 0.1, 0.3 and 1.0 mg/kg, produced a bell-shaped dose response effect on DA efflux in the mPFC and HIP. SB-399885 potentiated risperidone (1.0 mg/kg)-induced DA efflux in both regions. The increase in the HIP, but not the mPFC, DA efflux by 0.3 mg/kg risperidone was also potentiated by SB-399885, 3 mg/kg. These results suggest that the combined blockade of 5-HT6 and D2 receptors may contribute to the potentiation of haloperidol- and risperidone-induced DA efflux in the mPFC or HIP. The present data provides additional evidence in support of a possible therapeutic role for 5-HT6 receptor antagonism, as an addition on therapy, to enhance cognitive function in schizophrenia.     

Nicotine improves working memory span capacity in rats following sub-chronic ketamine exposure

Ketamine, an NMDA-receptor antagonist, produces cognitive deficits in humans in a battery of tasks involving attention and memory. Nicotine can enhance various indices of cognitive performance, including working memory span capacity measured using the odor span task (OST). This study examined the effects of a sub-chronic ketamine treatment to model cognitive deficits associated with schizophrenia, and to evaluate the effectiveness of nicotine, antipsychotic clozapine, and the novel mGlu2/3 agonist, LY404039, in restoring OST performance. Male hooded Lister rats were trained in the OST, a working memory task involving detection of a novel odor from an increasing number of presented odors until they exhibited asymptotic levels of stable performance. Sub-chronic ketamine exposure (10 and 30 mg/kg i.p. for 5 consecutive days) produced a dose-dependent impairment that was stable beyond 14 days following exposure. In one cohort, administration of graded doses of nicotine (0.025-0.1 mg/kg) acutely restored the performance in ketamine-treated animals, while significant improvements in odor span were observed in control subjects. In a second cohort of rats, acute tests with clozapine (1-10 mg/kg) and LY404039 (0.3-10 mg/kg) failed to reverse ketamine-induced deficits in doses that were observed to impair performance in the control groups. These data suggest that sub-chronic ketamine exposure in the OST presents a valuable method to examine novel treatments to restore cognitive impairments associated with neuropsychiatric disorders such as schizophrenia. Moreover, it highlights a central role for neuronal nicotinic receptors as viable targets for intervention that may be useful adjuncts to the currently prescribed anti-psychotics.     

Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice

We compared the effects of subchronic clozapine and haloperidol administration on the expression of SNAP-25 and synaptophysin in an animal model of schizophrenia based on the glutamatergic hypothesis. Mice were first treated with a non-competitive NMDA antagonist MK-801 (0.3 mg/kg/day) or saline for 5 days, and then clozapine (5 mg/kg/day), haloperidol (1 mg/kg/day) or saline was administered for two weeks. The locomotion test, as a behavioral model of the positive symptoms of schizophrenia, was applied after MK-801/saline administration on day 6 for acute effects and after antipsychotic/saline administration on day 19 for enduring effects on mice activity. Memory function was assessed by the Novel Object Recognition (NOR) test, one day after the last day of antipsychotic/saline administration (day 20). Western Blotting technique was used to determine SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Both antipsychotics reversed the enhanced locomotion effects of MK-801. MK-801 and haloperidol decreased recognition memory performance. On the other hand, clozapine did not compromise memory. It also did not reverse the negative effects of MK-801 on memory performance. MK-801 did not change SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Clozapine increased hippocampal SNAP-25, decreased hippocampal synaptophysin expression, whereas frontal SNAP-25 and synaptophysin expressions remained unchanged. Haloperidol had no effects on levels of SNAP-25 and synaptophysin in the frontal cortex and hippocampus. These findings support the idea that the differential effects of clozapine might be related to its plastic effects and synaptic reorganization of the hippocampus.     

住院精神分裂症患者利培酮、氯氮平治疗的成本效益比较

目的 比较利培酮和氯氮平治疗住院精神分裂症病人的疗效和费用。方法 利培酮组３０例（男性１６例,女性１４例,平均年龄２６．８岁）,氯氮平组２６例（男性１２例,女性１４例,平均年龄３０．６岁）,ＢＰＲＳ评分〉３０分。比较两组病人住院期间的所有治疗费用及出院时疗效。结果 利培酮组与氯氮平组疗效相当,氯氮平组除住院期间主药费用小于利培酮,其他费用均高于利培酮。结论 利培酮与氯氮平疗效相当,住院总费用小于氯氮平,是一种安全且经济有效的抗精神病药物。     

Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study

This study aimed to determine the effect of olanzapine and other antipsychotic drugs on cognitive functions after 6months of treatment. Baseline, 3month and 6month psychopathological and cognitive evaluations were made. Thirty-eight partially responsive outpatients with DSM-IV chronic schizophrenia diagnosis were included in the study. On the indication of their attending psychiatrists, 21 patients initiated treatment with olanzapine, and 17 remained on their previous treatment with other antipsychotic drugs. Cognitive assessments were blind to medication and psychopathological status.The olanzapine group presented a significantly greater improvement in negative symptomatology and verbal memory than the comparison group in repeated-measures of MANOVAs between baseline, 3month and 6month assessments. These differences remained statistically significant after covarying out gender, treatment with other atypical antipsychotics, biperidene doses and changes in positive and negative symptoms. In order to match previous differences between groups, cognitive baseline scores for each test were introduced as covariates, resulting in a significant improvement for the olanzapine group in negative symptomatology and the interference task of the Stroop test.We then re-analyzed the data, dividing the comparison group into two groups: risperidone-treated patients (n=9) and patients receiving conventional antipsychotic drugs (n=8). Post-hoc analyses between groups were carried out with baseline cognitive assessment as covariate. The olanzapine group improved significantly more than the risperidone group in negative symptomatology and in the interference task of Stroop test. The improvement in the number of categories of the Wisconsin Card Sorting Test was higher in risperidone patients than in those receiving olanzapine or conventional antipsychotic treatment. Conventional antipsychotic drugs did not present a significant improvement over atypical antipsychotic drugs in any cognitive function.In summary, in patients suffering from chronic schizophrenia, atypical antipsychotic agents were associated with slight differential improvements over time in attentional, verbal memory and executive functions compared with conventional neuroleptic drugs. No differential improvements were found in social functioning, verbal fluency, non-verbal domains of memory or visuo-motor abilities.     

Chronic underactivity of medial frontal cortical β2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats

Nicotinic receptor decreases in the frontal cortex and hippocampus are important mediators of cognitive impairment in both schizophrenia and Alzheimer's disease. Drug treatments for these diseases should take into account the impacts of compromised brain function on drug response. This study investigated the impact of compromised nicotinic receptor activity in the frontal cortex in rats on memory function. Since both Alzheimer's disease and schizophrenia can involve psychosis, antipsychotic drugs are often given. The impacts of antipsychotic drugs on cognitive function have been found to be quite variable. It is the hypothesis of this and previous studies that the cognitive effects of antispychotic drugs on cognitive function depend on the integrity of brain systems involved in cognition. Previously in studies of the hippocampus, we found that chronic inhibition of β2-containing nicotinic receptors with dihydro-β-erythrodine (DHβE) impaired working memory and that this effect was attenuated by the antipsychotic drug clozapine. In contrast, chronic hippocampal α7 nicotinic receptor blockade with methyllycaconitine (MLA) potentiated the clozapine-induced memory impairment which is seen in rats without compromised nicotinic receptor activity. The current study determined medial frontal cortical α7 and β2-containing nicotinic receptor involvement in memory and the interactions with antipsychotic drug therapy with clozapine. Chronic DHβE and MLA infusion effects and interactions with systemic clozapine were assessed in female rats tested for memory on the radial-arm maze. Antipsychotic drug interactions with chronic systemic nicotine were investigated because nicotinic procognitive treatment has been proposed. The same local infusion DHβE dose that impaired memory with hippocampal infusion did not impair memory when infused in the medial frontal cortex. Frontal DHβE infusion potentiated clozapine-induced memory impairment, whereas previously the memory impairment caused by hippocampal DHβE infusion was attenuated by clozapine. Frontal cortical MLA infusions at a dose that previously was found to potentiate the clozapine-induced memory impairment with hippocampal infusion had no significant effect when infused into the medial frontal cortex. The location and subtype of nicotinic receptor underactivity are critical determinates for clozapine effects on memory. Patients with hippocampal β2-containing nicotinic receptor loss may be well treated with clozapine therapy, while those with frontal cortical β2-containing receptor loss may have a potentiated memory impairment caused by clozapine.     

Clozapine treatment attenuated somatic and affective signs of nicotine and amphetamine withdrawal in subsets of rats exhibiting hyposensitivity to the initial effects of clozapine.

BACKGROUND: Based on the phenomenologic similarity between symptoms of drug withdrawal and the negative symptoms of schizophrenia (e.g., anhedonia), we hypothesized that treatment with clozapine may be effective against nicotine and amphetamine withdrawal. METHODS: A rate-independent discrete-trial threshold procedure was used to assess brain stimulation reward in rats prepared with electrodes in the lateral hypothalamus. Somatic signs of nicotine withdrawal were also assessed. RESULTS: Clozapine administration (.75 or 1.5 mg/kg) during nicotine or amphetamine withdrawal did not affect the threshold elevations associated with drug withdrawal. The.75 mg/kg clozapine dose reversed the increased number of somatic signs of nicotine withdrawal. Ten days of clozapine treatment (3 mg/kg/b.i.d.) before exposure to nicotine prevented the threshold elevations in a subset of rats and the increases in somatic signs in all subjects. Fourteen-day pretreatment with clozapine (6 mg/kg/day) decreased the duration of amphetamine withdrawal. CONCLUSIONS: Correlational analyses indicated that the ability of clozapine to prevent the affective aspects of drug withdrawal depended on low sensitivity to acute clozapine under baseline conditions. The results are consistent with the clinical situation where clozapine is partially effective against the negative symptoms of schizophrenia and more effective in some individuals than others. These results indicate that lack of sensitivity to the initial negative effects of clozapine may predict its a subsequent therapeutic response. Finally, the data suggest that there may be commonalities in the neurosubstrates mediating affective aspects of drug withdrawal and the negative symptoms of schizophrenia.     

Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling stimulus is inhibited by a preceding stimulus of a lower intensity. Most often this is tested in the auditory mode. PPI is impaired in a variety of clinical states, most notably schizophrenia. PPI is easily modeled in experimental animals and serves as a useful basis for determining the neural bases for behavioral plasticity. In the current study we examined the interactions of N-methyl-D-aspartate (NMDA) glutamate and nicotinic cholinergic receptor systems in the expression of PPI. Female Sprague-Dawley rats were tested for auditory PPI after s.c. injections of the NMDA antagonist dizocilpine (also known as MK-801), the prototypic nicotinic agonist nicotine or both. Vehicle (saline) injections served as the control. Nicotine (0.2-0.8 mg/kg) by itself caused a modest but significant dose-related improvement in PPI. Dizocilpine (25-100 microg/kg) caused a dramatic dose-related impairment in PPI. Interestingly, the low to moderate doses of nicotine potentiated the PPI impairment by dizocilpine. In a second experiment nicotine and dizocilpine interactions with the atypical antipsychotic drug clozapine were assessed. As in the first experiment, nicotine potentiated the adverse effects of dizocilpine on PPI. The combination of nicotine with clozapine effectively attenuated the PPI impairment caused by dizocilpine when neither alone was effective. Inasmuch as PPI is impaired in schizophrenia, its reversal by the antipsychotic drug clozapine may depend on co-administration of nicotine by smoking in the patients. Development of nicotinic-based co-treatments for schizophrenia may achieve this benefit of nicotine without the hazards of smoking. Sensory modulation deficit, which is a syndrome of sensory over-responsiveness may also benefit from such combination therapy.     

Clozapine inhibits development and expression of nicotine-induced locomotor sensitization in rats

It has been shown that clozapine, the prototype of atypical antipsychotics, significantly reduces daily cigarette use and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of clozapine on nicotine abuse is limited. Aim of this study was to determine whether clozapine would inhibit the development and expression of nicotine-induced locomotor sensitization in rats. To investigate the effect of clozapine on the development of nicotine-induced locomotor sensitization, rats were pretreated with clozapine (2.5-10 mg/kg) 30 min before the nicotine (0.5 mg/kg), and locomotor activity was recorded for 15 min. This procedure was repeated every day for eight sessions. After a 3-day drug-free period, rats were challenged with nicotine (0.5 mg/kg). To reveal effect of clozapine on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 3-day drug-free period, rats were pretreated with clozapine (2.5-10 mg/kg) or vehicle 30 min before the nicotine (0.5 mg/kg) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Clozapine pretreatment (2.5-10 mg/kg) blocked the development and the expression of nicotine-induced locomotor sensitization in rats. Our results suggest that atypical antipsychotic clozapine can prevent the effects of nicotine in an animal model of dependence, which represents early adaptations in initiation and continuation of addictive behavior.     

Effects of clozapine on memory function in the rat neonatal hippocampal lesion model of schizophrenia

Clozapine is an effective atypical antipsychotic drug used to treat schizophrenia. It has the advantage of producing fewer extrapyramidal motor side effects than typical antipsychotic drugs such as haloperidol. Schizophrenia involves more than the hallmark symptom of psychosis. Substantial cognitive impairment is also seen. Effective drug treatments against the cognitive impairment of schizophrenia need to be developed. The current study was conducted to determine the effects of clozapine on working memory in the rat neonatal hippocampal lesion model of schizophrenia, which includes symptoms of cognitive impairment. Infant Sprague-Dawley rats were given ibotenic acid lesions of the hippocampus on day 7 of age (using the day of birth as day 0). Controls were given vehicle infusions. In adulthood, the rats were trained on the 8-arm radial maze using the win-shift procedure. After 6 sessions of training, the lesioned rats and their controls were administered repeated injections of saline or clozapine (2.5 mg/kg) for the next 12 sessions of training. The females had significant radial-arm maze choice accuracy impairments caused by either clozapine or the hippocampal lesion, but the combination of the two treatments had no additive effect. The males showed a different pattern of effects. Intact males did not show a significant clozapine-induced impairment, whereas males with hippocampal lesions did show significant clozapine-induced impairment although hippocampal lesions by themselves did not significantly impair male choice accuracy. These data show that clozapine can cause memory impairment and it potentiates rather than reverses hippocampal lesion-induced deficits. There are critical sex-related differences in these effects.     

Nicotine and clozapine cross‐prime the locus coeruleus noradrenergic system to induce long‐lasting potentiation in the rat hippocampus

A priming‐challenge schedule of nicotine treatment causes long‐lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)‐dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta‐adrenoceptor sensitive LLP effects. Clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine, clozapine or saline. Twenty‐one to twenty‐eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP‐DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine‐ and clozapine‐primed rats, and not in saline‐primed rats, thus indicating a cross‐priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine‐primed rats. Furthermore, systemic treatment with clonidine (an α2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine‐induced LLP in nicotine‐ and clozapine‐primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine. © 2013 Wiley Periodicals, Inc.     

Neurocognitive effects of clozapine,olanzapine, risperidone,and haloperidol in patients with chronic schizophrenia or schizoaffective disorder

OBJECTIVE: Newer antipsychotic drugs have shown promise in ameliorating neurocognitive deficits in patients with schizophrenia, but few studies have compared newer antipsychotic drugs with both clozapine and conventional agents, particularly in patients who have had suboptimal response to prior treatments. METHOD: The authors examined the effects of clozapine, olanzapine, risperidone, and haloperidol on 16 measures of neurocognitive functioning in a double-blind, 14-week trial involving 101 patients. A global score was computed along with scores in four neurocognitive domains: memory, attention, motor function, and general executive and perceptual organization. RESULTS: Global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were superior to those seen with haloperidol. Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with other treatments. Patients treated with risperidone exhibited improvement in memory that was superior to that of both clozapine and haloperidol. Clozapine yielded improvement in motor function but not more than in other groups. Average effect sizes for change were in the small to medium range. More than half of the patients treated with olanzapine and risperidone experienced "clinically significant" improvement (changes in score of at least one-half standard deviation relative to baseline). These findings did not appear to be mediated by changes in symptoms, side effects, or blood levels of medications. CONCLUSIONS: Patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs, and there may be differences between atypical antipsychotic drugs in their patterns of cognitive effects.     

A parametric study of the acute effects of antipsychotic drugs on glucose sensitivity in an animal model

The therapeutic use of atypical antipsychotics is associated with a high incidence of metabolic side-effects. In the present study we examined the acute effects of both high and low-dose atypical antipsychotic drugs and one typical drug on alterations in glucose and insulin parameters using a rodent model. The effects of administration of clozapine (2 mg/kg; 20 mg/kg), olanzapine (1.5 mg/kg; 15 mg/kg), risperidone (0.5 mg/kg; 2.5 mg/kg) and haloperidol (0.1 mg/kg; 1.0 mg/kg) on glucose sensitivity and insulin resistance were determined through HOMA-IR values in fasted rats and glucose clearance during a glucose tolerance test. Acute effects were determined 60, 180 or 360 min following drug administration. The atypical antipsychotics produced significant dose and time dependent effects on fasting plasma glucose and insulin concentrations, HOMA-IR values, insulin resistance and glucose intolerance. The greatest effect on glucose dysregulation was noted primarily with clozapine and olanzapine; however, all four treatments caused significant increases in fasting glucose and/or insulin levels with the high dose, 60 min post-drug administration. Together, these findings indicate that acute administration of antipsychotic drugs has potent effects on metabolic regulation of glucose and insulin sensitivities, which may contribute to metabolic side-effects seen in humans.     

Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation

Subanesthetic doses of N-methyl- -aspartate (NMDA) receptor antagonists such as ketamine and phencyclidine precipitate psychotic symptoms in schizophrenic patients. In addition, these drugs induce a constellation of behavioral effects in healthy individuals that resemble positive, negative, and cognitive symptoms of schizophrenia. Such findings have led to the hypothesis that decreases in function mediated by NMDA receptors may be a predisposing, or even causative, factor in schizophrenia. The present study examined the effects of the representative atypical (clozapine) and typical (haloperidol) antipsychotic drugs on ketamine- induced increases in -2-deoxyglucose (2-DG) uptake in the rat brain. As previously demonstrated, administration of subanesthetic doses of ketamine increased 2-DG uptake in specific brain regions, including medial prefrontal cortex, retrosplenial cortex, hippocampus, nucleus accumbens, basolateral amygdala, and anterior ventral thalamic nucleus. Pretreatment of rats with 5 or 10 mg/kg clozapine alone produced minimal or no change in 2-DG uptake, yet clozapine completely blocked ketamine-induced changes in 2-DG uptake in all brain regions studied. In striking contrast, a dose of haloperidol (0.5 mg/kg) that produces a substantial cataleptic response, potentiated, rather than blocked, ketamine-induced activation of 2-DG uptake. These results demonstrate, in a model with potential relevance to schizophrenia, a striking neurobiological difference between the actions of prototypical typical and atypical antipsychotic drugs. The dramatic blockade by clozapine of ketamine-induced brain metabolic activation suggests that antagonism of the consequences of reduced NMDA receptor function could contribute to the superior therapeutic effects of this atypical antipsychotic agent. The results also suggest that this model of ketamine-induced alterations in 2-DG uptake may be extremely useful for understanding the complex neural mechanisms of atypical antipsychotic drug action.     

Abnormalities in visually guided saccades suggest corticofugal dysregulation in never-treated schizophrenia.

BACKGROUND: Previous studies have reported intact visually guided saccades in schizophrenia, but these are limited by potential acute and long-term pharmacological treatment effects, small sample sizes, and a failure to follow patients over time. METHODS: Visually guided saccades were examined in 44 antipsychotic-naive patients experiencing their first episode of schizophrenia prior to treatment and again after 6, 26, and 52 weeks of antipsychotic treatment. Thirty-nine matched healthy individuals were followed over the same period. RESULTS: Before treatment, patients showed faster saccade latencies to unpredictable visual targets, suggesting reduced inhibitory regulation of brainstem saccade generators by neocortical attentional systems. Risperidone treatment reduced this deficit, suggesting a facilitation of attentional function, but haloperidol treatment did not. However, there was also a modest decline in saccade accuracy after risperidone treatment. The ability to sustain fixation of static central and peripheral targets was unimpaired before and after treatment. CONCLUSIONS: These findings provide evidence for impairments in neocortical attentional systems that cause reduced corticofugal regulation of brainstem systems in schizophrenia. This dysfunction appears to be minimized by the atypical antipsychotic risperidone but at the cost of a subtle reduction in saccade accuracy, possibly mediated via adverse effects on cerebellar vermis function.