Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.     

The effect of chronic treatment with typical and atypical antipsychotics on working memory and jaw movements in three- and eighteen-month-old rats

The effects of chronic treatment with typical and atypical antipsychotics on acquisition, working memory, motor activity, and rat tardive dyskinesia (TD) were studied in 3- and 18-month-old Sprague-Dawley rats. Acquisition and working memory were studied in eight-arm radial mazes. TD liability of antipsychotic drugs (APD) was evaluated in rat model of TD in which spontaneous repetitive jaw movements (RJM) occur during withdrawal from neuroleptic treatment. Motor behavior was assessed using the traverse beam test. D1 and D2 receptor occupancy was determined in the rat brain during treatment with typical and atypical antipsychotics. Chronic administration of clozapine, haloperidol, and risperidone impaired acquisition of the eight-arm radial maze in both young and aging rats while olanzapine had no effect. Retention tests showed that aging rats made more errors than the adults and that the antipsychotics haloperidol and risperidone significantly impaired retention in both age groups. Evaluation of motor behavior revealed that typical and atypical antipsychotics used in comparable doses in young rats had no effect on motor behavior, whereas in aging rats performance was impaired by clozapine, haloperidol, and risperidone but not by olanzapine. RJM responses were increased during washout from haloperidol treatment in young and aging rats whereas olanzapine, clozapine, and risperidone had no effect. D2 receptor occupancy in haloperidol- and risperidone-treated rats was above 70% while olanzapine and clozapine receptor occupancy was below 70%, which is the threshold for the appearance of extrapyramidal syndrome (EPS) and TD.     

Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder

OBJECTIVE: The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder. METHOD: In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period). RESULTS: Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain. CONCLUSIONS: The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small.     

Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration

Apart from their differential propensities to block dopamine D2 and serotonin 5-HT2 receptors, the molecular mechanisms underlying the clinical efficacy of typical and atypical antipsychotics in schizophrenia are largely unknown. Given recent interest in the effects of antipsychotics on neurotrophic and other growth related factors, the effects of antipsychotics on brain-derived neurotrophic factor (BDNF), a neurotrophin crucial to the structural integrity of adult neurons, were investigated in male Wistar rats. Chronic (19 day) but not acute (45 min) antipsychotic administration significantly altered levels of hippocampal BDNF mRNA. In addition, whereas chronic treatment with the strong D2 receptor-blocker haloperidol significantly downregulated hippocampal BDNF mRNA, the selective 5-HT2 receptor-blocker ritanserin significantly upregulated CA1 hippocampal BDNF mRNA in comparison to controls. Since high doses of risperidone and clozapine produce potent inhibition of both 5-HT2 and D2 receptors, while lower doses produce significantly greater 5-HT2 vs. D2 receptor blockade, a dose-response study was employed to determine whether low doses of these atypical antipsychotics would also upregulate hippocampal BDNF mRNA in the absence of significant D2 receptor blockade. Whereas chronic haloperidol and high-dose risperidone significantly downregulated hippocampal BDNF mRNA, intermediate and lower doses of risperidone and clozapine were, unlike ritanserin, without effect when compared to controls. Thus, although the long-term downregulation of hippocampal BDNF mRNA may underlie the different clinical profiles of certain antipsychotics, this effect seems to be associated with antipsychotic doses that not only cause significant D2 receptor inhibition, but are usually associated with side effects rather than therapeutic efficacies.     

Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics

Although atypical antipsychotics have been associated with improvements in cognitive function in schizophrenia, the neurochemical basis for such effects is not well understood. Candidate neurotransmitter systems primarily involve dopamine and serotonin. The current study explored this issue by examining the cognitive abilities, social function and quality of life in patients with schizophrenia who were medicated with atypical antipsychotics. Comparisons were done for matched schizophrenia patients who were on antipsychotics with (i) an affinity for multiple receptors (olanzapine, clozapine, quetiapine) versus those that have preferential affinity for dopamine receptors (risperidone, amisulpride); and patients on medication with (ii) a high affinity for serotonin (5HT-2A) receptors (risperidone, olanzapine, clozapine) versus those with a low (or no) affinity for 5HT-2A receptors (quetiapine, amisulpride). No differences emerged between groups on any cognitive or social variable when the groups were compared for the dopaminergic properties of antipsychotic medication. By contrast, differences did emerge when patients were compared on the 5HT-2A affinity of their antipsychotic medications. Patients on low 5HT-2A-affinity antipsychotics exhibited a better performance on a measure of selective attention and adjustment to living. These findings accord with the notion that serotonergic mechanisms are important determinants of both the cognitive and the social effects of the atypical antipsychotics.     

Reduced basal and phencyclidine-induced expression of heat shock protein-70 in rat prefrontal cortex by the atypical antipsychotic abaperidone

The effect of antipsychotic treatment on basal and phencyclidine (PCP)-induced heat shock protein-70 (hsp70) mRNA expression was studied in the rat striatum and in the prefrontal cortex. Abaperidone, a novel drug with an atypical antipsychotic profile, was compared, at pharmacologically equivalent doses, with the atypical antipsychotics clozapine and risperidone and also with haloperidol, a classical antipsychotic. Abaperidone and clozapine reduced basal hsp70 mRNA expression in the rat striatum and in the prefrontal cortex. No change in either region was found after haloperidol, whereas risperidone reduced hsp70 mRNA in the striatum but not in the prefrontal cortex. The N-methyl-D-aspartate (NMDA) receptor antagonist PCP significantly elevated hsp70 mRNA levels in the prefrontal cortex, an elevation that was potentiated by haloperidol and prevented by all of the atypical antipsychotics tested. Since hsp70 has been associated to some schizophrenia symptoms, we suggest that reduced hsp70 in the prefrontal cortex, a cortical area that plays a critical role in the etiology of many schizophrenia symptoms, may be linked to an atypical profile of antipsychotics, such as clozapine, and possibly also abaperidone.     

Die Wirkung von Antipsychotika auf glutamaterge Neurotransmission im Tiermodell

Post-mortem investigations have confirmed that glutamatergic NMDA, AMPA, and kainate receptors are involved in the pathophysiology of schizophrenia. It is still unclear, however, whether the altered number of receptors is caused by the disease itself or the medication. Therefore, animal models were investigated for effects of antipsychotic medication after treatment periods of up to 6 months, the results of which are summarized here. Generally, NMDA receptor binding was found to be increased in striatum and nucleus accumbens after therapy with haloperidol, whereas clozapine only increased the number of receptors in nucleus accumbens. While haloperidol led to an increase in AMPA receptors in the posterior cingulate gyrus, striatum, insular cortex, and n. accumbens, clozapine was found to elevate ligand binding in the anterior cingulate gyrus and infralimbic cortex. Although kainate receptor binding was increased in hippocampus by both antipsychotics, clozapine was significantly more effective. In conclusion, data reveal different effects from the typical neuroleptic haloperidol and the atypical antipsychotic clozapine. The results suggest that post-mortem findings in patients with schizophrenia may at least partially be explained by drug effects and plasticity changes induced by long-term medication with antipsychotics.     

Increasing D2 affinity results in the loss of clozapine's atypical antipsychotic action

Typical antipsychotics (haloperidol) give rise to severe motor side-effects while atypical antipsychotics like clozapine do not. Action at several neurotransmitter receptors have been implicated. To identify the critical mechanisms involved we synthesized an 8-C1 isomer of clozapine which showed an equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D1, D4, M1) but differed in having a 10-fold higher affinity at the dopamine D2/3 receptor. When tested in a series of animal models indicative of the typical/atypical distinction (catalepsy, striatal gene-induction, prolactin elevation) isoclozapine lost atypical properties and behaved like a typical antipsychotic. Simultaneous in vivo receptor occupancy studies confirmed that alterations in D2 receptor occupancy were most closely related to loss of atypicality by clozapine's isomer isoclozapine. The implications for the design of future antipsychotics is discussed.     

Atypical neuroleptics in child- and adolescent psychiatry

Atypical neuroleptic drugs have enriched our treatment programs, especially in childhood and adolescent schizophrenia. Reviewed here is the use of atypical neuroleptics in children and adolescents with a schizophrenic disorder. The receptor binding profile and pharmacological properties, indications, side effects, clinical application, and trials of atypical neuroleptic drugs are compared to the classical neuroleptic drug haloperidol in the treatment of adolescent schizophrenia. Special attention is paid to the most common atypical neuroleptics clozapine, olanzapine and risperidone since most studies are carried out with these compounds, most often with clozapine. More clinically controlled trials have to be conducted since only one has been performed to date. The place of atypical neuroleptic drugs is discussed and further studies are necessary in order to differentiate, and eventually broaden the spectrum of the indications tested thus far.     

On the trail of a cognitive enhancer for the treatment of schizophrenia

The aim of this critical review is to address that the study of cognition and antipsychotics is not always driven by logic and that research into real pro-cognitive drug treatments must be guided by a better understanding of the biochemical mechanisms underlying cognitive processes and deficits. Many studies have established that typical neuroleptic drugs do not improve cognitive impairment. Atypical antipsychotics improve cognition, but the pattern of improvement differs from drug to drug. Diminished cholinergic activity has been associated with memory impairments. Why atypical drugs improve aspects of cognition might lie in their ability to increase dopamine and acetylcholine in the prefrontal cortex. An optimum amount of dopamine activity in the prefrontal cortex is critical for cognitive functioning. Another mechanism is related to procedural learning, and would explain the quality of the practice during repeated evaluations with atypical antipsychotics due to a more balanced blockage of D2 receptors. Laboratory studies have shown that clozapine, ziprasidone, olanzapine, and risperidone all selectively increase acetylcholine release in the prefrontal cortex, whereas this is not true for haloperidol and thioridazine. A few studies have suggested that cholinomimetics or AChE inhibitors can improve memory functions not only in Alzheimer's disease but also in other pathologies. Some studies support the role of decreased cholinergic activity in the cognitive deficits while others demonstrate that decreased choline acetyltransferase activity is related to deterioration in cognitive performance in schizophrenia. Overall, results suggest the hypothesis that the cholinergic system is involved in the cognitive dysfunctions observed in schizophrenia and that increased cholinergic activity may improve these impairments. Furthermore, a dysfunction of glutamatergic neurotransmission could play a key role in cognitive deficits associated with schizophrenia. Further meta-analysis of various clinical trials in this field is required to account for matters on the grounds of evidence-based medicine.     

Effects of atypical antipsychotics on the syndromal profile in treatment-resistant schizophrenia

BACKGROUND: There has been considerable support for the observation that atypical antipsychotics have a broader range of therapeutic effects than traditional antipsychotics. We are exploring whether this expanded clinical efficacy can also be seen in patients with treatment-resistant schizophrenia. METHOD: The subjects were 157 treatment-resistant inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week double-blind trial and rated with a standard measure of clinical antipsychotic efficacy (Positive and Negative Syndrome Scale [PANSS]). Factor analysis at baseline and endpoint together with changes in 5 PANSS-derived factors were examined. Data were gathered from June 1996 to December 1999. RESULTS: The underlying PANSS factor structure, as indicated by the factor loadings, was essentially identical at baseline and endpoint. At baseline, the excitement factor was followed by the positive, negative, cognitive, and depression/anxiety factors, explaining 49.4% of the total variance. At endpoint, the positive factor was followed by the negative, excitement, cognitive, and depression/anxiety factors, explaining 55.5% of the total variance. The endpoint data indicated statistically significant (p <.05) improvements over time on the positive factor for all 3 atypicals, but not for haloperidol. The negative factor showed significant improvement for clozapine and olanzapine, with significant worsening for haloperidol. Clozapine, olanzapine, and risperidone were superior to haloperidol on the negative factor, while clozapine was also superior to risperidone. The cognitive factor showed significant improvement for all atypicals, as did the depression/anxiety factor. Only clozapine showed improvement on the excitement factor and was superior to both haloperidol and risperidone. CONCLUSIONS: Treatment with atypical antipsychotics did not substantially change the underlying PANSS 5-factor structure. However, antipsychotic treatment with all 3 atypical medications was associated with significant improvements on 3 of 5 syndromal domains (positive, cognitive, and depression/anxiety) of schizophrenia. Clozapine and olanzapine also showed improvement on the negative factor. Only clozapine was associated with improvement on the excitement domain. This finding confirms that atypicals are associated with improvement of an expanded spectrum of symptoms in treatment-resistant patients.     

Disruption of prepulse inhibition following N-methyl-D-aspartate infusion into the ventral hippocampus is antagonized by clozapine but not by haloperidol: a possible model for the screening of atypical antipsychotics

The present study tested the effects of the typical neuroleptic haloperidol and an atypical neuroleptic clozapine on ventral hippocampus stimulation-induced disruption of prepulse inhibition (PPI). Bilateral infusions of 0.7 microg NMDA into the ventral hippocampus disrupted PPI. The impairment of PPI following the infusion was completely normalized 24 h after the infusion. This disruption of PPI was antagonized by clozapine (5.0 mg/kg), but not by haloperidol (0.2 mg/kg). Since disruption of PPI is considered to constitute an animal model of schizophrenia that is related to the deficit of sensorimotor gating observed in schizophrenic patients, these results suggest that PPI disruption induced by intra-ventral hippocampal infusions of NMDA may serve as an animal model for the selective detection of atypical antipsychotics.     

ARE THE COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS INFLUENCED BY THEIR AFFINITY TO 5HT-2A RECEPTORS?

It is well documented that atypical antipsychotics have an influence on cognitive function in patients with schizophrenia, although the neurochemical basis for this effect is not well understood. One suggestion is that the effects are exerted through action on 5HT-2A receptors, which leads to changes in the level of dopamine in the prefrontal cortex. The following study explored this hypothesis by comparing the cognitive effects of the atypical antipsychotics which have a high affinity for 5HT-2A receptors, with those that have little or no affinity to these receptors. Forty-four patients with a DSM-IV diagnosis of schizophrenia were recruited within 6 weeks of starting one of the atypical antipsychotics: clozapine, olanzapine, risperidone, quetiapine, or amisulpride. The patients were divided into two groups according to the 5HT-2A affinity of the individual medications (high 5HT-2A affinity--clozapine, olanzapine, risperidone vs. low 5HT-2A affinity--quetiapine, amisulpride). Patients were tested on a broad range of neuropsychological measures after 9 months and 18 months of treatment. The high 5HT-2A affinity group showed a decrement in performance on tests of visual recognition memory and planning ability. In contrast, the low-5HT-2A affinity group showed improvements on these measures in addition to others. The 5HT-2A affinity of the atypical antipsychotics is an important determinant of their cognitive effects.     

Antipsychotics increase microtubule-associated protein 2 mRNA but not spinophilin mRNA in rat hippocampus and cortex

Antipsychotic (neuroleptic) drugs induce structural alterations in synaptic terminals and changes in the expression of presynaptic protein genes. Whether there are also changes in corresponding postsynaptic (dendritic) markers has not been determined. We describe the effect of 14-day treatment with typical (haloperidol, chlorpromazine) or atypical (clozapine, olanzapine, risperidone) antipsychotics on the expression of two dendritic protein genes, microtubule-associated protein 2 (MAP2) and spinophilin, using in situ hybridization, in the rat hippocampus, retrosplenial, and occipitoparietal cortices. MAP2 mRNA was increased modestly in the dentate gyrus and retrosplenial cortex by chlorpromazine, risperidone, and olanzapine and in the occipitoparietal cortex by chlorpromazine, haloperidol, and risperidone. None of the antipsychotics affected spinophilin mRNA in any area. Overall, these results show a modulation of MAP2 gene expression, likely reflecting functional or structural changes in the dendritic tree in response to some typical and atypical antipsychotics. The lack of change in spinophilin mRNA suggests that dendritic spines are not affected selectively by the drugs. The data provide further evidence that antipsychotics regulate genes involved in synaptic structure and function. Such actions may underlie their long-term effects on neural plasticity in areas of the brain implicated in the pathology of schizophrenia.     

Positive correlation between reduction of handwriting area and D2 dopamine receptor occupancy during treatment with neuroleptic drugs.

We investigated the relationship between fine extrapyramidal-motor symptoms (reduction of handwriting area) and D2 dopamine receptor occupancy under neuroleptic treatment. The handwriting of 18 schizophrenic patients before and during treatment with typical (haloperidol, haloperidol decanoate) and atypical (clozapine, risperidone) neuroleptic drugs was examined. Data analysis of the handwriting's examination was carried out with a planimetric computer programme. At the time of the second test of handwriting, D2 receptor occupancy was determined with single photon emission tomography (SPET) using [(123)I]iodobenzamide ((123)I-IBZM). In all patients, a reduction of handwriting area and a D2 receptor occupancy were found. The correlation between reduction of handwriting area and D2 receptor occupancy for typical and atypical neuroleptic drugs was linear and statistically significant (r=0.9; P > 0.001). Our findings point to the possibility that the reduction of handwriting area may be used as a clinical indicator of D2 receptor occupancy under treatment with neuroleptic drugs.     

Elevation of prolactin levels by atypical antipsychotics.

OBJECTIVE: Atypical antipsychotics are thought not to elevate prolactin levels. The authors examined data suggesting that atypical antipsychotics do elevate prolactin levels but more transiently than typical antipsychotics. METHOD: Prolactin levels in 18 male patients with schizophrenia who were receiving atypical antipsychotics were monitored over the 24-hour period following administration of their daily oral dose of risperidone, olanzapine, or clozapine. RESULTS: The baseline prolactin levels in patients receiving risperidone (mean=27 ng/ml, SD=14) were abnormally high, but baseline prolactin levels in patients receiving olanzapine (mean=9 ng/ml, SD=5) and clozapine (mean=9 ng/ml, SD=5) were not high. All three atypical antipsychotics caused a doubling of prolactin levels over baseline levels 6 hours after medication administration. CONCLUSIONS: These data suggest that these atypical antipsychotics raise prolactin levels, although the increases with olanzapine did not reach statistical significance. This suggests that the differences in the effects on prolactin levels of atypical and typical antipsychotics are not categorical but lie in the degree and duration of dose-induced prolactin elevation, attributable to the differential binding properties of each drug on pituitary dopamine D(2) receptors.     

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.     

Dopamine and incentive learning: A framework for considering antipsychotic medication effects

Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-fos, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-fos expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia.     

Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice

There is considerable evidence that schizophrenia is associated with immune system dysregulation. For example, blood and cerebrospinal fluid (CSF) levels of proinflammatory cytokines are significantly increased in schizophrenic patients, and their normalization correlates with improvement in psychotic symptoms. In fact, typical and atypical antipsychotics are reported to modulate immune function in in vitro and in vivo studies. In the present study, we examined the anti-inflammatory effect of antipsychotics, clozapine, olanzapine, risperidone and haloperidol, on serum cytokine levels in lipopolysaccharide (LPS)-treated mice. Atypical antipsychotics, such as clozapine, olanzapine and risperidone, but not haloperidol, suppressed tumor necrosis factor (TNF)-α and interleukin (IL)-6, and up-regulated IL-10. Moreover, only clozapine, robustly increased the serum levels of IL-10. Clozapine reproduced its anti-inflammatory feature in polyinsinic–polycytidylic acid sodium salt (Poly[I:C])-induced inflammation. Thus, the anti-inflammatory effect of clozapine would adapt to inflammation induced by some varieties of antigens. Several receptor ligands, such as 8-OH-DPAT, ketanserin, prazosin and scopolamine, were also examined as to their anti-inflammatory effects on serum cytokine levels in LPS-treated mice. Ketanserin and prazosin, but not 8-OH-DPAT nor scopolamine, behaved similarly to atypical antipsychotics. However, the remarkable increase of serum IL-10 level observed in clozapine was not detected in ketanserin and prazosin. These results suggest the unique efficacy of atypical antipsychotics in the suppression of proinflammatory cytokines, and the increase of anti-inflammatory cytokine, IL-10.     

Comparison between olanzapine and haloperidol on procedural learning and the relationship with striatal D2 receptor occupancy in schizophrenia

The striatum is known to play a primary role in procedural learning. In this study, the authors simultaneously assessed the effects of two antipsychotic drugs on procedural learning and on striatal dopamine (D2) receptor occupancy. Twenty-seven patients receiving either olanzapine or haloperidol as antipsychotic medication were assessed with the Computed Visual Tracking Task (CVTT) and Single Photon Emission Computed Tomography (SPECT) following the administration of Iodine 123-IBZM (123I-IBZM), a radioligand with a high affinity and specificity for the D2 receptors. The results showed poorer procedural learning in the haloperidol-treated patients than in normal control subjects, while no difference could be found between olanzapine-treated patients and normal control subjects. In the haloperidol but not the olanzapine group, significant correlations were found between procedural learning deficits and striatal D2 receptor occupancy. However, there was no significant difference in D2 receptor occupancy between olanzapine- and haloperidol-treated patients, and this may be related to the high doses of olanzapine and low doses of haloperidol administered. The authors concluded that: 1) striatal D2 receptor blockade may alter procedural learning in humans; and 2) olanzapine may have a protective effect on procedural learning, even at doses that produce striatal D2 receptor occupancy as high as that found with haloperidol. This protective effect of olanzapine may be related to its atypical pharmacological properties.