Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?

During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between "typical" and "atypical" antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D(2) receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D(2) receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D(2) blockade is probably the most important-if not the only-criterion that determines "atypicality". Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D(2) receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.     

Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study.

Typical antipsychotic drugs act on the dopaminergic system, blocking the dopamine type 2 (D2) receptors. Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors, and a high degree of occupancy of the serotoninergic receptors 5-HT2A. Whether these different pharmacological actions produce different effects on brain structure remains unclear. We explored the effects of different types of antipsychotic treatment on brain structure in an epidemiologically based, nonrandomized sample of patients at the first psychotic episode. Subjects were recruited as part of a large epidemiological study (AESOP: aetiology and ethnicity in schizophrenia and other psychoses). We evaluated 22 drug-free patients, 32 on treatment with typical antipsychotics and 30 with atypical antipsychotics. We used high-resolution MRI and voxel-based methods of image analysis. The MRI analysis suggested that both typical and atypical antipsychotics are associated with brain changes. However, typicals seem to affect more extensively the basal ganglia (enlargement of the putamen) and cortical areas (reductions of lobulus paracentralis, anterior cingulate gyrus, superior and medial frontal gyri, superior and middle temporal gyri, insula, and precuneus), while atypical antipsychotics seem particularly associated with enlargement of the thalami. These changes are likely to reflect the effect of antipsychotics on the brain, as there were no differences in duration of illness, total symptoms scores, and length of treatment among the groups. In conclusion, we would like to suggest that even after short-term treatment, typical and atypical antipsychotics may affect brain structure differently.     

Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Background  Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the “prototypical” or “gold standard” atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years. Objectives  Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed. Results  Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine’s cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine’s cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs. Conclusions  There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While low-dose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine’s discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.     

Pharmacology of second-generation antipsychotics: a validity of the serotonin-dopamine hypothesis]

New atypical antipsychotic drugs such as risperidone, olanzapine and quetiapine, that have been modeled on the prototype agent clozapine and developed since the 1990's, are now referred to as second-generation antipsychotics (SGA). It has been proposed by Meltzer (1989) that the interaction between serotonin (5-HT) and dopamine (DA) systems may play a critical role in the mechanism of action for atypical antipsychotics because potent 5-HT2A receptor antagonism together with relatively weak D2 receptor antagonism could differentiate most atypical antipsychotics from typical antipsychotics. This serotonin-dopamine hypothesis has become a useful model for studying and developing new drugs to achieve a significant antipsychotic effect with lower incidence of extrapyramidal side effects compared to first-generation antipsychotics. In contrast, Kapur and Seeman (2001) argued the alternative "fast-off" theory that clozapine occupies D2 receptors to a similar extent as typical antipsychotics do and then rapidly dissociates from D2 receptors. This paper reviews the current issues on the serotonin-dopamine hypothesis and recent research on the role of 5-HT receptor subtypes in the mechanism of action for SGA. In particular, SGA-induced DA release in the prefrontal cortex, possibly through the functional activation of 5-HT1A receptors by 5-HT2A and D2 receptor-mediated interaction, may be the basis for the cognitive effects of SGA.     

Subjective response to antipsychotics of schizophrenia patients treated in routine clinical practice: a naturalistic comparative study

In routine practice, subjective response to antipsychotics is becoming a critical outcome measure among schizophrenia patients. This study sought to compare subjective response to atypical (risperidone and olanzapine) and typical antipsychotic drugs. Using a naturalistic cross-sectional design, we examined subjective response to antipsychotics (satisfaction with medication and subjective tolerability), psychopathology, side effects, emotional distress, and awareness in schizophrenia patients stabilized on atypical (n = 78) and typical (n = 55) drugs. Analysis of variance and multiple regression analysis were applied. We found that atypical drugs were superior to typical antipsychotics in both measures of subjective response, which were positively correlated (r = 0.52, P < 0.001). Poor subjective response was associated with severity of emotional distress, negative, and activation symptoms in the atypical group and with extrapyramidal side effects and positive symptoms in the typical group. Awareness of treatment is a positive factor that accounted for 20% and 34% of variation in the subjective responses to atypical and typical antipsychotic drugs, respectively. Demographic variables, age of onset, illness duration, and adjunctive drugs did not relate significantly to subjective response to antipsychotic drugs. Thus, atypical drugs are characterized by better subjective response compared with typical antipsychotics; their determinants differed considerably. Satisfaction with medication together with subjective tolerability needs to be considered in clinical trials.     

Discriminative stimulus properties in rats of the novel antipsychotic quetiapine

Rats discriminated the novel antipsychotic quetiapine (Seroquel). Full generalization was seen with the novel ("atypical") antipsychotics, clozapine, olanzapine, and risperidone. Generalization was not seen with the older "typical" antipsychotics, haloperidol, chlorpromazine, and loxapine, or with the novel atypical antipsychotic, amisulpride. The pattern of generalization resembled that seen in rats trained to discriminate a low dose (1.25 mg/kg) of clozapine, which dissociates most novel antipsychotics from typical antipsychotics. However, the failure of the novel antipsychotic amisulpride to generalize demonstrates that this bioassay does not detect all novel antipsychotics. These data suggest that the discrimination of antipsychotics such as quetiapine may be of value in the development of novel antipsychotics, although the relationship between the discriminative properties of such drugs and their clinical actions is unclear.     

Extrapyramidal symptoms with atypical antipsychotics : incidence, prevention and management.

The treatment of schizophrenia changed drastically with the discovery of antipsychotic medications in the 1950s, the release of clozapine in the US in 1989 and the subsequent development of the atypical or novel antipsychotics. These newer medications differ from their conventional counterparts, primarily based on their reduced risk of extrapyramidal symptoms (EPS). EPS can be categorised as acute (dystonia, akathisia and parkinsonism) and tardive (tardive dyskinesia and tardive dystonia) syndromes. They are thought to have a significant impact on subjective tolerability and adherence with antipsychotic therapy in addition to impacting function. Unlike conventional antipsychotic medications, atypical antipsychotics have a significantly diminished risk of inducing acute EPS at recommended dose ranges. These drugs may also have a reduced risk of causing tardive dyskinesia and in some cases may have the ability to suppress pre-existing tardive dyskinesia. This paper reviews the available evidence regarding the incidence of acute EPS and tardive syndromes with atypical antipsychotic therapy. Estimates of incidence are subject to several confounds, including differing methods for detection and diagnosis of EPS, pretreatment effects and issues surrounding the administration of antipsychotic medications. The treatment of acute EPS and tardive dyskinesia now includes atypical antipsychotic therapy itself, although other adjunctive strategies such as antioxidants have also shown promise in preliminary trials. The use of atypical antipsychotics as first line therapy for the treatment of schizophrenia is based largely on their reduced risk of EPS compared with conventional antipsychotics. Nevertheless, EPS with these drugs can occur, particularly when prescribed at high doses. The EPS advantages offered by the atypical antipsychotics must be balanced against other important adverse effects, such as weight gain and diabetes mellitus, now known to be associated with these drugs.     

In vivo receptor occupancy of NRA0045, a putative atypical antipsychotic, in rats.

We have previously reported that (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045) is a novel antipsychotic agent with affinities for dopamine D4, 5-hydroxytryptamine 2A (5-HT2A) and alpha1 receptors. In the present study, in vivo receptor occupancy of 5-HT2A, alpha1, dopamine D2 and D3 receptors by NRA0045 was assessed, based on in vivo and ex vivo receptor binding, and findings were compared to reference antipsychotic drugs (haloperidol, risperidone, clozapine). Intraperitoneal administration of haloperidol highly occupied the dopamine D2 receptor in the striatum and nucleus accumbens, and alpha1 adrenoceptors in the frontal cortex. Occupation of the 5-HT2A receptor in the frontal cortex and the dopamine D3 receptor in the nucleus accumbens and islands of Cajella was moderate. By contrast, atypical antipsychotics such as risperidone and clozapine dose-dependently occupied the 5-HT2A receptor in the frontal cortex, with moderate to negligible occupancy of the D2 receptor in the striatum and the nucleus accumbens. Clozapine and risperidone also occupied the alpha1 adrenoceptor in the frontal cortex, and clozapine did not occupy the dopamine D3 receptor. As seen with other atypical antipsychotics, intraperitoneal administration of NRA0045 dose-dependently occupied the 5-HT2A receptor and the alpha1 adrenoceptor in the frontal cortex, while it was without effect on dopamine D2 and D3 receptors in the striatum, nucleus accumbens and islands of Cajella. Thus, the strong occupancy of 5-HT2A and alpha1 receptors is involved in the pharmacological action of NRA0045.     

Improvement of prefrontal brain function in endogenous psychoses under atypical antipsychotic treatment.

Typical and atypical antipsychotics are thought to exert their effects on different neurotransmitter pathways with specific action of atypical compounds on the prefrontal cortex, but studies directly investigating the effect of those drugs on neurophysiological measures of prefrontal brain function are sparse. We therefore investigated the influence of different antipsychotics on an electrophysiological marker of prefrontal brain function (NoGo anteriorization, NGA) and neuropsychological test scores. For this purpose, 38 patients with endogenous psychoses were investigated at the beginning of a stationary psychiatric treatment and at a 6-week-follow-up. Patients were treated with typical or atypical antipsychotics, or a combination of both. They underwent psychopathological diagnostic and neuropsychological testing, as well as electrophysiological investigations during a Continuous Performance Test. The results indicate that typical and atypical antipsychotics differentially affected the development of the NGA over the course of the treatment, typical antipsychotics tending to result in decreased values at follow-up, and atypical antipsychotics stabilizing, or increasing this parameter. Performance in tests of frontal lobe function generally declined under typical antipsychotics and improved with atypical compounds, changes in Stroop interference correlated with changes in the NGA. We conclude that typical and atypical antipsychotics differ regarding their effect on prefrontal brain function in schizophrenia, atypical neuroleptics often showing a more favorable impact than conventional antipsychotics on respective parameters.     

Characterization of atypical antipsychotic drugs by a late decrease of striatal alpha1 spectral power in the electropharmacogram of freely moving rats

BACKGROUND AND PURPOSE: Drug administration modifies the balance of neurotransmitter-controlled ion channel activity and consequently the firing pattern of local neuronal populations and intracerebral field potentials. Fast Fourier Transformation of these field potentials provides an electropharmacogram depicting drug-induced changes within defined frequency ranges. The present investigation was undertaken to investigate the difference between atypical and typical antipsychotic drugs. EXPERIMENTAL APPROACH: Adult Fisher rats were implanted with 4 bipolar concentric steel electrodes using a stereotactic surgical procedure. Field potentials from four selected brain areas in freely moving rats were used to analyse the frequency content of the electropharmacogram after administration of 4 clinically used atypical antipsychotic drugs. KEY RESULTS: Atypical antipsychotics exerted effects similar to those reported for typical antipsychotics, on the electropharmacogram during the first hour after administration, whereas clear differences emerged during the second and third hour after dosing. During the latter period, only atypical antipsychotic drugs produced a statistically significant decrease in alpha1 and beta1 spectral power, especially within the striatum, somewhat less in the cortex. CONCLUSIONS AND IMPLICATIONS: Previous studies have attributed alpha1 frequency changes to the influence of 5-hydroxytryptamine (5-HT) and the present data are consistent with additional binding of atypical drugs to 5-HT receptors. This implies that a change in the balance between dopaminergic and 5-hydroxytryptaminergic neurotransmission (activation of both) is likely to underlie the relative lack of extrapyramidal side effects characteristic of atypical antipsychotics and also for their higher efficacy in the treatment of mood and cognition deficits in schizophrenics.     

The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs

Atypical antipsychotic drugs such as clozapine, fluperlapine, and melperone produce weak catalepsy in rodents, and minimal extrapyramidal symptoms and serum prolactin elevations in humans, compared to typical antipsychotic drugs such as haloperidol. The biological basis for these differences has been attributed to relatively weak blockade at D2 dopamine (DA) receptors, various effects at D1 receptors, or potent serotonin2 (5-HT2) antagonism, although other possibilities exist. To clarify the relative importance of actions at D1, D2, and 5-HT2 receptors for identification of candidate typical and atypical drugs, we determined the negative log of the Ki (pKi) value of 21 typical and 17 atypical antipsychotic drugs for the striatal D1 and D2 and frontal cortex 5-HT2 receptors of rodent brain. Cluster analysis identified that the 5-HT2/D2 ratio was the most successful means of utilizing this data to classify typical and atypical antipsychotic drugs correctly. A 92 percent accuracy was achieved.     

Face-to-face questionnaire survey on the use of multiple antipsychotics and the manifestation of side effects in outpatients with schizophrenia

We investigated the use of multiple antipsychotics and the manifestation of side effects in outpatients with schizophrenia and compared the results of patients who received 1 antipsychotic (monotherapy) with those of patients who received more than 1 antipsychotic (multidrug therapy). To achieve this, we visited 8 community life-support centers and conducted a face-to-face questionnaire survey with 47 outpatients. Sixteen (34%) of these patients had received monotherapy and 31 (66%), multidrug therapy. Complaints involving the central nervous system, anticholinergic symptoms, metabolic symptoms (weight gain, increase in blood glucose, etc.), and extrapyramidal symptoms were seen across the patients. The average incidence of side effects was 2.2 per person in the monotherapy group and 4.8 in the multidrug-therapy group. The number of nonantipsychotic drugs used concomitantly in the monotherapy group was also smaller than that used in the multidrug-therapy group (2.3 and 5.0 per person, respectively). Further, we analyzed the 47 patients as described above; 20 patients received typical antipsychotics (TA group), 10 patients received atypical antipsychotics (AA group), and 17 patients received both typical and atypical antipsychotics (MIX group). The average incidence of side effects in the TA, AA, and MIX groups was 2.8, 3.2, and 5.5 per person, respectively, and the number of nonantipsychotic drugs used concomitantly was 2.2, 3.2, and 6.1, respectively. On the basis of our results, it can be suggested that monotherapy with an atypical antipsychotic can reduce both the number of nonantipsychotic drugs used concomitantly and the average incidence of side effects.     

氟西汀与抗精神病药相互作用

氟西汀是抗抑郁药的一线药,可与典型抗精神病药物、非典型抗精神病药物发生药物相互作用.氟西汀通过抑制细胞色素P450酶CYP2D6、CYP2C9、CYP3A4、CYP2C19、CYP1A2等,使其血药浓度升高,增加抗精神病药物的不良反应.临床应重视氟西汀与抗精神病药物的相互作用.     

Possible dose–side effect relationship of antipsychotic drugs: relevance to cognitive function in schizophrenia

Management of adverse events is a major concern of clinicians who use antipsychotic drugs. The incidence of motor side effects is dose dependent. Atypical antipsychotic drugs are less likely to induce neurologic side effects compared with typical (conventional) antipsychotics, such as haloperidol. Some recent, large-scale studies have shown that the incidence of metabolic side effects often associated with atypical agents does not differ among typical and atypical antipsychotics. Cognitive function, such as verbal learning memory, working memory, executive function, verbal fluency and attention/information processing, is the most influential determinant of outcome in patients with schizophrenia. Atypical antipsychotic drugs have been shown to be more efficacious in treating cognitive disturbances of schizophrenia compared with typical antipsychotic drugs. Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes, such as the 5-HT_1A receptor, are considered to mediate the ability of antipsychotic drugs to enhance cognition. On the other hand, treatment with some atypical agents, such as risperidone, may deteriorate working memory in some people with early-stage schizophrenia. The paradoxical side effects of these antipsychotic drugs in terms of cognition may be attributable to dose, duration of treatment and type of cognitive domain. Further research will add to the worldwide endeavor to develop more effective psychotropic drugs accompanied with minimal side effects, for the improvement of cognition, adherence and long-term outcome in patients with schizophrenia or other major psychiatric illnesses.     

Basic biology of clozapine: electrophysiological and neuroendocrinological studies

The effects of clozapine and other purported atypical antipsychotics were compared with those of typical antipsychotics within the neuroendocrine axis of the rat. Atypical antipsychotics (e.g., clozapine, thioridazine, melperone, setoperone and RMI 81582) differed from typical antipsychotics (e.g., haloperidol, chlorpromazine, cis-flupentixol and fluphenazine) in that they produced only a brief elevation in serum concentrations of prolactin but marked increases in serum or plasma concentrations of corticosterone and ACTH. Moreover, atypical antipsychotics, but not typical antipsychotics, acutely increased the activity of tuberoinfundibular dopamine neurons, as judged from the accumulation of DOPA in the median eminence after inhibition of decarboxylase activity. The effects of atypical antipsychotics on tuberoinfundibular dopamine neurons and corticosterone secretion were mimicked by neurotensin. It would appear that atypical antipsychotics elicit unique neuroendocrine responses that differentiate these agents from typical antipsychotic drugs.     

Double activity imaging reveals distinct cellular targets of haloperidol, clozapine and dopamine D(3) receptor selective RGH-1756

Acute administration of typical (haloperidol) and atypical (clozapine) antipsychotics results in distinct and overlapping regions of immediate-early gene expression in the rat brain. RGH-1756 is a recently developed atypical antipsychotic with high affinity to dopamine D(3) receptors that results in a unique pattern of c-Fos induction. A single injection of either antipsychotic results in c-fos mRNA expression that peaks around 30 min after drug administration, while the maximum of c-Fos protein induction is seen 2 h after challenge. The transient and distinct temporal inducibility of c-fos mRNA and c-Fos protein was exploited to reveal and compare cellular targets of different antipsychotic drugs by concomitant localization of c-fos mRNA and c-Fos immunoreactivity in brain sections of rats that were timely challenged with two different antipsychotics. Double activity imaging revealed that haloperidol, clozapine and RGH-1756 share cellular targets in the nucleus accumbens, where 40% of all labeled neurons displayed both c-fos mRNA and c-Fos protein. Haloperidol activates cells in the caudate putamen, while clozapine-responsive, single labeled neurons were dominant in the prefrontal cortex and major island of Calleja. RGH-1756 targets haloperidol-sensitive cells in the caudate putamen, but cells that are activated by clozapine and RGH-1756 in the major island of Calleja are different.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

The influence of psychotropic drugs on cerebral cell death: female neurovulnerability to antipsychotics

Tissue transglutaminase (tTG) is a marker for apoptosis, and its protein level is known to be increased in post-mortem Alzheimer's and Huntington's disease brains. tTG is increased in the cerebrospinal fluid of patients with Alzheimer's disease. However, the influence of psychotropic medication on acute cell death has not been studied so far in vivo, although some experiments performed in vitro suggest that antipsychotic drugs are neurotoxic. The protein level of tTG was examined in the cerebrospinal fluid obtained from 29 patients under neuroleptic medication in the last 24 h before lumbar puncture (eight patients diagnosed with Alzheimer's disease and 21 patients with other neurological diseases), and compared with those from 55 patients without antipsychotic medication (25 Alzheimer's patients and 30 others). In addition, the influence of several other psychotropic drugs on apoptosis was analysed. A significant influence (P<0.01) of antipsychotic drugs for both the Alzheimer's and the non-Alzheimer's group was found with respect to tTG protein levels in cerebrospinal fluid. By contrast to the male subgroups, the female groups showed a strong influence of neuroleptics on cerebral cell death. Surprisingly, atypical antipsychotics did not differ from typical neuroleptics in neurotoxicity. By contrast, no influence of antidepressants, cholinesterase-inhibitors, nootropics, tranquilizers and tramadol on cerebral cell death was found. The results suggest that typical and atypical antipsychotic drugs may induce cerebral cell death, especially in female patients. Subjects with Alzheimer's disease might be even more vulnerable to any antipsychotic. Therefore, subsequent research should aim to identify atypical neuroleptics without neurotoxicity. A limit on the use of first- and second-generation antipsychotics in elderly patients is proposed. Finally, the possible connection between the observed increased cerebral cell death and tardive dyskinesia, the most threatening side-effect in antipsychotic therapy, is discussed.     

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review

RATIONALE: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. OBJECTIVE: This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. METHODS: Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. RESULTS: Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. CONCLUSIONS: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.     

我院2009-2012年门诊抗精神病药用药分析

目的：调查我院2009-2012年精神科门诊抗精神病药物的应用情况。方法：采用药物的限定日剂量（DDD）分析法和金额排序法,对我院2009-2012年精神科门诊抗精神病药进行统计分析。结果：抗精神病药使用金额在2010,2011和2012年分别以34.84%,22.24%和16.92%的速度增长;典型抗精神病药用药频度（DDDs）有下降的趋势,非典型抗精神病药DDDs逐年增长。结论：非典型抗精神病药物已广泛应用于精神科临床,成为精神疾病药物治疗的主要药物。