Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients withneuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.     

The dopamine-serotonin relationship in clozapine response

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.     

Acute effects of styrene inhalation on the neuroendocrinological system of rats and the different effects in male and female rats

There have been several epidemiological and experimental studies about styrene from the neuroendocrinological viewpoint. Some reported that styrene exposure affected the neuroendocrinological system and enhanced prolactin (PRL) secretion, but others have denied those effects. It was assumed that styrene exposure caused depletion of dopamine (DA), which is a PRL inhibitor, and that, in consequence, the PRL level increased. However, not only DA but also many other factors control PRL secretion. Therefore, the mechanism of hypersecretion of PRL has not yet been clearly elucidated. In addition, effects of styrene on the female reproductive system have been reported, but the susceptibility needs to be further studied. Therefore, to investigate what causes hypersecretion of PRL and how different the susceptibility is in males and females, we studied acute effects of styrene exposure on the neuroendocrinological system in male and female rats. Immediately after exposure to 150 ppm styrene vapor for 10 days (8 h/day), male and female rats were killed, and blood and brain samples were collected. The styrene concentration in blood, hormones such as PRL, growth hormone (GH) and thyroid-stimulating hormone (TSH) in plasma and neurotransmitters in various brain regions were measured. The styrene concentration in the blood of female rats was higher than that in male rats, and the PRL level was significantly increased in female exposed rats compared with controls. No significant change was observed in male rats. We did not observe any significant changes in DA, 5-hydroxytryptamine (5-HT) or their metabolites. Because neurotransmitters were not affected in either male or female rats, the mechanism enhancing PRL secretion remains unclear. These results suggest that styrene exposure may cause hypersecretion of PRL and that the sensitivity to styrene exposure of the female may be higher than that of the male.     

Chronic nicotine treatment increases dopamine levels and reduces dopamine utilization in substantia nigra and in surviving forebrain dopamine nerve terminal systems after a partial di-mesencephalic hemitransection

Summary In order to further study the previously demonstrated protective action of chronic nicotine treatment on lesioned meso-striatal dopamine (DA) pathways, the following study was carried out on DA utilization in these lesioned neurons. Male Sprague-Dawley rats were partially hemitransected at the meso-diencephalic junction and treated with nicotine (0.125 mg · kg^–1 · h^–1) by means of Alzet minipumps implanted subcutaneously for 2 weeks. The overall serum nicotine level obtained was 64.6 ± 2.7 ng · ml^–1.The results demonstrated that partial di-mesencephalic hemitransections produced a marked reduction of DA fluorescence (quantitative histofluorimetry) on the lesioned side in the nucleus caudatus putamen, anterior nucleus accumbens and posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Furthermore, studies on changes in DA utilization as evaluated 2 h after tyrosine hydroxylase inhibition showed an augmentation in the -methyl-(±)-p-tyrosine methyl ester (-MT)-induced depletion of the DA stores on the hemitransected side in comparison with the operated side of the sham-operated animals. On the hemitransected side chronic nicotine treatment increased DA stores in the DA nerve terminals of the nucleus caudatus putamen and the posterior lateral tuberculum olfactorium. No significant effects were observed on the intact side. Following chronic nicotine treatment a marked and preferential attenuation of the -MT-induced depletion of DA stores was seen in the various DA nerve terminal systems of the forebrain on the hemitransected side. In the substantia nigra reduced DA levels (HPLC) were demonstrated on the hemitransected side, while no effects on the non-operated side were observed. Also an increase of the -MT-induced depletion of the DA stores was seen on the hemitransected side in comparison with the operated side of the sham-operated animals. In contrast, on the non-operated side an attenuation of the a MT-induced depletion of the DA stores was found. Following chronic nicotine treatment the lesion induced reduction of the nigral DA stores on the hemitransected side was counteracted, as was the lesion induced increase in the -MT-induced depletion of DA stores, which was replaced by a reduction of the -MT-induced depletion of the nigral DA stores. However, on the non-operated side an increased DA depletion was observed after -MT treatment in rats treated chronically with nicotine. Chronic nicotine treatment under the present conditions did not significantly alter serum levels of corticosterone and reduced prolactin serum levels in sham-operated rats.The present results indicate that a partial hemitransection produces marked increases in DA utilization of the forebrain and of the substantia nigra on the lesioned side; whereas on the non-operated side a reduction in nigral DA utilization was found. On the hemitransected side chronic nicotine treatment increases DA stores of the nucleus caudatus putamen, tuberculum olfactorium and substantia nigra, suggesting a protective action of nicotine. Chronic nicotine treatment preferentially and substantially reduces striatal, accumbens and nigral DA utilization on the lesioned side. On the non-operated side chronic nicotine treatment abolished the lesion-induced reduction of DA utilization in the substantia nigra. These results are in support of the hypothesis that a protective action of chronic nicotine treatment on ascending DA systems may be produced via a desensitization of excitatory nicotine cholinoceptors regulating the ascending DA pathways, leading to reduced firing rates and thus to reduced energy demands. The endocrine system does not seem to be involved in these effects.Abbreviations ACC dif anterior part of nucleus accumbens - ACC dot posterior part of nucleus accumbens - LAUD cent central part of nucleus caudatus - CAUD marg marginal zone of nucleus caudatus - CAUD med medial part of nucleus caudatus - DA dopamine - HPLC high performance liquid chromatography - -M -methyl-(±)-p-tyrosine methyl ester - TUB dif posterior lateral part of the olfactory tubercle - TUB dot posterior medial part of the olfactory tubercle Send offprint requests to A. M. Janson at the above address     

Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine,the prototype atypical antipsychotic

Rationale. Clozapine has been shown to increase extracellular dopamine (DA) and noradrenaline (NA) in the medial prefrontal cortex (mPFC). A recent study of ours suggested that extracellular DA in the PFC originates not only from dopaminergic but also from noradrenergic terminals, its release being controlled by α₂-adrenoceptors. Objectives. Since clozapine binds to α₂-adrenoceptors, the possibility that it might co-release DA and NA was studied. Methods. By means of microdialysis coupled to HPLC with electrochemical detection, the effect of clozapine on extracellular DA and NA in the mPFC, densely innervated by DA and NA, was compared to that in the occipital cortex, equally innervated by NA but receiving few DA projections. Results. Extracellular NA was found to be the same in the two cortices, consistent with homogeneous NA innervation. On the other hand, extracellular DA in the occipital cortex was only 29% lower than in the mPFC, in spite of the scarce dopaminergic innervation in the occipital cortex. Clozapine (10 mg/kg IP) increased extracellular DA and NA not only in the mPFC (by about 320% and 290%, respectively) but also in the occipital cortex (by 560% and 230%, respectively). Administration of the α₂-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D₂-agonist quinpirole (0.1 mg/kg IP) was ineffective. Conclusions. The results suggest that clozapine, by inhibiting α₂-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC. Electronic Publication     

Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects

The effects of chronic treatment with clozapine (20 mg/kg per day), ritanserin (0.5 mg/kg per day), haloperidol (0.5 mg/kg per day), or the combination of haloperidol and ritanserin, on dopamine (DA) and serotonin (5-HT) metabolism were studied. Chronic haloperidol treatment decreased DA metabolism in nucleus caudatus. Chronic ritanserin treatment failed to alter striatal or mesolimbic DA metabolism but decreased the concentrations of 5-HT and 5-hydroxyindoleacetic acid in the nucleus raphe dorsalis. The effects of chronic haloperidol were not altered by concomitant ritanserin administration. In comparison, chronic clozapine treatment affected neither DA nor 5-HT metabolism. These results show that the biochemical effects of chronic haloperidol treatment on the major ascending DA neurons cannot be modulated by concomitant 5-HT₂ receptor blockade.     

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects

Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy [“therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D₁ antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT₂ serotonergic/DA D₁ and D₂ antagonist) and DOD 647 (DA D₁ and D₂ antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses. Received: 31 October 1997/Final version: 9 November 1998     

Modulation of reward and aversion processes in the rat diencephalon by neuroleptics: Differential effects of clozapine and haloperidol

The effects of clozapine and haloperidol on self-stimulation in rats were investigated in a shuttle-box that provides concurrent rate-independent indexes of the rewarding and aversive components of intracranial stimulation. The use of two concurrent measures of performance permits the differentiation of specific reward modulation effects from the variety of nonspecific performance decrements that these drugs may produce. Clozapine produced a dose-dependent reduction in reward that could be clearly dissociated from its nonspecific effects. In contrast, the apparent reduction in reward produced by haloperidol could not be dissociated from a nonspecific performance decrement. Consequently, the attenuation of self-stimulation produced by haloperidol does not indicate a direct role for dopamine in modulating reward. It is suggested that the attenuation of reward produced by neuroleptics reflects a reduction in noradrenergic transmission, whereas their nonspecific effects reflect their blockade of dopamine receptors.     

Seroquel (ICI 204,636) restores prepulse inhibition of acoustic startle in apomorphine-treated rats: Similarities to clozapine

Seroquel (ICI 204,636) is a mixed D₂/5HT₂ antagonist with a preclinical profile suggestive of potential antipsychotic efficacy. We compared seroquel to clozapine in an animal model of sensorimotor gating deficits in shizophrenic patients. Like schizophrenic patients, rats treated with apomophrine (APO) exhibit deficits in prepulse inhibition (PPI) of acoustic startle. The ability of antipsychotics to restore PPI in APO-treated rats correlates (R _s=0.991) with their clinical potency. Seroquel and clozapine both restore PPI in APO-treated rats. Seroquel's restoration of PPI in apomorphine-treated rats follows simple monotonic ascending dose-response properties, and is not accompanied by consistent changes in startle reflex amplitude. Seroquel's profile in this PPI model mimics that of other antipsychotics.     

Adverse effects of clozapine

Adverse effects related to clozapine were assessed within a post-marketing drug surveillance program, the AMÜP study, in two university psychiatric departments. In a randomly selected sample of patients (intensive drug monitoring) ADRs of any type were observed in 76% of clozapine-treated inpatients. Sedation, hypersalivation, increase in transaminases, and EEG changes were most frequently observed, but only rarely required changes in therapy. In 8.1% of 959 patients exposed to clozapine in the total inpatient population of the participating hospitals ADR led to withdrawal of clozapine; in 3.9% reactions judged as severe and potentially life-threatening occurred. Among these latter toxic delirium prevailed. In addition, four cases of severe cardiovascular and respiratory dysregulation were observed with the combination of clozapine and benzodiazepines. These cases and one case of sudden death under clozapine and haloperidol treatment are presented in some detail. The results obtained for clozapine are compared to data from this drug surveillance program for other neuroleptics.     

Raclopride lessens the ability of clozapine to suppress alcohol drinking in Syrian golden hamsters

Emerging evidence suggests that the atypical antipsychotic clozapine decreases alcohol consumption in patients with schizophrenia, while typical antipsychotics, all of which are potent dopamine (DA) D2 receptor antagonists, do not. We have proposed that clozapine, through its weak DA D2 receptor blocking action, coupled with its ability to potentiate noradrenergic and serotonergic activity, may ameliorate a dysfunction in the mesocorticolimbic DA reward circuitry that underlies alcohol use disorder in patients with schizophrenia. In prior studies, we have demonstrated that clozapine also decreases alcohol drinking in the Syrian golden hamster, but haloperidol does not. The purposes of the current study were: (1) to further assess the effect of clozapine (2 or 4 mg/kg/day, s.c.) on alcohol consumption in hamsters, using a continuous access, 2-bottle choice paradigm; and (2) to examine whether clozapine’s effect on alcohol drinking is affected by increasing its DA D2 blockade through adjunctive use of the potent DA D2 receptor antagonist raclopride (2, 4, or 6 mg/kg/day, s.c.). The major findings were: (1) clozapine suppressed both initiation and maintenance of alcohol drinking in hamsters; and (2) these effects of clozapine were lessened when raclopride was given adjunctively with clozapine. These data suggest that clozapine may limit alcohol drinking in the golden hamster (and possibly in patients with schizophrenia) in part because of its weak blockade of the DA D2 receptor.     

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.     

Long-term experience with clozapine in Denmark: research and clinical practice

In Denmark, the use of clozapine has increased markedly (15–25% per year) since 1983, when the drug was relaunched — after its withdrawal in 1975. Several factors have contributed to this development: 1) the interesting pharmacology of clozapine, especially the atypical influence on dopamine transmission, including a relatively high D-1/D-2 receptor affinity ratio, 2) the potent anti-anxiety and anti-psychotic effect in severe and otherwise therapy-resistent psychotic patients, and 3) the lack of extrapyramidal side effects. A special monitoring form (for registration of total and differential leucocyte counts, ECG, body weight, drugs, doses and reason for possible withdrawal of the clozapine) is used in most Danish psychiatric institutions. This form secures the regular control of vital parameters and serves as an instrument for surveys of the use of clozapine in Denmark. Also, more selective studies are being carried out, e.g., on the effect of clozapine monotherapy versus combined therapy, and on the influence of clozapine on cardiovascular functions, including left ventricular output (echocardiography).     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.     

In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels

We previously reported that depletion of brain tyrosine attenuated the acute clozapine (CLZ)-induced increase in medial prefrontal cortex (MPFC) dopamine (DA) levels. This effect was now examined after chronic CLZ treatment. Male rats received CLZ (10 mg kg⁻¹ day⁻¹) in drinking water for 21 days. On day 18, a cannula was stereotaxically implanted over the MPFC. A microdialysis probe was inserted on day 20. On day 21 after a stable baseline was reached, rats received an acute injection of vehicle (VEH) or a tyrosine- and phenylalanine-free mixture of neutral amino acid [NAA(−)] (total 1 g kg⁻¹, i.p., two injections, 1 h apart) followed by CLZ (10 mg kg⁻¹, i.p.) or VEH. Basal tyrosine or norepinephrine (NE) levels were not different between the groups, but basal DA was higher in the group treated chronically with CLZ (p<0.05). Acute CLZ (10 mg kg⁻¹, i.p.) increased MPFC DA and NE levels to 370% and 510% of baseline, respectively, and similarly in rats chronically pretreated with CLZ or VEH. NAA(−) did not affect basal MPFC DA or NE levels but significantly attenuated acute CLZ-induced DA (220% of baseline) and NE (330% of baseline) levels (p<0.01) in rats pretreated chronically with CLZ or with VEH. These data demonstrate that even after chronic CLZ administration, the acute CLZ-induced increases in MPFC DA and NE levels depend on the availability of brain tyrosine. Judicious manipulation of brain tyrosine levels may provide a useful probe as well as a mechanism for enhancing psychotropic drug actions.     

奎硫平与氯氮平治疗精神分裂症的对照研究

目的 研究奎硫平治疗精神分裂症的疗效和安全性。方法 对58例精神分裂症患者随机分为两组，奎硫平研究组30例，氯氮平组28例，于治疗前和治疗后4、8周末进行阳性和阴性症状量表（PMNSS）及副反应量表（TESS）评定疗效和副反应。结果 两组之间疗效无显著差异，奎硫平组副反应少于氯氮平组。结论 奎硫平是一种安全有效的抗精神病药物。     

Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: Studies with chronic clozapine and haloperidol

Rats were chronically injected with saline, clozapine, or haloperidol and tested for alterations in dopamine (DA)-mediated behavior, DA receptor binding, and both acetylcholine (ACH) concentration and cholien acetylase activity. Behaviorally, chronic haloperidol significantly enhanced apomorphine-induced chewing and sniffing stereotypies, associated with DA nigrostriatal activation, while clozapine selectively enhanced apomorphine locomotor activity and cage-floor crossing, behavior associated with DA mesolimbic activation. Biochemically, chronic haloperidol significantly enhanced ³H-spiroperidol binding in striatum and in mesolimbic loci (nucleus accumbens/olfactory tuberele) while chronic clozapine failed to produce such enhancement. Acute haloperidol induced an initial decrease in striatal ACH concentration followed by a return of ACH to normal levels within 1 week. There was no change in choline acetylase activity during the same time interval. These findings suggest that haloperidol may inhibit DA mechanisms in both the nigrostriatal and mesolimbic systems, but that the effect of clozapine on DA mechanisms may be specific to mesolimbic rather than striatal structures. At the same time, the lack of effect of clozapine on ³H-spiroperidol binding may indicate that behaviorally important changes in DA sensitivity can develop independent of changes in post-synaptic DA receptors. The pattern of cholinergic changes with chronic haloperidol suggests that the increase in striatal DA receptor number seen with chronic treatment re-establishes DA inhibition of cholinergic firing within the striatum.     

氯氮平与氯丙嗪治疗精神分裂症的疗效分析

目的：比较氯氮平与氯丙嗪治疗精神分裂症疗效。方法：36例精神分裂症随机分成氯氮平组(18例)和氯丙嗪组(18例)，采用简明精神症状量表(BPRS)及临床疗效评定量表(CGI)，于治疗前、治疗后2、4、6周分别进行评定。结果：氯氮平组和氯丙嗪组在治疗前后BPRS评分差异无显著性(P＞0．05)，但疗效总评(GI)评分中第四周氯氮平组高于氯丙嗪组，但总体疗效相似(P＞0．05)。结论：氯氮平与氯丙嗪对治疗精神分裂症疗效相似。     

喹硫平与氯氮平治疗精神分裂症对照研究

目的：探讨国产喹硫平治疗精神分裂症的疗效和安全性。方法：将96例符合《中国精神障碍分类与诊断标准》第3版（CCMD-3）的精神分裂症患者随机分为两组,分别给予喹硫平（研究组,n=48）和氯氮平（对照组,n=48）治疗,疗程8周。分别于治疗前及治疗第2、4、6、8周末采用阳性和阴性症状量表（PANSS）和副反应量表（TESS）评定临床疗效和不良反应。结果：喹硫平组显效率70.8%,有效率91.7%。氯氮平组显效率72.9%,有效率93.7%。两组间显效率（X2=0.05,P〉0.05）有效率（X2=0.15,P〉0.05）的差异无统计学意义。两组间治疗后各时点PANSS总分、阳性症状、阴性症状以及一般病理症状各项分值均低于治疗前,而治疗后各时点组间差异无统计学意义（P〉0.05）。喹硫平组的嗜睡、便秘、头疼头晕、乏力、流涎的发生率分别为12.5%,4.17%,6.3%,4.2%和2.1%,明显低于氯氮平组（分别为45.8%,18.6%,20.8%,29.2%和39.6%）,两组差异均有统计学意义（X2=13.04,P〈0.01;X2=5.03,P〈0.05;X2=4.36,P〈0.05;X2=10.8,P〈0.01;X2=20.46,P〈0.05）结论：国产喹硫平治疗精神分裂症疗效确切,不良反应少,有利于患者对治疗的依从性,是一种安全有效的抗精神病药物。     

Switch from neuroleptics to clozapine does not influence pituitary–gonadal axis hormone levels in male schizophrenic patients

Hypothalamic dopaminergic and serotonergic inputs participate in the regulation of pituitary hormones, and drugs that block central dopamine and serotonin receptors are expected to influence the hypothalamus–pituitary–gonadal (HPG) and –adrenal (HPA) axes. In schizophrenic patients, the switch from neuroleptics to clozapine influences prolactin and cortisol secretion, but there is no information on possible changes on HPG-axis hormones. We measured the plasma levels of testosterone (TST), LH, FSH, as well as of prolactin (PRL) and cortisol (CORT), in a group of male patients with schizophrenia during treatment with classical neuroleptics with no satisfactory therapeutic response (31 pts, age 30.3±8.5, range 18–50), and 6 weeks later, after switch to treatment with clozapine (CLZ) in doses from 100 to 600 mg daily (mean 328 mg). Psychopathology was assessed using the Brief Psychiatric Rating Scale. The hormone levels were also compared to those of a control group of 38 healthy males. Treatment with CLZ resulted in a reduction in the BPRS score by 30% in the mean. Plasma PRL was reduced from 39.9±26.1 to 8.3±5.0 ng/ml (P<0.001), CORT from 150±42 to 118±39 ng/ml (P<0.003), while LH, FSH, and TST remained unaltered. Compared to healthy controls, patients had higher PRL and CORT levels while on neuroleptics, and no significant differences to any of the estimated hormones, after switch to clozapine. The results show that switching from classical neuroleptics to treatment with clozapine does not have any substantial effect on the HPG-axis hormone plasma levels, although it reduces substantially the levels of prolactin and cortisol.