Ziprasidone: a new atypical antipsychotic

This paper reviews the clinical pharmacology, efficacy and safety of the new atypical antipsychotic, ziprasidone. All published citations regarding ziprasidone were retrieved and reviewed using a MEDLINE search (completed for citations to early 2001). In addition, abstracts from recent scientific meetings presenting data not yet published were reviewed. Like other new antipsychotic medications, ziprasidone fits the profile of an atypical agent, exerting efficacy in positive and negative symptoms of psychosis, as well as affective symptoms, with a low risk of neurological and neuroendocrinological side effects. Unlike newer agents, it does not appear to be associated with weight gain in most patients.     

Ziprasidone: a new atypical antipsychotic

This paper reviews the clinical pharmacology, efficacy and safety of the new atypical antipsychotic, ziprasidone. All published citations regarding ziprasidone were retrieved and reviewed using a Medline^® search (completed for citations to early 2001). In addition, abstracts from recent scientific meetings presenting data not yet published were reviewed. Like other new antipsychotic medications, ziprasidone fits the profile of an atypical agent, exerting efficacy in positive and negative symptoms of psychosis, as well as affective symptoms, with a low risk of neurological and neuroendocrinological side effects. Unlike newer agents, it does not appear to be associated with weight gain in most patients.     

非典型抗精神分裂症新药:卡利拉嗪

卡利拉嗪是一种新型非典型抗精神病药,于2015年9月18日经美国FDA批准用于治疗精神分裂,本文对该药的药理作用、临床应用、用法用量、药品不良反应等方面进行综述。     

新型抗精神病药：哌罗匹隆

哌罗匹隆是一种新型非典型抗精神病药,主要药理机制是5-羟色胺(5-HT)和多巴胺D_2受体拮抗作用。与传统抗精神病药相比,哌罗匹隆对阳性症状、阴性症状和情感症状均有较好疗效,锥体外系不良反应和致催乳素升高作用轻微。哌罗匹隆是一种安全有效的非典型抗精神病药。     

Aripiprazole, a novel atypical antipsychotic drug

Before the 1990s, treatment of psychoses centered on conventional agents whose tolerability was limited by extrapyramidal side effects (EPS). The past decade has seen the emergence of a newer generation of antipsychotic agents, first with clozapine and followed shortly by risperidone, olanzapine, quetiapine, and ziprasidone. These agents have been touted as providing better negative symptom efficacy, less impaired cognition, and lower risk of extrapyramidal syndromes. However, evolving evidence suggests that several drugs in this class may be associated with significant weight gain and lipid abnormalities. Aripiprazole, a new atypical antipsychotic drug, displayed efficacy similar to that of haloperidol and risperidone and superior to that of placebo in numerous clinical trials. Aripiprazole does not cause significant prolactin elevation and is associated with a low rate of clinically significant weight gain compared with other atypical antipsychotics. Patients receiving aripiprazole experienced EPS at a rate similar to that seen with placebo. Aripiprazole provides a new treatment option with limited adverse effects for patients in need of antipsychotic therapy.     

新型非典型抗精神病药:鲁拉西酮

鲁拉西酮为一新型非典型抗精神病药,属于苯并异噻唑衍生物,为多巴胺D_2和5-羟色胺2A(5-HT_(2A))受体拮抗剂。2010年10月28日美国食品和药物管理局批准鲁拉西酮上市,其商品名为Latuda,用于治疗成人精神分裂症。鲁拉西酮的有效剂量范围为40～120mg·d~(-1),推荐起始剂量为40mg·d~(-1),一般最大推荐剂量为80mg·d~(-1),应与食物同时服用。鲁拉西酮常见不良反应有嗜睡、静坐不能、恶心、帕金森病以及焦虑。本文对鲁拉西酮的药理作用、药动学、药物相互作用、临床评价和安全性等进行综述。     

Paliperidone: a new extended-release oral atypical antipsychotic

Paliperidone extended release (ER) is the most recent atypical antipsychotic to become available for the treatment of schizophrenia. It has a unique extended-release delivery system, allowing once/day dosing with steady plasma concentrations of the medication. Several randomized, double-blinded, placebo-controlled trials have shown paliperidone ER to be efficacious in the management of acute schizophrenia as well as for the prevention of symptom recurrence when compared with placebo. Patients in the treatment groups receiving daily doses ranging from 3 to 12 mg displayed generalized symptom improvement using the Positive and Negative Syndrome Scale (PANSS) and improved functioning on the Personal and Social Performance Scale. Paliperidone ER has been shown to be generally safe and tolerable. At its recommended dose of 6 mg daily, the reported extrapyramidal symptom adverse events are similar to placebo, and weight gain is very modest. However, at higher doses, weight gain and extrapyramidal symptoms are more elevated. Paliperidone ER has the potential to offer advantages over its parent compound and other second generation agents, and may aid in ensuring compliance among persons with schizophrenia. At present, there are no published data from a comparative trial with paliperidone ER versus its parent compound or other second-generation antipsychotic agents.     

Paliperidone: a new extended-release oral atypical antipsychotic

Paliperidone extended release (ER) is the most recent atypical antipsychotic to become available for the treatment of schizophrenia. It has a unique extended-release delivery system, allowing once/day dosing with steady plasma concentrations of the medication. Several randomized, double-blinded, placebo-controlled trials have shown paliperidone ER to be efficacious in the management of acute schizophrenia as well as for the prevention of symptom recurrence when compared with placebo. Patients in the treatment groups receiving daily doses ranging from 3 to 12 mg displayed generalized symptom improvement using the Positive and Negative Syndrome Scale (PANSS) and improved functioning on the Personal and Social Performance Scale. Paliperidone ER has been shown to be generally safe and tolerable. At its recommended dose of 6 mg daily, the reported extrapyramidal symptom adverse events are similar to placebo, and weight gain is very modest. However, at higher doses, weight gain and extrapyramidal symptoms are more elevated. Paliperidone ER has the potential to offer advantages over its parent compound and other second generation agents, and may aid in ensuring compliance among persons with schizophrenia. At present, there are no published data from a comparative trial with paliperidone ER versus its parent compound or other second-generation antipsychotic agents.     

Cardiovascular risks of atypical antipsychotic drug treatment

Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are generally better tolerated than conventional antipsychotics since most do not cause debilitating extrapyramidal symptoms. They are associated though with an array of cardiovascular adverse events that may affect morbid-mortality of schizophrenic patients. Orthostatic hypotension, electrocardiographic changes and metabolic syndrome (MS) are the main cardiovascular effects of atypical antipsychotics. They contribute to the overall disease burden associated with schizophrenia even though the benefit risk of such treatments still is highly favourable.We aim to review the main cardiovascular side effects of new atypical oral antipsychotics, the pharmacological mechanisms involved, and to which drugs they are particularly attributed.     

新型非典型抗精神病药:依匹哌唑

依匹哌唑为一新型非典型抗精神病药,2015年7月10日由美国食品和药物管理局批准上市,用于精神分裂症与抑郁障碍的辅助治疗。依匹哌唑的作用机制尚未完全清楚,其治疗精神分裂症或抑郁症的机制可能通过对5-HT_(1A)和多巴胺D_2受体的部分激动作用和对5-HT_(2A)受体的拮抗作用起效。依匹哌唑常见的不良反应有体重增加和静坐不能。临床研究表明,依匹哌唑对精神分裂症与抑郁障碍的辅助治疗有效且安全性和耐受性好。本文对依匹哌唑的药理学、药动学、临床评价和安全性等进行介绍。     

新型非典型抗精神病药:卡利拉嗪

卡利拉嗪为一新型非典型抗精神病药,主要用于精神分裂症和双相躁狂发作急性期或双相Ⅰ型障碍混合发作的治疗,其作用机制为多巴胺D_2和D_3受体以及5-HT_(1A)受体部分激动剂,对D3受体的选择性更高。卡利拉嗪治疗精神分裂症和双相障碍的推荐剂量范围分别为每日1.5~6 mg和3~6 mg。卡利拉嗪治疗的耐受性好,常见的不良反应有锥体外系症状、静坐不能等。本文对卡利拉嗪的药理学、药动学、临床疗效和安全性等进行介绍。     

Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology.

Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D(2)-dopamine receptors and relatively high affinities for 5-HT(2A) serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D(2)-dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT(2B)-, hD(2L)-, and hD(3)-dopamine receptors, but also has significant affinity (5-30 nM) for several other 5-HT receptors (5-HT(1A), 5-HT(2A), 5-HT(7)), as well as alpha(1A)-adrenergic and hH(1)-histamine receptors. Aripiprazole has less affinity (30-200 nM) for other G protein-coupled receptors, including the 5-HT(1D), 5-HT(2C), alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(2)-adrenergic, and H(3)-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT(2B) receptors and displays partial agonist actions at 5-HT(2A), 5-HT(2C), D(3), and D(4) receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D(2)-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D(2)-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D(2)-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has "functionally selective" actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of "functionally selective" activation of D(2) (and possibly D(3))-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors--particularly 5-HT receptor subtypes (5-HT(1A), 5-HT(2A)).     

非典型抗精神病药——哌罗匹隆

哌罗匹隆是一类非典型抗精神病药，疗效肯定，锥体外系反应等药物不良反应较少。本文就哌罗匹隆的药理作用、药代动力学特征及与其他药物的相互作用做一综述。     

Remoxipride — a new potential antipsychotic drug

Remoxipride, a new potential antipsychotic drug, was administered over 4 days at two dose levels, 70 and 140 mg t.i.d., to eight healthy male volunteers. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. Remoxipride exhibited essentially linear pharmacokinetics. Only minor deviations in biochemical and physiological safety parameters were found. The drug was well tolerated by all subjects at the 70 mg dose level. At 140 mg akathisia appeared in seven subjects. The drug induced a rapid and transient increase in plasma prolactin concentrations at both dose levels after single doses. During steady state, a significant reduction in the prolactin response was observed as compared to after the first dose.     

An electroencephalographical study on timiperone, a new antipsychotic drug

This investigation was undertaken to analyze the EEG synchronizing effects of timiperone in cats. The effects of timiperone on the brain-stem reticular and hypothalamic activating system, diffuse and specific thalamic projection system, and caudate spindle were investigated by the electroencephalographic method. Timiperone produced a weak inhibition of EEG arousal response induced by electrical stimulation of the sciatic nerve almost without affecting that which was induced by stimulation of the mesencephalic reticular formation. Furthermore, timiperone suppressed the activation of neocortical EEG in response to stimulation of the posterior hypothalamus more selectively than that of limbic EEG. Neither the recruiting response to stimulation of the centro-median nucleus of the thalamus nor the augmenting response to stimulation of the ventro-postero-lateral nucleus of the thalamus was modified by timiperone. In addition, timiperone significantly potentiated the caudate spindle. The EEG effects of haloperidol were qualitatively similar to those of timiperone. These results indicate that the synchronizing effect of timiperone may be mediated by a suppression of an ascending reticular activating system and may influence the conscious levels and sleep-wakefulness cycle in cats.     

Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology

Aripiprazole (Abilify) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia. Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors (GPCRs) [especially dopamine (D2) and 5-HT1A] and antagonistic action at others (especially 5-HT2A). Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia. In short-term studies rapid onset of action (within one week) has been demonstrated. Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder. At recommended doses, aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder. There is only limited information available on the use of aripiprazole in children and adolescents, and pilot data suggest that a revised dosing strategy, based on weight, is indicated in this population. In the long-term studies, the use of aripiprazole was associated with continued efficacy, good compliance and increased time-to-relapse. Aripiprazole represents the first functionally selective atypical antipsychotic drug.     

Quetiapine fumarate (Seroquel): a new atypical antipsychotic

The goal of antipsychotic drug development efforts over the past 10 years has been to develop agents with increased efficacy and safety and fewer of the side effects commonly associated with the older antipsychotic medications. The newer agents, often called atypical antipsychotics, are effective in treating both the positive and negative symptoms of schizophrenia and are associated with fewer neurological- and endocrine-related side effects compared to the older agents. As a result, patients are likely to remain on therapy longer, preventing relapses and costly hospitalizations. Quetiapine fumarate (Seroquel) is the most recently introduced atypical antipsychotic and is indicated for the management of the manifestations of psychotic disorders and schizophrenia. Quetiapine, like clozapine (the archetypal atypical antipsychotic), interacts with a broad range of neurotransmitter receptors and has a higher affinity for serotonin (5-HT(2A)) receptors relative to dopamine (D(2)) receptors in the brain. Further, quetiapine's pharmacological effects appear selective for the mesolimbic and mesocortical dopamine systems, which are believed to be the areas of the brain responsible for the therapeutic effects of antipsychotics. In contrast to most standard antipsychotics and some atypical antipsychotics, quetiapine's effects on the nigrostriatal dopamine system, which is responsible for the extrapyramidal (or motor) side effects, are minimal. Quetiapine also has minimal activity on dopamine receptors in the tuberoinfundibular dopamine system, thereby avoiding the problem of hyperprolactinemia, common with the standard antipsychotics and some atypical antipsychotics. Because of these properties, quetiapine is an effective antipsychotic agent with a relatively benign side effect profile. Several large, placebo- and active-controlled, multicenter trials have shown quetiapine to be effective against both positive (e.g., hallucinations, delusions) and negative symptoms (e.g., emotional withdrawal, apathy) and to have benefits in reducing hostility, aggression and affective symptoms. Patients on long-term treatment report high compliance, good satisfaction, increased ability to function and improvements consistent with a better quality of life. Because of quetiapine's excellent tolerability profile, its use is particularly appropriate in patients especially sensitive to adverse effects, e.g., elderly patients with psychotic symptoms and other neurological disorders such as Parkinson's and Alzheimer's disease.     

Systemic administration of amperozide,a new atypical antipsychotic drug,preferentially increases dopamine release in the rat medial prefrontal cortex

The putative atypical antipsychotic drug amperozide (APZ) shows high affinity for serotonin 5-HT₂ receptors but only low affinity for dopamine (DA) D₂ receptors. By employing microdialysis, we examined the effects of APZ on extracellular concentrations of DA in the nucleus accumbens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to affect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, SC) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a greater release of DA in the MPC (+ 127 and + 279%) than in the NAC (+ 52 and + 98%). The selective 5-HT₂ receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA output in the MPC (+ 25 and + 47%) compared with the NAC (+ 19 and + 21%). In contrast, the selective D₂ receptor antagonist raclopride (0.5 and 2.0 mg/kg, SC) increased DA release in the NAC (+ 65 and + 119%) to a greater extent than in the MPC (+ 45 and + 67%). These data suggest that the 5-HT₂ receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in the MPC. Infusion of low doses (1,10 µM, 40 min) of APZ through the probe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 µM, 40 min) resulted in a more pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in the MPC is most likely mediated at a level other than the terminal region. Taken together, the present results provide support for the notion that 5-HT₂ receptor antagonism may be of considerable significance for the action of atypical antipsychotic drugs on mesolimbocortical dopaminergic neurotransmission.     

Extended-release paliperidone: efficacy, safety and tolerability profile of a new atypical antipsychotic

Extended-release paliperidone is a new atypical antipsychotic chemically related to the well-known antipsychotic risperidone. It has been formulated in an osmotic controlled-release oral delivery system that minimizes peak-trough fluctuations and, by obviating dose-titration, allows once-daily dosing with a therapeutically active dose from the first day. Its pharmacokinetic profile is characterized by a mean time-to-peak plasma concentration of 24.1 hours and an elimination half-life of approximately 24 hours. A dose of 6 mg of paliperidone extended-release (ER) provides a mean striatal D2 receptor occupancy of 64%, approaching the accepted lower receptor occupancy threshold required for optimal antipsychotic activity without causing extrapyramidal symptoms. It undergoes minimal hepatic biotransformation and is mainly excreted unchanged in the urine with four metabolic products. Three pivotal randomized, double-blind, placebo-controlled, parallel-group six-week trials investigated the efficacy, safety and tolerability of paliperidone ER at doses of 3-15 mg/day. All doses produced a significant reduction in schizophrenia symptomatology, with an onset of effect as of day 4. Personal and social functioning also improved as measured by the Personal and Social Performance scale. A prevention of recurrence study showed that paliperidone ER effectively prolonged the time-to-recurrence versus placebo. Paliperidone ER was efficacious in young, elderly and recently diagnosed schizophrenia patients. Beneficial effects on sleep assessed objectively and subjectively with minimal daytime somnolence were demonstrated. Overall, it was well-tolerated and had placebo-like discontinuation rates for adverse events. There were some dose-related extrapyramidal symptoms, mostly mild to moderate in intensity and associated with minimal changes in the rating scales that assessed extrapyramidal symptom severity. Although prolactin elevation occurred with paliperidone ER, only few prolactin-related adverse events were reported. There were no signals for metabolic dysfunction in terms of glucose, insulin, lipid or triglyceride changes or any indicators of clinically relevant cardiac events. Body weight increased slightly, but the changes were acceptable in the context of the doses likely to be used clinically, and patients with higher initial body mass index gained less weight as has been reported for other antipsychotics.