Typical Neuroleptic Agents Research Articles

Clinical utilization of atypical antipsychotics in pregnancy and lactation.

To analyze the available literature regarding the safety of atypical antipsychotics in pregnancy and lactation in order to recommend evidence-based strategies for pharmacologic management of psychosis in these conditions. We summarized the results from articles identified via MEDLINE/PubMed/TOXNET (1993-January 31, 2004), using the key terms pregnancy, lactation, breast-feeding, human milk, psychotropic drugs, atypical antipsychotics, olanzapine, quetiapine, risperidone, clozapine, ziprasidone, and aripiprazole. Retrospective studies, clinical observations, and case reports regarding the 6 atypical antipsychotics mentioned above were selected and analyzed. Extensive manual review of pertinent journals and textbooks was also performed. Reviewed studies show that olanzapine and clozapine apparently do not increase the teratogenic risk if administered to pregnant women, while evidence on quetiapine, risperidone, aripiprazole, and ziprasidone is still limited. In contrast, available information is not able to exclude unwanted serious effects associated with the use of all atypical antipsychotics on mother-infant dyads. Furthermore, more than a few studies suggest increased hyperglycemic risk for pregnant women related to atypical antipsychotic therapy during gestation. Finally, published evidence about the effects on long-term infant neurodevelopment of drug exposure through both placenta and breast milk is represented only by sporadic case reports. It is well known that potential consequences of an untreated psychotic episode may be severe and may lead to the mother attempting suicide and/or infanticide. For these reasons, clinicians need to help mothers weigh both fetal and neonatal risks of exposure to drugs against the potential risk they and their infant may incur if the psychiatric illness is not treated. On the other hand, atypical antipsychotics in pregnancy and breast-feeding do not show evident advantages in safety when compared with typical neuroleptic agents. Therefore, we suggest that the most relevant parameters for selecting the best clinical option for pregnant and breast-feeding women with schizophrenia and related disorders remain strongly related to 3 main points: (1). cautious evaluation of the risk/benefit ratio of fetal and neonatal drug exposure, (2). degree of severity of maternal psychiatric illness, and (3). careful preliminary choice of drugs characterized by a balanced safety/efficacy profile.

A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book

Background In recent years, numerous studies have examined whether new-generation antipsychotic agents impact cognitive impairment in patients with schizophrenia when compared with conventional antipsychotic treatment. The working assumption of such studies, supported by narrative reviews, is that the conventional antipsychotic medications have little or no effect on cognition. The studies concerning the effects of conventional neuroleptics on cognition, however, have never been analyzed quantitatively. In this meta-analysis, we revisit the question of whether typical agents might have enhancing effects on cognition. Methods The meta-analysis included studies that 1) compared the effects of typical neuroleptic agents with those of placebo or no medication on cognition; 2) examined adult patients identified as having schizophrenia; and 3) produced adequate data to estimate an effect size. Studies were identified by searches of computerized literature databases and by cross-referencing included studies. The effect size calculated was d, the difference between the means in cognitive measures of patients with schizophrenia taking and not taking conventional neuroleptic medication, divided by the pooled SD. Critically, when multiple measures were reported in a single article, effect sizes were combined so as to minimize the possibility that one study had undue weight simply because of the number of cognitive outcome variables that it contained. These results were corrected for bias due to sample size, with each of the effect sizes weighted by the reciprocal of its variance. The final sample after exclusion of outliers comprised 208 effect sizes from 34 studies. Results With a random-effects model, effect sizes from the primary studies were weighted according to sample size and averaged. The resulting mean effect size was .22 (95% confidence interval = .10, .34). The result is positive, in that the range did not include zero and was of low moderate size. No moderating effects of study design or patient qualities were found to be significant. With the same procedures, effect sizes for individual neurocognitive domains were computed. Effect sizes were generally in the .13–.29 range for the majority of cognitive functions, whereas motor function was impacted negatively (−.11). Unexpectedly, medication dose did not correlate with effect size. Conclusions Typical antipsychotic medication provides modest-to-moderate gains in multiple cognitive domains. Given unavoidable methodologic limitations of the primary studies, current findings suggest that the impact of conventional medication on cognitive function should be re-evaluated.

Economic Outcomes of Risperidone in Comparison to Typical Neuroleptic Agents for Treatment-Resistant Psychosis: A Community-Based Study

Objective: To compare the costs of treatment for psychosis with risperidone and typical neuroleptics in severely ill outpatients treated in a community mental health setting. Methods: This was an open, retrospective, controlled cohort comparison of actual costs of psychiatric treatment in a group of 17 patients treated with risperidone for psychotic disorders and 15 typical neuroleptic-treated controls matched for severity of illness. Assignment to the two groups was nonrandomized, and outcome data were gathered for the duration of the study for each subject, with dropouts included. Results: Risperidone use did not lead to increased treatment expenses compared with typical neuroleptic use in a mean of approximately nine months follow-up. The median overall cost per patient per year was $2,703 in the risperidone group, compared with $2,551 in the typical neuroleptic group (p = 0.64). Increased drug costs (mean expenses per patient per year: $1,631 for risperidone vs. $357 for typical neuroleptics; p = 0.005) were offset by reduced expenses due to decreased hospitalization rates (mean expenses per patient per year: $1,379 for risperidone vs. $3,920 for typical neuroleptics; p = 0.04). Use of other outpatient services did not significantly differ between the two groups. Conclusions: Use of risperidone led to lower hospitalization rates in this severely ill sample and did not lead to greater overall expense than typical neuroleptic use.

Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism.

Clozapine (CZP) is an atypical antipsychotic drug that does not appear to block striatal dopamine receptors. In six patients who met the criteria of HIV-associated psychosis and who had previously developed moderate parkinsonism as a result of the use of typical neuroleptic agents, CZP was added in an open, rising dose study. Subjects were evaluated at baseline after at least 7 days without neuroleptic drugs and then monthly for 3 months of the experimental treatment using three rating scales: Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). A significant reduction in psychopathology as represented in the BPRS total score (54.2 at baseline versus 23.9 at month 3) and CGI (2 and 8, respectively) was obtained with a mean CZP dose of 27.08 mg/day. Parkinsonism also improved by an average of 76.5% at the end of the study. One patient did not complete the study as a result of a progressive decrease in leukocyte count while on CZP. These preliminary results suggest that the pharmacologic properties of CZP may be of value in the management of HIV-psychotic patients.

An Open Trial of Clozapine in Thirty-Six Adolescents with Schizophrenia

A retrospective study of 36 adolescents with schizophrenia treated in open clinical trials with clozapine, following treatment failure on at least 2 conventional neuroleptic medications, demonstrated that 75% (27 of 36) showed notable symptomatic improvement. Four adolescents (11%) showed an essentially complete remission of symptoms. The majority of patients became able to participate in a comprehensive rehabilitation program. Positive symptoms of schizophrenia were more responsive to clozapine than were negative symptoms, but certain negative symptoms showed some modest improvement. Three patients (8%) did not respond to clozapine, and six patients (17%) required discontinuation of treatment due to adverse effects, so a total of 25% of these adolescents did not respond to clozapine treatment. Leukopenia (without agranulocytosis) was observed in 8% (three patients), which is consistent with findings in adults. Unexpectedly, some extrapyramidal symptoms were observed. Mean dose was 330 mg daily (range, 50-800 mg daily), and the mean duration of these open clinical trials was 154 days. In prior treatments with typical neuroleptic agents, these 36 adolescents with schizophrenia had shown nonresponse, worsening of symptoms, or significant adverse effects. Although controlled research protocols are needed to evaluate this medication in adolescents, these clinical data suggest that clozapine may enrich the range of possible therapeutic interventions for adolescents with schizophrenia that is resistant to typical neuroleptic treatment. However, the safety of this treatment in adolescents requires considerably greater study, especially in view of the extrapyramidal side effects observed in some adolescents.

HP 818: A centrally acting analgesic with neuroleptic properties

AbstractHP 818 (1‐benzoyl‐6‐fluoro‐3‐(1‐methyl‐4‐piperidinyl)‐1H‐indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED50 values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self‐stimulation assays (ED50 values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine‐ and apomorphine‐induced stereotypy, indicative of D2‐dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.

A comparison of the abilities of typical neuroleptic agents and of thioridazine, clozapine, sulpiride and metoclopramide to antagonise the hyperactivity induced by dopamine applied intracerebrally to areas of the extrapyramidal and mesolimbic system

Dopamine injected directly into the caudate-putamen, nucleus accumbens or tuberculum olfactorium of rat brain, following a nialamide pretreatment, caused dose-dependent hyperactivity. The hyperactivity was more intense after injections into the nucleus accumbens, but was limited by the development of stereotyped biting when larger doses of dopamine were injected into the caudat-putamen or tuberculum olfactorium. Haloperidol, fluphenazine and pimozide were shown to antagonise, in a dose-dependent manner, the hyperactivity induced by dopamine from all 3 areas. Pimozide appeared equieffective against the 3 hyperactivity responses but haloperidol and fluphenazine more readily antagonised the dopamine hyperactivity mediated from the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium. Sulpiride, clozapine and thioridazine also caused dose-dependent reductions in the hyperactivity induced by dopamine injections into the caudate—putamen, nucleus accumbens and tuberculum olfactorium, although the doses required to effect this inhibition were notably larger than for the typical neuroleptics. Generally, these atypical agents were also least effective as antagnnists of the hyperactivity following intrastrial dopamine. Metoclopramide differed from all other agents tested in failing to antagonise the hyperactivity induced by dopamine injections into the nucleus accumbens. However, the responses to dopamine from the caudate-putamen and tuberculum olfactorium were both antagonised by metoclopramide, the striatal response being the least sensitive. The α-and β-adrenergic blocking agents, aceperone and propranolol, failed to reduce the hyperactivity induced by dopamine injections into the caudate—putamen, nucleus accumbens or tuberculum olfactorium. The abilities of the agents tested to antagonise a hyperactivity induced by dopamine in the striatum or in the mesokimbic areas, the nucleus accubens and tuberculum olfactorium, are compared with the potential of these agents to induce extrapyramidal side effects and to exert an antipsychotic action in man.

Antagonism of the hyperactivity induced by dopamine applied intracerebrally to the nucleus accumbens septi by typical neuroleptics and by clozapine, sulpiride and thioridazine

Dopamine administered intracerebrally to the nucleus accumbens septi was shown to induce a dose-dependent hyperactivity following pretreatment with nialamide. This effect was optimum following the injection of 50 μg dopamine. The hyperactivity induced by this dose of dopamine was inhibite by the i.p. injection of both the typical neuroleptic agents, haloperidol, fluphenazine, pimozide and clothiapine (0.5–.5 mg/kg i.p.), and the atypical neuroleptics clozapine, sulpiride and thioridazine (0.5–20 mg/kg i.p.) although, generally, the doses required of the latter were in the order of 20–100 times those of the typical agents to produce and equivalent effect. In contrast, cataleptic doses of metoclopramide (10–30 mg/kg i.p.) failed to reduce the dopamine-induced hyperactivity: aceperone and propanolol were similarly ineffective. However, inhibition of hyperactivity was recorded following the peripheral administration of the antimanic drug, IB503. It is suggested that the ability of a drug to antagonise the hyperactivity induced by the injection of dopamine into the nucleus septi may be of value in the detection of antipsychotic activity.