Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although emotional dysfunction in patients with schizophrenia is thought to be associated with poorer outcomes in terms of overall quality of well-being, only a few basic studies have examined the biochemical effect of antipsychotics on emotional function. In this investigation, we examined differences in the effects of aripiprazole and haloperidol on the conditioned fear response in methamphetamine-sensitized and fear-conditioned rats in an in vivo microdialysis study. Aripiprazole is the first antipsychotic drug with an action involving partial dopamine D(2) receptor agonism, thus differing from haloperidol, a typical antipsychotic that shows selective dopamine D(2) receptor full antagonism. After exposure to a conditioned stimulus, methamphetamine-sensitized rats exhibited significantly higher dopamine release in the amygdala than unsensitized rats. We considered this hypersensitivity of dopamine release to be a biochemical marker of hypersensitivity and vulnerability to stress in psychosis. In the present study, we found that aripiprazole and haloperidol equally suppressed the marked increase in extracellular dopamine levels in fear-conditioned rats, whereas haloperidol increased and aripiprazole decreased tonic dopamine levels. In conclusion, the effect of an antipsychotic drug is likely to be involved in attenuation of the phasic increase in dopamine associated with the fear response, at least in the amygdala. In addition, the contrasting effects of haloperidol and aripiprazole on tonic dopamine levels in the amygdala are likely due to the difference in their actions (selective dopamine D(2) receptor full antagonist vs. partial agonist, respectively).
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PMID:Aripiprazole and haloperidol suppress excessive dopamine release in the amygdala in response to conditioned fear stress, but show contrasting effects on basal dopamine release in methamphetamine-sensitized rats. 1947 71

Aripiprazole, a partial dopamine agonist has been reported to help reduce symptoms of tardive dyskinesia (TD). In a prospective, open label study of a series of cases, we examined the effectiveness of aripiprazole in reducing TD symptoms. Six clinically stable patients with schizophrenia or Schizoaffective disorder and a moderate to severe TD participated in this study. They were systematically cross-titrated from their current medication to aripiprazole and maintained for 16 weeks. The mean extra pyramidal symptom score measured by Abnormal Involuntary Movement Scale (AIMS) improved from a baseline score of 15.8 to final score of 5 (paired t-test; P=0.0009). The severity of psychiatric symptoms remained unchanged. This study supports our hypothesis that clinically stable patients with moderate tardive dyskinesia who are under treatment with other first- or second-generation antipsychotics may benefit from switching to aripiprazole with a reduction of TD symptoms but with out any significant benefit in psychiatric symptoms. The results need to be viewed with caution and not considered as indicative of a viable treatment option for TD as this is an open label study, and a small sample size.
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PMID:Use of aripiprazole in tardive dyskinesia: an open label study of six cases. 1949 47

It seems that the efficacy of aripiprazole for treating schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole has also received approval for the treatment of bipolar disorder as adjunctive therapy or monotherapy (manic or mixed episodes) as well as an augmentation therapy of major depressive disorder (MDD) by the US FDA. The overall safety and tolerability of aripiprazole is favorable compared to other atypical antipsychotics across the approved indications. Aripiprazole showed a minimal propensity for clinically significant weight gain and metabolic disruption. However, extrapyramidal side effects, such as akathisia, are reported and may limit its clinical use in some cases, particularly in patients with bipolar disorder and MDD. This review focuses on the tolerability and safety of aripiprazole across a broad spectrum of psychiatric disorders while taking into consideration results from registrational studies as well as findings from studies in the naturalistic setting. In conclusion, whereas the comparative safety and tolerability of aripiprazole has not been systematically evaluated in comparator studies, tolerability and safety issues commonly associated with atypical antipsychotics such as weight gain and metabolic syndrome are less prominent with aripiprazole.
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PMID:A review of the safety and tolerability of aripiprazole. 1950 66

Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance, and diabetes mellitus. There are few options for olanzapine responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo-controlled, double-blind crossover study that examined 15 mg/d aripiprazole's effects on weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment, there were significant decreases in weight (P = 0.003) and body mass index (P = 0.004) compared with placebo. Total serum cholesterol (P = 0.208), high-density lipoprotein cholesterol (HDL-C; P = 0.99), HDL-2 (P = 0.08), HDL-3 (P = 0.495), and low-density lipoprotein cholesterol (P = 0.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (P = 0.001), total very low-density lipoprotein cholesterol (VLDL-C; P = 0.01), and VLDL-1C and VLDL-2C (P = 0.012) decreased significantly during the aripiprazole treatment phase. The VLDL-3C tended lower during aripiprazole, but the decrease was not significant (P = 0.062). There was a decrease in C-reactive protein comparing aripiprazole treatment to placebo, although it did not reach significance (P = 0.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity.
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PMID:Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. 2063 76

Aripiprazole is an atypical antipsychotic that has been shown to be more effective than placebo and at least as effective as haloperidol and risperidone in the treatment of schizophrenia and schizoaffective disorder. Despite having a well defined licensed dose range, the optimum dose for aripiprazole is yet to be established. Aripiprazole exhibits high affinity for dopamine D(2) receptors, with near maximal receptor occupancy at a dose of 30 mg. Even doses as low as 2 mg, thought not to be clinically effective, have produced striatal D(2) receptor occupancies exceeding 70%, higher than the accepted threshold for antipsychotic effect. In this review we examined the efficacy data from short-term studies of aripiprazole in relapsed schizophrenia or schizoaffective disorder, in order to establish a dose-response relationship for aripiprazole. Results of five fixed-dose studies suggest that the threshold for clinical effect is between 5 and 10 mg/day. In addition, the highest response rate is seen at 10 mg/day. Doses above 20 mg/day do not appear to provide any additional benefit and may be associated with a smaller change in symptom scores. In summary, the data available so far indicate that the optimum dose for aripiprazole is 10 mg/day and that doses above 20 mg/day provide no additional benefit.
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PMID:Aripiprazole: dose-response relationship in schizophrenia and schizoaffective disorder. 1968 67

We studied the effects of antipsychotics and a hypnotic on sleep disturbance in schizophrenia using an animal model of the disease. Electrodes for the electroencephalogram (EEG) and electromyogram (EMG) were chronically implanted into the cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalograph for 6 h (10:00 - 16:00). SleepSign ver. 2.0 was used for EEG and EMG analysis. Haloperidol and olanzapine had an antagonizing effect on the increases in sleep latency and total awake time and the decrease in total non-rapid eye movement (NREM) sleep time induced by MK-801. Olanzapine also antagonized the decrease in total rapid eye movement (REM) sleep time induced by MK-801. Aripiprazole antagonized only the increase in sleep latency induced by MK-801, whereas, risperidone, quetiapine, and flunitrazepam had no effect in the changes of sleep-wake pattern induced by MK-801. Olanzapine increased delta activity and decreased beta activity during NREM sleep. In contrast, flunitrazepam had an opposite effect. It was clarified that haloperidol and olanzapine were effective for decrease of sleep time in this animal model of schizophrenia. In addition, aripiprazole showed a sleep-inducing effect in schizophrenia model rat. On the other hand, flunitrazepam showed no beneficial effect on sleep disturbance in schizophrenia model rat.
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PMID:Effects of some antipsychotics and a benzodiazepine hypnotic on the sleep-wake pattern in an animal model of schizophrenia. 1972 30

Increasing evidence suggests that 5-HT1A receptors are involved in the pathophysiology and treatment of schizophrenia. This paper investigated 5-HT1A receptor mRNA expression and binding density in female rats treated with aripiprazole (2.25 mg/kg/day), olanzapine (1.5 mg/kg/day), haloperidol (0.3 mg/kg/day) or vehicle (control) orally three times/day for 1 or 12 weeks. Animals were sacrificed 48 h after the last administration. Aripiprazole significantly increased 5-HT1A receptor binding density by 33% in the CA1 region of the hippocampus and by 21% in the medial posterodorsal nuclei of posterior amygdala (MeP) compared to the control group after 1 week of treatment. Olanzapine significantly decreased 5-HT1A receptor binding density by 17-22% in Layers I-IV of the cingulate cortex after 1 week of treatment. Neither of these antipsychotic drugs affected 5-HT1A receptor binding density after 12 weeks drug treatment. As expected, haloperidol treatment did not have any significant effect on 5-HT1A binding density after 1 or 12 weeks of treatment. 5-HT1A receptor mRNA expression was not altered by antipsychotic treatment in any brain region. The results indicate that aripiprazole and olanzapine have differential effects on 5-HT1A receptor expression, which may contribute to their distinct profiles in improving negative symptoms and cognitive deficits in schizophrenia. Aripiprazole and olanzapine may produce adaptation and desensitization of 5-HT1A receptor expression after long term treatment.
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PMID:The effects of antipsychotic drugs administration on 5-HT1A receptor expression in the limbic system of the rat brain. 1977 83

Based on NMDA hypofunction hypothesis for negative symptoms and cognitive deficits in schizophrenia, MK-801-induced animal models of schizophrenia may help us understand the different effects between typical and atypical antipsychotics. On the other hand, the mitogen-activated protein kinase (MAPK) signaling pathways may participate in antipsychotic actions. The aim of this study was to investigate the effects of aripiprazole on MK-801-induced prepulse inhibition (PPI) disruption and MAPK phosphorylation in mice. To clarify the effects of aripiprazole on MK-801-induced PPI disruption, we measured PPI of 51 ddY male mice after aripiprazole was administered 15 min prior to the injection of MK-801, and measured activation of cytosol and nuclear MAPK phosphorylation by western blotting. Aripiprazole (4.0 mg/kg) significantly reversed the MK-801 (0.15 mg/kg)-induced PPI deficits. Pretreatment of aripiprazole (40 mg/kg) had a tendency to suppress MK-801 (1.0 mg/kg)-induced pMEK/MEK (Ser218/222) activation. In addition, aripiprazole treatment showed a significant decrease of pERK/ERK. Our data suggested that aripiprazole may reverse MK-801-induced PPI deficits through regulation of MAPK phosphorylation in the same way as the atypical antipsychotic drug, clozapine.
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PMID:Effects of aripiprazole on MK-801-induced prepulse inhibition deficits and mitogen-activated protein kinase signal transduction pathway. 2008 64

Alcohol dependence is a costly and socially devastating illness. The dopamine system has received increased attention due to the consensus that dopaminergic dysfunction is at the core of the addiction process. Agents that modulate this system might be beneficial in reducing craving, reward, and relapse. Aripiprazole is a 3(rd) generation atypical antipsychotic U.S. Food and Drug Administration-approved for the treatment of schizophrenia, bipolar disorder, and treatment-resistant major depression. Its principal mechanism of action appears to be associated with partial agonism at the D2 dopamine receptor. Nevertheless, relatively recent pre-clinical data shows that aripiprazole might exert its action by way of agonism, partial agonism, and antagonism at both dopamine and serotonin receptors. In animal models of alcoholism aripiprazole produced an overall decrease in drinking behavior. Clinical trials with aripiprazole in alcoholics have shown some positive, but inconsistent, results. Given aripiprazole's putative activity on frontal-subcortical circuits subserving reward/craving and impulsive behavior, it might prove to be beneficial for neuropsychiatric conditions in which dysregulation of reward and impulsivity, among them alcoholism, are at the core of the syndrome. This article proposes a potential role for aripiprazole in alcoholism treatment, and suggests that more randomized controlled trials should be designed at appropriate doses to better understand aripiprazole's potential role as a treatment option. More options are needed to treat alcoholics that fall into different subgroups (e.g., those with impulsive disorders), or non-responsive to available treatments. Early results with aripiprazole are promising and warrant further exploration.
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PMID:Aripiprazole: a drug with a novel mechanism of action and possible efficacy for alcohol dependence. 2020 15

When aripiprazole (ABILIFY) received its approval in Germany for the treatment of schizophrenia, a hospital-based postmarketing surveillance study was initiated in order to gain further insights concerning safety and efficacy of the antipsychotic under real-life conditions. Efficacy was rated by using standard CGI, GAF, and SF-12 instruments, whereas safety was evaluated according to the reports on adverse effects. Data from 799 patients with schizophrenia from 122 psychiatric hospitals returned for evaluation. Eighty percent of the patients were treated for 4 weeks with 10-30 mg/day aripiprazole (mean modal dose 15 mg/day). Within the observation period significant improvements of CGI, GAF, and SF-12 ratings was observed. Aripiprazole was tolerated well by the patients. Most frequent adverse effects were insomnia, irritability, restlessness, nausea and vomiting, in general being moderate to mild and corresponding to the known tolerability profile of aripiprazole. The results demonstrate that the administration of aripiprazole can result in an improvement of the symptoms of schizophrenia within 4 weeks in a real-life hospital-based in- and outpatient setting.
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PMID:Clinical use of aripiprazole in patients with schizophrenia: a real-life setting results from the German Postmarketing Surveillance Study. 2021 86


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