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The dimeric derivative of aripiprazole was synthesized via the two notable synthetic technologies as a key step: (1) efficient aldehyde bis-arylation by Bi(OTf)(3) and (2) facile Wynberg amination at room temperature. The synthesis has established the structural identity with the minor contaminant sometimes present in Aripiprazole.
BACKGROUND: Delirium is a common condition frequently seen in consultation-liaison psychiatry. It is especially common among medically compromised patients and is an indicator of the severity of the medical illness. In addition, it is associated with a higher morbidity, mortality or longer hospitalization. Traditionally, haloperidol has been used to treat delirium-associated agitation. However, atypical antipsychotics are being increasingly used to treat delirium. METHODS: Two case studies of delirium that were treated with 30 mg and 15 mg aripiprazole were described. The improvement of delirium was monitored using the Mini-Mental Status Exam (MMSE) and Delirium Rating Scale (DRS). RESULTS: In both cases, the patients' confusion, disorientation, and agitation improved within 7 days of treatment. In the first case, the patient's MMSE score improved from 5 to 28, while his DRS score decreased from 28 to 6. In the second case, her MMSE score improved from 7 to 27, while her DRS score went down from 18 to 6. CONCLUSIONS: To the best of our knowledge, this is the first report on the utilization of aripiprazole in the successful treatment of delirium. Although these cases showed positive results, future studies should be performed in order to further substantiate its use in delirium treatment.
Aripiprazole is a newer atypical antipsychotic agent used for effective treatment of schizophrenia. It significantly reduces unwanted side effects of older typical antipsychotics by targeting, with high affinity, dopamine D2/D3 and serotonin 5-HT1A/5-HT-2A receptors. Its documented mechanism of action makes it an unlikely agent to cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present the first reported case of SIADH caused by aripiprazole in a patient with history of schizophrenia without other precipitating factors to explain hyponatremia or SIADH.
Dopamine receptor antagonism is associated not only with antipsychotic action, but also with the generation of extrapyramidal side-effects of antipsychotic medications. Positron emission tomography studies reveal that an approximate 60-70% blockade of the D2 receptors is required for typical antipsychotics to be efficacious, but a blockade of > or =75-80% results in acute extrapyramidal side-effects. The newer atypical antipsychotics have a lower propensity to produce extrapyramidal side-effects. A new class of antipsychotics with a novel pharmacological profile and improved tolerability have emerged, comprising the 'dopamine-serotonin system stabilizers' of which aripiprazole is the first agent. We present the case of a patient who developed parkinsonism during treatment with aripiprazole.
OBJECTIVE: We conducted this 6-week open-label trial to examine the effects of adjunctive aripiprazole in clozapine-treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia. METHOD: Ten clozapine-treated subjects received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. Eighty percent were male, the mean age was 38.7 +/- 8.9 years and the mean clozapine dose was 455 +/- 83 mg daily. RESULTS: There was a significant decrease in weight (P = 0.003), body mass index (P = 0.004), fasting total serum cholesterol (P = 0.002) and total triglycerides (P = 0.04) comparing baseline to study endpoint. There was no significant change in total Positive and Negative Syndrome Scale scores. CONCLUSION: This combination may be useful for clozapine-associated medical morbidity and must be studied in placebo-controlled double-blind randomized trials to determine efficacy and safety.
OBJECTIVE: Problems related to illegal amphetamine use have become a major public health issue in many developed countries. To date, evidence on the effectiveness of psychosocial treatments has remained modest, and no pharmacotherapy has proven effective for amphetamine dependence. METHOD: Individuals meeting DSM-IV criteria for intravenous amphetamine dependence (N=53) were randomly assigned to receive aripiprazole (15 mg/day), slow-release methylphenidate (54 mg/day), or placebo for 20 weeks. The study was terminated prematurely due to unexpected results of interim analysis. An intention-to-treat analysis was used. The primary outcome measure was the proportion of amphetamine-positive urine samples. RESULTS: Patients allocated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (odds ratio=3.77, 95% CI=1.55-9.18), whereas patients who received methylphenidate had significantly fewer amphetamine-positive urine samples than patients who had received placebo (odds ratio=0.46, 95% CI=0.26-0.81). CONCLUSIONS: Methylphenidate is an effective treatment for reducing intravenous drug use in patients with severe amphetamine dependence.
This paper is an overview of recently published research concerning the neuroleptic drug aripiprazole. Aripiprazole is an antipsychotic drug with high affinity for D(2)- and D(3)-receptors and the dopamine autoreceptor. It also has serotonin 5-HT(1A)-receptor partial agonist and 5-HT(2A)-receptor antagonist properties. It is prescribed in the treatment of schizophrenia and is under the treatment of schizophrenia and schizoaffective investigation for treatment of bipolar disorder. The drug is given by mouth in an initial dose of 10 or 15 mg once daily. The dose may be adjusted at intervals of not less than 2 weeks up to a maximum of 30 mg daily. It appears to be useful in disorder and has a better side-effect profile than haloperidol.
Second-generation antipsychotic medications offer a broader range of therapeutic efficacies than first-generation agents. Consequently, our field has witnessed a rapid expansion of the use of second-generation antipsychotic drugs for several conditions beyond psychosis. The use of second-generation antipsychotic medications has been most pronounced in mood disorders, especially in bipolar disorders. Information about the agents clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole in terms of their efficacy and tolerability in bipolar disorder is now available. Aripiprazole, a new agent whose proposed mechanism(s) of action differs from that of other agents, has been shown in placebo-controlled comparative trials in bipolar patients to be an effective and well tolerated treatment option for this patient group. The role of second-generation antipsychotic medications in the therapeutic armamentarium for bipolar disorders will be determined by clinical experience, by additional phase IV studies and by trials that compare second-generation antipsychotics with each other and also with mood-stabilizing medications. There is also a pressing need for additional information on the long-term efficacy and safety of each second-generation antipsychotic agent during maintenance therapy for bipolar disorders.
OBJECTIVE: Delirium is a common condition frequently seen in consultation-liaison psychiatry. It is especially common among medically compromised patients, and is an indicator of the severity of the medical illness. In addition, it is associated with a higher morbidity, mortality, and longer hospitalization. Traditionally, haloperidol has been used to treat agitation as it may occur in delirium. However, atypical antipsychotics are being increasingly used to treat delirium. METHOD: In this article, we will describe two cases of delirium successfully treated with aripiprazole. RESULTS: Both patients had significant improvement in their delirium as measured by the delirium rating scale. CONCLUSION: Aripiprazole appears to be effective in reducing the symptoms of delirium.
OBJECTIVE: Substance abuse is extremely common in patients with bipolar disorders, although minimal data are available on the treatment of this important clinical population. Aripiprazole is an atypical antipsychotic that is approved for the treatment of mania and that has a novel mechanism of action, acting as a dopamine-2 receptor partial agonist, thereby increasing dopamine release in some parts of the brain and decreasing dopa-mine release in other brain regions. Dopamine release is implicated in substance use, and both dopaminergic agonists and antagonists have been examined for the treatment of substance abuse. To our knowledge, dopa-mine receptor partial agonists have not been investigated for treatment of substance abuse in humans. METHOD: Twenty antipsychotic-treated patients with bipolar or schizoaffective disorder and current substance abuse were switched to open-label aripipra-zole using an overlap and taper method. At baseline, diagnoses were confirmed using the Mini-International Neuropsychiatric Interview based on DSM-IV criteria. Psychiatric symptoms, side effects, and substance use and craving were assessed over 12 weeks. Psychiatric symptoms were assessed with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS). Substance craving was assessed with visual analogue scales, and side effects were monitored using the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Barnes Akathisia Scale, and patient report. Study enrollment was from April 2003 to February 2004. RESULTS: Significant baseline-to-exit improvement in HAM-D (p = .002), YMRS (p = .021), and BPRS (p = .000) scores were observed without a significant change in antipsychotic-induced side effect scales. In 17 participants with current alcohol dependence, significant reductions in dollars spent on alcohol (p = .042) and alcohol craving (p = .003) were found. In 9 participants with cocaine-related disorders, significant reductions in cocaine craving (p = .014), but not use, were found. CONCLUSION: A change to aripiprazole was associated with symptomatic improvement. Limitations of the study include a small sample size, high attrition, and an open-label design. Controlled trials in dual-diagnosis patients are needed to confirm these findings.
Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butyloxy}-3,4-dihydro-2(1H)-quinolinone, is an atypical antipsychotic medication inaugurating the newest class of atypical antipsychotics: the partial dopamine agonists. It has a particularly long half-life of elimination and variable metabolism secondary to genetic polymorphism. We report an unintentional overdose of 195 mg (17.1 mg/kg) of aripiprazole in a 2.5 year-old child. This patient exhibited CNS depression not requiring respiratory support and without significant cardiovascular effects. CNS effects persisted for almost 2 weeks postingestion.
Neuroleptic malignant syndrome (NMS) is a rare disorder seen most often in patients exposed to antipsychotic medications. This syndrome is generally manifested by hyperthermia, muscle rigidity, autonomic instability, altered mental status, tremors, elevated serum creatinine phosphokinase and leucocytosis. It was first described by Delay during the 1960s. It is considered a medical emergency and is fatal if not promptly addressed. It is clinically relevant not only to psychiatrists but all clinicians since patients taking neuroleptics are seen by physicians from virtually every specialty. Relevant studies report a mortality rate of 10-20%. Conditions that share some features of NMS but have different treatment regimens include serotonergic syndrome, lethal catatonia, malignant hyperthermia, infections and various heat disorders. The importance of recognition and prompt intervention can not be overemphasized. Fever is a predominant symptom in NMS. The authors present an unusual case of NMS in a schizophrenic patient without fever who had been on aripiprazole. To date, there are only three possible reported cases of NMS related to aripiprazole. This case report serves to remind clinicians of the essential features in the diagnosis and management of NMS.
RATIONALE: Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D(3) and (less potently) D(2) receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936-950, 2004a; Millan et al., J Pharmacol Exp Ther 309:903-920, 2004b; Millan et al., J Pharmacol Exp Ther 309:921-935, 2004c). OBJECTIVES: To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents. MATERIALS AND METHODS: Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline. RESULTS: S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (+/-) S31411, and to its inactive (-) distomer, S32601. Apomorphine, and the selective D(3)/D(2) receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D(4) and D(1)/D(5) receptor agonists were ineffective. The selective D(3) vs D(2) receptor partial agonist, BP897, did not substitute for S32504 and the selective D(3) receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D(2) vs D(3) receptor antagonists, L741,626 and S23199, and by the D(2)/D(3) antagonists, raclopride and haloperidol. The D(2)/D(3) receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties. CONCLUSION: The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D(2) receptors Antipsychotics known to act as partial agonists at D(2)/D(3) receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites.
OPC-14597 {aripiprazole; 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl) butyloxy)-3,4-dihydro-2(1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest affinity for D2L and D2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D2L receptors, although the metabolite DM-1451 behaved as a pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D2L/D2S rather than D3 or D4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D2) in distinct cellular locales.
We report the case of an elderly woman with Alzheimer's disease, risk factors for vascular dementia, and atrium-ventricular blockade, who presented with severe agitation and psychosis. She was treated with aripiprazole and assessed with the Neuropsychiatric Inventory (NPI) over the course of 14 weeks. NPI scores showed a marked decrease in psychosis and agitation at week 4, and complete recovery at week 14, except for depression.
Ten aripirazole (CAS 129722-12-9) derivatives were prepared and examined for dopamine receptor antagonist activity. The structures of these newly synthesized compounds were confirmed by their elemental analyses and by IR, 1H-NMR and mass spectra. It was demonstrated that all the new compounds have dopamine receptor antagonist activity to a certain extent. Three compounds showed more potent activity than aripiprazole.
The discovery of antipsychotic medications has revolutionized the treatment of schizophrenia and other psychotic disorders. However, side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), electrocardiogram (ECG) changes, weight gain, and metabolic disturbances indicate the continued need to develop new agents. The introduction of atypical drugs such as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone has widened our choices. This article provides an overview of the pharmacology, efficacy, and techniques for the clinical use of aripiprazole, a novel agent with a unique pharmacological profile.
The treatment of the Gilles de la Tourette syndrome (GTS) is often challenging. One reason for this is the high neuropsychiatric cormorbidity in terms of ADHD or obsessive-compulsive symptoms. Dopaminergic modulation e.g. with antidopaminergic medication is an important part of the medical therapy aimed at motor and vocal tics. We report recent experiences with treatment with aripiprazole, a novel antipsychotic agent, which not only improved motor and vocal tics but also ameliorated some behavioural symptoms of the GTS cluster. Furthermore, we discuss possible pharmacological mechanisms for the observed effects.