Keck Jr PE, McElroy SL.
Aripiprazole: a partial
dopamine D2 receptor agonist antipsychotic.
Investig Drugs. 2003 Apr;12(4):655-62.
"This paper reviews the clinical
pharmacology, efficacy and safety of the novel antipsychotic drug aripiprazole.
All published citations regarding aripiprazole were reviewed using a Medline((R))
search (completed for citations through mid-year, 2002). In addition, abstracts
from recent scientific meetings presenting data not yet published (nor peer-reviewed)
were reviewed. Aripiprazole has a unique mechanism of action as a dopamine D2
partial agonist, serotonin 5-HT(1A) partial agonist and serotonin 5-HT(2A) antagonist.
Like other new antipsychotics, aripiprazole has the profile of an atypical agent,
with efficacy in the treatment of positive and negative symptoms of psychosis
as well as mood symptoms, a low rate of neurological side effects and no significant
adverse effect on serum prolactin concentrations. In addition, aripiprazole was
not associated with significant weight gain or QTc prolongation in both acute
and long-term treatment trials." [Abstract]
V, Fourie J, Ozdener F.
Aripiprazole (Otsuka Pharmaceutical Co).
Curr Opin Investig Drugs 2002 Jan;3(1):113-20
in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual
dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the
potential treatment of psychoses including schizophrenia , . A
regulatory filing for schizophrenia in the US was submitted at the end of 2001
. The compound entered phase III trials in Japan in 1995 . Although
presynaptic dopamine autoreceptor agonists may be efficacious in the treatment
of schizophrenia, they may also potentially increase the risk for exacerbation
of psychosis through stimulation of postsynaptic dopaminergic receptors ,
, . However, earlier neuropharmacology studies have shown that
aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic
effect at the postsynaptic D2 receptors , , , ,
. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy,
without causing catalepsy , . Moreover, in contrast to classical
antipsychotics that produce disabling movement disorders, aripiprazole does not
cause an upregulation of D2 receptors or an increase in expression of the c-fos
mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects
(EPS) during aripiprazole treatment , , , . Collectively,
aripiprazole is an important atypical antipsychotic candidate with a favorable
safety profile. Moreover, the mechanism of action of aripiprazole differentiates
it from both typical and atypical antipsychotics and hence, may provide important
leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January
2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500
million . In February 2001, Credit Suisse First Boston predicted sales
of US $403 million in 2005 ." [Abstract]
Aripiprazole: a review of its pharmacology and clinical use.
J Clin Pract. 2003 Jan-Feb;57(1):49-54.
"Atypical antipsychotics generally
have a lower propensity for extrapyramidal side-effects (EPSE), hyperprolactinaemia
and tardive dyskinesia than that associated with typical antipsychotics but may
still produce troublesome side-effects, such as weight gain, cardiac rhythm changes
and impaired glucose tolerance. Aripiprazole is a new atypical antipsychotic with
a unique receptor binding profile that combines partial agonist activity at D2
and 5HT1A receptors with potent antagonism at 5HT2A receptors. Clinical studies
in acute schizophrenic relapse, chronic schizophrenia and acute mania show it
is robustly more effective than placebo. Once-daily aripiprazole 15-30 mg is as
effective as haloperidol 10 mg/day and risperidone 6 mg/day in short-term treatment
of schizophrenia and more effective than haloperidol 7-10 mg/day in maintenance
of response in chronic schizophrenia. Aripiprazole appears to be well tolerated,
with most studies suggesting a frequency of adverse effects similar to placebo.
Aripiprazole seems not to cause significant EPSE, hyperprolactinaemia, excessive
weight gain or cardiac rhythm disturbance. Limited data suggest that aripiprazole
is not associated with impaired glucose tolerance." [Abstract]
SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G,
Aripiprazole, an Antipsychotic With a Novel Mechanism
of Action, and Risperidone vs Placebo in Patients With Schizophrenia and Schizoaffective
Arch Gen Psychiatry. 2003 Jul; 60(7): 681-90.
Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity
at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This
multicenter trial examined the efficacy, safety, and tolerability of aripiprazole
in patients with acute exacerbation of schizophrenia or schizoaffective disorder.
METHODS: In this 4-week double-blind study, 404 patients were randomized to 20
mg/d (n = 101) or 30 mg/d (n = 101) of aripiprazole, placebo (n = 103), or 6 mg/d
of risperidone (n = 99). Efficacy assessments included Positive and Negative Syndrome
Scale (PANSS) scores and Clinical Global Impression scores. Safety and tolerability
evaluations included extrapyramidal symptoms and effects on weight, prolactin,
and corrected QT (QTc) interval. RESULTS: Aripiprazole (20 and 30 mg/d) and risperidone
(6 mg/d) were significantly better than placebo on all efficacy measures. Separation
from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole
and risperidone and for PANSS negative scores with aripiprazole. There were no
significant differences between aripiprazole and placebo in mean change from baseline
in the extrapyramidal symptom rating scales. Mean prolactin levels decreased with
aripiprazole but significantly increased 5-fold with risperidone. Mean change
in QTc interval did not differ significantly from placebo with any active treatment
group. Aripiprazole and risperidone groups showed a similar low incidence of clinically
significant weight gain. CONCLUSIONS: Aripiprazole is effective, safe, and well
tolerated for the positive and negative symptoms in schizophrenia and schizoaffective
disorder. It is the first non-D2 receptor antagonist with clear antipsychotic
effects and represents a novel treatment development for psychotic disorders."
JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW.
and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia
and schizoaffective disorder.
J Clin Psychiatry. 2002 Sep;63(9):763-71.
Aripiprazole is an investigational agent for treating schizophrenia that has a
novel pharmacologic profile. The present study investigated the efficacy, safety,
and tolerability of aripiprazole and haloperidol compared with placebo. METHOD:
A 4-week, double-blind, randomized study, conducted at 36 U.S. centers between
July 1997 and June 1998, compared aripiprazole (15 mg/day, 30 mg/day) to placebo,
with haloperidol (10 mg/day) as an active control. Fixed doses of each agent were
administered from day 1 throughout the study. A total of 414 patients with a primary
DSM-IV diagnosis of schizophrenia or schizoaffective disorder were randomized.
Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total,
PANSS positive, PANSS negative, PANSS-derived Brief Psychiatric Rating Scale (BPRS)
core, Clinical Global Impressions (CGI)-Severity of Illness, and mean CGI-Improvement
scores. Safety and tolerability evaluations included extrapyramidal symptoms (EPS),
weight gain, serum prolactin level, and QTc interval. RESULTS: Both doses of aripiprazole
and haloperidol, 10 mg, produced statistically significant (p < or = .05) improvements
from baseline in PANSS total, PANSS positive, PANSS-derived BPRS core, and CGI-Severity
scores and significantly lower CGI-Improvement scores at endpoint, compared with
placebo. Aripiprazole, 15 mg, and haloperidol, 10 mg, significantly improved PANSS
negative score compared with placebo. Both aripiprazole doses and haloperidol
separated from placebo for PANSS total scores at week 2. Unlike haloperidol, aripiprazole
was not associated with significant EPS or prolactin elevation at endpoint compared
with placebo. There were no statistically significant differences in mean changes
in body weight across the treatment groups versus placebo, and no patients receiving
aripiprazole experienced clinically significant increases in QTc interval. CONCLUSION:
Aripiprazole, effective against positive and negative symptoms, is a safe and
well-tolerated potential treatment for schizophrenia and schizoaffective disorder."
TA, Carson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG; Aripiprazole Study
Aripiprazole for the prevention of relapse in stabilized patients
with chronic schizophrenia: a placebo-controlled 26-week study.
Clin Psychiatry. 2003 Sep; 64(9): 1048-56.
"BACKGROUND: Aripiprazole is
a novel antipsychotic for the management of schizophrenia. This study investigated
the efficacy, safety, and tolerability of aripiprazole in preventing relapse in
adult chronic schizophrenia patients experiencing ongoing stable symptomatology.
METHOD: In this 26-week, randomized, double-blind, placebo-controlled, parallel-group,
multi-center study, 310 patients with DSM-IV schizophrenia (mean Positive and
Negative Syndrome Scale [PANSS] total score = 82) were randomly assigned to receive
a once-daily fixed dose of aripiprazole, 15 mg, or placebo. The primary outcome
measure was time to relapse following randomization. Secondary objectives were
to assess the efficacy, safety, and tolerability of aripiprazole, 15 mg, compared
with placebo, in the study population. The study was conducted between Dec. 21,
2000, and Aug. 20, 2001. RESULTS: The time to relapse following randomization
was significantly (p < .001) longer for aripiprazole compared with placebo.
More patients relapsed with placebo (N = 85; 57%) than aripiprazole (N = 50; 34%);
the relative risk of relapse for the aripiprazole group was 0.59 (p < .001).
Aripiprazole was significantly superior to placebo from baseline to endpoint in
PANSS total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale, and
Clinical Global Impressions-Severity of Illness scale (CGI-S) scores and demonstrated
significantly better mean Clinical Global Impressions-Global Improvement scale
scores (p < or = .01 for all comparisons except CGI-S: .01 < p < or =
.05). Aripiprazole was well tolerated, with no evidence of marked sedation and
no evidence of hyperprolactinemia or prolonged heart rate-corrected QT interval
(QTc). Extrapyramidal symptoms were comparable in the aripiprazole and placebo
groups. Modest mean weight loss at endpoint was evident in both groups. CONCLUSION:
Aripiprazole, 15 mg once daily, is an effective, well-tolerated treatment for
prevention of relapse in patients with chronic, stable schizophrenia." [Abstract]
S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus
R, Pigott T.
Efficacy and safety of aripiprazole vs. haloperidol
for long-term maintenance treatment following acute relapse of schizophrenia.
J Neuropsychopharmacol. 2003 Dec; 6(4): 325-37.
"Aripiprazole is a novel
atypical antipsychotic for the treatment of schizophrenia. It is a D2 receptor
partial agonist with partial agonist activity at 5-HT1A receptors and antagonist
activity at 5-HT2A receptors. The long-term efficacy and safety of aripiprazole
(30 mg/d) relative to haloperidol (10 mg/d) were investigated in two 52-wk, randomized,
double-blind, multicentre studies (using similar protocols which were prospectively
identified to be pooled for analysis) in 1294 patients in acute relapse with a
diagnosis of chronic schizophrenia and who had previously responded to antipsychotic
medications. Aripiprazole demonstrated long-term efficacy that was comparable
or superior to haloperidol across all symptoms measures, including significantly
greater improvements for PANSS negative subscale scores and MADRS total score
(p&0.05). The time to discontinuation for any reason was significantly greater
with aripiprazole than with haloperidol (p=0.0001). Time to discontinuation due
to adverse events or lack of efficacy was significantly greater with aripiprazole
than with haloperidol (p=0.0001). Aripiprazole was associated with significantly
lower scores on all extrapyramidal symptoms assessments than haloperidol (p&0.001).
In summary, aripiprazole demonstrated efficacy equivalent or superior to haloperidol
with associated benefits for safety and tolerability. Aripiprazole represents
a promising new option for the long-term treatment of schizophrenia." [Abstract]
SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto
Aripiprazole in the treatment of schizophrenia: safety and tolerability
in short-term, placebo-controlled trials.
2003 Jun 1;61(2-3):123-36.
"Aripiprazole is a novel antipsychotic with
a unique mechanism of action. Presented here is a pooled analysis of safety and
tolerability data from all completed short-term, placebo-controlled trials in
schizophrenia from the aripiprazole clinical development program. Data were analyzed
from five 4- to 6-week double-blind multicenter studies of patients hospitalized
with acute relapse of schizophrenia or schizoaffective disorder randomized to
aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole
doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports,
EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole
was well tolerated, with similar AE incidence rates to placebo, and lower rates
than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective
EPS assessments demonstrated no significant differences between aripiprazole and
placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes
Akathisia scores, and significant reductions in Abnormal Involuntary Movement
Scale (AIMS) scores from baseline vs. placebo (p</=0.01). Haloperidol showed
increased SAS and Barnes Akathisia scores over placebo (p</=0.01). There was
minimal mean weight change with aripiprazole (+0.71 kg) and haloperidol (+0.56
kg), and a lack of QT(c) prolongation. Serum prolactin increased with haloperidol,
but not aripiprazole. In conclusion, aripiprazole shows a favorable safety and
tolerability profile with low potential for EPS, weight gain, prolactin elevation,
QT(c) prolongation, and sedation. Aripiprazole's safety profile may offer benefits
in schizophrenia treatment." [Abstract]
Goodnick PJ, Jerry JM.
safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia
and schizoaffective disorder.
J Clin Psychiatry 2002 Sep;63(9):763-71
"BACKGROUND: Aripiprazole is an investigational agent for treating schizophrenia
that has a novel pharmacologic profile. The present study investigated the efficacy,
safety, and tolerability of aripiprazole and haloperidol compared with placebo.
METHOD: A 4-week, double-blind, randomized study, conducted at 36 U.S. centers
between July 1997 and June 1998, compared aripiprazole (15 mg/day, 30 mg/day)
to placebo, with haloperidol (10 mg/day) as an active control. Fixed doses of
each agent were administered from day 1 throughout the study. A total of 414 patients
with a primary DSM-IV diagnosis of schizophrenia or schizoaffective disorder were
randomized. Efficacy measures included the Positive and Negative Syndrome Scale
(PANSS) total, PANSS positive, PANSS negative, PANSS-derived Brief Psychiatric
Rating Scale (BPRS) core, Clinical Global Impressions (CGI)-Severity of Illness,
and mean CGI-Improvement scores. Safety and tolerability evaluations included
extrapyramidal symptoms (EPS), weight gain, serum prolactin level, and QTc interval.
RESULTS: Both doses of aripiprazole and haloperidol, 10 mg, produced statistically
significant (p < or = .05) improvements from baseline in PANSS total, PANSS
positive, PANSS-derived BPRS core, and CGI-Severity scores and significantly lower
CGI-Improvement scores at endpoint, compared with placebo. Aripiprazole, 15 mg,
and haloperidol, 10 mg, significantly improved PANSS negative score compared with
placebo. Both aripiprazole doses and haloperidol separated from placebo for PANSS
total scores at week 2. Unlike haloperidol, aripiprazole was not associated with
significant EPS or prolactin elevation at endpoint compared with placebo. There
were no statistically significant differences in mean changes in body weight across
the treatment groups versus placebo, and no patients receiving aripiprazole experienced
clinically significant increases in QTc interval. CONCLUSION: Aripiprazole, effective
against positive and negative symptoms, is a safe and well-tolerated potential
treatment for schizophrenia and schizoaffective disorder." [Abstract]
DE, Carson WH, Saha AR, Liebeskind A, Ali MW, Jody D, Ingenito GG.
patients to aripiprazole from other antipsychotic agents: a multicenter randomized
Psychopharmacology (Berl). 2003 Apr;166(4):391-9.
Epub 2003 Feb 28.
"RATIONALE. Switching patients from one antipsychotic
to another can lead to tolerability problems or transient symptom exacerbations.
It is important to compare switching strategies to determine which methods produce
the best possible patient outcomes. OBJECTIVE. To investigate the efficacy, safety
and tolerability of three dosing strategies for switching chronic, stable patients
with schizophrenia from current oral antipsychotic monotherapy to once-daily oral
aripiprazole monotherapy. METHOD. Patients in this 8-week, open-label, outpatient
study were randomized to: 1) immediate initiation of 30 mg/day aripiprazole with
simultaneous immediate discontinuation of current antipsychotic; 2) immediate
initiation of 30 mg/day aripiprazole while tapering off current antipsychotic
over 2 weeks; or 3) up-titrating aripiprazole to 30 mg/day over 2 weeks, while
simultaneously tapering off current antipsychotic. Efficacy assessments included
PANSS, CGI-S, and CGI-I scores. Safety assessments included: adverse events (AEs)
recording, evaluation of extrapyramidal symptoms (EPS), vital signs, ECG, and
clinical laboratory tests. RESULTS. Efficacy with aripiprazole was maintained
during the study with numerical improvements compared with baseline in all three
groups. The overall incidence of AEs was broadly comparable across all groups,
and AEs were generally mild to moderate in severity and time-limited. Discontinuations
due to AEs were comparable across the groups. No deterioration in EPS occurred
in any group. The reduction in body weight and plasma prolactin levels following
switch to aripiprazole were comparable across the three groups. CONCLUSION. Any
of the three strategies evaluated can be used safely for switching patients to
aripiprazole from antipsychotic monotherapy. Furthermore, patients' symptoms may
continue to improve after switching to aripiprazole." [Abstract]
Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi
T, Altar CA.
The antipsychotic aripiprazole is a potent, partial
agonist at the human 5-HT(1A) receptor.
Eur J Pharmacol
2002 Apr 26;441(3):137-40
a novel antipsychotic with partial agonist activity at dopamine D2 receptors,
bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in
Chinese hamster ovary cell membranes and displayed potent, partial agonism at
5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP
gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor
antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall
efficacy of aripiprazole against symptoms of schizophrenia, including anxiety,
depression, cognitive and negative symptoms, and to its favorable side-effect
profile. Combined with previous studies demonstrating the potent partial agonism
of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is
the first dopamine-serotonin system stabilizer." [Abstract]
PJ, Rodriguez L, Santana O.
Antipsychotics: impact on prolactin
Expert Opin Pharmacother 2002 Oct;3(10):1381-91
"Hyperprolactinaemia has been associated with a variety of side effects including
amenorrhoea, galactorrhoea, sexual dysfunction, breast engorgement and osteoporosis.
Since the mid-1970s, the impact of antipsychotics on human prolactin (hPrl) levels
has been investigated. Baseline levels of hPrl were found to be similar in healthy
controls and patients who were diagnosed as having schizophrenia. Short-term acute
studies done after single parenteral or oral doses of phenothiazines found rapid
two- to tenfold increases in hPrl. Similar increases were found in longer term
studies that reported increases of three times in both men and women after 3 days
that doubled again after several weeks of treatment. A study of longer term injectable
fluphenazine enanthate found that elevation induced by a single injection lasted
up to 28 days. The same results with significant increases have been reported
with the butyrophenone, haloperidol. Substantial increases are found after single
injections (up to nine times) and after weeks of treatment (up to three times
sustained). Thus, early literature believed that there might be an association
between these induced changes and response to therapy. However, prolactin is secreted
by the anterior pituitary and is under inhibitory control of dopamine released
from the tuberoinfundibular neurones. Thus, increases in prolactin are due to
antipsychotic impact on tuberoinfundibular tract, one of four dopamine-related
tracts. With the application of clozapine and other atypical antipsychotics, it
was found that medications can successfully treat psychosis without increasing
hPrl. In fact, early single-dose trails found clozapine to reduce hPrl by 16%.
Later studies replicated this result and also found that up to 6 weeks of administration
led to reductions in hPrl of up to 80%. Risperidone, however, has been found to
persistently elevate hPrl in studies, despite its impact on other receptor sites.
Olanzapine, quetiapine and ziprasidone have all been found to have little effect
or produce decreases in hPrl. Most recently, aripiprazole, in early studies, appears
to produce significant reductions in hPrl while maintaining therapeutic efficacy
for psychosis." [Abstract]
JM, Lewine JD, Edgar JC, Davis JT, Miller GA, Torres F, Tuason VB.
brain magnetic activity in schizophrenia patients treated with aripiprazole.
Psychopharmacol Bull 1998;34(1):101-5
"This magnetoencaphalographic (MEG)
study was conducted as part of a multicenter clinical trial to study the efficacy
of aripiprazole. Participants included 5 DSM-IV schizophrenia subjects and 10
age-matched normal controls. The schizophrenia subjects underwent a second MEG
recording after 8 weeks of open-label treatment with aripiprazole. Overall, control
subjects showed no abnormal spontaneous magnetic brain activity. At washout, 3
patients showed increased delta and theta activity along with paraxosymal bitemporal
slow waves. In 2 of these patients, the slow waves were generated in the superior
temporal plane, as determined by dipole modeling. In the third patient, the slow
waves appeared to have been generated at multiple regions throughout the temporal
and inferior parietal lobes. As a group, schizophrenia patients, when compared
with normal controls, demonstrated significant decreases in alpha peak frequency
and power. Following treatment, aripiprazole had a significant normalizing effect
on delta and theta activity. Patients on aripiprazole continued to demonstrate
significant abnormalities in alpha frequency and power." [Abstract]
S, Koprivica V, Dunn R, Tottori K, Kikuchi T, Altar CA.
In vivo effects
of aripiprazole on cortical and striatal dopaminergic and serotonergic function.
J Pharmacol. 2004 Jan 1; 483(1): 45-53.
"In vivo microdialysis was used
to monitor the effects of oral aripiprazole and olanzapine on basal extracellular
concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic
acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex
and striatum of conscious, freely moving rats. Acute aripiprazole administration
did not affect dopamine output, but produced moderate increases in DOPAC and HVA
concentrations, in medial prefrontal cortex or striatum of drug-nai;ve rats. Similarly,
aripiprazole did not affect dopamine output but produced moderate elevations in
DOPAC and HVA concentrations in the striatum of chronic aripiprazole-pretreated
rats. Olanzapine produced comparatively larger elevations in dopamine, DOPAC,
and HVA in both regions, which, in the striatum, were diminished after chronic
olanzapine exposure. Aripiprazole reduced extracellular 5-HIAA concentrations
in the medial prefrontal cortex and striatum of drug-nai;ve rats, but not in chronic
aripiprazole-pretreated rats. Together, these data provide in vivo evidence of
aripiprazole-induced changes in forebrain dopaminergic and serotonergic function
that may reflect its partial agonist activity at presynaptic dopamine D(2) and
5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors." [Abstract]
Nakai S, Hirose T, Uwahodo Y, Imaoka T, Okazaki H, Miwa
T, Nakai M, Yamada S, Dunn B, Burris KD, Molinoff PB, Tottori K, Altar CA, Kikuchi
Diminished catalepsy and dopamine metabolism distinguish aripiprazole
from haloperidol or risperidone.
Eur J Pharmacol. 2003 Jul
4; 472(1-2): 89-97.
"Catalepsy and changes in striatal and limbic dopamine
metabolism were investigated in mice after oral administration of aripiprazole,
haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day)
aripiprazole compared with acute (single dose) treatment across a wide dose range,
whereas catalepsy duration persisted with chronic haloperidol treatment. At the
time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine
metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small
increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory
tubercle. Dopamine metabolism was essentially unchanged in both regions after
chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated
DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained
elevated with chronic treatment. The subtle effects of aripiprazole on striatal
and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration,
illustrate fundamental differences in dopamine neurochemical actions and behavioral
sequelae of aripiprazole compared to haloperidol or risperidone." [Abstract]
J, Sakai M, Miyoshi R, Mataga N, Fukamauchi F, Kito S.
expression of c-fos mRNA in rat prefrontal cortex, striatum, N. accumbens and
lateral septum after typical and atypical antipsychotics: an in situ hybridization
Neurochem Int 1996 Oct;29(4):435-42
regional difference in the expression of c-fos mRNA induced by typical and atypical
antipsychotics was determined in prefrontal cortex, striatum, N. accumbens and
lateral septum in rats by in situ hybridization. Two typical antipsychotics, haloperidol
(2 mg/kg) and fluphenazine (2 mg/kg), and three atypical antipsychotics, (-)sulpiride
(100 mg/kg), clozapine (20 mg/kg) and OPC-14597 (40 mg/kg), were used. Brains
were fixed with 4% paraformaldehyde 45 min after drug administration (i.p.). Brain
sections of 30 microns-thickness were made in a cryostat and hybridized with 35S-labelled
for c-fos oligonucleotide probe. These sections were apposed to X-ray films and
the autoradiograms were semi-quantitatively analysed by computer-assisted densitometry.
All antipsychotics used increased c-fos mRNA expression in N. accumbens shell,
a region of the forebrain associated with limbic systems. On the other hand, two
typical antipsychotics (haloperidol and fluphenazine) that cause a high incidence
of acute motor side effects increased the expression of c-fos mRNA in the dorsolateral
striatum, an extrapyramidal region primarily involved in motor control. Only clozapine
induced c-fos mRNA in the medial prefrontal cortex and lateral septum. These results
strongly suggest that the shell region of N. accumbens may be a common site of
therapeutic action of antipsychotics." [Abstract]
S, Harano M, Yokoo H, Tanaka M.
Antagonistic effects of OPC-14597,
a novel antipsychotic drug, on quinpirole- and (-)-sulpiride-induced changes in
evoked dopamine release in rat striatal slices.
Pharmacol 1997 Feb;49(2):206-8
"The effects of a newly synthesized quinolinone
derivative, 7-[4-(4-(2,3-dichlorophenyl)-1-piperazinyl) butoxy)-3,4-dihydro-2-(1H)-quinolinone
(OPC-14597), a novel antipsychotic drug, on electrically evoked dopamine release
in rat striatal slices were investigated. OPC-14597 (0.1-10 microM) had no effect
on the dopamine release evoked in the striatal slices. The decrease induced by
quinpirole, a dopamine receptor agonist, in evoked dopamine release was attenuated
by superfusion with OPC-14597 (1 and 10 microM) which by itself had no effect
on evoked dopamine release. The increase induced by (-)-sulpiride, a dopamine
receptor antagonist, in evoked dopamine release was, moreover, also attenuated
by 1 and 10 microM OPC-14597. These findings indicate that OPC-14597 antagonizes
both dopamine agonist- and antagonist-induced changes in evoked dopamine release
in striatal slices in rats." [Abstract]
T, Amano T, Todo N, Sasa M.
Inhibition by a putative antipsychotic
quinolinone derivative (OPC-14597) of dopaminergic neurons in the ventral tegmental
Eur J Pharmacol 1996 Aug 22;310(1):1-8
effects of the newly synthesized quinolinone derivative, OPC-14597 (7- inverted
question mark4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy inverted question
mark-3, 4-dihydro-2(1 H)-quinolinone), on dopaminergic neuronal activity in the
ventral tegmental area were examined using both in vivo microiontophoretic methods
in chloral hydrate-anesthetized rats and the tight-seal whole-cell patch-clamp
technique in thin-slice preparations of the rat brain. Neurons in the ventral
tegmental area were classified as type I or type II according to their responses
to antidromic stimulation of the nucleus accumbens, probably corresponding to
dopaminergic and non-dopaminergic neurons, respectively. Antidromic spikes elicited
by nucleus accumbens stimulation were inhibited by microiontophoretic application
of dopamine and OPC-14597 in type I, but not in type II neurons. Although the
OPC-14597-induced inhibition was antagonized by simultaneous application of domperidone
benzimidazol-2-one; dopamine D2 receptor antagonist), SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,
5-tetrahydro-1 H-3-benzazepine hydrochloride; dopamine D1 receptor antagonist)
had no such effect. Spontaneous firing of type I neurons was also inhibited by
iontophoretically applied OPC-14597 and dopamine, whereas that of type II neurons
was unaffected. The inhibitory effect of OPC-14597 on the spontaneous firing of
type I neurons was antagonized by domperidone, but not by SCH 23390. In a whole-cell
patch-clamp study using a thin-slice preparation of the rat brain, bath application
of OPC-14597 induced hyperpolarization accompanied by inhibition of spontaneously
occurring action potentials in the large neurons (> 20 microns in diameter)
in a concentration-dependent manner. These results suggest that OPC-14597 acts
on dopaminergic neurons in the ventral tegmental area as a dopamine D2 receptor
agonist to inhibit neuronal activities, probably by increasing membrane potassium
Dopamine system stabilizers,
aripiprazole, and the next generation of antipsychotics, part 1, "Goldilocks"
actions at dopamine receptors.
J Clin Psychiatry 2001 Nov;62(11):841-2
"Dopamine system stabilizers are a potential new class of antipsychotic agents
without motor side effects. All known effective antipsychotics act at D2 receptors.
A novel concept for an antipsychotic without motor side effects is to stabilize
these receptors rather than block them harshly." [Abstract]
JK, Goa KL.
CNS Drugs 2002;16(11):779-86;
"Aripiprazole is a quinolinone derivative and the first
of a new class of atypical antipsychotics. The drug has partial agonist activity
at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at
5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective
disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol
10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week,
placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole
than the risperidone group. Efficacy of aripiprazole was observed at week 1 in
several trials and was sustained throughout the study periods. Aripiprazole was
superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia.
In a 52-week trial involving patients with acute relapsing disease, aripiprazole
was similar to haloperidol as assessed by time to failure to maintain response
and was superior in ameliorating negative and depressive symptoms. The incidence
of extrapyramidal symptoms during aripiprazole therapy was similar to that with
risperidone and placebo but lower than with haloperidol. Compared with placebo,
the proportion of patients with increased plasma prolactin levels and QTc prolongation
was similar in patients treated with aripiprazole 15 to
30 mg/day but was significantly increased with haloperidol and risperidone."
Am J Health Syst Pharm. 2003
Dec 1; 60(23): 2437-45.
"The pharmacology, pharmacokinetics, clinical
efficacy, adverse effects, drug interactions, and dosage and administration of
aripiprazole are discussed. Aripiprazole is a third-generation antipsychotic agent
indicated for use in the treatment of schizophrenia. Unlike other antipsychotics,
aripiprazole demonstrates mixed D2 and serotonin (5-HT1A) receptor agonist-antagonist
activity that is hypothesized to improve schlzophrenia's positive and negative
symptoms; the drug has been referred to as a dopamine-serotonin stabilizer. Aripiprazole
is well absorbed, with peak plasma concentrations occurring within three to five
hours after administration. The oral availability is 87%. The mean elimination
half-life is about 75 hours for aripiprazole and 94 hours for its active metabolite.
In controlled, randomized, multicenter trials, aripiprazole has demonstrated efficacy
in the treatment of schizophrenia comparable to that of haloperidol and superior
to placebo. In a single clinical trial, aripiprazole was superior to placebo in
the treatment of acute mania. The most frequent adverse effects are headache,
anxiety, insomnia, nausea, vomiting, and lightheadedness. Because aripiprazole
is a substrate of both cytochrome P-450 isoenzymes 3A4 and 2D6, there is a potential
for other drugs to affect its metabolism. The recommended starting dosage is 10
or 15 mg daily, preferably administered with meals. Aripiprazole offers an alternative
to second-generation antipsychotic agents in the treatment of schizophrenia."
PJ, Jerry JM.
Aripiprazole: profile on efficacy and safety.
Expert Opin Pharmacother 2002 Dec;3(12):1773-81
trade mark, Bristol-Myers Squibb) is the most recent addition to the new class
of atypical antipsychotic medications, following the release of clozapine, risperidone,
olanzapine, quetiapine and ziprasidone. Aripiprazole exhibits typical antagonism
at dopamine (D2) receptors in the mesolimbic pathway, as well as having unique
partial agonist activity at D2 receptors in the mesocortical pathway. As exemplified
by other atypical antipsychotics, it displays strong 5-HT(2a) receptor antagonism
and is similar to ziprasidone in also having agonistic activity at the 5-HT(1a)
receptor. Among the atypical antipsychotics, aripiprazole displays the lowest
affinity for alpha(1)adrenergic (alpha(1)), histamine (H1) and muscarinic (M1)
receptors. This combination of effects may be responsible for its efficacy in
positive and negative symptoms of schizophrenia and in bipolar disorder. Similarly,
this profile may be the reason for the low rates of reported side effects observed.
This includes general adverse events, a low incidence of reported weight gain
and a low liability for inducing movement disorders. Other early data suggest
that aripiprazole may induce reductions in plasma prolactin, as well as in plasma
glucose and lipid profiles. Finally, results also support the proposition that
aripiprazole may lead to reductions in corrected QT interval and have minimal
drug interactions." [Abstract]
PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G; Aripiprazole
A placebo-controlled, double-blind study of the efficacy
and safety of aripiprazole in patients with acute bipolar mania.
J Psychiatry. 2003 Sep;160(9):1651-8.
"OBJECTIVE: The authors compared
the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for
treatment of patients in an acute manic or mixed episode of bipolar disorder.
METHOD: This 3-week, multicenter, double-blind study randomly assigned 262 bipolar
disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day
(reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained
hospitalized for at least 2 of the weeks. The primary efficacy measure was mean
change from baseline in total score on the Young Mania Rating Scale; response
was defined as a decrease in score of > or =50%. RESULTS: Aripiprazole produced
statistically significant mean improvements in total score on the Young Mania
Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced
a significantly higher response rate (40% versus 19%). For key efficacy variables
(response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version
scores for severity of illness [mania] and change from preceding phase [mania]),
aripiprazole separated from placebo by day 4. The completion rate was significantly
higher with aripiprazole than with placebo (42% versus 21%). Discontinuations
due to adverse events did not differ significantly between the aripiprazole and
placebo groups. There were no significant changes in body weight versus placebo,
and aripiprazole was not associated with elevated serum prolactin or QTc prolongation.
CONCLUSIONS: Aripiprazole had significantly greater efficacy than placebo for
the treatment of bipolar disorder patients in acute manic or mixed episodes and
was safe and well tolerated in this randomized controlled trial." [Abstract]
Partial dopamine agonists in the treatment of psychosis.
J Neural Transm 2002 Mar;109(3):411-20
"The discovery and characterization
of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in
2000. Along with his many insights about dopamine pharmacology, came his proposal
of the existence and critical role of dopamine autoreceptors in the overall regulation
of dopamine-mediated neurotransmission. In this paper, the rationale, the putative
mechanisms, and pertinent clinical data are reviewed to support the idea of the
clinical relevance of dopamine agonists, especially partial agonists, in the treatment
of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia
in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical
relevance was not a reality before the application of (-)-3PPP. These clinical
results are presented. Moreover, now a partial dopamine agonist, aripiprazole,
has been developed and will likely be marketed by BMS and Otsuka for the treatment
of psychosis and will be the first drug in this class to be commercially available.
Partial dopamine agonists represent the next new class of antipsychotic drugs,
effective in treating schizophrenia." [Abstract]
CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman
Interactions of the novel antipsychotic aripiprazole (OPC-14597)
with dopamine and serotonin receptor subtypes.
"OPC-14597 inverted question markaripiprazole;
inverted question mark 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." [Abstract]
Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu
LX, Sibley DR, Roth BL, Mailman R.
Aripiprazole, A Novel Atypical
Antipsychotic Drug with a Unique and Robust Pharmacology.
2003 May 21 [Epub ahead of print].
"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))." [Abstract]
F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer
S, Wong DF.
Dopamine D2 and D3 receptor occupancy in normal humans
treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron
emission tomography and [11C]raclopride.
"Aripiprazole (OPC 14597) is an antipsychotic drug
that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor.
It is being developed for treatment of patients with schizophrenia. The purpose
of this study was to determine whether a dose response following graduated doses
of aripiprazole could be quantified and correlated with its occupancy of the D2
and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor
occupancy in fifteen normal male human brains was measured using positron emission
tomography (PET) with [11C]raclopride. PET studies were performed before and after
two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy
was quantified with two kinetic modeling methods without using a blood input function.
Administration of aripiprazole for 14 days resulted in a dose-dependent receptor
occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg,
and 30 mg per day. These results suggest that an adequate occupancy can be obtained,
and this may be useful to predict an appropriate therapeutic dose for an individual
patient. Interestingly, even at striatal D2 receptor occupancy values above 90%,
which occurred with the higher doses, extrapyramidal side effects (EPS) were not
observed. This underlines aripiprazole's unique mechanism of action as a partial
dopamine receptor agonist, which might become a novel principle in the treatment
of schizophrenia." [Abstract]
Grunder G, Carlsson A, Wong DF.
of new antipsychotic medications: occupancy is not just antagonism.
Gen Psychiatry. 2003 Oct; 60(10): 974-7.
"Antagonism of D2-like dopamine
receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic
drugs. Positron emission tomographic studies suggest that the antipsychotic effect
of dopamine receptor antagonists occurs within a therapeutic window between 60%
and 80% (striatal) D2 receptor occupancy. The incidence of extrapyramidal side
effects increases above the 80% threshold. However, the novel atypical antipsychotic
drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors
at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole
is no higher than with placebo. The most likely explanation for this finding is
aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular
pharmacologic feature characterizes a new class of atypical antipsychotics that
does not match the original concept of a therapeutic occupancy window for antagonist
antipsychotics. When not involving pure antagonists, it implies a need to adjust
the expected receptor occupancy (measured using positron emission tomography)
for the therapeutic window." [Abstract]
KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB.
Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist
at human dopamine D2 receptors.
J Pharmacol Exp Ther 2002
"Aripiprazole is the first next-generation atypical
antipsychotic with a mechanism of action that differs from currently marketed
typical and atypical antipsychotics. Aripiprazole displays properties of an agonist
and antagonist in animal models of dopaminergic hypoactivity and hyperactivity,
respectively. This study examined the interactions of aripiprazole with a single
population of human D2 receptors to clarify further its pharmacologic properties.
In membranes prepared from Chinese hamster ovary cells that express recombinant
D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled
and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated
inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating
agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced
the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect
was seen with concentrations of EEDQ that did not alter the maximal inhibitory
effect of dopamine. Consistent with the expected effects of a partial agonist,
increasing concentrations of aripiprazole blocked the action of dopamine with
maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy
of aripiprazole relative to that of dopamine varied from 25% in cells that lacked
spare receptors for dopamine to 90% in cells with receptor reserve. These results,
together with previous studies demonstrating partial agonist activity at serotonin
5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors,
support the identification of aripiprazole as a dopamine-serotonin system stabilizer.
The receptor activity profile may underlie the unique activity of aripiprazole
in animals and its antipsychotic activity in humans." [Abstract]
HY, Li Z, Kaneda Y, Ichikawa J.
Serotonin receptors: their key role
in drugs to treat schizophrenia.
Biol Psychiatry. 2003 Oct; 27(7): 1159-72.
mechanisms have been postulated to play a critical role in the action of the new
generation of antipsychotic drugs (APDs) that are usually referred to as atypical
APDs because of their ability to achieve an antipsychotic effect with lower rates
of extrapyramidal side effects (EPS) compared to first-generation APDs such as
haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol.
Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with
weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features
that differentiate clozapine and other apparent atypical APDs from first-generation
typical APD. This hypothesis is consistent with the atypical features of quetiapine,
olanzapine, risperidone, and ziprasidone, which are the most common treatments
for schizophrenia in the United States and many other countries, as well as a
large number of compounds in various stages of development. Subsequent research
showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism
and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce
an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most
recently introduced atypical APD, and a D2 receptor partial agonist, may also
owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A
antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast,
the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry
158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with
the "slow" off rate of most atypical APDs, including olanzapine, risperidone
and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal
neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of
DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons
in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely
to be important sites of action of the atypical APDs. At the same time, evidence
has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors
for some of the effects of some of the current APDs. Thus, 5-HT has joined DA
as a critical target for developing effective APDs and led to the search for novel
drugs with complex pharmacology, ending the exclusive search for single-receptor
targets, e.g., the D3 or D4 receptor, and drugs that are selective for them."
A, Miki S, Seto M, Kikuchi T, Morita S, Ueda H, Misu Y, Nakata Y.
a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does
not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum.
Eur J Pharmacol 1997 Feb 19;321(1):105-11
"Aripiprazole, a quinolinone
derivative, is a new dopaminergic agent which has been recently developed and
demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal
motor side effects. Here, we found that aripiprazole competed [3H]spiperone binding
with a 100-fold higher affinity than [3H]SCH23390 binding, and inhibited the quinpirole-induced
facilitation of high-affinity GTPase activity in rat striatal membranes. The effects
of chronic administration of aripiprazole and haloperidol on dopamine D2 receptor
binding and mRNA level in rat striata were examined by a [3H]spiperone binding
assay and a ribonuclease protection assay. Haloperidol induced a significant rise
in Bmax of [3H]spiperone binding at 1 mg/kg and in the level of dopamine D2L receptor
mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase
the Bmax of [3H]spiperone binding non-significantly, and had no effect on the
level of dopamine D2L receptor mRNA. These results indicated that aripiprazole
had an antagonistic activity to dopamine D2 receptors with a high affinity, but
that the potency of aripiprazole to up-regulate dopamine D2 receptors in the striatum
was much smaller than that of haloperidol. This small up-regulation may be related
to the ability to aripiprazole to act without side effects including tardive dyskinesia."
Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro
Y, Morita S.
(OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine
autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity.
J Pharmacol Exp Ther 1995 Jul;274(1):329-36
"The effects of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2
(1H)- quinolinone (OPC-14597), a derivative of the dopamine (DA) autoreceptor
agonist 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392),
on DA receptors were biochemically and behaviorally studied and compared with
those of OPC-4392. Both OPC-14597 and OPC-4392 inhibited reserpine- and gamma-butyrolactone
(GBL)-induced increase in tyrosine hydroxylase activity in the mouse and rat brain.
The effects of OPC-14597 were comparable to those of OPC-4392 and were completely
antagonized by haloperidol. OPC-14597, unlike apomorphine, did not evoke postsynaptic
DA receptor-stimulating behavioral signs such as hyperlocomotion in the reserpinized
mice and contralateral rotation in rats with unilateral striatal 6-hydroxydopamine
lesions. Both OPC-14597 and OPC-4392 inhibited such apomorphine-induced postsynaptic
behavioral changes as stereotypy and hyperlocomotion in mice and rats and rotation
in rats with unilateral striatal kainic acid lesions. The anti-apomorphine effects
of OPC-14597 were about 30 to 140 times greater than those of OPC-4392 and were
observed at doses that inhibit the increases in tyrosine hydroxylase activity.
The affinities of OPC-14597 for 3H-spiperone-labeled D2 receptors in the rat frontal
cortex, limbic forebrain and striatum were higher than those of OPC-4392. These
results suggest that OPC-14597 is a unique antipsychotic drug candidate, being
a DA autoreceptor agonist that has a stronger postsynaptic D2 receptor antagonistic
activity than that of OPC-4392." [Abstract]
A, Seto M, Sugita S, Hide I, Hirose T, Koga N, Kikuchi T, Nakata Y.
Differential effects on D2 dopamine receptor and prolactin gene expression
by haloperidol and aripiprazole in the rat pituitary.
Res Mol Brain Res 1998 Apr;55(2):285-92
to D2 receptors and quantitative ribonuclease protection assay for both isoforms
(D2L and D2S receptor) of the D2 receptor mRNA and the prolactin mRNA were performed
on pituitaries from the control rat and from the rat injected orally daily with
either haloperidol (2 mg/kg) or aripiprazole (24 mg/kg) for 21 days. Haloperidol
treatment increased the [3H]spiperone-binding by 28%, the levels of D2L and D2S
receptor mRNA by 41% and 38%, respectively, and the level of prolactin mRNA by
26%. In contrast, the treatment with aripiprazole, a newly developed atypical
antipsychotic with reduced side effects, decreased the [3H]spiperone-binding by
24% and the levels of D2L and D2S receptor mRNA by 23% and 23%, respectively,
and did not have any effect on the level of prolactin mRNA. The same treatment
with sulpiride (100 mg/kg) increased the levels of D2L and D2S receptor mRNA by
59% and 62%, respectively, but treatment with clozapine (25 mg/kg) did not cause
any effect. Neither treatment changed the ratio of the level of D2S receptor mRNA
to the level of D2L receptor mRNA in the pituitary. These findings indicate that
D2 receptor densities in the pituitary are influenced differentially by the treatment
with these antipsychotics, which could be induced at least partly by the changes
in the levels of mRNA without any effects on the splicing mechanisms and thus
affect the plasticity of the prolactin mRNA expression." [Abstract]
T, Domae M, Yamada K, Furukawa T.
Effects of the novel antipsychotic
agent 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro -2(1H)-quinolinone
(OPC-14597) on prolactin release from the rat anterior pituitary gland.
J Pharmacol Exp Ther 1996 Apr;277(1):137-43
"The effects of a novel antipsychotic
agent, 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2 (1H)-quinolinone
(OPC-14597, generic name aripiprazole), on prolactin (PRL) release from isolated
rat anterior pituitary slices and on the serum PRL levels were investigated in
male rats. In in vitro experiments on the isolated anterior pituitary, the spontaneous
PRL release was decreased by talipexole, a dopamine D2 receptor full agonist,
in a dose-dependent manner to 36% of the basal release, and the decrease was antagonized
by haloperidol, a D2 receptor antagonist. OPC-14597 also decreased the release
of PRL at the same concentration range with a maximal decrease to 78%, the potency
being weaker than that of talipexole. The decrease in PRL release induced by OPC-14597
was completely antagonized by haloperidol. Moreover, OPC-14597 antagonized the
inhibition of PRL release induced by talipexole. In in vivo experiments, haloperidol
increased the serum PRL levels to 8 times the basal PRL level, whereas talipexole
decreased the levels to 49% of the basal level. OPC-14597 increased the serum
PRL levels by 2-fold and also antagonized the talipexole-induced decrease. The
hyperprolactinemia induced by estrogen, which was inhibited by talipexole but
enhanced by haloperidol, was enhanced by OPC-14597, whereas the hyperprolactinemia
induced by reserpine, which was inhibited by talipexole but elevated by haloperidol,
was inhibited by OPC-14597. In addition, the OPC-14597-induced inhibition was
antagonized by haloperidol. These results suggest that OPC-14597 has a mixed agonist/antagonist
profile at D2 receptors on lactotroph cells and thereby exerts either an antagonistic
or an agonistic action, depending on the preexisting tone of the dopaminergic
neuronal activities." [Abstract]
A, Satoh Y, Hashimoto K.
In vivo canine model comparison of cardiohemodynamic
and electrophysiological effects of a new antipsychotic drug aripiprazole (OPC-14597)
Toxicol Appl Pharmacol 2001 Jun 1;173(2):120-8
"The cardiovascular effects of aripiprazole were assessed in comparison with
those of haloperidol using a halothane-anesthetized canine model with monophasic
action potential monitoring. Aripiprazole (n = 6) or haloperidol (n = 6) was infused
over 10 min at escalating doses of 0.03, 0.3, and 3.0 mg/kg with intervals of
20 min between doses. Clinically relevant plasma concentrations were obtained
after 0.03-0.3 mg/kg of aripiprazole as well as haloperidol. After 0.03-0.3 mg/kg
of aripiprazole, positive chronotropic, inotropic, and dromotropic effects, shortening
of the ventricular effective refractory period (ERP) and repolarization phase,
and decrease of total peripheral resistance were observed in a dose-related manner.
However, in the presence of a beta-blocking dose of esmolol (0.1 mg/kg/min), these
changes were not induced. After 3.0 mg/kg of aripiprazole administration, cardiac
effects induced by the lower doses were attenuated or disappeared, while the negative
chronotropic, dromotropic, and hypotensive actions and prolongation of ERP and
repolarization phase were induced. After 0.03 mg/kg of haloperidol, no significant
change was observed, except for the decrease of the peripheral resistance. After
0.3-3.0 mg/kg of haloperidol, negative chronotropic, inotropic, and hypotensive
actions, intraventricular conduction delay, and prolongation of ventricular ERP
and repolarization phase were observed in a dose-related manner accompanied by
further decrease of the peripheral resistance. The inhibitory effects of aripiprazole
on cardiovascular parameters in dogs were less potent than those of haloperidol
at clinically relevant exposures, moreover, aripiprazole, unlike haloperidol,
neither induced early afterdepolarization nor prolonged the ventricular electrical
vulnerable period. Therefore, aripiprazole can be considered safer to use than