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Mechanism of Action of Aripiprazole

By Flavio Guzman, MD. Last updated: November 1, 2016 at 2:08 am

As with other drugs in psychopharmacology, the mechanism of action of aripiprazole in


schizophrenia has not been fully elucidated.
From a pharmacological perspective, aripiprazole is different to other antipsychotic agents, as
it is the only approved antipsychotic that reduces dopaminergic neurotransmission through D2
partial agonism, not D2 antagonism.
The following presentation discusses current thinking on the mechanism of action of
aripiprazole (scroll down to see a summary with images).

Summary
If you dont have time to go through the entire video, this summary highlights the most
important concepts explained in the presentation.
Aripiprazole binds to a number of CNS receptors, this includes effects as:
o partial D2 agonist
o partial 5-HT1A agonist
o 5-HT2A antagonist

This
image depicts aripiprazole binding to three different receptors: D2, 5HT1A, 5HT2A
What are the implications of D2 partial agonism? Aripiprazole binds to the D2
receptor with the same affinity than dopamine, but has a lower intrinsic efficacy, so the
response it triggers is lower than dopamine but higher than an antagonist.
Aripiprazole as partial agonist: note that the signal is lower than dopamine but higher than
an antagonist
As partial agonist at D2 receptors, it modulates neurotransmission in dopaminergic
pathways (mainly mesolimbic and mesocortical pathway).
According to the dopamine theory of schizophrenia, overactivity of the mesolimbic
pathway may trigger positive symptoms (hallucinations, delusions).

Positive symptoms of schizophrenia might be the result of an overactivation of the


mesolimbic pathway.
Aripiprazole might decrease activity in the mesolimbic pathway through partial D2
agonism, which would in turn reduce positive symptoms.
Aripiprazole reduces dopaminergic activity in the mesolimbic pathway through partial D2
agonism.
The dopamine theory of negative and cognitive symptoms suggests that there is a
hypofunction of dopaminergic neurotransmission in the mesocortical pathway.

Dopaminergic activity in the mesocortical pathway is thought to be reduced in schizophrenia


One postulated mechanism of action of aripiprazole in schizophrenia is the ability of
the drug to increase dopaminergic activity from a subnormal level to normal activity in
the mesocortical pathway.
Partial D2 agonism might increase dopaminergic activity in the mesocortical pathway.

Key Points
Aripiprazole is a partial agonist at D2 receptors.
It may act as an antipsychotic by:
o Lowering dopaminergic neurotransmission in the mesolimbic pathway.
o Enhancing dopaminergic activity in the mesocortical pathway.
It has a lower risk of EPS and hyperprolactinemia than other antipsychotics.

Aripiprazole Indications: FDA-Approved and Off-Label Uses

Aripiprazole is a second-generation (atypical) antipsychotic approved for the treatment of


schizophrenia, bipolar disorder, depression and autism spectrum disorders.
This article explores FDA-approved indications, dosing and evidence base for common off-
label uses.

FDA-approved indications
Aripiprazole was originally approved in 2002 for the treatment of schizophrenia. Currently,
the FDA has approved aripiprazole for the treatment of bipolar disorder (mania and mixed
episodes and as maintenance treatment), as adjunctive treatment for major depressive
disorder (2006) and for autism spectrum disorders (2007).
Below is a list of approved indications and dosing, this information has been extracted from
the product prescribing information [1].

For oral formulations (tablet, orally disintegrating tablet and oral solution):

Recommended Maximum
Indication Initial Dose
Dose Dose
Schizophrenia
Adults 10-15 mg/day 10-15 mg/day 30 mg/day
Recommended Maximum
Indication Initial Dose
Dose Dose
Adolescents 2 mg/day 10 mg/day 30 mg/day
Bipolar Disorder
Treatment of manic or
mixed episodes
Bipolar Mania 15 mg/day 15 mg/day 30 mg/day
Adults
Monotherapy
Bipolar Mania 10-15 mg/day 15 mg/day 30 mg/day
Adults
Adjunt to lithium or
valproate
Bipolar Mania 2 mg/day 10 mg/day 30 mg/day
Pediatric patients
Monotherapy or adjunct
to lithium or valproate

Maintenance treatment

Maintenance treatment Doses not available


of bipolar I disorder in product
monograph.

Major Depressive
Disorder
Adjunct to 2-5 mg/day 5-10 mg/day 15 mg/day
antidepressants for the
treatment of MDD

Autism Spectrum
Disorders
Irritability associated 2 mg/day 5-10 mg/day 15 mg/day
with autistic disorder.
Pediatric patients

For the IM injection:


Indication Initial Dose Maximum dose

Agitation associated with 9.75 mg/1.3 mL 30 mg/day


schizophrenia or bipolar mania. injected IM injected IM
Adults
List of selected off-label uses
The table below summarizes the findings of a comparative effectiveness review by the
Agency for Healthcare Research and Quality [2].
Most of the uses listed in the table lack of controlled trials, which highlights the need for new
studies assessing the evidence for the use of aripiprazole in different clinical conditions.

Off-label Use Evidence


Anxiety
Generalized anxiety disorder No trials
Social Phobia No trials
Attention-deficit hyperactivity
disorder
No co-occuring disorders No trials
Bipolar Children Low or very low evidence of efficacy
Mentally retarded children No trials
Dementia
Overall Moderate or high evidence of efficacy
Psychosis Low or very low evidence of efficacy
Agitation Low or very low evidence of efficacy
Depression
MDD monotherapy No trials
Eating disorders No trials
Insomnia No trials
Obsessive-compulsive disorder
Augmentation with SSRI No trials
Augmentation of citalopram No trials
Personality disorder
Borderline personality disorder Low or very low evidence of efficacy
Schizotypal personality disorder No trials

Post-traumatic stress disorder No trials


Substance abuse
Alcohol Moderate or high evidence of
inefficacy

Cocaine No trials
Off-label Use Evidence
Methamphetamine Low or very low evidence of
inefficacy

Methadone users No trials

Tourette's syndrome No trials

More Information on Off-Label Use

Anxiety disorders
Katzman MA. Aripiprazole: a clinical review of its use for the treatment of anxiety disorders
and anxiety as a comorbidity in mental illness. Journal of affective disorders. 2011;128:S11-
S20.
A number of studies have shown atypical antipsychotics to be effective in anxiety, and
currently available data suggest that aripiprazole augmentation in patients with anxiety
disorders is likely as effective as other atypical antipsychotic drugs.
Although there have been no randomized, controlled trials, aripiprazole has been found
to be effective in treating anxiety disorders in two open-label trials.
This combined with the larger data base demonstrating its utility in bipolar disorder and
depression, its safety profile and its unique mechanism of action, make aripiprazole for
anxiety an intriguing avenue of exploration.

Dementia
De Deyn PP, Drenth AF, Kremer BP, Oude Voshaar RC, Van Dam D. Aripiprazole in the
treatment of Alzheimers disease. Expert opinion on pharmacotherapy. 2013(0):1-16
In randomized placebo-controlled clinical trials, aripiprazole shows modest efficacy in the
treatment of AD-related psychosis. Neuropsychiatric symptoms alleviated were
predominantly psychotic features and agitation. In individual trials, aripiprazole was generally
well tolerated, serious side effects were seldom reported and included accidental injury and
somnolence. Meta-analyses however demonstrated increased mortality as a class effect for
atypical, but also for typical antipsychotics.
No increased cardiovascular outcomes, cerebrovascular accidents, increased appetite or
weight gain were demonstrated in meta-analyses for aripiprazole-treated patients with
psychosis of dementia. Aripiprazole was found to induce sedation.
Aripiprazole should only be used in selected patient populations resistant to non-
pharmacological treatment with persisting or severe psychotic symptoms and/or agitation, and
in which symptoms lead to significant morbidity, patient suffering and potential self-harm.
The indication for continuing treatment should be revised regularly.

Eating disorders
Trunko ME, Schwartz TA, Duvvuri V, Kaye WH. Aripiprazole in anorexia nervosa and
lowweight bulimia nervosa: Case reports. International Journal of Eating Disorders.
2011;44(3):269-75
There has been much interest in the use of atypical antipsychotics in anorexia nervosa (AN).
However, newer, more weight-neutral medications have not been studied in AN, and there are
no reports of the use of antipsychotics in bulimia nervosa (BN).
Method
We report on the treatment of eight patients (five with AN and three with BN) with
aripiprazole for time periods of four months to more than three years.
Results
All individuals had reduced distress around eating, fewer obsessional thoughts about food,
weight and body image, significant lessening of eating-disordered behaviors, and gradual
weight restoration where appropriate. Depression, generalized anxiety, and cognitive
flexibility improved as well.
Discussion
In summary, these findings support the need to perform controlled trials of aripiprazole in AN
and BN.

Pharmacokinetics of Aripiprazole: Clinical Summary

Formulations:
Tablets
Orally disintegrating tablets
Liquid formulation
IM injection

General pharmacokinetics and drug interactions

Half-life:
aripiprazole: 75 hours
dehydro-aripiprazole: 94 hours

Elimination

Mainly through hepatic metabolism involving two P450 enzymes:


CYP3A4: dose adjustment might be needed in the presence of inhibitors or inducers.
CYP2D6: dose adjustment might be needed in the presence of inhibitors.

Pharmacokinetics of aripiprazole: metabolism by cytochrome P450 3A4


Ph
armacokinetics of aripiprazole: metabolism by cytochrome P450 2D6

Pharmacokinetics of oral administration

Absorption:
Peak plasma concentrations occur within 3 to 5 hours.
Can be admininistered with or without food.
According to the manufacturer, a study found that plasma concentrations from the oral
solution were higher than that from the tablet formulation.
Distribution:
Volume of distribution in studies after IV administration is of 404 L or 4.9L/Kg
(extense extravascular distribution)
Aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins
(primarily albumin)

Pharmacokinetics of IM administration:
Median times to the peak plasma concentration: 1 hours and 3 hours.
In one pharmacokinetic study [Boulton,2008], intramuscular aripiprazole
demonstrated more rapid attainment of plasma aripiprazole concentrations than oral
aripiprazole (78% and 5% of peak plasma concentration [Cmax] values at 0.5 hours
postdose, respectively).

Aripiprazole Lauroxil Extended-Release Injectable (ARISTADA)

Highlights of prescribing information


To be administered by intramuscular injection in the deltoid (441 mg dose only) or
gluteal (441 mg, 662 mg or 882 mg) muscle by a healthcare professional.
For patients nave to aripiprazole, establish tolerability with oral aripiprazole prior to
initiating treatment with ARISTADA.
ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered
monthly or 882 mg dose every 6 weeks.
In conjunction with the first ARISTADA injection, administer treatment with oral
aripiprazole for 21 consecutive days.
Dosing regimen adjustments may be required for missed doses.
Dose adjustments are required for:
o 1) known CYP2D6 poor metabolizers
o 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4
inducers for more than 2 weeks.

Dosage forms and strengths

ARISTADA is a white to off-white aqueous extended-release suspension provided in a single-


use pre-filled syringe for intramuscular injection in the deltoid or gluteal muscle at the 441 mg
dose strength and in the gluteal muscle at dose strengths of 662 mg and 882 mg.
ARISTADA is available as described in the following table:

Aristada presentations

Dosage and administration

Schizophrenia treatment
ARISTADA is only to be administered as an intramuscular injection by a healthcare
professional. For patients who have never taken aripiprazole, establish tolerability with oral
aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral
aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing
information of oral aripiprazole for the recommended dosage and administration of the oral
formulation.
Depending on individual patients needs, treatment with ARISTADA can be initiated at a dose
of 441 mg, 662 mg or 882 mg administered monthly, which corresponds to 300 mg, 450 mg
and 600 mg of aripiprazole, respectively. Treatment may also be initiated with the 882 mg
dose every 6 weeks.
Administer ARISTADA either in the deltoid muscle (441 mg dose only) or gluteal muscle
(441 mg, 662 mg or 882 mg).

Table 1: ARISTADA Dosing Frequency and Site of Injection


Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as
shown in Table 2.

Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose

In conjunction with the first ARISTADA injection, administer treatment with oral aripiprazole
for 21 consecutive days. Dose may be adjusted as needed. When making dose and dosing
interval adjustments, the pharmacokinetics and prolonged-release characteristics of
ARISTADA should be considered [see Clinical Pharmacology

Missed Doses
When a dose is missed, administer the next injection of ARISTADA as soon as possible. If the
time elapsed since the last ARISTADA injection exceeds the length of time noted in Table 3,
use oral aripiprazole supplementation with the next ARISTADA injection as recommended
below.

Table 3: Recommendation for Concomitant Oral Aripiprazole Supplementation

Following Missed Doses

Early Dosing
The recommended ARISTADA dosing interval is either monthly for the 441 mg, 662 mg and
882 mg doses or every 6 weeks for 882 mg dose and should be maintained. In the event of
early dosing, an ARISTADA injection should not be given earlier than 14 days after the
previous injection.

Dose Adjustments for CYP450 Considerations


Refer to the prescribing information for oral aripiprazole for recommendations regarding
dosage adjustments due to drug interactions, for the first 21 days when the patient is taking
oral aripiprazole concomitantly with the first dose of ARISTADA.

Aripiprazole for Schizophrenia

Aripiprazole (Abilify, BMS) is a second-generation antipsychotic approved in 2002 for the


treatment of schizophrenia. Oral and intramuscular formulations are available.
This page summarizes the most relevant papers on the use of aripiprazole for the management
of schizophrenia. We have selected mostly review papers that focus on efficacy and
tolerability of this drug.
Use the contents navigation bar to browse abstracts.

Aripiprazole: a review of its use in the management of schizophrenia in adults.

CNS drugs Croxtall JD, Adis, Auckland, New Zealand. demail@adis.co.nz


Published: Feb 2012

Abstract:
Oral aripiprazole (Abilify) is an atypical antipsychotic agent that is approved worldwide for
use in adult patients with schizophrenia. It is a quinolinone derivative that has a unique
receptor binding profile as it exhibits both partial agonist activity at dopamine D(2) receptors
and serotonin 5-HT1A receptors and antagonist activity at 5-HT(2A) receptors.
In several well designed, randomized, clinical trials of 4-6 weeks duration, aripiprazole
provided symptomatic control for patients with acute, relapsing schizophrenia or
schizoaffective disorder. Furthermore, following 26 weeks treatment, the time to relapse was
significantly longer for patients with chronic, stabilized schizophrenia receiving aripiprazole
compared with those receiving placebo. Using a variety of efficacy outcomes, aripiprazole
showed a mixed response when evaluated against other antipsychotic agents in randomized
clinical trials.
Longer-term data showed that improvements in remission rates and response rates favoured
aripiprazole over haloperidol, although, the time to failure to maintain a response was not
significantly different between the treatment arms. On the other hand, improvements in
positive and negative symptom scores mostly favoured olanzapine over aripiprazole,
although, the time to all-cause treatment discontinuation was not significantly different
between the two treatments.
Several open-label, switching trials showed that aripiprazole provided continued control of
symptoms in patients with schizophrenia or schizoaffective disorder. Using a variety of
efficacy outcomes or quality-of-life scores, longer-term treatment generally favoured patients
switched to receive aripiprazole compared with standard-of-care oral antipsychotics.
Aripiprazole was generally well tolerated in patients with schizophrenia. In particular, its use
seems to be associated with a lower incidence of extrapyramidal symptoms than haloperidol
and fewer weight-gain issues than olanzapine. Aripiprazole also showed a favourable
cardiovascular tolerability profile and its use was associated with a reduced risk of metabolic
syndrome than placebo or olanzapine. As a consequence, aripiprazole may provide a more
cost-effective treatment option compared with other atypical antipsychotics.
In conclusion, oral aripiprazole provides an effective and well tolerated treatment alternative
for the acute and long-term management of patients with schizophrenia.

A review of the safety and tolerability of aripiprazole.


Expert opinion on drug safety Pae CU, Catholic University of Korea College of Medicine,
Holy Family Hospital, Department of Psychiatry, Sosa-Dong, Wonmi-Gu, Bucheon 420-717,
Kyounggi-Do, Republic of Korea. pae@catholic.ac.kr Published: May 2009

Abstract:
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.

Aripiprazole versus typicals for schizophrenia.

Cochrane database of systematic reviews (Online)


Bhattacharjee J, El-Sayeh HG, Published: 2008

Abstract:
Background: Aripiprazole is a relatively new antipsychotic drug, said to be the prototype of a
new third generation of antipsychotics; the so-called dopamine-serotonin system stabilisers. In
this review we examine how the efficacy and tolerability of aripiprazole differs from that of
typical antipsychotics.
Objectives: To evaluate the effects of aripiprazole compared with other typical antipsychotics
for people with schizophrenia and schizophrenia-like psychoses.
Search strategy: We searched the Cochrane Schizophrenia Group Trials Register (May 2007)
which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE
and PsycINFO.
Selection Criteria: We included all randomised trials comparing aripiprazole with typical
antipsychotics in people with schizophrenia or schizophrenia-like psychosis.
Data collection and analysis: We extracted data independently. For dichotomous data we
calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat
basis, based on a random effects model. We calculated numbers needed to treat/harm
(NNT/NNH) where appropriate. For continuous data, we calculated weighted mean
differences (WMD) again based on a random effects model. We have contacted
representatives of Bristol Myers Squibb pharmaceuticals (UK) for additional and missing
data.
Main results: We included nine randomised trials involving 3122 people comparing
aripiprazole with typical antipsychotic drugs. None of the studies reported on relapse our
primary outcome of interest. Attrition from studies was high and data reporting poor.
Participants given aripiprazole were comparable to those receiving typical drugs in improving
global state and mental state.
Aripiprazole provided a significant advantage over typical antipsychotics in terms of fewer
occurrences of extra-pyramidal symptom (n=968, 3 RCT, RR 0.46 CI 0.3 to 0.9, NNT 13 CI
17 to 10), and particularly akathisia (n=897, 3 RCT, RR 0.39 CI 0.3 to 0.6, NNT 11 CI 14 to
9). Fewer participants given aripiprazole developed hyperprolactinaemia (n=300, 1 RCT, RR
0.07 CI 0.03 to 0.2, NNT 2 CI 3 to 1) and raised fasting blood glucose (n=360, 1 RCT, RR
0.65 CI 0.5 to 0.9, NNT 8 CI 14 to 6).
Aripiprazole presented a lesser risk of sinus tachycardia (n=289, 1 RCT, RR 0.09 CI 0.01 to
0.8, NNT 22 CI 63 to 13) and blurred vision (n=308, 1 RCT, RR 0.19 CI 0.1 to 0.7, NNT 14
CI 25 to 10); but enhanced risk of occurrence of dizziness (n=957, 3 RCTs, RR 1.88 CI 1.1 to
3.2, NNH 20 CI 33 to 14) and nausea (n=957, 3 RCTs, RR 3.03 CI 1.5 to 6.1, NNH 17 CI 25
to 13).
Attrition rates were high in both groups, although significantly more participants in the
aripiprazole group completed the study in the long term (n=1294, 1 RCT, RR 0.81 CI 0.8 to
0.9 NNT 8 CI 5 to 14).
Authors conclusions: Aripiprazole is not much different from typical antipsychotic drugs
with respect to efficacy. However it presents significant advantages in terms of tolerability
due to its favourable adverse effects profile. This might enhance its effectiveness in
encouraging compliance. Clearly reported pragmatic short, medium and long term
randomised controlled trials are required to replicate and validate these findings and
determine the position of aripiprazole in everyday clinical practice.
Intramuscular aripiprazole: a review of its use in the management of agitation in
schizophrenia and bipolar I disorder.

CNS drugs Sanford M, Scott LJ, Wolters Kluwer Health | Adis, Auckland, New Zealand.
demail@adis.co.nz
Published: 2008

Abstract:
An intramuscular formulation of the atypical antipsychotic aripiprazole (Abilify) has been
developed and is approved in the EU for use in agitation and disturbed behaviour associated
with schizophrenia. In the US, it is approved for the treatment of agitation associated with
schizophrenia or bipolar I disorder (manic or mixed).
In large, well designed trials, intramuscular aripiprazole was an effective and generally well
tolerated treatment for agitation associated with schizophrenia, schizoaffective disorder,
schizophreniform disorder or bipolar I disorder. Intramuscular aripiprazole was more effective
than placebo in these patient populations and was noninferior to intramuscular haloperidol in
those with agitation associated with schizophrenia and its related disorders.
Aripiprazole is associated with a low risk for extrapyramidal symptoms (EPS), cardiac
effects, hyperprolactinaemia, weight gain and other metabolic disturbances.
Head-to-head trials comparing intramuscular aripiprazole with other intramuscular atypical
antipsychotics are required before the relative position of each of these agents can be fully
determined.
In the meantime, intramuscular aripiprazole, with its favourable tolerability profile, is a
valuable treatment option for agitation in patients with schizophrenia, schizoaffective
disorder, schizophreniform disorder or bipolar I disorder.
Aripiprazole treatment for patients with schizophrenia: from acute treatment to
maintenance treatment. Expert review of neurotherapeutics

Park MH, Han C, Pae CU, Lee SJ, Patkar AA, Masand PS, Fleischhacker WW,
Department of Neuropsychiatry, Division of Child and Adolescent Psychiatry, Seoul National
University College of Medicine, Seoul, Republic of Korea.
Published: Nov 2011

Abstract:
The most current treatment guidelines for schizophrenia recommend more than 1 year of
maintenance therapy after the first psychotic episode, and more than 5 years of maintenance
therapy after multiple psychotic episodes. Approximately two-thirds of such patients are
known to relapse within 1 year and almost 90% of such patients may recur within 2 years. To
maintain adequate consistent treatment, balancing the efficacy and safety/tolerability should
be one of the most important clinical issues. In this respect, aripiprazole appears to be a good
treatment option owing to its comparable efficacy, favorable safety and tolerability profile,
including low incidence of parkinsonian symptoms, lack of prolactin elevation, decreased
adrenergic and anticholinergic side effects, less weight gain and low incidence of metabolic
syndrome. Hence this article aims to summarize the currently available clinical trial data of
aripiprazole published from a number of large-scale randomized controlled studies, including
a newer formulation of intramuscular injection as well as a once-monthly intramuscular depot
formulation, to update knowledge of treatment options in patients with schizophrenia.

Aripiprazole versus placebo for schizophrenia

Cochrane database of systematic reviews (Online)


Belgamwar RB, El-Sayeh HG, Lymebrook Mental Health Centre, Bradwell Hospital Site,
Newcastle Under Lyme, Staffordshire, UK, ST5 4LD.
Published: 2011

Abstract:
Background: First generation typical antipsychotics such as chlorpromazine and
haloperidol have been the mainstay of treatment up until the introduction of the second
generation atypical antipsychotics such as risperidone and olanzapine. Typical and atypical
antipsychotics do provide a treatment response for most people with schizophrenia, whether a
reduction in psychotic episodes or a lessening in the severity of their illness. However, a
proportion of people still do not respond adequately to antipsychotic medication. Additionally,
atypical and especially typical antipsychotics are associated with serious adverse effects,
which can often compromise compliance with medication and therefore increase the
incidences of relapse. In this review we examine the effects of aripiprazole compared with
placebo.
Objectives: To evaluate the effects of aripiprazole compared with placebo for people with
schizophrenia and schizophrenia-like psychoses.
Search methods: We searched the Cochrane Schizophrenia Group Trials Register (January
2008) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE,
MEDLINE and PsycINFO. For this update, we carried out an initial search in May 2007 and a
second search in August 2008.
Selection criteria: We included all randomised trials comparing aripiprazole with placebo in
people with schizophrenia or schizophrenia-like psychosis.
Data collection and analysis: We extracted data independently. For dichotomous data we
calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat
basis based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH)
where appropriate. For continuous data, we calculated mean differences (MD) again based on
a fixed-effect model.
Main results:Despite the fact that 2585 people participated in nine randomised aripiprazole
studies, we were unable to extract any usable data on death, service outcomes, general
functioning, behaviour, engagement with services, satisfaction with treatment; economic
outcomes or cognitive functioning. In general, study attrition was very large for all studies
over four weeks duration. There was high attrition in most of the included studies. Fewer
people left the aripiprazole group compared with those in the placebo group (n = 2585, 9
RCTs, RR 0.73 CI 0.60 to 0.87). Compared with placebo, aripiprazole significantly decreased
relapse in both the short (n = 310, 1 RCT, RR 0.59 CI 0.45 to 0.77) and medium term (n =
310, 1 RCT, RR 0.66 CI 0.53 to 0.81). It also produced better compliance with study protocol
(n = 2275, 8 RCTs, RR 0.74 CI 0.59 to 0.93). Aripiprazole may decrease prolactin levels
below those expected from placebo (n = 305, 2 RCT, RR 0.21 CI 0.11 to 0.37). Insomnia
(23%) and headaches (15%) were commonly reported in both groups, with no significant
difference.
Authors conclusions: Aripiprazole may be effective for the treatment of schizophrenia.
Aripiprazole has a lower risk of raised prolactin and prolongation of the QTc interval. Clearly
reported pragmatic short-, medium- and long-term randomised controlled trials should be
undertaken to determine its position in everyday clinical practice.

Aripiprazole in schizophrenia and schizoaffective disorder: A review

Clinical therapeutics Stip E, Tourjman V, Centre de Recherche Fernand Seguin, Hpital L.-
H. Lafontaine, Universit de Montral, Qubec, Canada. emmanuel.stip@umontreal.ca
Published: 2010

Abstract:
During the past decade, there has been some progress in the pharmacotherapy of
schizophrenia and schizoaffective disorder. Current evidence supports the use of various
second-generation, or atypical, antipsychotic medications, although few of these agents have
been associated with long-term efficacy and tolerability. Aripiprazole is an atypical
antipsychotic that has been found to improve positive and negative symptoms of
schizophrenia with a favorable adverse-effect profile.
This article reviews the efficacy and tolerability of aripiprazole in the context of
recommended management strategies for schizophrenia and schizoaffective disorder, and in
comparison with first-generation and other second-generation antipsychotics.
A search of MEDLINE (1999-May 2009) was conducted for reports of short- and long-term
clinical studies of atypical antipsychotics (including aripiprazole) and meta-analyses of
randomized controlled trials comparing first- and second-generation antipsychotics (including
aripiprazole) in the treatment of schizophrenia or schizoaffective disorder. The search terms
were schizophrenia; schizoaffective disorder; pharmacogenetics; adverse effects; tardive
dyskinesia AND atypical antipsychotics; aripiprazole; aripiprazole, schizophrenia, AND
double-blind studies; and atypical antipsychotics AND adverse effects. The reference lists of
identified articles were reviewed for additional relevant publications. Only full study
publications were included.
Based on the clinical evidence, including data from short-term (4-8 weeks) and long-term (26-
52 weeks) randomized, double-blind clinical trials, aripiprazole has been associated with
improvements in positive, negative, cognitive, and affective symptoms of schizophrenia and
schizoaffective disorder.
It has been associated with long-term (up to 52 weeks) symptom control in schizophrenia, as
well as with efficacy in treatment-resistant schizophrenia. Common adverse effects associated
with aripiprazole were nausea, insomnia, and agitation. These effects were usually transient.
The evidence suggests that aripiprazole is unlikely to be associated with clinically significant
weight gain or dyslipidemia, increased prolactin levels, or prolongation of the QTc interval.
Compared with placebo, aripiprazole has been reported to have a relatively low potential for
inducing metabolic syndrome.
Based on the evidence reviewed, aripiprazole monotherapy appears to be effective and well
tolerated in treating the positive, negative, and cognitive symptoms of schizophrenia and
schizoaffective disorder. It was associated with a low risk for the common adverse effects of
antipsychotic therapy, including metabolic and endocrine alterations.

The acute efficacy of aripiprazole across the symptom spectrum of schizophrenia: a


pooled post hoc analysis from 5 short-term studies.
The Journal of clinical psychiatry Janicak PG, Glick ID, Marder SR, Crandall DT,
McQuade RD, Marcus RN, Eudicone JM, Assuno-Talbott S, Department of Psychiatry,
Rush University Medical Center, Chicago, Illinois 60612, USA. pjanicak@rush.edu
Published: Jan 2009

Abstract:
Objective: To evaluate the efficacy of aripiprazole across a range of symptoms-positive,
negative, disorganized thought, depression/anxiety, and hostility-in schizophrenia and
schizoaffective disorder.
Pooled data were analyzed from 5 short-term, double-blind, multicenter studies (published
between 1997 and 2007) involving patients hospitalized with acute exacerbation of
schizophrenia (5 studies) or schizoaffective disorder (2 studies) and randomly assigned to
aripiprazole (N = 875), haloperidol (N = 193), risperidone (N = 95), or placebo (N = 406).
Aripiprazole doses ranged from 2 to 30 mg/day. Patients receiving the ineffective 2-mg dose
were excluded from the primary analyses presented here. Factor analysis of Positive and
Negative Syndrome Scale (PANSS) data was used to evaluate changes from baseline with
aripiprazole on 5 symptom factors-positive, negative, disorganized thought,
depression/anxiety, and hostility-in 2 population subsets-schizophrenia and schizoaffective
disorder.
Pairwise comparisons were made as follows for schizophrenia: aripiprazole versus placebo in
all 5 studies; aripiprazole, haloperidol, and placebo in 3 studies; and aripiprazole, risperidone,
and placebo in 1 study. Patients with schizoaffective disorder in 2 studies were included in the
comparison of aripiprazole and placebo.
Aripiprazole was significantly better than placebo in improving all 5 PANSS factor scores
from baseline (each p < .001) in the schizophrenia dataset. In schizoaffective disorder,
aripiprazole was significantly better than placebo for the improvement of positive (p <or= .05)
and hostility (p <or= .01) factor scores. Analysis of the 3 studies involving haloperidol
showed that aripiprazole was significantly better than placebo in improving all 5 factors (p
<or= .01), whereas haloperidol produced significantly greater improvements than placebo in 3
factors (positive, disorganized thought, and hostility) (each p < .001).
There was no difference between aripiprazole and haloperidol on any factor. Analysis of the
study involving risperidone showed that both drugs were better than placebo for all 5 factors
with the exception of the depression/anxiety factor, in which only risperidone separated from
placebo. There was no difference between aripiprazole and risperidone on any factor.
In this large dataset, aripiprazole was associated with improvements in a broad range of
symptom domains in the short-term treatment of schizophrenia and schizoaffective disorder.

Aripiprazole for Mania

Aripiprazole is approved for the treatment of manic episodes in type I bipolar disorder.
In this page you can find abstracts of review articles, guideline comments and controlled trials
on the use of aripiprazole for the management of mania.

Review Articles

Aripiprazole: a review of its use in the management of mania in adults with bipolar I
disorder.

Dhillon S,
Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz
Published: Jan 2012

Abstract:
Aripiprazole (Abilify) is an atypical antipsychotic indicated for the treatment of mania
associated with bipolar I disorder. It is unique in its class, as it is a partial agonist of dopamine
D(2) and D(3), and serotonin 5-HT(1A) receptors and a modest antagonist of 5-HT(2A)
receptors.
This article reviews the pharmacological properties, clinical efficacy and tolerability of oral
aripiprazole in the management of mania associated with bipolar I disorder in adults. In well
designed clinical trials in patients with recent manic or mixed episodes associated with bipolar
I disorder, oral aripiprazole monotherapy or adjunctive therapy to lithium or valproate
improved symptoms of mania following short-term (12 weeks) or maintenance (100
weeks) treatment. In addition, maintenance treatment with aripiprazole (as monotherapy or
adjunctive therapy) prevented the recurrence of any mood episodes or manic episodes (but not
depressive episodes) in patients who had previously been stabilized and maintained on
aripiprazole.
Aripiprazole was generally well tolerated in these studies and was associated with a low risk
of prolactin elevation, corrected QT interval prolongation and metabolic disturbances.
Extrapyramidal symptoms occurred in up to 28% of aripiprazole recipients, but after longer-
term treatment (100 weeks), symptom severity did not differ significantly from that in
placebo recipients.
Aripiprazole treatment generally did not increase body weight to a clinically relevant extent;
however, more patients receiving aripiprazole monotherapy than placebo had clinically
significant body weight gain during 100 weeks treatment. Additionally, in a comparative trial,
aripiprazole monotherapy was at least as effective as haloperidol monotherapy in terms of
improving symptoms of mania, but had the advantage of a lower incidence of some adverse
events, such as extrapyramidal symptom-related adverse events.
Further trials comparing aripiprazole with other agents, including atypical antipsychotics,
would help to definitively position aripiprazole relative to these agents.
Current guidelines recommend aripiprazole as a first-line option (as monotherapy or
adjunctive therapy) for the short-term treatment of mania associated with bipolar I disorder,
and as a first-line (as monotherapy) or second-line (as adjunctive therapy) option for
preventing the recurrence of mood episodes during longer-term therapy.

Advances in the treatment of mania: aripiprazole

Actas espaolas de psiquiatra


Vieta E, Franco C, Programa de Trastornos Bipolares, Instituto Clnico de Neurociencias,
Hospital Clnic, Universitat de Barcelona, IDIBAPS, CIBER-SAM, Barcelona.
evieta@clinic.ub.es
Published:

Abstract:
Aripiprazole is a dopamine partial agonist antipsychotic drug that has just been approved in
Europe for its use in the treatment of acute mania and for the prevention of manic episodes in
bipolar disorder. Its efficacy in mania is superior to that of placebo, both as monotherapy and
as adjunctive therapy, and comparable to that of haloperidol and lithium.
From the safety perspective it is remarkable that it is not highly sedative and does not impair
the metabolic parameters.
The advantages of a non-sedative and metabolically neutral antimanic drug are particularly
relevant in the long-term, due to their impact on cognition and quality of life. The experience
on its use in routine clinical practice indicates that in order to avoid phenomena such as
activation, abrupt worsening or akathisia, it is recommendable to start treatment with low
doses and to increase them progressively, especially in those patients who are already
receiving other drugs; moreover, it is advisable not to stop abruptly any ongoing treatment,
unless there is an emergency, to transiently prescribe a concomitant benzodiazepine, and to
maintain the dose that proved efficacious during the short term treatment during maintenance
therapy.
Clinical Guidelines and Expert Opinion

Goodwin GM, Abbar M, Schlaepfer TE, Grunze H, Licht RW, Bellivier F, Fountoulakis KN,
Altamura AC, Pitchot W, gren H, Holsboer-Trachsler E, Vieta E,
Warneford Hospital, Oxford University, UK. Guy.Goodwin@psych.ox.ac.uk
Published: Dec 2011

Abstract:
Aripiprazole is an atypical antipsychotic with a pharmacological and clinical profile distinct
from other atypical antipsychotics.A European multidisciplinary advisory panel of university-
based experts in bipolar disorders convened in April 2010 to review new clinical guidelines
for the management of mania and the role of aripiprazole in its treatment.
This report describes the consensus reached on how best to use aripiprazole in the treatment
of mania.Current guidelines recommending aripiprazole for first-line treatment of mania have
not generally translated to clinical practice. The panel agreed that clinicians may not feel
sufficiently knowledgeable on how to use aripiprazole effectively in mania, and that the
perception that aripiprazole is less sedating than other antipsychotics may hamper its use.
There was consensus about the importance of ensuring that clinicians understood the
distinction between antimanic efficacy and sedation. Most acutely manic patients may require
night-time sedation, but continuous daytime sedation is not necessarily indicated and may
interfere with long-term compliance.
If sedation is necessary, guidelines recommend the use of adjunctive benzodiazepines only for
a short-time.Clinical practice guidelines widely recommend aripiprazole as a first-line
treatment for mania. Although clinical trials may not represent all patient subpopulations, they
show that aripiprazole is well tolerated and has a long-term stabilizing potential.
The successful use of aripiprazole rests on using the appropriate initial dose, titrating and
adjusting the dose as needed and using appropriate concomitant medication to minimize any
short-term adverse events. Low incidence of sedation makes aripiprazole a reasonable long-
term treatment choice. If short-term sedation is required an adjunctive sedative agent can be
added and removed when no longer needed.
Clinical considerations should influence treatment choice, and a better distinction between
sedation and antimanic effects should be an educational target aimed to overcome potential
barriers for using non-sedative antimanic agents such as aripiprazole.
Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from
acute mania to long-term maintenance.

Expert opinion on pharmacotherapy


de Bartolomeis A, Perugi G, University of Napoli Federico II, Laboratory of Molecular
Psychiatry and Unit of Treatment Resistant Psychosis, Department of Neuroscience, Napoli,
Italy.
Published: Oct 2012

Abstract:
INTRODUCTION: Bipolar disorder is characterized by a complex set of symptoms,
including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of
patients with bipolar disorder is mandatory to prevent symptom relapse and episode
recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence
combinations of mood stabilizers and antipsychotics are widely utilized in patients showing
no or partial response to, as well as intolerance to, monotherapies. This may offer a
therapeutic advantage, however, the possibility of an increased incidence of side effects
should be considered.
AREAS COVERED: This paper reviews the current treatment guidelines for the treatment of
bipolar disorder and examines the rationale behind the use of aripiprazole in combination with
mood stabilizers for acute and long-term treatment of bipolar disorder.
EXPERT OPINION: The combination of aripiprazole and mood stabilizers seems to offer an
effective and relatively well-tolerated option for the treatment of acute mania and for the
maintenance treatment of patients with bipolar I disorder. The combination presents a lower
risk of metabolic side effects compared with other combination therapies, but increases the
risk of extrapyramidal side effects with long-term treatment. The aripiprazole-valproate
combination seems to be particularly promising in the treatment of patients with
comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar
disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to
confirm these observations and to provide a useful insight for improving the use of drug
combinations in bipolar patients.
A UK panel consensus on the initiation of aripiprazole for the treatment of bipolar mania.

International journal of psychiatry in clinical practice


Dratcu L, Bobmanuel S, Davies W, Farmer A, George M, Rana T, Singh M, Turner M,
Maudsley Hospital, South London and Maudsley NHS Foundation Trust, London, UK.
Luiz.Dratcu@slam.nhs.uk
Published: Oct 2012
Abstract:
The objective of this consensus paper is to provide practical guidance on why and how
aripiprazole, with its distinct pharmacological and side effect profile, should be used for
treatment of acute bipolar mania.An advisory panel of UK healthcare professionals, with
extensive experience of prescribing aripiprazole for acute bipolar mania, met to discuss its use
in this setting.The panel agreed that aripiprazole is effective in treating bipolar mania when
prescribed and dosed appropriately, in both the short and long term, as monotherapy or in
combination with a mood stabilizer.
Unlike other atypical agents, aripiprazole has antimanic effects that are not associated with
sedation, which is beneficial for patients, particularly in the long term. If rapid tranquillization
is required when initiating aripiprazole in acutely disturbed patients, short-term coprescription
of a benzodiazepine is recommended. Most side effects associated with aripiprazole occur
within the first 1-3 weeks and are usually transient and easily treatable.
Aripiprazole poses low risk of metabolic side effects, sexual dysfunction, and anhedonia,
which can facilitate treatment adherence and help improve clinical outcomes.Aripiprazole is
an effective first-line treatment for acute bipolar mania with a favorable safety/tolerability
profile.

Controlled Trials

Combination treatment with aripiprazole and valproic acid for acute mania: an 8-week, single-
blind, randomized controlled trial.

Clinical neuropharmacology
Jeong HG, Lee MS, Ko YH, Han C, Jung IK, Department of Psychiatry, Korea University
Guro Hospital, Korea University College of Medicine, Seoul, Korea.
Published: May 2012

Abstract:
Despite the fact that combination treatment for patients with acute bipolar is prevalent in
clinical practice, the outcomes of adjunct treatment with aripiprazole and a mood stabilizer
have rarely been reported. The aim of this single-blind, randomized, controlled trial was to
investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid
(Ari+Val), compared with haloperidol plus valproic acid (Hal+Val), in acute manic
patients.Treatment efficacy was prospectively assessed for 8 weeks in 42 patients with acute
mania using the Young Mania Rating Scale and the Clinical Global Impression-Severity of
illness scale.
Emergent adverse events were assessed by the Drug-Induced Extrapyramidal Symptoms
Scale and the Liverpool University Neuroleptic Side Effect Rating Scale.Both Ari+Val and
Hal+Val produced a high rate of response (85.7% and 92.9%, respectively) and remission
(82.1% and 85.7%, respectively) after the 8-week trial. Changes in the Young Mania Rating
Scale and the Clinical Global Impression-Severity of illness scale over the study period and
time to remission and response were not significantly different between the 2 groups.
Patients treated with Ari+Val showed significantly fewer extrapyramidal adverse events than
those treated with Hal+Val (t = -2.048, F = 40, P = 0.048). However, significant weight gain
was more prevalent in the Ari+Val group than the Hal+Val group (t = 2.055, F = 40, P =
0.046).Our findings suggest that both combination strategies with Ari+Val and Hal+Val are
beneficial for acute manic episode.
Although patients receiving Ari+Val showed fewer extrapyramidal symptoms than those
taking Hal+Val, careful consideration of adverse events such as weight gain and sedation is
warranted.
Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-
controlled study

The British journal of psychiatry: the journal of mental science


Young AH, Oren DA, Lowy A, McQuade RD, Marcus RN, Carson WH, Spiller NH,
Torbeyns AF, Sanchez R, Institute of Mental Health, Department of Psychiatry, University of
British Columbia, Vancouver, Canada. allanyoun@gmail.com
Published: Jan 2009

Abstract:
Well-tolerated and effective therapies for bipolar mania are required.To evaluate the efficacy
and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with
bipolar I disorder experiencing manic or mixed episodes.Patients were randomised to double-
blind aripiprazole (15 or 30 mg/day; n=167), placebo (n=153) or haloperidol (5-15 mg/day,
n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated
patients remained on masked treatment for 9 additional weeks.Mean change in Young Mania
Rating Scale Total score (primary end-point) at week 3 was significantly greater with
aripiprazole (-12.0; P<0.05) and haloperidol (-12.8; P<0.01) than with placebo (-9.7).
Improvements were maintained to week 12 for aripiprazole (-17.2) and haloperidol (-17.8).
Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with
haloperidol than aripiprazole (53.3% v. 23.5%).Clinical improvements with aripiprazole were
sustained to week 12. Aripiprazole was generally well tolerated.
Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-
blind, placebo- and lithium-controlled study.

Journal of affective disorders

Keck PE, Orsulak PJ, Cutler AJ, Sanchez R, Torbeyns A, Marcus RN, McQuade RD,
Carson WH, Psychopharmacology Research Program, Department of Psychiatry, University
of Cincinnati College of Medicine, and Linder Center of HOPE, Mason, Ohio 45267, USA.
paul.keck@uc.edu
Published: Jan 2009

Abstract:
To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect
monotherapy for acute bipolar mania.Patients with acute bipolar I mania (DSM-IV-TR:
YMRS > or =20), manic or mixed (with or without psychotic features) were randomized to
double-blind aripiprazole (15-30 mg/day; n=155), placebo (n=165) or lithium (900-1500
mg/day; n=160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on
blinded treatment for 9 additional weeks. The primary outcome was the mean change from
baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean
change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12.
Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS
Total score from baseline to Day 2 (-4.3 vs.-2.8; p=0.003), and up to Week 3 (-12.6 vs. -9.0;
p<0.001). Significant improvement in YMRS Total score was also seen with lithium versus
placebo at Week 3 (-12.0 vs. -9.0; p=0.005). Improvements in YMRS Total score were
maintained to Week 12 for aripiprazole (-14.5) and lithium (-12.7).
Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium
(45.8%) than placebo (34.4%; both p<0.05, LOCF); increasing to Week 12 with aripiprazole
(56.5%) and lithium (49.0%). Most common adverse events with aripiprazole were headache,
nausea, akathisia, sedation, and constipation; with lithium were nausea, headache,
constipation, and tremor.Aripiprazole provided statistically significant improvement of acute
mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of
improvement to Week 12 was similar with aripiprazole and lithium.
Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients
partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study.

The American journal of psychiatry


Vieta E, Tjoen C, McQuade RD, Carson WH, Marcus RN, Sanchez R, Owen R, Nameche L,
Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS,
Villarroel 170/Rossello 140, 08036 Barcelona, Spain. evieta@clinic.ub.es
Published: Oct 2008

Abstract:
The authors evaluated the efficacy and safety of adjunctive aripiprazole in bipolar I patients
with mania partially nonresponsive to lithium/valproate monotherapy.This multicenter,
randomized, placebo-controlled study included outpatients experiencing a manic or mixed
episode (with or without psychotic features). Patients with partial nonresponse to
lithium/valproate monotherapy (defined as a Young Mania Rating Scale total score >/=16 at
the end of phases 1 and 2, with a decrease of </=25% between phases) with target serum
concentrations of lithium (0.6-1.0 mmol/liter) or valproate (50-125 mug/ml) were randomly
assigned in a 2:1 ratio to adjunctive aripiprazole (N=253; 15 or 30 mg/day) or placebo
(N=131) for 6 weeks.
Mean improvement from baseline in Young Mania Rating Scale total score at week 6 (primary
endpoint) was significantly greater with aripiprazole (-13.3) than with placebo (-10.7).
Significant improvements in Young Mania Rating Scale total score with aripiprazole versus
placebo occurred from week 1 onward. In addition, the mean improvement in Clinical Global
Impression Bipolar Version (CGI-BP) severity of illness (mania) score from baseline to week
6 was significantly greater with aripiprazole (-1.9) than with placebo (-1.6). Discontinuation
rates due to adverse events were higher with aripiprazole than with placebo (9% versus 5%,
respectively).
Akathisia was the most frequently reported extrapyramidal symptom-related adverse event
and occurred significantly more frequently among those receiving aripiprazole (18.6%) than
among those receiving placebo (5.4%). There were no significant differences between
treatments in weight change from baseline to week 6 (+0.55 kg and +0.23 kg for aripiprazole
and placebo, respectively; last observation carried forward).
Adjunctive aripiprazole therapy showed significant improvements in mania symptoms as
early as week 1 and demonstrated a tolerability profile similar to that of monotherapy studies.
A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients
with acute bipolar mania.

The American journal of psychiatry

Keck PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G,


Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati College of
Medicine, PO Box 670559, Cincinnati, OH 45267-0559, USA. paul.keck@uc.edu
Published: Sep 2003
Abstract:
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.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%.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.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.

Aripiprazole for Depression

Aripiprazole was approved by the FDA as adjunct to antidepressants for the treatment of
major depressive disorder in 2007.
This page curates review articles, meta-analyses and randomized controlled trials on the role
of aripiprazole as augmentation strategy in the management of depression.
Review Articles

Aripiprazole in major depressive disorder. CNS drugs Weber J, Lyseng-


Williamson KA, Scott LJ, Wolters Kluwer Health | Adis, Auckland, New Zealand.
Published: 2008

Abstract:
Aripiprazole, an oral quinolinone, is the first atypical antipsychotic agent to be approved in
the US as adjunctive treatment in adult patients with major depressive disorder (MDD).
In two large, well-designed trials in patients with MDD who had an inadequate response to
standard antidepressant therapy, 6 weeks adjunctive therapy with aripiprazole 2-20 mg/day
improved mean Montgomery Asberg Depression Rating Scale (MADRS) total scores
(primary endpoint) to a significantly greater extent than adjunctive placebo treatment.
Improvements in mean MADRS total score during the double-blind phase favoured
adjunctive aripiprazole treatment from 1-2 weeks onward, with per-protocol subgroup
analyses showing that mean changes were not affected by the specific standard antidepressant
therapy used, age or sex of the patient or the mean MADRS total scores at the start of double-
blind adjunctive therapy.
In general, secondary endpoint scores, including those for the Sheehan Disability Scale,
Clinical Global Impression (CGI) Improvement scale and CGI Severity of Illness scale,
improved to a significantly greater extent with adjunctive aripiprazole than with adjunctive
placebo treatment, with significantly higher response and remission rates in the aripiprazole
groups. In these two pivotal trials, adjunctive aripiprazole 2-20 mg/day was generally well
tolerated, with most treatment-emergent adverse events being of mild to moderate severity.

Aripiprazole as adjunctive therapy for patients with major depressive disorder:


overview and implications of clinical trial data.

CNS drugs Pae CU, Forbes A, Patkar AA, Department of Psychiatry, Bucheon St. Marys
Hospital, The Catholic University of Korea College of Medicine, Bucheon, Kyounggi-Do,
Republic of Korea. pae@catholic.ac.kr
Published: Feb 2011

Abstract:
Aripiprazole was initially approved to treat schizophrenia and later approved for bipolar
mania, as a monotherapy and an adjunctive therapy (manic or mixed episodes), and for
irritability associated with autism.
Aripiprazole is a partial agonist at dopamine D(2) and D(3) and serotonin 5-HT1A receptors,
and is an antagonist at 5-HT(2A) receptors. This profile, and convincing preliminary data
from small-scale studies, provided the rationale for the large-scale exploration of aripiprazole
for unipolar depression. Recently, three 6-week, large-scale, randomized, double-blind,
placebo-controlled clinical trials demonstrated clinically meaningful efficacy for aripiprazole
as an adjunctive therapy to antidepressants for treating major depressive disorder (MDD).
In November 2007, aripiprazole was approved by the US FDA as an adjunctive therapy to
antidepressants for treating MDD, with support from two of the above-mentioned trials. In the
trials, aripiprazole was demonstrated to be safe and well tolerated, and showed a minimal
trend for weight gain over the course of a 6-week treatment. The incidence of akathisia was
higher than that reported in studies of patients with schizophrenia; however, most cases were
mild to moderate and infrequently lead to discontinuation (5/1090 from all three trials).
This comprehensive review provides an overview of the data from all three 6-week studies
(including a pooled analysis) and from an unpublished 52-week, open-label extension study,
to inform physicians and facilitate reasonable treatment decisions. In addition, specific issues
associated with the use of aripiprazole as an adjunctive therapy in patients with MDD,
including possible early treatment effect, appropriate timing of therapy initiation, appropriate
dosing and duration of treatment, possible differential effect on depressive subgroups and
long-term tolerability, are also discussed.

Neurobiological bases and clinical aspects of the use of aripiprazole in treatment-


resistant major depressive disorder.

Journal of affective disorders Blier P, Blondeau C, University of Ottawa Institute of Mental


Health Research, Canada. pierre.blier@rohcg.on.ca
Published: Jan 2011

Abstract:
Addition of atypical antipsychotics to the therapeutic regimen of patients with unipolar major
depressive disorder not responding adequately to their treatment has become a common
intervention. With all these agents the observation that low doses that are ineffective in
schizophrenia, and thus not blocking dopamine D2 receptors effectively, indicate that their
beneficial action is attributable to their action at other receptors.
Preclinical research has shown that atypical antipsychotics can reverse the suppression of
firing of norepinephrine neurons produced by selective serotonin reuptake inhibitors through
their antagonism of 5-HT2(A) receptors. In the case of aripiprazole, three large placebo-
controlled studies in more than 1,000 patients individually concluded to significant
antidepressant responses and remissions after a six-week treatment.
Aripiprazole addition did not produce more discontinuations due to adverse events than
placebo. The most frequently encountered adverse events were akathisia and restlessness.
Weight gain was minimal but significant in two of the three studies, suggesting that this side
effect is not major problem. There was no significant laboratory abnormalities noted with this
strategy. It is proposed that because of its long half-life (approximately 3 days), the doses of
aripiprazole were escalated too rapidly in these controlled trials. More gradual titration may
lead in routine clinical practice to better outcomes, minimizing side effects and improving
remission rates. Copyright 2011 Elsevier B.V. All rights reserved.

Current evidence for aripiprazole as augmentation therapy in major depressive


disorder.

Expert review of neurotherapeutics Khan A, Department of Psychiatry and Behavioral


Sciences, Duke University, Durham, NC, USA. akhan@nwcrc.net
Published: Oct 2008

Abstract:
Aripiprazole (Abilify) is the first atypical antipsychotic approved as adjunctive therapy for the
treatment of major depressive disorder. The pharmacological basis of the action of
aripiprazole in major depressive disorder remains unclear, but it may be related to its potent
partial agonism of the dopamine D(2)/D(3) receptors, partial agonism of the 5-
hydroxytryptamine (5-HT)(1A) receptor and antagonism of the 5-HT(2A) receptor.
This article reviews findings on the efficacy and tolerability of aripiprazole from two identical
placebo-controlled trials and from smaller open-label and retrospective studies. At doses of 2-
15 mg/day aripiprazole was efficacious and well tolerated as adjunctive therapy to
antidepressants in patients who had not responded to monotherapy.

Meta-analyses
Efficacy of adjunctive aripiprazole in patients with major depressive disorder who showed
minimal response to initial antidepressant therapy.

International clinical psychopharmacology

Nelson JC, Thase ME, Bellocchio EE, Rollin LM, Eudicone JM, McQuade RD, Marcus RN,
Berman RM, Baker RA, Department of Psychiatry, University of California San Francisco,
401 Parnassus Ave, San Francisco, CA 94143, USA. CraigN@lppi.ucsf.edu
Published: May 2012

Abstract:
To evaluate the efficacy of adjunctive aripiprazole in patients with minimal response to prior
antidepressant therapy (ADT). Pooled data from three randomized, double-blind, placebo-
controlled studies assessing the efficacy of adjunctive aripiprazole to ADT in patients with
major depressive disorder who had a minimal response [< 25% reduction on the
Montgomery-sberg Depression Rating Scale (MADRS)] to an 8-week prospective ADT.
During the 6-week, double-blind adjunctive phase, response was defined as at least 50%
reduction in the MADRS score and remission as at least 50% reduction in MADRS score and
a MADRS score = 10. Rates were examined using analysis of covariance and Cochran-
Mantel-Haenszel tests. Kaplan-Meier curves were used to calculate time to response and
remission. Of 1038 patients, 72% (n=746) exhibited a minimal response to ADT (ADT
minimal responder).
Time to response and remission were significantly shorter for ADT minimal responders
receiving aripiprazole+ADT versus adjunctive placebo+ADT. ADT minimal responders on
aripiprazole+ADT showed significantly greater improvements in MADRS score at endpoint
compared with minimal responders on placebo+ADT (-10.3 vs. -6.5, P<0.0001). In addition,
ADT minimal responders exhibited significantly higher response rates with aripiprazole+ADT
than placebo+ADT (36 vs. 19%, respectively, P<0.0001) and higher remission rates (24 vs.
12%, respectively, P<0.0001).
The numbers needed to treat with aripiprazole+ADT were six for response and eight for
remission. Aripiprazole augmentation had a rapid and clinically meaningful effect in ADT
minimal responders.

Aripiprazole in major depression and mania: meta-analyses of randomized placebo-controlled


trials.

General hospital psychiatry

Arbaizar B, Dierssen-Sotos T, Gmez-Acebo I, Llorca J, Unit of Mental Health, Hospital de


Laredo, Laredo, Spain.
Published:

Abstract:
We performed meta-analyses to obtain pooled estimates from controlled clinical trials on the
efficacy of aripiprazole in major depression disorder and manic phase of bipolar disorder.A
search was performed in Medline/PubMed using aripiprazole AND depressive disorder
and aripiprazole AND bipolar disorder as keywords, and randomized controlled trial as
limit. The last search was performed by April 30, 2009. References in the selected articles
were revised to identify other studies.
We selected four placebo-controlled clinical trials on aripiprazoles effect on major
depression, and three on aripiprazoles effect on bipolar disorder. Studies performed in
patients with comorbidity or devoted to measuring the effect of aripiprazole for maintenance
therapy were excluded. We extracted, in duplicate, data on number of patients, withdrawals,
changes in Montgomery-Asberg Depression Rating Scale and Young Mania Rating Scale
(YMRS), response and remission rates, and side effects.
Aripripazole is effective in increasing response rates in depressive patients (response rate in
the aripiprazole group minus response rate in the placebo group: 7.7%, 95% CI: 1.5-14.2) and
manic patients (difference in response rates: 15.7%, 95% CI: 9.7-21.8). It also improves by 3
points the scores in YMRS. Evidence of improving remission rates is unavailable. Some side
effects were more frequent in patients taking aripiprazole; this was the case of akathisia,
especially in depressive trials (rate difference: 20.3%, 95% CI: 16.9-23.7), and nausea in
manic patients (rate difference: 10.5%, 95% CI: 7.4-13.5). Insomnia and restlessness were
also more frequent in depressive patients taking aripiprazole
We found evidence suggesting that aripiprazole is effective in both depressive and manic
patients, but has relevant side effects. Further research is needed to identify its benefits for
comorbid patients and its long-term effect.

Randomized Controlled Trials


Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled
study in patients with inadequate response to antidepressants.

CNS spectrums
Berman RM, Fava M, Thase ME, Trivedi MH, Swanink R, McQuade RD, Carson WH, Adso
n D, Taylor L, Hazel J, Marcus RN, Neuroscience Global Clinical Research at Bristol-Myers
Squibb, Wallingford, CT 06492, USA. Robert.Berman@bms.com
Published: Apr 2009

Abstract:
Effective management of major depressive disorder (MDD) continues to be a challenging task
for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of
adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and
independently replicated the positive findings of two similar trials.
Patients (N=1,147) with MDD experiencing a major depressive episode and a history of
inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received
single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine,
paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to
confirm inadequate response to antidepressants; 349 patients with inadequate response were
randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole
(n=177; 2-20 mg/day).
Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale
(MADRS) Total score from baseline (week 8) to endpoint (week 14).Clinically significant
improvements in depressive symptoms as assessed by decreases in the MADRS Total score
were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001).
Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14,
36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were
high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%).For
some patients with MDD who do not obtain adequate symptom relief with antidepressant
monotherapy, adjunctive therapies can significantly improve depressive symptoms.
As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than
adjunctive placebo. This, and previous studies, have shown that discontinuations due to
adverse events were low and completion rates were high, and has indicated that both
antidepressant and aripiprazole in combination were relatively well-tolerated and safe.
This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that
aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for
patients with MDD who do not respond adequately to standard antidepressant monotherapy
(ClinicalTrials.gov study NCT00105196).

The efficacy and safety of aripiprazole as adjunctive therapy in major depressive


disorder: a second multicenter, randomized, double-blind, placebo-controlled study.

Journal of clinical psychopharmacology


Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, Trivedi MH, Thas
e ME, Berman RM, Bristol-Myers Squibb, Wallingford, CT 06492, USA.
Published: Apr 2008

Abstract:
Nonresponse to one or more antidepressants is common and an important public health
problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to
standard antidepressant therapy (ADT) in patients with major depressive disorder who
showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective
ADT.
The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week
randomization phase. During prospective treatment, patients experiencing a major depressive
episode (17-item Hamilton Rating Scale for Depression total score > or = 18) received single-
blind adjunctive placebo plus clinicians choice of ADT (escitalopram, fluoxetine, paroxetine
controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate
response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n =
191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d).
The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression
Rating Scale total score from end of prospective treatment phase to end of randomized
treatment phase (last observation carried forward). Mean change in Montgomery-Asberg
Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than
placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive
aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs
17.4%; P < 0.001).
Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole
were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%).
Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs
adjunctive aripiprazole [3.7%]).
Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term
study for patients who are nonresponsive to standard ADT.

The efficacy and safety of aripiprazole as adjunctive therapy in major depressive


disorder: a multicenter, randomized, double-blind, placebo-controlled study.

The Journal of clinical psychiatry

Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, Khan A,
Bristol-Myers Squibb Co., Wallingford, Conn. 06492, USA. Robert.Berman@bms.com
Published: Jun 2007

Abstract:
To assess the efficacy and safety of aripiprazole versus placebo as adjunctive treatment to
standard antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who
showed an incomplete response to 1 prospective and 1 to 3 historical courses of ADT within
the current episode.The study comprised a 7- to 28-day screening phase, an 8-week
prospective treatment phase, and a 6-week double-blind treatment phase. Patients with DSM-
IV-TR-defined MDD were enrolled between June 16, 2004, and April 27, 2006.
During prospective treatment, patients received ADT: escitalopram, fluoxetine, paroxetine
controlled-release, sertraline, or venlafaxine extended-release, each with single-blind,
adjunctive placebo. Incomplete responders continued ADT and were randomly assigned to
double-blind, adjunctive placebo or adjunctive aripiprazole (2-15 mg/day with fluoxetine or
paroxetine; 2-20 mg/day with all others).
The primary efficacy endpoint was the mean change from end of prospective treatment to end
of double-blind treatment (week 14, last observation carried forward) in Montgomery-Asberg
Depression Rating Scale (MADRS) total score (analysis of covariance).A total of 178 patients
were randomly assigned to adjunctive placebo and 184 to adjunctive aripiprazole. Baseline
demographics were similar between groups (mean MADRS total score of 26.0). Mean change
in MADRS total score was significantly greater with adjunctive aripiprazole (-8.8) than
adjunctive placebo (-5.8; p < .001). Adverse events (AEs) that occurred in > or = 10% of
patients with adjunctive placebo or adjunctive aripiprazole were akathisia (4.5% vs. 23.1%),
headache (10.8% vs. 6.0%), and restlessness (3.4% vs. 14.3%).
Discontinuations due to AEs were low with adjunctive placebo (1.7%) and adjunctive
aripiprazole (2.2%); only 1 adjunctive aripiprazole-treated patient discontinued due to
akathisia.In patients with MDD who showed an incomplete response to ADT, adjunctive
aripiprazole was efficacious and well tolerated.

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