Clinical Research Report: Abilify, Pharmacology, and Safety Guidelines

This clinical research report provides a comprehensive overview of Abilify (aripiprazole), a psychotropic drug used to treat bipolar I disorder and schizophrenia. The report details the drug's mechanism of action, therapeutic benefits, and various forms of administration, including tablets, oral solutions, and injections. It highlights the efficacy of Abilify in managing manic episodes and psychotic symptoms, supported by clinical studies comparing it to placebos and other medications like haloperidol and lithium. Furthermore, the report addresses the risks associated with Abilify, including potential side effects such as anxiety, restlessness, tardive dyskinesia, and hyperglycemia. It also explores the pharmacokinetics of aripiprazole, including its metabolism and elimination pathways. Finally, the report references relevant ICH safety guidelines and the requirements for non-clinical safety studies, offering a detailed analysis of Abilify within a clinical research context.

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Clinical research
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Drug; Abilify
Overview of therapeutic area and drug description
Abilify is a psychotropic drug that is available as tablets and in oral solution form. Its active
ingredient is Aripiprazole; 7-[-4-[4-(2,3-dichlorophenyl)-1-pepirazinyl]butoxy]-3,4-
digydrocarbostyril. Fig. 1 below shows the chemical structure of the medicine
Figure.1; chemical structure of Aripiprazole
Abilify is an antipsychotic medicine for patients with bipolar I disorder and schizophrenia. It
contains aripiprazole as the active substance. Schizophrenia is a complicated mental disorder
where the patients abnormally interpret reality. It is often characterized by hallucinations, some
sort of disordered thinking and delusion. It is a condition that requires lifelong treatment,
however, early intervention and treatment may be very significant in getting the mild symptoms
in control thus reducing cases of serious complications (Andersen, 2017 p.67). Causes of
Schizophrenia still remain unknown but scientists believe it is brought by a combination brain
chemistry, genetics as well as environmental factors. When unattended to, Schizophrenia may
result into serious complications that tends to affect every area of one’s life (Saklad, Kreys,
Phan, 2015 p.90). Known complications that may be brought by a persistent case of
Schizophrenia comprise of depression, instances of social isolations, aggression, financial

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problems and homelessness as well as suicidal thoughts and behavior. For Schizophrenia, Abilify
is used to treat patients that are fifteen years and older.
Bipolar I disorder on the other hand is a form of mental illness. Individuals affected by this
particular condition often experience manic behaviors once in their lifetime. This is a period that
is usually characterized by elevated periods of abnormality and high energy that tends to disrupt
normal life patterns (Kahn & Giannopoulou, 2015 p.65). Evidence shows that anyone can
develop bipolar I disorder. Statistics indicate that about 2.7% of the United States population is
suffering from bipolar I disorder. This condition is associated with an inflated self-image, hyper
sexuality, high energy and issues of substance abuse. Abilify is used in the treatment of maniac
episodes that are often caused by the condition. For patients who have had maniac episodes
before, Abilify is used to prevent new ones. It can be used for up to a period of twelve weeks and
its advised for patients that are aged thirteen years and above.
Why abilify is approved
Abilify is available in many forms; both liquid and tablets. It is also available in solution form
used in injection. The solution form in mostly preferred because its effective in controlling
disturbed behavior and agitation for patients suffering diagnosed by both bipolar I disorder and
Schizophrenia. It is as well important to note that Abilify can only be obtain strictly after a
doctor’s prescription. Unlike other similar drugs, Abilify works in quite a different way
(D'Alessandro, 2012 p.85). It contains aripiprazole as the active substance that attaches in the
brain to receptors for two substances known as serotonin (5HT) and dopamine. These two
substances are believed to play a very crucial role in the development of both Schizophrenia and
bipolar I disorder. Through attacking of these two sites of the brain aripiprazole helps aids in the

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normalization of the entire activities of the brain thus reducing any maniac and psychotic
symptoms and preventing them from reoccurring again in future.
Benefits of Abilify as shown in studies
Abilify has shown to a very reliable medicine as a result of the numerous benefits it has had in
the past in the treatment of Schizophrenia and bipolar I disorder. In Schizophrenia for instance,
Abilify has proven to be effective at treating symptoms of Schizophrenia using unique standard
rating scales such as the Negative and Positive syndrome scales as well as PANSS. In a recent
study, Abilify showed to be more effective that placebo as far as reducing symptoms is
concerned (Breggin, 2017 p.102). Besides, Abilify has also proven to be just as effective as
haloperidol an antipsychotic medicine in countering symptoms of mental illness and instability.
Furthermore, in another study of five hundred and forty-four patients, Abilify was injected to
patients with symptoms of disturbed behavior and mild cases of agitation and patients showed
improvement over a period of twenty-four hours indicating it is more effective than placebo and
similar to haloperidol. It is as well important to note that Abilify can only be obtain strictly after
a doctor’s prescription. Unlike other similar drugs, Abilify works in quite a different way
For bipolar I disorder, Abilify has also proven to be very effective in countering maniac episodes
and psychotic symptoms using a standard measure for instance, the Young-Mania Rating Scale
(YMRS). In a study four out of the five studies undertaken, Abilify proved to be more effective
that placebo in countering psychotic symptoms (Shirley & Perry, 2017 p.12). Two of the five
studies also indicated that Abilify has similar effects as that of lithium and haloperidol. Besides,
in another study of two hundred and night six children and adolescents, Abilify showed to be
more effective that placebo in the treatment of patients aged above thirteen years old. Finally, in
another study of two hundred and night one patients treated by injection for agitation, Abilify

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made patients show improvement in about two hours and was similar to lorazepam, another
medicine used in the treatment of agitation.
Risks associated with abilify
Just like any other medicine Abilify also has some risks associated with it. In adults, especially
when taking the drug by mouth there are case if anxiety, restlessness, tremor, headaches,
vomiting, dizziness, nausea, sleeplessness, dyspepsia, diabetes and constipation. For adolescents
the side effects are not that different from that of the adults (Mustafa et al, 2019 p.65). However,
it is essential to note that sleepiness, akathisia, extrapyramidal disorder and tiredness are among
the commonly noted cases for adolescents (Citrome, 2016 p.78).Apart from taking the drug
orally, there is also a risk factor associated by taking the drug via injection. Common cases are of
nausea, sleepiness and dizziness that happens to up to ten out of a hundred patients.
While most of the reported side effects of Abilify are minor, there are serious cases that have
been reported too. Among these is tardive dyskinesia, a common side effects of a majority of
antipsychotic medications. Tardive dyskinesia is a very complicated medical condition that is
characterized by jerky and stiff movements in one’s face and other parts of the body without
control (Aggarwal, Schrimpf, Lauriello, 2018 p.89). Most patients of tardive dyskinesia have
been reported to wave their arms, blink their eyes and sticking their tongues out without even
meaning to do so. It is, however, important to note that not all patients taking Abilify do
experience tardive dyskinesia, but there rarely reported cases are often severe (Kim et al, 2014
p.51). Apart from tardive dyskinesia, Abilify is also associated with non-teratogenic effects when
taken by pregnant women. It is believed that neonates that have been exposed to abilify
especially during the third trimester of pregnancy are often at a risk of withdrawal and
extrapyramidal cases that follow right after delivery (Fellner, 2017 p.88). Evidence shows that

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these complications have varied in severity. Reported cases have ranged from being self-limited
to intensive care and to prolonged hospitalization. Abilify may be used during pregnancy only
under a physician prescription (Bristol-Myers, 2015 p.67). It should only be prescribed if the
impending benefits fully justifies the potential risk to the fetus Another sever risk associated with
abilify is dysphagia. As such it should be used in caution especially for patients at a risk of
aspiration pneumonia. Aspiration pneumonia has been reported to the cause of morbidity and
increased mortality rate among elderly patients.
Hyperglycemia is also another sever risk effect associated with abilify. Hyperglycemia is a
medical condition that in most extreme cases it results to a coma or death. Several cases of
patients that have suffered commas and death have been reported after the use of abilify. As
such, patients with Hyperglycemia should be monitored on regular basis to stay in check with
their glucose control (Saklad, Kreys, Phan, 2015).Here, those found with the risk for diabetes
should immediately undergo a baseline as well as periodic fasting blood glucose testing. It is also
critical that all patients administered by Abilify be closely monitored for any symptom of
Hyperglycemia. Including general weakness, polyuria and polydipsia. All patients that show any
mild sign of Hyperglycemia should undergo the fasting blood glucose testing (Diomšina,
Rasmussen, Danileviciute, 2015 p.45). Besides, Hyperglycemia has been reported in case where
Abilify has been discontinued. As such it is essential that patients are administered with
transitional medication once abilify has been discontinued. Rapid weight gain and orthostatic
hypotension are also in the long list of severe risk factors for abilify. Sudden weight gain has
been observed for patients under the use of abilify. For this reason, clinical weight monitoring is
required for all patients under abilify dosage.

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Orthostatic hypotension is as well associated with abilify. As such it should be used with caution
especially by patients with known heart and cardiovascular complications. These conditions
often predispose patients to hypotension and should therefore be regulated and closely monitored
by a doctor. Two of the five studies also indicated that Abilify has similar effects as that of
lithium and haloperidol. Besides, in another study of two hundred and night six children and
adolescents, Abilify showed to be more effective that placebo in the treatment of patients aged
above thirteen years old.
Even though abilify has proven to be very effective, it is associated with cases of uncontrolled
unusual urges and random seizures. Some patients taking abilify have reported cases of having
usual urges such as gambling, sex and binge eating as well as compulsive shopping (Kahn &
Giannopoulou, 2015 p.201). In the case where such symptoms start portraying themselves,
patients should immediacy seek medical attention. Seizures and convulsions are also other side
effects associated with abilify. Patients using abilify have been reported to have succumbed to
random and unpredictable seizures and convulsions especially those aged above forty years.
Pharmacokinetics of Abilify
The activity of abilify as a drug is primarily dependent on its active ingredient aripiprazole. It is
as well dependent on dehydro-aripiprazole, but in the latter to a much lesser extent. It is believed
that the mean elimination half-lives are about seventy-five hours for aripiprazole and ninety
hours for dehydro-aripiprazole (Sawyer et al, 2014 p.39). Besides, steady states are often attained
after a maximum of fourteen days of dosing. The drug accumulation is predictable in terms of
single-dose pharmacokinetics. Evidence shows that at a relatively steady state, the
pharmacokinetics of the its active ingredients is dose proportional. Elimination of aripiprazole is

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usually through hepatic metabolism but in this case involving CYP3A4, CYP2D6 and P450
isozymes.
Aripiprazole is metabolized by three pathways. Pathways include hydroxylation,
dehydrogenation and N-dealkylation. Based on evidence from corresponding in vitro studies N-
dealkylation is catalyzed y CYP3A4 whilst CYP2D6 and CYP3A4 are responsible for
hydroxylation and dehydrogenation respectively. At a relatively steady state, the active
metabolite ingredient in abilify represents an approximate of 40% of aripiprazole AUC in
plasma.
In addition, 8% of Caucasians do not have the capacity to metabolize substrates of CYP2D6 and
for that reason are classified as poor metabolizers while the rest are said to be extensive
metabolizers. Poor metabolizers often have an increase in aripiprazole exposure to up to 80%
and relatively 30% decrease in exposure to active metabolite as compared to extensive
metabolizers.
Review of safety guidelines
Several safety guidelines have been provided by the ICH regarding the use of various
medications including abilify. Among the long list of the provided safety guidelines in
Reproductive toxicology and toxic kinetics and pharmacokinetics. The former has been
subdivided into two sub groups. First is detection of toxicity to reproduction for medical
products and toxicity to male fertility. This guideline was finalized in June 1993 under Step 4.
This guideline clearly outlines the guidelines on test for reproductive toxicity. Here, periods of
treatment have been clearly defined and animals to be used identified in order to reflect on the
extent of human exposure to the drug.
It is as well essential to note that the addendum to the primary guideline stipulated above in
regard to male fertility was finalized on November 1995 under Step 4 but was later amended in
1995 under the regular maintenance process (Price & Marzani-Nissen, 2012 p.28). The

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amendments were brought into place to provide a much better description of the testing concept
as well as recommendations that address pre-mating treatment, flexibility, durations and
observations. The second guideline under reproductive toxicity is the revision of s5 guideline on
detection toxicity to reproduction for human pharmaceuticals. First and foremost, it is essential
to note that this particular issue was officially endorsed by the ICH steering committee in 2015
under step 4 of the ICH process. It incorporated experience gained with the test done on
pharmaceuticals using both the paradigms and novel testing paradigms as well as various
advancements in technological, scientific and regulatory knowledge. It is quite unique because
unlike the former, for this guideline the ICH provides human safety assurance similar to those
provided by other current testing paradigms. Besides, this revision was also meant to provide a
much greater clarity as well as alignment with the provided ICH guidelines such as ICH S9 and
ICH SR9(R1).
Apart Reproductive toxicity, toxicokinetics and pharmacokinetics is also another guideline that
that has been provided by ICH. Here there are three section S3A, S3A Q and as as well as S3B.
S3A provides of the assessment of systematic exposure in toxicity studies. This safety guideline
was finalized in October 1994 under Step 4. (Oberbarnscheidt, Miller, Henry, 2015 p.88). It
gives clear on developing test strategies in toxic kinetics and also identifies the need to help in
the translation and interpretation of toxicology findings and in that way promoting rational study
coupled with design development.
S3A provides for the guidance for repeated dose tissue distribution studies. This particular
guideline was finalized in October 1994 under step 4. It was designed to provide guidance on
specific circumstances where repeated dose tissue distribution studies should be put under
consideration. An example a circumstance where this should be considered is when appropriate

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data cannot be obtained and derived from other known sources. Furthermore, this guideline
provides for recommendations on the conduct of such studies (McKeage, 2014 p.71). Section 3A
Q &As is a guideline on questions and answers that provides for the assessment of systemic
exposure but mainly focusing on micro sampling. It was brought into play by the ICH steering
committee on October 2014. It is clear that since officially reaching step 4 and upon publication
within the ICH regions, it was conclusive that experiences by all parties on implementation of
the S3A guidelines of toxicokinetics are resulted into need for clarification. The section
containing question and answer was developed by the S3A implementation working group in
order to enhance the implementation of 23A guidelines and more so to address both benefit and
use of micro sampling in studies.

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References
Aggarwal, A., Schrimpf, L. and Lauriello, J., 2018. Aripiprazole Long-Acting Injectable for
Maintenance Treatment of Bipolar I Disorder in Adults. Clinical schizophrenia & related
psychoses, 11(4), pp.221-223.
Andersen, J., 2017. The Effects of Abilify on Memory, Coordination, and Stereotypy in CD-1
Mice.
Breggin, P.R., 2017. Neuroleptic (Antipsychotic) Drugs: An Epidemic of Tardive Dyskinesia
and Related Brain Injuries Afflicting Tens of Millions. In The Sedated Society (pp. 123-161).
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Bristol-Myers Squibb, U.S., 2015. Food and Drug Administration approves Abilify
(aripiprazole) for the treatment of irritability associated with autistic disorder in pediatric patients
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Citrome, L., 2016. Aripiprazole long-acting injectable formulations for schizophrenia:
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pharmacology, 9(2), pp.169-186.

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D'Alessandro, T.M.M., 2012. Low-dose Abilify® and the treatment of disruptive behaviors in
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