Aripiprazole
Encyclopedia
Aripiprazole is an atypical antipsychotic
and antidepressant
used in the treatment of schizophrenia
, bipolar disorder
, and clinical depression
. It was approved by the US Food and Drug Administration
(FDA) for schizophrenia on November 15, 2002; for acute manic
and mixed episodes
associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007; and to treat irritability in children with autism on 20 November 2009. Aripiprazole was developed by Otsuka
in Japan
, and in the United States
, Otsuka America
markets it jointly with Bristol-Myers Squibb
.
or bipolar disorder
.
such as lithium
or valproate
. This use is also supported by a handful of studies. Aripiprazole is at least as effective as haloperidol
at reducing manic symptoms, and is much better tolerated by patients.
Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness (with one finding a reduction in anhedonia
symptoms), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo. One study reported depression as a side effect of the drug.
. It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, and irritability.
The British National Formulary
recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis
, dyskinesia
, orthostasis, tachycardia
, nervousness, dizziness, headache, excessive non-stop crying, and anxiety
. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.
and CYP3A4
. Coadministration with medications that inhibit (e.g. paroxetine
, fluoxetine
) or induce (e.g. carbamazepine
) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole. As such, anyone taking aripiprazole should be aware that their dosage of aripiprazole may need to be decreased.
Aripiprazole may change the subjective effects of alcohol. One study
found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study
found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole.
is different from those of the other FDA-approved atypical antipsychotic
s (e.g., clozapine
, olanzapine
, quetiapine
, ziprasidone
, and risperidone
). Rather than antagonizing
the D2 receptor
, aripiprazole acts as a D2 partial agonist
(Ki = 0.34 nM). Aripiprazole is also a partial agonist at the 5-HT1A receptor
(Ki = 1.65 nM), and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor
(Ki = 0.8 nM). It also antagonizes the 5-HT7 receptor
(Ki = 39 nM) and acts as a partial agonist at the 5-HT2C receptor
(Ki = 15 nM), both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy. Aripiprazole has moderate affinity for histamine (Ki = 61 nM), α-adrenergic (Ki = 57 nM), and D4 receptors as well as the serotonin transporter
, while it has no appreciable affinity for cholinergic muscarinic receptors.
D2 and D3 receptor
occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.
Most atypical antipsychotics bind preferentially to extrastriatal
receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.
Recently, it has been demonstrated that in 5-HT7 receptor knockout mice
, aripiprazole does not reduce immobility time in the forced swim test (FST), and actually increases it. This implicates 5-HT7 antagonism as playing a major role in aripiprazole's antidepressant effects, similarly to amisulpride
.
Aripiprazole produces 2,3-dichlorophenylpiperazine
(DCPP) as a metabolite
similarly to how trazodone
and nefazodone
reduce to 3-chlorophenylpiperazine (mCPP) and niaprazine
converts to 4-fluorophenylpiperazine (pFPP). It is unknown whether DCPP contributes to aripiprazole's pharmacology in any way, but the possibility cannot be excluded.
of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6
and CYP3A4
. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine. When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels.
however, due to a pediatric extension, a generic will not become available until at least April 20, 2015. Barr Laboratories
(now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act
in March 2007. On November 15, 2010, this challenge was rejected by a United States district court
in New Jersey
.http://scholar.google.com/scholar_case?case=11631258476117214535&hl=en&as_sdt=2&as_vis=1&oi=scholarrhttp://www.bloomberg.com/news/2010-11-15/bristol-myers-partner-otsuka-wins-ruling-on-schizophrenia-treatment-patent.html
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
and antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
used in the treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, and clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
. It was approved by the US Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) for schizophrenia on November 15, 2002; for acute manic
Manic
Manić is a suburban settlement of Belgrade, the capital of Serbia. It is located in the municipality of Barajevo.Manić developed on the eastern slopes of the Kosmaj mountain...
and mixed episodes
Mixed state (psychiatry)
In the context of mental disorder, a mixed state is a condition during which symptoms of mania and depression occur simultaneously...
associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007; and to treat irritability in children with autism on 20 November 2009. Aripiprazole was developed by Otsuka
Otsuka Pharmaceutical Co.
, abbreviated OPC, is a pharmaceutical company headquartered in Tokyo, Osaka and Naruto, Japan. The company was established August 10, 1964, and currently has approximately 27,000 employees worldwide. The company focuses on pharmaceuticals related to nutrition...
in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, and in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, Otsuka America
Otsuka Pharmaceutical Co.
, abbreviated OPC, is a pharmaceutical company headquartered in Tokyo, Osaka and Naruto, Japan. The company was established August 10, 1964, and currently has approximately 27,000 employees worldwide. The company focuses on pharmaceuticals related to nutrition...
markets it jointly with Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
.
Medical uses
Aripiprazole is used for the treatment of schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
or bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
.
Bipolar disorder
Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults. Several double-blind, placebo-controlled trials support this use. In addition, it is often used as maintenance therapy, either on its own or in conjunction with a mood stabilizerMood stabilizer
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
such as lithium
Lithium pharmacology
Lithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
or valproate
Sodium valproate
Sodium valproate or valproate sodium is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy, anorexia nervosa, panic attack, anxiety disorder, posttraumatic stress disorder, migraine and bipolar disorder, as well as other psychiatric conditions requiring...
. This use is also supported by a handful of studies. Aripiprazole is at least as effective as haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
at reducing manic symptoms, and is much better tolerated by patients.
Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness (with one finding a reduction in anhedonia
Anhedonia
In psychology and psychiatry, anhedonia is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. hobbies, exercise, social interaction or sexual activity....
symptoms), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo. One study reported depression as a side effect of the drug.
Major depression
In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. It has not been FDA-approved for use as monotherapy in unipolar depression.Autism
In 2009, the United States FDA approved aripiprazole to treat irritability in persons with autismAutism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
. It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, and irritability.
Cocaine dependency
Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behaviour in animal models without significantly affecting other rewarding behaviours (such as food self-administration).Methamphetamine dependency
The book Addiction Medicine mentions studies, suggesting aripiprazole would be counter-therapeutic as treatment for methamphetamine dependency because it increased methamphetamine's stimulant and euphoric effects, and increased the baseline level of desire for methamphetamine. The author mentions studies that suggest that dopamine agonist treatment would be counter-therapeutic for methamphetamine/amphetamine dependency.Frequent
- akathisiaAkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
- headache
- agitation
- anxiety
- unusual tiredness or weakness
- nausea and vomiting
- an uncomfortable feeling in the stomach
- constipation
- increased production of salivaSalivaSaliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
- light-headedness
- insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
- sleepiness
- shaking
- blurred vision
- sexual dysfunction
Infrequent
- Uncontrollable twitching or jerking movements, tremorTremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s, seizure, and weight gain. Some people may feel dizzyDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, especially when getting up from a lying or sitting position, or may experience a fast heart rate. - Neuroleptic malignant syndromeNeuroleptic malignant syndromeNeuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
(Combination of feverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, muscle stiffness, faster breathingHyperventilationHyperventilation or overbreathing is the state of breathing faster or deeper than normal, causing excessive expulsion of circulating carbon dioxide. It can result from a psychological state such as a panic attack, from a physiological condition such as metabolic acidosis, can be brought about by...
, sweatingSweatingPerspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, reduced consciousness, and sudden change in blood pressureBlood pressureBlood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and heart rateHeart rateHeart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
.) - Suicidal thoughts and suicideSuicideSuicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
attempts - Painful and/or sustained erectionErectionPenile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...
- Tardive dyskinesiaTardive dyskinesiaTardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
(As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.) - StrokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
(While taking aripiprazole some elderly patients with dementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
have suffered from strokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or 'mini' strokeTransient ischemic attackA transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
.) - AllergicAllergyAn Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
reaction (such as swelling in the mouthMouthThe mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth....
or throatThroatIn vertebrate anatomy, the throat is the anterior part of the neck, in front of the vertebral column. It consists of the pharynx and larynx...
, itchItchItch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
ing, rashRashA rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
), speech disorderSpeech disorderSpeech disorders or speech impediments are a type of communication disorders where 'normal' speech is disrupted. This can mean stuttering, lisps, etc. Someone who is unable to speak due to a speech disorder is considered mute.-Classification:...
, nervousnessAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, agitationPsychomotor agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, fainting, reports of abnormal liver testLiver function testsLiver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
values, inflammation of the pancreasPancreatitisPancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
, muscle pain, weakness, stiffness, or cramps.
Discontinuation
Aripiprazole should be discontinued gradually, with careful consideration from the prescribing doctor, to avoid withdrawal symptoms or relapse.The British National Formulary
British National Formulary
The British National Formulary is a medical and pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about all medicines available on the National Health Service , including indication,...
recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis
Diaphoresis
Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions.Diaphoretic is the state of perspiring profusely, or something that has the power to cause increased perspiration....
, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
, orthostasis, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, nervousness, dizziness, headache, excessive non-stop crying, and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.
Overdosage
Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these patients were elevated by up to 3-4 fold over normal therapeutic levels, yet to date no deaths have been recorded.Drug interactions
Aripiprazole is a substrate of CYP2D6CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
and CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Coadministration with medications that inhibit (e.g. paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
) or induce (e.g. carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole. As such, anyone taking aripiprazole should be aware that their dosage of aripiprazole may need to be decreased.
Aripiprazole may change the subjective effects of alcohol. One study
found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study
found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole.
Pharmacology
Aripiprazole's mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is different from those of the other FDA-approved atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s (e.g., clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
, olanzapine
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, quetiapine
Quetiapine
Quetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
, ziprasidone
Ziprasidone
Ziprasidone was the fifth atypical antipsychotic to gain FDA approval . In the United States, Ziprasidone is Food and Drug Administration approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients...
, and risperidone
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
). Rather than antagonizing
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
the D2 receptor
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
, aripiprazole acts as a D2 partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
(Ki = 0.34 nM). Aripiprazole is also a partial agonist at the 5-HT1A receptor
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
(Ki = 1.65 nM), and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(Ki = 0.8 nM). It also antagonizes the 5-HT7 receptor
5-HT7 receptor
The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin The 5-HT7 receptor is coupled to Gs and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various...
(Ki = 39 nM) and acts as a partial agonist at the 5-HT2C receptor
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
(Ki = 15 nM), both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy. Aripiprazole has moderate affinity for histamine (Ki = 61 nM), α-adrenergic (Ki = 57 nM), and D4 receptors as well as the serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
, while it has no appreciable affinity for cholinergic muscarinic receptors.
D2 and D3 receptor
Dopamine receptor D3
D dopamine receptor is a protein that in humans is encoded by the DRD3 gene.This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that...
occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.
Most atypical antipsychotics bind preferentially to extrastriatal
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.
Recently, it has been demonstrated that in 5-HT7 receptor knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
, aripiprazole does not reduce immobility time in the forced swim test (FST), and actually increases it. This implicates 5-HT7 antagonism as playing a major role in aripiprazole's antidepressant effects, similarly to amisulpride
Amisulpride
Amisulpride , is an atypical antipsychotic used to treat psychosis in schizophrenia and episodes of mania in bipolar disorder. In small doses it is also used to treat depression. It was introduced by Sanofi-Aventis in the 1990s.-Pharmacology:Amisulpride functions primarily as a D2 and D3 receptor...
.
Aripiprazole produces 2,3-dichlorophenylpiperazine
2,3-Dichlorophenylpiperazine
2,3-Dichlorophenylpiperazine is a chemical compound. It is both a precursor in the synthesis of aripiprazole and one of its metabolites. It is unknown whether 2,3-DCPP is pharmacologically active similarly to its close analogue 3-chlorophenylpiperazine .- See also :* Aripiprazole* mCPP* pCPP*...
(DCPP) as a metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
similarly to how trazodone
Trazodone
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
and nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
reduce to 3-chlorophenylpiperazine (mCPP) and niaprazine
Niaprazine
Niaprazine is a sedative-hypnotic drug of the phenylpiperazine class. It has been used in the treatment of sleep disturbances since the early 1970s in several European countries, including France, Italy, and Luxembourg...
converts to 4-fluorophenylpiperazine (pFPP). It is unknown whether DCPP contributes to aripiprazole's pharmacology in any way, but the possibility cannot be excluded.
Pharmacokinetics
Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3–5 hours after oral dosing. BioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
and CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine. When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels.
Patent status
Otsuka's US patent on aripiprazole expires on October 20, 2014;however, due to a pediatric extension, a generic will not become available until at least April 20, 2015. Barr Laboratories
Barr Pharmaceuticals
Barr Pharmaceuticals was a global specialty pharmaceutical company that operated in more than 30 countries worldwide. Barr were engaged in the development, manufacture and marketing of generic and proprietary pharmaceuticals, biopharmaceuticals and active pharmaceutical ingredients.-History:Barr...
(now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act
Drug Price Competition and Patent Term Restoration Act
-Overview:The Drug Price Competition and Patent Term Restoration Act, informally known as the "Hatch-Waxman Act" [Public Law 98-417], is a 1984 United States federal law which established the modern system of generic drugs...
in March 2007. On November 15, 2010, this challenge was rejected by a United States district court
United States district court
The United States district courts are the general trial courts of the United States federal court system. Both civil and criminal cases are filed in the district court, which is a court of law, equity, and admiralty. There is a United States bankruptcy court associated with each United States...
in New Jersey
New Jersey
New Jersey is a state in the Northeastern and Middle Atlantic regions of the United States. , its population was 8,791,894. It is bordered on the north and east by the state of New York, on the southeast and south by the Atlantic Ocean, on the west by Pennsylvania and on the southwest by Delaware...
.http://scholar.google.com/scholar_case?case=11631258476117214535&hl=en&as_sdt=2&as_vis=1&oi=scholarrhttp://www.bloomberg.com/news/2010-11-15/bristol-myers-partner-otsuka-wins-ruling-on-schizophrenia-treatment-patent.html
Dosage forms
- Intramuscular injection, solution: 9.75 mg/mL (1.3 mL)
- Solution, oral: 1 mg/mL (150 mL) [contains propylene glycolPropylene glycolPropylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound with formula C3H8O2 or HO-CH2-CHOH-CH3...
, sucroseSucroseSucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
400 mg/mL, and fructoseFructoseFructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
200 mg/mL; orange cream flavor] - Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
- Tablet, orally disintegrating: 10 mg [contains phenylalaninePhenylalaninePhenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]