Aug 27, 2019 in Analysis

Summary

Atypical antipsychotic drugs, also called second-generation antipsychotics, allow physicians to help patients suffering from bipolar mania and schizophrenia. They cause less extrapyramidal side effects compared to first-generation antipsychotics, thus making patient’s general level of functioning better. Aripiprazole created by Otsuka Pharmaceutical was approved by the FDA in 2002. It is sold under the brand name, Abilify, and is one of the frequently prescribed second-generation antipsychotics in the United States. Otsuka Pharmaceutical first researched dopamine autoreceptors as well as antagonism at presynaptic dopamine autoreceptors based on the dopamine hyperactive theory of schizophrenia. Aripiprazole was developed due to the prevailing dopamine hypothesis of schizophrenia, according to which the abnormalities of dopaminergic neurotransmission in the brain cause schizophrenia. Emergence of this drug is an outstanding event because the first-generation antipsychotics are of no effect in almost 40% cases of treatment of patients suffering from schizophrenia. Aripiprazole mechanism of action in schizophrenia is not fully clarified yet. It connects with numerous CNS receptors resulting in the following effects: 5-HT2A antagonist, partial 5-HT1A agonist and partial D2 agonist. The medication has severe side-effects that include vomiting, nausea, orthostatic hypotension, weight gain, and mild sedation. Originally, FDA approved aripiprazole for the treatment of schizophrenia. Nowadays, it is approved for the treatment of bipolar disorder, major depressive disorder, and autism spectrum disorders. The use of Abilify is expanding with more and more evidence of its effectiveness and advantages appearing.

Introduction

Over the last ten years, pharmaceutical companies in the United States introduced five new atypical antipsychotic drugs, also known as second-generation antipsychotics. The medicine allows physicians to cure the patients suffering from bipolar mania and schizophrenia while avoiding the unpleasant and dangerous side effects of the antipsychotic drugs of the first generation. The second-generation antipsychotics have less extrapyramidal side effects; the risk of developing tardive dyskinesia is lower, and the general level of functioning of the patient is more improved compared to the first-generation antipsychotics (Citrome and Volavka 49). Aripiprazole (Abilify) is frequently prescribed second-generation antipsychotic in the United States. The sales of Abilify in 2010 equaled to 4.6 $ billion and reached 5.2 $ billion in 2011 (Lindsley 630). The objective of the paper is to discuss aripiprazole with the information regarding its history, chemical name, category, important pharmaceutical characteristics. In addition, it aims at making final conclusion whether the researched drug has more benefits or drawbacks for the current healthcare industry market concerning patients’ treatment.

Atypical Antipsychotic Drugs

Drug History

The dopaminergic neurotransmission hyperactivity plays one of the major roles within the development of schizophrenia. The discovery of this fact resulted in the creation of the dopamine receptor antagonistic activity theory of schizophrenia, which emerged in 1970s. Consequently, the drugs the common name of which is antipsychotics were invented. Medical industry later developed serotonin-dopamine antagonists. Professor Arvid Carlsson questioned the drugs existing on the market, as he believed they were responsible for the firing and releasing of the dopaminergic neurons. In 1972, Carlsson assumed that presynaptic dopamine autoreceptors that could regulate the synthesis of dopamine negatively should exist. Otsuka Pharmaceutical first researched dopamine autoreceptors and antagonism at presynaptic dopamine autoreceptors based on the dopamine hyperactive theory of schizophrenia. The research has resulted in introduction of aripiprazole by the company, an antipsychotic that is clinically effective and is not a D2 receptor antagonist. In 2002, the U.S. Food and Drug Administration approved aripiprazole as a medication for schizophrenia introduced by Otsuka Pharmaceutical.

Category and Chemical Name

Systematic (IUPAC) name of aripiprazole is 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one. Chemically, aripiprazole has no relation to any of other antipsychotic agents. Its pharmacological mechanism of action is new. Aripiprazole combines partial agonist action at D2, D3 and serotonin1A (5-HT1A) receptors with antagonist action at serotonin2A (5-HT2A) and D2 receptors (Burris et al. 381). Emergence of this drug is an outstanding event in the sphere of antipsychotic agents because the first-generation antipsychotics are ineffective in approximately 40% cases of treating the patients with schizophrenia. Whereas the typical antipsychotics have a positive impact on the patients, they cannot cure the symptoms of schizophrenia such as apathy and anhedonia. Extrapyramidal effects of typical antipsychotics result in discontinuation of treatment in the growing number of cases (Robinson et al. 1227).

Aripiprazole was developed due to the prevailing dopamine hypothesis of schizophrenia, according to which the abnormalities of dopaminergic neurotransmission in the brain cause schizophrenia. Currently, the hypothesis suggests that a biphasic disturbance in dopaminergic pathways leads to this disorder. The unique pharmacodynamic profile of aripiprazole is its partial agonist activity aimed at dopaminergic and serotonergic receptors. It resulted in the presumption that the drug would reduce the unwanted D2 antagonist activity in the following pathways: mesocortical, nigrostriatal and tuberoinfundibular (Lindsley 630).

Pharmacology

From the perspective of pharmacokinetics and disposition, aripiprazole is available in tablets of 2, 5, 10, 15, 20 and 30 mg. The tablets are for oral administration only. For schizophrenia, the effective daily dose range is 10-30 mg while daily dosage for bipolar I disorder is 15-30 mg (Bowles and Levin 687). The drug is also available in 1 ml nonrefrigerated solution. An injectable form of aripiprazole is for intramuscular use. Approved in 2006, it is prescribed for quick agitation control in adults. The injection of aripiprazole is for usage single-doze vials that contain 9.75 mg aripiprazole in 1.3 mL of diluent. The initial dose recommended for an adult is 9.75 mg intramuscularly. Aripiprazole distributes itself outside the vascular system and penetrates the brain. It should be taken once a day without regard to meals. Within 3-5 hours, peak plasma concentration occurs. Aripiprazole has an elimination half-life of 75 hours, and its main metabolite, dehydroaripiprazole, has 94 hours (Davenport, McCarthy, and Buck 522). The drug metabolizes foremost in the liver. Generally, there is no need to adjust dosage of aripiprazole due to the age, gender, smoking status, rental or hepatic status and race of the patient who undergoes treatment.

Mechanism of Action and Indications

Aripiprazole mechanism of action in patients suffering from schizophrenia is not fully clarified yet. This medication connects with numerous CNS receptors resulting in the effects such as 5-HT2A antagonist, partial 5-HT1A agonist, and partial D2 agonist. Being a partial agonist at D2 receptors, aripiprazole transposes neurotransmission in dopaminergic pathways, mainly mesocortical and mesolimbic ones (De Deyn et al. 463). An overactivation of the mesolimbic pathway might be the reason of positive symptoms of schizophrenia. Aripiprazole is likely to reduce the activity in the mesolimbic pathway due to the partial agonism of D2 that would reduce the positive symptoms (Stahl 75). More therapeutic benefits can emerge by modulation of central serotonergic pathways.

Negative Possibilities

As any other antipsychotic, aripiprazole has severe side effects such as vomiting, nausea, orthostatic hypotension, weight gain, and mild sedation. The most common side effects are difficulty with speaking, hyper salivation, loss of balance control, muscle stiffness/jerking/trembling, limb stiffness, shuffling walk, uncontrolled movements, and twisting movements. Less common ones include blurred vision, headache, giddiness, nervousness, spasms of eyelids, and breathing and swallowing troubles. Rare side effects are convulsions, accelerated heartbeat, increase or drop of blood pressure, tiredness, uncontrolled movements, puffing of the cheeks, abrupt loss of consciousness, and some others. Medicines such as anticholinergics (risk of overheating), benzodiazepines (increase the risk of side effects), carbamazepine or rifampin (decrease efficiency), alpha-blockers, and medicine for high blood pressure (aripiprazole may increase their side effects) may interact with aripiprazole.

Beneficial Uses

Originally, FDA approved aripiprazole for the schizophrenia treatment. Nowadays, it is approved for the cases of bipolar disorder, major depressive disorder, and disorders related to the spectrum of autism. The table below demonstrates the approved indications by FDA as well as dozing used as aripiprazole oral formulation (Otsuka Pharmaceutical Co).

Indication of the Illness Initial Dose of the Drug Recommended Dose per Day Maximum Dose per Day
Case of Schizophrenia
Adults 10-15 mg per day 10-15 mg per day 30 mg per day
Bipolar Disorder Cases Treatment of episodes that include manic or mixed emotional outbursts
Bipolar Mania Case Adults Group Monotherapy 15 mg per day 15 mg per day 30 mg per day
Bipolar Mania Case Adults Group Adjunt to lithium or valproate 10-15 mg per day 15 mg per day 30 mg per day
Bipolar Mania Pediatric patients Group Monotherapy or adjunct to lithium or valproate 2 mg per day 10 mg per day 30 mg per day
Maintenance treatment description
Bipolar I disorder maintenance treatment Not Available in doses.
Major Depressive Disorder Cases
Adjunct to antidepressants for the treatment of MDD 2-5 mg per day 5-10 mg per day 15 mg per day
Autism Spectrum Disorders Cases
Irritability that comes within the autistic disorder treatment. Pediatric patients 2 mg per day 5-10 mg per day 15 mg per day

Selected off-label usages of aripiprazole are listed below (Otsuka Pharmaceutical Co).

Off-label Usage Evidence provided
Bipolar Disorder within Children Low or very low efficacy evidence
Dementia  
Overall Moderate or high efficacy evidence
Psychosis Low or very low efficacy evidence
Agitation Low or very low efficacy evidence
Emotional Intensity Disorder Low or very low efficacy evidence
Abuse of Substance  
Alcoholic drinks Moderate or high inefficacy evidence
Methamphetamine Low or very low inefficacy

Future Expansion

The profits from the sales of Abilify are huge as the drug costs from $800 to $1000 per month in the United States. The use of Abilify is expanding, with more evidence of its effectiveness and advantages appearing. However, it will take years to evaluate the long-term effectiveness and danger of aripiprazole and its successor sufficiently. Currently, aripiprazole as an atypical antipsychotic is very promising.

Concluding Position

Being an atypical antipsychotic, aripiprazole is one of the major drugs on the market being affective in treating bipolar disorder and schizophrenia. In addition, it includes other uses related to depression and certain symptoms of autism. Whereas the drug has multiple side effects and can result in serious threat to fetus, I would personally state that it is effective and has an overall positive impact on the well-being of the patients that suffer from schizophrenia and bipolar disorders. The finding of the following paper reveals that patients who have been using aripiprazole for more than two weeks have demonstrated lower level of depressed mood. Although the drug is not perfect, I support the idea that it should be on a marketplace while it is good for acute and maintenance treatment of schizophrenia in the prevailing number of cases.

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