In: Drug

17 Jun 2010


Although early antipsychotic agents, such as (GlaxoSmithKline) and haloperidol (Haldol®, Ortho-McNeill) showed great promise initially, their limitations became evident when extrapyramidal side effects were associated with their use. Subsequently, the novel atypical antipsychotics, such as (Novartis), risperidone drug (Risperdal canadian, Janssen), canadian olanzapine (Eli Lilly), quetiapine fuma-rate (Seroquel canadian, AstraZeneca),  Pfizer), demonstrated fewer extrapyramidal side effects, thus providing an option for practitioners. However, patients taking these agents experienced various side effects, including weight gain, hyperglycemia, dyslipidemia, and, in certain cases, an increased QT interval.

Aripiprazole is a new anti-psychotic agent with a proposed unique mechanism of action. As a dopamine system stabilizer (DSS), it appears to be significantly better at regulating the positive and negative symptoms associated with schizophrenia than placebo and has shown to be as efficacious as risperidone and haloperidol in its response to those symptoms. After submitting a New Drug Application to the Food and Drug Administration (FDA) in October 2001, Bristol-Myers Squibb and Otsuka America Pharma, Inc., received approval in November 2002 to market aripiprazole.


The brain normally stabilizes dopamine neurotransmission by attaining a balance between presynaptic and postsynaptic dopamine 2 (D2) receptors. The two systems work in conjunction, activating receptors in areas of the brain where dopamine concentrations are too low and inactivating receptors where they are too high. Presynaptic dopamine receptors that are responsible for controlling dopamine release are less sensitive than postsynaptic receptors in detecting dopamine levels.

Neurotransmission of dopamine continues until levels build sufficiently to stimulate the presynaptic receptors. This feedback mechanism inhibits the release of excessive dopamine. The goals of treatment, therefore, are to enhance understimulated dopamine neurons and to reduce the overactive neurons in the mesocortical areas of the brain while regulating normal physiological prolactin and motor functions.

The dopamine system stabilizer is unique: when dopaminergic activity is excessive, it reduces dopaminergic transmission. When dopamine levels are deficient, the system also enhances activity but does so only until dopamine is within normal parameters, thereby preventing hyperactivity of dopamine neurons, which can result in psychosis. The restoration of dopamine activity in the brain’s cortical regions regulates cognitive and negative symptoms as well as prolactin and motor activity.

Because aripiprazole possesses both stimulatory and inhibitory properties, it has been referred to as a partial agonist. This possibly misleading term can cause clinicians to believe that the efficacy of aripiprazole is incomplete. In a study by Burris et al., aripiprazole’s interactions with human dopamine 2-like (D2L) receptors were evaluated to further clar­ify its pharmacological properties. In membranes prepared from Chinese hamster ovary (CHO) cells that expressed recombinant D2L receptors, aripiprazole bound the D2 receptor with high affinity. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone.

Inoue et al. analyzed the effects of aripiprazole on the prolactin secretion of 6-day-old anterior pituitary cell cultures. Their results suggested that aripiprazole regulates dopaminergic transmission by exerting D2 agonism or antagonism as a function of high or low receptor availability.

Although we know that a relationship between antipsychotic activity and dopamine receptor binding ability exists, recent attention has targeted the 5-hydroxytryptamine (5-HT1A ) receptor as an option in treating antipsychotic behavior. Was also observed to have potent partial agonist activity at human 5-HT1A, a finding that might lend itself to the overall efficacy against symptoms of schizophrenia.

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