The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

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Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

https://cdr.lib.unc.edu/downloads/z603r057q

Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology.

Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. 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. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.

Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D2 Receptors

Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.

Serotonin receptors: their key role in drugs to treat schizophrenia.

Background: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. Methods: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n=101) or 30 mg/d (n=101)ofaripiprazole,placebo(n=103),or6mg/dofrisperidone (n=99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and ClinicalGlobalImpressionscores.Safetyandtolerabilityevaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. Results: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Meanprolactinlevelsdecreasedwitharipiprazolebutsignificantlyincreased5-foldwithrisperidone.Meanchange in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar lowincidence of clinically significant weight gain. Conclusions: Aripiprazole is effective, safe, and well toleratedforthepositiveandnegativesymptomsinschizophreniaandschizoaffectivedisorder.Itisthefirstnon-D2receptorantagonistwithclearantipsychoticeffectsandrepresents a novel treatment development for psychotic disorders. Arch Gen Psychiatry. 2003;60:681-690

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Aripiprazole, an Antipsychotic With a Novel Mechanism of Action, and Risperidone vs Placebo in Patients With Schizophrenia and Schizoaffective Disorder

The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor.

Background
Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.

Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies

In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function.

Aripiprazole: A dopamine-serotonin system stabilizer

The present invention relates to a method of treating a patient suffering from a disorder of the central nervous system associated with 5-HT 1A receptor subtype, comprising as an active ingredient a carbostyril derivative or a salt thereof represented by the formula (1): wherein the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single or a double bond.

Shaun Jordan

Papers

The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor.

Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies

In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function.

Aripiprazole: A dopamine-serotonin system stabilizer

5-HT1A Receptor Subtype Agonist