Pharmacodynamics +<unk>  Site Ki (nM) Action Ref 98–1,080 Blocker 2,090 Blocker 3,220 Blocker 5-HT1A 1.7–5.6 Partial agonist 5-HT1B 830 5-HT1D 68 5-HT1E 8,000 5-HT2A 3.4–35 Antagonist 5-HT2B 0.11-0.36 Inverse agonist 5-HT2C 15–180 Partial agonist 5-HT3 628 5-HT5A 1,240 5-HT6 214–786 Antagonist 5-HT7 9.6–39 Antagonist α1A 25.9 α1B 34.4 α2A 74.3 α2B 102 α2C 37.9 β1 141 β2 163 D1 265–1,170 D2 0.34 Partial agonist D2L 0.74–0.9 Partial agonist D3 0.8–9.7 Partial agonist D4 44–514 Partial agonist D5 95–2,590 H1 27.9–61 H2 >10,000 H3 224 H4 >10,000 M1 6,780 M2 3,510 M3 4,680 M4 1,520 M5 2,330 () 4,001 Antagonist Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat).<unk> 's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D2). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors, D3, and partially D4 and is a partial activator of serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7). It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter.<unk>  acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms. It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors.<unk>  is also a partial agonist of the D3 receptor. In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but<unk>  appears to be less preferential in this regard, as binding rates are high throughout the brain.<unk>  is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%). It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%), and like other atypical antipsychotics, displays a functional antagonist profile at this receptor. The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor. At the 5-HT2B receptor,<unk>  acts as a potent inverse agonist. Unlike other antipsychotics,<unk>  is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity; this property may underlie the minimal weight gain seen in the course of therapy. At the 5-HT7 receptor,<unk>  is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor.<unk>  also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors. Since the actions of<unk>  differ markedly across receptor systems<unk>  was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4).<unk>  was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that<unk>  has 'functionally selective' actions. The 'functional-selectivity' hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially 'sensed' by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of<unk>  at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the 'functional selectivity' hypothesis. Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of<unk>  may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an antiobsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as antiobsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation.<unk>  has a favorable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that<unk>  may have antiobsessional and anorectic actions in humans. Wood and Reavill's (2007) review of published and unpublished data proposed that, at therapeutically relevant doses,<unk>  may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day<unk>  resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor. It has been suggested that the low occupancy of the 5-HT1A receptor by<unk>  may have been an erroneous measurement however.<unk>  acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its agonist activity on D2 receptors,<unk>  may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduced. Pharmacokinetics<unk>  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. Bioavailability 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<unk>  concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.
Aripiprazole
Electroconvulsive therapy
Risperidone
Clozapine
Olanzapine
Asenapine
Ziprasidone
Lorpiprazole