Table 4.
Comparison of biochemical and pharmacological properties of representative antipsychotics, haloperidol, clozapine, risperidone, aripiprazole and ITI-007.
| Haloperidol (2) | Clozapine (3) | Risperidone (4) | Aripiprazole (5) | ITI-007 (7) | |||||
|---|---|---|---|---|---|---|---|---|---|
| Receptor binding (Ki, nM) | |||||||||
| D2 | 2.0 | 144 | 4.9 | 0.34 | 32 | ||||
| D1 | 83 | 189 | 147 | 1960 | 52 | ||||
| D3 | 4.0 | 270 | 3.6 | 0.8 | > 100 | ||||
| D4 | 15 | 39 | 4.4 | 44 | 108 | ||||
| D5 | 147 | 235 | 563 | 2590 | > 100 | ||||
| 5-HT1A | 1202 | 105 | 427 | 1.7 | 1480 | ||||
| 5-HT2A | 70 | 5.2 | 0.17 | 3.4 | 0.54 | ||||
| 5-HT2C | 5000 | 10.7 | 12 | 15 | 173 | ||||
| α1A adrenergic | 12 | 1.6 | 5.0 | 26 | 73 | ||||
| α1B adrenergic | 8 | 7.0 | 9.0 | 35 | 31 | ||||
| H1 histamine | 3002 | 2.0 | 15 | 61 | > 1000 | ||||
| M1 muscarinic | >10000 | 14 | >10,000 | 6780 | > 1000 | ||||
| SERT | 3256 | 1624 | > 10,000 | 1080 [120] | 61 | ||||
| NET | 2112 | 3168 | 5454 | 2093 | > 1000 | ||||
| DAT | > 10,000 | > 10,000 | > 10,000 | 3215 | > 1000 | ||||
| Ratio of Ki values | |||||||||
| D2/5-HT2A | 0.029 | 28 | 29 | 0.10 | 59 | ||||
| 5-HT2C/5-HT2A | 71 | 2.1 | 71 | 4.4 | 320 | ||||
| H1/5-HT2A | 43 | 0.38 | 88 | 18 | > 1850 | ||||
| Mechanism of action (receptor functionality) | D2 and D3 inverse agonist [142] | Antagonist at dopaminergic, adrenergic, cholinergic, histaminergic and serotonergic receptors [143] |
Antagonist at serotonin 5-HT2, dopamine D2, adrenergic α1 and α2, and histaminergic H1 receptors [144] | D2 and 5-HT1A partial agonist; 5-HT2A antagonist [108] |
5-HT2A antagonist; post synaptic antagonist and pre-synaptic partial agonist at dopamine D2 receptors; glutamatergic phosphoprotein modulator; serotonin reuptake inhibitor [23] | ||||
| Blockade of Amphetamine-induced hyperlocomotion ED50 (mg/kg, PO) | 0.04 [23] | 4.27 [145] | 0.33 [23] | 4.65 [23] | 0.95 [23] | ||||
| Ratio of effective dose for catalepsy induction/effective dose for blockade of hyperlocomotion | 1 [146, 147] | 10 [146] | 5 [146] | 12 [146, 148] | >30 [23] | ||||
| Target dosage for the treatment of adult schizophrenia | 2- 5 mg every 4- 8 hours [149] | 300 – 450 mg/day; 900 mg/day maximum | 4 – 8 mg/day; 16 mg/day maximum | 10 – 15 mg/day recommended dose; 30 mg/day maximum | 40 – 60 mg/day [124, 125] |
||||
| Haloperidol (2) | Clozapine (3) | Risperidone (4) | Aripiprazole (5) | ITI-007 (7) | |||||
| Dose frequency | Every 4- 8 hours | Three times a day | once or twice daily | Once daily | Once daily | ||||
| Dose titration requirement | Required | Required to achieve efficacious dose | Required to achieve efficacious dose | Required to achieve maximum dose | None | ||||
| Dopamine D2 receptor occupancy at therapeutic doses | 53 – 74% at 2 mg/day [150]; 53 – 88% at 1 – 5 mg/day [151] |
24.5% at 250 mg/day; < 60% at 400 – 600 mg/day [152, 174] | 73% at 4 mg/day [153, 182] | 83.5 ± 3.2% at 15 mg/day; 96.8 ± 5.3% at 40 mg/day [154, 155] | ~ 40% at 60 mg/day [125, 156] | ||||
| Approved indications | Schizophrenia; control of tics and vocal utterances of Tourette’s Disorder [149] | Treatment-Resistant Schizophrenia; reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders [143] | Schizophrenia; acute manic or mixed episodes associated with bipolar I disorder; treatment of irritability associated with autistic disorder [144] |
Schizophrenia; acute treatment of manic and mixed episodes associated with bipolar I disorder; adjunctive treatment of MDD; irritability associated with autistic Disorder; treatment of Tourette’s disorder [108] | Investigational new drug currently in phase III clinical development | ||||
| Other indications in phase III clinical trials | Schizophrenia; bipolar depression | ||||||||