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Receptor Binding Profiles of Atypical Antipsychotics: Mechanisms of Therapeutic Actions and Adverse Side Effects 5H Mechanisms of Therapeutic Actions and Adverse Side Effects T1A H 1 T1 All antipsychotics (both conventional and atypical) bind to some degree at dopamine D2 receptors. It is believed that D2 antagonism mediates antipsychotics’ ability to reduce positive symptoms of schizophrenia, including hallucinations and delusions. What sets the atypical antipsychotics apart from conventionals is the propensity of atypicals to bind additional receptors in antagonistic or agonistic manners. Binding to additional dopaminergic, serotonergic, adrenergic, and cholinergic receptors has additional consequences, such as lessening some of the symptoms of schizophrenia or mitigating side effects caused by D2 antagonism. For example, in addition to D2 antagonism, most atypical antipsychotics also act in an antagonistic fashion at serotonin 5HT2A receptors. This 5HT2A antagonism is theorized to reduce the extrapyramidal symptoms (EPS) and hyperprolactinemia caused by chronic D2 antagonism. 1 D 2A aripiprazole 2C The vast molecular polypharmacy of atypical antipsychotics is associated not only with additional therapeutic benefits; binding to some receptor types increases a drug’s propensity to cause adverse side effects. Chronic D2 antagonism is linked with EPS, tardive dyskinesia, and hyerprolactinemia, which are common side effects associated with conventional antipsychotics. Although additional binding properties of atypical antipsychotics lower the risk of some D2 antagonism-associated side effects, the more complex binding profiles of atypical antipsychotics can lead to other serious side effects. Most notably, the binding of atypical antipsychotics to 5HT2C, M3, and/or H1 receptors has been linked with cardiometabolic effects that can greatly compromise a patient’s physical well-being D2 5HT7 D3 T1A 5H 5HT2A 5H H 1 1 T1 B/D 2A 2B 5HT2B asenapine 2C 5HT2C D1 A 5HT2A 5H 5HT2B D1 5HT2A 1 Each atypical antipsychotic agent has a binding profile that differs from other antipsychotics. An antipsychotic’s binding profile is a summation of the receptors to which it binds, the strength of the binding to individual receptor types (binding affinity or Ki), and the action of the drug on that receptor type (antagonism, partial agonism, etc.). The unique binding profile lends each antipsychotic both efficacy in reducing symptoms and propensity to cause particular side effects. Two different antipsychotics may have similar adverse effects associated with them due to having similar binding properties for certain receptor types. Conversely, one antipsychotic may be more effective at reducing affective symptoms than another due to its ability to bind a particular receptor type with adequate affinity. paliperidone 5HT7 D2 D3 2C D2 B 5H 1 iloperidone D2 T1A 5H lurasidone 5HT7 D2 D4 Therapeutic Effects D2 Antag D2 PA +++ D3 +++ +++ + ++ ? ++ +++ + +++ +++ +++ + +++ +++ ++ +++ + +++ +++ Reduced positive symptoms Reduced positive symptoms Reduced positive symptoms; Reduced negative symptoms; Procognitive; Antidepressant Unknown EPS; Relatively lower Hyperprolactinemia; risk of EPS Increased negative symptoms; Side Effects Increased negative symptoms; Increased cognitive deficits; Sedation + weak binding affinity (100>Ki<1000) ++ moderate binding affinity (10>Ki<100) +++ strong binding affinity (1>Ki<10) ++++ very strong binding affinity (Ki<1) ? No data yet available * Binding property due primarily to the metabolite norquetiapine 5HT1A +++ ++ + ++ +++ + +* + ++ 5HT2A ++ ++++ ++ +++ ++ +++ ++++ ++* ++++ ++++ 5HT2C ++ ++++ ++ + + ++ ++ +* ++ ++ Reduced EPS; Reduced EPS; Antidepressant Reduced Reduced hyperprolactinemia; hyperprolactinemia Antidepressant; Anxiolytic Unknown Cardiometabolic Cardiometabolic 5HT7 +++ ++++ ++ ++ ++++ + +++ ++* +++ +++ α1 ++ +++ +++ +++ ++ ++ +++ +++ +++ ++ Reduced Reduced circadian rhythm nightmares dysfunction; Reduced negative symptoms; Procognitive Unknown Dizziness; Sedation; Hypotension M1 + +++ M3 ++ H1 ++ +++ +++ ++ 1 2B quetiapine 5HT2C 2C NET 1E 5HT D1 D2 D3 X ++ ++* Reduced EPS ++ ++* Reduced EPS +++ ++ +++* ++ ++ 5HT2A 1 risperidone 2C Hypnotic D4 D3 D2 5HT2A Constipation; Sedation; Dry mouth; Blurred vision Cardiometabolic; Constipation; Sedation; Dry mouth; Blurred vision Cardiometabolic; Sedation 5H T1 B/D ziprasidone 5HT7 5HT7 T6 5H D2 Drug Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone T6 D1 5HT2A 5HT2A 1 D 5H 1E D3 M4 H 1 5HT2B 5HT7 2C 5HT D4 M3 2A 2B clozapine 3 M2 T1 2A T 5H M1 X 5HT2A 1 5HT2C D4 D2 D3 X H 1 5HT2B 2C 5HT2C M4 T1 1 olanzapine T1A M3 D4 D3 M4 1 5H M2 T1 5H X M1 5HT7 5H 5H T6 T5 M3 H 1 5HT7 5HT2B M2 5HT2A T6 5H M1 5H 5HT2A X D3 D2 Correll CU. Eur Psychiatry 2010;25(Suppl 2):S12-21. Nasrallah HA. Mol Psychiatry 2008;13(1):27-35. National Institutes of Mental Health Psychoactive Drug Screening Program. Cited 2012 Aug. Available from: http://pdsp.med.unc.edu/indexR.html. Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008 Presented at the 2012 NEI Global Psychopharmacology Congress. This poster is supported by an unrestricted educational grant from Sunovion Pharmaceuticals Inc.