Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy

The relationship between clinically effective antipsychotic drug dosage and binding affinity to cloned dopamine (DA) and serotonin receptor subtypes was analyzed in an effort to elucidate the contribution of individual receptor subtypes to medication response. Clinically effective dose and binding affinity to D2 DA receptor were modestly correlated for typical antipsychotic medications (r=0.54, p=0.046), but surprisingly were not correlated for atypical antipsychotics (r=0.41, p=0.31). For typical antipsychotics, a more robust inverse relationship was observed between medication dose and 5-HT2C affinity (r=-0.68, p=0.021). The strongest correlation for typical antipsychotics was observed between drug dosage and 5-HT2C/D2 binding affinity ratio (r=-0.81, p=0.003). For atypical antipsychotics, no significant correlations were identified between medication dosage and 5-HT2C, 5-HT2A, 5-HT2C/D2, or 5-HT2A/D2 receptor-binding affinities. In contrast, atypical antipsychotic medication dosage was highly correlated with the ratios of D2 (5-HT2A/5-HT1A) (r=0.80, p=0.031), and D2 (5-HT2C/5-HT1A) (r=0.78, p=0.038) binding affinities. These observations demonstrate an interaction between D2 and 5-HT2C receptor effects contributing to positive symptom response for typical antipsychotic medications, suggesting that signaling through 5-HT2C receptors interacts with and improves antipsychotic effects achieved via D2 receptor blockade. This analysis also demonstrates that, in contrast to typical antipsychotics, therapeutic effects of atypical antipsychotic medications are determined by opposing interactions among three different domains: (1) increasing D2 DA receptor-binding affinity enhances antipsychotic potency. (2) Increasing 5-HT2C and 5-HT2A receptor-binding affinities also facilitate antipsychotic efficacy. (3) Increasing 5-HT1A receptor-binding affinity, in contrast, reduces antipsychotic efficacy.

Table 1. Antipsychotic Medication Dopamine Receptor K
_i Values

Figure and tables index

	Clininically effective dose (mg)	Ki Values (nM)
Drug		D1	D2	D2 short	D2 long	D3	D4	D4.2	D4.4	D5
Amisulpride	400–800		1.3			2.4	>1000
Aripiprazole	5–30	387	0.95		0.74	4.5	>1000			1676
Benperidol	12–16		0.027				0.066
Chlorpromazine	300–900	112	2.0		5.4	5.0	10.8	26.2	15.9	133
Chlorprothixene	50–400		3.3				0.64
Clozapine	300–900	189	431	143.3	196	646	22.5	45.2	30	235
Fluphenazine	2–15	24	0.54			3	35			12
Haloperidol	2–15	83	2	1.21	2.34	12	3.88	6.93	15	147
Loxapine	25–100	54	10		22.3	30	10.9	14	5.9	75
Mesoridazine	100–400		4.3			2.6	9.1
Molindone	20–100		17.8			47.7	3433
Olanzapine	10–20	58	72	34.6	33.2	63	17.1	44.2	40.5	90
Perphenazine	8–64		0.56			0.43	28.5
Pimozide	2–10	>10 000	2.51			2.84	1.8
Quetiapine	250–800	712	567	555	702	483	2276	1233		1738
Remoxipride	200–400		243		125	1109	2527
Risperidone	2–8	60.6	4.9	4.73	6.0	12.2	7.12	16.7	26.3	16
Sertindole	12–24		4.14	5.8	4.87	5.76	9.29	17.67
Thioridazine	200–800	89	10	8.6		53	10.65			216
Thiothixene	5–30	51	1.4			185	6.4	548		261
Trifluoperazine	5–30		1.12			0.45	38	178
Ziprasidone	80–160	30	4.0	4.2	4.6	17	500.8	35.3		152

 Normal font=PDSP certified data.

 Italic font=PDSP K

Table 2. Antipsychotic Medication Serotonin Receptor K
_i Values

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	Clininically effective dose (mg)	Ki Values (nM)
Drug		5-HT1A	5-HT1B	5-HT1D	5-HT1E	5-HT1F	5-HT2A	5-HT2B	5-HT2C	5-HT3	5-HT5A	5-HT6	5-HT7
Aripiprazole	5–30	5.6	833	63	8000		17.5	0.36	22.4	628	1241	574	10
Chlorpromazine	300–900	3115	1489	452	344		3.32		15.55	977	118	12	21
Chlorprothixene	50–400						0.43
Clozapine	300–900	105	398	2132	966	130	9.15	7.38	14.9	241	3857	17	18
Fluphenazine	2–15	145	334	334	540		21		983	>10 000	145	28	8
Haloperidol	2–15	1202	165	7606	>10 000	>5000	118.6	1204	5580	>10 000	2247	3666	378
Loxapine	25–100	2456	388	3468	1399		4.38		13.3	190	776	33	88
Mesoridazine	100–400								157			380
Molindone	20–100	3797					4653		10 000			1008	3053
Olanzapine	10–20	2063	509	1582	2408	310	4.90	11.8	14.2	202	1212	6.0	105
Perphenazine	8–64	421					5.6		132			17	23
Pimozide	2–10	650					48.35		2112			71	0.5
Quetiapine	250–800	431	1109	>10 000	2402	2240	526		1843	>10 000	3120	1864	308
Remoxipride	200–400						6225
Risperidone	2–8	427	53.6	29.2	>10 000	1240	0.481	41.6	33.4	>10 000	205.8	2241	6.6
Sertindole	12–24	280	60	96	430	360	0.387		0.9			5.4	28
Thioridazine	200–800	108	109	579	194		21.5		53	>10 000	364	57	99
Thiothixene	5–30	410	151	659	>10 000		50		1356	1863	361	208	15
Trifluoperazine	5–30	950					74		378			144	291
Ziprasidone	80–160	76	4	9	1279		0.73		13	>10 000	291	61	6

 Normal font=PDSP certified data.

 Italic font=PDSP K
_i database mean.

Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy