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

Next table | Previous table | Figure and tables index

	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

Двенадцать антидепрессантов нового поколения

Estrogen in the Fight Against Schizophrenia

Many American women are prescribed estrogen to combat the negative effects of menopause, such as bone loss and mood swings. Now, new evidence from a Tel Aviv University study suggests that hormone replacement therapy might also protect them -- and younger women -- from schizophrenia as well.


Prof. Ina Weiner of Tel Aviv University's Department of Psychology and her doctoral student Michal Arad have reported findings suggesting that restoring normal levels of estrogen may work as a protective agent in menopausal women vulnerable to schizophrenia. Their work, based on an animal model of menopausal psychosis, was recently reported in the journal Psychopharmacology.

"We've known for some time that when the level of estrogen is low, vulnerability to psychotic symptoms increases and anti-psychotic drugs are less likely to work. Now, our pre-clinical findings show why this might be happening," says Prof. Weiner.

A hormonal treatment to address a behavioral condition

In their study, Weiner and Arad removed the ovaries of female rats to induce menopause-like low levels of estrogen and showed that this led to schizophrenia-like behavior. The researchers then tried to eliminate this abnormal behavior with an estrogen replacement treatment or with the antipsychotic drug haloperidol. Estrogen replacement therapy effectively alleviated schizophrenia-like behavior but haloperidol had no effect on its own. Haloperidol regained its effect in these rats when supplemented by estrogen.

"When the level of estrogen was low, we could see psychotic-like behavior in the animals. Moreover, the sensitivity to psychosis-inducing drugs went up, while the sensitivity to anti-psychotic drugs went down," Prof. Weiner says. This is exactly what we observe in women with low estrogen levels," she says. "But we also found that estrogen, all by itself, combats psychosis in both male and female rats." Furthermore, in low amounts estrogen increases the effectiveness of anti-psychotic drugs.

Prof. Weiner points out that the medical community is hotly debating the pros and cons of estrogen replacement as an add-on to conventional treatment in schizophrenia. Detractors point to higher chances of cervical cancer and heart attacks in those who receive estrogen supplements. But according to her study, which looked at very specific factors possibly related to schizophrenia, estrogen replacement therapy could have positive behavioral effects, she concludes.

Assessing the possibility for prevention

During the course of a woman's lifetime, estrogen levels do not remain constant. During her reproductive years, these levels are affected by the menstrual cycle. There are also dramatic changes in the levels of estrogen just after a woman gives birth -- a change, which can trigger "post-partum blues," and in extreme cases lead to clinical depression and psychosis.

As a preventative therapy, estrogen could be given to women at certain points in time when they are most at risk for schizophrenia, Prof. Weiner suggests: in their mid-twenties and later during the menopausal years.

"Antipsychotic drugs are less effective during low periods of estrogen in the body, after birth and in menopause," says Prof. Weiner. "Our research links schizophrenia and its treatment to estrogen levels. Men seem less likely to begin schizophrenia after their 40s, which also suggests that estrogen is the culprit."


http://www.sciencedaily.com/releases/2010/01/100120112212.htm

Deep Brain Stimulation for Treatment Resistant Depression

Deep Brain Stimulation for Treatment Resistant Depression

Preventing Bipolar I Relapse: Results of the BALANCE Trial

Preventing Bipolar I Relapse: Results of the BALANCE Trial

Relapse rates were high overall, but better with lithium–valproate combination or lithium monotherapy than with valproate monotherapy.

Most treatment guidelines for bipolar disorder list lithium and valproate as first-line mood stabilizers, although lithium prescriptions have declined recently. In a randomized, open-label, multisite, international, 2-year trial, researchers compared the effectiveness of lithium, valproate, and their combination in preventing relapse.

First, 459 nonacutely ill patients with bipolar I disorder (74% without history of mood-stabilizer maintenance) received the combination at minimally effective doses (typically, for 4–8 weeks). The 330 participants who tolerated combination treatment were then randomized to continue the combination or to receive either monotherapy (the other drug was gradually withdrawn). Treatment groups were balanced for multiple illness characteristics.

Drug adherence was good, and follow-up covered 589.8 person-years. Relapse, defined as intervention for a new mood episode, occurred in 54% of combination-treatment recipients, 59% of lithium recipients, and 69% of valproate recipients. Combination treatment and lithium were statistically similar to each other in efficacy and superior to valproate. Combination therapy appeared most effective in preventing manic episodes and lithium in preventing depressive episodes. Results were not affected by baseline severity, polarity of the most recent episode, drug doses, blood levels, or when events in the first 3 months were excluded.

Comment: This study suggests that the most effective agents for preventing relapse are lithium–valproate combination and lithium monotherapy (numbers needed to treat, 7 and 10, compared with valproate alone). However, the high relapse rates suggest a serious need for new treatments.

Study limitations include the open treatment allocation, and the absence of both a placebo group and a systematic assessment of symptoms. Its strengths are its real-world design, diverse patient population, presence of a clinical endpoint (i.e., need for treatment change), and enrollment of patients who tolerated both drugs (in contrast to some previous studies).

Lithium is often underused. Its use may have declined because of clinicians' concerns about thyroid and renal effects, their reluctance to do the necessary monitoring, or the vigorous marketing of valproate. These results clarify that more patients should be given lithium, probably alone initially and then in combination with valproate.

— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry January 11, 2010

Citation(s):

Geddes JR et al. for the BALANCE Investigators and Collaborators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial. Lancet 2009 Dec 23; [e-pub ahead of print]. (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961828-6/fulltext)

http://psychiatry.jwatch.org/cgi/content/full/2010/111/1