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Clozapine treatment and its effect on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine
Clozapine Treatment and Its Effect on Neuroendocrine Responses Induced by the Serotonin Agonist, m-Chlorophenylpiperazine Ren6 S. Kahn, Michael Davidson, Larry J. Siever, Serge Sevy, and Kenneth L. Davis
The effects of clozapine treatment on neuroendocrine responses induced by the serotonin agonist, m.chiorophenylpiperazine (mCPP) were examined, mCPP and placebo were administered after a 2-week drug-free period and again after .5 weeks of clozapine treatment in nine schizophrenic inpatients. Adrenocorticotropic hormone (ACTH), prolactin, and mCPP levels were measured. CIozapine treatment completely blocked mCPP-induced A CTH and prolactin release suggesting that clozapine blocks serotonin receptors that mediate these hormone responses. Key Words: Schizophrenia, serotonin, mCPP, hormones, clozapine
Introduction Clozapine has been proven to be effective in some treatment refractory schizophrenics (Kane et al 1988). It has been suggested that clozapine's superiority is due to its blockade of serotonin (5hydroxytryptamine, 5HT) receptor subtypes, such as 5HT2 and/or 5HTIc receptors, in contrast to conventional neuroleptics (Canton et al 1990; Meltzer 1989). Although haloperidol or chlorpromazine have no effect on cortisol and temperature responses induced by the 5HTI~ agonist, MK-212, clozapine blocks the temperature and cortisol rise induced by MK-212 in rats [but not the cortisol rise induced by the selective 5HTs, agonist 8-OHDPAT] (Nash et al 1988). This study examined whether chronic administration of clozapine blocked responses induced by the 5HT agonist, m-chlorophenylpiperazine (mCPP), in schizophrenic patients, mCPP was selected because it reli-
From the Department of Psychiatry, Mount Sinai School of Medicine/Bronx Veterans Administration Hospital, New York, NY. Address reprint request to: Dr. Rent S. Kahn, Department of Psychiatry, University Hospital Utrecht, Heidelberglaan 100. 3584 CX Utrecht, The Netherlands. Received July 7,1993: revised November 22,1993. © i 994 Society of Biological Psychiatry
ably increases adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels in human subjects, effects that appear to be 5HT mediated (see Kahn and Wetzler 1991 ). In a previous study, mCPP (0.35 mg/kg PO) increased ACTH and prolactin in schizophrenic patients as compared to placebo (but it did not affect temperature or behavioral responses) (Kahn et al 1992). Thus, in order to examine the effect of clozapine on 5HT receptors, this study tested whether clozapine blocked mCPP's effect on ACTH and prolactin release in a new cohort of nine schizophrenic patients.
Methods Nine schizophrenic men who were inpatients participated in this study (age: 41.0 4- 14.3 years; age of onset of illness: 23.6 -- 8.1 years; number of previous hospitalizations: 6.3 ± 4.4; total months hospitalized: 54.0 -- 87.4) after giving written informed consent. All subjects had normal laboratory (including thyroid indices) and physical exams, and were free of drug and alcohol abuse for at least 6 months. All subjects were diagnosed as schizophrenic based 0006-3223/94/$07.00
9 !0
aIOLPSYCHIATRY
R.S. Kahn et al
1994;35:909-912
on DSM-III-R criteria. After a minimum 2-week drug-free period (mean time drug-free: 18.9 + 3.6 days) (except for occasional use of up to 1000 mg of chloral hydrate/24 hr), and a minimum of 3 months free of depot neuroleptic, mCPP (0,35 mg/kg PO) and placebo were administered in a double-blind design. Clozapine was subsequently started at a dose of 25 mg qhs and raised by approximately 25 mg/day to a maximum of 600 rag/day but a minimum of 400 rag/day [mean dose at end of study: 577.8 -4- 66.7 mg/day]. Both the mCPP and placebo challenge tests were repeated in the 5th week of clozapine treatment. The mCPP challenge procedure has been described earlier (Kahn et al 1992). Subjects fasted from I 1 PM on the night before the day of the procedure, At 9 AM an indwelling intravenous catheter was inserted. At 10 AM. subjects received orally either 0.35 mg/kg mCPP or identical placebo capsules in a randomized double-blind design. Time between procedures was minimally 72 hr. Blood samples were drawn at 30-rain intervals from 9 AM to 1:30 PM and assessed for ACTH and prolactin, mCPP was measured in samples drawn I, 2 and 3 hr after administration of capsules. ACTH, prolactin, and mCPP were assayed as described in Kahn et al (1992). To examine the effect of clozapine on mCPP-induced ACTH and prolactin responses repeated measures analysis of variance (ANOVA) with two repeated measures (Treatment: drug-free and clozapine; and Time: 0, 30, 60. 90, 120, 150, 180, and 210 rain after administration of capsules) was conducted on placebo-corrected ACTH and prolactin values (obtained by subtracting the values on placebo from those obtained after active mCPP challenge). When significant main effects for Treatment or significant Treatment x Time interactions were found, responses to mCPP and placebo were compared for each treatment using ANOVA with two repeated measures (Test: mCPP and placebo; and Time),
Results Baseline ACTH concentrations did not differ on the mCPP and placebo test days, but clozapine significantly lowered ACTH concentrations as compared to the drag-free ( o f f clozapine) condition (baseline ACTH concentrations: placebo challenge day off clozapine: 13,4 _+ 7.4 pg/ml; mCPP challenge day off clozapine: 13.1 _ 8,3 pg/ml; placebo challenge day on clozapine: 10,0 _+ 6.5 ng/ml; mCPP challenge day on clozapine: 9,9 _ 6,2 pg/ml; F = ! 7.89, df= 1,8, p = 0.003), Clozapine did not affect baseline prolactin concentrations (F-- 0,861, d f = 1,8,p -- 0,381), Table I depicts the placebo-corrected mCPP-induced ACTH and prolactin responses (expressed as area-under-the-curve) off and on cIozapine for each of the nine subjects. As Figure i indicates, clozapine significantly blocked mCPP-induced ACTH release (main effect treatment: F =
4.82, df = 1,8, p = 0.060; main effect time: F = 2.95, df = 7,56, p = 0.01 l; Treatment x Time: F = 3.84, df = 7,56, p = 0.002). mCPP significantly raised ACTH levels during the drug-free condition (main effect test: F = 4.638, df= 1,8, p = 0.063; main effect time: F = 3.53, df = 7,56, p = 0.003; Test × Time: F - 4.037, df = 7,56, p = 0.001), but not during clozapine treatment (main effect test: F = !.786, df = 1,8, p = 0.218; main effect time: F = 2.266, df = 7,56, p = 0.042; Test × Time: F = 0.586, df= 7,56,p = 0.59). As Figure 2 indicates, clozapine blocked mCPP-induced prolactin release (main effect treatment: F = 4.021, df= 1,8, p = 0.08; main effect time: F - 5.837, d f - 7,56, p = 0.0001; Treatment × Time: F = 2.328, df = 7,56, p = 0.037). mCPP significantly raised prolactin levels during the drug-free condition (main effect test: F = 6.486, df = !,8, p = 0,034; main effect time: F = 2.057, df = 7,56, p = 0.064; Test x Time: F = 4.627. df = 7,56. p = 0.0001), but not during clozapine treatment (main effect test: F = 0.332, df= 1,8,p-0.56; main effect time: F = 1.575, d f = 7,56,p = 0.162; Test × Time: F = 1.418, df = 7,56, p = 0,217). Clozapine treatment raised mCPP blood levels (drug-free: 6,2 __. 7.6; 8,6 +_ 8.7; 7.4 _.+ 6.5 ng/ml: on-clozapine: 4.8 _+ 4.4, I 1.9 ± 5.5, 1 1 . 8 - 6.8 ng/ml; main effect treatment: F--" !.69, d f - 1.8, p = 0.230; main effect time: F = 6.92, df = 2,16, p = 0.007; Treatment × Time: F = 4,88, df = 2,16, p = 0,022), When data were analyzed as change from baseline or when mCPP concentrations were used as covariates, results did not change.
Table !. The Placebo-Corrected mCPP-induced ACTH and Prola¢tin Responses Case
Age
Dose
ACTH I
ACTH2
PROL I
PROL2
I 2 3 4 5 6
600 400 600 600 600 600 600 600 600
1182 7903 4180 2574 229 3145
132 -2613 406 -2804 -663 1195
-597 22 756 372 270 321
8 9
28 67 41 57 36 26 51 31 32
Mean SD
41 14
578 67
146 366
7
-668
104
2013 -27
-765 -7
III 1207 867 357 -312 390 456 2499 -18
2281 2635
-557 1348
617 838
102
96 -30
Dose: clozapine dose (mgldey) at lime of challenge tests, ACTH I: ACTH response expressed as placebo-conected area-under-the-curve (pg/ml/210 rain) offclozapine, ACTH2: ACTH response expressed as placebo-corrected area-under-the-curve (pg/ml/2 I0 rain) on clozapine. PROL I: Prolactin responseexpressedas placebo-corrected area-under-the-curve (ng/dl/210 rain) offclozapine. PROL2: Prolactin responseexpressedas placebo-corrected area-ueder-thc-curve (ng/ml/2 |0 rain) on clozapine. The ~-under-the-curve was calculated using the time when mCPP or placebo was adminisle~l at baseline. Placebo-conected values were obtained by subtracting
the valueson placebofrom thoseon mCPP.
Clozapine and Its Effect on Neuroendocrine Response
BIOLPSYCHIATRY
91 !
1994;35:909-912
PROLACTIN RESPONSES
28
T IO 24
_/
9"
•
I
20
g 16 7
12 . . . . .
l,
30
60
90 120 150 TIME IN MINUTES
180
210
Figure I. Group mean and standard error of the mean ACTH plasma concentrations (pglml) after administration of placebo (open symbols) and mCPP (closed symbols) while drug-free (circles) and during the 5th week of treatment (squares).
Discussion Chronic (5-week) administration of clozapine blocked ACTH and prolactin responses induced by the 5HT agonist, mCPP, in schizophrenic patients, suggesting that clozapine blocks 5HT receptors in schizophrenic patients. This is consistent with an earlier (not placebo controlled) study reporting that clozapine blocked prolactin responses induced by the 5HT releasing agent, fenfluramine, in schizophrenic patients (Lemus et al 1991). Interestingly, clozapine blocked mCPP-induced ACTH and prolactin release despite raising mCPP blood levels. Because mCPP-induced ACTH/cortisol and prolactin appear, at least partly, 5HT,c mediated (Seibyl et ai 1991) and since clozapine displays the highest affinity to 5HT,~ receptors of all neuroleptics tested (Canton et al 1990),
60
60
2io
TIME IN MINUTES Figure 2. Group mean and SEM prolactin plasma concentrations (ng/mi) after administration of placebo (open symbols) and mCPP (closed symbols) while drug-free (circles) and during the 5th week of ciozapine treatment (squares). •
results of this study suggest that ciozapine may be a 5HT,c antagonist. The finding that clozapine decreased baseline ACTH levels may indicate that it decreases serotonergic tone. The fact that it did not affect prolactin levels agrees with previous studies (Meltzer 1989) and suggests clozapine's DA antagonistic effects are not pronounced. Whether the ability of clozapine to block 5HT receptors is related to its unique clinical efficacy needs to be further studied. That this may be so is suggested by the finding that patients who responded to clozapine displayed higher ACTH responses to mCPP than patients who failed to benefit from clozapine (Kahn et ai 1993). Thus, blockade of SHT receptors may be an important potential target for action of atypical neuroleptic drugs.
References Canton H, Verriele L, Colpaert FC (1990): Binding of typical and atypical antipsychotics to 5HTlc and 5HT2 sites: clozapine potently interacts with 5HTI c sites. Fur J Pharmacol 191:9396. Kahn RS, Wetzler S (199 i ): m-Chlorophenylpiperazineas a probe of serotonin receptors: A review.Biol Psychiatry 30:1139-1166. Kahn RS, Siever L, Gabriel S, et al (1992): Serotonin function in schizophrenia: Effects of m-chlorophenylpiperazinein schizophrenic patients and healthy subjects. Psychiatry Res 43:1-12.
Kahn RS. Davidson M. Siever L. Gabriel S. Apter S. Davis KL (I 993): Serotonin function and treatment response to clozapine in schizophrenic patients. Am J Psychiatry 150:1337-I 342. Kane J. HonigfeldG. Singer J. Meltzer H (I 988): Clozapine for the treatment-resistant schizophrenic. Arch Ge, Psychiatry 45:789-796. Lemus CZ, Lieberman JA, Johns CA, et ai (1991): Hormonal response to fenfluraminechallenges in ciozapine-treated schizophrenic patients. Biol Psychiatry 29:691-694.
912
BIOL PSYCHIATRY
1994;35:909-912
Meltzer HY (! 989): Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizophrenia, Psychopharmacology 99:S ! 8-$27. Nash JF, Meltzer HY, Gudelsky GA (! 988): Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Etlr J Pharmacol 151:463-.-469.
R.S. Kahn et al
Seibyl JP, Krystal JH, Price LH, et al (1991): Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to metachlorophenylpiperazine in healthy subjects. Psychiatry Res 38:227-236.
The effects of clozapine treatment on neuroendocrine responses induced by the serotonin agonist, m.chiorophenylpiperazine (mCPP) were examined, mCPP and placebo were administered after a 2-week drug-free period and again after .5 weeks of clozapine treatment in nine schizophrenic inpatients. Adrenocorticotropic hormone (ACTH), prolactin, and mCPP levels were measured. CIozapine treatment completely blocked mCPP-induced A CTH and prolactin release suggesting that clozapine blocks serotonin receptors that mediate these hormone responses. Key Words: Schizophrenia, serotonin, mCPP, hormones, clozapine
Introduction Clozapine has been proven to be effective in some treatment refractory schizophrenics (Kane et al 1988). It has been suggested that clozapine's superiority is due to its blockade of serotonin (5hydroxytryptamine, 5HT) receptor subtypes, such as 5HT2 and/or 5HTIc receptors, in contrast to conventional neuroleptics (Canton et al 1990; Meltzer 1989). Although haloperidol or chlorpromazine have no effect on cortisol and temperature responses induced by the 5HTI~ agonist, MK-212, clozapine blocks the temperature and cortisol rise induced by MK-212 in rats [but not the cortisol rise induced by the selective 5HTs, agonist 8-OHDPAT] (Nash et al 1988). This study examined whether chronic administration of clozapine blocked responses induced by the 5HT agonist, m-chlorophenylpiperazine (mCPP), in schizophrenic patients, mCPP was selected because it reli-
From the Department of Psychiatry, Mount Sinai School of Medicine/Bronx Veterans Administration Hospital, New York, NY. Address reprint request to: Dr. Rent S. Kahn, Department of Psychiatry, University Hospital Utrecht, Heidelberglaan 100. 3584 CX Utrecht, The Netherlands. Received July 7,1993: revised November 22,1993. © i 994 Society of Biological Psychiatry
ably increases adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels in human subjects, effects that appear to be 5HT mediated (see Kahn and Wetzler 1991 ). In a previous study, mCPP (0.35 mg/kg PO) increased ACTH and prolactin in schizophrenic patients as compared to placebo (but it did not affect temperature or behavioral responses) (Kahn et al 1992). Thus, in order to examine the effect of clozapine on 5HT receptors, this study tested whether clozapine blocked mCPP's effect on ACTH and prolactin release in a new cohort of nine schizophrenic patients.
Methods Nine schizophrenic men who were inpatients participated in this study (age: 41.0 4- 14.3 years; age of onset of illness: 23.6 -- 8.1 years; number of previous hospitalizations: 6.3 ± 4.4; total months hospitalized: 54.0 -- 87.4) after giving written informed consent. All subjects had normal laboratory (including thyroid indices) and physical exams, and were free of drug and alcohol abuse for at least 6 months. All subjects were diagnosed as schizophrenic based 0006-3223/94/$07.00
9 !0
aIOLPSYCHIATRY
R.S. Kahn et al
1994;35:909-912
on DSM-III-R criteria. After a minimum 2-week drug-free period (mean time drug-free: 18.9 + 3.6 days) (except for occasional use of up to 1000 mg of chloral hydrate/24 hr), and a minimum of 3 months free of depot neuroleptic, mCPP (0,35 mg/kg PO) and placebo were administered in a double-blind design. Clozapine was subsequently started at a dose of 25 mg qhs and raised by approximately 25 mg/day to a maximum of 600 rag/day but a minimum of 400 rag/day [mean dose at end of study: 577.8 -4- 66.7 mg/day]. Both the mCPP and placebo challenge tests were repeated in the 5th week of clozapine treatment. The mCPP challenge procedure has been described earlier (Kahn et al 1992). Subjects fasted from I 1 PM on the night before the day of the procedure, At 9 AM an indwelling intravenous catheter was inserted. At 10 AM. subjects received orally either 0.35 mg/kg mCPP or identical placebo capsules in a randomized double-blind design. Time between procedures was minimally 72 hr. Blood samples were drawn at 30-rain intervals from 9 AM to 1:30 PM and assessed for ACTH and prolactin, mCPP was measured in samples drawn I, 2 and 3 hr after administration of capsules. ACTH, prolactin, and mCPP were assayed as described in Kahn et al (1992). To examine the effect of clozapine on mCPP-induced ACTH and prolactin responses repeated measures analysis of variance (ANOVA) with two repeated measures (Treatment: drug-free and clozapine; and Time: 0, 30, 60. 90, 120, 150, 180, and 210 rain after administration of capsules) was conducted on placebo-corrected ACTH and prolactin values (obtained by subtracting the values on placebo from those obtained after active mCPP challenge). When significant main effects for Treatment or significant Treatment x Time interactions were found, responses to mCPP and placebo were compared for each treatment using ANOVA with two repeated measures (Test: mCPP and placebo; and Time),
Results Baseline ACTH concentrations did not differ on the mCPP and placebo test days, but clozapine significantly lowered ACTH concentrations as compared to the drag-free ( o f f clozapine) condition (baseline ACTH concentrations: placebo challenge day off clozapine: 13,4 _+ 7.4 pg/ml; mCPP challenge day off clozapine: 13.1 _ 8,3 pg/ml; placebo challenge day on clozapine: 10,0 _+ 6.5 ng/ml; mCPP challenge day on clozapine: 9,9 _ 6,2 pg/ml; F = ! 7.89, df= 1,8, p = 0.003), Clozapine did not affect baseline prolactin concentrations (F-- 0,861, d f = 1,8,p -- 0,381), Table I depicts the placebo-corrected mCPP-induced ACTH and prolactin responses (expressed as area-under-the-curve) off and on cIozapine for each of the nine subjects. As Figure i indicates, clozapine significantly blocked mCPP-induced ACTH release (main effect treatment: F =
4.82, df = 1,8, p = 0.060; main effect time: F = 2.95, df = 7,56, p = 0.01 l; Treatment x Time: F = 3.84, df = 7,56, p = 0.002). mCPP significantly raised ACTH levels during the drug-free condition (main effect test: F = 4.638, df= 1,8, p = 0.063; main effect time: F = 3.53, df = 7,56, p = 0.003; Test × Time: F - 4.037, df = 7,56, p = 0.001), but not during clozapine treatment (main effect test: F = !.786, df = 1,8, p = 0.218; main effect time: F = 2.266, df = 7,56, p = 0.042; Test × Time: F = 0.586, df= 7,56,p = 0.59). As Figure 2 indicates, clozapine blocked mCPP-induced prolactin release (main effect treatment: F = 4.021, df= 1,8, p = 0.08; main effect time: F - 5.837, d f - 7,56, p = 0.0001; Treatment × Time: F = 2.328, df = 7,56, p = 0.037). mCPP significantly raised prolactin levels during the drug-free condition (main effect test: F = 6.486, df = !,8, p = 0,034; main effect time: F = 2.057, df = 7,56, p = 0.064; Test x Time: F = 4.627. df = 7,56. p = 0.0001), but not during clozapine treatment (main effect test: F = 0.332, df= 1,8,p-0.56; main effect time: F = 1.575, d f = 7,56,p = 0.162; Test × Time: F = 1.418, df = 7,56, p = 0,217). Clozapine treatment raised mCPP blood levels (drug-free: 6,2 __. 7.6; 8,6 +_ 8.7; 7.4 _.+ 6.5 ng/ml: on-clozapine: 4.8 _+ 4.4, I 1.9 ± 5.5, 1 1 . 8 - 6.8 ng/ml; main effect treatment: F--" !.69, d f - 1.8, p = 0.230; main effect time: F = 6.92, df = 2,16, p = 0.007; Treatment × Time: F = 4,88, df = 2,16, p = 0,022), When data were analyzed as change from baseline or when mCPP concentrations were used as covariates, results did not change.
Table !. The Placebo-Corrected mCPP-induced ACTH and Prola¢tin Responses Case
Age
Dose
ACTH I
ACTH2
PROL I
PROL2
I 2 3 4 5 6
600 400 600 600 600 600 600 600 600
1182 7903 4180 2574 229 3145
132 -2613 406 -2804 -663 1195
-597 22 756 372 270 321
8 9
28 67 41 57 36 26 51 31 32
Mean SD
41 14
578 67
146 366
7
-668
104
2013 -27
-765 -7
III 1207 867 357 -312 390 456 2499 -18
2281 2635
-557 1348
617 838
102
96 -30
Dose: clozapine dose (mgldey) at lime of challenge tests, ACTH I: ACTH response expressed as placebo-conected area-under-the-curve (pg/ml/210 rain) offclozapine, ACTH2: ACTH response expressed as placebo-corrected area-under-the-curve (pg/ml/2 I0 rain) on clozapine. PROL I: Prolactin responseexpressedas placebo-corrected area-under-the-curve (ng/dl/210 rain) offclozapine. PROL2: Prolactin responseexpressedas placebo-corrected area-ueder-thc-curve (ng/ml/2 |0 rain) on clozapine. The ~-under-the-curve was calculated using the time when mCPP or placebo was adminisle~l at baseline. Placebo-conected values were obtained by subtracting
the valueson placebofrom thoseon mCPP.
Clozapine and Its Effect on Neuroendocrine Response
BIOLPSYCHIATRY
91 !
1994;35:909-912
PROLACTIN RESPONSES
28
T IO 24
_/
9"
•
I
20
g 16 7
12 . . . . .
l,
30
60
90 120 150 TIME IN MINUTES
180
210
Figure I. Group mean and standard error of the mean ACTH plasma concentrations (pglml) after administration of placebo (open symbols) and mCPP (closed symbols) while drug-free (circles) and during the 5th week of treatment (squares).
Discussion Chronic (5-week) administration of clozapine blocked ACTH and prolactin responses induced by the 5HT agonist, mCPP, in schizophrenic patients, suggesting that clozapine blocks 5HT receptors in schizophrenic patients. This is consistent with an earlier (not placebo controlled) study reporting that clozapine blocked prolactin responses induced by the 5HT releasing agent, fenfluramine, in schizophrenic patients (Lemus et al 1991). Interestingly, clozapine blocked mCPP-induced ACTH and prolactin release despite raising mCPP blood levels. Because mCPP-induced ACTH/cortisol and prolactin appear, at least partly, 5HT,c mediated (Seibyl et ai 1991) and since clozapine displays the highest affinity to 5HT,~ receptors of all neuroleptics tested (Canton et al 1990),
60
60
2io
TIME IN MINUTES Figure 2. Group mean and SEM prolactin plasma concentrations (ng/mi) after administration of placebo (open symbols) and mCPP (closed symbols) while drug-free (circles) and during the 5th week of ciozapine treatment (squares). •
results of this study suggest that ciozapine may be a 5HT,c antagonist. The finding that clozapine decreased baseline ACTH levels may indicate that it decreases serotonergic tone. The fact that it did not affect prolactin levels agrees with previous studies (Meltzer 1989) and suggests clozapine's DA antagonistic effects are not pronounced. Whether the ability of clozapine to block 5HT receptors is related to its unique clinical efficacy needs to be further studied. That this may be so is suggested by the finding that patients who responded to clozapine displayed higher ACTH responses to mCPP than patients who failed to benefit from clozapine (Kahn et ai 1993). Thus, blockade of SHT receptors may be an important potential target for action of atypical neuroleptic drugs.
References Canton H, Verriele L, Colpaert FC (1990): Binding of typical and atypical antipsychotics to 5HTlc and 5HT2 sites: clozapine potently interacts with 5HTI c sites. Fur J Pharmacol 191:9396. Kahn RS, Wetzler S (199 i ): m-Chlorophenylpiperazineas a probe of serotonin receptors: A review.Biol Psychiatry 30:1139-1166. Kahn RS, Siever L, Gabriel S, et al (1992): Serotonin function in schizophrenia: Effects of m-chlorophenylpiperazinein schizophrenic patients and healthy subjects. Psychiatry Res 43:1-12.
Kahn RS. Davidson M. Siever L. Gabriel S. Apter S. Davis KL (I 993): Serotonin function and treatment response to clozapine in schizophrenic patients. Am J Psychiatry 150:1337-I 342. Kane J. HonigfeldG. Singer J. Meltzer H (I 988): Clozapine for the treatment-resistant schizophrenic. Arch Ge, Psychiatry 45:789-796. Lemus CZ, Lieberman JA, Johns CA, et ai (1991): Hormonal response to fenfluraminechallenges in ciozapine-treated schizophrenic patients. Biol Psychiatry 29:691-694.
912
BIOL PSYCHIATRY
1994;35:909-912
Meltzer HY (! 989): Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizophrenia, Psychopharmacology 99:S ! 8-$27. Nash JF, Meltzer HY, Gudelsky GA (! 988): Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Etlr J Pharmacol 151:463-.-469.
R.S. Kahn et al
Seibyl JP, Krystal JH, Price LH, et al (1991): Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to metachlorophenylpiperazine in healthy subjects. Psychiatry Res 38:227-236.