770
BIOL PSYCHIATRY 1991 ;30:770-778
The MCPP Challenge Test in Schizophrenia: Hormonal and Behavioral Responses Naveed Iqbal, Gregory M. Asnis, Scott Wetzler, Rene S. Kahn, Stanley
R
"~ .....
-' " ' - - - ' ~ -
~"
"~'^""
In a neuroendocrine challenge paradigm, the present study investigated responses of schizophrenic patients to m-chlorophenylpiperazine (MCPP), a serotonin (5-hydroxytryptamine, 5HT) agonist. In an oral dose of 0.25 mglkg, MCPP was administered in a placebo-controlled double-blind design to male schizophrenic patients (n = 7) and normal male controls (n = 8). Behavioral (Positive and Negative Syndrome Scale; PANSS) and hormonal (cortisol, prolactin) variables were measured over the subsequent 210 min. The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p < 0.05), with specific worsening of PANSS-positive symptoms (p < 0.025) and PANSS activation (p < 0.001). In addition, the schizophrenic patients showed significantly lower cortisol (p < 0.05)andprolactin (p < 0°05) responses than the normal subjects. The schizophrenic patients had lower peak MCPP blood levels than the normal subjects, although this difference was not statistically significant. The findings are discussed in terms of 5HT receptor(s) sensitivity and the pharmacokinetics of MCPP in schizophrenia.
Introduction A serotonin (5-hydroxytryptamine, 5HT) hypothesis for schizophrenia was proposed in the 1950s. It was based on the observation that lysergic acid diethylamide (LSD) had psychotomimetic properties inducing clinical states reminiscent of schizophrenia, and that, in addition, LSD had 5HT antagonistic properties (Gaddum and Hameed 1954; Woolley 1958). Nonetheless, the 5HT hypothesis was quickly superseded by the introduction of neuroleptics with powerful dopamine (DA) antagonistic properties. Consequently, for ,,he past 30 years, the DA hypothesis has dominated biological research in schizophrenia. Recently, the 5HT hypothesis of schizophrenia has generated renewed interest. Reviewing the literature, some of our group (Bleich et al 1988) have previously suggested that 5HT2 receptor sensitivity of schizophrenic patients with prominent negative syndromes (type II schizophrenia) might be increased. This hypothesis was partly based ,an the observed therapeutic effects of selective 5HT2 blockers and atypical neuroleptics with From t!-e Department of Psychiatry, Albert Einstein College of Medicine/Montcfiore Medical Center, Bronx, NY Address reprint requests to Naveed lqbal, M.D., Schizophrenia Clinic, Department of Psychiatry, Montefiore Medical Center, 1! 1 East 210th St., Bronx, NY 10467. Received August 14, 1990; revised April 29, 1991.
© 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
MCPP in Schizophrenia
BIOL PSYCHIATRY
"/7 I
1991:30:'170-- "r~8
5HT2 antagonistic properties. These compounds (i.e., ritanserin, setoperone, and risperidone) have antipsychotic effects, with a preference for negative symptoms (Gelders et al 1985; Ceulemans et al 1985; Janssen et al 1988). Similarly, the therapeutic efficacy of clozapine, the widely used atypical neuroleptic with DA antagonistic properties, may also be attributed to its effects on the 5HT2 receptor system (either alone or in conjunction with the DA system) (Meltzer et al 1989). Conversely, hallucinogens of the LSD type have been shown to strongly bind to postsynaptic 5HT2 receptors (Giennon et al 1984). Findings from biological investigations of the 51-1T-ergic system in schizophrenia have been confusing. For instance, studies of [3Hl-imipJ,~mine binding, platelet uptake, and cerebrospinai fluid (CSF) 5-hydroxyindoieacetic acid (5HiAA) have all produced inconsistent results (see Bieich et al 1988 for a review). Our research group has focused on the challenge paradigm to study 5HT receptor sensitivity, measuring neuroendocrine and behavioral responses after administration of a 5HT agonist. Preliminary 5HT challenge studies in schizophrenia have produced inconsistent findings using 5HT precursors (tryptophan and 5-hydroxytrytophan) (Cowen et al 1985; Hoshino et al 1985; van Praag et ~l 1987a), and a 5HT presynaptic agonist (fenfluramine) (Lerer et al 1988). This inconsistency may be due to the nonselectivity of these challengers (van Praag et al 1987a). A metabolite of trazadone, m-chlorophenylpiperazine (MCPP), appears to be a more appropriate challenge agent. MCPP binds potently to 5HTI a, 5HTld, and 5HT2 receptors in human cortex (Hamik and Peroutka 1989) and to 5HTld, and 5HT2 receptors in human cortex (Hamik and Peroutka 1989) and to 5HTlc (Hoyer 1988) and 5HT3 (Kilpatrick et al 1987) receptors in rat brain. Although MCPP also binds to 5HTlb receptors (Hoyer 1988), this may not be clinically relevant as the 5HTlb receptor has not been found in human brain (Hoyer et ai 1986). MCPP also binds potently to alpha-2-adrenergic receptors in humans (Hamik and Peroutka 1989) and rats (Smith and Suckow 1985), but it does not affect noradrenergic (NA) release in animals (Fuller et al 1981). MCPP (0.25 mg and 0.5 rag, p.o.) reliably increases cortisol, prolactin, and adrenocorticotropin (ACTH) release, as well as the induction of anxiety in normal individuals, and these effects are blocked by metergoline, a mixed 5HTI/5HT2 antagonist (Mueller et al 1985). Similarly, a case study has been reported that the anxiogenic effect of MCPP could be blocked by both metergoline and methysergide, another 5HTI/SHT2 antagonist. Although MCPP has aipha-2-adrenergic binding affinity, metergoiine and methysergide have no effects on the NA system, therefore, the hormonal and behavioral effects of MCPP appear unrelated to stimulation of alpha-2-adrenergic receptors. Thus, MCPP has been used by several investigators to study 5HT receptor sensitivity in various patient populations, including those with major depression, panic disorder (PD) (Charney et al 1987), and obsessive-compulsive disorder (Zohar et al 1987; Charney et al 1988). For example, the augmented anxiety and hormonal response to MCPP in PD patients may be indicative of 5HT receptor hypersensitivity in (a subgroup of) those patients. In the present study, we attempted to investigate 5HT receptor sensitivity of schizophrenic patients using the MCPP challenge paradigm. Based on the 5HT2 receptor hypersensitivity hypothesis (Bleich et al 1988), we made two predictions: (1) the schizophrenic patients would have an augmented hormonal response to MCPP compared with normal subjects, and (2) MCPP would cause an exacerbation of psychotic symptomatology in schizophrenic patients. A dose of 0.25 mg/kg MCPP p.o. was selected because it has
772
BIOL PSYCHIATRY 1991 ;30:770-778
N. Iqbal et al
previously been shown to identify patients with putative 5HT receptor hypersensitivity in term3 of their hormonal and behavioral responses.
Methods
Subjects Seven male schizophrenic patients were selected from the inpatient (n = 5) and outpatient (n = 2) services at Montefiore Medical Center (mean age 32.7, SD 14.0 years). Eight normal male controls were paid volunteers recruited by advertisement in a community newspaper (mean age 27.5, SD 6.8 years). In order to ascertain lifetime history of psychiatric illness, the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer 1978) was administered to all subjects. The patients met Research Diagnostic Criteria (RDC) (Spitzer et al 1978) fGr chronic schizophrenia of at least 2 years duration (range 2-35 years), and they were medication free for a 2-week period prior to parti, :padon in the challenge tests. Five patients met RDC criteria for paranoid subtype and 2 met criteria for undifferentiated subtype. Six of the 7 patients had previously been treated with a variety of typical neuroleptic medications throughout the course of their illness. The normal subjects all met RDC criteria for "never mentally ill." All subjects were within 25% of their ideal body weight, had normal laboratory and physical exams, and gave written informed consent prior to participation in the study.
Procedure Utilizing a double-blind design, subjects participated in two challenge tests placebo and 0.25 mg/kg MCPP orally which were separated by a l-week interval. Subjects fasted (except for water intake) from 11 PM on the night preceding the procedure. At 9 AM, an indwelling intravenous catheter was inserted into an antecubital vein. Subjects were not allowed to drink, eat, smoke, or sleep during the procedure. After a l-hr adaptation period, subjects received identical tablets containing either placebo or drug. Blood samples were collected for plasma prolactin, cortisol, and MCPP concentrations immediately before the time of infusion (time O) and at 30, 60, 90, 120, 150, 180, and • c.., .... :"" ttlklilllUl~UiiJ.li.lILIqi ° ~ ' - : - : ° ' - " : ^ - O~" ,-,tt~ ..,, mm II.311tLIV~'Ili~ l "-Llig; tablets. A research psychiatrist used an abbreviated version of the Positive and Negative Syndrome Scale (PANSS) (Kay et al 1987) to rate the behavior and mental status of the schizo?hrenic subj~cts du~ng the challenge procedure at time 0, and at 60, 120, 180, and 210 min following administration of the tablets. The PANSS involves a formalized interview procedure followed by 1-7 point ratings of schizophrenic symptoms for which level of symptom severity is operationalized. The full-length PANSS consists of 30 symptoms. For the purpose of this study, only those 19 symptoms that could be rated repeatedly at hourly intervals were retained. A total psychopathology score was generated from the sum of the 19 symptoms, and additional scores were calculated for its seven specific components: positive syndrome, negative syndrome, activation, thought disturbance, paranoid/belligerence, anergia, and depression. Studies on the standardization of this instrument have supported its reliability, validity, and sensitivity to change with medications (Kay et al !987, 1988; Kay 1989). Prolactin and cortisel levels were determined by a homologous double antibody ra-
BIOL PSYCHIATRY
MCPP in Schizophrenia
773
1991 ;30:770-778
radioimmunoassay using reagents purchased from Diagnostic Products Corporation (Los Angeles, CA). The lower limit of sensitivity for cortisol and prolactin was 1.3 and 2 ng/ ml, respectively. The interassay coefficient of variance for cortisol and prolactin was 8.2% and 7.5%, respectively, and the intraassay coefficient of variance for cortisol and prolactin was 5.5% and 5.2%, respectively. Laboratory analyses were carried out blind to the nature of the tests. All samples from a single subject were run in the same assay. MCPP was obtained from Aldrich Chemical Company (Milwaukee, Wl). The identity and purity of MCPP were verified by high performance liquid chromatography by the Nathan Kline Laboratories (Rockland, NY). A standard calibration curve and a quality control sample wa~ n,,ra with each day's analysis. The relative standard deviation for within-day analyses as well as for day-to-day assays was 3.5%. The lower limit of detection for MCPP in plasma was about 2 ng/ml.
Data Analysis Hormonal release was calculated using placebo-correlated change-from-baseline scores. Accordingly, at each point in time, the subjects" change-from-baseline value on placebo was subtracted from his change-from-baseline value on MCPP. Repeated measures multivariate analyses of variance were then conducted with one repeated measure (time: 0, 30, 60, 90, 120, 150, 180, and 210 min) and one group variable (schizophrenics versus normal controls). For the schizophrenic subjects, behavioral response on the PANSS was calculated using delta (peak-minus-baseline) values, and significance of the difference between MCPP and placebo response was analyzed by paired t-test.
Results MCPP The schizophrenic patients had a peak MCPP blood level of 7.3 ng/dl (SD 10.0) as compared with 22.4 ng/dl (SD 24.1) for the normal subjects. Given the small number of subjects, this difference was not statistically significant (t = 1.53, p = 0.15). Using an area-under-curve analysis, there was not a significant group difference (t = 1.47, p = 0.17). Two of the schizophrenic patients had trace or nondetectable levels of MCPP. For LU_I ~. LL l i
~lt~l, llp~,
peak
LO Sl l ~J l_k., Jl l l ~ I| t .~.V. .~ I ~S. . . . .~.N. .I.~. .I I ~ lli~l~l,r~Iif~lkl i ~ , - I n~ ".
I.~ "~f~ ~;~ ,~¢~o,-h~,~;n;eh-,~t;,,~n . ~ t ~ I ~ f ' ~ D D 4f.~t.t' 111111 ~11,~.,1 C L l ~ l U t l l t l t l l t g a u L a l l d t v l l l ~Jlt ,,tvA~,,,,,..g ~. •
Behavioral Response Table 1 presents the PANSS behavioral data for the schizophrenic subjects on placebo versus MCPP. A paired t-test revealed a significant difference on total psychopathology (df = 6, t = 2.71, p < 0.05), indicating overall worsening of symptoms on MCPP. Both of the patients with trace or nondetectable levels of MCPP had a behavioral response to the drug. Predicated on this finding, we analyzed the component scores to clarify the nature of the drug-related changes. The results showed significant drug/placebo differences that were specific to the positive syndrome (t = 3.29, df = 6, p < 0.02) and activation (t = 9.30, df = 6, p < 0.001) components. In this abbreviated PANSS, the positive syndrome was composed of the symptoms of conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, and hostility. Activation was composed of excitement, tension, and mannerisms and posturing.
774
N. lqbal et al
BIOL PSYCHIATRY 1991 ;30:770--778
Table 1. Behavioral Response of Schizophrenic Patients (n = 7) on Placebo and MCPP Placebo
MCPP
Paired t tests =
PANSS Scale
Mean
SD
Mean
SD
t
p
Total psychopathology Positive syndrome Negative syndrome Activation Thought disturbance Paranoid/belligerence Anergia Depression
1.57 0.71 0.29 0.29 0.57 0.43 0.00 0.29
2.64 !. ! ! 0.76 0.49 !.51 0.54 0.00 0.49
9.14 3.29 2.29 2.00 1.65 1.86 1.29 1.00
7.47 2.93 3.25 0.58 !.68 2 04 ! .89 ! .00
2.71 3.29 ! .49 9.30 2.27 2.09 !.80 1.70
BIOL PSYCHIATRY 1991 ;30:770-778
The MCPP Challenge Test in Schizophrenia: Hormonal and Behavioral Responses Naveed Iqbal, Gregory M. Asnis, Scott Wetzler, Rene S. Kahn, Stanley
R
"~ .....
-' " ' - - - ' ~ -
~"
"~'^""
In a neuroendocrine challenge paradigm, the present study investigated responses of schizophrenic patients to m-chlorophenylpiperazine (MCPP), a serotonin (5-hydroxytryptamine, 5HT) agonist. In an oral dose of 0.25 mglkg, MCPP was administered in a placebo-controlled double-blind design to male schizophrenic patients (n = 7) and normal male controls (n = 8). Behavioral (Positive and Negative Syndrome Scale; PANSS) and hormonal (cortisol, prolactin) variables were measured over the subsequent 210 min. The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p < 0.05), with specific worsening of PANSS-positive symptoms (p < 0.025) and PANSS activation (p < 0.001). In addition, the schizophrenic patients showed significantly lower cortisol (p < 0.05)andprolactin (p < 0°05) responses than the normal subjects. The schizophrenic patients had lower peak MCPP blood levels than the normal subjects, although this difference was not statistically significant. The findings are discussed in terms of 5HT receptor(s) sensitivity and the pharmacokinetics of MCPP in schizophrenia.
Introduction A serotonin (5-hydroxytryptamine, 5HT) hypothesis for schizophrenia was proposed in the 1950s. It was based on the observation that lysergic acid diethylamide (LSD) had psychotomimetic properties inducing clinical states reminiscent of schizophrenia, and that, in addition, LSD had 5HT antagonistic properties (Gaddum and Hameed 1954; Woolley 1958). Nonetheless, the 5HT hypothesis was quickly superseded by the introduction of neuroleptics with powerful dopamine (DA) antagonistic properties. Consequently, for ,,he past 30 years, the DA hypothesis has dominated biological research in schizophrenia. Recently, the 5HT hypothesis of schizophrenia has generated renewed interest. Reviewing the literature, some of our group (Bleich et al 1988) have previously suggested that 5HT2 receptor sensitivity of schizophrenic patients with prominent negative syndromes (type II schizophrenia) might be increased. This hypothesis was partly based ,an the observed therapeutic effects of selective 5HT2 blockers and atypical neuroleptics with From t!-e Department of Psychiatry, Albert Einstein College of Medicine/Montcfiore Medical Center, Bronx, NY Address reprint requests to Naveed lqbal, M.D., Schizophrenia Clinic, Department of Psychiatry, Montefiore Medical Center, 1! 1 East 210th St., Bronx, NY 10467. Received August 14, 1990; revised April 29, 1991.
© 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
MCPP in Schizophrenia
BIOL PSYCHIATRY
"/7 I
1991:30:'170-- "r~8
5HT2 antagonistic properties. These compounds (i.e., ritanserin, setoperone, and risperidone) have antipsychotic effects, with a preference for negative symptoms (Gelders et al 1985; Ceulemans et al 1985; Janssen et al 1988). Similarly, the therapeutic efficacy of clozapine, the widely used atypical neuroleptic with DA antagonistic properties, may also be attributed to its effects on the 5HT2 receptor system (either alone or in conjunction with the DA system) (Meltzer et al 1989). Conversely, hallucinogens of the LSD type have been shown to strongly bind to postsynaptic 5HT2 receptors (Giennon et al 1984). Findings from biological investigations of the 51-1T-ergic system in schizophrenia have been confusing. For instance, studies of [3Hl-imipJ,~mine binding, platelet uptake, and cerebrospinai fluid (CSF) 5-hydroxyindoieacetic acid (5HiAA) have all produced inconsistent results (see Bieich et al 1988 for a review). Our research group has focused on the challenge paradigm to study 5HT receptor sensitivity, measuring neuroendocrine and behavioral responses after administration of a 5HT agonist. Preliminary 5HT challenge studies in schizophrenia have produced inconsistent findings using 5HT precursors (tryptophan and 5-hydroxytrytophan) (Cowen et al 1985; Hoshino et al 1985; van Praag et ~l 1987a), and a 5HT presynaptic agonist (fenfluramine) (Lerer et al 1988). This inconsistency may be due to the nonselectivity of these challengers (van Praag et al 1987a). A metabolite of trazadone, m-chlorophenylpiperazine (MCPP), appears to be a more appropriate challenge agent. MCPP binds potently to 5HTI a, 5HTld, and 5HT2 receptors in human cortex (Hamik and Peroutka 1989) and to 5HTld, and 5HT2 receptors in human cortex (Hamik and Peroutka 1989) and to 5HTlc (Hoyer 1988) and 5HT3 (Kilpatrick et al 1987) receptors in rat brain. Although MCPP also binds to 5HTlb receptors (Hoyer 1988), this may not be clinically relevant as the 5HTlb receptor has not been found in human brain (Hoyer et ai 1986). MCPP also binds potently to alpha-2-adrenergic receptors in humans (Hamik and Peroutka 1989) and rats (Smith and Suckow 1985), but it does not affect noradrenergic (NA) release in animals (Fuller et al 1981). MCPP (0.25 mg and 0.5 rag, p.o.) reliably increases cortisol, prolactin, and adrenocorticotropin (ACTH) release, as well as the induction of anxiety in normal individuals, and these effects are blocked by metergoline, a mixed 5HTI/5HT2 antagonist (Mueller et al 1985). Similarly, a case study has been reported that the anxiogenic effect of MCPP could be blocked by both metergoline and methysergide, another 5HTI/SHT2 antagonist. Although MCPP has aipha-2-adrenergic binding affinity, metergoiine and methysergide have no effects on the NA system, therefore, the hormonal and behavioral effects of MCPP appear unrelated to stimulation of alpha-2-adrenergic receptors. Thus, MCPP has been used by several investigators to study 5HT receptor sensitivity in various patient populations, including those with major depression, panic disorder (PD) (Charney et al 1987), and obsessive-compulsive disorder (Zohar et al 1987; Charney et al 1988). For example, the augmented anxiety and hormonal response to MCPP in PD patients may be indicative of 5HT receptor hypersensitivity in (a subgroup of) those patients. In the present study, we attempted to investigate 5HT receptor sensitivity of schizophrenic patients using the MCPP challenge paradigm. Based on the 5HT2 receptor hypersensitivity hypothesis (Bleich et al 1988), we made two predictions: (1) the schizophrenic patients would have an augmented hormonal response to MCPP compared with normal subjects, and (2) MCPP would cause an exacerbation of psychotic symptomatology in schizophrenic patients. A dose of 0.25 mg/kg MCPP p.o. was selected because it has
772
BIOL PSYCHIATRY 1991 ;30:770-778
N. Iqbal et al
previously been shown to identify patients with putative 5HT receptor hypersensitivity in term3 of their hormonal and behavioral responses.
Methods
Subjects Seven male schizophrenic patients were selected from the inpatient (n = 5) and outpatient (n = 2) services at Montefiore Medical Center (mean age 32.7, SD 14.0 years). Eight normal male controls were paid volunteers recruited by advertisement in a community newspaper (mean age 27.5, SD 6.8 years). In order to ascertain lifetime history of psychiatric illness, the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer 1978) was administered to all subjects. The patients met Research Diagnostic Criteria (RDC) (Spitzer et al 1978) fGr chronic schizophrenia of at least 2 years duration (range 2-35 years), and they were medication free for a 2-week period prior to parti, :padon in the challenge tests. Five patients met RDC criteria for paranoid subtype and 2 met criteria for undifferentiated subtype. Six of the 7 patients had previously been treated with a variety of typical neuroleptic medications throughout the course of their illness. The normal subjects all met RDC criteria for "never mentally ill." All subjects were within 25% of their ideal body weight, had normal laboratory and physical exams, and gave written informed consent prior to participation in the study.
Procedure Utilizing a double-blind design, subjects participated in two challenge tests placebo and 0.25 mg/kg MCPP orally which were separated by a l-week interval. Subjects fasted (except for water intake) from 11 PM on the night preceding the procedure. At 9 AM, an indwelling intravenous catheter was inserted into an antecubital vein. Subjects were not allowed to drink, eat, smoke, or sleep during the procedure. After a l-hr adaptation period, subjects received identical tablets containing either placebo or drug. Blood samples were collected for plasma prolactin, cortisol, and MCPP concentrations immediately before the time of infusion (time O) and at 30, 60, 90, 120, 150, 180, and • c.., .... :"" ttlklilllUl~UiiJ.li.lILIqi ° ~ ' - : - : ° ' - " : ^ - O~" ,-,tt~ ..,, mm II.311tLIV~'Ili~ l "-Llig; tablets. A research psychiatrist used an abbreviated version of the Positive and Negative Syndrome Scale (PANSS) (Kay et al 1987) to rate the behavior and mental status of the schizo?hrenic subj~cts du~ng the challenge procedure at time 0, and at 60, 120, 180, and 210 min following administration of the tablets. The PANSS involves a formalized interview procedure followed by 1-7 point ratings of schizophrenic symptoms for which level of symptom severity is operationalized. The full-length PANSS consists of 30 symptoms. For the purpose of this study, only those 19 symptoms that could be rated repeatedly at hourly intervals were retained. A total psychopathology score was generated from the sum of the 19 symptoms, and additional scores were calculated for its seven specific components: positive syndrome, negative syndrome, activation, thought disturbance, paranoid/belligerence, anergia, and depression. Studies on the standardization of this instrument have supported its reliability, validity, and sensitivity to change with medications (Kay et al !987, 1988; Kay 1989). Prolactin and cortisel levels were determined by a homologous double antibody ra-
BIOL PSYCHIATRY
MCPP in Schizophrenia
773
1991 ;30:770-778
radioimmunoassay using reagents purchased from Diagnostic Products Corporation (Los Angeles, CA). The lower limit of sensitivity for cortisol and prolactin was 1.3 and 2 ng/ ml, respectively. The interassay coefficient of variance for cortisol and prolactin was 8.2% and 7.5%, respectively, and the intraassay coefficient of variance for cortisol and prolactin was 5.5% and 5.2%, respectively. Laboratory analyses were carried out blind to the nature of the tests. All samples from a single subject were run in the same assay. MCPP was obtained from Aldrich Chemical Company (Milwaukee, Wl). The identity and purity of MCPP were verified by high performance liquid chromatography by the Nathan Kline Laboratories (Rockland, NY). A standard calibration curve and a quality control sample wa~ n,,ra with each day's analysis. The relative standard deviation for within-day analyses as well as for day-to-day assays was 3.5%. The lower limit of detection for MCPP in plasma was about 2 ng/ml.
Data Analysis Hormonal release was calculated using placebo-correlated change-from-baseline scores. Accordingly, at each point in time, the subjects" change-from-baseline value on placebo was subtracted from his change-from-baseline value on MCPP. Repeated measures multivariate analyses of variance were then conducted with one repeated measure (time: 0, 30, 60, 90, 120, 150, 180, and 210 min) and one group variable (schizophrenics versus normal controls). For the schizophrenic subjects, behavioral response on the PANSS was calculated using delta (peak-minus-baseline) values, and significance of the difference between MCPP and placebo response was analyzed by paired t-test.
Results MCPP The schizophrenic patients had a peak MCPP blood level of 7.3 ng/dl (SD 10.0) as compared with 22.4 ng/dl (SD 24.1) for the normal subjects. Given the small number of subjects, this difference was not statistically significant (t = 1.53, p = 0.15). Using an area-under-curve analysis, there was not a significant group difference (t = 1.47, p = 0.17). Two of the schizophrenic patients had trace or nondetectable levels of MCPP. For LU_I ~. LL l i
~lt~l, llp~,
peak
LO Sl l ~J l_k., Jl l l ~ I| t .~.V. .~ I ~S. . . . .~.N. .I.~. .I I ~ lli~l~l,r~Iif~lkl i ~ , - I n~ ".
I.~ "~f~ ~;~ ,~¢~o,-h~,~;n;eh-,~t;,,~n . ~ t ~ I ~ f ' ~ D D 4f.~t.t' 111111 ~11,~.,1 C L l ~ l U t l l t l t l l t g a u L a l l d t v l l l ~Jlt ,,tvA~,,,,,..g ~. •
Behavioral Response Table 1 presents the PANSS behavioral data for the schizophrenic subjects on placebo versus MCPP. A paired t-test revealed a significant difference on total psychopathology (df = 6, t = 2.71, p < 0.05), indicating overall worsening of symptoms on MCPP. Both of the patients with trace or nondetectable levels of MCPP had a behavioral response to the drug. Predicated on this finding, we analyzed the component scores to clarify the nature of the drug-related changes. The results showed significant drug/placebo differences that were specific to the positive syndrome (t = 3.29, df = 6, p < 0.02) and activation (t = 9.30, df = 6, p < 0.001) components. In this abbreviated PANSS, the positive syndrome was composed of the symptoms of conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, and hostility. Activation was composed of excitement, tension, and mannerisms and posturing.
774
N. lqbal et al
BIOL PSYCHIATRY 1991 ;30:770--778
Table 1. Behavioral Response of Schizophrenic Patients (n = 7) on Placebo and MCPP Placebo
MCPP
Paired t tests =
PANSS Scale
Mean
SD
Mean
SD
t
p
Total psychopathology Positive syndrome Negative syndrome Activation Thought disturbance Paranoid/belligerence Anergia Depression
1.57 0.71 0.29 0.29 0.57 0.43 0.00 0.29
2.64 !. ! ! 0.76 0.49 !.51 0.54 0.00 0.49
9.14 3.29 2.29 2.00 1.65 1.86 1.29 1.00
7.47 2.93 3.25 0.58 !.68 2 04 ! .89 ! .00
2.71 3.29 ! .49 9.30 2.27 2.09 !.80 1.70
