BIOL PSYCHIATRY 1992;32:457-461
457
BRIEF REPORTS
Anger and Anxiety Responses to m-Chlorophenylpiperazine in Generalized Anxiety Disorder Mark Germine, Andrew W. Goddard, Scott W. Woods, Dennis S. Chamey, and George R. Heninger
m-Chlorophenylpiperazine (MCPP) has become an important neuroendocrine and behavioral probe for scrotonin function. MCPP has prominent serotonergic properties, the most important of which behaviorally appears to be activation of the 5-HT:c receptor (Curzon and Kennett 1990; Kennett et al 1989). Anxiogenic effects of MCPP on social interaction in the rat are blocked by antagonists with high affinity for 5-HT:c and 5HT2 receptors, but not by selective antagonists of the 5-ITT2 receptor (Kennett et al 1989). In human healthy subjects, the anxiogenic action of MCPP is partially blocked by ritanserin, a selective 5-HT2 and 5-HT:c antagonist (Seibyl et al 1991). There are relatively few studies of neurobiological function in patients with generalized anxiety disorder (GAD) (Charney et al 1989), and no studies of serotonin function in GAD. The purpose of this study was to test the hypothesis that GAD patients are hypersensitive to the subjective ef'~ects of MCPP. Methods and Pr,~,cedures Ten successive clinic admissions v,ho met the DSM-III-R criteria for GAD as a l~,rincipal di-
From the Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Yale University Department of Psychiatry, 34 Park Street, New Haven, Connecticut, and the Yale University Departmentof Psychiatry,West Haven VA MedicalCenter, West Haven, Connecticut Address reprint requests to Andrew W. Goddard, AbrahamRibicoff Research Facilities, 34 Park Street, New Haven, CT 06519. Received November 12, 1991, revised May 21, 1992. © 1992 Society of Biological Psychiatry
agnosis were selected. Of the 10 patients, there were 8 females (mean age - standard deviation 38 +_ 8 yr) and 2 males (age 39 - 6 yr). Four patients (all female) had comorbid current or lifetime affeetive or other anxiety disorders: one had current panic disorder (PD) and atypicel depression, one had current obsessive-compulsive disorder, one had a history of major depression, and one had current social phobia. All patients were drug free for at least three weeks before the challenges. The nineteen healthy subjects were judged free of psychiatric illness based on a structured interview, and none reported a history of mental illness among first-degree relatives. None of the subjects reported taking a psychuactive medication within a month of the study, and all had negative urine drug screens. Thirteen of the healthy subjects were females (37 _ 7) and six were males (38 --- 11 hr). Data from this healthy subject cohort have been previously reported (Charney et al 1987). Each subject participat~:~ in two test sessions. He or she received an IV infusion of placebo (0.45% saline) over 20 minutes in one session and an I.V infusion of MCPP (0.1 mg/kg) in the other. Sessions were approximately seven days apart. The sequence of sessions was balanced so that 5 of 10 patients received placebo on the first day compared with nine of nineteen healthy subjects. All patients, research psychiatrists, and research nurses were blind to the medication state (placebo or MCPP) during the 0006-3223/92/$05.00
458
Brief Reports
BIOL PSYCHIATRY 1992;32:457-461
challenge period. The subjects fasted overnight for at least 10 hr and continued to fast during the tests. Ratings were obtained 15 and 0.5 rain prior to infusion, and at 30, 60, 90, and 150 min after. Behavioral ratings were completed by all subjects for thirteen mood states (talkative, happy, drowsy, nervous, sad, calm, depressed, anxious, energetic, fearful, mellow, high, and angry). Scoring was done on (g-100 mm visual analog scales, 0 representing none, 100 most ever,
Results Analysis of variance (ANO V A) comparisons of mood variables across groups showed significant triple interactions of diagnosis, medication state, and time f,~r talkative (F = 2.6, df = 4,104, p < 0.05), nervous (F = 4.0, df = 4,108, p < 0.005), anxious (F = 3.8, df ffi 43,108, p < 0.001), and angry (F = 5.4, df = 4,104, p < 0.0005). The number and level of significant ANOVAs and post-hoe t-tests is far greater than expected by chance alone. Student's t-tests comparing the MCPP/placebo differences (MCPP net effect) in the two groups at individual time points showed no significant differences for talkative ratings. Nervous ratings were significantly higher in the GAD group at 30 rain (p < 0.05), 60 min (p < 0.05), 90 min (p < 0.0005), and 150 rain (p < 0.01). Anxiety ratings were significantly higher in the GAD group at 30 rain (p < 0.05), 90 rain (p < 0.05), and 150 min (p < 0.005). Anger ratings were significantly higher in the GAD group at 30 min (p < 0.005), 60 min (p < 0.05), and 90 rain (p < 0.05). Figure 1 shows the time course of anxiety ratings for MCPP and placebo infusion in patients and healthy subjects. Of note is the significant drop in the anxiety level after placebo administration for GAD patients. This drop accounts for most of the greater MCPP/placebo difference in the GAD patients as compared with the healthy group. Data were similar for nervousness and fearfulness, both showing a relatively high baseline and sharp drop on the placebo day.
The most striking and statistically significant finding for the mood variables was the drug x diagnosis x time interaction for anger (Figure 2). Both the GAD and healthy subjects had low baseline anger ratings which were statistically indistinguishable. Among the GAD group, five had increases above baseline of 25 mm or more in anger ratings on the MCPP day. No healthy subjects exhibited an increase of 25 mm or more in anger rating. Of the patients that exhibited increase in anger of 25 mm or more, 4 out of 5 exhibited concurrent increases in anxiety over baseline of 25 mm or more while 1 out of 5 exhibited a more modest increase (18 mm). Of the five patients who exhibited a marked anger response, only one verbalized her anger spontaneously. This patient and two other patients who exhibited large increases in anger on MCPP were visibly upset and tearful. One other patient exhibited an irritable affect, while another showed no overt signs of anger.
Discussion The principal findings of the present study are: (I) that a prominent anger response to MCPP was observed in the patients, and (2) that GAD patients showed g~ater behavioral responses to MCPP in comparison with placebo than did healthy subjects on anxiety-related measures. The association of MCPP with an anger response in GAD patients was an unexpected finding in that increased anger has not been documented by any previous challenge studies using serotonergic agents in humans, although an increase in hostility has been noted in studies using MCPP in PD patients (Kahn et al 1988) and in patients with antisocial personality in the setting of substance abuse (Moss et al 1990). Much of the evidence from experimental animal and humans studies is consistent with serotonin suppressing predatory behavior and aggression, an effect opposite to our current findings. Systemic administration of PCPA, a tryptophan hydroxylase inhibitor that depletes serotonin, causes an increase in predatory behavior in cats, while electrical stimulation of the dorsal raphe nucleus in the cat inhibits hypotha-
Brief Reports
BIOL PSYCHIATRY 1992;32:457-461
7o 60t 50
459
--e- Active - ~ ~ Placebo
g40-J
2°t
xx
Baseline
30
60 TIME (mine)
90
180
7O i ...e- Active - o - Placebo
.°t
g e0 ,,E,404
t
% _ _ . _ _
Baseline
30
-
60 TIME (mine)
*
90
160
Figure 1. Visual analogue ratings of anxious mood after administration of placebo (open circles) and MCPP (closed circles) and normal controls (top) and GAD patients (bottom). Paired t-tests, MCPP net effect: x, p < 0.05; xx, p < 0.02; x~, p < 0.005. Student's t-test, MCPP net effect, patients vs healthy subjects: t, p < 0.05; tt, p < 0.005.
lamically elicited predatory behavior (Siegal and Port 1988). A study of chronic administration of MCPP in elderly depressed patients provides evidence for decreased aggressie~ in response to the agent (Mellow et al 1990). Injection of MCPP into the periaqueductal grey matter (PAG) of the rat inhibits aggressive responding to PAG stimulation Oenke et al 1990). A different role for serotonin is suggested by evidence in mice of increased serotoninergic activity in the amygdala under conditions of attack (Hanley et al 1990) and exposure to defeat (EIeftheriou and Church 1968). The remits of this study are consistent with
a serotonergic dysfunction in the regulation of anxious and angry mood in GAD. Panic disorder patients may have similar hypersensitive responses to MCPP (Kahn et al 1988). However, no significant hypersensitivity to MCPP was noted in a previous study of panic disorder patients using the same dosing paradigm and control group employed here (Charney et al 1987). In particular, the anger response to IV MCPF appears to be relatively specific to GAD patients, and is not observed in unmedicated patients with panic disorder, obsessive--compulsive disorder, posttraumatic stress disorder, major depression, or schizophrenia (Germine et al 1992). The rela-
Brief Reports
BIOL PSYCHIATRY 1992;32:457-461
460
30-
-e-
25-
e
Active Placebo
A
E 20-
~.'15-
g
457
BRIEF REPORTS
Anger and Anxiety Responses to m-Chlorophenylpiperazine in Generalized Anxiety Disorder Mark Germine, Andrew W. Goddard, Scott W. Woods, Dennis S. Chamey, and George R. Heninger
m-Chlorophenylpiperazine (MCPP) has become an important neuroendocrine and behavioral probe for scrotonin function. MCPP has prominent serotonergic properties, the most important of which behaviorally appears to be activation of the 5-HT:c receptor (Curzon and Kennett 1990; Kennett et al 1989). Anxiogenic effects of MCPP on social interaction in the rat are blocked by antagonists with high affinity for 5-HT:c and 5HT2 receptors, but not by selective antagonists of the 5-ITT2 receptor (Kennett et al 1989). In human healthy subjects, the anxiogenic action of MCPP is partially blocked by ritanserin, a selective 5-HT2 and 5-HT:c antagonist (Seibyl et al 1991). There are relatively few studies of neurobiological function in patients with generalized anxiety disorder (GAD) (Charney et al 1989), and no studies of serotonin function in GAD. The purpose of this study was to test the hypothesis that GAD patients are hypersensitive to the subjective ef'~ects of MCPP. Methods and Pr,~,cedures Ten successive clinic admissions v,ho met the DSM-III-R criteria for GAD as a l~,rincipal di-
From the Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Yale University Department of Psychiatry, 34 Park Street, New Haven, Connecticut, and the Yale University Departmentof Psychiatry,West Haven VA MedicalCenter, West Haven, Connecticut Address reprint requests to Andrew W. Goddard, AbrahamRibicoff Research Facilities, 34 Park Street, New Haven, CT 06519. Received November 12, 1991, revised May 21, 1992. © 1992 Society of Biological Psychiatry
agnosis were selected. Of the 10 patients, there were 8 females (mean age - standard deviation 38 +_ 8 yr) and 2 males (age 39 - 6 yr). Four patients (all female) had comorbid current or lifetime affeetive or other anxiety disorders: one had current panic disorder (PD) and atypicel depression, one had current obsessive-compulsive disorder, one had a history of major depression, and one had current social phobia. All patients were drug free for at least three weeks before the challenges. The nineteen healthy subjects were judged free of psychiatric illness based on a structured interview, and none reported a history of mental illness among first-degree relatives. None of the subjects reported taking a psychuactive medication within a month of the study, and all had negative urine drug screens. Thirteen of the healthy subjects were females (37 _ 7) and six were males (38 --- 11 hr). Data from this healthy subject cohort have been previously reported (Charney et al 1987). Each subject participat~:~ in two test sessions. He or she received an IV infusion of placebo (0.45% saline) over 20 minutes in one session and an I.V infusion of MCPP (0.1 mg/kg) in the other. Sessions were approximately seven days apart. The sequence of sessions was balanced so that 5 of 10 patients received placebo on the first day compared with nine of nineteen healthy subjects. All patients, research psychiatrists, and research nurses were blind to the medication state (placebo or MCPP) during the 0006-3223/92/$05.00
458
Brief Reports
BIOL PSYCHIATRY 1992;32:457-461
challenge period. The subjects fasted overnight for at least 10 hr and continued to fast during the tests. Ratings were obtained 15 and 0.5 rain prior to infusion, and at 30, 60, 90, and 150 min after. Behavioral ratings were completed by all subjects for thirteen mood states (talkative, happy, drowsy, nervous, sad, calm, depressed, anxious, energetic, fearful, mellow, high, and angry). Scoring was done on (g-100 mm visual analog scales, 0 representing none, 100 most ever,
Results Analysis of variance (ANO V A) comparisons of mood variables across groups showed significant triple interactions of diagnosis, medication state, and time f,~r talkative (F = 2.6, df = 4,104, p < 0.05), nervous (F = 4.0, df = 4,108, p < 0.005), anxious (F = 3.8, df ffi 43,108, p < 0.001), and angry (F = 5.4, df = 4,104, p < 0.0005). The number and level of significant ANOVAs and post-hoe t-tests is far greater than expected by chance alone. Student's t-tests comparing the MCPP/placebo differences (MCPP net effect) in the two groups at individual time points showed no significant differences for talkative ratings. Nervous ratings were significantly higher in the GAD group at 30 rain (p < 0.05), 60 min (p < 0.05), 90 min (p < 0.0005), and 150 rain (p < 0.01). Anxiety ratings were significantly higher in the GAD group at 30 rain (p < 0.05), 90 rain (p < 0.05), and 150 min (p < 0.005). Anger ratings were significantly higher in the GAD group at 30 min (p < 0.005), 60 min (p < 0.05), and 90 rain (p < 0.05). Figure 1 shows the time course of anxiety ratings for MCPP and placebo infusion in patients and healthy subjects. Of note is the significant drop in the anxiety level after placebo administration for GAD patients. This drop accounts for most of the greater MCPP/placebo difference in the GAD patients as compared with the healthy group. Data were similar for nervousness and fearfulness, both showing a relatively high baseline and sharp drop on the placebo day.
The most striking and statistically significant finding for the mood variables was the drug x diagnosis x time interaction for anger (Figure 2). Both the GAD and healthy subjects had low baseline anger ratings which were statistically indistinguishable. Among the GAD group, five had increases above baseline of 25 mm or more in anger ratings on the MCPP day. No healthy subjects exhibited an increase of 25 mm or more in anger rating. Of the patients that exhibited increase in anger of 25 mm or more, 4 out of 5 exhibited concurrent increases in anxiety over baseline of 25 mm or more while 1 out of 5 exhibited a more modest increase (18 mm). Of the five patients who exhibited a marked anger response, only one verbalized her anger spontaneously. This patient and two other patients who exhibited large increases in anger on MCPP were visibly upset and tearful. One other patient exhibited an irritable affect, while another showed no overt signs of anger.
Discussion The principal findings of the present study are: (I) that a prominent anger response to MCPP was observed in the patients, and (2) that GAD patients showed g~ater behavioral responses to MCPP in comparison with placebo than did healthy subjects on anxiety-related measures. The association of MCPP with an anger response in GAD patients was an unexpected finding in that increased anger has not been documented by any previous challenge studies using serotonergic agents in humans, although an increase in hostility has been noted in studies using MCPP in PD patients (Kahn et al 1988) and in patients with antisocial personality in the setting of substance abuse (Moss et al 1990). Much of the evidence from experimental animal and humans studies is consistent with serotonin suppressing predatory behavior and aggression, an effect opposite to our current findings. Systemic administration of PCPA, a tryptophan hydroxylase inhibitor that depletes serotonin, causes an increase in predatory behavior in cats, while electrical stimulation of the dorsal raphe nucleus in the cat inhibits hypotha-
Brief Reports
BIOL PSYCHIATRY 1992;32:457-461
7o 60t 50
459
--e- Active - ~ ~ Placebo
g40-J
2°t
xx
Baseline
30
60 TIME (mine)
90
180
7O i ...e- Active - o - Placebo
.°t
g e0 ,,E,404
t
% _ _ . _ _
Baseline
30
-
60 TIME (mine)
*
90
160
Figure 1. Visual analogue ratings of anxious mood after administration of placebo (open circles) and MCPP (closed circles) and normal controls (top) and GAD patients (bottom). Paired t-tests, MCPP net effect: x, p < 0.05; xx, p < 0.02; x~, p < 0.005. Student's t-test, MCPP net effect, patients vs healthy subjects: t, p < 0.05; tt, p < 0.005.
lamically elicited predatory behavior (Siegal and Port 1988). A study of chronic administration of MCPP in elderly depressed patients provides evidence for decreased aggressie~ in response to the agent (Mellow et al 1990). Injection of MCPP into the periaqueductal grey matter (PAG) of the rat inhibits aggressive responding to PAG stimulation Oenke et al 1990). A different role for serotonin is suggested by evidence in mice of increased serotoninergic activity in the amygdala under conditions of attack (Hanley et al 1990) and exposure to defeat (EIeftheriou and Church 1968). The remits of this study are consistent with
a serotonergic dysfunction in the regulation of anxious and angry mood in GAD. Panic disorder patients may have similar hypersensitive responses to MCPP (Kahn et al 1988). However, no significant hypersensitivity to MCPP was noted in a previous study of panic disorder patients using the same dosing paradigm and control group employed here (Charney et al 1987). In particular, the anger response to IV MCPF appears to be relatively specific to GAD patients, and is not observed in unmedicated patients with panic disorder, obsessive--compulsive disorder, posttraumatic stress disorder, major depression, or schizophrenia (Germine et al 1992). The rela-
Brief Reports
BIOL PSYCHIATRY 1992;32:457-461
460
30-
-e-
25-
e
Active Placebo
A
E 20-
~.'15-
g
