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Amphetamine disrupts P50 suppression in normal subjects
Amphetamine Disrupts P50 Suppression in Normal Subjects Gregory A. Light, Dolores Malaspina, Mark A. Geyer, Bruce M. Luber, Eliza A. Coleman, Harold A. Sackeim, and David L. Braff Background: P50 suppression is viewed as an operational measure of sensory “gating” that is reduced in patients with schizophrenia and their family members. Previous reports have demonstrated that neural gating is regulated by monoaminergic tone in rodent models of P50 suppression. Methods: In this study, 11 healthy subjects participated in P50 event-related potential recordings at baseline and after either oral administration of dextroamphetamine (.3 mg/kg) or placebo, to determine if the administration of a monoaminergic agonist produces P50 suppression deficits similar to those observed in patients with schizophrenia. Results: As hypothesized, amphetamine disrupted the suppression of the P50 event-related potential. There was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t10 ⫽ 3.15, p ⬍ .01, mean difference ⫽ ⫺44.1%, d ⫽ ⫺2.5) relative to the baseline P50 condition. A comparison of P50 suppression in the placebo and amphetamine conditions (both after a baseline recording session) revealed a significant amphetamine-induced disruption of P50 suppression (t6 ⫽ 3.71, p ⬍ .01, mean difference ⫽ ⫺54.4%, d ⫽ ⫺3.14). Conclusions: The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. The findings are consistent with several careful examinations of suppression deficits in rodent models that have identified the monoaminergic regulation of P50 suppression. These data indicate that amphetamine induces a disruption of P50 suppression in normal subjects. Biol Psychiatry 1999; 46:990 –996 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, suppression, gating, eventrelated potential, EEG, amphetamine, monoamines
From the Department of Psychiatry, University of California, San Diego, La Jolla, CA (GAL, MAG, DLB); and the Departments of Medical Genetics and Biological Psychiatry, New York State Psychiatric Institute, New York, NY (DM, BML, EAC, HAS). Address reprint requests to David L. Braff, MD, Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804. Received November 10, 1998; revised January 26, 1999; accepted February 2, 1999.
© 1999 Society of Biological Psychiatry
Introduction
T
he suppression of the P50 component of the auditory event-related potential has been used in neuropsychiatric research for over 15 years (e.g., Adler et al 1982; Clementz et al 1998b). The P50 wave is a small amplitude, positive event-related potential (ERP) that occurs about 50 msec after a stimulus, and is typically measured in response to repeated auditory stimuli (e.g., clicks). P50 suppression is measured by averaging multiple electroencephalographic responses to click pairs separated by about 500 msec, and then assessing the percentage reduction in amplitude of the P50 response from the first to the second click. In the P50 suppression paradigm, normal subjects exhibit robust (e.g., 60% to 80%) suppression (see Light and Braff 1998 for P50 studies with normal subjects), whereas patients with schizophrenia exhibit diminished suppression (Adler et al 1982; Boutros et al 1991; Cardenas et al 1993; Clementz et al 1997a; Clementz et al 1997b; Clementz et al 1998a; Erwin et al 1991; Freedman et al 1996; Jin et al 1997; Judd et al 1992; Nagamoto et al 1989; Ward et al 1996). There is also evidence that suppression deficits may be related more generally to the state of psychosis, because patients with bipolar disorder exhibit P50 suppression deficits when they are acutely psychotic but not when they are in remission (Baker et al 1987; Franks et al 1983). The P50 suppression deficits of patients with schizophrenia has prompted further studies to better understand the clinical correlates and neurophysiological features of this finding (Braff and Geyer 1990). P50 suppression deficits occur in “unaffected” family members of patients with schizophrenia (Adler et al 1992; Clementz et al 1998b; Freedman et al 1997; Siegel et al 1984; Waldo et al 1995; Waldo et al 1988; Waldo et al 1991; Waldo et al 1994). Freedman et al (1997) have also reported a linkage between P50 gating and the alpha-7 nicotinic receptor of chromosome 15 band q14, associating a schizophrenialinked neurophysiological defect with a specific genetic locus. Dopaminergic involvement in P50 suppression has been 0006-3223/99/$20.00 PII S0006-3223(99)00034-7
Amphetamine Disrupts P50 Suppression
examined in human studies by contrasting normal subjects with unmedicated patients with schizophrenia and with those medicated with typical neuroleptics. The unmedicated patients with schizophrenia exhibited reduced amplitude of the P50 response to the first click compared to normal subjects. Among patients with schizophrenia treated with conventional neuroleptic medications, P50 amplitude to the initial stimulus was greater, but P50 suppression remained reduced (Freedman et al 1983). Clozapine, the only atypical neuroleptic medication studied in conjunction with P50 measures, has been shown to improve P50 suppression in patients with schizophrenia (Nagamoto et al 1996; Nagamoto et al 1999). Some studies have also included psychotic patients with bipolar disorder and schizophrenia to investigate the specificity of P50 suppression failure. Franks and coworkers (1983) observed deficits in P50 gating in acute, psychotic bipolar patients, similar to the deficits observed in patients with schizophrenia. However, among patients with mania but not schizophrenia, the reduced suppression returned to normal levels as the clinical state improved. This finding pointed to both a psychosis-linked state-related P50 suppression deficit and a more enduring, schizophrenialinked, trait-related P50 suppression deficit. To investigate neurotransmitter mediators of P50 suppression deficits in these patient groups, Baker and coworkers (1990) found that the reduced P50 suppression in manic subjects was correlated with increased plasma levels of the noradrenergic metabolite 3-methoxy,4-hydroxyphenylglycol (MHPG). Animal models of P50 generation and suppression have also implicated monoaminergic neurotransmitter systems in the modulation of the N40 wave, which is the rodent analog of the P50 in humans (Adler et al 1988; Adler et al 1986; Johnson et al 1998; Stevens et al 1991; Stevens et al 1996b; Stevens et al 1993). Adler and coworkers (1986) demonstrated that acute administration of dextroamphetamine decreased the amplitude of the first response and the suppression of the N40 ERP component in the rat. The authors noted that “catecholamines have significant modulatory effects on the gating, amplitude, and latency of P50 in humans and rats.” They also noted that haloperidol reversed or normalized the suppression deficits induced by dextroamphetamine. Stevens and colleagues (1993) observed that N40 suppression was disrupted by the ␣2-selective noradrenergic antagonist, yohimbine. The yohimbine-induced increase in endogenous noradrenergic tone, caused by the blockade of inhibitory feedback mechanisms, resulted in disrupted sensory gating. The finding that yohimbine disrupts sensory gating in the animal model of this deficit has also been extended to normal human subjects. Specifically, yohimbine-induced increases in noradrenergic transmission have been shown to impair P50 suppression tran-
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siently in normal subjects (Adler et al 1994). Buttressing the importance of monoaminergic tone and gating, there is an animal model literature demonstrating that prepulse inhibition (a different measure of gating) is reduced by amphetamine or direct dopamine agonists in an antipsychotic-sensitive manner (Mansbach et al 1988). Furthermore, the disruption of prepulse inhibition produced by amphetamine is prevented by central dopamine depletion (Swerdlow et al 1990). There is a dearth of studies examining amphetamine effects on gating measures in humans. In this study, we hypothesized that P50 suppression would be diminished after an amphetamine challenge in healthy normal subjects.
Methods and Materials Subjects Eleven healthy, normal men (age 21 to 36 years; mean ⫽ 26) were recruited from bulletin board advertisements at the New York State Psychiatric Institute (NYSPI). The subjects were part of a larger, randomized study, which examined the effects of catecholaminergic tone on smooth pursuit eye movements (SPEM) and other measures recorded on separate testing days at least 1 week apart. The SPEM data and experimental design have been previously published (Malaspina et al 1994). P50 data collected after the amphetamine and placebo challenge are reported in the present study. All subjects did not participate in all phases of the SPEM study. Therefore, P50 data was available for all 11 subjects who completed the amphetamine challenge. Additionally, 7 of the 11 subjects participated in both amphetamine and placebo conditions (these were counterbalanced) and the P50 data from this subset of subjects will be examined separately to control for potential order effects. Structured psychiatric interviews of subjects by staff physicians revealed no personal history of schizophrenia, affective or anxiety disorders, substance abuse, or current medication treatment (Malaspina et al 1994). Family history revealed no firstdegree relatives with schizophrenia. Axis II disorders were not assessed. All subjects had normal physical examinations and ECG evaluations. The study was approved by the NYSPI Institutional Review Board and all participants gave informed consent for the study.
Procedures Subjects were required to fast overnight prior to the test day. All test sessions began with a baseline P50 recording followed by the administration of the amphetamine or placebo challenge. Oral dextroamphetamine sulfate (.3 mg/kg free base dose) or oral placebo was administered and 2 hours later the P50 recording was repeated. A blood sample was taken for measuring amphetamine levels prior to ERP recording. Blood levels of amphetamine were similar among all participants (mean ⫽ 45 ng/mm, 2.0 SEM) and were “not detectable” after placebo administration. We expected that oral amphetamine would have a rapid onset (1 hour) and sustained effects over approximately 6 hours (Angrist
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et al 1987). Vital signs were monitored throughout the test day. Amphetamine induced mild elevations of systolic and diastolic blood pressure (⬍15 mm Hg) and pulse (⬍30 beats/minute) that resolved before discharge from the laboratory and required no treatment. None of the subjects became psychotic after the administration of the amphetamine. As previously reported by Malaspina and colleagues (1994), a retrospective review of clinical notes indicated that subjects in the amphetamine condition were more euphoric and talkative. Additionally, amphetamine resulted in an increased reporting of vigor and decreased ratings of fatigue using the Profile of Mood Scale documented in the abovementioned publication. The 7 subjects that participated in both phases (amphetamine and placebo challenges) of the experiment were retested after a 7-day “waiting period” following the initial session in order to ensure drug effect washout and reduce potential short-term practice effects. All subjects, technicians, and raters were blind to drug condition throughout the study. Subjects and research staff were told that the challenge could be either amphetamine or placebo and that the same condition could be repeated if they underwent the testing on a second day.
P50 Measures During the P50 evoked potential recordings, participants were seated in a comfortable recliner and instructed to relax with their eyes open and focused on a fixation point. Fifty 110 dB click pairs were presented every 10 sec with a 500 msec interclick interval. The stimuli were generated using computer-driven pulses with a .3 msec duration that were amplified with a Realistic SA-10 amplifier with the tone control at maximum treble. The output of this amplifier was fed to a Jensen X-20 speaker. Electrical responses were recorded with gold cup electrodes between the vertex and linked earlobes. A ground electrode was placed on the forehead. Eye movements and blinks were monitored with EOG recording. Resistance of all electrodes was less than 5 kohms. The evoked response was amplified with a Grass model 7P511J amplifier with a bandpass of .1 to 300 Hz, with no 60 Hz notch filter. The response was digitized at 1000 samples/ sec and individual trials were stored on a PDP-11/24 computer. Peak amplitudes and latencies were determined offline, blind to subject and condition. EEG and EOG channels were screened for artifact postacquisition and trials containing artifact (⫾ 75 V EOG or EEG channel) were not included in waveform averaging. Artifact-free epochs were averaged and digitally bandpass-filtered (5 to 50 Hz) in the frequency domain using the Scan Reader Station (Neurosoft Inc., Sterling, VA). The filter had 12 dB/octave high and low-pass slopes similar in gain characteristics reported by Jerger and colleagues (1992). The P50 component was identified in a manner consistent with previous studies (Clementz et al 1997b; Nagamoto et al 1989). The P50 was defined as the most positive deflection 40 to 80 msec following stimulus presentation. P50 amplitude was defined as the absolute difference between the P50 peak and the preceding negative trough. Evoked potential waveforms were
Table 1. P50 Measuresa
P50 Response to click 1 Amplitude Latency P50 Response to click 2 Amplitude Latency Percent P50 suppression
Baseline
Amphetamine
Baseline
Placebo
4.6 (3.4) 58.4 (7.3)
4.2 (3.0) 55.6 (4.5)
3.4 (2.2) 56.7 (4.2)
2.7 (2.3) 56.3 (6.2)
1.1 (1.2) 60 (6.3) 76.9 (17.8)
2.0 (1.3) 58.5 (5.1) 32.8 (40.1)
1.1 (1.0) 0.25 (.3) 61.8 (8.6) 55 (5.3) 70.8 (20.1) 87.2 (17.3)
a Means and standard deviations of P50 measures obtained from baselineamphetamine (n ⫽ 11) and the baseline-placebo (n ⫽ 7) phases of the experiment.
examined visually and latencies and amplitudes were recorded manually. Percent P50 suppression was calculated using the formula [(1 ⫺ S2 amplitude/S1 amplitude) ⫻ 100], as per our previously reported methods (Clementz et al 1997b; Clementz et al 1998a; Clementz et al 1998b; Judd et al 1992).
Statistical Analyses In addition to standard statistical tests, the following two measures of effect size were utilized for descriptive purposes: mean differences and standardized mean differences (d) (Cohen 1994). Multivariate solutions to within-subjects, repeated measures analyses (4 levels: session A: baseline, amphetamine; session B: baseline, placebo) were performed for the 7 subjects who completed both the amphetamine and placebo challenges. In each challenge condition, a baseline P50 recording was obtained. The following planned comparisons of P50 suppression were also conducted following omnibus session analysis: baseline versus amphetamine, baseline versus placebo, and amphetamine versus placebo. These first two comparisons contained data collected on the same day of testing. In contrast, the amphetamine versus placebo comparison used data obtained after at least a one week interval. In order to examine all available data from subjects who underwent an amphetamine challenge, the 4 additional subjects who completed only the amphetamine challenge were included (n ⫽ 11) in a separate follow-up analysis to determine if amphetamine elicited a significant disruption of P50 suppression in this larger (11 vs. 7) cohort. The rationale for this planned contrast was to examine all subjects with available P50 data from the amphetamine challenge and to increase the statistical power, if necessary, for this comparison.
Results There were no significant differences between P50 amplitudes or latencies across the different conditions. Table 1 provides means and standard deviations of the P50 variables. Using only the subset of 7 subjects who completed both drug challenge conditions, a within-subjects repeated measures analysis of variance revealed a significant difference in the 4 test sessions (baseline, amphetamine,
Amphetamine Disrupts P50 Suppression
Figure 1. Distributions of P50 suppression across the difference conditions. Significantly reduced P50 suppression occurred during the amphetamine challenge condition. Six of the 7 subjects showed a decrement of P50 suppression following the administration of amphetamine. In striking contrast, P50 suppression improved (or stayed the same) in 5 of the 7 subjects after placebo administration.
baseline, placebo) (F 3,4 ⫽ 7.4, p ⬍ .05). Planned follow-up analysis indicated that amphetamine induced a statistically significant disruption of P50 suppression compared to the initial baseline session (t 6 ⫽ 3.1, p ⬍ .05; mean difference in P50 suppression between 2 sessions ⫽ ⫺56%, d ⫽ ⫺3.44). A priori follow-up analysis of the placebo challenge condition failed to yield statistically significant differences on P50 latency, amplitude, or suppression between the baseline recording and placebo conditions. A direct comparison of P50 suppression in the placebo and amphetamine challenge conditions (both following an initial baseline recording session), however, revealed a significant amphetamine-induced disruption of
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P50 suppression (t 6 ⫽ 3.71, p ⬍ .01, mean difference in P50 suppression between 2 sessions ⫽ ⫺54.4%, d ⫽ ⫺3.14). The final planned comparison of the initial baseline recordings to the recordings obtained after the amphetamine challenge using all available subjects who completed this phase of the study (n ⫽ 11) yielded no appreciable differences in the outcome of the statistical analysis. As noted above, there was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t 10 ⫽ 3.15, p ⬍ .01, mean difference ⫽ ⫺44.1%, d ⫽ ⫺2.5) relative to the initial baseline P50 condition. A graphical depiction of the reduction in P50 suppression following the administration of the amphetamine and placebo challenges after baseline recordings is presented in Figure 1. Figure 2 provides the grand average event-related potential waveforms recorded during the different experimental conditions.
Discussion The results of this study indicate that amphetamine, an indirect monoaminergic agonist, disrupts P50 suppression in normal subjects. This decrement in the suppression measure is similar to the reduction observed in patients with schizophrenia (Clementz et al 1998b), and is consistent with data obtained from animal models of the effects of amphetamine on neural gating and central inhibition (Adler et al 1988; Adler et al 1986; Johnson et al 1998; Stevens et al 1991; Stevens et al 1996b; Stevens et al 1993). Thus, monoaminergic influences appear to modulate critical components of the neural systems underlying P50 suppression. An amphetamine-induced increase in noradrenergic transmission may explain the disruption of normal P50 suppression in this study. Johnson and Adler (1993) found that exposing normal subjects to a stressful situation, the
Figure 2. Grand average waveforms. The left panel contains the ERPs generated during the baseline conditions and the right panel contains waveforms generated during the amphetamine challenge conditions. In both graphs, the waveform with the solid line depicts the response to the first click and the dashed line is the response to the second click. The P50 component is the up-facing peak occurring in the 40 to 80 msec range as indicated by the arrow.
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cold-pressor test, transiently impaired P50 suppression. The cold-pressor task has been associated with increased noradrenergic neuronal transmission. Furthermore, administration of yohimbine, a presynaptic ␣2-antagonist that increases release of norepinephrine, also reduces P50 suppression in humans (Adler et al 1994) and N40 suppression in animals (Stevens et al 1993). The finding that amphetamine reduces P50 suppression in normal subjects is also consistent with evidence of dopaminergic modulation of gating mechanisms and may extend to the findings in schizophrenia. Evidence supporting the dopamine hypothesis stems from observations of increased or altered central dopaminergic transmission in schizophrenia and the fact that effective antipsychotic medications block dopamine receptors (Creese et al 1976; Creese et al 1996; Seeman et al 1976; Snyder 1976; Snyder 1977). D2-dopamine receptor antagonists reduce psychotic symptoms. Conversely, high doses of amphetamine in normal subjects may lead to psychotic symptoms similar to those observed in schizophrenia patients (Snyder 1973). Imaging studies of neuroleptic-naive patients with schizophrenia have also revealed increased dopaminergic outflow and a high occupancy of central D2dopamine receptors in patients who are treated with clinically effective doses of classical antipsychotic drugs (Farde 1997; Sedvall 1990; Sedvall 1992; Sedvall et al 1995; Wiesel 1989). Additionally, recent studies have indicated abnormal functioning of presynaptic dopaminergic neurons in schizophrenia patients (see Farde 1997 for a review). Stevens and colleagues (1996b) have investigated the role of dopamine receptors in N40 gating in the rat and concluded that “amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency [in gating] occurs through postsynaptic dopamine receptor activation.” In a recent review of P50 and nicotinic receptor functioning in patients with schizophrenia, Adler and colleagues (1998) argued that the fact that P50 suppression is not normalized in patients with schizophrenia by treatment with dopamine antagonist medications (Freedman et al 1983), suggests that the suppression deficit may not be accounted for by simple dopaminergic neuronal mechanisms. In contrast, the unique ability of clozapine to restore the suppression deficit in patients with schizophrenia (Nagamoto et al 1996; Nagamoto et al 1999) points to the potential role of more complex neurotransmitter system interactions. Adler and colleagues speculated that the normalizing effect of clozapine on P50 suppression in patients with schizophrenia may be due to a cascade of neurotransmitter mechanisms affecting nicotinic-cholinergic or serotonergic receptors. A rodent study of N40 using depth electrodes in different brain regions has indicated that the generation
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and suppression of this middle latency component occurs in the CA3 region of the hippocampus (Bickford-Wimer et al 1990). The hippocampal recordings also revealed that N40 suppression was disrupted by amphetamine and that the effect of amphetamine could be reversed by haloperidol. The responses recorded in the CA3 region behaved similarly to the recordings made at the scalp, supporting the notion that in rodents and humans, respectively, the N40 and P50 may be generated by the CA3 region of the hippocampus. The finding of hippocampal involvement in the suppression of middle latency ERP components in response to auditory stimuli was supported further by studies of inbred mouse strains (Stevens et al 1996a). The effects of amphetamine are no doubt due to complex interactions between the monoamines released by amphetamine and other circuitry, such as the hippocampal– acetylcholine system. This study is limited by its inclusion of only male subjects, since gender is known to be a significant source of variance in the phenomenology of schizophrenia (see Canuso et al 1998; Salem and Kring 1998). Furthermore, gender differences have been observed in inhibitory gating paradigms with females showing less P50 suppression (Hetrick et al 1996) and less prepulse inhibition of startle (Swerdlow et al 1993). The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. Furthermore, while P50 suppression is trait-related in schizophrenia, data indicate that it is state-related in other psychiatric disorders (Baker et al 1987; Baker et al 1990; Franks et al 1983). The findings presented in this paper are consistent with several careful examinations of suppression deficits in rodent models that have implicated monoaminergic regulation of P50 ERP suppression. Because amphetamine has relatively nonspecific effects on monoaminergic neurotransmitter systems, future research should focus on the effects of more selective pharmacologic agents on P50 suppression. Still, whatever the putative underlying mechanisms may be, these findings confirm that amphetamine induces a deficit in P50 suppression in normal subjects that is similar to the deficits seen in patients with schizophrenia. Future drug challenge studies may enable us to gain further insights into the neurobiologic basis of P50 suppression in normal and schizophrenic subjects.
This work was supported in part by grants from the National Institute of Mental Health awarded to DM (1 KO7 MH00824) and to DB and MG (5-R37-MH42228), as well as VISN 22 Mental Illness, Research, Education, and Clinical Center (MIRECC) support (DB, MG) from the Veteran’s Administration.
Amphetamine Disrupts P50 Suppression
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noradrenergic modulation of amphetamine-induced changes in auditory gating. Brain Res 555:91–98. Stevens KE, Luthman J, Lindqvist E, Johnson RG, Rose GM (1996b): Effects of neonatal dopamine depletion on sensory inhibition in the rat. Pharmacol Biochem Behav 53:817– 823. Stevens KE, Meltzer J, Rose GM (1993): Disruption of sensory gating by the alpha 2 selective noradrenergic antagonist yohimbine. Biol Psychiatry 33:130 –132. Swerdlow NR, Auerbach P, Monroe SM, Hartston H, Geyer MA, Braff DL (1993): Men are more inhibited than women by weak prepulses. Biol Psychiatry 34:253–260. Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990): Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology 100:413– 416. Waldo M, Myles-Worsley M, Madison A, Byerley W, Freedman R (1995): Sensory gating deficits in parents of schizophrenics. Am J Med Genet 60:506 –511. Waldo MC, Adler LE, Freedman R (1988): Defects in auditory sensory gating and their apparent compensation in relatives of schizophrenics. Schizophr Res 1:19 –24. Waldo MC, Carey G, Myles-Worsley M, et al (1991): Codistribution of a sensory gating deficit and schizophrenia in multi-affected families. Psychiatry Res 39:257–268. Waldo MC, Cawthra E, Adler LE, et al (1994): Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings. Schizophr Res 12:93– 106. Ward PB, Hoffer LD, Liebert BJ, Catts SV, O’Donnell M, Adler LE (1996): Replication of a P50 auditory gating deficit in Australian patients with schizophrenia. Psychiatry Res 64: 121–135. Wiesel FA (1989): Positron emission tomography in psychiatry. Psychiatr Dev 7:19 – 47.
From the Department of Psychiatry, University of California, San Diego, La Jolla, CA (GAL, MAG, DLB); and the Departments of Medical Genetics and Biological Psychiatry, New York State Psychiatric Institute, New York, NY (DM, BML, EAC, HAS). Address reprint requests to David L. Braff, MD, Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804. Received November 10, 1998; revised January 26, 1999; accepted February 2, 1999.
© 1999 Society of Biological Psychiatry
Introduction
T
he suppression of the P50 component of the auditory event-related potential has been used in neuropsychiatric research for over 15 years (e.g., Adler et al 1982; Clementz et al 1998b). The P50 wave is a small amplitude, positive event-related potential (ERP) that occurs about 50 msec after a stimulus, and is typically measured in response to repeated auditory stimuli (e.g., clicks). P50 suppression is measured by averaging multiple electroencephalographic responses to click pairs separated by about 500 msec, and then assessing the percentage reduction in amplitude of the P50 response from the first to the second click. In the P50 suppression paradigm, normal subjects exhibit robust (e.g., 60% to 80%) suppression (see Light and Braff 1998 for P50 studies with normal subjects), whereas patients with schizophrenia exhibit diminished suppression (Adler et al 1982; Boutros et al 1991; Cardenas et al 1993; Clementz et al 1997a; Clementz et al 1997b; Clementz et al 1998a; Erwin et al 1991; Freedman et al 1996; Jin et al 1997; Judd et al 1992; Nagamoto et al 1989; Ward et al 1996). There is also evidence that suppression deficits may be related more generally to the state of psychosis, because patients with bipolar disorder exhibit P50 suppression deficits when they are acutely psychotic but not when they are in remission (Baker et al 1987; Franks et al 1983). The P50 suppression deficits of patients with schizophrenia has prompted further studies to better understand the clinical correlates and neurophysiological features of this finding (Braff and Geyer 1990). P50 suppression deficits occur in “unaffected” family members of patients with schizophrenia (Adler et al 1992; Clementz et al 1998b; Freedman et al 1997; Siegel et al 1984; Waldo et al 1995; Waldo et al 1988; Waldo et al 1991; Waldo et al 1994). Freedman et al (1997) have also reported a linkage between P50 gating and the alpha-7 nicotinic receptor of chromosome 15 band q14, associating a schizophrenialinked neurophysiological defect with a specific genetic locus. Dopaminergic involvement in P50 suppression has been 0006-3223/99/$20.00 PII S0006-3223(99)00034-7
Amphetamine Disrupts P50 Suppression
examined in human studies by contrasting normal subjects with unmedicated patients with schizophrenia and with those medicated with typical neuroleptics. The unmedicated patients with schizophrenia exhibited reduced amplitude of the P50 response to the first click compared to normal subjects. Among patients with schizophrenia treated with conventional neuroleptic medications, P50 amplitude to the initial stimulus was greater, but P50 suppression remained reduced (Freedman et al 1983). Clozapine, the only atypical neuroleptic medication studied in conjunction with P50 measures, has been shown to improve P50 suppression in patients with schizophrenia (Nagamoto et al 1996; Nagamoto et al 1999). Some studies have also included psychotic patients with bipolar disorder and schizophrenia to investigate the specificity of P50 suppression failure. Franks and coworkers (1983) observed deficits in P50 gating in acute, psychotic bipolar patients, similar to the deficits observed in patients with schizophrenia. However, among patients with mania but not schizophrenia, the reduced suppression returned to normal levels as the clinical state improved. This finding pointed to both a psychosis-linked state-related P50 suppression deficit and a more enduring, schizophrenialinked, trait-related P50 suppression deficit. To investigate neurotransmitter mediators of P50 suppression deficits in these patient groups, Baker and coworkers (1990) found that the reduced P50 suppression in manic subjects was correlated with increased plasma levels of the noradrenergic metabolite 3-methoxy,4-hydroxyphenylglycol (MHPG). Animal models of P50 generation and suppression have also implicated monoaminergic neurotransmitter systems in the modulation of the N40 wave, which is the rodent analog of the P50 in humans (Adler et al 1988; Adler et al 1986; Johnson et al 1998; Stevens et al 1991; Stevens et al 1996b; Stevens et al 1993). Adler and coworkers (1986) demonstrated that acute administration of dextroamphetamine decreased the amplitude of the first response and the suppression of the N40 ERP component in the rat. The authors noted that “catecholamines have significant modulatory effects on the gating, amplitude, and latency of P50 in humans and rats.” They also noted that haloperidol reversed or normalized the suppression deficits induced by dextroamphetamine. Stevens and colleagues (1993) observed that N40 suppression was disrupted by the ␣2-selective noradrenergic antagonist, yohimbine. The yohimbine-induced increase in endogenous noradrenergic tone, caused by the blockade of inhibitory feedback mechanisms, resulted in disrupted sensory gating. The finding that yohimbine disrupts sensory gating in the animal model of this deficit has also been extended to normal human subjects. Specifically, yohimbine-induced increases in noradrenergic transmission have been shown to impair P50 suppression tran-
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siently in normal subjects (Adler et al 1994). Buttressing the importance of monoaminergic tone and gating, there is an animal model literature demonstrating that prepulse inhibition (a different measure of gating) is reduced by amphetamine or direct dopamine agonists in an antipsychotic-sensitive manner (Mansbach et al 1988). Furthermore, the disruption of prepulse inhibition produced by amphetamine is prevented by central dopamine depletion (Swerdlow et al 1990). There is a dearth of studies examining amphetamine effects on gating measures in humans. In this study, we hypothesized that P50 suppression would be diminished after an amphetamine challenge in healthy normal subjects.
Methods and Materials Subjects Eleven healthy, normal men (age 21 to 36 years; mean ⫽ 26) were recruited from bulletin board advertisements at the New York State Psychiatric Institute (NYSPI). The subjects were part of a larger, randomized study, which examined the effects of catecholaminergic tone on smooth pursuit eye movements (SPEM) and other measures recorded on separate testing days at least 1 week apart. The SPEM data and experimental design have been previously published (Malaspina et al 1994). P50 data collected after the amphetamine and placebo challenge are reported in the present study. All subjects did not participate in all phases of the SPEM study. Therefore, P50 data was available for all 11 subjects who completed the amphetamine challenge. Additionally, 7 of the 11 subjects participated in both amphetamine and placebo conditions (these were counterbalanced) and the P50 data from this subset of subjects will be examined separately to control for potential order effects. Structured psychiatric interviews of subjects by staff physicians revealed no personal history of schizophrenia, affective or anxiety disorders, substance abuse, or current medication treatment (Malaspina et al 1994). Family history revealed no firstdegree relatives with schizophrenia. Axis II disorders were not assessed. All subjects had normal physical examinations and ECG evaluations. The study was approved by the NYSPI Institutional Review Board and all participants gave informed consent for the study.
Procedures Subjects were required to fast overnight prior to the test day. All test sessions began with a baseline P50 recording followed by the administration of the amphetamine or placebo challenge. Oral dextroamphetamine sulfate (.3 mg/kg free base dose) or oral placebo was administered and 2 hours later the P50 recording was repeated. A blood sample was taken for measuring amphetamine levels prior to ERP recording. Blood levels of amphetamine were similar among all participants (mean ⫽ 45 ng/mm, 2.0 SEM) and were “not detectable” after placebo administration. We expected that oral amphetamine would have a rapid onset (1 hour) and sustained effects over approximately 6 hours (Angrist
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et al 1987). Vital signs were monitored throughout the test day. Amphetamine induced mild elevations of systolic and diastolic blood pressure (⬍15 mm Hg) and pulse (⬍30 beats/minute) that resolved before discharge from the laboratory and required no treatment. None of the subjects became psychotic after the administration of the amphetamine. As previously reported by Malaspina and colleagues (1994), a retrospective review of clinical notes indicated that subjects in the amphetamine condition were more euphoric and talkative. Additionally, amphetamine resulted in an increased reporting of vigor and decreased ratings of fatigue using the Profile of Mood Scale documented in the abovementioned publication. The 7 subjects that participated in both phases (amphetamine and placebo challenges) of the experiment were retested after a 7-day “waiting period” following the initial session in order to ensure drug effect washout and reduce potential short-term practice effects. All subjects, technicians, and raters were blind to drug condition throughout the study. Subjects and research staff were told that the challenge could be either amphetamine or placebo and that the same condition could be repeated if they underwent the testing on a second day.
P50 Measures During the P50 evoked potential recordings, participants were seated in a comfortable recliner and instructed to relax with their eyes open and focused on a fixation point. Fifty 110 dB click pairs were presented every 10 sec with a 500 msec interclick interval. The stimuli were generated using computer-driven pulses with a .3 msec duration that were amplified with a Realistic SA-10 amplifier with the tone control at maximum treble. The output of this amplifier was fed to a Jensen X-20 speaker. Electrical responses were recorded with gold cup electrodes between the vertex and linked earlobes. A ground electrode was placed on the forehead. Eye movements and blinks were monitored with EOG recording. Resistance of all electrodes was less than 5 kohms. The evoked response was amplified with a Grass model 7P511J amplifier with a bandpass of .1 to 300 Hz, with no 60 Hz notch filter. The response was digitized at 1000 samples/ sec and individual trials were stored on a PDP-11/24 computer. Peak amplitudes and latencies were determined offline, blind to subject and condition. EEG and EOG channels were screened for artifact postacquisition and trials containing artifact (⫾ 75 V EOG or EEG channel) were not included in waveform averaging. Artifact-free epochs were averaged and digitally bandpass-filtered (5 to 50 Hz) in the frequency domain using the Scan Reader Station (Neurosoft Inc., Sterling, VA). The filter had 12 dB/octave high and low-pass slopes similar in gain characteristics reported by Jerger and colleagues (1992). The P50 component was identified in a manner consistent with previous studies (Clementz et al 1997b; Nagamoto et al 1989). The P50 was defined as the most positive deflection 40 to 80 msec following stimulus presentation. P50 amplitude was defined as the absolute difference between the P50 peak and the preceding negative trough. Evoked potential waveforms were
Table 1. P50 Measuresa
P50 Response to click 1 Amplitude Latency P50 Response to click 2 Amplitude Latency Percent P50 suppression
Baseline
Amphetamine
Baseline
Placebo
4.6 (3.4) 58.4 (7.3)
4.2 (3.0) 55.6 (4.5)
3.4 (2.2) 56.7 (4.2)
2.7 (2.3) 56.3 (6.2)
1.1 (1.2) 60 (6.3) 76.9 (17.8)
2.0 (1.3) 58.5 (5.1) 32.8 (40.1)
1.1 (1.0) 0.25 (.3) 61.8 (8.6) 55 (5.3) 70.8 (20.1) 87.2 (17.3)
a Means and standard deviations of P50 measures obtained from baselineamphetamine (n ⫽ 11) and the baseline-placebo (n ⫽ 7) phases of the experiment.
examined visually and latencies and amplitudes were recorded manually. Percent P50 suppression was calculated using the formula [(1 ⫺ S2 amplitude/S1 amplitude) ⫻ 100], as per our previously reported methods (Clementz et al 1997b; Clementz et al 1998a; Clementz et al 1998b; Judd et al 1992).
Statistical Analyses In addition to standard statistical tests, the following two measures of effect size were utilized for descriptive purposes: mean differences and standardized mean differences (d) (Cohen 1994). Multivariate solutions to within-subjects, repeated measures analyses (4 levels: session A: baseline, amphetamine; session B: baseline, placebo) were performed for the 7 subjects who completed both the amphetamine and placebo challenges. In each challenge condition, a baseline P50 recording was obtained. The following planned comparisons of P50 suppression were also conducted following omnibus session analysis: baseline versus amphetamine, baseline versus placebo, and amphetamine versus placebo. These first two comparisons contained data collected on the same day of testing. In contrast, the amphetamine versus placebo comparison used data obtained after at least a one week interval. In order to examine all available data from subjects who underwent an amphetamine challenge, the 4 additional subjects who completed only the amphetamine challenge were included (n ⫽ 11) in a separate follow-up analysis to determine if amphetamine elicited a significant disruption of P50 suppression in this larger (11 vs. 7) cohort. The rationale for this planned contrast was to examine all subjects with available P50 data from the amphetamine challenge and to increase the statistical power, if necessary, for this comparison.
Results There were no significant differences between P50 amplitudes or latencies across the different conditions. Table 1 provides means and standard deviations of the P50 variables. Using only the subset of 7 subjects who completed both drug challenge conditions, a within-subjects repeated measures analysis of variance revealed a significant difference in the 4 test sessions (baseline, amphetamine,
Amphetamine Disrupts P50 Suppression
Figure 1. Distributions of P50 suppression across the difference conditions. Significantly reduced P50 suppression occurred during the amphetamine challenge condition. Six of the 7 subjects showed a decrement of P50 suppression following the administration of amphetamine. In striking contrast, P50 suppression improved (or stayed the same) in 5 of the 7 subjects after placebo administration.
baseline, placebo) (F 3,4 ⫽ 7.4, p ⬍ .05). Planned follow-up analysis indicated that amphetamine induced a statistically significant disruption of P50 suppression compared to the initial baseline session (t 6 ⫽ 3.1, p ⬍ .05; mean difference in P50 suppression between 2 sessions ⫽ ⫺56%, d ⫽ ⫺3.44). A priori follow-up analysis of the placebo challenge condition failed to yield statistically significant differences on P50 latency, amplitude, or suppression between the baseline recording and placebo conditions. A direct comparison of P50 suppression in the placebo and amphetamine challenge conditions (both following an initial baseline recording session), however, revealed a significant amphetamine-induced disruption of
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P50 suppression (t 6 ⫽ 3.71, p ⬍ .01, mean difference in P50 suppression between 2 sessions ⫽ ⫺54.4%, d ⫽ ⫺3.14). The final planned comparison of the initial baseline recordings to the recordings obtained after the amphetamine challenge using all available subjects who completed this phase of the study (n ⫽ 11) yielded no appreciable differences in the outcome of the statistical analysis. As noted above, there was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t 10 ⫽ 3.15, p ⬍ .01, mean difference ⫽ ⫺44.1%, d ⫽ ⫺2.5) relative to the initial baseline P50 condition. A graphical depiction of the reduction in P50 suppression following the administration of the amphetamine and placebo challenges after baseline recordings is presented in Figure 1. Figure 2 provides the grand average event-related potential waveforms recorded during the different experimental conditions.
Discussion The results of this study indicate that amphetamine, an indirect monoaminergic agonist, disrupts P50 suppression in normal subjects. This decrement in the suppression measure is similar to the reduction observed in patients with schizophrenia (Clementz et al 1998b), and is consistent with data obtained from animal models of the effects of amphetamine on neural gating and central inhibition (Adler et al 1988; Adler et al 1986; Johnson et al 1998; Stevens et al 1991; Stevens et al 1996b; Stevens et al 1993). Thus, monoaminergic influences appear to modulate critical components of the neural systems underlying P50 suppression. An amphetamine-induced increase in noradrenergic transmission may explain the disruption of normal P50 suppression in this study. Johnson and Adler (1993) found that exposing normal subjects to a stressful situation, the
Figure 2. Grand average waveforms. The left panel contains the ERPs generated during the baseline conditions and the right panel contains waveforms generated during the amphetamine challenge conditions. In both graphs, the waveform with the solid line depicts the response to the first click and the dashed line is the response to the second click. The P50 component is the up-facing peak occurring in the 40 to 80 msec range as indicated by the arrow.
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cold-pressor test, transiently impaired P50 suppression. The cold-pressor task has been associated with increased noradrenergic neuronal transmission. Furthermore, administration of yohimbine, a presynaptic ␣2-antagonist that increases release of norepinephrine, also reduces P50 suppression in humans (Adler et al 1994) and N40 suppression in animals (Stevens et al 1993). The finding that amphetamine reduces P50 suppression in normal subjects is also consistent with evidence of dopaminergic modulation of gating mechanisms and may extend to the findings in schizophrenia. Evidence supporting the dopamine hypothesis stems from observations of increased or altered central dopaminergic transmission in schizophrenia and the fact that effective antipsychotic medications block dopamine receptors (Creese et al 1976; Creese et al 1996; Seeman et al 1976; Snyder 1976; Snyder 1977). D2-dopamine receptor antagonists reduce psychotic symptoms. Conversely, high doses of amphetamine in normal subjects may lead to psychotic symptoms similar to those observed in schizophrenia patients (Snyder 1973). Imaging studies of neuroleptic-naive patients with schizophrenia have also revealed increased dopaminergic outflow and a high occupancy of central D2dopamine receptors in patients who are treated with clinically effective doses of classical antipsychotic drugs (Farde 1997; Sedvall 1990; Sedvall 1992; Sedvall et al 1995; Wiesel 1989). Additionally, recent studies have indicated abnormal functioning of presynaptic dopaminergic neurons in schizophrenia patients (see Farde 1997 for a review). Stevens and colleagues (1996b) have investigated the role of dopamine receptors in N40 gating in the rat and concluded that “amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency [in gating] occurs through postsynaptic dopamine receptor activation.” In a recent review of P50 and nicotinic receptor functioning in patients with schizophrenia, Adler and colleagues (1998) argued that the fact that P50 suppression is not normalized in patients with schizophrenia by treatment with dopamine antagonist medications (Freedman et al 1983), suggests that the suppression deficit may not be accounted for by simple dopaminergic neuronal mechanisms. In contrast, the unique ability of clozapine to restore the suppression deficit in patients with schizophrenia (Nagamoto et al 1996; Nagamoto et al 1999) points to the potential role of more complex neurotransmitter system interactions. Adler and colleagues speculated that the normalizing effect of clozapine on P50 suppression in patients with schizophrenia may be due to a cascade of neurotransmitter mechanisms affecting nicotinic-cholinergic or serotonergic receptors. A rodent study of N40 using depth electrodes in different brain regions has indicated that the generation
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and suppression of this middle latency component occurs in the CA3 region of the hippocampus (Bickford-Wimer et al 1990). The hippocampal recordings also revealed that N40 suppression was disrupted by amphetamine and that the effect of amphetamine could be reversed by haloperidol. The responses recorded in the CA3 region behaved similarly to the recordings made at the scalp, supporting the notion that in rodents and humans, respectively, the N40 and P50 may be generated by the CA3 region of the hippocampus. The finding of hippocampal involvement in the suppression of middle latency ERP components in response to auditory stimuli was supported further by studies of inbred mouse strains (Stevens et al 1996a). The effects of amphetamine are no doubt due to complex interactions between the monoamines released by amphetamine and other circuitry, such as the hippocampal– acetylcholine system. This study is limited by its inclusion of only male subjects, since gender is known to be a significant source of variance in the phenomenology of schizophrenia (see Canuso et al 1998; Salem and Kring 1998). Furthermore, gender differences have been observed in inhibitory gating paradigms with females showing less P50 suppression (Hetrick et al 1996) and less prepulse inhibition of startle (Swerdlow et al 1993). The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. Furthermore, while P50 suppression is trait-related in schizophrenia, data indicate that it is state-related in other psychiatric disorders (Baker et al 1987; Baker et al 1990; Franks et al 1983). The findings presented in this paper are consistent with several careful examinations of suppression deficits in rodent models that have implicated monoaminergic regulation of P50 ERP suppression. Because amphetamine has relatively nonspecific effects on monoaminergic neurotransmitter systems, future research should focus on the effects of more selective pharmacologic agents on P50 suppression. Still, whatever the putative underlying mechanisms may be, these findings confirm that amphetamine induces a deficit in P50 suppression in normal subjects that is similar to the deficits seen in patients with schizophrenia. Future drug challenge studies may enable us to gain further insights into the neurobiologic basis of P50 suppression in normal and schizophrenic subjects.
This work was supported in part by grants from the National Institute of Mental Health awarded to DM (1 KO7 MH00824) and to DB and MG (5-R37-MH42228), as well as VISN 22 Mental Illness, Research, Education, and Clinical Center (MIRECC) support (DB, MG) from the Veteran’s Administration.
Amphetamine Disrupts P50 Suppression
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noradrenergic modulation of amphetamine-induced changes in auditory gating. Brain Res 555:91–98. Stevens KE, Luthman J, Lindqvist E, Johnson RG, Rose GM (1996b): Effects of neonatal dopamine depletion on sensory inhibition in the rat. Pharmacol Biochem Behav 53:817– 823. Stevens KE, Meltzer J, Rose GM (1993): Disruption of sensory gating by the alpha 2 selective noradrenergic antagonist yohimbine. Biol Psychiatry 33:130 –132. Swerdlow NR, Auerbach P, Monroe SM, Hartston H, Geyer MA, Braff DL (1993): Men are more inhibited than women by weak prepulses. Biol Psychiatry 34:253–260. Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990): Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology 100:413– 416. Waldo M, Myles-Worsley M, Madison A, Byerley W, Freedman R (1995): Sensory gating deficits in parents of schizophrenics. Am J Med Genet 60:506 –511. Waldo MC, Adler LE, Freedman R (1988): Defects in auditory sensory gating and their apparent compensation in relatives of schizophrenics. Schizophr Res 1:19 –24. Waldo MC, Carey G, Myles-Worsley M, et al (1991): Codistribution of a sensory gating deficit and schizophrenia in multi-affected families. Psychiatry Res 39:257–268. Waldo MC, Cawthra E, Adler LE, et al (1994): Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings. Schizophr Res 12:93– 106. Ward PB, Hoffer LD, Liebert BJ, Catts SV, O’Donnell M, Adler LE (1996): Replication of a P50 auditory gating deficit in Australian patients with schizophrenia. Psychiatry Res 64: 121–135. Wiesel FA (1989): Positron emission tomography in psychiatry. Psychiatr Dev 7:19 – 47.