Psychopharmacology (1991) 105 :247-252 003331589100202M
Psychopharmacology
© Springer-Verlag 1991
Mood responses of remitted schizophrenics to methylphenidate infusion Delbert Robinson, 1' 2 David Mayerhoff, 1' 2 Jose Alvir, 1 T o m Cooper, 3 and Jeffrey Lieberman a' z 1 Department of Psychiatry, P.O. Box 38, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, NY 11004, USA 2 Department of Psychiatry, Albert Einstein College of Medicine, New York, NY, USA 3 New York State Psychiatric Institute, New York, NY, USA Received March 26, 1990 / Final version February 12, 1991
Abstract. To investigate the mood response of schizoph-
renic subjects to psychostimulant challenge, 29 neuroleptic-treated subjects (22 with schizophrenia and 7 with schizoaffective disorder) in clinical remission received two infusions, one with methylphenidate 0.5 rag/ kg and the other with normal saline, under double-blind conditions. Twenty-five of these subjects were withdrawn from neuroleptics and given a second set of double-blind infusions. Infusion mood responses were classified as euphoric, neutral, mixed or dysphoric. Subjects were also rated as either psychotic symptom activators to the infusion or no change in psychotic symptoms. Overall response by mood category was as follows: 35.2% euphoric, 50% neutral, 5.6% mixed and 9.3% dysphoric. Mood responses were not correlated with sex, methylphenidate plasma levels or diagnostic distinctions between schizophrenia and schizoaffective disorder. Although they occurred infrequently, dysphoric and mixed mood responses were associated with high rates of psychotic activation. Comparing subjects on and off neuroleptics, subjects on neuroleptics had more euphoric responses than the same subjects off neuroleptics. This increased number of euphoric responses in subjects taking neuroleptics compared to off neuroleptics suggests that neuroleptic treatment status may be an important factor in assessing psychostimulant use in schizophrenia patients. Key words: Psychostimulants - Methylphenidate - Schizophrenia - Schizoaffective disorder - Mood response - Catecholamines
Psychostimulant drugs produce agonistic effects on catecholamine neurotransmission by releasing biogenic amines from storage sites in presynaptic nerve terminals and blocking their reuptake (Scheel-Kruger 1971 ; Ferris et al. 1972; Groves and Rebec 1976, Moore 1978). Within this group of compounds, there are differences in bioOffprint requests to: D. Robinson
chemical effects. Methylphenidate exerts its effects by releasing catecholamines from reserpine-sensitive stores while amphetamine mainly releases catecholamines from a smaller cytosolic reserpine-insensitive pool (ScheelKruger 1971, Chieuh and Moore 1975a, b). Also, compared to amphetamine, methylphenidate preferentially releases dopamine over norepinephrine in the rat (Ferris et al. 1972). Because of these known biochemical effects on neurotransmission, psychostimulants have been used as pharmacologic probes of psychiatric disorders. The rationale underlying this strategy is that behavioral changes following psychostimulant administration must be related to the biochemical effects of the psychostimulant. By observing which, if any, aspects of a disorder change after psychostimulant administration, one can make hypotheses about the role of catecholamine systems in the disorder studied. In schizophrenia research, psychostimulants have been used primarily to study the pathophysiologic mechanisms of psychosis. The ability of chronic psychostimulant usage to produce a psychotic syndrome resembling paranoid schizophrenia in normal subjects (Connetl 1958; Angrist and Gershon 1970; Griffith et al. 1972; Bell 1973) has been used to support the hypothesis that dopamine overactivity in the central nervous system is present in schizophrenia (Snyder 1973; Meltzer and Stahl 1976). Additional support for this hypothesis is the finding that approximately 40% of schizophrenic subjects have a psychotogenic response to acute doses of psychostimulants which do not provoke psychotic symptoms in normals (Lieberman etal. 1987a). The effects of psychostimulants on mood have been studied mostly in normal subjects and patients with affective disorders. In normals, psychostimulant challenge predominantly produces feelings of well-being, elation, vigor and talkativeness although depression and sedation occur in some subjects (Brown 1977; Smith and David 1977; Dommisse et al. 1984). Similarly, euthymic bipolar subjects predominantly respond to psychostimulant challenge with activation and euphoric mood (Wald et al. 1978; Silberman et at. 1981 ; Meyen-
248 d o r f f et al. 1985). In subjects with m a j o r d e p r e s s i o n , m o o d r e s p o n s e s to p s y c h o s t i m u l a n t challenge h a v e been r e p o r t e d r a n g i n g f r o m elevated m o o d to n o effect to d y s p h o r i a . ( S i l b e r m a n et al. 1981; B r o w n a n d B r a w l e y 1983; Sabelli et al. 1983; Joyce et al, 1986; B a x t e r et at. 1988). G i v e n the m o o d effects o f p s y c h o s t i m u l a n t s in n o r m a l subjects a n d affective d i s o r d e r p a t i e n t s , we exa m i n e d the m o o d r e s p o n s e o f s c h i z o p h r e n i c s in remission to a p s y c h o s t i m u l a n t challenge with i n t r a v e n o u s m e t h y l p h e n i d a t e . We also w i s h e d to e x a m i n e the relat i o n s h i p b e t w e e n the p s y c h o t o g e n i c a n d m o o d a l t e r i n g p r o p e r t i e s o f m e t h y l p h e n i d a t e in this p o p u l a t i o n .
Materials and methods The inclusion criteria and methylphenidate infusion procedure used in this study have been described in a previous communication (Lieberman et al. 1987b). In summary, subjects for this study were medically healthy outpatients aged 18-50 years old who fulfilled Research Diagnostic Criteria (Spitzer et al. 1977) for schizophrenia or schizoaffective disorder, mainly schizophrenic. Prior to the methylphenidate infusion, all subjects had been in a state of remission for at least 6 months while on neuroleptic maintenance treatment. Criteria for being in remission were: 1) a rating of no greater than 2 on either the severity of delusions or on the severity of hallucinations items on the Schedule for Affective Disorders and Schizophrenia - Psychosis and Disorganization (SADS+PD) (Spitzer and Endicott 1978) scale, 2)a rating no greater than 3 on the S A D S + P D items for incoherence or for bizarre behavior, 3) catatonic motor behavior not present, and 4) the sum of the scores on factors III, IV and V of the Brief Psychiatric Rating Scale (BPRS) (Overall and Gotham 1962) of less than 24. Each subject while on neuroleptics received two infusions, one of methylphenidate and one of placebo, I week apart in a randomized order under double-blind conditions. Each subject then had a second set of infusions, again with methylphenidate and placebo, under double-blind conditions, after their neuroleptics had been stopped and they had been drug-free for 20 days (or 40 days if they had been on long-acting injectable neuroleptics). Subjects for this study included those subjects in our previous report who had both sets of infusions in addition to some subjects who completed the protocol after the submission of our previous report. All infusion procedures followed the same protocol. At 8:30 a.m., subjects were brought to a special procedures room. They were put into a supine position on a hospital bed and an indwelling catheter was inserted into a forearm vein. During the next ]05 min, the subject was assessed with a variety of rating instruments including the SADS÷PD, BPRS, Taylor and Abrams scale for emotional blunting and Clinical Global Impression Scale. After this preinfusion baseline, subjects were given either 0.5 mg/kg methylphenidate or an equivalent volume of saline solution by intravenous push over a period of 120 s. Subjects were interviewed formally and observed continuously for 80 rain following the infusion. Subjects were then rated for peak response during the post infusion period using the SADS+PD, BPRS and Taylor and Abrams scale. Further, a written narrative of the subject's response during the entire procedure was recorded. The infusion procedure, rating scales and narrative were all done by one of the authors (JAL). During the infusion procedure, blood was collected at three intervals for methylphenidate levels. These samples were collected at 20 rain, 60 min and 80 rain after the double-blind methylphenidate infusion. Samples were collected in ammonium and potassium oxalate tubes, spun for 15 min and the plasma frozen at - 2 0 ° centigrade pending assay. Methylphenidate levels were determined by gas chromatography using a modification of the technique of Hungund et al. (1978). Two of the authors (DR and DM) who were not present during the infusion procedures independently classified each subject's re-
sponse to the infusion on the dimensions of psychotic activation and mood response. These were based on comparisons of subjects' preinfusion baseline states with their postinfusion responses to active methylphenidate. Data used to make these determinations were the infusion narrative summaries and the BPRS ratings. BPRS items used to assess psychotic activation were conceptual disorganization, grandiosity, suspiciousness, hallucinatory behavior and unusual thought content. Items used to assess mood change were guilt feelings, grandiosity, depressive mood and excitement. For psychotic symptoms, subjects were rated as either psychotic symptom activators to the infusion or no change in psychotic symptoms. Mood responses to the infusion were classified as either euphori= responses, neutral (i.e., no change), dysphoric responses or mixed (combining euphoric and dysphoric symptoms) responses. We classified subjects' responses by these categories instead of using only the BPRS ratings because this allowed us to integrate the rating scale data with the narrative summaries. In assessing mood changes, we thought that the narrative summaries could provide important information about the timing and the clinical intensity of mood changes which might be lost if we used only the BPRS ratings. The classifications reported are a consensus rating of infusion response made jointly by DR and DM.
Results T w e n t y - n i n e subjects c o m p l e t e d the first set o f infusions with m e t h y l p h e n i d a t e a n d p l a c e b o while o n neuroleptics. W h e n w i t h d r a w n f r o m n e u r o l e p t i c s , f o u r subjects h a d a r e l a p s e o f their p s y c h o t i c s y m p t o m s before t h e y were s c h e d u l e d to h a v e the s e c o n d set o f infusions. These subjects were n o t given the s e c o n d set o f infusions. Thus, 25 subjects h a d b o t h sets o f i n f u s i o n s (one set while o n n e u r o l e p t i c s a n d o n e set while o f f neuroleptics). T h e original s a m p l e o f 29 subjects ( 5 5 % male) h a d a m e a n ( ± S D ) age o f 30.1 +_6.8 years. T w e n t y - t w o subjects h a d a d i a g n o s i s o f s c h i z o p h r e n i a , five h a d a d i a g n o s i s o f schizoaffective d i s o r d e r , d e p r e s s e d t y p e a n d two h a d a d i a g n o s i s o f schizoaffective d i s o r d e r , m a n i c t y p e b y Research D i a g n o s t i c C r i t e r i a ( R D C ) . B o t h schizoaffective g r o u p s were classified as m a i n l y s c h i z o p h r e n i c u n d e r R D C . Subjects were s t u d i e d relatively early in the course o f their illness with a m e a n ( ± S D ) age at first h o s p i t a l i z a t i o n o f 2 3 . 7 + 4 . 7 years. Subjects h a d h a d a m e a n (_+ SD) o f 3.1 + 2.3 h o s p i t a l i z a t i o n s . A l l subjects were stable a n d f u n c t i o n i n g in the c o m m u n i t y with a m e a n ( ± S D ) d u r a t i o n o f r e m i s s i o n p r i o r to the first i n f u s i o n o f 2 7 . 7 _ 16.6 weeks. Subjects' r e s p o n s e s to the infusions are p r e s e n t e d in Fig. 1. A s c a n be seen in this figure, the overall m o o d responses o f the subjects were v a r i a b l e with the p r e d o m i n a n t r e s p o n s e s b e i n g either e u p h o r i c o r n e u t r a l with m u c h fewer m i x e d o r d y s p h o r i c responses. Overall, 29 p a t i e n t s u n d e r w e n t a t o t a l o f 54 infusions. O f the responses, 35.2% were e u p h o r i c , 5 0 % were neutral, 5.6% were m i x e d a n d 9 . 3 % were d y s p h o r i c . O f the 25 p a t i e n t s w h o u n d e r w e n t b o t h sets o f infusions, 11 ( 4 4 % ) p a t i e n t s h a d the s a m e r e s p o n s e to b o t h a n d 14 ( 5 6 % ) p a t i e n t s c o n v e r t e d their r e s p o n s e ( f r o m e u p h o r i c to n e u t r a l etc.). We e x a m i n e d several v a r i a b l e s to d e t e r m i n e their relat i o n s h i p to the m o o d responses o f p a t i e n t s (Table 1). T h e first o f these was the r e l a t i o n s h i p b e t w e e n p s y c h o t i c a c t i v a t i o n a n d m o o d r e s p o n s e to the infusion. T h e r e
249 was a significant association between psychotic activation (present or absent) and m o o d response (euphoric, neutral, mixed, dysphoric) in the data from all 54 infusions (Fisher's Exact Test, 2-tailed, P = 0 . 0 1 2 ) and from infusions with subjects on neuroleptics (Fisher's Exact Test, 2-tailed, P = 0.049). Further, there was a trend towards an association between psychotic activation and m o o d response in infusions with subjects off of neu-
Mood Response:
roleptics (Fisher's Exact Test, 2-tailed, P = 0.059). Examining all infusions, the categories o f euphoric or neutral m o o d responses had more subjects who experienced psychotic activation than did the categories o f mixed or dysphoric m o o d response. However, although infrequently occurring compared to euphoric or neutral m o o d responses, mixed and dysphoric m o o d response had a high percentage (100% and 60%, respectively) of subjects with psychotic activation. Post hoc, we dichotomized m o o d response into responses with a dysphoric component (combining mixed and dysphoric response) and responses without a dysphoric component (combining euphoric and neutral responses). Using these categories, there was a significant association between psychotic activation and m o o d responses with a dysphoric component for infusions with subjects on neuroleptics (Fisher's Exact Test, 2-tailed, P = 0.015) and for all infusions (Fisher's Exact Test, 2-tailed, P = 0 . 0 1 2 ) but not for infusions with subjects off neuroleptics (Fisher's Exact Test, 2-tailed, P = 0.358). We next considered the possibility that the high rates o f psychotic activation in subjects with mixed or dysphoric m o o d response could be the result o f the distressing effects of psychotic symptoms producing dysphoric feelings in some subjects. If this occurred, subjects who had psychotic activation and mixed or dysphoric m o o d responses to one infusion should on the other infusion either have had a pattern of: 1) consistent psychotic activation with mixed or depressed mood, or 2) no psychotic activation with an euphoric or neutral m o o d response. Only three of the six subjects who had psychotic activation and a mixed or dysphoric m o o d response to one o f the infusions had this pattern of response. Of the other three subjects, two had psychotic activation and a dysphoric response on one infusion and psychotic activation and a neutral response on the other infusion and one subject had psychotic activation on both infusions but a euphoric response on one infusion and a dysphoric response to the other infusion. Besides the effects of psychotic activation, we also examined diagnostic subtypes in relation to m o o d responses but found no distinctive pattern of m o o d responses to the infusions by diagnosis. There also was
Off Neuroleptics (Patient Number)
On Neuroleptics (Patient Number)
E~oric
Neutral
DFs~horie
27 Fig. 1. Infusion responses. (*) Patients with psychotic activation Table 1. Infusion responses
Psychotic activation RDC diagnosis: Schizophrenia Schizoaffective, depressed Schizoaffective, manic Sex: male female
Neutral responses
On neuroleptics N=13
Off neuroleptics N=6
On neuroleptics N=13
3
4
2
3
1
2
2
1
9
5
10
10
t
1
2
2
4
1
1
3
-
2
1
3 3
6 7
9 5
1 -
1 1
2 -
3
7 6
Number of responses in each category
Mixed responses
Dysphoric responses
Euphoric responses
Off On Off On Off neuroleptics neuroleptics neuroleptics neuroleptics neurolepfics N=I4 N=I N=2 N=2 N=3
250 Table 2, Methylphenidate ptasma levels
20 rain sample
60 min sample
80 min sample
On neuroleptics
Off neuroleptics
On neuroleptics
Off neuroteptics
On neuroleptics
Off neuroleptics
Mood response: Euphoric responses Neutral responses Mixed responses Dysphoric responses
131.0 + 41.8 99.8 + 38.9 98.0+_46.7
105.5 _+53.6 144.3 _+41.7 132.0_+ 0.0 112.5_+ 2.1
82.3 _+18.1 80.3 _+34.6 69.0+_21.2
65.7-+ 27.1 94.3 _+29.7 83.0± 0.0 68.0_+ 1.4
66.0 _+11.7 72.2 _+33.1 55.5_+ 10.6
56.5 + 15.0 75.0 _+23.8 71.0_ 0.0 59.0_+ 12.7
Psychotic activation: No psychotic activation Psychotic activation Total sample
117.9_+42.9 94.7±33.5 114.8 _+42.1
143.9+__32.4 98.8_+46.1" 129.1 _+43.9
82.9-1-_27.0 67.3_+ 1 5 . 3 81.4 _+27.0
94.4-+24.0 64.2_+23.4** 83.9 _+28.3
70.0+24.8 56.7± 7.8 67.8 _+23.5
74.3-+19.5 54.2_+15.3'** 68.5 +_20.3
Mean (-+ standard deviation) in ng/ml * No psychotic activation versus psychotic activation, SS = 6534.7, df= 1, F= 4.65, P= 0.053 ** No psychotic activation versus psychotic activation, SS = 2801.6, df= t, F= 4.96, P = 0.048 *** No psychotic activation versus psychotic activation, SS = 1302.9. df= 1, F= 3.94, P= 0.070 no relationship between sex and mood response or sex and psychotic activation from methylphenidate infusion in either the on or off neuroleptic conditions. The effects of methylphenidate plasma levels on mood responses and psychotic activation are presented in Table 2. In 14 subjects blood samples for methylphenidate assay were collected at 20, 60 and 80 rain after methylphenidate infusion. Peak methylphenidate levels occurred at the first sample in all but one patient. Analyses of the peak and overall methylphenidate levels (using all three samples) o f patients by mood response and psychotic activation revealed no significant relationships between methylphenidate levels and mood response on and off neuroleptics or psychotic activation while on neuroleptics. Off neuroleptics, subjects with psychotic activation had significantly lower 60-min methylphenidate levels and a trend toward lower 20- and 80-min methylphenidate levels compared to subjects without psychotic activation. Next, we looked at the effect of neuroleptic condition on methylphenidate levels. At all three time points sampled, there were no significant differences in methylphenidate levels between the on and off neuroleptic conditions. Finally, we examined the effects of neuroleptic condition on m o o d responses to the infusions. O f the 25 subjects who had infusions both on and offneuroleptics, 13 (52%) had a euphoric response on neuroleptics while only 6 (24%) had a euphoric response off neuroleptics (X 2 =6.96, df= 1, P=0.008). This neuroleptic effect on m o o d response to methylphenidate is in contrast to the lack of a significant effect of neuroleptic condition on psychotic activation (7 of 25 subjects on neuroteptics were psychotic activators and 10 of 25 subjects off neuroleptics were psychotic activators, ( X ~ 1.94, df= 1, P = 0 . 1 6 ) . Discussion
Our primary finding was an overall variability in the mood responses of stable schizophrenic subjects to methylphenidate infusion with the predominant responses being either euphoric or neutral. This heterogeneity of
m o o d response to psychostimulant challenge is consistent with the variability in m o o d response seen in subjects with other psychiatric disorders such as depression (Silberman et al. 1981 ; Sabelli et al. 1983; Brown and Brawley 1983; Joyce 1986). Although infrequent compared to euphoric or neutral m o o d responses, mixed and dysphoric responses were associated with a high rate of psychotic activation. Some o f the subjects with mixed or dysphoric responses and psychotic activation had a pattern of response to both infusions consistent with the hypothesis that the distressing experience o f psychotic symptoms may have contributed to a dysphoric mood state. However, an equal number of subjects had a pattern of response inconsistent with this. Also contrary to the hypothesis that psychotic symptoms produced dysphoric feelings in subjects is our finding that in 12 o f the 18 (66.7%) instances of psychotic activation subjects had a euphoric or neutral m o o d response. Since neuroleptic pretreatment has been reported to reduce or abolish the euphoric and activating responses of euthymic bipolar subjects to methylphenidate infusion (Wald et al. 1978) and the cocaine " h i g h " in volunteer cocaine addicts given intravenous cocaine, (Sherer 1988), we had anticipated fewer euphoric responses in our subjects while on neuroleptics than when off neuroleptics. To explain the larger number of euphoric responses in our subjects when on compared to off neuroleptics, we initially hypothesized that the euphoric subjects on neuroleptics might have had a neuroleptic-induced dysphoric, apathetic or akinetic state which methylphenidate counteracted. A second review of the euphoric subjects' infusion records showed this to be unlikely, since the infusion records described substantial activation, elevation in m o o d and disinhibition in the euphoric subjects. A second possibility is that methylphenidate was producing a therapeutic effect on negative symptoms as has been previously reported (Angrist et at. 1982). However, if this was the case, we would have expected to see a similar or greater reduction in negative symptoms in the off neuroleptic condition which was not the case. Third, we also considered the possibility that a pharmacokinetic
251 effect of neuroleptics on methylphenidate plasma levels could have influenced the number of euphoric responses on neuroleptics. Analysis of the methylphenidate levels, however, showed no significant differences in methylphenidate levels in the on or off neuroleptic condition. Finally, we hypothesized that the differences in number of euphoric responses on and off neuroleptics might represent a partial attenuation by neuroleptics of methylphenidate's effects. Examining mood response as a function of dose of psychostimulant given, psychostimulants have been reported to produce more pure euphoric responses at lower doses and more mixed or dysphoric responses at higher doses (Angrist 1983; Post and Contel 1983). Thus, if neuroleptic treatment partially attenuated the mood effects of methylphenidate, subjects could have more euphoric responses on neuroleptics than off neuroleptics because of a suppression of dysphoric or mixed responses by neuroleptics. However, if this were the case, one would expect that subjects who converted from a euphoric response on neuroleptics to another mood response off neuroleptics would tend to have more dysphoric or mixed responses to the infusion off neuroleptics. This did not happen in our sample. Of the eight subjects who converted from a euphoric response on neuroleptics to another mood response pattern off neuroleptics, six (75%) had a neutral response and only two (25%) had a mixed response. One possible explanation for the discrepancy between our findings and the effects of neuroleptic pretreatment on mood response to psychostimulant challenges in bipolar subjects and cocaine addicts is the length of neuroleptic treatment. In both the studies of Wald et al. and Sherer, haloperidol was given as a single dose before psychostimulant administration. In contrast, our subjects when on neuroleptics had been taking them for long periods of time as treatment for their psychotic symptoms. If chronic neuroleptic treatment induced neurotransmitter changes different from those of acute treatment, chronic neuroleptic treatment in our subjects could have produced neurotransmitter changes which resulted in differences in mood response compared to that of acute neuroleptic treatment. The larger number of euphoric responses to methylphenidate in our subjects while on neuroleptics as compared to off neuroleptics has implications for our understanding of psychostimulant use in schizophrenic patients. Chronic neuroleptic treatment may influence psychostimulant use in schizophrenic subjects in a variety of ways, including producing a dysphoric or akinetic state which the patient may try to counteract with psychostimulant use. Besides these effects, our study suggests that neuroleptic treatment may also modify schizophrenic subjects' mood responses to psychostimulants compared to their off neuroleptic responses. If neuroleptic treatment is associated with more euphoric responses to psychostimulants than the off neuroleptic condition, neuroleptic treatment status may be an important factor in assessing psychosfimulant use in schizophrenic patients. In evaluating our findings, several aspects of our study must be considered. First, our sample size, al-
though large compared to most previous psychostimulant challenge studies, was small enough to decrease our power to detect differences in some of our comparisons. Second, our use of the categories of euphoric, neutral, dysphoric or mixed mood changes as the end point measures of mood response may have obscured relationships which could have been detected with continuous variables. However, in our case, we chose to use the categorical end points because they corresponded to clinically meaningful states and because they allowed us to integrate information from written accounts of the infusion with information from a standard rating scale, the BPRS. Third, our assessments were all done by a clinician rater. The results of subjects self-ratings may have been different. Fourth, in our study, we assessed mood for the predominant response over the entire 80 min observation period after methylphenidate was given. The observation period used is important in comparing our results to previous studies given the effects of time from administration on mood responses elicited by psychostimulants (Checkly 1978; Nunnberger et al. 1982). Finally, we did not test for the reproducibility of mood response to active methylphenidate given on different occasions to the same subject while on the same medication regime. This information would have been useful in assessing our results. However, in designing a study, the need for information must be weighed against the potential adverse effects, both physical and psychological, to subjects from each procedure. In this study, subjects were tested both on and off neuroleptics. We did not think that the increased knowledge to be acquired justified the risks to subjects of serial methylphenidate infusions both on and off neuroleptics in this first study. Given our results, however, a future study designed specifically to test the reproducibility of mood response in schizophrenic subjects to methylphenidate would be of interest. In summary, subjects in our study had heterogeneous mood responses to methylphenidate infusion. Mood responses were not correlated with sex, methylphenidate plasma levels or diagnostic distinctions between schizophrenia or schizoaffective disorder. Although they occurred infrequently, dysphoric and mixed mood responses were associated with high rates of psychotic activation. Comparing subjects on and off neuroleptics, subjects on neuroleptics had more euphoric responses than the same subjects off neuroleptics. Future studies of mood response in schizophrenics to methylphenidate are warranted to extend our findings and to clarify the mechanisms of mood regulation in schizophrenic disorders. Acknowledgements. We wish to thank Paul Bermanzohn, MD, Bruce Kinon, MD and Anthony Loebel, MD tbr their suggestions in the preparation of this manuscript.
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(1986) Endocrine and behavioral responses to methylphenidate in depression. Psychol Med 16: 531-540 Lieberman JA, Kane JM, Alvir J (1987a) Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 91:415-433 Lieberman JA, Kane JM, Sarantakos S, Gadaleta D, Woerner M, Alvir J, Ramos-Lorenzi J (1987b) Prediction of relapse in schizophrenia. Arch Gen Psychiatry 44:59%603 Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2:t9-76 Meyendorff E, Lerer B, Moore NC, Bow J, Gershon S (1985) Methylphenidate infusion in euthymic bipolars: effect of carbamazepine pretreatment. Psychiatry Res 16:303-308 Moore KE (1978) The actions of amphetamine on neurotransmitters: a brief review. Biol Psychiatry 12: 451-462 Nunnberger JI, Gershon ES, Simmons S, Ebert M, Kessler LR, Dibble ED, Jimerson SS, Brown GM, Gold P, Jimerson DC, Guroff J J, Storch FI (1982) Behavioral, biochemical and neuroendocrine responses to amphetamine in normal twins and "well-state" bipolar patients. Psychoneuroendocrinology 7:163-176 Overall J, Gorham D (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10 : 149-165 Post RM, Contel NR (1983) Human and animal studies of cocaine: implications for development of behavioral pathology. In: Creese I (ed) Stimulants: neurochemical, behavioral, and clinical perspectives. Raven Press, New York, pp 169-203 Sabelli HC, Fawcett J, Javaid JI, Bargi S (1983) The metbylphenidate test for differentiating desipramine-responsive from nortriptyline-responsive depression. Am J Psychiatry 140: 212-214 Scheel-Kruger J (1971) Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the cathecholamines in the brain. Eur J Pharmacol 14:47-59 Sherer MA (1988) Intravenous cocaine: psychiatric effects, biological mechanisms. Biol Psychiatry 24:865-885 Silberman EK, Reus VI, Jimerson DC, Lynott AM, Post RM (1981) Heterogeneity of amphetamine response in depressed patients. Am J Psychiatry 138:1302-1307 Smith RC, Davis JM (1977) Comparative effects of d-amphetamine, /-amphetamine and methylphenidate on mood in man. Psychopharmacology 53 : 1-12 Snyder SH (1973) Amphetamine psychosis: a "model" schizophrenia mediated by catecholamines. Am J Psychiatry 130:61-67 Spitzer RL, Endicott J (1978) Schedule for affective disorders and schizophrenia - psychosis and disorganization scale. New York State Psychiatric Institute, New York Spitzer RL, Endicott J, Robbins E (1977) Research Diagnostic Criteria (RDC) for a selected group of functional disorders, 3rd ed. New York State Psychiatric Institute, New York Wald D, Ebstein RP, Belmaker RH (1978) Haloperidol and lithium blocking of the mood response to intravenous methylphenidate. Psychopharmacology 57: 83-87
Psychopharmacology
© Springer-Verlag 1991
Mood responses of remitted schizophrenics to methylphenidate infusion Delbert Robinson, 1' 2 David Mayerhoff, 1' 2 Jose Alvir, 1 T o m Cooper, 3 and Jeffrey Lieberman a' z 1 Department of Psychiatry, P.O. Box 38, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, NY 11004, USA 2 Department of Psychiatry, Albert Einstein College of Medicine, New York, NY, USA 3 New York State Psychiatric Institute, New York, NY, USA Received March 26, 1990 / Final version February 12, 1991
Abstract. To investigate the mood response of schizoph-
renic subjects to psychostimulant challenge, 29 neuroleptic-treated subjects (22 with schizophrenia and 7 with schizoaffective disorder) in clinical remission received two infusions, one with methylphenidate 0.5 rag/ kg and the other with normal saline, under double-blind conditions. Twenty-five of these subjects were withdrawn from neuroleptics and given a second set of double-blind infusions. Infusion mood responses were classified as euphoric, neutral, mixed or dysphoric. Subjects were also rated as either psychotic symptom activators to the infusion or no change in psychotic symptoms. Overall response by mood category was as follows: 35.2% euphoric, 50% neutral, 5.6% mixed and 9.3% dysphoric. Mood responses were not correlated with sex, methylphenidate plasma levels or diagnostic distinctions between schizophrenia and schizoaffective disorder. Although they occurred infrequently, dysphoric and mixed mood responses were associated with high rates of psychotic activation. Comparing subjects on and off neuroleptics, subjects on neuroleptics had more euphoric responses than the same subjects off neuroleptics. This increased number of euphoric responses in subjects taking neuroleptics compared to off neuroleptics suggests that neuroleptic treatment status may be an important factor in assessing psychostimulant use in schizophrenia patients. Key words: Psychostimulants - Methylphenidate - Schizophrenia - Schizoaffective disorder - Mood response - Catecholamines
Psychostimulant drugs produce agonistic effects on catecholamine neurotransmission by releasing biogenic amines from storage sites in presynaptic nerve terminals and blocking their reuptake (Scheel-Kruger 1971 ; Ferris et al. 1972; Groves and Rebec 1976, Moore 1978). Within this group of compounds, there are differences in bioOffprint requests to: D. Robinson
chemical effects. Methylphenidate exerts its effects by releasing catecholamines from reserpine-sensitive stores while amphetamine mainly releases catecholamines from a smaller cytosolic reserpine-insensitive pool (ScheelKruger 1971, Chieuh and Moore 1975a, b). Also, compared to amphetamine, methylphenidate preferentially releases dopamine over norepinephrine in the rat (Ferris et al. 1972). Because of these known biochemical effects on neurotransmission, psychostimulants have been used as pharmacologic probes of psychiatric disorders. The rationale underlying this strategy is that behavioral changes following psychostimulant administration must be related to the biochemical effects of the psychostimulant. By observing which, if any, aspects of a disorder change after psychostimulant administration, one can make hypotheses about the role of catecholamine systems in the disorder studied. In schizophrenia research, psychostimulants have been used primarily to study the pathophysiologic mechanisms of psychosis. The ability of chronic psychostimulant usage to produce a psychotic syndrome resembling paranoid schizophrenia in normal subjects (Connetl 1958; Angrist and Gershon 1970; Griffith et al. 1972; Bell 1973) has been used to support the hypothesis that dopamine overactivity in the central nervous system is present in schizophrenia (Snyder 1973; Meltzer and Stahl 1976). Additional support for this hypothesis is the finding that approximately 40% of schizophrenic subjects have a psychotogenic response to acute doses of psychostimulants which do not provoke psychotic symptoms in normals (Lieberman etal. 1987a). The effects of psychostimulants on mood have been studied mostly in normal subjects and patients with affective disorders. In normals, psychostimulant challenge predominantly produces feelings of well-being, elation, vigor and talkativeness although depression and sedation occur in some subjects (Brown 1977; Smith and David 1977; Dommisse et al. 1984). Similarly, euthymic bipolar subjects predominantly respond to psychostimulant challenge with activation and euphoric mood (Wald et al. 1978; Silberman et at. 1981 ; Meyen-
248 d o r f f et al. 1985). In subjects with m a j o r d e p r e s s i o n , m o o d r e s p o n s e s to p s y c h o s t i m u l a n t challenge h a v e been r e p o r t e d r a n g i n g f r o m elevated m o o d to n o effect to d y s p h o r i a . ( S i l b e r m a n et al. 1981; B r o w n a n d B r a w l e y 1983; Sabelli et al. 1983; Joyce et al, 1986; B a x t e r et at. 1988). G i v e n the m o o d effects o f p s y c h o s t i m u l a n t s in n o r m a l subjects a n d affective d i s o r d e r p a t i e n t s , we exa m i n e d the m o o d r e s p o n s e o f s c h i z o p h r e n i c s in remission to a p s y c h o s t i m u l a n t challenge with i n t r a v e n o u s m e t h y l p h e n i d a t e . We also w i s h e d to e x a m i n e the relat i o n s h i p b e t w e e n the p s y c h o t o g e n i c a n d m o o d a l t e r i n g p r o p e r t i e s o f m e t h y l p h e n i d a t e in this p o p u l a t i o n .
Materials and methods The inclusion criteria and methylphenidate infusion procedure used in this study have been described in a previous communication (Lieberman et al. 1987b). In summary, subjects for this study were medically healthy outpatients aged 18-50 years old who fulfilled Research Diagnostic Criteria (Spitzer et al. 1977) for schizophrenia or schizoaffective disorder, mainly schizophrenic. Prior to the methylphenidate infusion, all subjects had been in a state of remission for at least 6 months while on neuroleptic maintenance treatment. Criteria for being in remission were: 1) a rating of no greater than 2 on either the severity of delusions or on the severity of hallucinations items on the Schedule for Affective Disorders and Schizophrenia - Psychosis and Disorganization (SADS+PD) (Spitzer and Endicott 1978) scale, 2)a rating no greater than 3 on the S A D S + P D items for incoherence or for bizarre behavior, 3) catatonic motor behavior not present, and 4) the sum of the scores on factors III, IV and V of the Brief Psychiatric Rating Scale (BPRS) (Overall and Gotham 1962) of less than 24. Each subject while on neuroleptics received two infusions, one of methylphenidate and one of placebo, I week apart in a randomized order under double-blind conditions. Each subject then had a second set of infusions, again with methylphenidate and placebo, under double-blind conditions, after their neuroleptics had been stopped and they had been drug-free for 20 days (or 40 days if they had been on long-acting injectable neuroleptics). Subjects for this study included those subjects in our previous report who had both sets of infusions in addition to some subjects who completed the protocol after the submission of our previous report. All infusion procedures followed the same protocol. At 8:30 a.m., subjects were brought to a special procedures room. They were put into a supine position on a hospital bed and an indwelling catheter was inserted into a forearm vein. During the next ]05 min, the subject was assessed with a variety of rating instruments including the SADS÷PD, BPRS, Taylor and Abrams scale for emotional blunting and Clinical Global Impression Scale. After this preinfusion baseline, subjects were given either 0.5 mg/kg methylphenidate or an equivalent volume of saline solution by intravenous push over a period of 120 s. Subjects were interviewed formally and observed continuously for 80 rain following the infusion. Subjects were then rated for peak response during the post infusion period using the SADS+PD, BPRS and Taylor and Abrams scale. Further, a written narrative of the subject's response during the entire procedure was recorded. The infusion procedure, rating scales and narrative were all done by one of the authors (JAL). During the infusion procedure, blood was collected at three intervals for methylphenidate levels. These samples were collected at 20 rain, 60 min and 80 rain after the double-blind methylphenidate infusion. Samples were collected in ammonium and potassium oxalate tubes, spun for 15 min and the plasma frozen at - 2 0 ° centigrade pending assay. Methylphenidate levels were determined by gas chromatography using a modification of the technique of Hungund et al. (1978). Two of the authors (DR and DM) who were not present during the infusion procedures independently classified each subject's re-
sponse to the infusion on the dimensions of psychotic activation and mood response. These were based on comparisons of subjects' preinfusion baseline states with their postinfusion responses to active methylphenidate. Data used to make these determinations were the infusion narrative summaries and the BPRS ratings. BPRS items used to assess psychotic activation were conceptual disorganization, grandiosity, suspiciousness, hallucinatory behavior and unusual thought content. Items used to assess mood change were guilt feelings, grandiosity, depressive mood and excitement. For psychotic symptoms, subjects were rated as either psychotic symptom activators to the infusion or no change in psychotic symptoms. Mood responses to the infusion were classified as either euphori= responses, neutral (i.e., no change), dysphoric responses or mixed (combining euphoric and dysphoric symptoms) responses. We classified subjects' responses by these categories instead of using only the BPRS ratings because this allowed us to integrate the rating scale data with the narrative summaries. In assessing mood changes, we thought that the narrative summaries could provide important information about the timing and the clinical intensity of mood changes which might be lost if we used only the BPRS ratings. The classifications reported are a consensus rating of infusion response made jointly by DR and DM.
Results T w e n t y - n i n e subjects c o m p l e t e d the first set o f infusions with m e t h y l p h e n i d a t e a n d p l a c e b o while o n neuroleptics. W h e n w i t h d r a w n f r o m n e u r o l e p t i c s , f o u r subjects h a d a r e l a p s e o f their p s y c h o t i c s y m p t o m s before t h e y were s c h e d u l e d to h a v e the s e c o n d set o f infusions. These subjects were n o t given the s e c o n d set o f infusions. Thus, 25 subjects h a d b o t h sets o f i n f u s i o n s (one set while o n n e u r o l e p t i c s a n d o n e set while o f f neuroleptics). T h e original s a m p l e o f 29 subjects ( 5 5 % male) h a d a m e a n ( ± S D ) age o f 30.1 +_6.8 years. T w e n t y - t w o subjects h a d a d i a g n o s i s o f s c h i z o p h r e n i a , five h a d a d i a g n o s i s o f schizoaffective d i s o r d e r , d e p r e s s e d t y p e a n d two h a d a d i a g n o s i s o f schizoaffective d i s o r d e r , m a n i c t y p e b y Research D i a g n o s t i c C r i t e r i a ( R D C ) . B o t h schizoaffective g r o u p s were classified as m a i n l y s c h i z o p h r e n i c u n d e r R D C . Subjects were s t u d i e d relatively early in the course o f their illness with a m e a n ( ± S D ) age at first h o s p i t a l i z a t i o n o f 2 3 . 7 + 4 . 7 years. Subjects h a d h a d a m e a n (_+ SD) o f 3.1 + 2.3 h o s p i t a l i z a t i o n s . A l l subjects were stable a n d f u n c t i o n i n g in the c o m m u n i t y with a m e a n ( ± S D ) d u r a t i o n o f r e m i s s i o n p r i o r to the first i n f u s i o n o f 2 7 . 7 _ 16.6 weeks. Subjects' r e s p o n s e s to the infusions are p r e s e n t e d in Fig. 1. A s c a n be seen in this figure, the overall m o o d responses o f the subjects were v a r i a b l e with the p r e d o m i n a n t r e s p o n s e s b e i n g either e u p h o r i c o r n e u t r a l with m u c h fewer m i x e d o r d y s p h o r i c responses. Overall, 29 p a t i e n t s u n d e r w e n t a t o t a l o f 54 infusions. O f the responses, 35.2% were e u p h o r i c , 5 0 % were neutral, 5.6% were m i x e d a n d 9 . 3 % were d y s p h o r i c . O f the 25 p a t i e n t s w h o u n d e r w e n t b o t h sets o f infusions, 11 ( 4 4 % ) p a t i e n t s h a d the s a m e r e s p o n s e to b o t h a n d 14 ( 5 6 % ) p a t i e n t s c o n v e r t e d their r e s p o n s e ( f r o m e u p h o r i c to n e u t r a l etc.). We e x a m i n e d several v a r i a b l e s to d e t e r m i n e their relat i o n s h i p to the m o o d responses o f p a t i e n t s (Table 1). T h e first o f these was the r e l a t i o n s h i p b e t w e e n p s y c h o t i c a c t i v a t i o n a n d m o o d r e s p o n s e to the infusion. T h e r e
249 was a significant association between psychotic activation (present or absent) and m o o d response (euphoric, neutral, mixed, dysphoric) in the data from all 54 infusions (Fisher's Exact Test, 2-tailed, P = 0 . 0 1 2 ) and from infusions with subjects on neuroleptics (Fisher's Exact Test, 2-tailed, P = 0.049). Further, there was a trend towards an association between psychotic activation and m o o d response in infusions with subjects off of neu-
Mood Response:
roleptics (Fisher's Exact Test, 2-tailed, P = 0.059). Examining all infusions, the categories o f euphoric or neutral m o o d responses had more subjects who experienced psychotic activation than did the categories o f mixed or dysphoric m o o d response. However, although infrequently occurring compared to euphoric or neutral m o o d responses, mixed and dysphoric m o o d response had a high percentage (100% and 60%, respectively) of subjects with psychotic activation. Post hoc, we dichotomized m o o d response into responses with a dysphoric component (combining mixed and dysphoric response) and responses without a dysphoric component (combining euphoric and neutral responses). Using these categories, there was a significant association between psychotic activation and m o o d responses with a dysphoric component for infusions with subjects on neuroleptics (Fisher's Exact Test, 2-tailed, P = 0.015) and for all infusions (Fisher's Exact Test, 2-tailed, P = 0 . 0 1 2 ) but not for infusions with subjects off neuroleptics (Fisher's Exact Test, 2-tailed, P = 0.358). We next considered the possibility that the high rates o f psychotic activation in subjects with mixed or dysphoric m o o d response could be the result o f the distressing effects of psychotic symptoms producing dysphoric feelings in some subjects. If this occurred, subjects who had psychotic activation and mixed or dysphoric m o o d responses to one infusion should on the other infusion either have had a pattern of: 1) consistent psychotic activation with mixed or depressed mood, or 2) no psychotic activation with an euphoric or neutral m o o d response. Only three of the six subjects who had psychotic activation and a mixed or dysphoric m o o d response to one o f the infusions had this pattern of response. Of the other three subjects, two had psychotic activation and a dysphoric response on one infusion and psychotic activation and a neutral response on the other infusion and one subject had psychotic activation on both infusions but a euphoric response on one infusion and a dysphoric response to the other infusion. Besides the effects of psychotic activation, we also examined diagnostic subtypes in relation to m o o d responses but found no distinctive pattern of m o o d responses to the infusions by diagnosis. There also was
Off Neuroleptics (Patient Number)
On Neuroleptics (Patient Number)
E~oric
Neutral
DFs~horie
27 Fig. 1. Infusion responses. (*) Patients with psychotic activation Table 1. Infusion responses
Psychotic activation RDC diagnosis: Schizophrenia Schizoaffective, depressed Schizoaffective, manic Sex: male female
Neutral responses
On neuroleptics N=13
Off neuroleptics N=6
On neuroleptics N=13
3
4
2
3
1
2
2
1
9
5
10
10
t
1
2
2
4
1
1
3
-
2
1
3 3
6 7
9 5
1 -
1 1
2 -
3
7 6
Number of responses in each category
Mixed responses
Dysphoric responses
Euphoric responses
Off On Off On Off neuroleptics neuroleptics neuroleptics neuroleptics neurolepfics N=I4 N=I N=2 N=2 N=3
250 Table 2, Methylphenidate ptasma levels
20 rain sample
60 min sample
80 min sample
On neuroleptics
Off neuroleptics
On neuroleptics
Off neuroteptics
On neuroleptics
Off neuroleptics
Mood response: Euphoric responses Neutral responses Mixed responses Dysphoric responses
131.0 + 41.8 99.8 + 38.9 98.0+_46.7
105.5 _+53.6 144.3 _+41.7 132.0_+ 0.0 112.5_+ 2.1
82.3 _+18.1 80.3 _+34.6 69.0+_21.2
65.7-+ 27.1 94.3 _+29.7 83.0± 0.0 68.0_+ 1.4
66.0 _+11.7 72.2 _+33.1 55.5_+ 10.6
56.5 + 15.0 75.0 _+23.8 71.0_ 0.0 59.0_+ 12.7
Psychotic activation: No psychotic activation Psychotic activation Total sample
117.9_+42.9 94.7±33.5 114.8 _+42.1
143.9+__32.4 98.8_+46.1" 129.1 _+43.9
82.9-1-_27.0 67.3_+ 1 5 . 3 81.4 _+27.0
94.4-+24.0 64.2_+23.4** 83.9 _+28.3
70.0+24.8 56.7± 7.8 67.8 _+23.5
74.3-+19.5 54.2_+15.3'** 68.5 +_20.3
Mean (-+ standard deviation) in ng/ml * No psychotic activation versus psychotic activation, SS = 6534.7, df= 1, F= 4.65, P= 0.053 ** No psychotic activation versus psychotic activation, SS = 2801.6, df= t, F= 4.96, P = 0.048 *** No psychotic activation versus psychotic activation, SS = 1302.9. df= 1, F= 3.94, P= 0.070 no relationship between sex and mood response or sex and psychotic activation from methylphenidate infusion in either the on or off neuroleptic conditions. The effects of methylphenidate plasma levels on mood responses and psychotic activation are presented in Table 2. In 14 subjects blood samples for methylphenidate assay were collected at 20, 60 and 80 rain after methylphenidate infusion. Peak methylphenidate levels occurred at the first sample in all but one patient. Analyses of the peak and overall methylphenidate levels (using all three samples) o f patients by mood response and psychotic activation revealed no significant relationships between methylphenidate levels and mood response on and off neuroleptics or psychotic activation while on neuroleptics. Off neuroleptics, subjects with psychotic activation had significantly lower 60-min methylphenidate levels and a trend toward lower 20- and 80-min methylphenidate levels compared to subjects without psychotic activation. Next, we looked at the effect of neuroleptic condition on methylphenidate levels. At all three time points sampled, there were no significant differences in methylphenidate levels between the on and off neuroleptic conditions. Finally, we examined the effects of neuroleptic condition on m o o d responses to the infusions. O f the 25 subjects who had infusions both on and offneuroleptics, 13 (52%) had a euphoric response on neuroleptics while only 6 (24%) had a euphoric response off neuroleptics (X 2 =6.96, df= 1, P=0.008). This neuroleptic effect on m o o d response to methylphenidate is in contrast to the lack of a significant effect of neuroleptic condition on psychotic activation (7 of 25 subjects on neuroteptics were psychotic activators and 10 of 25 subjects off neuroleptics were psychotic activators, ( X ~ 1.94, df= 1, P = 0 . 1 6 ) . Discussion
Our primary finding was an overall variability in the mood responses of stable schizophrenic subjects to methylphenidate infusion with the predominant responses being either euphoric or neutral. This heterogeneity of
m o o d response to psychostimulant challenge is consistent with the variability in m o o d response seen in subjects with other psychiatric disorders such as depression (Silberman et al. 1981 ; Sabelli et al. 1983; Brown and Brawley 1983; Joyce 1986). Although infrequent compared to euphoric or neutral m o o d responses, mixed and dysphoric responses were associated with a high rate of psychotic activation. Some o f the subjects with mixed or dysphoric responses and psychotic activation had a pattern of response to both infusions consistent with the hypothesis that the distressing experience o f psychotic symptoms may have contributed to a dysphoric mood state. However, an equal number of subjects had a pattern of response inconsistent with this. Also contrary to the hypothesis that psychotic symptoms produced dysphoric feelings in subjects is our finding that in 12 o f the 18 (66.7%) instances of psychotic activation subjects had a euphoric or neutral m o o d response. Since neuroleptic pretreatment has been reported to reduce or abolish the euphoric and activating responses of euthymic bipolar subjects to methylphenidate infusion (Wald et al. 1978) and the cocaine " h i g h " in volunteer cocaine addicts given intravenous cocaine, (Sherer 1988), we had anticipated fewer euphoric responses in our subjects while on neuroleptics than when off neuroleptics. To explain the larger number of euphoric responses in our subjects when on compared to off neuroleptics, we initially hypothesized that the euphoric subjects on neuroleptics might have had a neuroleptic-induced dysphoric, apathetic or akinetic state which methylphenidate counteracted. A second review of the euphoric subjects' infusion records showed this to be unlikely, since the infusion records described substantial activation, elevation in m o o d and disinhibition in the euphoric subjects. A second possibility is that methylphenidate was producing a therapeutic effect on negative symptoms as has been previously reported (Angrist et at. 1982). However, if this was the case, we would have expected to see a similar or greater reduction in negative symptoms in the off neuroleptic condition which was not the case. Third, we also considered the possibility that a pharmacokinetic
251 effect of neuroleptics on methylphenidate plasma levels could have influenced the number of euphoric responses on neuroleptics. Analysis of the methylphenidate levels, however, showed no significant differences in methylphenidate levels in the on or off neuroleptic condition. Finally, we hypothesized that the differences in number of euphoric responses on and off neuroleptics might represent a partial attenuation by neuroleptics of methylphenidate's effects. Examining mood response as a function of dose of psychostimulant given, psychostimulants have been reported to produce more pure euphoric responses at lower doses and more mixed or dysphoric responses at higher doses (Angrist 1983; Post and Contel 1983). Thus, if neuroleptic treatment partially attenuated the mood effects of methylphenidate, subjects could have more euphoric responses on neuroleptics than off neuroleptics because of a suppression of dysphoric or mixed responses by neuroleptics. However, if this were the case, one would expect that subjects who converted from a euphoric response on neuroleptics to another mood response off neuroleptics would tend to have more dysphoric or mixed responses to the infusion off neuroleptics. This did not happen in our sample. Of the eight subjects who converted from a euphoric response on neuroleptics to another mood response pattern off neuroleptics, six (75%) had a neutral response and only two (25%) had a mixed response. One possible explanation for the discrepancy between our findings and the effects of neuroleptic pretreatment on mood response to psychostimulant challenges in bipolar subjects and cocaine addicts is the length of neuroleptic treatment. In both the studies of Wald et al. and Sherer, haloperidol was given as a single dose before psychostimulant administration. In contrast, our subjects when on neuroleptics had been taking them for long periods of time as treatment for their psychotic symptoms. If chronic neuroleptic treatment induced neurotransmitter changes different from those of acute treatment, chronic neuroleptic treatment in our subjects could have produced neurotransmitter changes which resulted in differences in mood response compared to that of acute neuroleptic treatment. The larger number of euphoric responses to methylphenidate in our subjects while on neuroleptics as compared to off neuroleptics has implications for our understanding of psychostimulant use in schizophrenic patients. Chronic neuroleptic treatment may influence psychostimulant use in schizophrenic subjects in a variety of ways, including producing a dysphoric or akinetic state which the patient may try to counteract with psychostimulant use. Besides these effects, our study suggests that neuroleptic treatment may also modify schizophrenic subjects' mood responses to psychostimulants compared to their off neuroleptic responses. If neuroleptic treatment is associated with more euphoric responses to psychostimulants than the off neuroleptic condition, neuroleptic treatment status may be an important factor in assessing psychosfimulant use in schizophrenic patients. In evaluating our findings, several aspects of our study must be considered. First, our sample size, al-
though large compared to most previous psychostimulant challenge studies, was small enough to decrease our power to detect differences in some of our comparisons. Second, our use of the categories of euphoric, neutral, dysphoric or mixed mood changes as the end point measures of mood response may have obscured relationships which could have been detected with continuous variables. However, in our case, we chose to use the categorical end points because they corresponded to clinically meaningful states and because they allowed us to integrate information from written accounts of the infusion with information from a standard rating scale, the BPRS. Third, our assessments were all done by a clinician rater. The results of subjects self-ratings may have been different. Fourth, in our study, we assessed mood for the predominant response over the entire 80 min observation period after methylphenidate was given. The observation period used is important in comparing our results to previous studies given the effects of time from administration on mood responses elicited by psychostimulants (Checkly 1978; Nunnberger et al. 1982). Finally, we did not test for the reproducibility of mood response to active methylphenidate given on different occasions to the same subject while on the same medication regime. This information would have been useful in assessing our results. However, in designing a study, the need for information must be weighed against the potential adverse effects, both physical and psychological, to subjects from each procedure. In this study, subjects were tested both on and off neuroleptics. We did not think that the increased knowledge to be acquired justified the risks to subjects of serial methylphenidate infusions both on and off neuroleptics in this first study. Given our results, however, a future study designed specifically to test the reproducibility of mood response in schizophrenic subjects to methylphenidate would be of interest. In summary, subjects in our study had heterogeneous mood responses to methylphenidate infusion. Mood responses were not correlated with sex, methylphenidate plasma levels or diagnostic distinctions between schizophrenia or schizoaffective disorder. Although they occurred infrequently, dysphoric and mixed mood responses were associated with high rates of psychotic activation. Comparing subjects on and off neuroleptics, subjects on neuroleptics had more euphoric responses than the same subjects off neuroleptics. Future studies of mood response in schizophrenics to methylphenidate are warranted to extend our findings and to clarify the mechanisms of mood regulation in schizophrenic disorders. Acknowledgements. We wish to thank Paul Bermanzohn, MD, Bruce Kinon, MD and Anthony Loebel, MD tbr their suggestions in the preparation of this manuscript.
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