Plasma amine metabolites before and after withdrawal from neuroleptic treatment in chronic schizophrenic inpatients

233

Psychiatry Research, 25233-242 Elsevier

Plasma Amine Metabolites Before and After Withdrawal From Neuroleptic Treatment in Chronic Schizophrenic Inpatients Darrell G. Kirch, George Jaskiw, and Richard J. Wyatt Received

Markku

Linnoila,

Daniel

R. Weinberger,

May 5. 1986; revised version received February 27, 1988; accepted March 19, 1988.

Abstract. Plasma catecholamine metabolites were measured in paired blood samples from 22 subjects with chronic schizophrenia. One sample was drawn while patients were on a stable dose of neuroleptic medication; the second was drawn 6

weeks after discontinuation of medication. In comparison with baseline values during neuroleptic treatment, there was a significant increase in the plasma concentration of the norepinephrine metabolite, 3-methoxy+hydroxyphenylglycol (MHPG), and a trend toward an increase in the plasma concentration of the dopamine metabolite, homovanillic acid (HVA), in the medication-free subjects. There were no significant correlations between plasma MHPG or HVA concentrations and the corresponding ratings of psychopathology for these patients. Key Words. Schizophrenia, acid, tardive dyskinesia.

3-methoxy-4hydroxyphenylglycol,

homovanillic

Despite decades of investigation, the pathological neurochemical mechanisms in schizophrenia remain obscure. The leading biochemical hypothesis of the etiology of schizophrenia is that the psychotic symptoms associated with the illness result from increased dopaminergic activity in the central nervous system (CNS). Although considerable indirect evidence supports the dopamine hypothesis of schizophrenia, attempts to measure concentrations of catecholamines and their metabolites in brain, blood, urine, and cerebrospinal fluid (CSF) from schizophrenic patients have led to

inconclusive and at times conflicting results (Meltzer and Stahl, 1976; Haracz, 1982; Wyatt, 1985). The difficulty in collecting brain tissue for post-mortem analyses or performing lumbar punctures to obtain CSF from large numbers of schizophrenic subjects has turned increasing attention toward the measurement of plasma amine metabolites as a potential index of CNS catecholamine activity. Recent studies indicate that the

Darrell G. Kirch, M.D., is Senior Staff Fellow, Neuropsychiatry Branch, National Institute of Mental Health (NIMH), St. Elizabeths Hospital, Washington, DC. George Jaskiw, M.D., is Senior Staff Fellow, Clinical Brain Disorders Branch, NIMH, St. Elizaheths Hospital, Washington, DC. Markku Linnoila, M.D., Ph.D., is Clinical Director, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. Daniel R. Weinhexger, M.D., is Chief, Clinical Brain Disorders Branch, NIMH, St. Elizaheths Hospital, Washington, DC. Richard J. Wyatt, M.D., is Chief, Neuropsychiatry Branch, NIMH, St. Elizabeths Hospital, Washington, DC. (Reprint requests to Dr. D.G. Kirch, NIMH at St. Elizaheths, William A. White Bldg., 2700 Martin Luther King Ave., S.E., Washington, DC 20032, USA.) 0165-1781/88/$03.50 @ 1988 Elsevier Scientific Publishers Ireland Ltd.

234 severity of psychosis in schizophrenia correlates positively with the plasma concentration of homovanillic acid (HVA), a major dopamine metabolite (Pickar et al., 1984, 1986; Davis et al., 1985). We have examined the relationship between plasma catecholamine metabolites and psychosis in a group of schizophrenic subjects during a stable phase of neuroleptic treatment and again 6 weeks after withdrawal from medication. Data regarding plasma concentrations of amine metabolites were examined in relation to clinical variables, ratings of psychiatric symptoms, and computed tomographic (CT) brain scan results. Methods Twenty-two subjects (14 males, 8 females), who were voluntary inpatients in the National Institute of Mental Health Intramural Research Program located at Saint Elizabeths Hospital, participated in the study. Each subject met DSM-ZZZ(American Psychiatric Association, 1980) diagnostic criteria for schizophrenia (13 undifferentiated and 9 paranoid). Their mean age was 27.0 (range: 18-41 years). The mean age of onset of illness for the subjects was 19.2 (range: 13-28 years). All were free of significant coexisting medical or neurological disease. On serial neurological examinations, seven subjects had significant persistent abnormal movements consistent with tardive dyskinesia (TD). After admission to the program, the subjects entered a stabilization phase during which they were treated in double-blind fashion with a coded liquid form of the neuroleptic they had been taking before admission. The mean daily dose of neuroleptic (in chlorpromazine equivalents) during this stabilization phase was 1,736 mg (range 200-5,000 mg). These doses appear to be fairly high but, in general, reflect the fact that most patients were on modest to high doses of high-potency neuroleptics (primarily haloperidol), which appear as very high doses when converted to chlorpromazine equivalents. The subjects were withdrawn from other psychotropic medications that had been administered before admission. They were allowed to remain on anticholinergic medications, and these were also administered in coded double-blind fashion. After withdrawal from any nonneuroleptic psychotropic medications, the patients were observed for an additional period of at least 4 weeks to verify that their clinical state was in fact stable. The patients were then withdrawn from neuroleptic medication without tapering, in double-blind fashion, and placed on coded placebo. Anticholinergic medications were also changed to a coded placebo, although in some cases of patients on high doses of neuroleptics the anticholinergic agent was continued for the first few days on placebo neuroleptic to protect the patient during the neuroleptic washout phase. The medication-free state was maintained for 6 weeks. Paired blood samples were drawn from each subject, one just before the last dose of active neuroleptic medication and the second 6 weeks after neuroleptic withdrawal. Both blood samples were drawn at 8 a.m., with the subject at bedrest after an overnight fast. The sample was immediately centrifuged, with the plasma then stored at -60 “C. Plasma concentrations of both HVA and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined using high performance liquid chromatography as previously described (Chang et al., 1983; Scheinin et al., 1983). The intra-assay and interassay coefficients of variation for the plasma HVA determinations were 2% and 670, respectively, and for plasma MHPG determinations were 6% and 12% respectively. Nineteen subjects also had a CT brain scan, allowing calculation of ventricle-brain ratio (VBR) by manual planimetry (Synek and Reuben, 1976) and a determination of generalized and prefrontal cortical atrophy using a visual scale with reference photographs of “standard” scans showing a range of atrophy (Shelton et al., 1988). All subjects were rated daily by nursing staff without knowledge of their medication status using a scaled modified version (available from the authors on request) of the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962). There are 23 items scaled from 0 (absent) to 6 (severe). Items that cannot be rated on a given day are denoted to be missing values rather than

235 scored by 0, and the mean item score for all rated items rather than the total BPRS score (which might appear to be falsely low if some items could not be rated) was used for statistical analyses. The mean of the seven daily BPRS scores for the last week on neuroleptic and that for the sixth week drug-free were used for the data analyses. Statistical comparisons of the amine metabolite concentrations immediately before and 6 weeks after drug withdrawal, as well as comparisons of BPRS scores at the paired blood sampling points before and after neuroleptic withdrawal, were performed using a matched pairs t test. Correlations between amine metabolite concentrations, BPRS mean item and syndrome scores, and CT brain scan variables were performed using the Pearson correlation coefficient. Results As shown in Table 1, there was a significant @ < 0.01) increase in plasma MHPG 6 weeks after discontinuation of neuroleptic treatment. For the group as a whole, the increase was from 15.0 pmol/ml to 18.2 pmol/ml, a rise of21.3%. Overall, 17 patients showed an increase in plasma MHPG, while only 5 patients showed a decrease after discontinuation of neuroleptic medication. A weak trend toward an increase in plasma HVA was also noted, but this did not attain statistical significance (p = 0.19). The increase in HVA for the group as a whole was from 58.8 pmol/ ml to 65.4 pmol/ ml, a rise of 1 I .2%. Overall, 12 patients showed an increase in HVA after discontinuation of neuroleptic treatment, while 10 patients showed a decrease. After 6 weeks off neuroleptic medication, the patients as a group showed a definite exacerbation of symptoms. There was a significant (p < 0.01) overall increase in psychopathology, with a BPRS mean item score during the neuroleptic stabilization period of 1.31 and a corresponding mean item score after 6 weeks medication-free of 1.78 (representing a 36% increase). When individual BPRS syndromes were examined (Fig. l), a statistically significant exacerbation of symptoms was seen for the ” “activation,” and “positive symptoms” syndromes but not “hostility-suspiciousness, or “negative symptoms” syndromes. for the “anxiety,” “depression,” To examine further the association between plasma amines and specific psychopathology, the correlations between the concentrations of plasma MHPG and HVA and the BPRS syndrome and mean item scores for each individual during both neuroleptic stabilization and the medication-free period were examined. The patients showed a relatively broad range of severity of illness, with the individual mean item scores on neuroleptic ranging from 0.37 to 2.88 and drug-free ranging from 0.79 to 3.46. There was no significant correlation when the plasma MHPG or HVA concentration for each subject was paired with the corresponding BPRS syndrome scores or the mean item score at the time of blood sampling. Moreover, there was no significant correlation when the difference (medication-free value minus baseline neuroleptic treatment value) in MHPG or HVA concentration for each individual was paired with the corresponding change in any specific BPRS syndrome or the mean item score for that subject. A number of other variables were examined. Seven subjects who demonstrated persistent TD on and off neuroleptic medication were compared with 15 subjects without TD. There was no significant difference between the groups in either MHPG or HVA concentration. Likewise, there was no significant correlation between the concentrations of these amine metabolites and the variables of age, onset of illness, or dose of neuroleptic; note, however, that the range of both age and onset was relatively

236 narrow. There also was no significant correlation between plasma MHPG or HVA (or the change in either metabolite after neuroleptic withdrawal) and VBR or cortical atrophy as determined from CT brain scans. Table 1. Plasma HVA and MHPG concentrations (pmol/ml) for 22 schizophrenic subjects immediately before and 6 weeks after withdrawal from chronic neuroleptic medication HVA Subjects

Neuroleptic

MHPG Drug-free

Neuroleptlc

Drug-free

1

60.4

57.0

25.0

25.8

2

34.6

26.4

9.5

11.6

3

57.9

55.9

12.2

18.7

4

45.1

57.2

15.2

17.4

5

74.3

65.9

13.3

15.9

6

75.9

116.4

23.5

36.7

7

62.0

100.0

10.0

13.4

8

63.5

69.4

12.2

12.5

9

55.1

61.5

16.5

10.3

10

67.1

51.6

10.3

14.6

11

52.7

62.6

14.3

13.7

12

68.5

39.4

14.4

15.0

13

44.0

69.5

20.1

24.2

14

25.2

51.1

20.5

21.7

15

41.3

89.9

16.7

23.9

16

28.1

41.8

16.7

12.9

17

47.9

38.4

11.2

15.8

18

93.4

61.7

15.4

27.9 24.7

19

97.5

85.5

16.6

20

78.0

55.2

17.5

16.6

21

44.1

76.5

9.3

16.3

22

76.9

104.7

10.6

10.2

58.8 19.4

65.4 22.8

15.0 4.4

18.2 6.7

Group mean SD

Note. HVA = homovanillic acid. MHPG = 3-methoxy-4-hydroxyphenylglycol

Discussion If the psychosis observed in schizophrenia is indeed the result of increased CNS dopaminergic activity, one might expect to observe increased concentrations of dopamine metabolites in the CSF of medication-free patients. On the other hand, CNS dopamine receptor supersensitivity could actually lead to a functional decrease in both presynaptic dopamine release and the concentrations of metabolites. A number of human and animal studies suggest that increased CNS dopaminergic activity is reflected by significant increases in CSF concentrations of metabolites, particularly HVA (Papeschi et al., 1971; Bacopoulos et al., 1978, 1979, 1980; Kendler et al., 1981). Investigations of patients with schizophrenia directed at documenting

237 Fig. 1. Group BPRS syndrome scores and mean item scores for 22 schizophrenic subjects Immediately before and 6 weeks after withdrawal from chronic neuroleptlc medication •z3

NeurolepticTreatment

0

Six Weeks Drug-Free

N=22

p < 0.05 p
r

pxo.01

BPRS Syndromes and Mean Item Score BPRS = Brief Psychiatric Rating Scale.

such an increase in CSF amine metabolites, however, have failed to provide a definitive answer. It is hardly surprising that in different studies and often under dissimiliar conditions (in particular, variations in the status of neuroleptic treatment), CSF HVA has been noted to be increased (Persson and Roos, 1969; Rimon et al., 1971; Bowers, 1973; Fyro et al., 1974; van Praag and Korf, 1975; Post and Goodwin, 1975; Sedvall and Wode-Helgodt, 1980); decreased (Post et al., 1975; Bowers, 1976); or not different from controls (Berger et al., 1980). In examinations of patients with persistent TD, there also has been no consensus regarding alterations in dopaminergic activity as measured in the CSF (Chase et al., 1970; Aratb et al., 1984). Because of the difficulty in obtaining CSF samples, investigators have recently focused on the concentration of HVA in plasma as a potential index of CNS dopaminergic neurotransmission. Results from both animal studies and clinical investigations indicate that a significant fraction of plasma HVA may originate in the brain. Therefore, plasma HVA may have potential utility as a marker for CNS dopaminergic activity (Bacopoulos et al., 1978,1979,1980; Heninger et al., 1980; Kendler et al., 198 1, 1982; Maas et al., 1985), although concern remains about the effect of “peripheral” factors. This has given rise to recent investigations of plasma HVA concentrations in patients with schizophrenia. We previously reported a positive correlation between plasma HVA and the severity of abnormal involuntary movements in a group of psychotic patients on neuroleptic medication (Kirch et al., 1983). Bowers et al. (1984)

238 noted a better response to haloperidol in patients who had higher mean plasma HVA concentrations before and during the first week of treatment. Pickar et al. (1984) reported a positive correlation between the severity of psychosis and plasma HVA concentrations. That study made use of serial sampling of.pksma HVA, initially while patients were medication-free and subsequently through a course of neuroleptic treatment. In an extension of that study, they have confirmed a similar relationship between plasma HVA and increasing global psychosis scores while patients were withdrawn from neuroleptic medication (Pickar et al., 1986). Likewise, Davis et al. (1985) also noted a positive correlation between plasma HVA before neuroleptic treatment and global psychosis scores both before and after treatment in schizophrenic patients. Although in the present study we noted a trend toward an increase in plasma HVA 6 weeks after neuroleptic withdrawal, the increase did not attain statistical significance. Concentrations increased after withdrawal in 12 patients, but decreased in 10. Moreover, there was no significant correlation between any of the individual BPRS syndromes and absolute concentrations of HVA during neuroleptic treatment or at the time of medication-free sampling. Similarly, there were no significant correlations between the change in the BPRS syndrome scores and the change in HVA concentrations as patients went from neuroleptic treatment to the medication-free state. In clinical studies that attempt to monitor HVA as a marker of CNS processes, attention to potential sources of variance is clearly warranted. One factor that has been studied is diet, a variable that some have proposed might significantly increase plasma HVA. Recent data from Davidson et al. (1987), however, demonstrate that the effect on plasma HVA of a meal high in monoamines has essentially disappeared 14 hours later (after an overnight fast). Other investigators have reported that even a low monoamine meal may be followed by a rise in plasma HVA in a subgroup of patients (Kendler et al., 1983). The subjects in the present study were not on a controlled low monoamine diet but did fast overnight (approximately 15 hours) before blood sampling. The use of an overnight fast at both blood sampling points, together with other recent data showing high test-retest reliability in plasma HVA measures for paired samples (separated by an interval of up to 6 weeks) taken from the same subjects after an overnight fast (Baker et al., 1988), indicate that the method used in the present study was a valid approach. Another potential source of variance is that of activity. Studies have reported that plasma HVA was not significantly affected by either standing or walking for 30 min (Davidson et al., 1987), but was increased after moderate exercise (Kendler et al., 1983), again indicating that the method used in the present study of collecting samples early in the morning at bedrest was probably adequate to control the effects of activity on HVA. It is of interest to note that the group mean plasma HVA concentration in our subjects while on neuroleptic treatment (58.8 pmol/ ml) was virtually identical to that observed by Pickar et al. (1986) in their patients during neuroleptic treatment. The assays for both studies were performed by one of us (M.L.) in the same laboratory. The differences between the studies were that we failed to observe as great an increase in HVA when patients were withdrawn from neuroleptic medication and that we were unable to confirm an association between HVA and both ratings of psychopathology and treatment response. These differences are difficult to explain but may relate to the

239 severity and chronicity of illness in our subjects. In spite of a mean age of 27, the subjects had a mean duration of illness of 7.8 years, reflecting their relatively early onset of schizophrenia. In most cases, referral to the research program stemmed from the patient’s being “refractory” to conventional treatment. Fig. 1 illustrates that the cohort was composed predominantly of chronically symptomatic, relatively treatment resistant patients. Even while stable on neuroleptic treatment before withdrawal, most patients demonstrated significant psychopathology and, when drug-free, the group as a whole showed a modest 36% increase in BPRS scores. Quite simply, our observations regarding amine metabolites may not be applicable to a group of patients with a form of schizophrenia that is less chronic, less severe, and/or more treatmentresponsive. In contrast to the lack of a significant increase in HVA after drug withdrawal, we did observe a significant increase in plasma MHPG, a major metabolite of norepinephrine. Fewer data have been presented regarding possible noradrenergic abnormalities in schizophrenia. Some investigators have posited, however, that a subset of patients with schizophrenia, in particular those with more florid paranoid symptoms, may demonstate noradrenergic abnormalities (Farley et al., 1978, 1979; Lake et al., 1980; Hornykiewicz, 1982; Sternberg et al., 1982). Pickar et al. (personal communication), in an expansion of their earlier work on plasma HVA, have noted an increase in plasma MHPG in schizophrenic patients after discontinuation of neuroleptic medication. It has been reported that clonidine, a drug that has partial a,-adrenergic agonist properties in the CNS, may be an effective antipsychotic agent (Freedman et al., 1982). In our own patient sample, the absolute concentrations of MHPG and the change in MHPG concentration going from neuroleptic treatment to the medication-free state did not correlate significantly with any behavioral ratings on the BPRS, including the “hostility-suspiciousness*’ and “positive symptoms” syndromes. Since MHPG is a norepineprine metabolite, and plasma norepinephrine is affected by many factors (Lake and Ziegler, 1985), MHPG in the plasma may significantly reflect “peripheral” influences. The element of activity, in particular, remains of concern. Motor activity has been shown to affect plasma norepinephrine concentrations (Lake and Ziegler, 1985). As illustrated in Fig. 1, the BPRS syndrome showing the most significant increase going from neuroleptic treatment to the medication-free state was that of “activation.” Although we did not see a significant correlation between individual activation ratings and amine concentrations, it is difficult to rule out the possibility that, in spite of collecting samples at bedrest, an overall increase in motor activity during the drug-free period was a factor contributing to the observed increases in plasma MHPG concentration. Ultimate resolution of the potential role of activity in studies of plasma MHPG and other monoamines will probably require more extensive testing using electronic activity monitors. In attempts to examine the biological heterogeneity of schizophrenia, some investigators have raised the possibility that those patients who display ventricular enlargement on CT brain scans may have a form of the illness that does not involve increased dopaminergic neurotransmission (Weinberger et al., 1980; Crow, 1982; van Kammen et al., 1983). This theory is based in part on the observation of some investigators that, as a group, patients with certain structural brain changes on CT scan appear to be less responsive to neuroleptic treatment (Weinberger et al., 1980; Schulz et al., 1983;

240 Luchins et al., 1983, 1984). More recent data have called into question theassociation between structural abnormalities on CT scan and psychopathology or treatment response (Shelton et al., 1988). We examined the relationship between CT brain scan data and the concentration of amine metabolites. There was no evidence of an association between atrophy, as demonstrated by either increased VBR or greater cortical atrophy scores (both generalized and prefrontal), and absolute concentrations of HVA or MHPG or the degree of change in these metabolites after neuroleptic withdrawal. Definitive confirmation of the dopamine hypothesis remains elusive. Clearly, neurotransmitters other than dopamine also merit close scrutiny in studies of schizophrenia. Future studies that make use of measurements of plasma amines will have to continue to address the issue of motor activity and other aspects of peripheral neurophysiological function as confounding variables. Concurrent studies of CSF, plasma, and urine amines could be especially valuable. Moreover, if abnormalities in catecholamine neurotransmission are limited to a subgroup of patients with schizophrenia, studies of amines will require much larger cohorts of research subjects, including both treatment-responsive and treatment-resistant patients. In addition, it would be important to determine any correlations between amine concentrations and the data obtained from both structural and functional brain imaging techniques. Acknowledgments. The authors thank Drs. David Pickar and Robert Freedman valuable comments, Diane Venable for expert technical assistance, and the nursing patients of our research units for their diligent participation in our studies.

for their staff and

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