CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal

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CSF Norepinephrine in Schizophrenia Is Elevated Prior to Relapse After Haloperidol Withdrawal Daniel P. van Kammen, Jeffrey Peters, Welmoet B . van Kammen, Ann Nugent, Kenneth L. Goetz, Jeffrey Yao, and Markku Linnoila

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that wasfollowed by replacement withplacebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-metho&-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and S-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.

Introduction Schizophrenia is a chronic disorder with episodes of increased psychotic symptoms or relapse (Strauss et al. 1985; Zubin et al. 1985). Episodes of psychotic decompensation can develop rapidly over a couple of days or gradually over several months. Behavioral prodromes of decompensation, such as sleep loss and increased arousal (Docherty et al. 1978; Szymanski et al. 1984), have been relatively well described. Studies of risk factors contributing to relapse have shown that discontinuation of neuroleptics (Dencker et al. 1986) and increased stress in the environment (Zubin et al. 1985) are associated with a high probability of relapse. Nonetheless, clinicians still find it virtually impossible to

From the Veterans Administration Medical Center (D.P.v.K., J.P., A.N., K.L.G., J.Y ,), Pittsburgh, and the Western Psychiatric hstitute and Clinic, University of Pittsburgh School of Medicine, Department of Psychiatry (D.P.v.K., J.P., W.B.V.K., K.L.G., J.Y.), Pittsburgh, PA; ad the National Institute of Alcohol Abuse and Alcoholism, DICBR-Laboratory of Clinical Studies (M.L.), Bethesda, MD. Supported in part by the VA Research Advisory Group and VA Merit Review funding. Address reprint IqUestS t0 Dr. Daniel P. van Kammen, Chief of Staff (1 I), Veterans Administration Medical Center, Highland Drive. Pittsburgh, PA 15206. Received January 30. 1988; revised July 26, 1988

This article 1s in the Public Domain

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177

predict accurately when an individual patient will relapse. Unfortunately, most prodromal symptoms are nonspecific and are hard to separate from normal fluctuations in schizophrenic symptomatology. Many patients may show behaviors similar to prodromal symptoms periodically, without relapse. Besides, individual patients display idiosyncratic prodromal behavior, which may be stable for a given individual from one episode to another (Herz and Melville 1980). The ability to predict relapse with biochemical measures could be important to clinicians and could increase our understanding of the relapse process. To study such a dynamic process as psychotic decompensation is difficult and requires a paradigm that allows patients to be studied when the risk of relapse is relatively high within a limited time period. Studying patients before and after neuroleptic withdrawal provides such an opportunity. Early attempts to pharmacologically identify patients who are at high risk for relapse after neuroleptic discontinuation often used a stimulant provocation test, e.g., d-amphetamine (Angrist et al. 1981; van Kammen et al. 1982) or methylphenidate (Liebetman et al. 1985, 1987). Recently, L-Dopa has been used for the same purpose (Davidson et al. 1987). We hypothesized that the worsening of psychosis and increased growth hormone release after stimulants could be mediated through the norepinephrine (NE) releasing properties of these drugs, as adequate neuroleptic treatment should block the dopaminergic effects (van Kammen et al. 1982; Farde et al. 1987). Elevated cerebrospinal fluid (CSF) and brain NE concentrations are among the most consistently replicated findings in schizophrenia (Homykiewicz 1982; van Kammen and Antelman 1984). We found CSF NE in drug-free patients to correlate negatively with sleep (van Kammen and Antelman 1984) and sometimes positively with psychosis (van Kammen and Gelemter 1987a). This variability indicates that CSF NE may vary with clinical state (van Kammen et al. 1986a). It also suggests that the timing of the LP in relation to the relapse process could be crucial in finding relationships among CSF NE, psychosis ratings, and hours of sleep during the night before the LP (Figure 1). In the present study, we examined CSF NE, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5hydroxyindoleacetic acid (5HIAA) before and after haloperidol withdrawal. We reported previously that CSF MHPG was increased in relapsed patients, but not in stable nomelapsed, drug-free patients (van Kammen et al. 1986). We have previously proposed that biological dysregulation precedes the actual psychotic episode (van Kammen et al. 1982, 1986). Studying patients before and after neuroleptic withdrawal provides an ideal paradigm for studying relapse under controlled conditions. The following questions raised by our earlier work are addressed in this paper: (1) Under which conditions do CSF NE concentrations correlate with the severity of psychosis? (2) What is the effect of haloperidol withdrawal on CSF NE concentration? (3) Is CSF NE, during chronic steady-state haloperidol treatment, higher in those patients who will relapse following haloperidol withdrawal?

MethcDds Subjects were 32 physically healthy male veterans with a DSM-III (1980) diagnosis of schizophrenia who were admitted voluntarily to the Schizophrenia Research Unit at the Highland Drive VA Medical Center in Pittsburgh, PA. All patients signed informed consent before entering the study and were placed on a low-monoamine, caffeine-restricted, and alcohol-free diet during hospitalization. For the duration of the study, patients as well as the nursing staff and the therapists were blind to the medication status of the

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RELATIONSHIP BETWEEN SLEEP AND PSYCHOTIC EXACERBATION Pt. 9052CA

I

3-

--Psychosis

2I HALOPERIDOL

PLACEBO

(15 mg)

10 2

4

6

8

10

12

14 16

18

20

22 24 26

28

30

32

34

M

38 40

42

44

DAYS

Figure 1. Three-day means of daily psychosis ratings and of hours of sleep at night of one patient are plotted together to show the timely relationshipof these two variables and relapse. *Time point when relapse criteria were met.

patients. All subjects received their medication or placebo replacements in unmarked identical-looking capsules. Patients with a history of serious neurological, endocrine, or other physical illnesses were excluded from the study. Premorbid functioning was scored using the scale designed by Cannon-Spoor et al. (1982). Patients and significant others were interviewed regarding first- and second-degree relatives with schizophrenia. Table 1 provides the clinical and demographic description of all participants. Twenty-five of these patients were reported previously in our CSF MHPG study (van Kammen et al. 1986b). If patients were taking neuroleptics other than haloperidol when entering the study, they were switched to an equivalent dose of haloperidol (Shader and Jackson 1985). All subjects were taking neuroleptics for at least 3 months before the first LP. Within a week of the first LP, haloperidol treatment was discontinued, and patients remained on placebo for 6 weeks or until they met relapse criteria, at which time a second LP was scheduled. Relapse occurred between 1 and 6 weeks (mean 22 days) following placebo replacement. Table 2 shows the demographic and clinical data in the relapsers and the nonrelapsers at . the time of the second LP. All LPs were scheduled between 8:00 and 8:30 AM, after fasting and bedrest since 10:00 PM the night before, with the patient in a lateral decubitus position. Spinal fluid (12 ml) was obtained through the space between the third and fourth vertebrae, immediately placed on ice, mixed, and stored at - 80°C in individual aliquots. CSF NE was measured with HPLC as described by Seppala et al. (1984). MHPG, HVA, and 5-HIAA were measured according to Scheinin et al. (1983). Patients were rated daily by the nursing staff and weekly by the therapists using the

BIOL PSYCHIATRY 1989;26:176-188

CSF NE and Relapse in Schizophrenia

Table 1, Clinical and Demographic

Description

of All Participants

Mean f Age 6-W

34.2 23.0 11.2 0.47

Age of onset (years) Duration of illness (years) Cannon-Spoor scoE (pre-morbid functioning) Haloperidol dose (mg/day)

f f 2 f

SD

n

7.61 4.71 6.56 0.146

32 32 32 32

12.8 2 9.45

32

DSM-III diagnosis

n

Percent

Paranoid schizophrenia Undifferentiated schizophrenia Schizoaffective disorder Total Family history of schizophrenia First-degree relatives Positive Negative Total Second-degree relatives Positive Negative Total

18 10 4 32

56.3 31.3 12.5 -

12 20 32

37.5 62.5 -

4 27 31

12.9 87.1 -

Table 2. Comparisons

179

between the Patients On and Off Haloperidol

for Whom Data in Both Conditions

Were Present Relapsers SD

n

Mean

SD

n

r-value

P

33.6 22.3 11.2 0.48

5.35 4.70 5.62 0.145

14 14 14 14

34.7 23.6 11.2 0.46

9.13 4.78 7.37 0.150

18 18 18 18

-0.45 -0.78 0.02 0.32

NS NS NS NS

14.7

8.04

14

11.4

18

0.99

NS

Mean Age (years)

Age of onset (years) Duration of illness (years) Cannon-Spoor score

Nonrelapsers

DSM-III diagnosis

n

Paranoid schizophrenia Undifferentiated schizophrenia Schizoaffective disorder Total Family history of schizophrenia First-degree relatives Positive Negative Total Second-degree relatives Positive Negative Total

7 5 2 14

Percent

10.40 n

Percent

X2

P

50.0 35.7 14.3 -

11 5 2 18

61.1 27.8 11.1 -

0.40

NS

5 9 14

35.7 64.3 -

7 11 18

38.9 61.1 -

0.0

NS

0 14 14

0.0 100.0 -

4 13 17

23.5 76.5 -

1.98

NS

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Table 3. Patients during

Total CSF NE’ CSF MHPG CSF HVA CSF 5-HIAA Sleepb Psychosis” BPRS clusters Thinking disturbance Anxious depression Paranoia Withdrawal/retardation Psychosis subscale BPRS total

haloperidol treatment

Patients during halopetidol withdrawal

Mean f SD

Mean +

0.66 34.7 169.9 89.1 7.1 6.0 7.8 6.6 5.7 7.1 17.8

k 5 * k k ”

0.364 7.46 64.86 35.15 0.83 2.09

rf: k 2 2 k

2.67 2.49 2.28 2.12 5.91

SD

n

f-value

P

0.66 39.5 178.9 99.6 6.1 6.8

5 f f 2 2 k

0.452 13.69 122.75 40.69 1.96 3.65

28 29 28 29 30 31

0.00 -1.99 -0.41 - 1.61 2.56 - 1.29

NS 0.057 NS NS 0.016 NS

8.2 7.0 7.3 6.9 19.9

+ k f 2 2

4.27 3.12 3.34 3.20 8.36

31 31 31 32 31

-0.54 -0.66 - 2.46 0.34 - 1.43

NS NS 0.02 NS NS

“Bunney-Hamburg psychosis ratings the day before the LP. ‘Sleep: hours of sleep as recorded by the nursing staff the night before the LP ‘NE, MHPG. HVA, and 5-HIAA are expressed in pmohnl CSF.

Bunney-Hamburg scale for psychosis, depression, and mania (BH) (Bunney and Hamburg 1963). The therapists also rated the subjects weekly using the Brief Psychiatric Rating Scale (BPRS) (Overall et al. 1967). Criteria for relapse consisted of a mean 3-day increase of 3 points or more in the psychosis item of the BH, compared to the mean ratings of this item during the last 7 days of haloperidol treatment (van Kammen et al. 1982), and also a lo-point increase in the BPRS psychosis subscale (Lieberman et al. 1985, 1987) compared to the BPRS of the last week of haloperidol. After haloperidol withdrawal, 14 patients relapsed in l-6 weeks (mean 22 days), and 18 did not. Night-time hours of sleep were calculated between the time the patient went to bed in the evening and 6:30 AM (mandatory time for the patient to wake up). The sleep status of the patient was checked every half hour during the night. If the patient was asleep at the time of checking, he was considered to be asleep for the previous half hour.

Statistical Analysis Students’ t-tests and Pearson’s correlation coefficients were used to compare the ratings and biochemical measures between the groups and to correlate the biochemical results with the behavioral observations. Nonparametric analyses provided similar results (data not provided).

Results Table 3 shows the differences in CSF, NE, MHFG, HVA, 5-HIAA, sleep, and psychosis ratings for all patients during haloperidol treatment and the haloperidol withdrawal phase. As shown on Table 4, both prior to halopexidol withdrawal and during the drug-free phase, the CSF NE was elevated in the patients who relapsed after haloperidol withdrawal, as com-

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CSF NE and Relapse in Schizophrenia

Table 4. Observations in Patients during Haloperidol Treatment and after Haloperidol Withdrawal Relapsers’ Mean k SD During haloperidol treatment CSF NE CSF MHPG CSF HVA CSF 5-HIAA Hours of sleep night before LP Psychosis: Nurses’ Bunney-Hamburg rating (day before LP) BPRS clusters Thinking disturbance Anxious depression Paranoid/hostility Withdrawalktardation Psychosis subscale BPRS total After haloperidol withdrawal CSF NE CSF MHPG CSF HVA CSF S-HIAA Hours of sleep night before LP Psychosis: Nurses’ Bunney-Hamburg rating (day before LP) BPRS clusters Thinking disturbance Anxious depression Paranoid/hostility Withdrawal/retardation Psychosis subscale BPRS total

0.79 35.1 164.5 100.9 7.2

2 2 5 ? k

0.356 7.17 62.30 43.66 0.925

6.2 + 1.92

Nonrelapsers’ n

13 13 12 13 13 13

Mean f

0.52 34.3 175.6 82.1 7.1

2 k -c 2 2

SD

0.348 7.65 66.6 25.17 0.782

5.8 5 2.24

n

t-value

18 17 17 17 18

2.15 0.31 -0.45 1.39 0.17

0.04 NS NS NS NS

18

0.59

NS

P

8.1 6.1 7.0 7.4 19.5 55.6

? 2 + k k 5

2.20 2.25 2.08 2.44 4.85 7.37

14 14 14 14 14 14

7.6 6.9 4.9 6.9 16.7 51.4

4 k 4 k + 2

2.97 2.60 2.03 1.88 6.40 12.08

18 18 18 18 18 18

0.48 -0.92 2.89 0.61 1.38 1.14

NS NS 0.007 NS NS NS

0.91 46.2 162.4 103.6 5.0

f 2 ” 2 2

0.510 16.78 87.48 31.42 2.25

13 12 12 12 14

0.48 35.4 202.5 99.5 7.1

+ ? ? r ”

0.284 8.89 142.82 47.02 0.96

16 18 18 18 17

2.73 2.04 -0.87 0.26 -3.19

0.014 0.059 NS NS 0.005

18

10.28

0.00001

18 18 18 18 18 18

4.45 2.86 4.18 3.09 5.08 5.10

0.00001 0.008 0.001 0.006 0.00001 0.00001

10.4 2 1.65

14

11.3 8.7 9.7 8.7 26.5 71.4

13 13 13 14 13 13

f k ” f f k

3.92 3.30 3.33 3.52 7.72 16.55

4.1 k 1.78

5.9 5.8 5.6 5.4 15.1 45.7

k ” f 2 2 f

2.87 2.39 2.12 2.06 4.81 Il.51

“Refers to condition after haloperidol withdrawal

pared to the patients who did not relapse (Figure 2). Additionally, relative to the CSF NE levels measured during haloperidol treatment, during neuroleptic withdrawal CSF NE increased nonsignificantly in the relapsing patients (Table 5), whereas it decreased significantly in the nonrelapsing group (Table 6). During haloperidol treatment, CSF, MHPG, HVA, 5-HIAA, psychosis, and hours of sleep were not significantly different between the two patient groups. Despite the increased CSF NE levels in the relapsers relative to the nonrelapsers during haloperidol treatment, individual BPRS ratings were not significantly higher, withtheexceptionofthehostilityitem(2.3 k 0.91 versus 1.6 k 0.71,~ = 0.016). The two additional items, which form the paranoid subscale with the hostility item-suspiciousness(3.0 k 1.52versus2.1 + 1.13,~ = 0.067)anduncooperativeness(l.7 k 0.91 versus 1.2 + 0.73, p = 0. lo)--were nonsignificantly elevated. As a result, the paranoid-

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D.P. van Kammen et al.

CSF NE AND MHPG INCREASE WITH RELAPSE

H

H

PL PL

H

H

PL PL

Figure 2. CSF, NE, and MHF’Glevels before and after haloperidol withdrawal. hostility cluster was significantly higher in these patients (Table 4). The BPRS items anxiety (2.1 2 0.83versus2.8 -+ 1.15,~ = 0.045)andtension(2.6 f 0.85versus3.2 k 0.86,~ = 0.06) were significantly lower in this group during haloperidol treatment. As expected, in the drug-free condition, relapsing and nonrelapsing patients showed significant differences in all of the BPRS clusters (Table 4).

Table 5. Comparisons between Haloperidol- and Placebo-Treated Conditions in the Patients who Relapsed after Haloperidol Withdrawal

CSF NE CSF MHPG CSF HVA CSF 5-HIAA Hours of sleep night before LP Psychosis: Nurses’ Bunney-Hamburg rating (day before LP) BPRS clusters Thinking disturbance Anxious depression Paranoid/hostility Withdrawal/retardation Psychosis subscale BPRS total

During halopetidol treatment

After haloperidol withdrawal

Mean k SD

Mean zk SD

0.79 35.2 161.1 99.2 7.2

k k f k ”

6.2 f

8.0 6.1 6.9 7.4 19.3 55.1

-c -c k -c k 2

0.372 7.48 64.15 45.13 0.93

0.90 46.2 143.7 103.6 4.8

2 k -c k t

n

f-value

D

0.531 16.78 61.60 31.42 2.22

12 12 11 12 13

-0.69 - 2.08 0.75 -0.46 3.45

NS 0.061 NS NS ,005

1.92

10.5 f

1.66

13

-7.27

0.09001

2.27 2.33 2.14 2.44 4.99 7.42

11.3 8.7 9.7 8.7 26.5 71.4

3.92 3.30 3.33 3.52 1.72 16.55

13 13 13 14 13 13

- 2.92 -2.24 -2.25 -1.23 -2.79 -2.91

0.013 0.045 0.044 NS 0.016 0.013

2 t f -c f k

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CSF NE and Relapse in Schizophrenia

Table 6. Comparisons between Haloperidol and Placebo Treatment Conditions who Did Not Relapse following Haloperidol Withdrawal Haloperidoltreated Mean 2 SD

CSF NE CSF MHPG CSF HVA CSF 5-HIAA Sleep Psychosis BPRS clusters Thinking disturbance Anxious depression Paranoid/hostility Withdrawal/retardation Psychosis subscale BPRS total

0.56 34.3 175.6 82.1 7.1 5.8

2 2 k T I f

0.337 7.65 66.63 25.17 0.78 2.24

7.6 6.9 4.9 6.9 16.7 51.4

‘” 2 5 -c 2

2.97 2.60 2.03 1.88 6.4 12.1

183

in the Patients

Drug-free Mean f 0.48 34.9 201.6 96.7 7.1 4.1 5.9 5.8 5.6 5.4 15.1 45.7

k -c k ? 2 2

SD

n

f-value

P

0.284 8.83 147.16 46.88 0.96 1.78

16 17 17 17 17 18

2.33 -0.44 -0.79 - 1.66 0.00 3.59

0.034 NS NS NS NS 0.002

18 18 18 18 18 18

3.33 2.82 -1.17 2.32 1.32 2.43

0.004 0.012 NS 0.033 NS 0.026

-+ 2.87 ? 2.39 of: 2.12 * 2.06 lr: 4.81 + 11.5

The daily dose of haloperidol did not correlate with CSF NE on haloperidol (r = - 0.13, n = 18 p NS). When we compared the seven highest daily doses with the seven lowest for CSF NE on haloperidol, no significant differences were observed. Nor were the daily doses significantly different when we compared these doses in the patients with the highest CSF NE levels to those who had the five lowest levels. CSF NE was highly positively correlated with psychosis ratings and negatively with sleep in the drug-free relapsing patients (Table 7). Significant relationships between these variables were not observed in either group prior to haloperidol withdrawal or in the drug-free nonrelapsed patients. CSF MHPG correlated positively with sleep in the total group of haloperidol-treated patients. CSF NE and MHPG correlated significantly with each other in all groups, except in the haloperidol-treated patients who would later relapse (Table 7). CSF HVA and 5-HIAA were not significantly different in the relapsers and nonrelapsers, before or after haloperidol withdrawal (Tables 3 and 4).

Discussion Our data support the hypothesis that central NE activity is increased in patients with chronic schizophrenia who relapsed after neuroleptic withdrawal. Thus, CSF NE is probably not increased secondary to the psychotic symptoms. The data do not suggest that higher CSF NE levels during haloperidol treatment are drug induced. We propose that the elevated CSF NE is indeed a prerelapse or prodromal condition and is not caused by haloperidol treatment per se. Increased NE activity has been associated with paranoid schizophrenia (Lake et al. 1980; Stemberg et al. 1983). The increase in CSF NE in the relapsers on haloperidol was associated with increased paranoid symptomatology. This suggests that schizophrenic patients with paranoid symptoms may effectively be classified as stable and unstable patients. Such a state dependency may also explain why paranoid schizophrenia has been associated with both excellent (Goldstein 1970; Judd et al. 1973) and poor response to

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Table 7. Relationshipbetweeen CSF NE with Psychosis, Sleep and CSF MHPG, HVA and SHIAA Psychosis

Sleep

MHPG

HVA

5-HIAA

0.11

0.28

TOTAL GROUP CSF NE

Haloperidol

CSF NE Drug-free

CSF NE Haloperidol

CSF NE Drug-free

CSF NE Haloperidol

CSF NE Drug-free

r n P r n P

r n P r II P

r n P r n P

-0.02 30 NS 0.56 29 0.001

-0.10 12 NS 0.57 13 0.02

-0.02 18 NS 0.06 16 NS

0.04

0.20

30 NS -0.63 28 O.GQOl

29 NS 0.59 28 0.001

RELAPSERS -0.12 12 NS -0.55 13 0.027 NON-RELAPSERS 0.17 18 NS -0.37 15 NS

-0.19 12 NS 0.49 12 0.05

0.42 17 0.04 0.54 16 0.015

29 NS -0.14 28 NS

29 NS 0.06 28 NS

-0.12 12 NS 0.05 12 NS

0.37 12 NS 0.19 12 NS

0.38 17 NS -0.14 16 NS

0.07 17 NS - 0.03 16 NS

neuroleptics (Hollister et al. 1974). The subtle behavioral differences between the relapsers and nonrelapsers while on haloperidol require further study. The significantly lower BPRS ratings of anxiety and the increased CSF NE levels in the relapsers during haloperidol treatment are intriguing. Increased anxiety and tension are hypothesized to be caused by increased NE activity (Redmond and Huang 1979; Gray 1982). Several groups have found CSF NE to be elevated in drug-free patients (Gomes et al. 1980; Lake et al. 1980; Kemali et al. 1982; Gattaz et al. 1983). Moreover, we have previously found CSF NE to correlate with psychosis in some patients (Linnoila et al. 1985). Repeated CSF NE measurements intercorrelate significantly with each other in patients who had two drug-free LPs, but not in those with three or four (Linnoila et al. 1983). This may be due to the time lapse between the first and last LPs. This suggests that there may be episodic increases and decreases in CSF NE that are larger than those in CSF MHPG, HVA, or 5HIAA. Conceivably, after patients have responded to neuroleptic treatment and have shown a decrease in CSF NE (Stemberg et al. 1981), CSF NE may fluctuate in some patients during maintenance treatment, reflecting the episodic nature of the disorder. Whether or not such elevations eventually lead to a breakthrough psychosis during neuroleptic treatment cannot be answered by our study. At least during the drug-free condition, such episodic increases may affect clinical state. As our data indicate, the clinical state of the patient determines whether or not significant relationships or differences will be observed. If LPs are scheduled at standardized times after neuroleptic withdrawal, variable clinical states will be sampled. Psychosis ratings by themselves do not have to relate to CSF NE or MHPG levels, as patients can be chronically psychotic without being in the process of decompensation. Only in the decompensating patients

CSF NE and Relapse in Schizophrenia

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185

did we find the strongest relationships. As shown in Figure 1, the LPs took place as soon as the relapse criteria were met, i.e., when psychosis ratings increased beyond the preestablished threshold. After the LP had been obtained, the clinical state of most patients continued to deteriorate. We chose not to wait with the LP until the psychosis had peaked. The time of maximum psychotic decompensation was not used to measure CSF NE levels, as the degree of increase varies in different patients and may have a variable duration. This variability in intensity and time makes it hard to use maximum psychotic decompensation for timing the LP consistently. Several groups have studied CSF NE in schizophrenic patients off and on neuroleptics. The conflicting results may be understood in light of the present findings. In our clinically stable patients, we found a decrease in CSF NE after haloperidol withdrawal together with a small but significant decrease in psychosis ratings. The NE results in this group of nonrelapsers are similar to the findings of Zander et al. (198 1) and Bagdy et al. (1985), who reported a decrease in plasma and CSF NE levels following a 2-week withdrawal from chronic drug treatment in a group of schizophrenic patients. As clinically stable patients are more likely to participate in drug-free evaluations following drug withdrawal (Zander et al., 1981; Bagdy et al. 1985; Mueller-Spahn et al. 1986; Glazer et al., 1987), we speculate that the majority of the patients in these two studies were in a clinical state similar to our stable subgroup that showed a decrease in CSF NE after drug withdrawal. The decrease in psychotic symptoms after drug withdrawal has also previously been observed by us (van Kammen et al. 1978; Marder et al. 1979). The observed increased NE levels in the relapsing patients, on the other hand, seem to agree with the results of the study by Stemberg et al. (1981), who measured CSF NE before, during, and after short-term pimozide treatment. They found NE levels to decrease during pimozide treatment, but subsequently, to increase after drug withdrawal. This increase in CSF NE was associated with an increase in psychosis ratings and correlated with the time after pimozide withdrawal. The present results suggest that during maintenance drug treatment, CSF NE levels may increase when patients become biochemically unstable. In the presence of increased NE levels, the removal of DA receptor blockade seems to lead to psychotic decompensation. The correlations between CSF NE and MHPG in the off-drug relapsed (r = 0.49, p = 0.05) and stable patients (r = 0.54, p = 0.015) were very similar to each other, suggesting that the higher levels observed in the relapsers after haloperidol withdrawal were not due to changed NE metabolism. During haloperidol treatment, the relationships between CSF NE and MHPG were similar to the drug-free conditions in the nonrelapsers (t = 0.42), but were different in the relapsers (r = -0.19). The cause for this remains obscure. Whether or not plasma NE and MHPG show changes similar to the CSF levels (Zander et al. 1981; Kemali et al. 1982; Kopin et al. 1983; Bagdy et al. 1985) remains to be evaluated in subsequent studies. As NE and MHPG levels in any compartment, e.g., CSF, plasma, or urine, provide limited information, combined measures are needed for a more complete interpretation of the findings (Kopin et al. 1983; Linnoila et al. 1985, 1986; Maas et al. 1987). Why would CSF NE be elevated in haloperidol-treated schizophrenic patients who relapsed subsequently following withdrawal? There are several possible explanations for this phenomenon. First, CSF NE is elevated because of the distress a patient is experiencing. We have no evidence that this was the case. Actually the patients who later relapsed were less anxious, although more paranoid. Second, elevated CSF NE is produced by haloperidol treatment. Both groups were treated with similar doses of haloperidol,

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which makes this somewhat unlikely. Furthermore, the daily dose of haloperidol did not correlate significantly with CSF NE during haloperidol treatment (r = - 0.20, n = 31, p = 0.139). In th e relapsing patients, off-drug CSF NE levels did not correlate significantly with days off drug till time of LP (r = 0.25, n = 13, p NS). Third, elevated NE levels may be from cells that escape a haloperidol-induced nonresponsive state (Dinan and Aston-Jones 1985), which is analogous, but not identical, to the depolarization block in the DA neuronal system in animals treated with chronic haloperidol (Bunney and Grace 1978; Skirboll and Bunney 1979). If such an escape does occur in some patients, they could also be more vulnerable to relapse during neuroleptic treatment. Regardless of the explanation, elevated CSF NE seems to be associated with an increased risk of relapse after neuroleptic withdrawal. In the off-drug condition, this elevation is most likely not secondary to the increased symptomatology of psychotic decompensation. Despite strong evidence of a DA involvement in schizophrenia, NE activity may play a modulatory role in the psychotic decompensation process. The authors wish to thank the nursing staff under Doris McAdam, RN, Head Nurse, and the patients of the Schizophrenia Research Unit of the Highland Drive VA Medical Center for their cooperation and support. Debra Kirby typed the manuscript.

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