Urinary MHPG and ward behavior in unmedicated psychiatric patients

Psyc~hiorr~~ Rewawh.

10, 275-283

275

Elsevier

Urinary MHPG and Ward Psychiatric Patients KimT. Mueser, AlexanderJ. Received April&

Behavior

in Unmedicated

Rosen, Maurice W. Dysken, and Javaid I. Javaid

1983; revised version receivedseptember

14, 1983; accepted October 21, 1983.

Abstract. The relationship between urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and overt behaviors emitted in two hospital environments was examined in a group of 27 drug-free psychiatric patients. Depressed patients with high MHPG excretion ate less and engaged in less visual activity in the lunch environment. Schizophrenic patients but not depressive patients with high MHPG tended to have greater body activity during the gym environment. The implications of these findings for the identification of subtypes of depression and schizophrenia, and for an improved methodology in investivation of biobehavioral relations in clinical populations, are discussed. Key Words. MHPG, behavior, depression, schizophrenia, tions, psychopathology.

naturalistic

observa-

The catecholamine hypothesis of affective disorders (Bunney and Davis, 1965; Schildkraut, 1965) describes subgroups of depressed patients who suffer from an imbalance of brain norepinephrine (NE), NE metabolism, or both. Levels of 3-methoxy-4hydroxyphenylglycol (MHPG), a major brain metabolite of NE (Mannarino et al., 1963), are typically measured in urine, cerebrospinal fluid (CSF), and plasma to estimate central nervous sytem (CNS) NE activity. Most CSF MHPG originates in the spinal cord (Garelis et al., 1974), whereas 50% or more of urinary MHPG is thought to be derived from brain NE metabolism (Ebert and Kopin, 1975; Maas et al., 1979) and 24-hour MHPG samples provide a good estimate of overall brain NE turnover (Mahorney et al., 1981). The relationship between MHPG excretion and motor behavior is a controversial issue. Fluctuations in MHPG have been positively correlated with motor activity in different stages of manic-depressive illness (Greenspan et al., 1970; Bond et al., 1972; Deleon-Jones et al., 1973; Goodwin and Post, 1975) and muscular activity increases levels of catecholamines in the urine (von Euler and Hellner, 1952), suggesting that physical activity is related to NE turnover. Controlled exercise has been found to increase urinary MHPG in depressed patients (Ebert et al., 1972; Beckmann et al., 1979), but other studies did not find this relation for either depressed patients (Sweeney et al., 1978) or normals (Goode et al., 1973; Hollister et al., 1978; Sweeney et al., 1978). Tang et al. (198 1) reported that exercise caused an increase in plasma but not urinary MHPG in normals. Kim T. Mueser, M.A.. Alexander J. Rosen, Ph.D., Maurice W. Dysken, M.D., and Javaid I. Javaid, Ph.D., are from the Departments of Psychology and Psychiatry. University of Illinois at Chicago, and the Illinois State Psychiatric Institute. (Reprint requests to K.T. Mueser. University of Illinois at Chicago, Dept. of Psychology. P.O. Box 4348, Chicago, IL 60680. USA.) 0165-1781

83 $03.00 0 1983 Elsevier Science Publishers

B.V

276

Clinicians are often taught that retarded depressions respond better to imipramine and agitated depressions respond better to amitriptyline (van Praag, 1978). Some studies found that agitated depressions had higher pretreatment MHPG levels than retarded depressions (Cobbin et al., 1979; Sacchetti et al., 1979), but other studies did not support this (Deleon-Jones et al., 1975; Taube et al., 1978). A recent behavioral analysis of the effects of amitriptyline found that responders tended to have long speech pauses and long periods of head aversion during an interview, whereas nonresponders had many posture shifts and “body-focused self-adapters” (Ranelli and Miller, 1981). These findings appear to contradict the stereotype that amitriptyline responders, who tend to have elevated pretreatment MHPG (Maas et al., 1972; Beckmann and Goodwin, 1975), are ITlore agitated than nonresponders. However, the interview situation imposes severe constraints on the behavior observed. The present study examined a more complete range of naturally occurring behaviors in the ward setting to determine MHPG-behavior relations in a mixed group of psychiatric patients. Methods Subjects. Twenty-seven newly admitted patients at the Illinois State Psychiatric Institute (ISPI) were selected on the basis of the following criteria: (I) between the ages of 18 and 65; (2) DSM-III Axis 1 diagnosis of major depressive disorder. bipolar depression or mania, schizophrenia, or schizoaffective disorder (American Psychiatric Association, 1980); (3) no organic impairment; (4) availability for naturalistic observation; (5) ward behavior sufficiently manageable that pharmacological intervention would not be required during a 2-to 3-week drug-free period. Since subjects differed in their availability for study, depending on their willingness to take part in the ward activities or provide urine samples, there were some variations between subjects in the quantity of data collected. All subjects were observed on at least 4 different days, however. Subjects resided on one of the ISPI research wards with other psychiatric patients, some of whom were not included in the study. Sex, age. and diagnoses of the subjects are presented in Table I.

Table 1. Subject characteristics, and MHPG and MHPGkreatinine per 24 hours for different diagnostic groups Mean (SD) pg MHPG/mg creatinine

excretion

Diagnostic group

M

F

Mean age (years)

Schizophrenia

6

6

26.3

0.99

10.351

Unipolar depressed

1

7

41.4

0.88

10.37,

856.2

Bipolar depressed

2

1

30.0

0.84

io.201

1496.5

I460.5 I

Bipolar manic

1

1

34.5

2.17

‘0.931

1647.2

‘775.31

Schizoaffective depressed

0

2

39.0

1.10

(0.67,

593.2

Sex

Range 19-60

Range 0.30-3.11

Mean (SD) pg MHPG 1598.1

1955.1 /

In=lll

(333.5 I m=

1490.31 Range 251-3500

6)

277 Measurement. Twenty-four hour urine specimens were collected during a drug-free period and assayed using the electron capture gas-liquid chromatography method of Dekirmenjian and Maas (1970). Factors that influence the 24-hour urine MHPG excretion include sex, age, weight, body surface, and completeness of collection. Variability in MHPG excretion due to these factors can be reduced by covarying with 24-hour urinary creatinine excretion since the latter reflects changes due to sex and skeletal muscle mass (Gitlow et al., 1968; Maas et al., 1972). For this reason we have presented not only urinary M HPG data but M HPG/creatinine data as well. One schizophrenic and two depressed patients were dropped from the MHPG analyses because their low creatinine levels (< 500 mg) suggested that the samples were incomplete. Four of the 27 subjects had one M HPG determination made during the drug-free period, I3 subjects had two, seven had three, two had four, and one had five MHPG determinations. Means of these values were used in the analyses. MHPG

Behavioral Observation Instrument. Behavioral data were collected using the Observational Record of Inpatient Behavior (ORIB). The ORIB (Rosen et al., 1980) is a time-sampling instrument used to record eight separate categories of overt behavior: body activity (movement of torso), extremity activity (movement of arms or legs without body activity), interpersonal proximity (within an arm’s distance), social interaction (verbal or physical interpersonal exchange), scanning (eye or head movement, distinguished from fixation), laughing/smiling, participation (engagement in ongoing activity, e.g., eating during lunch, playing during gym time), and idiosyncratic behavior (repetitive movements, self-verbalization, bizarre behavior). Procedure for Behavioral Observations. A focal time-sampling procedure (Altman. 1974) was used. A patient’s behavior was observed for a 5-second interval. The behaviors were then

recorded in a binary fashion (occurrence/ nonoccurrence) during the following 20 seconds, and observed again for another 5 seconds until nine consecutive observations were obtained (45 total seconds of observation). These nine observations were summed individually for each behavior to form a single ORIB profile. The ORIB uses well-trained observers to insure high interrater reliability (correlation coefficients for trained raters range from 0.80 for laughing/smiling to 0.98 for participation; overall mean q 0.87; Rosen et al., 1980). At least two ORIB profiles were recorded for each patient per week. Behavioral means were calculated for each subject by averaging the number of observations made during the 2-to 3-week drug-free period. Behavioral observations were recorded by one rater at a time in two environments: in the gym between 9:15 and IO:00 a.m. and in the dayroom during lunch time, between I I:30 a.m. and noon. The gym is a 30 x 60 foot room where patients engage in activities such as volleyball, badminton, baseball, and dancing. The rater was stationed next to the door and was as unobtrusive as possible. The ward dayroom is a 20 x 40 foot room with four rectangular tables, each with six person seating capacity. Observations were recorded from the nurses’ station, within 20 feet of each patient. Eight different observers were used to collect the behavioral data. All observers were blind to DSM-III diagnoses; they neither interviewed the patients nor attended diagnostic and treatment meetings.

Results Pearson product-moment correlations computed for age vs. MHPG and age vs. MHPG/ creatinine ratio were not significant (r = -0.23, df= 22, NS; r = 0.06, df= 25, NS, respectively). Two-tailed t tests for MHPG differences between males and females were also not significant (t 0.35, df 22, NS; I = 0.85, df = 25, NS). Table I contains the means and standard deviations of M HPG and M HPG/ creatinine for the different diagnostic groups. One-way analyses of variance (ANOVAs) were computed comparing MHPG and MHPG/creatinine between unipolar depressed, bipolar depressed, and schizophrenic patients, neither of which was significant (F= 1.85, df=2, 17, NS; F 0.34, &= 2, 20, NS). q

q

q

278 The distribution of M HPG and M HPG; creatinine for depressed patients was also examined. To determine whether MHPG was more homogeneously distributed among depressed patients than schizophrenics, as was found by Taube et al. (1978), an F test was computed (schizoaffectives and manics excluded) which was marginally significant for MHPG (F= 3.15, &= 10,8,p
279 Table 2. Means of selected behaviors creatinine depressed and schizophrenic

for low and high groups

Depressed Low MHPG High MHPG (n = 8, (n = 3, R = 0.72) X=1.28)

Environment

pg MHPG/mg

Schizophrenic Low MHPG High MHPG’ (n = 5,

t

(n = 7,

x = 0.66)

x=1.23)

f

Lunch Scanning

6.3

4.4

2.92

7.1

6.6

0.8

Participation

8.3

6.5

3.53

6.8

6.8

0

Idiosyncratic

0

0

-

0.1

0.3

0.5

5.5

4.2

0.9

5.8

Gym Body activity

The two-tailed t tests compare low and high subgroups MHPG/24 hours. 1. n = 6 for gym environment. 2. p S 0.02. 3. p 2 0.01.

within the same diagnostic

2.92

8.0 category.??denotes

mean rg

Table 3. Means of selected behaviors for low and high pg MHPG depressed and schizophrenic groups Depressed Low MHPG High MHPG

Schizophrenic Low MHPG High MHPG’

(n = 5,

(n = 4,

(n = 7,

(n = 4,

x = 744.9)

x = 1475.5)

t

x = 1035.7)

x = 2560.2)

Scanning

6.2

5.5

0.8

7.1

6.5

1.0

Participation

8.3

7.5

1.1

7.4

6.1

1.92

Idiosyncratic

0

0

-

0.3

0.1

0.4

8.4

2.73

Environment

t

Lunch

Gym Body activity

5.4

6.2

The f tests compare low and high subgroups hours. 1. n = 3 for gym environment. 2. p 5 0.10. 3. p 5 0.03.

within

0.8

thesame

6.2

diagnostic

category.Xdenotes

mean rg MHPGI24

from the low MHPG patients in this sample and either behavior alone misclassifies only one patient. Schizophrenic patients with either low MHPG/creatinine or low MHPG had less bodyactivityduringgym than the high MHPG/creatininepatients(t=2.91, df=9,p< 0.02; t 2.70, df 8, p < 0.03) (Tables 2 and 3). There was also a weak tendency for schizophrenic patients with low MHPG, but not for the low MHPG/creatinine group, to eat more in the lunch environment (t = 1.9, df= 9, p < 0.10). q

q

Discussion The measurement

of directly

observable

discrete

behaviors

occurring

naturally

in

280 Fig. 1. Scanning and participation during lunch for low (n = 8) and high (n = 3) MHPGIcreatinine depressed patients

9

r

A

AA

A

Scanning 0 = highpg A -----

MHPG/mg

- bw I_cg MHPG/mg

creatinine (mean4.23) creatinine

(meaw.72)

Discrimination axis

Units for behaviors are expressed in average frequency sampled during a 3-minute period.

of occurrence

III nine 5-second

mtervals of observations

various hospital settings revealed that body activity in the gym environment was correlated with MHPG for the entire patient sample, but that this relation was present only among the schizophrenics, and not the depressives. This finding is in accord with the report of Taube et al. (1978) that MHPG excretion was correlated with clinical ratings of agitation in schizophrenic but not depressed patients. The lack of a relationship between directly recorded aspects of motor activity and M HPG in our group of depressed patients contributes to the accumulating evidence that the agitatedwithdrawal distinction in depression is not related to MHPG excretion (Deleon-Jones et al., 1975; Goodwin and Post, 1975; Taube et al., 1978). Visual activity during lunch time for the whole patient group was related to MHPG,‘creatinine excretion; a high rate of visual shifts (scanning) was associated with low MHPG;‘creatinine production. This relation between scanning and MHPG suggests that high levels of NE may increase visual fixation in a relatively sedentary environment, i.e.. during lunch time, with a consequent increase in focal attention to salient stimuli, a result that has been reported with amphetamine administration (Callaway and Stone. 1970). If visual activity, attentional process, or both are related to MHPG,‘creatinine excretion in depressed patients, then low NE patients might be expected to experience more difficulties in concentration (i.e., distractibility) than high NE patients. Eating behavior in the lunch-time environment was also related to MHPG: creatinine in the depressed patients. and more weakly to MHPG in the schizophrenic

281

patients. In both diagnostic groups patients with high MHPG ate less. Since noradrenergic stimulation decreases appetite (Goodman and Gilman, 1975) these results suggest that decreased appetite and weight loss may be a consequence of NE hyperactivity in a subgroup of depressed patients. It is possible that decreased appetite leads to visual fixation as a compensatory mechanism for dealing with somewhat aversive environmental situations. However, the precise nature of the relation between scanning and eating requires further elucidation. Patients with elevated MHPG levels also exhibited idiosyncratic behaviors during lunch time. Since approxiamtely half of the idiosyncratic behaviors observed were repetitive movements, this relation suggests a human parallel to amphetamineinduced stereotypies in animals. The other idiosyncratic behaviors, self-verbalizaton and bizarre behavior, may be the consequence of perseverative thinking induced by high levels of NE (Ellinwood et al., 1973). The finding that the two manic patients in this study engaged in higher rates of idiosyncratic behavior than the schizophrenics is consistent with the reports of McGuire and Polsky (1979) and Polsky and McGuire (1979), who also found higher rates of “pathological behavior” in manics than acute schizophrenics. There was no relation between idiosyncratic behavior and MHPG or MHPG/ creatinine in the gym because only a few patients exhibited these behaviors in this environment. The finding that MHPG tended to be distributed more hetergeneously in schizophrenics than in depressives (p < 0. IO) is consistent with the results of Taube et al. (1978). This result was not obtained for the MHPG/creatinine ratio in the present study and the ratio itself was not examined by Taube et al. The relatively small sample size studied here, the disproportionate number of women to men in the unipolar depressed group (7 to 1) and the use of numerous univariate tests of significance indicate that the present results should be interpreted with caution. However, the high reliability of the behavioral data and the unobtrusive and objective way in which the observations were made represent methodological advances in clinical psychopharmacology and suggest that a careful analysis of biobehavioral relations (e.g., Rosen et al., 1982) can contribute to a better understanding of specific drug effects in psychiatric populations. Acknowledgment. The authors express their thanks to the staffs on the ISPI research wards of 5 West and 9 East, and to Steve Sussman for his help in data collection. The research reported was supported in part by State of Illinois Department of Mental Health and Developmental Disabilities grants (nos. RD 83613 and RD 62202).

References Altman, J. Observational study of behavior: Sampling methods. Behavior. 49,227 (1974). American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. APA, Washington, DC (1980). Beckmann, H., Ebert, M.H., Post, R., and Goodwin, F.K. Effect of moderate exercise on urinary MHPG in depressed patients. Pharmacops_vchiatry, 12, 35 1 (1979). Beckmann. H., and Goodwin, F.K. Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Archives of Genera/ Ps_vchiatrv. 32, 17 (1975).

282

Bond, P.A., Jenner, F.A., 3-methoxy-4-hydroxyphenylglycol

and Sampson, G.A. Daily variations in two manic-depressive patients.

of the urine content Psychological

of

Medicine,

2, 81 (1972).

Bunney, General

W.E., Jr., and Davis, J.M.

Psychiatry,

13,483

Norepinephrine

in depressive

reactions.

Archives

af

(1965). G. Drugs

Callaway, E., and Stone, and Behavior. Wiley, New York (1970). Cobbin, D.M., Requin-Blow, B., Williams, L.R., and Williams, W.O. Urinary MHPG levels and tricyclic antidepressant drug selection. Archives of General Psychiatr,,, 36, I I I I (1979). Dekirmenjian, H., and Maas, J.W. An improved procedure of 3-methoxy-4-hydroxyphenylethylene glycol determination by gas-liquid chromatography. Analytical Biochemistry, 35, 113 (1970).

Deleon-Jones. F.. Maas. J.W., Dekirmenjian, H., and Fawcett, J.A. Urinary catecholamine metabolites during behavioral changes in a patient with manic depressive cycles. Science, 179, 300 (1973). Deleon-Jones, F., Maas. J.W., Dekirmenjian, H., and Sanchez, J. Diagnostic subgroups of affective disorders and their urinary excretion of catecholamine metabolites. American Journal of Psychiatry,

132, 1141 (1975).

Ebert, M.H., and Kopin. metabolites by Dopamine-Cl”.

1.J. Differential Transactions

labeling ofthe

of origins

Association

of urinary

qf American

catecholamine

Physicians.

8,256

(1975).

Ebert, M.H., Post, R.M.. and Goodwin, F.K. Effect of physical activity on urinary MHPG excretion in depressed patients. Lancer. II, 766 (1972). Ellinwood, E.H.. Jr., Sudilovsky. A.. and Nelson, C.M. Evolving behavior in the clinical and experimental amphetamine (model) psychosis. American Journal qf Psychiatq,, 130, 1088 (1973).

von Euler, O.S., and Hellner, S. Excretion of noradrenaline and adrenaline in muscular work. Acta Physiologica Scandinavica, 26, 183 (1952). Garelis, E., Young, S.N., Lal, S.. and Sourkes. T.L. Monoamine metabolites in lumbar CSF: The question of their origin in relation to clinical studies. Brain Research, 79, 1 (1974). Gitlow, S.E., Mendlowitz. M., Wilk, E.R.. Wilk., S., Wolf, R.L., and Bertani. L.M. Excretion of catecholamine catabolites by normal children. Journal sf Laboratory and Clinical Medicine,

72, 6 12 ( 1968).

Goode, D.J., Dekirmenjian, H.. Meltzer. H.Y., and Maas, J.W. Relation of exercise to MHPG excretion in normal subjects. Archives qf General Psychiatry, 29, 391 (1973). Goodman, L.S., and Gilman, A. The Pharmacological Basis of Therapeutics. 5th ed. Macmillan Publishing Co., New York (1975). Goodwin, F.K.. and Post, R.M. Studies of Amine Metabolites in Affective Illness and in Schizophrenia: A Comparative Analysis. In: Freedman, D.X.. ed. Biology of the Major Psychoses. Raven Press. New York, p. 299 (1975). Greenspan, K.. Schildkraut, J.J., Gordon, E.K.. Baer, L., Aronoff, M.S., and Durell, J. Catecholamine metabolism in affective disorders: 111. MHPG and other catecholamine metabolites in patients treated with lithium carbonate. Journal qf' Psychiatric Research, 7, 17 I (1970). Hollister, L.E., Davis. K.L.. Overall, J.E, and Anderson, T. Excretion of MHPG in normal subjects. Archives qf General Psychiatry. 35, 1410 (1978). Maas. J.W., Fawcett. J.A., and Dekirmenjian. H. Catecholamine metabolism, depressive illness, and drug response. Archives qf General Ps,)chiatr,s, 26, 252 (1972). Maas, J.W., Hattox. S.E., Greene, N.M., and Landis, D.H. 3-Methoxy-4_hydroxyphenylethylene glycol production by human brain in vivo. Science, 205, 1025 (1979). Mahorney, S.L.. Sullivan, J.L., and Taska, R.J. SHIAA and MHPG: Clinical implications and considerations. Journal qf Occuparional Psychiatry, 12, 32 (1981). Mannarino. E.. Kirschner, N., and Nashold. B.S. The metabolism of (Cr4) noradrenaline by cat brain in vivo. Journal qf Neurochemistrjl, 10, 373 (1963). McGuire, M.T., and Polsky. R.H. Behavioral changes in hospitalized acute schizophrenics. Journal

qf Ner\,ous and Mental Disease. 167, 65 I (1979).

283

Polsky, R., and McGuire, nal of Nervous

M.T. An ethological

van Praag, York (1978). Ranelli, C.J., and Miller, R.E. Behavioral American

analysis of manic-depressive

and Mental Disease, 167, 56 (1979). H. M. Psychotropic Drugs: A Guide for

Journal

of Psychiatry,

predictors

the Practitioner.

of amitriptyline

disorder.

Brunner/ response

Jour-

Maze], New in depression.

138, 30 (198 I).

Rosen, A.J., Tureff, S.E., Daruna, J.H., Johnson, P.B., Lyons, J.S., and Davis, J.M. Pharmacotherapy of schizophrenia and affective disorders: Behavioral correlates of diagnostic and demographic variables. Journal of Abnormal Psycholog.v, 89, 378 (1980). Rosen, A.J., Wirtshafter, D., Pandey, G.N., and Davis, J.M. Platelet monoamine oxidase activity and behavioral response to pharmacotherapy in psychiatric patients. Ps_vchiarr_v Research,

6, 49 ( 1982).

Sacchetti, E., Allaria. E., Negri, F., Biondi, P.A., Smeraldi, E.. and Cazzullo. C.L. 3Methoxy-4-hydroxyphenylglycol and primary depression: Clinical and pharmacological considerations. Biological Psychiatry, 14,473 (1979). Schildkraut, J.J. The catecholamine hypothesis of affective disorders: A review of supporting evidence. American Journal of Ps.vchiarrja. 122, 509 (I 965). Sweeney, D.R.. Maas, J.W.. and Heninger. G.R. Stateanxiety, physical activity and urinary 3-methoxy-4-hydroxyphenylethylene glycol excretion. Archives of General Psychiatry. 35, 1418 (1978).

Tang, S.W.. Stancer, H.C.. Takahashi, S., Shephard, R.J., and Warsh, J.J. Controlled exercise elevates plasma but not urinary MHPG and VMA. Psychiarry Research, 4, I3 (1981). Taube. S.L.. Kirstein, L.S., Sweeney, D.R. Heninger, G.R., and Maas. J.W. Urinary 3methoxy-4-hydroxyphenylglycol and psychiatric diagnosis. American Journal of Psychiarry, 135, 78 (1978).

Wilkinston, (1979).

L. Tests of significance

in stepwise

regression.

Ps_vcho/ogical

Bulletin.

86, I68