Growth hormone response to clonidine in neuroleptic-free patients with multidiagnostically defined schizophrenia

Psvchiatrv Research, 48:79-90 Elsevier

79

Growth Hormone Response to Clonidine in Neuroleptic-free Patients With Multidiagnostically Defined Schizophrenia Nicholas A. Keks, David L. Copolov, Dean P. McKenzie, Jayashri Kulkarni, Anne Hassett, Barbara Matheson, Christine Hill, Belinda Mackie, Bruce Singh, Judith Hirt, and Michael McLaughlin Received Ma?/ 22, 1992; revised version received December 31. 1992; accepted

January

19, 1993.

Abstract. The role of qadrenergic receptor sensitivity in schizophrenia was examined by measuring growth hormone (GH) response after the intravenous administration of clonidine (1.3 pg/ kg) in 26 healthy control subjects and 26 neuroleptic-free, acutely psychotic patients with at least 1 out of 11 possible diagnoses of schizophrenia derived from a multidiagnostic psychopathological assessment. GH responses were significantly (0.01) lower than control values in schizophrenias defined by E. Bleuler, M. Bleuler, Schneider, Langfeldt, Taylor and Abrams, and Cloninger, but not in DSM-III, World Health Organization, Feighner, Kraepelian, and Research Diagnostic Criteria (RDC) schizophrenias.

Eight patients with RDC schizoaffective disorder also had a blunted response. However, there were no correlations with any symptom measures. There were no differences between paranoid and nonparanoid patients, although there was a significant difference between nonparanoid patients and control subjects. These findings support the presence of noradrenergic dysfunction in some patients within the schizophrenia syndrome, possibly those whose illnesses have an affective component. The study also illustrates the need for simultaneous investigation of several different sets of diagnostic criteria for schizophrenia in neurobiological research.

Diagnosis,

Key Words.

acute psychosis, noradrenergic

mechanisms,

psycho-

endocrinology. Although brain dopaminergic dysfunction has been widely implicated in the pathogenesis of schizophrenia (Carlsson, 1988), there is also considerable support for noradrenergic dysfunction (Hornykiewicz, 1982; Lake et al., 1987) given the probable role of noradrenalin in memory, emotion, and arousal. The release of growth hormone (GH) in response to clonidine may be a measure of central noradrenergic activity. Clonidine stimulates GH release via qadrenergic receptors (Siever et al., 1982) that are probably postsynaptic and located in the hypothalamus (Tuomista and Mannisto, 1985).

Nicholas A. Keks, M.B., Ph.D., is Professor, Department of Psychological Medicine, Monash University, Alfred Hospital, Prahran, Victoria, Australia. David L. Copolov, M.B., Ph.D., is Co-Director; Dean P. McKenzie, B.A. (Hons) is Biostatistician; Jayashri Kulkarni, M.B., is Psychiatrist; Anne Hassett, M.B., is Psychiatrist; Christine Hill, B.A., R.P.N., is Research Nurse; Belinda Mackie, B.A., R.P.N., is Research Nurse; Bruce Singh, M.B., Ph.D., is Co-Director; and Judith Hirt and Michael McLaughlin, B.Sc., are Research Assistants, National Health and Medical Research Council Schizophrenia Research Unit, Mental Health Research Institute of Victoria, Parkville, Australia. (Reprint requests to Prof. N.A. Keks, Alfred Hospital, Commercial Rd., Prahan, Victoria 3081, Australia.) 016%1781/93’$06.00

@ 1993 El sevier Scientific

Publishers

Ireland

Ltd.

80

An impaired GH response to clonidine stimulation has been consistently observed in depression (Matussek et al., 1980; Checkley et al., 1981, 1984; Charney et al., 1982; Siever et al., 1982), particularly the endogenous subtype (Ansseau et al., 1988). Matussek et al. (1980) also reported lower GH responses in schizoaffective patients than in schizophrenic patients, but the latter group consisted of two simple, one hebephrenic, one catatonic, four paranoid, and one residual subtype patients. Subsequently, La1 et al. (1983) found no differences between chronic schizophrenic patients diagnosed by Feighner criteria and control subjects, whereas Miiller-Spahn et al. (1986) found blunted responses in DSM-III schizophrenic patients after 12 days of neuroleptic withdrawal, The issue of whether the GH response to clonidine is abnormal in schizophrenia is therefore unresolved. In part, the uncertainty could be due to the heterogeneity of schizophrenia and the fact that there is no agreement about the core and boundary characteristics of the syndrome (Brockington et al., 1978; Andreasen, 1987). A number of reputable diagnostic systems for schizophrenia are in use, and the various systems differ substantially from each other in the ways in which potentially important symptoms and subsyndromes are regarded. For instance, the widely used Research Diagnostic Criteria (RDC; Spitzer et al., 1978) exclude subjects with prominent affective manifestations, but Schneiderian schizophrenia can be diagnosed irrespective of affective symptoms (Berner et al., 1983). The failure to identify a neurobiological abnormality in schizophrenia may be due to an idiosyncrasy of the particular diagnostic system being used rather than to an absence of a dysfunction in all or some of the patients. Kendell (1982) suggested that neurobiological studies could address the absence of diagnostic agreement by simultaneously applying a number of diagnostic systems. At the National Health and Medical Research Council Schizophrenia Research Unit, we have used multidiagnostic psychopathological assessment to classify acutely psychotic, neuroleptic-free patients according to I I diagnostic systems for schizophrenia (as well as RDC schizoaffective and DSM-III other psychoses categories). It was thus possible to compare a,-adrenergic receptor function as reflected by the GH response to clonidine in a variety of diagnostic groups and control subjects.

Methods The 26 patients (22 men, 4 women) were all acute admissions to Royal Park Hospital, a state psychiatric facility with comprehensive responsibility for a region of Melbourne. To be included in the study, patients were required to have the following characteristics: (1) at least one diagnosis of schizophrenia on multidiagnostic assessment; (2) neuroleptic-free status for at least I month (3 months for depot neuroleptics) determined from all possible sources; (3) absence of stimulant, hallucinogen, or antidepressant use or alcohol abuse in the preceding month (a urinary drug screen was performed); (4) adequate knowledge of English; and (5) absence of significant physical illness and obesity (assessed by full physical evaluation, routine and specific investigations) or ingestion of prescribed medication that could interfere with the neuroendocrine assessment. Temazepam and chloral hydrate were allowed if needed for sleep. No medication was permitted within 12 hours of testing. The 26 healthy control subjects (I 7 men, 9 women) were staff members and students recruited within the hospital who needed to meet the same inclusion criteria as the patients, apart from a diagnosis of schizophrenia. Among the patients, I6 had never previously received neuroleptics, four had been

81 neuroleptic-free over 12 months, one between 12 and 6 months, two between 6 and 3 months, and three between 3 and 1 months. None of the women were menopausal. After detailed clinical evaluation, the psychopathological assessment was carried out with the Royal Park Multidiagnostic Instrument for Psychosis (MIP; McGorry et al., 1986, 1990). This instrument uses several sources of information and serial interview to gather the data that is used, through the application of multiple algorithms, to assign patients to 11 diagnostic systems of schizophrenia. For the DSM-III system (American Psychiatric Association, 1980) diagnoses other than schizophrenia were also generated. In the RDC system (Spitzer et al., 1978) schizoaffective disorder was diagnosed. Two raters involved in the study were tested for interrater reliability; the mean K coefficient for all 11 diagnostic systems of schizophrenia was 0.77. Two raters who subsequently joined the study were trained until interrater reliability with an experienced rater was satisfactory. During neuroendocrine testing, which occurred on the second or third day of hospitalization, patients were also rated on the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) by one of the raters, using the zero to six severity scale version. After a fast from midnight, testing began at 9 a.m., and blood pressure was measured by a Dynamap (Criticon) monitor. A 20-gauge Venflon cannula was inserted into a forearm vein and kept patent with heparinized saline (50 units/ml) in the cannula dead space. After 15 minutes, two blood samples were taken at 15minute intervals. Forty-five minutes after cannulation, clonidine hydrochloride (Boeringer Ingelheim), 1.3 pg/ kg (Checkley et al., 1984) in IO-ml normal saline, was injected at the rate of 1 ml/minute. Further blood samples were then taken at 15, 30, 45, 60, 75, and 90 minutes after the clonidine infusion began (t = 0). Plasma was separated by centrifugation at 2,500 rpm and frozen. The GH assay was Melbourne, by performed at the Medical Research Centre, Prince Henry’s Hospital, radioimmunoassay. Interassay and intra-assay coefficients of variation were 6-8s and 3.3%, respectively, at a GH concentration of 19-22 mU/l (1 mU/l equals 0.44 ng/ml). The lower limit of sensitivity of the assay was 0.6 mu/l. During testing, patients were not permitted to sleep and remained supine throughout the procedure. For the purposes of analysis, basal GH concentrations were represented by the average of the three preinjection values: t = -30, t = -15, and t = 0. The GH response to clonidine was measured by calculating the geometric area under the response curve between t = 0 minutes and t = 90 minutes (AUC). All analyses were repeated with age as a covariate. Table 1 gives the details of each individual patient. Subjects with a GH concentration > 6 mU/l (at baseline) were excluded from the definitive analysis because elevated baseline GH levels may indicate a natural ultradian cycle of GH occurring and this interferes with measurement of the GH response (Sakeuma and Knobile, 1970; Checkley, 1980; Nutt, 1989). This diminished the control group by nine subjects (n = 17: 12 men, 5 women) but excluded none of the patients. Table 2 lists the characteristics of the I I overlapping patient groups and the control group that entered the analysis. Eleven patients met the criteria of six or more diagnostic systems, whereas three patients had only one diagnosis of schizophrenia. For each diagnostic system, patients with a positive diagnosis were compared with control subjects by independent sample t tests. As preliminary analyses found control and patient group variances to be heterogeneous, all analyses were carried out on the ranks of the GH responses (Conover and Iman, 1981). Due to the large number of comparisons and the correlations that were performed, an a level of 0.01 was used throughout. An attempt was then made to ascertain which diagnostic system showed the greatest differences from control subjects. For each diagnostic system, the multiple product-moment coefficient of correlation (R) for the relationship between the dependent variable (GH response) and group membership (control, system absent, and system present) was calculated. Group membership was first assumed to have a linear effect (e.g., lowest for controls, highest for system present) and then analyzed using dummy variables (Pedhazur, 1982). The use of dummy variables allows the effect of the presence of a particular diagnostic system to be ascertained. Both procedures for assessing the effect of group membership generated R’s that were compared across diagnostic systems by the method of Meng et al. (1992). Further details of the technique have been reported by Keks et al. (1992).

30

43

26 36

41 45

39

26 30

20 26

31.1

16

17

18 19

20 21

22

23 24

25 26

Mean

60.0 78.0

86.0 70.0

69.0

87.0 68.0

70.0 72.0

92.0

67.0

71.0 71.0

81.0

79.0 76.0 56.0

67.0

75.0 77.0

5,9 5.11

3,5,11(atypical psychosis) 1,5,7

1,2,3,4,5,6,7,8,9,10,11

2,3,4,5,6,7,8,9,10,11 (atypical psychosis)

1,2,3,6,7,&9

1,2,3,5,9,11 1,2,3,6,9,11

1,2,3,4,5,6,7,8,9,10

1,2,6,7,8,10,11

3,5,6(major depression with psychoticfeatures) 1,2,6,7,8,10,11

1,ZW

5,6,7(bipolar, mixed) 6 (atypical psychosis) 3,4,5(bipolar, mixed)

1,2,5.6,8,9,10,11

5,7 (bipolarmanic) 5,6,7,9,11 (atypical psychosis)

1,ZW,WZ7,8,9

1 11 (paranoid)

3,4,6(schizoaffective) 3,5,9,11(schizoaffective)

1,2,6,8,9,10

Diagnostic assignment’

5.0

22.8

29 17

15 28

33

14 35

24 27

20

20

27 24

22

22 22 21

22

22 19

16

23 24

24 23

21

BPRS

1.55

1.28

1.10 1.20

1.00 1.60

5.70

1.20 0.90

1.50 3.90

0.80

0.10

0.00 0.00

0.00

1.20 0.00 4.50

0.80

1.30 0.80

0.00

0.00 4.30

0.70 0.00

0.80

Baseline GH (mU/I)

6.33

3.99

0.59 1.48

6.37 1.20

0.27

12.90 2.04

1.30 5.40

0.83

0.12

1.50 5.70

29.70

1.30 0.00 1.20

0.82

4.60 7.90

1.80

12.50 1.20

0.80 1.50

0.80

GH AUC (mU.min/l)

1 Key to dlagnostlc assignments: 1 DSM-III; 2 Research Diagnostic Criteria: 3 E. Bleuler: 4 M Bleuler. 5. Schneider, 6. Langfeldt. 7 Kraepelln, 8 Felghner: 9 World Health Organlzatlon (International Pilot Study of Schuophrenla). 10 Taylor 8 Abrams. 11 Cloninger Where DSM-/I/ schlzophrenla IS not diagnosed. other DSM-f/I diagnoses are given in parentheses, 2. Female patients

Note.BPRS = Brief Psychiatnc Rating Scale. GH = growth hormone AUC = area under the curve.

6.78

28 21

142 15

SD

35

13

61.0

18

33 35 37

26 37

7 82

9

27

6

10 112 122

75.0 59.0

24 24

4 5

70.0 72.0

29 29

61.5

34

Weight (kg)

1

Age (yr)

2 3

Patient No.

Table 1. Age, diagnoses of schizophrenia, BPRS scores, and stimulated GH concentrations for all patients

83

Table 2. Age, total BPRS score, and illness duration for schizophrenia diagnosed by 11 systems, schizoaffective disorder (RDC), and the control group (+ SD) Illness Diagnostic system

n (MS)

Cloninger

13 (12,l)

29.8 f

6.0

23.6 + 9.5

3.4 f 2.8

Langfeldt

15 (12,3)

32.7 i

7.8

23.1 f 5.7

4.8 + 4.9

WHO-IPPS

13 (12,l)

32.6 +

8.7

22.5 f 9.4

6.9 + 4.3

Schneider

16 (13,3)

30.6 +

7.8

22.5 f 9.0

3.2 + 3.7

DSM-III

13 (13,O)

30.7 f

7.7

20.5 -t 7.2

6.4 + 4.4

RDC

12 (12,O)

32.5 f

8.7

21.5 +I 8.3

6.7 i 4.5

Kraepelin

10 (9,l)

34.2 +

8.1

22.5 k 6.7

4.7 * 5.9

E. Bleuler

12 (10,2)

33.8 +

7.1

22.8 + 9.7

5.7 k 5.3

Feighner

10 (10,O)

32.8 +

9.3

22.7 f 6.7

6.7 + 5.0

Age (yr)

BPRS

duration (yr)

Taylor & Abrams

7 (70)

32.1 f 10.6

25.0 f 6.3

5.7 i 5.7

M. Bleuler

6 (5,l)

36.7 +

7.3

24.8 f 7.6

4.5 f 5.4

RDC schizoaffective

8 (5,3)

29.8 f

4.7

23.8 f 6.3

1.2 + 1.2

Controls

17 (12,5)

24.9 + 5.8

-

-

Note. BPRS = Brief Psychiatric Rating Scale. WHO-IPPS = World Health Organization-lnternatlonal Pilot Study of Schizophrenia. RDC = Research Diagnostic Criteria.

In addition to the comparison of diagnostic systems, the effect of selected symptoms from the multidiagnostic instrument (hallucinations, delusions, disturbance of association, depressed mood, suicidal ideation, and depressive subsyndrome) on GH response was assessed by multiple regression and a nonparametric tree-building (McKenzie and Low, 1992) algorithm known as KnowledgeSEEKER (First Mark Technologies Ltd., 1990; Biggs et al., 1991). The latter technique has been applied to neuroendocrine data by Keks et al. (1992).

Results As shown in Table 3, patient groups with schizophrenia defined by the criteria of E. Bleuler, M. Bleuler, Schneider, Langfeldt, Taylor and Abrams, Kraepelin, and Cloninger had significantly lower GH responses than the control group. Responses in DSM-III, World Health Organization, Feighner, Kraepelin, and RDC schizophrenias did not differ from responses in control subjects. There were no differences in basal GH concentrations. When the effects of age were taken into account by employing analysis of covariance, patients diagnosed by the criteria of M. Bleuler were no longer significantly different from control subjects. Fig. 1 shows response curves for DSM-III and Schneiderian schizophrenias and control subjects, while Fig. 2 shows the corresponding scattergram of responses. A method based upon that of Keks et al. (1992), described earlier, found there to be no significant difference (z = 1.53, p = 0.13) between Schneiderian schizophrenia, which accounted for the most variance in GH response (R* = 0.19), and the Kraepelinian diagnostic system (R* = 0.14), which accounted for the least. The effects of group membership on GH response were linear in both cases (highest for control subjects, lowest for diagnostic system present).

84

Table 3. Ranked growth hormone responses to clonidine, in schizophrenic patients diagnosed by 11 systems and control subjects (31 SD) Diagnostic system

n (W)

Schneider

16 (13,3)

t test: AUC, patients vs. controls

Ranked AUC (mU.min/l) 17.25 i

9.35

t

df

P

4.18

31

0.000

Langfeldt

15 (10,5)

1737k13.19

3.55

30

0.001

DSM-III

21.58 f 16.51

2.28

28

0.030

WHO-IPSS

13 (8,5) 13 (10,3)

20.92 + 15.26

2.50

28

0.018

Cloninger

13 (10,3)

18.69 f 11.25

3.35

28

0.002

E. Bleuler

12 (93)

19.63 f 11.50

3.04

27

0.005

RDC

12 (93)

20.63 + 15.82

2.47

27

0.020

Feighner

10 (614)

20.10 i 17.05

2.36

25

0.026

Kraepelin

10 (7,3)

21.55 i 13.82

2.32

25

0.029

Taylor & Abrams

7 (5,2)

12.29 i 10.50

3.87

22

0.001

M. Bleuler

6 (5,l)

12.50 +

3.79

21

0.001'

17 (125)

6.75

33.88 + 13.08

Note. AUC = area under the curve. WHO-IPPS Schizophrenia. RDC = Research Diagnostic Critem

= World

Health

Organization-International

Pilot Study

of

1. Not significant when age was entered as a covanate.

Fig. 1. Growth hormone response to clonidine of schizophrenic patients diagnosed by DSM-I//, Kraepelinian, and Scheiderian criteria and control subjects 0

CONrROL5

.

DSM-I”

.

KRAEPEUN

0

I

SCHNEIDER

/

T

45

60

II

I -30

-IS

0

IS

30

TIME (min)

75

90

85

Fig. 2. Growth hormone response (area under the curve) to clonidine for each patient with DSM-I/, Kraepelinian, and Schneiderian schizophrenias and control subjects i------.

. .

:* .*. . .* 0. : .’

CONTROLS

.

.* 8

. . .

. ..

.a. ..

-*:p

“Z:’

DSM 111

SCHNEIDER

KRAEPELIN

Eight patients (5 men, 3 women) had RDC schizoaffective disorder. In contrast to those with RDC schizophrenia, the schizoaffective patients manifested a blunted GH response (ranked AUC 17.63 + SD 19.13 mU.minute/l,p < 0.01). When patients with DSM-IZZ schizophrenia were subdivided according to the presence or absence of the DSM-Illparanoid subtype, there were overall differences in the ranked GH response to clonidine between paranoid schizophrenic patients (n = 6, ranked GH AUC = 24.25 f SD 17.08 mu/l), nonparanoid schizophrenic patients (n = 8, ranked GH AUC = 16.56 f SD 12.88 mu/l) and control subjects (n = 17, ranked GH AUC = 33.88 & SD 13.08 mu/l) (F = 4.48; df = 2, 28; p < 0.05). Post hoc Scheffe (1953) tests demonstrated no difference between paranoid schizophrenic patients and nonparanoid schizophrenic patients, or between paranoid schizophrenic patients and control subjects. There was, however, a significant difference between nonparanoid schizophrenic patients and control subjects. There were no significant correlations (at the 0.01 level) between basal or stimulated GH concentration and total BPRS score (r = -0.13, p = 0.56) BPRS depressive mood item score (r = 0.58,~ = 0.046), and the four BPRS factor (Overall, 1974) scores: anxious depression (r = 0.13, p = 0.51) thinking disturbance (r = -0.17, p = 0.40), withdrawal (r = -0.18, p = 0.38), and hostility (r = -0.03, p = 0.88).

86 With regard to symptoms derived from the multidiagnostic instrument (hallucinations, delusions, disturbance of association, depressed mood, suicidal ideation, and full depressive syndrome), one-way analyses of variance found there to be no significant (0.01) differences in GH response among control subjects, patients with the symptom present, and patients with the symptom absent. Independent sample t tests did not demonstrate differences between symptom absent and symptom present, while no model could be constructed using stepwise multiple regression (Pedhazur, 1982) or the KnowledgeSEEKER tree-building algorithm (Biggs et al., 1991). There were also no significant correlations between basal or stimulated GH concentrations and age, illness duration, or neuroleptic-free period. Analyses were repeated with all subjects included (i.e., control subjects with elevated basal GH concentrations) and with male subjects only. The results generated were similar to those given above. Discussion Our findings show that patients with schizophrenia defined by 5 of the 1I diagnostic systems have a blunted GH response to clonidine, when compared with control subjects. Table 4 indicates the essential features of the diagnostic systems of schizophrenia used in this study. It is striking that all but one of the diagnostic systems associated with the blunted response are nonselective with respect to the presence or absence of affective symptomatology and may thus include patients with affective syndromes. The exception is the system of Taylor and Abrams, which may be excessively restrictive in its criteria (McGuffin et al., 1984). The possibility that the presence of affective disturbance is linked to blunting of GH response to clonidine in some patients with schizophrenia is further supported by the abnormal response in RDC schizoaffective, but not schizophrenic patients. These findings are consistent with those of Matussek et al. (1980), who reported blunted responses in ICD-8 schizoaffective patients. On the other hand, no significant correlations were found with BPRS depression subscores. Also, the presence or absence of depression-related symptoms and subsyndromes as rated by the multidiagnostic instrument could not be linked to endocrine responses. An explanation for the apparent discrepancy may be that the reliability and validity of isolated symptoms are substantially lower than those of diagnostic categorization (Buchsbaum and Haier, 1983). Furthermore, the link with affective dysfunction may be more complex than can be reflected in cross-sectional symptom evaluation, which is state-dependent. Mitchell et al. (1988) found that the blunted GH response to clonidine in endogenous depression reflected a trait. rather than a state, abnormality. Our study confirms the findings of La1 et al. (1983) of no difference in GH response between schizophrenic patients diagnosed by Feighner criteria and control subjects. The report of Miiller-Spahn et al. (1986) of a blunted GH response in patients with DSM-III schizophrenia differed substantially from our study, which involved acutely psychotic neuroleptic-free patients rather than the chronic patients drug-free for 12 days tested by Miiller-Spahn et al. (1986).

Nonaffective symptoms Absent affective syndrome

Delusionsihallucmationsithought disorder Absent significant affective disorder

Requires formal thought drsorder First rank symptoms Absence of affect disturbance Clear consciousness

Requrres certain posrtive psychotic symptoms Excluded by: early waking, depressed facies, elation, diagnosis of affective disorder

Requires three of: dissocration of thought, alteration of emotional expression, catatonic symptoms, delusions/hallucinations Affective symptoms not specified

Delusions/hallucinations Manic spending spree decreases likelihood of diagnosis

Some positive and/or negative symptomatology required Affective symptoms not considered

Requires positive psychotic symptoms

Requires positive psychotic symptoms Affective symptoms not considered

Requires five of: association disturbance, affect disturbance, autism, ambivalence, attention disturbance, abulia, intact simple functioning and acting disturbance

RDC

Feighner

Taylor & Abrams

WHO-IPSS

M. Bleuler

Cloninger

Kraepelin

Cangfeldt

Schneider

E. Bleuler

1. Where the

Continuous > 6 Deterioration

Specified psychotic symptoms Affective bluntrng Absence/brevity of full manic or depressive syndrome

origrnal source did not provide criteria, those from the instrument used rn the study are given.

Cross-sectional

Insidious onset Persistent symptoms Cross-sectional

Persistent symptomatology essential

Cross-sectronal

Cross-sectional

Cross-sectional

Cross-sectional

>6 months’ duration

At least 2 weeks’ duration

Course

Symptoms

DSM-//I

Diagnostic system

Table 4. Abbreviated criteria’ for 11 diaqnostic.systems of schizophrenia

Excludes coarse brain disease

Premorbrd schizoid tracts

Poor insight

No organicrty No drugs/alcohol

Poor premorbid history Family history Onset <40 yrs Absence of drugs/alcohol for >I yr

Onset before 45 yrs Nonorganrc

Other characteristics

88

The findings with respect to the GH response to clonidine are particularly interesting when contrasted with our reports about the prolactin response to low dose haloperidol challenge (Keks et al., 1990, 1992). Abnormal responses were present in diagnostic systems that excluded affective syndromes; responses were normal in schizophrenia defined by the criteria of Schneider and M. Bleuler. Kraepelinian schizophrenia showed the greatest difference from the control group on the stimulated prolactin response. Similar evaluation failed to reveal the superiority of one diagnostic system over the others with respect to the blunting of the GH response to clonidine. The number of subjects in this study was substantially smaller than in Keks et al. (1992). It should be noted that comparison between diagnostic systems requires complex statistical techniques because the subject groups are overlapping and therefore not independent, invalidating conventional statistics. The possibility of down-regulation of a,-adrenergic receptors in some patients with schizophrenia suggested by our findings is also supported by reports of impaired 3-methoxy4hydroxyphenylglycol response to clonidine (Sternberg et al., 1982) and of a trend toward fewer a,-adrenergic receptors in the locus ceruleus of schizophrenic brains at post-mortem (Ko et al., 1986). The conclusions from this study must be treated with caution as the numbers of subjects in different comparison groups were small, the patient groups were overlapping to variable extents, and paired matching between patients and control subjects was not carried out. However, if the blunted GH response to clonidine is a marker of depression, then the findings in this study appear to be consistent with the possibility that the marker may also be linked to the occurrence of depression within the schizophrenia syndrome. Appreciation of the potential importance of a noradrenergic contribution to the mechanism of action of clozapine (Baldessarini and Frankenburg, 1991) strongly suggests the need for further research in this area, given the findings of our study. A number of studies have found evidence of elevated norepinephrine levels in the plasma, cerebrospinal fluid, and brain of patients with schizophrenia, particularly with the paranoid subtype of illness (Lake et al., 1987). While we did not find evidence of abnormality in our paranoid patients, we did find that blunted GH responses occurred in nonparanoid schizophrenic patients when compared with control subjects. Finally, this study demonstrates that apparently minor differences in criteria between diagnostic systems do generate significantly different results on a biological measure. It would appear that the diagnostic system used in a monodiagnostic study must be regarded as another potential confounding variable. Multidiagnostic psychopathological assessment appears to offer a viable exploratory strategy in the clarification of a syndrome for which there is no diagnostic gold standard. References American

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1319-22,

1987.

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