A double-blind study with ceruletide in chronic schizophrenic patients: Biochemical and clinical results

Ps_vchintr.v Research. Elsevier

19, l-l

A Double-Blind Schizophrenic Margot Albus, and Manfred Received 1985.

Februar!

Study With Ceruletide Patients: Biochemical

Klaus von Gellhorn, Ackenheil

Ursula

Miinch,

in Chronic and Clinical Dieter

Results

Naber,

20. 1985; revised version received October 4, 1985; accepted November

2.5,

Abstract. We evaluated ceruletide, a cholecystokininlike peptide. in a doubleblind, placebo-controlled study of 20 male chronic schizophrenic patients. After baseline investigations, IO patients received 0.3 pg/ kg body weight ceruletide, and IO patients received placebo (normal saline) intramuscularly once weekly for 3 consecutive weeks. Psychopathology was rated on the Brief Psychiatric Rating Scale and the Nurses’ Observation Scale for Inpatient Evaluation. Blood was drawn on the same days for estimation of norepinephrine. epinephrine, /3endorphin, cortisol, and prolactin. There were no significant changes in biochemical parameters. With regard to psychopathology, no significant differences in behavioral ratings were found between the ceIuletide- and placebo-treated groups. Furthermore, there were no changes in either positive or negative symptoms of schizophrenia secondary to ceruletide. Contrary to uncontrolled studies, we failed to show antipsychotic properties of ceruletide. Key Words. Ceruletide, catecholamines.

therapeutic

effects,

chronic

schizophrenics,

hormones,

There is no doubt about the antipsychotic efficacy of neuroleptics, which act mainly through blockade of the dopamine receptor. However, neuroleptics are of limited value in many chronic schizophrenic patients who have prominent “negative symptoms,” such as flattening of affect, lack of speech, and loss of impetus (Johnstone et al., 1978). Lecrubier et al. (1980) postulated an overactivity of dopaminergic function in patients with predominantly “positive symptoms” (e.g., hallucinations, delusions, and thought disorder) and a hypoactivity of dopaminergic activity in patients with mainly negative symptoms. According to this hypothesis, only positive symptoms are improved by neuroleptic blockade of postsynaptic dopamine receptors. King et al. (1982) proposed that psychotic individuals exhibit an instability in dopaminergic function. This instability could be caused by other neuronal systems. Neuropeptides have increasingly become a focus of attention in schizophrenic research. H’bkfelt et al. (1980a, 1980b) showed that cholecystokinin, in its predominant form as a C-terminal octapeptide (CCK-8), exists in cortical brain areas as well as

Margot Albus, M.D.. Ursula Miinch, M.D.. and Dieter Naber, M.D., are Residents, Klaus van Cellhorn, M.D.. is Research Fellow, and Manfred Ackenheil, M.D.. is Professor at the Psychiatric Hospital of the University of Munich. (Reprint requests to Dr. M. Albus. Psychiatric Hospital, University of Munich, Nussbaumstr. 7, D-8000 Munich 2. FRG.) 0165-1781 46. $03.50 @ 1986 Elsevier Science

Publishers

B.V.

2

in mesolimbic, mesencephalic, but not nigrostriatal dopamine neurons. In addition, CCK has been reported to reduce the number of binding sites at the dopamine receptor via activation of the CCK receptors (Fuxe et al., 1980). These results confirm that CCK acts as neuromodulator and is part of an inhibitory feedback system that modulates dopamine release via action at the autoreceptors and modifies dopamine receptor sensitivity. Zetler (198 1a, 198 16) showed cataleptic as well as antistereotypic effects of CCK-8 and caerulein in mice. These neuroleptic-like effects found in rodents, along with the results of receptor studies, suggest that cholecystokinin and the closely related decapeptide, ceruletide, may have an antipsychotic potency. In an open trial, Moroji et al. (1982a, 1982b) found a marked and long-lasting improvement in both negative and positive symptoms of 20 chronic schizophrenic patients. Nair et al. (1983), also in an open study, observed rapid improvement after the addition of CCK-33 to an unchanged regimen of neuroleptic therapy. In constrast to these open studies, Hommer et al. (1984) failed to find an improvement in either the positive or negative symptoms of 12 chronic schizophrenic patients after ceruletide treatment in a double-blind, crossover design. Moreover, in another double-blind, crossover study, Lotstra et al. (1984) reported no improvement after intravenous administration of ceruletide (3 pg/ kg body weight) in neurolepticfree schizophrenics. Because the crossover design in these studies may have obscured drug-placebo differences, we conducted a double-blind, noncrossover study to examine further the effects of ceruletide in chronic schizophrenic patients. Methods Patients.

Twenty male chronic schizophrenic patients (mean age 44.2; range 32-60). who met Research Diagnostic Criteria (RDC) for schizophrenia (Spitzer et al., 1978) participated in the study. All patients were in good physical health and had maintenance neuroleptic therapy for at least 5 years (mean 15.5, SD 9.6) with a last daily dosage of I, 117 * 1,30 1 mg chlorpromazine equivalents (Davis, 1974). The patients had a preponderance of negative symptoms (e.g.. anergia, lack of interest, loss of impetus, apathy, and affective flattening), to neuroleptic therapy.

which did not respond

Study Design.

All patients were maintained on their previous neuroleptic medication, which had not been altered for at least 1 month before the trial. Ceruletide treatment was assigned at random in a double-blind, placebo-controlled design. Ten patients received 0.3 pg/kg body weight ceruletide, and 10 patients received placebo (normal saline) intramuscularly once a week for 3 consecutive weeks (on days 0. 7, and 14) at 8 a.m. under basal conditions. Symptom

Assessment. The Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1979) was used to rate psychopathology 2 weeks before (at baseline: day -14), during ceruletide administration (days 0, 7, and 14), and 1 and 2 weeks after treatment (days 21 and 28). Nursing staff completed the Nurses’ Observation Scale for Inpatient Evaluation (NOSIE) (Honigfeld et al., 1976) on the same days. Tardive dyskinesia was rated according to Heinrich et al. (1968), and parkinsonian side effects were assessed by the rating scales of Webster (1968) and Simpson and Angus ( 1970). Biochemical Parameters. Two weeks before ceruletide treatment (day-14). blood samples were collected 20 minutes after a cannula had been inserted, and norepinephrine (NE), epinephrine (E), P-endorphin (P-E), cortisol (COR), and prolactin (PRL) were measured. During ceruletide treatment at days 0. 7. and 14. blood was collected again for estimation of

3

PRL, P-E, COR, NE, and E 20 minutes after insertion of the i.v., as well as 60 minutes after ceruletide administration. Additional samples were drawn for evaluation of NE, E, and /3-E 20 and 40 minutes after ceruletide administration. PRL, COR, and /3-E were measured with a double-antibody radioimmunoassay; NE and E, by high performance liquid chromatography and electrochemical detection (Hjemdahl et al., 1979). Statistical Analysis. To analyze changes in each group due to ceruletide or placebo, and to eliminate baseline chance differences between the groups, a two-way repeated measures analysis of variance (ANOVA) covarying out baseline values (day -14) was carried out. The two factors used were drug vs. placebo and periods of measurement (five for clinical ratings, three for biochemical data). To evaluate differences between periods of measurement, Student’s I tests or U tests were performed for each parameter. A Spearman rank correlation matrix was used to examine correlational analyses between biochemical and clinical data.

Results The ceruletide and placebo groups did not differ significantly in age, duration of illness, duration of neuroleptic therapy, last daily neuroleptic dosage, or diagnosis. Data. There were no significant differences between the ceruletide and placebo groups in any of the subscores of the BPRS or in BPRS total score during the treatment periods (e.g., no significant main effects in the analysis of covariance). A significant time effect, which reflects an improvement in both groups, was shown for BPRS total score and the subscores anergia (ANER), thought disturbances (THOT), activation (ACTV), and hostility (HOST). Anxiety/depression (ANDP) was the only subscore that showed a significant interaction between time and ceruletide vs. placebo factor (Table I). Post hoc t tests showed significant @ < 0.01) improvement in this Clinical

Table 1. Changes in Brief Psychiatric Rating Scale (BPRS) total score and subscores during ceruletide (CER) and placebo (PLAC) treatment Analysis Day BPRS scales

Drug

BPRS

total Anergia

Anxietydepression Thought disturbance Activation

Hostility

of covariance

7 d

14 d

21 d

28 d

df

0.90

-2.50

-0.37

-5.00

-3.50

4172

11.98

0.54

-2.37

-5.00

-7.64

-6.37

4/72

0.96

-14 Mean f SD

0 d

CER

47.0 +_ 9.0

PLAC

43.6 ? 6.5

F

P 0.0001 NS

CER

17.2 i 3.6

0.00

-0.50

-1.50

-2.00

-1.40

4/72

5.72

PLAC

14.9 I? 3.4

-1.00

-1.73

-1.53

-2.55

-2.35

4/72

0.26

CER

7.5 + 3.5

-0.20

0.10

0.50

0.20

1.20

4/72

1.21

NS

PLAC

8.5 z!z3.4

0.35

-0.64

-0.73

-1.55

-1.00

4172

3.66

0.03

CER

10.3 ?I 4.7

0.40

-0.50

-1.10

-1.20

-1.50

4172

7.25

0.001

PLAC

8.2 k 3.3

0.18

-0.28

-0.45

-1.28

-1.09

4/72

0.56

CER

5.4 i- 3.1

0.80

-0.50

-0.50

-0.60

0.00

4/72

6.78

PLAC

6.5 k 1.9

0.73

0.64

-0.45

-0.81

-1.00

4/72

2.89

CER

6.6 t 3.8

-0.10

-1.10

-1.10

-1.40

-1.80

4/72

6.30

PLAC

5.6 f 3.1

0.26

-0.37

-0.65

-1.46

-1.10

4172

0.44

0.008 NS

NS 0.002 NS 0.001 NS

R RB R RB R RB R RB R RB R RB

Difference Id1 = mean at days 0, 7, 14, 21. and 28 minus mean at day -14 I= baseline). Negative value reflects improvement; positive value reflects worsening. R = time effect, RB = interaction group X time, p ( Greenhouse-Geisseri, NS = p z 0.05.

subscore in the placebo group during the entire treatment, whereas the ceruletide group slightly worsened. The analysis of covariance showed a significant time effect for the NOSIE scores “social competence,” “irritability,” “manifest psychosis,” and “retardation” (df= 4/ 72, F between 3.9 and 6.38, p between 0.02 and 0.001). Again, there was neither a significant main effect nor a significant interaction between group and time (Table 2). The side effects of ceruletide were minimal. Only one patient complained of mild abdominal distress. In addition, ratings of extrapyramidal symptoms showed neither significant changes during the time course nor significant differences between the groups. Table 2. NOSIE scores at baseline, during treatment, and after weekly administration of either 0.3 pg/kg ceruletide or placebo Day

NOSIE scales

Drug

0

7

21

28

Social

Ceruletide

35.6f

9.2

43.2k5.3

30.Ok7.4

38.0-+ 4.7

39.0k6.1

38.2t5.7

Placebo

34.2f

6.8

41.01?r8.6

39.9k8.9

38.4+

7.5

39.2k9.3

41.4i-9.2

6.1

6.3

competence Irritability

Manifest psychosis Retardation

NOSIE=

-14

14

Ceruletide

22.22

17.41k5.7

19.6k6.1

19.8+

18.8k6.0

20.2k6.0

Placebo

25.2f11.2

20.2k8.1

20.027.8

24.0+10.4

23.0k9.6

20.4k7.8

Ceruletide

16.0?

6.1

13.0f6.9

13.4k8.3

13.82

8.0

13.4k6.8

13.827.0

Placebo

16.42

7.0

12.024.8

11.2+4.1

12.61

4.1

10.823.2

10.6k2.5

Ceruletide

18.41

4.5

17.2t3.7

16.814.1

20.4+

3.8

17.225.3

16.8k5.8

Placebo

18.0?

4.3

15.2k4.7

15.8k5.0

15.82

4.8

16.0k5.2

12.824.8

Nurses’ Observation

Scale for inpatient

Evaluation.

Results presented

as meankSD.

Biochemical Parameters. The two-way repeated measures ANOVA did not reveal a significant main effect, time effect. or interaction for any of the biochemical measures, and there were no significant differences between the group means. Moreover, changes in neurochemical parameters were not significantly correlated with changes in psychopathology. Discussion This controlled study failed to demonstrate an effect of ceruletide, at doses of 3 pg/ kg body weight, on positive or negative symptoms of schizophrenia. The significant time effects found for clinical ratings reflect an improvement in both groups. The only significant interaction found, for ANDP (time x group), does not reflect therapeutic effects of ceruletide. The discrepancy between the findings in this study and the results of Moroji et al. ( 1982b) and Nair et al. (1983) may be partially explained by differences in patient characteristics, study design, and type of peptide administered. The patients in the open studies were younger, with a less chronic course and a shorter duration of illness. Differences in symptom assessment may also account for the diverging results. Nair et al. (1983) used a shorter rating interval than that in the present study. Like Nair et al., we also found an improvement up to 14 days after CCK-33 administration, but in both groups. Thus, the improvement observed in the two open studies may reflect

5 Table 3. Baseline values of norepinephrine, epinephrine, P-endorphin, cortisol, and prolactin under neuroleptics (day -14) and after additional i.m. administration of 0.3 pg/kg body weight ceruletide i.m. (days 0,7, and 14) Analysis of covariance

Variable (n = 19)

Drug

Day -14

Norepinephrine

CER

610+362

508zk199

622t310

531-t302

PLAC

536k319

452?164

4741150

446+163

CER

36+15

61 t46

3Ok17

PLAC

57242

6Ok40

47225

fpg/mll Epinephrine ipg/mll p-Endorphin (

pg/O.l

Cortisol (/Jg/dl) Prolactin rng/mll

ml

1

Day 0

Day 7

F

p

2/34

3.16

NS

2/34

2.58

NS

RB

32+14

2/34

1.69

NS

R

53k27

2134

1.36

NS

RB

Day 14

cff

R

CER

8.520.8

10.2i1.5

8.9tl.O

9.Ok2.1

2/34

2.70

NS

R

PLAC

9.523.4

11.3k2.3

11.4t2.7

ll.Ok3.1

2/34

0.72

NS

RB

CER

13.Ok4.0

15.5k6.4

14.813.7

13.8t4.1

2/34

0.56

NS

R

PLAC

13.2t3.8

12.8k2.7

13.6k2.6

12.7t2.4

2/34

0.43

NS

RB

CER

6.2k4.8

5.9f4.3

5.6k3.9

6.1k4.5

2/34

0.42

NS

R

PLAC

7.4k5.4

6.4k4.4

6.424.4

6.6k4.6

2/34

0.16

NS

RB

group

X time,

CER = ceruletide; PLAC = placebo. Analysis of variance: R = time effect, p [Greenhouse-Gelsser , NS = p > 0.05. Results presented as mean&SD.

RB = interactjon

rater bias. This interpretation is in line with the findings of the other controlled studies. Most of the observed improvement is most likely related to the increased attention patients received and does not seem to be drug specific. This factor of unspecified increased care and attention could not be excluded in the open studies. It is also unlikely that ceruletide, which has been shown to be more potent than CCK-8 with respect to central nervous system (CNS) effects (Zetler, 1981a, 198 lb), is less effective than other CCK analogues in schizophrenia. All controlled studies used this compound and all challenge the findings of Moroji et al. (19820, 19826) also using ceruletide, and Nair et al. (1983) administering CCK-33. In addition to the lack of therapeutic efficacy of ceruletide, no effects on neurochemical parameters were observed in our study. There were no significant changes in P-E, NE, E, and PRL. The findings of Zetler (19810, 19816) suggest that ceruletide, due to its action on the dopaminergic system, should have elevated PRL levels. However, the lack of elevation in this study might reflect the fact that the tuberoinfundibular dopamine receptor blockade was already maximal with the preexisting neuroleptic therapy. The absence of ceruletide effects on extrapyramidal symptoms in our study favors this interpretation. Moreover, the tuberoinfundibular dopaminergic system may be functionally different from the mesolimbic and nigrostriatal dopaminergic system (Demarest et al., 1983). In view of the studies that show an influence of either caerulein or CCK-8 on dopamine receptors (Fuxe, 1980) and dopamine-mediated behavior (Zetler, 198 la, 198 16). the lack of efficacy on schizophrenic symptoms is surprising. One possible explanation is that neither CCK-8 nor ceruletide crosses the blood-brain barrier or, if so, only in amounts too small to exert pharmacological effects. However, Hommer and Skirboll (1983) modified dopamine autoreceptor sensitivity by peripheral administration of cholecystokinin. Likewise, Zetler ( 198 la, I98 lb) certainly observed

6 central effects after subcutaneous administration. It may be that higher dosages are necessary to yield positive results. Animal studies reporting CNS effects of CCK generally used much higher dosages than any of the therapeutic studies. Due to their wide distribution and high concentration in the CNS and their interaction with dopamine and other neurotransmitters, CCK analogues continue to interest psychiatric researchers. Results of the controlled studies to date suggest that future investigations should focus on other analogues that have enhanced brain uptake and, therefore, may prove to be more efficacious than ceruletide.

analogues

Acknowledgment.

This study was supported

by the “Deutsche

Forschungsgemeinschaft.”

References Davis, J.M. Dose equivalence

of the antipsychotic

drugs. Journal

of Ps_vchiatric Research,

11,

65 ( 1974).

Demarest, K.T. Lawson-Wendling, K.L., and Moore, K.E. &Amphetamine and ybutyrolactone alteration of dopamine synthesis in the terminals of nigrostriatal and mesolimbic neurons. Biochemical Pharmacology, 32, 69 1 ( 1983). Fuxe, K.. Andersson. K., Locatelli, V., Agnati, L.F.; Hiikfelt, R., Skirboll, L., and Mutt, V. Cholecystokinin peptides produce marked reduction of dopamine in discrete areas in the rat brain following intraventricular injection. European Journal qf’Pharmacolog.v, 67,329 (1980). Heinrich, K., Wegener, 1.. and Bender, H.J. Spate extrapyramidale Hyperkinesen bei neuroleptischer Langzeittherapie. Pharmakops)bchiatrie, 1, 169 (1968). Hjemdahl. P., Daleskog, M., and Kahan, T. Determination of plasma catecholamines by high performance liquid chromatography with electrochemical detection: Comparison with a radioenzymatic method. Life Sciences, 25, 131 (1979). Hokfelt, T.. Rehfeld, J.F., Skirboll, L., Ivemark, B., Goldstein, M., and Markey, K. Evidence for coexistence of dopamine and CCK in mesolimbic neurons. Nature, Lond. 285,476 ( 1980~). Hokfelt, T., Skirboll, L.. Rehfeld, J.F., Goldstein, M., Markey, K., and Dann, 0. A subpopulation of mesencephalic dopamine neurons projecting to limbic areas contains a cholecystokinin-like peptide: Evidence from immunohistochemistry combined with retrograde tracing. Neuroscience, 5, 2093 (1980h). Hommer, D.W.. Pickar, D., Roy, A.. Ninan. P., Boronow, J., and Paul, S.M. The effect of ceruletide in schizophrenia. Archives of’ General Psychiarry, 41, 541 (1984). Hommer, D.W., and Skirboll. L. Cholecystokinin-like peptides potentiate apomorphineinduced inhibition of dopamine neurons. European Journal of‘Pharmacologt1, 91, 15 1 (1983). Honigfeld, G., Gillis, R.D.. and Klett. C.J. NOSIE: Nurses’ Observation Scale for Inpatient Evaluation. In: Guy, W., ed. ECDEU Assessment Manualfor Psychopharmacology. National Institute of Mental Health, Rockville, MD. p. 265 (1976). Johnstone, E.C., Crow, T.J., Frith, C.D., Carney. M.W.P., and Price, J.S. Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet, I, 848 (I 978). B.A., and Barchas, J.D. Dopamine neuronal King. R.J.. Raese, J.D.. Hubermann, instability: A model for the schizophreniform psychoses. Ps.vchopharmaco/og~~ Bulletin, 18(3), 70 ( 1982).

7

Lecrubier. Y., Puech. A., Simon, P., and Widlocher, D. Schizophrenic: hypofonctionement du systeme dopaminergique_Une hypothese bipolaire. Medicale,

Hyper

ou

Psyhologie

12, 2431 (1980).

Lotstra, F., Verbanck, P.. Mendlewicz, J., and Vanderhaeghen, J.J. No evidence of antipsychotic effect of caerulein in schizophrenic patients free of neuroleptics: A double-blind crossover study. Biological Ps.vchiatry, 19,877 (1984). Moroji, T., Watanabe. N.. Aoki. N.. and Itoh, S. Antipsychotic effects of caerulein, a decapeptide chemically related to cholecystokinin octapeptide, on schizophrenia. International Pharmacopswhiatry,

17, 255 (1982~).

Moroji, T., Watanabe, N., Aoki, N., and Itoh, S. Antipsychotic effects of ceruletide (caerulein) on chronic schizophrenia. Archives of Genernl Psy-hiatry, 39,485 (1982b). Nair, N.P.V., Bloom, D.M., Nestoros, J.N.. and Schwartz. G. Therapeutic efficacy of cholecystokinin in neuroleptic-resistant schizophrenic subjects. Psychopharmacology Bulletin, 19(l),

134 (1983).

Overall, Assessment

J.E., and Gorham, Manualfor

D.R. Brief Psychiatric Rating Scale. In: Guy, W., ed. ECDEU Rev. ed. National Institute of Mental Health,

Ps_vchopharmaco/ogy.

Rockville, MD, p. 157 (1976). Simpson, G.N.. and Angus, J.W.S. A rating scale for extrapyramidal side effects. Acta P.~ychiatrica Scandinavica. Suppl. 212, I I (1970). Spitzer, R.L., Endicott, J.. and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of Genera/ Ps_tlchiatry, 35, 773 (1978). Webster, D.D. Critical analysis of disability in Parkinson’s disease. Modern Treatment, 5, 257 ( 1968).

Zetler, G. Central depressant effects of caerulein and cholecystokinin octapeptide (CCK-8) differ from those of diazepam and haloperidol. Neuropharmacolog~, 20, 277 (1981~). Zetler, G. Central effects of ceruletide analogues. Peptides, Suppl. 2, 65 (1981b).