Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs

ELSEVIER Psychiatry Research 58 (1995) 217-225

PSYCHIATRY

RESEARCH

Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants,

mood stabilizers, and antipsychotic drugs

Michael Maes*a*b, Filip Goossensc, Simon ScharpC”, Joseph Calabrese b, Roger Desnydera, Herbert Y. Meltzerb

Tlinical Research Center, Menial Health, University Department of Psychiatry, AZ Stuivenberg. 267 Lange Beeldekensstraat, 2060 Antwerp. Beigium

bDepartment of Psychiatry, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106, USA

‘Department of Medical Biochemistry, University of Antwerp, Universiteitsplein, Wilrijk, Belgium

Received 27 July 1994; revision received 18 January 1995; accepted 5 July 1995

Abstract

The activity of prolyl endopeptidase (PEP), a serine proteinase, has been found to be significantly lower in the blood of patients with major depression than in normal volunteers. The present study investigates plasma PEP activity in 25 major depressed, 10 manic, and 14 schizophrenic subjects versus 30 normal volunteers. It also examines the effects of antidepressants, valproate, and neuroleptic drugs on plasma PEP activity. PEP activity was significantly lower in major depressed subjects than in normal volunteers and in patients with mania and schizophrenia. In depressed subjects, plasma PEP activity was significantly increased during treatment with antidepressant drugs, such as fluoxetine. Plasma PEP activity was significantly increased in manic and schizophrenic subjects compared with normal volunteers. In manic subjects, short-term treatment with valproate had a significant suppressive effect on PEP activity. No significant effects of neuroleptics on PEP activity could be found in the schizophrenic patients. The results support the hy- pothesis that lower PEP activity could play a role in the pathophysiology of major depression, while increased PEP activity may be related to psychotic conditions, such as mania and schizophrenia.

Keywords: Fluoxetine; Valproate; Neuroleptics; Peptides; Peptidases; Proteinases

1. Introduction

Major depression was recently reported to be characterized by lower serum prolyl endopeptidase

l Corresponding author, Clinical Research Center, Mental Health, University Department of Psychiatry, AZ Stuivenherg, 267 Lange Beeldekensstraat, 2060 Antwerp, Belgium; Fax: +32 3 6332814.

(PEP) activity (Maes et al., 1994). PEP (EC 3.4.21.26; postproline cleaving enzyme) is a cytosolic endopeptidase that cleaves peptide bonds on the side of proline in oligopeptides (Walter et al., 1971, 1980; Kato et al., 1980; Wilk, 1983). High PEP activity is observed in muscle, kidney, testes, submandibular gland, thyroid gland, adre-

nal gland, liver, thymus, and cerebral cortex (Kato

Ol65-1781/95/W9.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-1781(95)02698-V

218 M. h4aes et al. /Psychiatry Research 58 (1995) 217-225

et al., 1980; Wilk, 1983). PEP may cleave many neuropeptides or hormones that have been shown to be involved in the pathophysiology of mood disorders - for example, thyrotropin-releasing hormone (TRH), P-endorphin, luteinizing-hormone- releasing hormone (LH-RH), arginine vasopressin (AVP) (Camargo et al., 1983; Wilk, 1983; Ward et al., 1987), and perhaps corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) (Maes et al., 1994). Therefore, lower PEP activity in major depression could, in theory, be involved in many of the neuroendocrine perturbations in mood disorders, such as hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis as well as HP-thyroid axis and HP-gonadal (through LH-RH) dysfunctions (review: Maes et al., 1994). However, the effects of (sub)chronic treatment with antidepressants on PEP activity have not yet been examined.

Disorders in peptide-metabolizing enzymes may also be present in schizophrenia (Beckmann et al., 1984; Reichelt et al., 1987; Wiegant et al., 1988). Low molecular weight hyperpeptiduria has been detected in schizophrenia (Reichelt et al., 1981), and this phenomenon may be caused by diminished peptidase activity (Abassi et al., 1992; Watanabe et al., 1993). Moreover, it has been shown that antipsychotic drugs may induce the activity of some peptidases in vivo, thereby increas- ing peptide metabolism (Traficante and Turnbull, 1982; Konkoy et al., 1993; Wahlbeck et al., 1993). Some studies of neuropeptide concentrations in schizophrenia have found significant alterations in neurally active peptides, such as substance P, neurotensin, TRH, fi-endorphin, and AVP (reviews: Berger et al., 1986; Nemeroff et al., 1987), all of which are substrates of PEP (Camargo et al., 1983; Wilk, 1983; Ward et al., 1987). The putative involvement of PEP activity in the pathophysiology of schizophrenia revolves not only on the degradation or processing of the endorphin and nonendorphin neurally active peptides, but other functions as well. Indeed, PEP inhibitors may facilitate the acquisition of active and passive avoidance responses and retard the ex- tinction of these responses in the rodent (Napri and Kaneto, 1987; Taira and Kaneto, 1987; Yoshimoto et al., 1987). Also, neuroleptics and

some peptides alter the active and passive avoidance learning in rats (De Wied et al., 1978). PEP also has an important role in memory pro- cesses (Nakajima et al., 1992). Indeed, known PEP inhibitors exhibit anti-amnesic properties in rodents (Nakajima et al., 1992). Y-29794, a PEP inhibitor that may penetrate the brain and com- petitively inhibit rat brain PEP, was found to potentiate the effect of TRH on the release of acetylcholine in the rat hippocampus (Nakajima et al., 1992).

However, no research has examined whether alterations in PEP activity are pertinent to schizophrenia or other psychotic conditions, such as mania. The present study was carried out to examine plasma PEP activity in major depression, schizophrenia, and mania. It also explored the effects of treatments with psychotropic drugs such as antidepressants, neuroleptics, and mood stabilizers (i.e., valproate) on PEP activity.

2. Methods

2.1. Subjects

Seventy-nine subjects participated in this study: 30 healthy volunteers, 14 schizophrenic patients (6 undifferentiated, 4 paranoid schizophrenic, and 4 residual; all chronic or subchronic type); 10 manic patients (bipolar I subtype); and 25 major depressed patients (14 drug free, 11 treated with > 20 mg of fluoxetine for > 2 months). All patients and normal volunteers gave written informed consent before participating in the studies. Patients were admitted to the psychiatric ward of the University Hospitals of Cleveland, Ohio, USA. The patients were categorized according to DSM-III-R criteria (American Psychiatric Association, 1987) on the basis of a structured interview, the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978). Patients with other Axis I diagnoses, such as organic mental disorder, substance use disorder (l/2 year before participating in the studies), and schizoaffective disorder, were omitted from these studies. Severity of illness was assessed by means of the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) in depressed subjects; the Brief Psychiatric Rating Scale

M. Maes et al. /Psychiatry Research 58 (1995) 217-225 219

(BPRS; O-6 version; Rhoades and Overall, 1988) in schizophrenic patients; and a mania subscale, which was extracted from the SADS and contains the items of the Young Mania Rating Scale (YMRS; Young et al., 1978; i.e., elevated mood, less sleep, more energetic, efficient thinking, gran- diosity, future plans, racing thoughts, extreme health, accelerated speech, motor hyperactivity, high activity, and irritability).

The normal volunteers were free of any medica- tion for at least 1 month before blood sampling. None of them were regular drinkers or had ever taken psychotropic drugs. They were screened and excluded for present, past, and family history of mental disorder by means of structured interviews. All subjects were medically healthy; they had normal physical examinations, normal values of blood and urine tests (e.g., serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, and y-glutamyltransferase), hematocrit, serum electrolytes, renal tests (blood urea and creatinine), and a normal electrocardiogram. All subjects were free of any drugs known to interfere with immune or endocrine function. They were also free of chronic illnesses known to affect the immune system and of acute infectious or inflam- matory reactions for at least 2 weeks before the study.

Depressed patients in an acute episode of major depression were drug free for a median of 18 (range 8- > 60) days. Seven of these patients were treated with fluoxetine ( 5: 20 mg/day) for a median of 54 (range: 29-161) days. The seven other depressed patients were treated with typical antidepressants (i.e., nortriptyline, amitriptyline, or imipramine) for a median of 59 (range: 34- 138) days. In the 14 schizophrenic patients, the median of the drug-free period before baseline blood sampling was 25.5 (range: 8- > 60 days) days, and the median of treatment with neuroleptics was 60 (range: 18-183) days. Patients who had been tak- ing parenteral neuroleptics 3 months before the study were not included. Seven schizophrenic patients were treated with haloperidol (range: 4-20 mg), and the seven others were treated with other typical neuroleptics such as perphenazine (range: 8-48 mg) and thioridazine (range: 750-1000 mg). The manic subjects were withdrawn from all drugs

for r7 days; the median of the treatment period was 14 days (range: 12-23 days); the mean dose of valproate was 1400 ( f 592) mg/day.

2.2. Procedures After an overnight fast, an intravenous cannula

was inserted at 08:30 h in the antecubital vein of the subjects. Plasma treated with ethylenedi- aminetetra-acetic acid for assay of PEP activity was sampled at 08:45 h. All schizophrenic, manic, and the drug-free depressed patients had blood sampled in baseline conditions and after treatment with psychotropic drugs (see 2.1. Subjects). PEP activity has been determined by a fluorometric method, as described previously (Goossens et al., 1992). The analytical intra-assay and interassay coefficients of variation were 5.9% and 1 l.O%, respectively. All PEP assays were carried out at the same time.

2.3. Statistics Analysis of variance (ANOVA) and analysis of

covariance (ANCOVA) were used to evaluate group mean differences. Multiple post hoc com- parisons among group means were checked with Fisher’s least significant difference procedure. Re- peated measures ANOVA was used to examine the differences in PEP activity or clinical scores before and after treatment. Analysis of contingency (x2 test) assessed the independence of classification systems, while the test of goodness-of-tit (x2 test ascertained normality of distribution. Square root transformations of PEP activity were used to reach normality of distribution or to adjust for heteroge- neity of variance between study groups.

3. Results

3.1. Demographic data Table 1 lists the demographic data of the sub-

jects in this study. There were no significant differences in age between normal, depressed (either medicated or unmedicated), and manic subjects (F = 0.8; df = 3, 61; P = 0.5). Schizophrenic patients were younger than all other subjects (F = 3.9; df = 4,74; P = 0.007). There were no significant differences in sex ratio between the five diagnostic groups (x2 = 2.1, df = 4, P = 0.7). By

220 M. Maes et al. /Psychiatry Research 58 (1995) 217-225

Table 1 Demographic data (n = 79)

Categories Male/female Age (years) ratio

Mean SD

Severity of illness

Mean SD

Healthy volunteers 18/12 35.2 10.2 Depression (unmedicated) 915 39.4 10.0 HRSD = 24.8 9.2 Depression (fluoxetine) 615 41.0 11.3 HRSD = 7.2 7.6 Mania 713 40.5 13.4 YMRS = 31.8 4.6 Sch’kophrenia 11/3 27.8 7.2 BPRS = 25.1 10.6

Note. HRSD, Hamilton Rating Scale for Depression (17~item version); YMRS, Young Mania Rating Scale; BPRS, Brief Psychiatric Rating Scale (O-6 version).

means of correlation analysis pooled over the five study groups (i.e., normal volunteers, unmedicated and fluoxetine-treated major depressed patients, manic patients, and schizophrenic patients), no significant relationships were found between age and PEP activity (r = 0.09, n = 79, P = 0.5). No significant relationships between age and PEP activity were found in any of the five study groups separately. ANCOVA (factorial design with the five diagnostic groups and sex as treatments) revealed no significant difference in PEP activity between men and women (F = 0.1; df = 1, 68; P = 0.7). Although no significant relationships between PEP activity and age or sex were found, we have controlled for possible age and gender effects by introducing both variables as covariates in AN- COVAs or multiple regression analyses.

3.2. PEP activity and diagnostic groups Fig. 1 shows the measurements of PEP activity

in normal volunteers and in unmedicated major depressed, manic, and schizophrenic patients. AN- COVA with age and sex as covariates found significant differences between the four study groups. Fisher’s least significant difference test showed significantly (P < 0.05) lower plasma PEP levels in unmedicated major depressed subjects versus normal, manic, or schizophrenic subjects, and significantly (P c 0.05) higher PEP activity in manic or schizophrenic subjects than in normal volunteers. No significant relationships were found between PEP values and severity of illness (i.e., HRSD scores in unmedicated major de-

pressed subjects, YMRS scores in unmedicated manic subjects, and BPRS scores in unmedicated schizophrenic subjects).

Fig. 2 shows plasma PEP activity in unmedicated versus fluoxetine-treated major depressed subjects. ANCOVA (with age and sex as covariates) showed that fluoxetine-treated depressed subjects had significantly higher PEP values than unmedicated major depressed subjects.

Fig. 3 shows the effects of treatment with antidepressants (fluoxetine or tricyclic antidepressants) in major depressed subjects. Repeated measures

Fig. 1. Plasma prolyl endopeptidase (PEP) activity (mean of square-root transformations with SE) in normal (I), unmedicated major depressed (2), manic (3), and schizophrenic (4) subjects. Analysis of covariance (with age and sex as covariates) demonstrated significant differences in PEP activity (F= 5.8; df = 3, 62; P = 0.002).

M. Maes et al. /Psychiatry Research 58 (1995) 217-22s 221

0.25

Fig. 2. Plasma prolyl endopeptidase (PEP) activity (mean of square-root transformations with SE) in unmedicated (1) vs. medicated (2) major depressed subjects. Analysis of covariance (with age and sex as covariates) revealed significantly higher PEP activity in medicated than in unmedicated depressed subjects (F= 6.8; df= 1, 21; P = 0.01).

ANOVA showed that PEP activity was signifkant- ly increased by subchronic treatment with those antidepressant drugs. The pretreatment HRSD score (mean f SD = 24.8 f 9.2) was significantly reduced (15.0 f 10.7) by subchronic treatment with antidepressant drugs (F = 8.6, P = 0.01). There were no significant relationships between the changes in PEP activity induced by antidepres-

0.71 I

0.6 -

0.5 -

0.4 -

Fig. 3. Dot-and-line diagram showing that subchronic treatment with fluoxetine or tricyclic antidepressants significantly increased plasma prolyl endopeptidase (PEP) activity in major depressed subjects (F= 6.4; d’= 1, 12; P = 0.02).

0.2

0.1

barcl ine pas-treatment

Fig. 4. Dot-and-line diagram showing that subchronic treatment with valproate significantly decreased plasma prolyl endopeptidase (PEP) activity in manic subjects (F = 8.5; df = 1,8; P = 0.02).

sants (i.e., A PEP = pretreatment - posttreatment PEP values) and changes in the HRSD score (i.e., A HRSD) (r = -0.56, P = 0.11).

Fig. 4 shows the effects of subchronic treatment with valproate on plasma PEP in manic subjects. Repeated measures ANOVA showed that valproate significantly reduced PEP activity. The mean pretreatment YMRS score (31.8 f 4.6) was significantly reduced (19.1 f 7.3) by treatment with valproate (F = 12.7; P = 0.007). There were no significant relationships between posttreatment PEP values or A PEP values (i.e., pretreatment - posttreatment) and the duration of treatment, dosage of valproate, or A YMRS. No significant effects of neuroleptic treatment on PEP activity could be found in patients treated either with haloperidol or other neuroleptics or in the total study group of schizophrenic patients (i.e., pretreatment PEP: mean f SD = 0.402 f 0.175) U/l; posttreatment PEP: 0.398 f 0.170 U/l; F= 0.0; df= 1, 10; P = 0.9).

4. Discussion

The major findings of this study are that (a) plasma PEP activity is lower in major depressed subjects than in normal volunteers or in manic and schizophrenic subjects; (b) manic and schizophrenic subjects have higher PEP levels than nor-

222 M. Maes et al. /Psychiatry Research 58 (1995) 217-225

ma1 volunteers; (c) treatment with antidepressants significantly increases PEP levels in depressed subjects; and (d) treatment with valproate signiticant- ly reduces PEP activity in manic patients.

As in one of our previous reports (Maes et al., 1994), this study found lower PEP levels in major depression than in normal volunteers. Interesting- ly, major depression is also characterized by lower enzyme activity of other peptidases such as dipep- tidy1 peptidase IV (Maes et al., 1991) and angiotensin-converting enzyme (ACE) (Maes et al., 1992) in the blood. Dipeptidyl peptidase IV and PEP share a similar substrate specificity; the former is a membrane-bound aminopeptidase, while the latter is a cytosolic endopeptidase (Nagaoka and Yamashita, 1985; Polgar and Szabo, 1992). These findings further underscore that perturbation in peptidases may play a role in the pathophysiology of major depression. The finding that low molecular weight hyperpeptiduria may occur in major depression (Saelid et al., 1985) is in agreement with a lower peptidase activity in that illness (Abassi et al., 1992; Watanabe et al., 1993). As discussed in our previous reports (Maes et al., 1991, 1992, 1994), diminished activity of these peptidases may be involved in the neuroendocrine (e.g., HPA-axis hyperactivity, HPT-axis disorders), immune, and perhaps neurochemical (e.g., sympatho-adrenal-system activity) pathophysiology of major depression.

Another finding of this study is that fluoxetine- treated major depressed subjects have significantly higher PEP levels than unmedicated patients. Likewise, PEP activity was significantly increased during therapy with antidepressants, while values in the unmedicated state did not differ from those of normal volunteers. Therefore, it is conceivable that antidepressant drugs, including selective serotonin reuptake inhibitors, induce PEP activity in vivo and/or that PEP activity closely reflects severity of major depression. In this respect, in vitro experiments in our laboratory showed that fluoxetine significantly increased PEP activity isolated from human platelets (Goossens et al., in prepara- tion). Thus, the increased PEP activity in fluoxetine-treated subjects observed in this study may result from intrinsic effects of fluoxetine in in- creasing PEP activity. Consequently, increased

PEP activity during treatment with antidepressants could increase the catabolism of the neurally active peptides, which are substrates of PEP (e.g., TRH, @-endorphin, LH-RH, AVP, substance P, and maybe CRH or ACTH). Therefore, it may be hypothesized that if lower PEP activity is related to some of the neuroendocrine disturbances in depression, treatment with antidepressants could modulate these perturbations through induction of PEP activity. In any case, the findings show that lower PEP activity is probably a state marker of major depression.

To our knowledge, this is the first report on increased PEP activity in schizophrenic patients compared with normal volunteers and major depressed subjects. Other groups have reported some evidence that defects in peptidases, such as ACE, may be present in schizophrenia (Beckmann et al., 1984; Reichelt et al., 1987). Also, low molecular weight peptiduria may be found in schizophrenia (Reichelt et al., 1981, 1987). The latter phenomenon may indicate diminished activity of some peptidases (Abassi et al., 1992; Watanabe et al., 1993). These findings, however, do not contradict the present findings of increased plasma PEP activity in schizophrenia. For example, schizophrenia could be accompanied by a selective reduction in activity of some peptidases, together with an increase in the activity of other peptidases such as PEP. The results of the present study are in agreement with findings that the concentrations of various neuropeptides, which are known substrates of PEP, are reduced in schizophrenia. For example, significant reductions in AVP and neurotensin were found in the cerebrospinal fluid (CSF) of some schizophrenic subjects, and TRH concentrations were significantly decreased in post-mortem brain (frontal cortex) of schizophrenic patients (review: Nemeroff et al., 1987). How- ever, the findings of increased concentrations of substance P and neurotensin in post-mortem brain or in CSF of schizophrenic subjects (review: Nemeroff et al., 1987) do not corroborate the the- sis that increased PEP activity may be related to perturbations in these neurally active peptides. The present study was unable to find any significant effects of typical neuroleptics, including haloperidol, on plasma PEP activity. Other find-


ings indicate that antipsychotic drugs may induce the activity of peptidases such as aminopeptidases (Traficante and Turnbull, 1982), neutral endopeptidase 24.11 (enkephalinase) (Konkoy et al., 1993), and ACE (Wahlbeck et al., 1993). Moreover, the findings that neuroleptics may alter the breakdown of &endorphin and neurotensin (Davis and Culling-Berglund, 1987; Konings et al., 1990) suggest that antipsychotic agents may modify the activity of some peptidases.

This is also the first report that PEP activity is significantly higher in the plasma of manic patients than in normal volunteers and depressed subjects, and that treatment with valproate may reduce PEP activity. The results reported here suggest that increased PEP activity is a marker for psychotic conditions. Further research should examine the effects of antipsychotic agents and mood stabilizers, such as valproate, on PEP activity in vitro.

The origin of plasma PEP activity remains elusive. It is not known whether various PEP iso- enzyme forms exist in various organs or tissues (e.g., peripheral tissues versus the brain). Therefore, the clinical significance of the altered PEP activity in the blood and the relevance of our observations to PEP activity in the brain remain unclear. It has been argued, however, that the involvement of PEP in the catabolism of neuropeptides in vitro may suggest a role for PEP in the modulation of these neurally active peptides in vivo (Dalmaz et al., 1986). Moreover, there is some evidence that peripheral PEP concentrations may have relevance for the brain: (a) We have shown that depressed patients with lower peripheral PEP concentrations also exhibit an increased escape of ACTH and cortisol from suppression by dex- amethasone (Maes et al., 1994). It was suggested that the significant negative relationship between PEP activity and postdexamethasone ACTH or cortisol levels found in depression indicates that lower serum PEP activity plays a role in HPA axis overdrive through decreased degradation of AVP and possibly CRH or ACTH (Maes et al., 1994). (b) PEP may degrade peripheral neuropeptides, and the generated products may exert central effects. For example, angiotensin l-7 (Ag l-7) may be generated from Ag I by the action of

hypophysial-portal PEP, while Ag l-7 may stimu- late the release of hypothalamic vasopressin (Lawrence et al., 1992; Schiavone et al., 1988). (c) Smaller neuropcptides that can penetrate the brain and exert a central activity (e.g., oxytocin, vasopressin, and neurotensin) may be peripherally degraded by PEP, which therefore may modify the central effects of those neuropeptides. (d) In sheep, high PEP activity is observed in the hypophysial- portal plasma and median eminence, locations crucial to regulation of pituitary function (Lawrence et al., 1992). (e) Pituitary hormone peptides may be degraded by PEP, which may therefore affect the release or synthesis of peripheral target hormones (e.g., the ACTH- cortisol axis) and modify the central effects of these target hormones. (f) Comparison between PEP levels in sheep jugular and arterial plasma indicates that PEP is released from the vascular bed of the head and that the brain is probably a major source of PEP (Lawrence et al., 1992).

In conclusion, this study found lower plasma PEP activity in depression and higher PEP activity in mania and schizophrenia. Subchronic treatment with antidepressants may enhance PEP activity in depressed patients, while valproate may suppress PEP activity in manic patients.

Acknowledgments

The research reported was supported, in part, by the Nationaal Fonds voor Wetenschappelijk Onderzoek (NFWO) and the IUAP Program, Belgium; U.S. Public Health Service grants MH- 41684 and GCRC MOlRR00080; grants from the Elisabeth Severance Prentiss and John Pascal Sawyer Foundations; and the Michael Kaplen In- vestigator Award (to M.M.). H.Y.M. is the recipi- ent of a U.S. Public Health Service Research Career Scientist Award, MH-47808. The secretarial assistance of Mrs. M. Maes is greatly appreciated.

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Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs