4 Department of Psychiatry, Gyongyos Hospital, Gyongyos, Hungary. Accepted March 30, 1987. Summary. The clinical and biochemical effects of adjuvant ...
Journal of Neural Transmission
J Neural Transm (1988) 71:73-78
9 by Springer-Verlag1988
Effect of adjuvant reserpine treatment on catecholamine metabolism in schizophrenic patients under long-term neuroleptic treatment* G. Bagdy 1.* , Perenyi 1, E. Freeska I , A. Seregi2, M. I. K. Fekete2, L. Tothfalusi3, K. M a g y a r 3, A. Bela4, and M. Arato 1 1 National Institute for Nervous and Mental Diseases, Budapest, Hungary 2 Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary 3 Department of Pharmacodynamics, Semmelweis University of Medicine, Budapest, Hungary 4 Department of Psychiatry, Gyongyos Hospital, Gyongyos, Hungary Accepted March 30, 1987
Summary. The clinical and biochemical effects of adjuvant reserpine treatment were investigated in 12 chronic schizophrenic patients on long-term neuroleptic medication. The global severity of the symptoms using the Brief Psychiatric Rating Scale did not change significantly in the whole group, however, a moderate decrease in positive symptoms (factors though disturbance, activation and hostile-suspiciousness) was observed for 5 patients. Cerebrospinal fluid (CSF) noradrenaline levels showed a consistent decrease, but other biochemical parameters (CSF dopamine metabolites, platelet MAO and serum dopamine13-hydroxylase activities) did not change significantly. The changes of clinical symptoms and biochemical parameters did not show any correlation. Keywords: Schizophrenia, neuroleptics, reserpine, cerebrospinal fluid amines, metabolites, c-AMP, serum prolactin, enzymes.
Introduction Reserpine has been a remarkably valuable pharmacological agent in therapy and in research. Although reserpine was used as an antipsychotic drug and has been replaced by the development of neuroleptics, its combination with neuroleptics may be clinically helpful in the treatment of chronic, neurolepticresistant psychoses (Foote, 1958; Ban, 1969; Berlant, 1984). It is generally accepted that reserpine causes its physiological and behavioral effects by altering * This work was supported by the State Office for Technical Development. ** Current address: Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Building 10, Room 3D/41, Bethesda, MD 20892, U.S.A.
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m o n o a m i n e r g i c n e u r o t r a n s m i s s i o n via depletion o f m o n o a m i n e transmitter substances (Carlsson, 1965). It is, however, d e b a t a b l e whether these effects are due to the changes in brain 5 - h y d r o x y t r y p t a m i n e , d o p a m i n e ( D A ) or noradrenaline ( N A ) levels. It is also questionable whether the possible therapeutic effects o f reserpine in c o m b i n a t i o n with neuroleptics are the result o f a further reduction o f d o p a m i n e r g i c function or if noradrenergic mechanisms are also involved. The aim o f the present w o r k was to study the effect o f reserpine on the clinical state o f the patients, catecholamine and metabolite levels in cerebrospinal fluid (CSF), enzyme activities a n d prolactin ( P R L ) levels in the p l a s m a o f chronic schizophrenic patients on long-term neuroleptic treatment.
Material and methods Twelve chronic schizophrenic males who met the Research Diagnostic Criteria for schizophrenia (Spitzer et al., 1977) gave informed consent to participate in the study. The ages of the patients ranged from 30 to 53 (39.4 4- 8.1 years). They had been under continuous neuroleptic treatment for at least one year. Two patients received haloperidol, two fluspirilene, one of them in combination with methofenazine, seven methofenazine and one pimozide. Eight patients also received thioridazine in combination with the above neuroleptics. The mean dose in chlorpromazine equivalent was 658 + 362 mg/day. The dose of adjuvant reserpine-treatment was 3 x 1 mg/day. CSF and blood samples were obtained before and 14 days after the beginning of adjuvant reserpine therapy. All lumbar- and venipunctures were performed between 8 a.m. and 9 a.m. in sitting position, after a 10 h fast and bed rest. Aliquots (5 ml) of CSF were collected in plastic tubes, mixed and immediately frozen in dry ice. Blood pressure and heart rate were continuously monitored. Clinical condition was assessed by the same two raters using the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) and Clinical Global Impressions (CGI; Guy, 1976) before and after two weeks reserpine-treatment NA, adrenaline (A) and dihydroxy-phenylacetic acid (DOPAC) were measured by the radioenzymatic method described by Fekete et al. (1978), modified by Bagdy et al. (1983). The sensitivity of the method in the case of the catecholamines and DOPAC were three and 50 pg/reaction, respectively. Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured after deproteinization with perchloric acid by high-performance liquid chromatography with electrochemical detection (Palfreyman et al., 1982; Silverstein et al., 1984; Tyce et al., 1985). Twenty microliters of the supernatant were injected directly into the system which included a precolumn (BST-GMK) and a 4 x 250 mm, 7 gm reverse phase column (Separon C-18). The mobile phase comprised 80% 0.1 mol/1 citric acid and 20% methanol. A reciprocating pump (OE-312, Labor-MIM) was maintained a flow-rate 0.91 ml/min. An electrochemical detector with a thin-layer glassy carbon electrode (BAS) were used at a potential of 750 mV (Ag/AgC1 reference electrode). Electrode response increased linearly from 0 to 20 mg and the sensitivity was 80 pg for 5HIAA and 170 pg for HVA. CSF cyclic adenosine 3',5'-monophosphate (cAMP) was measured using a radioimmunoassay (RIA) with anti-cAMP antibodies developed in goats as described by Brooker et al. (1979). The variation coefficient in the range from five to 30 pg/ml was less, then 6%. Serum PRL-levels also were measured by a RIA, using a kit (CIS PRL). Serum dopamine-[3-hydroxylase (DBH) activity was determined according to the method of Nagatsu and Udenfriend (1972). The variation coefficient of the method varied between 15-1.9%, corresponding the enzyme activity of 4-80 nmol/min x ml. Platelet monoamine oxidase (MAO) activity was measured from platelet rich plasma (PRP) with two substrates. Determination of enzyme activity with tyramine was described elsewhere (Bagdy et al., 1983). In measurements performed with phenylethylamine (PEA, 2-phenyl/
Adjuvant reserpine treatment in chronic schizophrenia
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1-14C/ethylamine hydrochloride, Amersham) substrate concentration of 10-5 mol/1 was used for incubation, and extraction was performed with 2 x 2 ml toluene cocktail. Enzyme activity of PRP was related to platelet count. Intraassay scattering was 3.7%. Amines, metabolites and PRL are given in ng/ml, cAMP in pmol/mlo DBH activity was expressed as nmol octopamine/min x ml serum. MAO activity is given as nmol substrate/108 platelets x hour. All samples were measured in one assay. Statistical analyses were performed with Student's t-test and linear regression. Results The results of the neurochemical measurements are shown in Table 1. Only C S F NA-levels were found to decrease significantly during the s t u d y (Fig. 1), Table 1. Concentrations in CSF of NA, A, DOPAC, HVA, 5HIAA, cAMP (n= 11), serum PRL (n= 12), and enzyme activities (platelet MAO, serum DBH n = 12) before and two weeks after adjuvant reserpine-treatment in schizophrenic patients under long-term neuroleptic treatment
CSF NA ng/ml CSF A ng/ml CSF DOPAC ng/ml CSF HVA ng/ml CSF 5HIAA ng/ml CSF c-AMP pmol/ml Serum PRL ng/ml Serum DBH Activity nmol/min x ml Platelet MAO Activity, PEA nmol/108plat.xh
Day 0 Mean SD
Day 14 Mean SD
0.215 0.105 3.01 19.1 14.4 16.4 36.5 28.8 3.9
0.112" 0.082 2.98 20.5 18.7 17.0 61.3 29.8 4.0
0.068 0.040 1.25 8.8 10.1 7.9 44.1 16.7 1.9
0.035 0.021 1.08 7.9 11.7 6.8 41.9 17.4 1.7
* p
