Summary
The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14–22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 ± 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11–20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n=7) and nonresponders (n=8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Ackenheil M (1989) Clozapine: pharmacokinetic investigations and biochemical effects in man. Psychopharmacol 99: 32–37
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn. American Psychiatric Association, Washington
Andreasen NC (1982) Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychiatry 39: 784–788
Andreasen NC (1984a) The Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, Iowa City
Andreasen NC (1984b) The Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa, Iowa City
Andreasen NC, Flaum M, Arndt S, Alliger R, Swayze VW (1991) Positive and negative symptoms: assessment and validity. In: Marneros A, Andreasen NC, Tsuang MT (eds) Negative versus positive schizophrenia. Springer, Berlin Heidelberg New York Tokyo, pp 28–51
Arora RC, Meltzer HY (1991) Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm [Gen Sect] 85: 19–29
Baldessarini RJ, Huston-Lyons D, Campbell A, Marsh E, Cohen BM (1992) Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry [Suppl]: 12–16
Banki CM (1978) Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid and total blood serotonin content during clozapine treatment. Psychopharmacol 56: 195–198
Birmaher B, Baker R, Kapur S, Quintana H, Ganguli R (1992) Clozapine for the treatment of adolescents with schizophrenia. J Am Acad Child Adolesc Psychiat 31: 160–164
Blanz B, Schmidt MH (1993) Clozapine for schizophrenia. J Am Acad Child Adolesc Psychiat 32: 223–224
Boomsma F, Alberts G, Vaneijk L, Manintveld AJ, Schalekamp MADH (1993) Optimal collection and storage conditions for catecholamine measurements in human plasma and urine. Clin Chem 39: 2503–2508
Breier A (1995) Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 14: 187–202
Breier A, Buchanan RW, Waltrip RW, Listwak S, Holmes G, Goldstein DS (1994) The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. Neuropsychopharmacol 10: 1–7
Brunello N, Masotto C, Steardo L, Markstein R, Racagni G (1995) New insights into the biology of schizophrenia through the mechanism of action of clozapine. Neuropsychopharmacol 13: 177–213
Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148: 1474–1486
Frazier JA, Gordon CT, McKenna K, Lenane MC, Jih D, Rapoport JL (1994) An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiat 33: 658–663
Ganhao MF, Hattingh J, Hurwitz ML, Pitts NI (1991) Evaluation of a simple plasma catecholamine extraction procedure prior to high-performance liquid chromatography and electrochemical detection. J Chromatogr 564: 55–66
Gordon CT, Frazier JA, McKenna K, Giedd J, Zametkin A, Zahn T, Hommer D, Hong W, Kaysen D, Albus KE, Rapoport JL (1994) Childhood-onset schizophrenia: an NIMH study in progress. Schizophr Bull 20: 697–712
Green AI, Alam MY, Sobieraj JT, Pappalardo KM, Waternaux C, Salzman C, Schatzberg AF, Schildkraut JJ (1993) Clozapine response and plasma catecholamines and their metabolites. Psychiat Res 46: 139–149
Kahn RS, Davidson M (1993) On the value of measuring dopamine, norepinephrine and their metabolites in schizophrenia. Neuropsychopharmacol 8: 93–95
Kapur S, Remington G (1996) Serotonin-dopamine interaction and ist relevance to schizophrenia. Am J Psychiatry 153: 466–476
Kroesen S, Marksteiner J, Mahata M, Fischer Colbrie R, Saria A, Kapeller I, Winkler H (1995) Effects of haloperidol, clozapine and citalopram on messenger RNA levels of chromogranins A and B and secretogranin II in various regions of rat brain. Neurosci 69: 881–891
Kronig MH, Munne RA, Szymanski S, Safferman AZ, Pollack S, Cooper T, Kane JM, Lieberman JA (1995) Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 152: 179–182
Lake CR, Ziegler MG (1985) Techniques for the assessment and interpretation of catecholamine measurements in neuropsychiatric patients. In: Lake CR, Ziegler MG (eds) The catecholamines in psychiatric and neurologic disorders. Butterworth Publishers, Stone-Hane, pp 1–34
Lesch KP, Wolzin BL, Murphy DL, Riederer P (1993) Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 60: 2319–2322
Lieberman JA, John C, Pollack S, Masier S, Bookstein P, Cooper T, Iadorola M, Kane J (1991) Biochemical effects of clozapine in cerebrospinal fluid of patients with schizophrenia. In: Tamminga CA, Schulz S (eds) Schizophrenia research, vol 1. Raven Press, New York, pp 341–349
Meszaros K, Lenzinger E, Fureder T, Hornik K, Willinger U, Stompe T, Heiden AM, Resinger E, Fathi N, Gerhard E, Fuchs K, Miller-Reiter E, Pfersmann V, Sieghart W, Aschauer HN, Kasper S (1996) Schizophrenia and the dopamine beta hydroxylase gene: results of a linkage and association study. Psychiatr Genet 6: 17–22
Miller DD, Fleming F, Holman T, Perry PJ (1994) Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiat 55: 117–121
Moscarelli M, Maffei C, Cesana BM, Boato B (1987) An international perspective on assessment of negative and positive symptoms in schizophrenia. Am J Psychiatry 144: 1595–1598
Mozes T, Toren P, Chernauzan N, Mester R, Yoranhegesh R, Blumensohn R, Weizman A (1994) Clozapine treatment in very early onset schizophrenia. J Am Acad Child Adolesc Psychiat 33: 65–70
Naylor L, Dean B, Opeskin K, Pavey G, Hill C, Keks N, Copolov D (1996) Changes in the serotonin transporter in the hippocampus of subjects with schizophrenia identified using [3H]paroxetine. J Neural Transm 103: 749–757
Orellana-Vidal GP (1995) Locus coeruleus: implications for psychiatry. Acta Psiquiat Psicol Am Lat 41: 57–66
Overall JE, Gorham DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: 799–812
Pickar D, Owen RR, Litman RE, Konicki PE, Gutierrez R, Rapaport MH (1992) Clinical and biologic response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry 49: 345–353
Piscitelli SC, Frazier JA, McKenna K, Albus KE, Grothe DR, Gordon CT, Rapoport JL (1994) Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia-association with response. J Clin Psychiatry 55: 94–97
Pluto R, Bürger P (1988) Normal values of catecholamines in blood plasma determined by high-performance liquid chromatography with amperometric detection. Int J Sports Med 9: 75–78
Potkin SG, Bera R, Gulasekaram B, Costa J, Hayes S, Jin Y, Richmond G, Carreon D, Sitanggan K, Gerber B (1994) Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 55: 133–136
Remschmidt H, Martin M, Schulz E, Gutenbrunner C, Fleischhaker C (1991) The concept of positive and negative schizophrenia in child and adolescent psychiatry. In: Marneros A, Andreasen NC, Tsuang MT (eds) Negative versus positive schizophrenia. Springer, Berlin Heidelberg New York Tokyo, pp 219–242
Remschmidt H, Schulz E, Martin M (1992) Die Behandlung schizophrener Psychosen in der Adoleszenz mit Clozapine (Leponex). In: Naber D, Müller-Spahn F (Hrsg) Clozapine. Pharmakologie und Klinik eines atypischen Neuroleptikums. Schattauer, New York, S 99–119
Remschmidt H, Schulz E, Martin M (1994a) An open trial of clozapine in thirty-six adolescents with schizophrenia. J Child Adolesc Psychopharmacol 4: 31–41
Remschmidt H, Schulz E, Martin M, Warnke A, Trott GE (1994b) Childhood-onset schizophrenia: history of the concept and recent studies. Schizophr Bull 20: 727–745
Riederer P, Laux G (1992) Therapeutic drug monitoring of psychotropics: report of a consensus conference. Pharmacopsychiat 25: 271–272
Schulz E, Fleischhaker C, Remschmidt H (1995) Determination of clozapine and its major metabolites in serum samples of adolescent schizophrenic patients by high performance liquid chromatography. Data from a prospective clinical trial. Pharmacopsychiat 28: 20–25
Schulz E, Fleischhaker C, Remschmidt H (1996) Correlated changes in symptoms and neurotransmitter indices during maintenance treatment with clozapine or conventional neuroleptics in adolescents and young adults with schizophrenia. J Child Adolesc Psychopharmacol 6: 119–131
Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, McLean S, Guanowsky V, Howard HR, Lowe JA (1995) Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 275: 101–113
Siefen G, Remschmidt H (1986) Behandlungsergebnisse mit Clozapine bei schizophrenen Jugendlichen. Z Kinder Jugendpsychiat 14: 245–257
Towbin KE, Dykens EM, Pugliese RG (1994) Clozapine for early developmental delays with childhood-onset schizophrenia — protocol and 15-month outcome. J Am Acad Child Adolesc Psychiat 33: 651–657
van Kammen DP (1991) The biochemical basis of relaps and drug response in schizophrenia: review and hypothesis. Psychol Med 21: 881–895
van Kammen DP, Kelley M (1991) Dopamine and norepinephrine activity in schizophrenia. An integrative perspective. Schizophr Res 4: 173–191
Weier TB, Smith CT, Round JM, Betteridge DJ (1986) Stability of catecholamines in whole blood, plasma, and platelets. Clin Chem 32: 822–833
Yamamoto K, Ozawa N, Shinba T, Hoshino T, Yoshii M (1994) Possible noradrenergic dysfunction in schizophrenia. Brain Res Bull 35: 529–543
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schulz, E., Fleischhaker, C., Clement, H.W. et al. Blood biogenic amines during clozapine treatment of early-onset schizophrenia. J. Neural Transmission 104, 1077–1089 (1997). https://doi.org/10.1007/BF01273320
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01273320