Summary
The novel drug zimelidine 50–300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. During incubation of slices of rat brain cortex in plasma from the treated patients, the neuronal uptake of serotonin and noradrenaline was 51.7±10.2 and 82.8±9.6%, respectively, of the control values. The uptake inhibition both of serotonin and noradrenaline was correlated with the plasma level of norzimelidine (r=0.62 and 0.63, respectively). The major central metabolites of serotonin (5-HIAA) and noradrenaline (HMPG) in cerebrospinal fluid (CSF) decreased significantly (29 and 11%, respectively) during treatment with zimelidine. Although there was no mean change in the major dopamine metabolite (HVA) in CSF, the level during treatment (as percentage of the pretreatment level) was correlated with the effect on 5-HIAA in CSF. Thus, administration of zimelidine caused a relatively selective inhibition of serotonin uptake, mainly due to norzimelidine. A small but significant inhibition of noradrenaline uptake was also seen, but this effect was less pronounced than during chlorimipramine treatment. There was also an effect on the dopaminergic system, probably secondary to the action on serotonergic neurons.
Similar content being viewed by others
References
Åberg A, Holmberg G (1979) Preliminary clinical test of zimelidine (H 102/09), a new 5-HT uptake inhibitor. Acta Psychiatr Scand 59: 45–58
Åsberg M, Ringberger VA, Sjöqvist F, Thorén P, Träskman L, Tuck RJ (1977) Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine. Clin Pharmacol Ther 21: 201–207
Bertilsson L (1973) Quantitative determination of 4-hydroxy-3-methoxyphenyl glycol and its conjugates in cerebrospinal fluid by mass fragmentography. J Chromatogr 87: 147–153
Bertilsson L, Palmér L (1973) Determination of isomeric acid dopamine metabolites by mass fragmentography. Life Sci 13: 859–866
Bertilsson L, Atkinson AJ Jr, Althaus JR, Härfast Å, Lindgren JE, Holmstedt B (1972) Quantitative determination of 5-hydroxyindole-3-acetic acid in cerebrospinal fluid by gas chromatography-mass spectrometry. Anal Chem 44: 1434–1438
Bertilsson L, Åsberg M, Thorén P (1974) Differential effect of chlorimipramine and nortriptyline on cerebrospinal fluid metabolites of serotonin and noradrenalin in depression. Eur J Clin Pharmacol 7: 365–368
Carlsson A, Corrodi H, Fuxe K, Hökfelt T (1969a) Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-alpha-ethylmeta-tyramine. Eur J Pharmacol 5: 357–366
Carlsson A, Corrodi H, Fuxe K, Hökfelt T (1969b) Effect of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4-alpha-dimethyl-metatyramine. Eur J Pharmacol 5: 367–373
Hamberger B, Tuck JR (1973) Effect of tricyclic antidepressants on the uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices incubated in buffer or human plasma. Eur J Clin Pharmacol 5: 229–235
Mellström B, Tybring G (1977) Ion-pair liquid chromatography of steady-state plasma levels of chlorimipramine and demethylchlorimipramine. J Chromatogr 143: 597–605
Neckers LM, Biggio G, Moja E, Meek JL (1977) Modulation of brain tryptophan hydroxylase activity by brain tryptophan content. J Pharmacol Exp Ther 201: 110–116
Persson S-Å (1979) Effect of chlorimipramine on the synthesis and metabolism of dopamine in the rat striatum. Psychopharmacology 66: 13–17
Ross SB, Ögren SO, Renyi AL (1976) (Z)-Dimethyl-amino-1-(4-bromophenyl)-1-(3-pyridyl) propene (H 102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake. Acta Pharmacol Toxicol (Kbh) 39: 152–166
Ross SB, Renyi AL (1977) Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)-and (E)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl) allylamines and their secondary analogues. Neuropharmacology 16: 57–63
Siwers B, Ringberger VA, Tuck JR, Sjöqvist F (1977) Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients. Clin Pharmacol Ther 21: 194–200
Träskman L, Åsberg M, Bertilsson L, Cronholm B, Mellström B, Neckers LM, Sjöqvist F, Thorén P, Tybring G (1979) Plasma levels of chlorimipramine and its demethyl metabolite during treatment of depression. Clin Pharmacol Ther 26: 600–610
Westerlund D, Nilsson LB, Jaksch Y (1979) Straight phase ionpair chromatography of zimelidine and similar divalent amines. Part I: Bioanalysis. J Liquid Chromatogr 2: 373–405
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bertilsson, L., Tuck, J.R. & Siwers, B. Biochemical effects of zimelidine in man. Eur J Clin Pharmacol 18, 483–487 (1980). https://doi.org/10.1007/BF00874660
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00874660