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Zimelidine chemical structure
|ATC code |
|Elimination half-life||8.4 +/- 2.0 hours (parent compound)|
19.4 +/- 3.6 hours (norzimelidine)
|Legal status||Withdrawn from market|
|Routes of administration||Oral|
Zimelidine (Normud®, Zelmid®) was the first marketed selective serotonin reuptake inhibitor (SSRI) antidepressant. It is a pyridylallylamine, structurally different from other antidepressants. The substance was developed in the early 1980s by the Swedish company AstraZeneca following a search for drugs with structures similar to chlorpheniramine (it is a derivative of brompheniramine), an antihistamine with antidepressant activity. It was then licensed to other drug producers.
Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barré syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients. After its ban, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs.
Mechanism of action
The mode of action is a strong reuptake inhibition of serotonin from the synaptic cleft. Postsynaptic receptors are not acted upon.
Zimelidine was reported by Montplaisir and Godbout to be very effective for cataplexy in 1986, back when this was usually controlled by tricyclic antidepressants, which often had anticholinergic effects. Zimelidine was able to improve cataplexy without causing daytime sleepiness.
Most often reported were:
- Dry mouth, dryness of pharyngeal and nasal membranes
- Increased sweating (hyperhidrosis)
- MAO inhibitors - severe or life-threatening reactions possible
The former doses were 200 to 400mg daily in outpatients and up to 600mg in inpatients.
- Bruce G. Charlton, Self-management of psychiatric symptoms using over-the-counter (OTC) psychopharmacology: the S-DTM therapeutic model - self-diagnosis, self-treatment, self-monitoring. Medical Hypotheses 2005; 65: 823-828.
- ^ Caille G, Kouassi E, de Montigny C. (1986). Pharmacokinetic study of zimelidine using a new GLC method. Clinical Pharmacokinetics 8 (6): 530-40. PMID 6228368.
- ^ Godbout R, Montplaisir J. (1986). The effect of zimelidine, a serotonin-reuptake blocker, on cataplexy and daytime sleepiness of narcoleptic patients.. Clinical Neuropharmacology 9 (1): 46-51. PMID 2950994.
- ^ see Godbout et al. 1986
- Alhaider, A. A., & Mustafa, A. A. (1991). Enhancement of imipramine-induced rat brain !b-adrenoreceptor desensitization by subacute co-administration of trazodone, zimelidine, quipazine or 5-hydroxytryptophan: Psychopharmacology Vol 103(3) Mar 1991, 351-356.
- Ansseau, M., Papart, P., Pitchot, W., Timsit-Berthier, M., & et al. (1992). Dexamethasone suppression test and prediction of treatment response to selective antidepressants: European Psychiatry Vol 7(4) 1992, 191-194.
- Audi, E. A., de Aguiar, J. C., & Graeff, F. G. (1988). Mediation by serotonin of the antiaversive effect of zimelidine and propranolol injected into the dorsal midbrain central grey: Journal of Psychopharmacology Vol 2(1) 1988, 26-32.
- Balldin, J., Berggren, U., Bokstrom, K., Eriksson, M., & et al. (1994). Six-month open trial with Zimelidine in alcohol-dependent patients: Reduction in days of alcohol intake: Drug and Alcohol Dependence Vol 35(3) Jun 1994, 245-248.
- Barber, N. I., Teicher, M. H., & Baldessarini, R. J. (1989). Effects of selective monoaminergic reuptake blockade on activity rhythms in developing rats: Psychopharmacology Vol 97(3) Mar 1989, 343-348.
- Bayley, P. J., Bentley, G. D., & Dawson, G. R. (1998). The effects of selected antidepressant drugs on timing behavior in rats: Psychopharmacology Vol 136(2) Mar 1998, 114-122.
- Bengtsson, B.-O., Lundmark, J., & Walinder, J. (1991). No crossover reactions to citalopram or paroxetine among patients hypersensitive to zimeldine: British Journal of Psychiatry Vol 158 Jun 1991, 853-855.
- Bjorvatn, B., Neckelmann, D., & Ursin, R. (1992). The 5-HT-sub(1A) antagonist (Lambda )-alprenolol fails to modify sleep or zimeldine-induced sleep-waking effects in rats: Pharmacology, Biochemistry and Behavior Vol 42(1) May 1992, 49-56.
- Fasmer, O. B., Post, C., & Hole, K. (1987). Changes in nociception after acute and chronic administration of zimelidine: Different effects in the formalin test and the substance P behavioural assay: Neuropharmacology Vol 26(4) Apr 1987, 309-312.
- Gill, K., & Amit, Z. (1987). Effects of serotonin uptake blockade on food, water, and ethanol consumption in rats: Alcoholism: Clinical and Experimental Research Vol 11(5) Oct 1987, 444-449.
- Gunturkun, O., Grothues, A., Hautkappe, A., Vise, F., & et al. (1989). Serotonergic modulation of ingestive behavior in pigeons: Pharmacology, Biochemistry and Behavior Vol 32(2) Feb 1989, 415-420.
- Hilakivi, L. A., & Hilakivi, I. (1987). Increased adult behavioral "despair" in rats neonatally exposed to desipramine or zimeldine: An animal model of depression? : Pharmacology, Biochemistry and Behavior Vol 28(3) Nov 1987, 367-369.
- Kleinlogel, H., & Burki, H. R. (1987). Effects of the selective 5-hydroxytryptamine uptake inhibitors paroxetine and zimeldine on EEG sleep and waking stages in the rat: Neuropsychobiology Vol 17(4) 1987, 206-212.
- Kristofferson, A., Sohl-Akerlund, A., Hall, E., Bengtsson, B. O., & et al. (1994). Effect of zimeldine and its metabolites on: International Clinical Psychopharmacology Vol 9(3) Sep 1994, 179-185.
- Lesko, L. J., Fiore, D., Leslie, J., Narang, P. K., & et al. (1986). Estimation of protein binding of zimelidine and norzimelidine using cerebrospinal fluid and ultrafiltration: Research Communications in Psychology, Psychiatry & Behavior Vol 11(2-3) 1986, 95-111.
- Linnoila, M., Guthrie, S., Lane, E. A., Karoum, F., & et al. (1986). Clinical studies on norepinephrine metabolism: How to interpret the numbers: Psychiatry Research Vol 17(3) Mar 1986, 229-239.
- Lund, A., Mjellem-Joly, N., & Hole, K. (1991). Chronic administration of desipramine and zimelidine changes the behavioural response in the formalin test in rats: Neuropharmacology Vol 30(5) May 1991, 481-487.
- Lund, A., Tjolsen, A., & Hole, K. (1990). Antinociceptive effect of intrathecally-administered desipramine and zimelidine in rats: Neuropharmacology Vol 29(9) Sep 1990, 819-823.
- Maudhuit, C., Hamon, M., & Adrien, J. (1996). Effects of chronic treatment with zimelidine and REM sleep deprivation on the regulation of raphe neuronal activity in a rat model of depression: Psychopharmacology Vol 124(3) Apr 1996, 267-274.
- Maudhuit, C., Prevot, E., Dangoumau, L., Martin, P., Hamon, M., & Adrien, J. (1997). Antidepressant treatment in helpless rats: Effect on the electrophysiological activity of raphe dorsalis serotonergic neurons: Psychopharmacology Vol 130(3) Apr 1997, 269-275.
- McMahon, T. F., Weiner, M., Lesko, L., & Emm, T. (1987). Effects of age on antidepressant kinetics and memory in Fischer 344 rats: Pharmacology, Biochemistry and Behavior Vol 26(2) Feb 1987, 313-319.
- Melo, L. L., & Brandao, M. L. (1995). Involvement of 5-HT-sub(1A ) and 5-HT-sub-2 receptors of the inferior colliculus in aversive states induced by exposure of rats to the elevated plus-maze test: Behavioural Pharmacology Vol 6(4) Jun 1995, 413-417.
- Montgomery, S. A., Gabriel, R., James, D., Hawley, C., & et al. (1989). Hypersensitivity to zimelidine without cross reactivity to fluoxetine: International Clinical Psychopharmacology Vol 4(Suppl 1) Jan 1989, 27-29.
- Montgomery, S. A., Gabriel, R., James, D., Hawley, C., & et al. (1989). The specificity of the zimelidine reaction: International Clinical Psychopharmacology Vol 4(1) Jan 1989, 19-23.
- Nystrom, C., & Hallstrom, T. (1987). Comparison between a serotonin and a noradrenaline reuptake blocker in the treatment of depressed outpatients: A cross-over study: Acta Psychiatrica Scandinavica Vol 75(4) Apr 1987, 377-382.
- Perrault, G., Morel, E., Zivkovic, B., & Sanger, D. J. (1992). Activity of litoxetine and other serotonin uptake inhibitors in the tail suspension test in mice: Pharmacology, Biochemistry and Behavior Vol 42(1) May 1992, 45-47.
- Sletvold, H., & Gotestam, K. G. (1989). Placebo and antidepressive effects: Zimelidine and doxepin in a double-blind extended placebo study on outpatients with minor depression: European Journal of Psychiatry Vol 3(3) Jul-Sep 1989, 151-156.
- Sommerfelt, L., & Ursin, R. (1987). The effects of zimeldine and alaproclate combined with a small dose of 5-HTP on waking and sleep stages in cats: Behavioural Brain Research Vol 24(1) Apr 1987, 1-10.
- Sommerfelt, L., & Ursin, R. (1993). The 5-HT-sub-2 antagonist ritanserin decreases sleep in cats: Sleep: Journal of Sleep Research & Sleep Medicine Vol 16(1) Jan 1993, 15-22.
- von Knorring, L., & Mornstad, H. (1986). Saliva secretion rate and saliva composition as a model to determine the effect of antidepressant drugs on cholinergic and noradrenergic transmission: Neuropsychobiology Vol 15(3-4) Sep 1986, 146-154.
- Zagrodzka, J., Wieczorek, M., & Romaniuk, A. (1994). Social interactions in rats: Behavioral and neurochemical alterations in DSP-4-treated rats: Pharmacology, Biochemistry and Behavior Vol 49(3) Nov 1994, 541-548.
- PubChem Substance Summary: Zimelidine National Center for Biotechnology Information.
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