Dothiepin
Tóm tắt
Dothiepin is a tricyclic antidepressant that is structurally related to amitriptyline. It appears that the antidepressant activity of dothiepin is mediated through facilitation of noradrenergic neurotransmission by uptake inhibition and possibly also by enhancement of serotoninergic neurotransmission. The overall therapeutic efficacy of dothiepin is very similar to that of amitriptyline. In addition, dothiepin appears to be comparable to imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone. Dry mouth is the most commonly reported side effect of therapeutic doses but the incidence of this and other anticholinergic side effects is less among patients treated with dothiepin than with amitriptyline. However, the sedative/anxiolytic activity of dothiepin is similar to that of amitriptyline. Dothiepin has not been associated with cardiotoxicity at therapeutic doses. Thus, many years of extensive clinical use have shown that dothiepin is now an established and effective antidepressant in both inpatients and outpatients with depressive symptoms of varying severity and coexisting anxiety. Its therapeutic equivalence to other tricyclics ensures its place as a treatment alternative in these disorders.
In vitro dothiepin and its metabolite northiaden facilitate noradrenergic neurotransmission through inhibition of the neuronal uptake of noradrenaline (norepinephrine). Dothiepin is a more potent inhibitor of 14C-serotonin uptake in human platelets in vitro than its metabolites, and may enhance brain serotonin synthesis by inhibition of the tryptophan-degrading enzyme tryptophan pyrrolase. Neurotransmitter receptor binding studies have indicated that dothiepin has low affinity at α1-and α2-adrenoceptors and serotonin 5HT1 and 5HT2-receptors. In comparison with other antidepressants, dothiepin has a relatively high affinity for guinea-pig ileum muscarinic receptors in vitro but in common with other antidepressants it is a relatively potent antagonist of histamine H1-receptors in vitro.
Repeated, but not acute, administration of dothiepin to rats preferentially antagonised serotonin-mediated behaviour despite the fact that in in vitro studies dothiepin and its metabolites were more effective inhibitors of noradrenaline uptake than serotonin uptake. Single oral doses of dothiepin and amitriptyline 25mg produced comparable increases in heart rates, and reductions in blood pressures, in both young and elderly healthy subjects. However, in a 6-week double-blind study in 184 outpatients with neurotic depression, amitriptyline produced significant increases in heart rate and electrocardiographic QT intervals in comparison with both dothiepin and placebo. A double-blind study involving administration of single oral doses of dothiepin and amitriptyline 25mg indicated that in elderly healthy subjects both dothiepin and amitriptyline produced marked reductions in salivary flow rate. Following oral administration to healthy subjects dothiepin is readily absorbed and peak plasma concentrations are achieved within 2 to 4 hours. Steady-state serum concentrations are achieved within 12 days with either 3 times daily or once daily administration. Dothiepin undergoes extensive hepatic metabolism to dothiepin-S-oxide, northiaden and northiaden-S-oxide, and its oral bioavailability is about 30% after first-pass hepatic metabolism. In healthy subjects the mean terminal elimination half-lives of dothiepin and its metabolites are 14 to 24 hours and 23 to 46 hours, respectively. In elderly healthy subjects the time to peak plasma concentration and the elimination half-life are prolonged, the AUC is increased and the absorption rate constant, volume of distribution and plasma clearance of dothiepin are reduced, compared with younger individuals Dothiepin is an effective antidepressant that has an onset of action of about 2 weeks when administered in doses up to 225 mg/day to patients with depression of different aetiologies. A single 50 to 150mg dose of dothiepin at night was as effective as 3 times daily administration. Double-blind controlled studies have demonstrated that the overall antidepressant efficacy of dothiepin is indistinguishable from that of amitriptyline. Other studies have suggested equivalence with imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone. In studies comparing dothiepin with amitriptyline, reductions in Hamilton Depression Rating Scale scores after 4 to 6 weeks were in the range 40 to 70%, with 66 to 74% of patients showing at least some improvement with both drugs. In addition, the sedative/anxiolytic activity of dothiepin appears to be equivalent to that of amitriptyline, mianserin, trazodone and the benzodiazepine alprazolam, and greater than that of chlordiazepoxide in patients with anxiety associated with depression. Preliminary studies have indicated that dothiepin has significant analgesic activity, compared with placebo, in patients with psychogenic facial pain, idiopathic fibromyalgia syndrome or rheumatoid arthritis. The most commonly reported adverse effects of treatment with dothiepin among 5755 patients evaluated for tolerability in non-comparative and double-blind comparative studies were dry mouth (24%), drowsiness (17%), gastrointestinal disorders (11%) and dizziness (10%). Overall, 52% of patients reported adverse effects of varying degrees of severity and 5% were withdrawn from treatment because of side effects. The results of comparative studies indicate that dothiepin treatment produces a lower incidence of side effects than treatment with amitriptyline. The usual starting dosage of dothiepin is 75 mg/day in divided doses, or as a single dose at night, increasing to 150 mg/day according to the severity of the depressive illness. In certain circumstances daily doses of up to 225mg may be used in hospital inpatients. Treatment of the elderly should be initiated with doses in the range 50 to 75 mg/day and increased thereafter with caution. Dosage recommendations for the United States include an initial dose of 50mg twice daily in most adult outpatients increasing to a maximum of 300 mg/day. Alternatively, 100mg increasing to 150mg could be administered once at night, with a total daily dose of 300mg. Higher doses should only be administered to hospitalised patients under supervision. Improvement in the symptoms of depression may be delayed for 2 to 4 weeks and patients should be closely monitored until their individual reaction to treatment has been defined. Dothiepin and other tricyclic antidepressants are contraindicated in patients receiving monoamine oxidase inhibitors, sympathomimetic agents or adrenergic neurone blocking drugs.
Tài liệu tham khảo
Ades J. Etude ouverte multicentrique du chlorhydrate de dosulepine (prothiaden 75mg) prescrit en ambulatoire par des psychiatres chez 1555 patients. Synapse 36: 76–80, 1987
Akhtar MJ, Davey A, Cox HE, Ancill RJ. A double blind study comparing mianserin and dothiepin: an application for computers in clinical psychiatry. British Journal of Clinical Practice 38: 316–319, 1984
Badawy AAB, Evans M. Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by acute administration of small doses of antidepressants. British Journal of Pharmacology 77: 059–067, 1982
Blacker R, Shanks NJ, Chapman N, Davey A. The drug treatment of depression in general practice: a comparison of nocte administration of trazodone with mianserin, dothiepin and amitriptyline. Psychopharmacology 95: S18–S24, 1988
Boening J. Report on a double blind comparison of two different regimens of dothiepin (Prothiaden). Journal of International Medical Research 11: 15–20, 1983
Buckett WR, Fletcher C, Hinds M, Mason R. Subsensitivity of cerebellar Purkinje cells to iontophoresed noradrenaline induced by chronic administration of dothiepin. British Journal of Pharmacology 86 (Suppl.): 270P, 1985a
Buckett WR, Luscombe GP. Dothiepin and desipramine induce different changes in noradrenergic and serotoninergic behaviour after subchronic treatment. British Journal of Pharmacology 80 (Suppl.): 638P, 1983
Buckett WR, Thomas PC. The antidepressant dothiepin reduces cortical β-adrenoceptor binding after subchronic oral administration to rats. British Journal of Pharmacology 75: 97P, 1982
Buckett WR, Thomas PC, Diggory GL, Luscombe GP. Neurochemical and behavioural down-regulation induced by the antidepressant dothiepin. In Burrows GD, Norman TR, Dennerstein L (Eds) Clinical and pharmacological studies in psychiatric disorders, pp. 250–255, J. Libbey, London, 1985b
Caruso I, Sarzi Puttini PC, Boccassini L, Santandrea S, Locati M, et al. Double blind study of dothiepin versus placebo in the treatment of primary fíbromyalgia syndrome. Journal of International Medical Research 15: 154–159, 1987
Claghorn JL, Mathew RJ, Johnstone EE. Dothiepin HC1 in the treatment of psychoneurosis. Psychopharmacology Bulletin 15: 94–95, 1979
Claghorn JL, Schroeder J, Goldsmith BJ. Comparison of the electrocardiographic effect of dothiepin and amitriptyline. Journal of Clinical Psychiatry 45: 291–293, 1984
Crampton EL, Dickinson W, Haran G, Marchant B, Risdall PC. The metabolism of dothiepin hydrochloride in vivo and in vitro British Journal of Pharmacology 64: 405P, 1978
Cropper M, Garner A, McEwan GD, Munt DF, Rushbrook LAW, et al. A double-blind comparative study of alprazolam and dothiepin hydrochloride in the treatment of anxiety associated with depression. Pharmatherapeutica 5: 76–82, 1987
Dachary JM, Darondel A, Ernst J, Vauterin C. A comparative clinical trial on Prothiaden Fort 75mg in hospitalised or ambulatory patients. Psychologie Médicale 17: 137–144, 1985
Dahl LE, Dencker SJ, Lundin L. A double-blind study of dothiepin hydrochloride (Prothiaden) and amitriptyline in outpatients with masked depression. Journal of International Medical Research 9: 103–107, 1981
Deering RB, Vallé-Jones JC. A general practitioner double-blind study of dothiepin hydrochloride (’Prothiaden’) and amitriptyline in depression. Current Medical Research and Opinion 2: 471–473, 1974
Diggory GL, Buckett WR. Decreased 5-HT2 but not 5-HT1 receptor binding in cortex of rat after chronic administration of dothiepin. Neuropharmacology 24: 275–278, 1985
Dorman T. Clinical trial comparison of a sustained release form of amitriptyline with dothiepin. Journal of International Medical Research 8: 286–292, 1980
Eilenberg D. A double blind comparative trial of dothiepin and imipramine for the treatment of depressive inpatients. New Zealand Medical Journal 91: 92–93, 1980
Evans L, Cox J. Dothiepin versus doxepin for reactive depression. Medical Journal of Australia 2: 147–148, 1981
Feinmann C, Harris M, Cawley R. Psychogenic facial pain: presentation and treatment. British Medical Journal 288: 436–438, 1984
Fort S, Bannister P, Manning A, Bolton R, Losowsky MS. Inappropriate antidiuretic hormone secretion associated with dothiepin. Lancet 2: 551, 1985
Fulton A, Norman TR, Cheng H, Burrows GD. Assessment of the antidepressant activity of dothiepin and its metabolites by preclinical tests. Journal of Affective Disorders 4: 261–269, 1982
Gadd EM, Norris CM, Beeley L. Antidepressants and galactorrhoea. International Clinical Psychopharmacology 2: 361–363, 1987
General Practitioner Research Group. A comparison between dothiepin and doxepin in the treatment of depression. Practitioner 216: 581–583, 1976
Glowinski J, Axelrod J. Inhibition of uptake of tritiated noradrenaline in the intact rat brain by imipramine and structurally related compounds. Nature 204: 1318–1319, 1964
Henry JA, Martin AJ. The risk-benefít assessment of antidepressant drugs. Medical Toxicology 2: 445–462, 1987
Herridge CF, Low-Beer L, Marsh BD. The use of dothiepin in long term treatment of depressive illness. Activitas Nervosa Superior 15: 87–88, 1973
Hollister LE. Psychiatric disorders. In Speight TM (Ed.) Avery’s drug treatment, 3rd ed., pp. 1137–1206, Churchill Livingstone, Edinburgh, 1987
Ishikawa K, Shibanoki S, Kubo T, Watabe S, Matsumoto A, et al. Effects of various tricylic antidepressants on amine uptake. European Journal of Pharmacology 120: 63–68, 1986
Johnson F, Sacco FA, Yellowley TW. Chlordiazepoxide and dothiepin compared in anxiety/depression in general practice. Practitioner 211: 362–364, 1973
Karrasch KF, Schulte RM, Zeit T. Dosulepin in der ambulanten Behandlung. Ergebnisse einer Multi-centrestudie mit 1866 dePressiven patienten. Medizinische Welt 38: 1453–1458, 1987
Kawahara K, Awaji T, Uda K, Sakai Y, Hashimoto Y. Urinary excretion of conjugates of dothiepin and northiaden (mono-N-demethyl-dothiepin) after an oral dose of dothiepin to humans. European Journal of Drug Metabolism and Pharmacokinetics 11: 29–32, 1986
Kazetska V, Zimanova J, Vojtechovsky M. Cardiotoxicity of prothiadene in clinical trials. Aggressologie 19: 203–209, 1978
Kopanski C, Türck M, Schultz JE. Effects of long-term treatment of rats with antidepressants on adrenergic-receptor sensitivity in cerebral cortex: structure-activity study. Neurochemistry International 5: 649–659, 1983
Kudo Y, Kawakita Y, Ichimar S, Inui M, Inoue O, et al. Efficacy test of dothiepin, an antidepressant, by double blind technique. Igaku no Ayumi 120: 136–156, 1985
Lambourn J, Rees JA. A general practitioner study of dothiepin and amitriptyline. Journal of International Medical Research 2: 210–213, 1974
Lipsedge MS, Linford Rees W, Pike DJ. A double-blind comparison of dothiepin and amitriptyline for the treatment of depression with anxiety. Psychopharmacologia 19: 153–162, 1971
Maguire KP, Burrows GD, Norman TR, Scoggins BA. Metabolism and pharmacokinetics of dothiepin. British Journal of Clinical Pharmacology 12: 405–409, 1981
Maguire KP, Norman TR, Mclntyre I, Burrows GD. Clinical pharmacokinetics of dothiepin: single-dose kinetics in patients and prediction of steady-state concentrations. Clinical Pharmacokinetics 8: 179–185, 1983
Maguire KP, Norman TR, Mclntyre I, Burrows GD, Davies B. Blood and plasma concentrations of dothiepin and its major metabolites and clinical response. Journal of Affective Disorders 4: 41–48, 1982
Mendlewicz J, Linkowski P, Rees JA. A double blind comparison of dothiepin and amitriptyline in patients with primary affective disorder: serum levels and clinical response. British Journal of Psychiatry 136: 154–160, 1980
Montgomery SA, Pinder RM. Do some antidepressants promote suicide? Psychopharmacology 92: 265–266, 1987
Mullin JM, Pandita-Gunawardena VR, Whitehead AM. A double blind comparison of fluvoxamine and dothiepin in the treatment of major affective disorder. British Journal of Clinical Practice 42: 51–55, 1988
Nakra BRS, Glass RC, Rees JA. Steady state serum concentrations of dothiepin and northiaden after two dosage regimens of dothiepin hydrochloride (Prothiaden). Journal of International Medical Research 5: 391–397, 1977
Ogura C, Kishimoto A, Mizukawa R, Hazama H, Honma H, et al. Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline. European Journal of Clinical Pharmacology 25: 811–814, 1983a
Ogura C, Kishimoto A, Mizukawa R, Kunimoto N, Hazama H, et al. Influence of single doses of dothiepin and amitriptyline on physiological measures and psychomotor performance in normal young and elderly volunteers. Neuropsychobiology 10: 103–107, 1983b
Pearce JB, Linford Rees W. A double blind comparison of three times daily and single nightly dosage of the tricyclic antidepressant dothiepin. Journal of International Medical Research 2: 12–19, 1974
Pierce D. A comparison of trazodone and dothiepin in depression. Neuropharmacology 19: 1219–1220, 1980
Queisnerová M, Svátek E, Mansfeld V. To the metabolism of dosulepin in man. Activitas Nervosa Superior 16: 179, 1974
Rees JA. Clinical interpretation of pharmacokihetic data on dothiepin hydrochloride (Dosulepin, Prothiaden). Journal of International Medical Research 9: 98–102, 1981
Rees JA, Marsh BD, Pike T. The outcome of dothiepin treatment in 1900 depressed patients. International Journal of Pharmacopsychiatry 10: 54–57, 1975
Rees JA, Risdall PC. An evaluation of a once daily dosage régime of dothiepin (Prothiaden). Journal of International Medical Research 4: 319–325, 1976
Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. Journal of Pharmacology and Experimental Therapeutics 230: 94–102, 19
Richelson E, Pfenning M. Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. European Journal of Pharmacology 104: 277–286, 1984
Rotrekl J, Nahunek K, Homola D, Švestka J, Sonevá V. The comparison of the cardiotoxic effect of prothiaden, imipramine and amitriptyline. Activitas Nervosa Superior 17: 232–233, 1975
Rysanek R, Nahunek K, Švestka J, Česková E, Burešová A. Cardiotoxicity of viloxazine and dosulepin compared. Activitas Nervosa Superior 24: 216–217, 1982
Rysanek R, Rotrekl J, Homola D, Náhunek K, Rodová A, et al. Mechanocardiographical comparison of the cardiotoxic effect of prothiaden and imipramine. Activitas Nervosa Superior 16: 183–184, 1974
Sarzi Puttini P, Cazzola M, Boccassini L, Santandrea S, Caruso I, et al. A comparison of dothiepin versus placebo in rheumatoid arthritis and the association of pain with depression. Journal of International Medical Research 16: 331–337, 1988
Shein K, Smith RE. Structure-activity relationships for the anticholinoceptor action of tricyclic antidepressants. British Journal of Pharmacology 62: 567–571, 1978
Sheth UK, Paul T, Desai NK, Pispati PK. Comparative effects of imipramine and dothiepin on salivary rate in normal volunteers. British Journal of Clinical Pharmacology 8: 475–478, 1979
South Wales Antidepressant Drug Trial Group. A double blind multicentre trial of fluoxetine and dothiepin in major depressive illness. International Clinical Psychopharmacology 3: 75–81, 1988
Špánková H, Ryšánek K, Köne J, Mlejnková M. Effect of prothiadene on the function and metabolism of human thrombocytes. Activatas Nervosa Superior 16: 180–181, 1974
Stratas NE. A double-blind study of the efficacy and safety of dothiepin hydrochloride in the treatment of major depressive disorder. Journal of Clinical Psychiatry 45: 466–469, 1984
Sulser F. Mode of action of antidepressant drugs. Journal of Clinical Psychiatry 44: 14–20, 1983
Takahashi R, Tsuiki D, Hironaka I, Kusumoto S, Kurihara M, et al. Comparison of clinical effect on depression of dosulepin and amitriptyline using double-blind technique. Clinical Evaluations 11: 201–228, 1983
Waite J, Grundy E, Arie T. A controlled trial of antidepressant medication in elderly in-patients. International Clinical Psychopharmacology 1: 113–126, 1986
Wander TJ, Nelson A, Okazaki H, Richelson E. Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro European Journal of Pharmacology 132: 115–121, 1986
Wheatley D. Interpreting significance in an antidepressant drug trial. International Clinical Psychopharmacology 2: 353–359, 1987
Yu DK, Dimmitt DC, Lanman RC, Giesing DH. Pharmacokinetics of dothiepin in humans: a single dose dose-proportionality study. Journal of Pharmaceutical Sciences 75: 582–585, 1986
Zapletálek M, Hajcman L, Komenda S. A comparison of the effect of prothiaden and chlordiazepoxide in the treatment of neuroses. Activatas Nervosa Superior 15: 119, 1973
Zusky P, Manschreck TC, Blanchard C, Rosenbaum J, Elliot C, et al. Dothiepin hydrochloride: treatment efficacy and safety. Journal of Clinical Psychiatry 47: 504–507, 1986