Drugs

, Volume 15, Issue 3, pp 198–217 | Cite as

Loxapine: A Review of its Pharmacological Properties and Therapeutic Efficacy as an Antipsychotic Agent

  • R. C. Heel
  • R. N. Brogden
  • T. M. Speight
  • G. S. Avery
Evaluations on New Drugs

Summary

Synopsis: Loxapine is a dibenzoxazepine, tricyclic compound recommended for the treatment of acute and chronic schizophrenia. In its therapeutic effectiveness and profile and incidence of side-effects, loxapine closely resembles the traditional antipsychotic agents. Although loxapine has tended to be less effective than some standard antipsychotic drugs in a few short-term (3 to 4 weeks) studies, it has been superior to a placebo and about as effective as chlorpromazine, haloperidol, trifluoperazine or thiothixene when evaluated after 4 to 12 weeks.

Like the phenothiazine (e.g. chlorpromazine) and butyrophenone (e.g. haloperidol) antipsychotic agents, loxapine causes a high incidence of extrapyramidal reactions. Sedation occurs frequently, especially during early stages of treatment. Other, less common side-effects such as anticholinergic effects (dry mouth, blurred vision, etc.), hypotension, tachycardia and precipitation of epileptic seizures, which occur with the older antipsychotic drugs, have also been reported with loxapine.

Pharmacodynamic studies: In animal studies, loxapine causes dopamine receptor blockade and behavioural changes similar to those seen with other antipsychotic agents, such as chlorpromazine and haloperidol. In studies in man, low doses did not produce changes in EEG sleep patterns or in sleep time in healthy subjects but therapeutic doses (50 to 100mg daily) increased total sleep time significantly when administered for 1 year to 4 patients with schizophrenia.

Pharmacokinetic studies: There are no published studies on the pharmacokinetic properties of loxapine. Unpublished data indicate that absorption in man is rapid after oral administration, peak levels of radioactivity occurring 2 hours after a radiolabelled dose. In rats the diencephalic and mesencephalic areas of the brain, as well as the lungs, appear to be preferential areas of distribution. In man metabolism is extensive and occurs rapidly, with only traces of unmetabolised drug present in the plasma 1 hour after oral dosing. Metabolic pathways include aromatic hydroxylation, oxidation, and desmethylation, and thus the major metabolites are hydroxyloxapine, hydroxyloxapine-N-oxide, loxapine-N-oxide and hydroxydesmethyl loxapine. Metabolites are partially conjugated to the glucuronide or sulphate forms before excretion, and the urinary excretion products (56 to 70% of administered radioactivity) consist mainly of the conjugated metabolites, while unconjugated metabolites are excreted primarily in the faeces (15 to 22% of administered radioactivity).

Therapeutic trials: Most clinical studies of loxapine have been short-term, double-blind comparative trials in patients with acute or chronic schizophrenia, using a traditional antipsychotic agent as the comparison drug. The numbers of patients tested in such studies have usually been relatively small, and may have been insufficient to detect minor differences, if they existed, between the study drugs. A few trials have used a placebo-control throughout the treatment period, but most have not. While in a few of the shorter-term (3 to 4 weeks) studies loxapine has been less effective than the standard drugs used, and only slightly more effective than a placebo, in the majority of longer-term trials in acute and chronic schizophrenia it has been significantly superior to a placebo, and about equieffective with chlorpromazine, haloperidol, trifluoperazine, and thiothixene, after 4 to 12 weeks of treatment (see table II). In the only longer-term controlled study to date, loxapine and haloperidol resulted in a similar improvement after administration to patients with acute schizophrenia for 1 year. In those patients who were diagnosed as having paranoid schizophrenia, loxapine appeared to be more effective; but further well-controlled, suitably designed studies in patients with paranoid schizophrenia, using equipotent doses of loxapine and the comparison drugs, are needed before such a specific effect for loxapine in this type of schizophrenia can be claimed. A small number of acutely ill patients have been treated with intramuscular loxapine for short periods of time (up to 200mg daily for 3 to 4 days), with most showing some improvement.

Side-effects: The overall profile of side-effects which occur with loxapine is very similar to that seen with other antipsychotic agents such as haloperidol and the phenothiazines. Extrapyramidial reactions, frequently requiring drug treatment, occur in about 40% of patients. Sedation occurs often with initial doses, but tolerance to this effect develops in many patients after the first few days. Less common side-effects such as anticholinergic actions, hypotension, and tachycardia, which occur with other antipsychotic drugs, have also occasionally been reported during loxapine administration. Precipitation of epileptic seizures and ocular changes (corneal pigmentation, lens abnormalities) have been noted in a few patients, but were not conclusively related to loxapine administration. Although tardive dyskinesia has not been reported in published studies, it is reasonable to expect that this troublesome condition could occur with loxapine, in view of the incidence of other extrapyramidal effects and its pharmacological profile of activity.

Dosage: In the treatment of schizophrenia a low starting dose (about 10mg twice daily) is recommended, but up to 50mg per day may be used in severely disturbed patients. Dosage should then be fairly rapidly increased over 7 to 10 days according to individual requirements and tolerance. The usual maintenance range is up to 100mg daily, but some patients may be adequately controlled on as little as 20mg daily. The lowest possible maintenance dose should be used to minimise adverse reactions. Although doses in excess of 250mg daily are not recommended by the manufacturer, up to 300mg per day has been used in a few clinical trials.

Keywords

Schizophrenia Haloperidol Chlorpromazine Antipsychotic Agent Current Therapeutic Research 

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References

  1. Arik, M.: Long-term treatment and rehabilitation of the chronic schizophrenic patient. Unpublished data (1974)Google Scholar
  2. Asper, H.; Baggiolini, M.; Burki, H.R.; Lauener, H.; Ruch, W. and Stille, G.: Tolerance phenomena with neuroleptics. Catalepsy, apomorphine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol. European Journal of Pharmacology 22: 287 (1973)Google Scholar
  3. Bishop, M.P. and Gallant, D.M. Loxapine: A controlled evaluation in chronic schizophrenic patients. Current Therapeutic Research 12: 594 (1970)PubMedGoogle Scholar
  4. Bishop, M.P.; Simpson, G.M.; Dunnett, C.W. and Kiltie, H.: Efficacy of loxapine in the treatment of paranoid schizophrenia. Psychopharmacology 51: 107 (1977)PubMedCrossRefGoogle Scholar
  5. Blacow, N.W. (Ed): Martindale. The Extra Pharmacopoeia, 26th edition, p. 1814 (The Pharmaceutical Press, London 1972)Google Scholar
  6. Brebbia, D.R.; Banchey, M.H. and Simpson, G.: The effects of two dibenzoxazepine drugs on sleep patterns. Unpublished data (1976)Google Scholar
  7. Brunetti, A.R.; Filho, M.P. and Grabowski, J.R.: A comparative study of loxapine and butyrophenone. A Folha Medica 73: 431 (1976)Google Scholar
  8. Charalampous, K.D.; Freemesser, G.F.; Malev, J. and Ford, K.: Loxapine succinate: A controlled double-blind study in schizophrenia. Current Therapeutic Research 16: 829 (1974)PubMedGoogle Scholar
  9. Chouinard, G.; De Montigny, C. and Kropsky, M.: Loxapine succinate in the treatment of newly admitted schizophrenic patients. Current Therapeutic Research 21: 73 (1977)PubMedGoogle Scholar
  10. Clark, C.J. and Downie, C.C.: A method for the rapid determination of the number of patients to include in a controlled clinical trial. Lancet 2: 1357 (1966)PubMedCrossRefGoogle Scholar
  11. Clark, M.L.; Huber, W.K.; Sullivan, J.; Wood, F. and Costiloe, J.P.: Evaluation of loxapine succinate in chronic schizophrenia. Diseases of the Nervous System 33: 783 (1972)PubMedGoogle Scholar
  12. Clark, M.L.; Paredes, A.; Costiloe, P.; Fulkerson, F.G. and Wood, F.: Evaluation of two dose levels of loxapine succinate in chronic schizophrenia. Diseases of the Nervous System 38: 7 (1977)PubMedGoogle Scholar
  13. Clark, M.L.; Paredes, A.; Costiloe, J.P; Wood, F. and Barrett, A.: Loxapine in newly admitted chronic schizophrenic patients. Journal of Clinical Pharmacology 15: 286 (1975)PubMedGoogle Scholar
  14. Coupet, J.; Szucs, U.A. and Greenblatt, E.N.: The effects of 2-chloro-11-(4-methyl-l-piperazinyl)-diberiz [b,f] [1,4] oxazepine (loxapine) and its derivatives on the dopamine-sensitive adenylate cyclase of rat striatal homogenates. Brain Research 116: 177 (1976)PubMedCrossRefGoogle Scholar
  15. Dube, K.C. and Kumar, N.: Loxapine succinate: A conparative study with chlorpromazine. Current Therapeutic Research 19: 653 (1976)PubMedGoogle Scholar
  16. Filho, U.V.; Caldeira, M.V.V. and Bueno, J.R.: The efficacy and safety of loxapine succinate in the treatment of schizophrenia: A comparative study with thiothixene. Current Therapeutic Research 18: 476 (1975)Google Scholar
  17. Floyd, A. and Gershon, S.: An investigation of the anti-anxiety properties of oxilapine. Diseases of the Nervous System 32: 559 (1971)PubMedGoogle Scholar
  18. Fruensgaard, K. and Jensen, K.: Treatment of acute psychotic patients with loxapine parenterally. Current Therapeutic Research 19: 164 (1976)PubMedGoogle Scholar
  19. Fruensgaard, K.; Konsgaard, S.; Jorgensen, H. and Jensen, K.: Loxapine versus haloperidol parenterally in acute psychosis with agitation. A double-blind study. Acta Psychiatrica Scandinavica 56: 256 (1977)CrossRefGoogle Scholar
  20. Gallant, D.M.; Bishop, G.; Steel, C.A. and Bishop, M.P.: Loxapine: A six-month evaluation in severely ill schizophrenic patients. Current Therapeutic Research 15: 205 (1973)PubMedGoogle Scholar
  21. Garcia, P.; Millan, S. and Mendez, H.: Dibenzoxazepine in psychotic patients. Neurolog. Neurocir. Psiquiatr. 11: 41 (1970)Google Scholar
  22. Gershon, S.; Hekimian, L.J.; Burdock, E.L and Kim, S.S.: Antipsychotic properties of loxapine succinate. Current Therapeutic Research 12: 280 (1970)PubMedGoogle Scholar
  23. Guerrero-Figueroa, R.; Gallant, D.M. and Downer, R.: Effects of dibenzoxazepine on cortical and subcortical structures of the central nervous system in the cat: prediction of the potential antipsychotic effects in man. Current Therapeutic Research 10: 88 (1968)PubMedGoogle Scholar
  24. Hollister, L.E.: Psychiatric Disorders, In Avery, G.S. (Ed), Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, p.798, (ADIS Press, Sydney; Lea and Febiger, Philadelphia; Churchill Livingstone, Edinburgh 1976)Google Scholar
  25. Kido, R.; Nirose, K.; Yamamoti, K.; Sawada, T.; Kojima, Y. and Eigyo, M.: The effects of 2-chloro-11(4-methylpiperazino)-dibenzo-[b,f] [1,4]-oxazepine (S-805) on the central nervous system. Pharmacometrics 3: 361 (1969)Google Scholar
  26. Kiloh, L.G.; Williams, S.E.; Grant, D.A. and Whetton, P.S.: A double-blind comparative trial of loxapine and trifluoperazine in acute and chronic schizophrenic patients. Journal of International Medical Research 4: 441 (1976)PubMedGoogle Scholar
  27. Latimer, C.N.: Neuropharmacologic evaluation of oxilapine, a potent pyschoactive agent. Journal of Pharmacology and Experimental Therapeutics 166: 151 (1969)PubMedGoogle Scholar
  28. Miller, R.J. and Hiley, C.R.: Anti-dopaminergic and anti-muscarinic effects of dibenzodiazepines. Relationship to drug-induced parkinsonism. Naunyn-Schmiedeberg’s Archives of Pharmacology 292: 289 (1976)Google Scholar
  29. Moore, D.F.: Treatment of acute schizophrenia with loxapine succinate (Loxitane®) in a controlled study with chlorpromazine. Current Therapeutic Research 18: 172 (1975)PubMedGoogle Scholar
  30. Moyano, C.Z.: A double-blind comparison of Loxitane™ loxapine succinate and trifluoperazine hydrochloride in chronic schizophrenic patients. Diseases of the Nervous System 36: 301 (1975)PubMedGoogle Scholar
  31. Mulas, A.; Crabai, F. and Pepeu, G.: The influence of repeated experience on the effects of scopolamine and of amphetamine on exploratory behaviour in the rat. Pharmacological Research Communications 2: 169 (1970)CrossRefGoogle Scholar
  32. Nair, N.P.V.; Decker, B.L. and Schwartz, G.: Loxapine succinate in the treatment of chronic schizophrenia. Current Therapeutic Research 20: 802 (1976)PubMedGoogle Scholar
  33. Nair, N.P.V.; Granich, A.; Davis, R.C. and Schwartz, G.: Loxapine succinate in the treatment of acute schizophrenia. Current Therapeutic Research 22: 628 (1977)Google Scholar
  34. O’Connell, R.A.; Jeewa, M. and Allen, K.: Loxapine concentrate in acute schizophrenia. Current Therapeutic Research 21: 101 (1977)PubMedGoogle Scholar
  35. Overall, J.E.; Hollister, L.E.; Pokorny, A.D.; Casey, J.F. and Katz, G.: Drug therapy in depressions. Controlled evaluation of imipramine, isocarboxazide, dextroamphetamine-amobarbital and placebo. Clinical Pharmacology and Therapeutics 3: 16 (1962)Google Scholar
  36. Paprocki. J.: The efficacy and tolerance of parenteral (I.M.) loxapine —A pilot study. A Folha Medica 73: 37 (1976)Google Scholar
  37. Paprocki, J.; Horizonte. B. and Versiani, M: A double-blind comparison between loxapine and haloperidol by parenteral route in acute schizophrenia. Current Therapeutic Research 21: 80 (1977)PubMedGoogle Scholar
  38. Paprocki. J.; Peixoto, M.P.B. and Andrade, N.M.: A controlled double-blind comparison between loxapine and haloperidol in acute newly hospitalised schizophrenic patients. A Folha Medica 70: 533 (1975)Google Scholar
  39. Pool, D.; Bloom, W.; Mielke. D.H.; Roniger, J.J. and Gallant, D.M.: A controlled evaluation of Loxitane in seventy-five adolescent schizophrenic patients. Current Therapeutic Research 19: 99 (1976)PubMedGoogle Scholar
  40. Rainaut, J.: Analyse statistique de 1’etude comparative double insu de l’activite de la loxapine et de la thioridazone. L’Encephale 1: 147 (1975)PubMedGoogle Scholar
  41. Ryan, G.M. and Matthews, P.A.: Phenytoin metabolism stimulated by loxapine. Drug Intelligence and Clinical Pharmacy 11: 429 (1977)Google Scholar
  42. Sayers, A.C.; Burki, H.R.; Ruch, W. and Asper, H.: Neuroleptic induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia (Berl.) 41: 97 (1975)CrossRefGoogle Scholar
  43. Schiele, B.C.: Loxapine succinate: A controlled double-blind study in chronic schizophrenia. Diseases of the Nervous System 36: 361 (1975)PubMedGoogle Scholar
  44. Selman, F.B.; McClure, R.F. and Helwig, H.: Loxapine succinate: A double-blind comparison with haloperidol and placebo in acute schizophrenics. Current Therapeutic Research 19: 645 (1976)PubMedGoogle Scholar
  45. Serafetinides, E.A.; Willis, D. and Clark, M.L.: The EEG effects of dibenzoxazepines (loxapine succinate) as compared to CPZ: EEG changes and drug side-effects. International Pharmacopsychiatry 6: 38 (1971)PubMedGoogle Scholar
  46. Shopsin, B.; Pearson, E.; Gershon, S. and Collins, P.: A controlled double-blind comparison between loxapine succinate and chlorpromazine in acute newly hospitalised schizophrenic patients. Current Therapeutic Research 14: 739 (1972)PubMedGoogle Scholar
  47. Simpson, G.M.; Branchey, M.H.; Lee, J.H. and Varga, E.: A two year trial of loxapine succinate in chronic psychotic patients. Diseases of the Nervous System 37: 305 (1976)PubMedGoogle Scholar
  48. Simpson, G.M. and Cuculic, Z.: A double-blind comparison of loxapine succinate and trifluoperazine in newly admitted schizophrenic patients. Journal of Clinical Pharmacology 16: 60 (1976)PubMedGoogle Scholar
  49. Squitino, B.S.G.; Coletty, E.B. and Lara, L.F.M.: Treatment of chronic schizophrenia. Loxapine, a new neuroleptic agent. A Folha Medica 74: 329 (1977)Google Scholar
  50. Steinbook, R.M.; Goldstein, B.J.; Brauzer, B.; Moreno, S.S. and Jacobson, A.F.: Loxapine: A double-blind comparison with chlorpromazine in acute schizophrenic patients. Current Therapeutic Research 15: 1 (1973)PubMedGoogle Scholar
  51. Van der Velde, C.D. and Kiltie, H.: Effectiveness of loxapine succinate in acute schizophrenia: A comparative study with thiothixene. Current Therapeutic Research 17: 1 (1975)PubMedGoogle Scholar
  52. Varga, E. and Simpson, G.M.: Loxapine succinate in the treatment of uncontrollable destructive behaviour. Current Therapeutic Research 13: 737 (1971)PubMedGoogle Scholar
  53. Wolpert, A.; White, L.; Dana, L.; Sugerman, A.A.; Arengo, A.D.; Simpson, G.M.; Bishop, M.P. and Gallant, D.M.: Clinical pharmacological trial of loxapine succinate. Journal of Clinical Pharmacology 10: 175 (1970)Google Scholar

Copyright information

© ADIS Press 1978

Authors and Affiliations

  • R. C. Heel
    • 1
  • R. N. Brogden
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.Australasian Drug Information ServicesBirkenhead, Auckland 10New Zealand

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