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

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 Unpublished data indicate that absorption in man is rapid after oral administration, peak levels of radioactivity occurring 2 hours after a radiolabelled dose.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.