DRUG INFORMATION QUARTERLY Depot antipsychotics revisited David Taylor Many typical antipsychotic drugs may be manu Sheffield, 1976), although this is not universally factured as alcohols, which react with carboxylic accepted. acids to form esters (organic salts). These compounds are highly oil-soluble, but are only sparingly soluble in aqueous fluids such as Fluphenazine (Table 1) blood. Thus, an oily solution of an antipsychotic Fluphenazine is available in some countries as can be injected into a muscle, where it forms a the enanthate and, more widely, as the decanoate reservoir or 'depot' of drug that is slowly ester. The decanoate compound is longer acting dissolved in the surrounding blood. Once and better tolerated (Van Praag & Dois, 1973). In released into the blood, drug esters are rapidly the UK, fluphenazine decanoate in sesame oil hydrolysed by endogenous esterase enzymes to may be administered every two to five weeks, produce the parent antipsychotic. Stable serum although shorter intervals are licensed in other concentrations of antipsychotics are usually countries. The plasma half-life as a single dose is engendered (although this is not always observed around eight days and in multiple dosing is in practice (Tuninger & Levander, 1996)), and around 20 days (Ereshefsky et al 1984). When administration need only take place every few first used widely, fluphenazine depots were weeks or so. Adherence can be assured and associated with depressive reactions. A true relapse rates are reduced (Groves & Mandel, association has been contested (Ayd, 1975), but 1975: Davis et al, 1994). it is probably best to avoid fluphenazine in those Disadvantages of depot injections include a with a history of depression. suspected (see Ayd, 1975) higher incidence of extrapyramidal adverse effects (and perhaps tardive dyskinesia), the prolonged nature of all Haloperidol decanoate adverse effects and the difficulty in adjusting the Haloperidol decanoate may be administered dose regimen to suit patient needs (the pharmaco- every four weeks but, with an apparent plasma kinetics of depot preparations are extremely half-life of three weeks (Reyntijens et al 1982). complex). Local complications can also occur, steady-state plasma levels are not reached for especially in older patients and when high doses around three months. Doses of up to 300 mg/ are injected (Hay, 1995). month are licensed but are often exceeded; the Depots are widely used in UKclinical practice. optimal dose appears to be around 150 mg/ Doses used seem to vary substantially, as do the month (Marr & Batchelor, 1982). Indeed, much choice of drug and the co-prescription of oral lower doses (30-50 mg/month) have been shown antipsychotics. This article briefly reviews the to be effective (Nyberg et al, 1995). Minor rather sparse and largely dated evidence base for differences in efficacy and tolerability occasion the use of depots and gives some practical ally have been detected between haloperidol guidance for clinical practice. decanoate and other depot formulations (Beres- ford & Ward, 1987). These observed differences Table 1. Fluphenazine decanoate, 50 mg weekly Depots available in the UK (n=7): resultant plasma levels of fluphenazine Fiupenthixol decanoate (from Ereshefsky et al, 1984) Flupenthixol decanoate dissolved in thin vege Time (weeks) table oil has been available since 1972. Peak plasma levels are reached approximately one 1 2-3 4-5 6 or more week after intramuscular administration and the plasma half-life is around 17 days after multiple Mean fluphenazine administrations (Jcrgensen, 1978; Davis et al plasma level (ng/ml) 0 0.58 1.09 1.73 1.99 1994). Flupenthixol decanoate may be given Note how the mean plasma levels increase without an every two to four weeks; it is said to improve increase in dosage and that the percentage increase is mood and cause fewer extrapyramidal effects highest at the start of therapy and lowest as steady than fluphenazine decanoate (Carney & state isapproached. Psychiatric Bulletin (1999), 23, 551-553 551 DRUG INFORMATION QUARTERLY are probably a result of the use of poorly pharmacokinetic profiles of different depot pre matched doses or dose schedules. parations. For example, peak plasma levels are reached only after a long period (which varies from one depot to another); antipsychotic re Pipothiazine palmitate sponse is also delayed; and steady-state plasma Pipothiazine palmitate is a piperidine phenothia- levels are reached only after several weeks or zine ester used in the UK and Europe. A lower months of continuous therapy. incidence of extrapyramidal effects might be predicted from the drug's chemistry, but there In an attempt to assure optimal evidence- based prescribing of depot medications, the are no unequivocal, practical data to support following guidance is suggested. this. Pipothiazine palmitate is suitable for administration at four-week intervals. Peak plasma levels are reached only in the second Give a test dose week following injection (Girard et al 1984). Depots are long-lasting, so any adverse effects that result from injection are likely to be long- Zuclopenthixol lived. Thus, a small test dose is essential to help avoid severe, prolonged adverse effects. Note, Zuclopenthixol (cis-Z-clopenthixol) is available however, that some extrapyramidal reactions as two esters with very different pharmacokinetic occur only after several doses (Warner & Wyman, properties. Zuclopenthixol acetate is a short- 1975). acting depot used in the acute treatment of psychosis. Peak plasma levels are reached after around 30 hours (Amdisen et al 1986) and Continue with the lowest therapeutic dose decline fairly quickly thereafter. A sedative effect In general, there are few data showing clear is apparent around two hours after injection, but dose-response effects for depot preparations significant changes in psychotic symptoms are throughout their licensed dosage range. There apparent only after eight hours, with the effect is some information that indicates that low doses persisting for at least 72 hours (Chakravarti et al are at least as effective as higher doses. Low 1990). Firm evidence for the superior therapeutic doses are likely to be better tolerated and are efficacy of this preparation over simple injections certainly less expensive. is lacking (Coutinho et al 1997). Zuclopenthixol decanoate is longer acting and may be adminis tered every two to four weeks, with good Administered at the longest possible licensed therapeutic effects (Dom et al 1978). interval Table 2 gives details of all the above-mentioned All depots can be administered safely at their depot antipsychotics. maximum licensed dosing intervals. There is no evidence to suggest that shortening the dose interval improves efficacy. Moreover, injections are painful, so less-frequent administration is Prescribing depots desirable. The 'observation' that some patients Depot medication is a useful therapeutic option deteriorate in the days before the next depot is in patients with psychosis who lack insight or due is probably fallacious. For some hours (or who are known to adhere poorly with oral even days with some preparations) plasma levels medication. However, their use is made of antipsychotics may continue to fall, albeit complicated by the complex and varied slowly, after the next injection has been given. Table 2. Depot antipsychotic preparations to peak time to frequency plasma levels steady state of administration DrugFlupenthixol (days)7-10 (months)2 (weeks)2-4 decanoate Fluphenazine decanoate 1-2 2 2-5 Haloperidol decanoate 3-99-10 32-3 2-4 Pipothiazine palmitate 42-4As Zuclopenthixol decanoate 4-71-2Approximate 2N/A Zuclopenthixol acetateTime required, but not (acute use only)Licensed less than 24 hours apart (From Currey et al, 1979; Davis et al. 1994; Ereshefsky eia/, 1984; Association of British Pharmaceutical Industry, 1996; Reynolds, 1996.) 552 Taylor DRUG INFORMATION QUARTERLY Thus patients are most at risk of deterioration CURREY.S. H.. WHELPTON.R, DESCHEPPER,P. J., ef a!(1979) immediately after a depot injection and not Kinetics of fluphenazlne after fluphenazine before it. Note also that, at steady state, plasma dlhydrochloride, enanthate and decanoate drug levels, even before each dose, are several administration to man. British Journal of Clinical times greater than levels during early 'acute' Pharmacology. 7. 325-331. DAVIS,J. M.. MATALÓN,L..WATANABE,M. D., et al (1994) treatment (Ereshefsky et al, 1984). Moreover, in Depot antipsychotic drugs: place in therapy. Drugs. 47. trials, true relapse seems only to occur three to 741-773. DOM. R., DE MESMAECKER.M.. VANDEN BROUCKE.T., et al six months after withdrawing depot therapy (1978) Maintenance treatment of chronic schizophrenic (Taylor, 1997). patients: a study with the long-acting thioxanthene derivative. cis(Z)-clopenthixol decanoate-sordinolR Adjust doses only after an adequate period of depot. Acta Psychiatrica Scandinava. 57. 299-304. ERESHEFSKY,L., SAKLAD,S. R., JANN, M. W., et al (1984) assessment Future of depot neuroleptic therapy: pharmacokinetic Attainment of peak plasma levels, therapeutic and pharmacodynamic approaches. Journal of Clinical effect and steady-state plasma levels are all Psychiatry. 45. 50. GIRARD.M.. GRANIER.F.. SCHMITT,L., et al (1984) Initial delayed with depot injections. Doses obviously results of a pharmacokinetic study of pipothiazine and should be reduced if adverse effects occur, but its palmitic ester. (Piportil L4) in a schizophrenic should be increased