Neurosciencesjournal.org

Monica Zolezzi, BPharm, MSc.
Long-acting injectable antipsychotics, also known as "depots", were developed in the late 1960s as an attempt toimprove compliance and long-term management of schizophrenia. Despite their availability for over 30 years,guidelines for their use and data on patients for whom long-acting injectable antipsychotics are most indicated aresparse and vary considerably. A review of the perceived advantages and disadvantages of using long-acting injectableantipsychotics is provided in this article, as well as a review of the literature to update clinicians on the currentadvances of this therapeutic option to optimize compliance and long-term management of chronic schizophrenia.
Neurosciences 2005; Vol. 10 (2): 126-131
chizophrenia is a chronic disorder for which it is hydrolyze the esterified compound and liberates the well recognized that lifelong treatment with parent antipsychotic.2,9,10 Although depot antipsychotics is necessary. Although quite antipsychotics have been available for over 30 successful in treating and preventing relapses,1,2 years, guidelines for their use and data on patients antipsychotics are not readily accepted by patients, for whom long-acting injectables are most indicated are sparse and vary considerably. In addition, long-acting injectable forms of these medications despite the fact that the use of depot antipsychotics were developed in an attempt to help medication has been extensively promoted to overcome patient compliance especially during the maintenance phase non-compliance with medications,8,10 their of this chronic condition.5 They are considered a acceptance by prescribers and patients remains useful therapeutic option in patients with psychosis variable.11 A review of the perceived advantages and who lack insight or are known to adhere poorly to disadvantages of using long-acting injectable oral medication.1,2,5-8 Long-acting injectable antipsychotics is provided in this article, as well as a antipsychotics, also known as "depot" formulations, review of the literature to update clinicians on the are traditionally manufactured as alcohols, which by current advances of this therapeutic option to esterification, form highly hydrophobic esters which optimize compliance in chronic schizophrenia.
are only sparingly soluble in aqueous fluids such as Advantages of long-acting injectable
blood.2 These esters are dissolved in a variety of antipsychotics. Assured compliance, with
oils (sesame seed, coconut or other vegetable oil associated and proven reduction in relapses, such as Viscoleo®).9 Once injected into a muscle, re-hospitalization and severity of relapse.1-2,5-7 these formulations form a reservoir or depots of Reduction in bio-availability problems. It is widely drug that is slowly dissolved in the surrounding known that some people metabolize antipsychotics extensively via the first-pass effect.6,12-14 Compared From the School of Pharmacy, The University of Auckland, Auckland, New Zealand.
Address correspondence and reprint request to: Dr. Monica Zolezzi, Lecturer in Clinical Pharmacy, School of Pharmacy, The University ofAuckland, Room 40018, Lower Ground Floor, Building 504, 85 Park Road, Grafton, Auckland, New Zealand. Tel. +64 9 373 7599 Ext. 82225. Fax.
+69 9 367 7192. E-mail: [email protected] Long-acting injectable antipsychotics . Zolezzi to oral medication, long-acting injectable of action of only 48-72 hours.23,24 This short-acting administration produces a more stable plasma depot appears to be particularly effective in the concentration, without the daily oscillations related treatment of manic relapse, drug-induced psychosis, to the repeated ingestion required for oral aggressive psychotic episodes and acute relapse medications.6,7,13,14 By being sure that the doses are symptoms of chronic schizophrenia.25 Its use in received, using long-acting injectable antipsychotics emergency psychiatry or acute psychotic states is should be able to facilitate better downward titration popular, as it obviates the need for repeated of doses to reduce the potential for side effects.7 intramuscular administration of other injectable Increased contact with the treatment team facilitates antipsychotics or benzodiazepines which have a initiation of efforts to deal timely with arising significantly shorter duration of action, usually problems the patient may be going through.7,15,16 requiring administration every 4-6 hours. Clinical Generally, patients have shown positive attitudes guidelines for the use of zuclopenthixol acetate toward long-acting injectable antipsychotics, even injection have suggested that it should be considered favoring this route of administration over the oral for patients who are not neuroleptic-naïve, and recommend it to be prescribed as a treatment course Disadvantages of long-acting injectable
rather than simply an "as required" (prn) medication antipsychotics. Difficulty in altering a dose if side
effects develop (such as tardive dystonia or Administration of long-acting injectable
neuroleptic malignant syndrome).6,7,10 Local antipsychotics. Long-acting injectable
complications with the administration technique, or when high doses are injected (pain, bleeding, intramuscular (IM) injection and are usually hematoma, leakage, inflammatory nodules) may considered to be quite painful. 19,23 Thus, the need for discourage patient compliance.6,10,13,18-20 Some a meticulous injection technique and using the most patients may not like the feeling of being under appropriate preparation and dose for an individual patient are essential for long-term success. Because Long-acting injectable atypical antipsychotics.
injections are painful, less-frequent administration is Atypical antipsychotics have been reported to have also desirable.10 Injections of long-acting numerous advantages over typical agents, and have risperidone are water based; thus they appear to be less painful than the traditional depot antipsychotic schizophrenia and related psychosis.21 Until injections.16,27 This may be useful when reassuring recently, all marketed atypical antipsychotics were some patients, particularly those who have only available orally; thus, the depot formulations experienced pain with other depots.15 The following were all for first-generation (or typical) tips may be used to minimize the pain associated high-potency antipsychotic agents. It was with the administration of long-acting injectable hypothesized that having a long-acting injectable antipsychotic formulations. 20,23,28-31 a) Massaging the atypical antipsychotic would ideally combine the muscle area overlying the injection site for about 10 benefits provided by this dosage form (improved seconds before injecting will help in relaxing the compliance) with the benefits of using atypical muscle. However, do not massage it after the agents (improved tolerability). In October 2003, the injection.31 b) Not more than 2-3 ml should be US Food and Drug Administration (FDA) agency administered at any one site. Also, post-injection approved the intramuscular, long-acting preparation muscular discomfort is more commonly associated of risperidone (Risperdal® Consta®, Janssen-Cilag with more concentrated drugs. Thus, whenever Inc),13,22 becoming the first long-acting injectable possible, use the preparation with the lowest atypical antipsychotic, now available in several concentration per ml (for example, Fluphenazine 25 other countries. The formulation of long-acting mg/ml or Haloperidol 50 mg/ml preparations). It injectable risperidone differs significantly from the has been suggested that haloperidol decanoate is ones described above for typical depot antipsychotic probably the most viscous of the depot preparations formulations, as its final presentation is an aqueous and, therefore, should not be given in volumes suspension rather than an esterified drug suspended exceeding 3 ml.13 c) Inject slowly, about 30 seconds in oil. This novel formulation incorporates per ml is adequate. A faster injection can increase risperidone inside a glycolide/lactide matrix and is pain.31 d) Rotate the injection sites. The deltoid’s available as powder microspheres which are posterior aspect (latitudinally about 1 cm behind the reconstituted to the aqueous suspension. After deltoid midline and longitudinally about 5 cm below injection, the microspheres undergo gradual the acromioclavicular joint) and the lateral gluteus hydrolysis, resulting in a slow release of risperidone (to avoid stimulating the sciatic nerve that runs down the medial gluteus) are suitable injection "Short-acting" depot? Zuclopenthixol acetate is
sites.20,27,31 e) Z-track injection technique has been a unique injectable antipsychotic agent. Although it recommended as the most suitable for depot is considered a depot formulation, it has a duration antipsychotics20,23 as with this method, skin and Neurosciences 2005; Vol. 10 (2) 127
Long-acting injectable antipsychotics . Zolezzi subcutaneous tissue are retracted to avoid creating a with a test dose of 1-2 mg/day of oral risperidone straight-line needle tract that would allow the ready for 2 consecutive days is recommended before the backflow of injected material. However, this first injection.15,33 Ideally, the patient would have technique may not be essential as the decanoate been stabilized on oral risperidone first; however, it preparations are viscous enough to prevent has been suggested that this approach may not be significant backflow, provided the injection is necessary with long-acting injectable risperidone. A slowly administered.27 f) Consider subcutaneous (SC) administration rather than IM, as it is less recommended in this population.16,33,34 If the patient painful. Subcutaneous administration may be is being switched from an oral antipsychotic which suitable for fluphenazine decanoate by using a caused EPSE, the anticholinergic agent used to treat 5/8-inch, 22-gauge needle for patients who fear long the EPSE should be continued until the oral needles or are particularly sensitive to pain.
antipsychotic is cleared from the body (in general, Haloperidol decanoate, however, is only suitable for about 2-3 weeks), but at a reduced dose.
IM administration.27,31 It is important to note that this Discontinue the anticholinergic if EPSE are no route of administration for fluphenazine decanoate longer present.15,33 If the patient is being switched is licensed only in the US, Canada, and some anticholinergic medication should be tapered and General recommendations for the use of
discontinued over at least one month after depot long-acting injectable antipsychotics. Once the
antipsychotic has been discontinued.33 Risperidone- decision to prescribe long-acting injectable naïve patients should be monitored for EPSE, and antipsychotic therapy has been made, following the anticholinergic medication started if deemed necessary.33 Full release of long-acting injectable suggested in order to achieve optimal therapeutic risperidone from the gradually hydrolyzing outcomes. In addition, Table 1 has been compiled
microspheres starts about 3 weeks after the as a guide for clinicians on various aspects of injection. Thus, supplemental oral risperidone is long-acting injectable antipsychotic medications.
recommended to cover for at least the first 3 weeks Typical depot antipsychotics. Prior to initiating
treatment with a depot antipsychotic, the patient Zuclopenthixol acetate. Zuclopenthixol acetate is
should first be stabilized on an antipsychotic drug administered by IM injection into the upper outer administered orally, following which the transition quadrant of the gluteal region.25 First dose varies to depot medication can be made with a decreased between 25-150 mg, but it is usually recommended potential for side effects. Although no reliable to start with 100 mg. The elderly, patients with formula yet exists to convert the dose of orally small stature or neuroleptic-naïve may be started at administered neuroleptic to the amount of depot 25-50 mg. Large young males may require up to medication that should be administered, the "oral to 150 mg.24 A course of injections (100 mg every depot dosing equivalency" proposed in Table 1 may
48-72 hours) is usually required to settle the patient.
be used as reference. Consider a test dose if the At least 24 hours must elapse between injections.23-25 patient has never been on a depot formulation The recommended maximum dose is 400 mg over 2 before.17 This may help to avoid severe, prolonged weeks or 4 injections (whichever comes first). Then, adverse effects. However, some extrapyramidal change to oral medication or to a long-acting reactions may occur even after several doses have injectable antipsychotic.23-25 Patients should be been given.2,15,18 Some patients may require monitored for common side effects, such as EPSE, intermittent short-term use of orally administered sedation and hypotension. All other parenteral anticholinergic medication during the first week antipsychotics should be ceased when patients are following a depot injection. As patients may be at receiving a course of zuclopenthixol acetate, an increased risk of developing extrapyramidal side including all "as required" medications. If extra effects (EPSE) at the time the drug concentration sedation is required, intramuscular lorazepam or reaches its peak.13 In general, side effects of depot midazolam may be given, but they cannot be mixed antipsychotic treatment are comparable to those in the same syringe.24 If other parenteral experienced by patients receiving effective doses of antipsychotics have been administered, it is recommended to wait at least 15 minutes after IV, Long-acting injectable risperidone.
commencing the course of zuclopenthixol acetate.
Administration by gluteal injection, using a This time frame will allow adequate assessment of customized needle (external diameter of 22 gauge, the full response of the parenteral antipsychotic.35 internal diameter of 20 gauge).32 No test dose is Zuclopenthixol acetate may be mixed in the same required for patients who have taken oral syringe with the first dose of flupenthixol decanoate risperidone in the past. For patients who have never or zuclopenthixol decanoate if the depot formulation taken oral risperidone, a hypersensitivity challenge for these antipsychotics is to be initiated.24,36
128 Neurosciences 2005; Vol. 10 (2)
Long-acting injectable antipsychotics . Zolezzi Table 1 - A guide for the use of long-acting injectable antipsychotics.2,5,8-10,12,13,22,23,31,33,35-38 Characteristics
Flupenthixol
Fluphenazine
Haloperidol
Pipothiazine
Zuclopenthixol
Risperidone
decanoate
decanoate
decanoate
palmitate
decanoate
* - Equivalencies must not be extrapolated beyond the maximum dose for the drug, †-No studies available, ‡-Requires oral supplementation for a minimum of 3 weeks after the injection, CPZ - chloropromazine Neurosciences 2005; Vol. 10 (2) 129
Long-acting injectable antipsychotics . Zolezzi In conclusion, as schizophrenia is a chronic 8. Valenstein M, Copeland LA, Owen R, Blow FC, Visnic S.
Adherence assessments and the use of long-acting illness, non-adherence to medications is a potential injectable antipsychotics in patients with schizophrenia. J
problem that may lead to higher relapse rates which Clin Psychiatry 2001; 62: 545-551.
in turn worsens long-term outcomes and leads to 9. Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the long-acting injectable antipsychotics are particularly important as they antipsychotics. Clin Pharmacokinetics 1985; 10: 315-333.
10. Taylor D. Long-acting injectable antipsychotics revisited.
may improve medication adherence and therefore Psychiatric Bulletin 1999; 23: 551-553.
reduce relapse rates and improve long-term 11. Walburn J, Gray R, Gournay K, Quraishi S, David AS.
outcomes in patients suffering with this chronic Systematic review of patient and nurse attitudes to long-acting injectable antipsychotic medication. Br J
Psychiatry 2001; 179: 300-307.
long-acting injectable-release formulations have the 12. Marder SR, Hubbard JW, Van Putten T, Midha KK.
advantage of causing less variable plasma Pharmacokinetics of long-acting injectable neuroleptic concentrations and possibly decreased side effects drugs: clinical implications. Psychopharmacology (Berl)
as compared to oral agents. The recent availability of long-acting injectable risperidone is providing 13. Kane J. Guidelines for the use of long-acting injectable atypical antipsychotics. J Clin Psychiatry 2004; 65:
patients with the advantage of combining all the benefits of using an atypical antipsychotic in a 14. Warner A, Wyman S. Delayed severe extrapyramidal long-acting formulation. It also provides an disturbance following frequent long-acting injectable alternative treatment for those patients who are phenothiazine administration. Am J Psychiatry 1975; 132:
hesitant to receive an injection because of the pain 15. Kane JM, Aguglia E, Altamura AC, Ayuso Gutierrez JL, involved. As injections of long-acting injectable Brunello N, Fleischhacker WW, et al. Guidelines for risperidone are water based, they appear to be less long-acting injectable antipsychotic treatment in painful than the traditional oil-based formulations.
schizophrenia. Eur Neuropsychopharmacol 1998; 8:
This may be useful when reassuring some patients, particularly those who have experienced pain with 16. Kane JM. Strategies for improving compliance in treatment of schizophrenia by using a long-acting formulation of an other long-acting injectable antipsychotics.
antipsychotic: clinical studies. J Clin Psychiatry 2003; 64
Pharmacists have a significant role in facilitating medication adherence. As long-acting injectable 17. Pereira S, Pinto R. A survey of the attitudes of chronic antipsychotic use may partially address the issue of psychiatric patients living in the community toward their
medication. Acta Psychiatr Scand 1997; 95: 464-468.
non-compliance among schizophrenics, pharmacists 18. Bloch Y, Mendlovic S, Strupinsky S, Altshuler A, Fennig need to be knowledgeable to encourage their safe S, Ratzoni G. Injections of long-acting injectable and effective prescribing, and to promote adherence antipsychotic medications in patients suffering from by maintaining patients, their families and schizophrenia: do they hurt?[comment]. J Clin Psychiatry
caregivers, well informed on this type of 19. Hay J. Complications at site of injection of depot neuroleptics. BMJ 1995; 311: 421.
20. Muldoon C. Preventing local complications of depot Acknowledgment. This article was supported by neuroleptics. BMJ 1995; 311: 1368.
21. Davis J, Chen N. Choice of maintenance medication for schizophrenia. J Clin Psychiatry 2003; 64 (Suppl 16):
24-33.
22. Janssen Pharmaceutical Products, Inc. Risperidone long-acting injection (Risperdal Consta) US prescribinginformation. Available from: URL: 1. Kane JM. Schizophrenia. N Engl J Med 1996; 334: 34-41.
2. Davis J, Metalon L, Watanabe MD, Blake L. Long-acting 23. Antipsychotic depot injections. British National Formulary injectable antipsychotic drugs. Place in therapy. Drugs
24. Aaes-Jorgensen T. Pharmacokinetics of three different 3. Kramer JA, Rosenheck R. Compliance with medication injectable zuclopenthixol preparations. Prog
regimens for mental and physical disorders. Psychiatr Serv
Neuropsychopharmacol Biol Psychiatry 1989; 13: 77-85.
25. Lundbeck Pharmaceutical Products, Inc. Zuclopenthixol 4. Fenton WS, Blyler CR, Heinssen RK. Determinants of acetate injection (Clopixol-Acuphase): Product medication compliance in schizophrenia: empirical and Monograph. Copenhagen; Lundbeck Pharmaceutical clinical findings. Schizophr Bull 1997; 23: 637-651.
26. Barnes C, Alderton D, Castle D. The development of 5. Love RC. Strategies for increasing treatment compliance: Clinical Guidelines for the use of Zuclopenthixol Acetate.
The role of long-acting antipsychotics. Am J Health Syst
Australasian Psychiatry 2002; 10: 54-58.
Pharm 2002; 59 (Suppl 8): S10-S15.
27. Kane JM, Eerdekens M, Lindenmayer JP, Keith SJ, Lesem 6. Barnes TR, Curson DA. Long-acting long-acting injectable M, Karcher K. Long-acting injectable risperidone: efficacy antipsychotics: a risk-benefit assessment. Drug Safety
and safety of the first long-acting atypical antipsychotic.
Am J Psychiatry 2003; 160: 1125-1132.
7. Gerlach J. Oral versus long-acting injectable administration 28. Fleishman M. Taking the ‘ouch’ out of IM antipsychotics.
of neuroleptics in relapse prevention. Acta Psychatr Scand
Current Psychiatry Online 2003 June; 2. Available from:
130 Neurosciences 2005; Vol. 10 (2)
Long-acting injectable antipsychotics . Zolezzi 29. McConnell EA. Clinical Do’s and Dont’s – Administering 34. Nasrallah HA. IM risperidone: Long-acting atypical antipsychotic. Current Psychiatry Online December 2003; a Z-track I.M. injection. Nursing 1999; 29: 26.
30. Patterson C. Injection Technique – Long-acting injectable drugs. Nurs Times 1998; 94: Suppl 1-2.
35. Taylor D, Paton C, Kervin R, editors. The Maudsley 2003 31. Bezchlinbnyk-Butler KZ, Jefries JJ, editors. Clinical Prescribing Guidelines. 7th ed. London: Taylor & Francis Handbook of Psychotropic Drugs. 13th ed. Seattle; 36. Bazire S. Psychotropic Drug Directory 2003/04. The Hogrefe & Huber Publishers; 2003.
professionals’ pocket handbook & aide memoire.
32. Ereshefsky L, Mascarenas CA. Comparison of the effects of Salisbury: Fivepin Publishing; 2003.
different routes of antipsychotic administration on 37. Schulz P, Rey MJ, Dick P, Tissot R. Guidelines for the pharmacokinetics and pharmacodynamics. J Clin
dosage of neuroleptics. II: Changing from daily oral to
long acting injectable neuroleptics. Int Clin
Psychiatry 2003; 64 (Suppl 16): 18-23.
Psychopharmacol 1989; 4 :105-114.
33. Marder SR, Conley R, Ereshefsky L, Kane JM, Turner MS.
38. Masand PS, Gupta S. Long-acting injectable antipsychotics Dosing and switching strategies for long-acting risperidone.
in the elderly. Guidelines for effective use. Drugs Aging
J Clin Psychiatry 2003; 64 (Suppl 16): 41-46.
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