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Psychopharmacology and adverse effects of antipsychotic long-acting injections: A review

  • David Taylor (a1) (a2)

Depot antipsychotics are widely used in clinical practice. Long-acting formulations of second-generation antipsychotics are now being developed and introduced.


To review the pharmacology, pharmacokinetics and adverse effect profiles of currently available antipsychotic long-acting injections (LAIs).


The psychopharmacological properties of first- and second-generation antipsychotic LAIs are reviewed using data available up to October 2008.


First-generation antipsychotic (FGA) LAIs are associated with a high rate of acute and chronic movement disorders. Risperidone LAI is better tolerated in this respect, but is associated with hyperprolactinaemia and weight gain. Olanzapine LAI causes weight gain and other metabolic effects but appears not to be associated with an important incidence of movement disorders.


Dosing of LAIs is complicated by delayed release of drug, changes in plasma levels without change in dose, and by the lack of data establishing clear dose requirements. All LAIs offer the prospect of assured adherence (although patients may still default on treatment) but their use is complicated by adverse effects, complex pharmacokinetics and confusion over dose–response relationships.

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Psychopharmacology and adverse effects of antipsychotic long-acting injections: A review

  • David Taylor (a1) (a2)
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The fast-off D2 theory

Kazuhiro Tajima-Pozo, Psychiatrist
04 January 2010

All of the FGAs have a high affinity for the D2 dopamine receptor in common, there being a strong correlation between the therapeutic doses of these drugs and receptor binding affinity (1). The importance of the dopaminergic receptor occupancy as an indicator of antipsychotic response and adverse effects has been demonstrated (2). Thus, it has been seen thata 65-70% striatal D2 receptor occupancy is associated with the antipsychotic effects while an occupancy greater than 80% significantly increases the risk of extrapyramidal effects. Therefore, a threshold between 60 and 80% of occupancy seems to represent the therapeutic window to minimize EPS risk of the FGAs (this model was not absolute and has its limitations). Interestingly, low doses of haloperidol (2-5 mg/day) should induce 60-80% receptor occupancy. Instead, a dose of 5 to 20 times more isgenerally prescribed in the clinical practice. This is partially supportedby the fact that the long-term treatment with FGAs induces an increase of the D2 receptors, which seems to be associated with a dopaminergic D2 supersensitivity. Thus, we could say that the dose must be increased in order to produce the same effect on the dopaminergic transmission (3).The fast-off D2 theory: there is no evidence that a drug can act as an effective antipsychotic is it does not have some degree of D2 occupancy. Recent in vitro studies have demonstrated that the antipsychotics are dissociated from the D2 receptors at very different rates, expressed as Koff value (4). The binding of an antipsychotic to a receptor is a dynamicprocess with continuous association and dissociation, and can be expressedas follows:

D + R = DR = D + RThe fast dissociation hypothesis proposes that the combination of a fast Koff and systemic transient occupancy of D2 is sufficient to produce an atypical antipsychotic effect. It is not necessary to induce activity in other receptors. It suggests that the fast dissociation drugs, whenused at adequately high doses that permit D2 blockage, modulate the dopaminergic system so as to permit a more appropriate functioning of the physiological systems, which would lead to that currently called the atypical antipsychotic effect.


1)Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and Serotonin2 pKi values. J Pharmacol Exp Ther 1989;251:238-46.2) Lieberman JA. Understanding the mechanism of action of atypical antipsychotic drugs: a review of compounds in use and development. Br J Psychiatry 1993;163:7-18.

3) Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. Apositron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 2000;57:553-9.

4)Seeman P, Tallerico T. Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and earlyclinical relapse upon withdrawal of clozapine or quetiapine. Am J Psychiatry 1999;156:876-84.
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The US haloperidol decanoate�s prescribing black hole

Louai Bilal, Psychiatrist
07 December 2009

We applaud the British Journal of Psychiatry for dedicating its November issue supplement for an important and long over-due review on theuse of long-acting antipsychotics. This review by Dr. Taylor noted that inthe USA for calculating monthly maintenance doses of haloperidol decanoate, up to 20 times the previous daily dose is permitted.1 To find out the origin of this, we consulted the FDA-approved manufacturer’s dosing guidelines and we found that it recommended such dosing mostly for those who are at a high risk for relapse or for those who developed “tolerance” to haloperidol due to chronic dosing. 2 The formula was based upon a lone pharmacokinetic study that was designed to test a loading dosetechnique on only 16 chronically ill patients with schizophrenia. 3 The authors sought to confirm that 20 times the oral dose used in the first month and subsequently dropped to 15-10 times the oral dose in later months, can sustain the haloperidol blood level without the need for oral supplementation. The study’s small sample size and the use of haloperidol blood level as the main outcome, raise questions about its suitability as basis for the manufacturer’s recommendation for dosing even for the patient population it designated. The authors had wisely recommended theirfindings be first replicated by a prospective, double-blind, randomized study. To the best of our knowledge this has not yet taken place. In fact,our search of the literature found only one randomized, controlled study that compared the efficacy and safety of different doses of haloperidol decanoate for relapse prevention. The highest dose used in that study was 200 mg/month. 4 In a recent Cochrane meta-analysis of haloperidol decanoate for schizophrenia, only one of eleven randomized, controlled trials noted any dosing of haloperidol decanoate > 200 mg/ month, but that trial failed to tease out any specific adverse effects or efficacy from those doses. 5 We concluded therefore that the evidence-base for the use of haloperidol decanoate doses greater than 200 mg/month is not sufficient to support its regular use. Though the current prevalence of high dose haloperidol decanoate use is not known, what we know is enough to advice against its widespread use.


1 Taylor D. Psychopharmacology and adverse effects of antipsychotic long-acting injections. Br J Psychiatry 2009; 195 (suppl 52): s13-9.

2 Haldol Decanoate Prescribing Information. Ortho-McNeil Pharmaceutical, Inc. Raritan NJ. Revised August 2008

3 Ereshefsky L, Toney G, Saklad S, Anderson C, Seidel D. A Loading-Dose Strategy for Converting Oral to Depot Haloperidol. Hospital and Community Psychiatry 1993; 44: 1155-61.

4 Kane JM, Davis JM, Schooler N, Marder S, Casey D, Brauzer B, et al.A multidose study of haloperidol decanoate in the maintenance treatment ofschizophrenia. Am J Psychiatry 2002; 159: 554-60.

5 Quraishi SN, David A, Brasil MA, Alheira FV. Depot Haloperidol Decanoate for Schizophrenia: a meta-analysis. Cochrane Database of Systematic Reviews 2000; 2. Art. No: CD001361
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