Continuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats

doi:10.1016/j.biopsych.2004.10.023

Biological Psychiatry

Volume 57, Issue 4, 15 February 2005, Pages 406-411

https://doi.org/10.1016/j.biopsych.2004.10.023 Get rights and content

Background

Continuous, but not intermittent, infusion with a conventional antipsychotic (haloperidol, HAL) can induce the vacuous chewing movement (VCM) syndrome in rats. The objective of this study was to determine whether continuous, versus intermittent, olanzapine (OLZ) infusion differently affects the development of VCMs.

Methods

Experiment 1: Animals were treated with 7.5 mg/kg/day of OLZ or vehicle (VEH) via either minipump (MP) or daily subcutaneous (SC) injections for 8 weeks. Experiment 2: A separate group of rats were treated with 15 mg/kg/day of OLZ, or 1 mg/kg/day of HAL or VEH via MP for 8 weeks. Dopamine D2 receptor occupancy levels were measured, ex vivo, with [3H]-raclopride.

Results

Experiment 1: Rats receiving 7.5 mg/kg/day of OLZ via MP (51% D2 occupancy), but not those receiving the same dose via daily SC injections (94% peak D2 occupancy), showed significant VCM levels compared with control animals (p = .02). Experiment 2: Both OLZ (67% D2 occupancy) and HAL (79% D2 occupancy) led to similar increases in VCMs compared with VEH (p = .005).

Conclusions

This study provides strong evidence that even an atypical antipsychotic like OLZ, which rarely gives rise to tardive dyskinesia in the clinic, can lead to the VCM syndrome in rats if the antipsychotic is administered in a method (via MP) that leads to continuous presence of the drug in the brain.

Section snippets

Animals

Adult male Sprague-Dawley rats (Charles River, Montreal, Canada), weighing 175–200 g at the start of the experiment, were housed two per cage in 19 × 10.5 × 8 inches transparent polycarbonate cages (Lab Products, Seaforth, Delaware) and maintained on a 12-hour light/dark cycle with continuous access to food and water. All procedures were carried out in accordance with The Animals for Research Act 1968–1969 of the Province of Ontario and the Guidelines of the Canadian Council on Animal Care.

Drug treatments

VCM behavior

A repeated-measures analysis of variance (ANOVA) comparing VCMs between treatment groups during the 8 weeks of treatment (Figure 1) revealed a significant dose effect [F(2,248) = 7.26, p = .003], a significant time effect [F(8,248) = 5.38, p < .001], and a significant dose × time effect [F(16,248) = 4.03, p < .001]. An ANOVA comparing average VCMs between different treatment groups over the last three test sessions was also significant [F(2,33) = 4.43, p = .02]. Post hoc Bonferroni analyses

Discussion

The results of the present study demonstrate a clear association between the emergence of the VCM syndrome and continuous versus transient D2 receptor occupancy and use of the atypical antipsychotic OLZ. Animals that received OLZ via daily SC injections did not develop VCMs beyond placebo values; however, rats that received OLZ via MP (a method that gives rise to continuous D2 occupancy) developed a high level of VCMs that was comparable to the HAL-treated group.

We suggest that the reason

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Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.
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All antipsychotic medications attenuate the symptoms of psychosis by interacting with dopamine D2 receptors and reducing dopamine-mediated neurotransmission. However, long-term antipsychotic treatment can produce neuroadaptations that are thought to lead to dopamine supersensitivity. In patients with schizophrenia, this dopamine supersensitivity could compromise treatment efficacy, promote relapse to psychosis and trigger movement disorders. Such effects have been seen in patients treated with either typical or atypical antipsychotics. In non-human animals, chronic exposure to antipsychotic medications, using clinically pertinent doses and modes of administration, can also evoke dopamine supersensitivity. This is indicated by an augmented behavioural response to dopamine agonists and tolerance to the antipsychotic-like effects of ongoing treatment. Here, we first describe antipsychotic-evoked dopamine supersensitivity in patients with schizophrenia and in laboratory animals. We then review approaches to prevent or reverse antipsychotic-evoked dopamine supersensitivity, based on preclinical animal studies. This evidence suggests that using atypical antipsychotics and regular but intermittent (versus continuous) antipsychotic dosing/D2 receptor occupancy is significantly less likely to produce dopamine supersensitivity. Lastly, we discuss potential neurobiological mechanisms. These include changes at the D2 receptor, but also other changes within and outside of the dopamine system. We conclude that in parallel to the search for new antipsychotic molecules, we need to better understand how different dosing regimens with currently used medications influence long-term outcome. There is also a pressing need to better characterize the development and expression of dopamine supersensitivity in humans. This will help determine the treatment strategies least likely to evoke dopamine supersensitivity.
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This effect is also interpreted in terms of dopamine supersensitivity (Samaha et al., 2007). It is suggested that DSP and TD are caused by an up-regulation of striatal D2 receptors leading to an enhanced dopamine-based activity in humans (Kornhuber et al., 1989; Mackay et al., 1982; Silvestri et al., 2000) and animal models (Jenner et al., 1982; Samaha et al., 2007; Seeman et al., 2005; Tarsy and Baldessarini, 1974) that show vacuous chewing movements (VCM) an accepted rodent proxy for TD symptoms (Turrone et al., 2003a; Turrone et al., 2003b; Turrone et al., 2005). However, changes in D2 receptor density have not been observed in all patients previously exposed to antipsychotics (Davis et al., 1991; Laruelle, 1998) and therefore the question of whether there is one precise mechanism mediating both the onset and offset of the antipsychotic response remains to be determined.
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Long-term antipsychotic treatment induces drug sensitization, enhancing the behavioral effects of the drug. While this in itself is considered a behavioral mechanism underlying the therapeutic effects of antipsychotic treatment (Kapur et al., 2006), it has also been demonstrated to underlie the drug-induced extrapyramidal motor syndrome and tardive dyskinesia observed in long-term antipsychotic treatment (Turrone et al., 2005). ARI is rapidly becoming more readily prescribed to treat schizophrenia, schizoaffective disorder and many other disorders in adolescents and children due to the effectiveness and reported less severe drug side effects (Docherty et al., 2010; Samaha et al., 2007; Takashi et al., 2009; Corell et al., 2011).
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Original articlesContinuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats

Background

Methods

Results

Conclusions

Section snippets

Animals

Drug treatments

VCM behavior

Discussion

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Biol Psychiatry

Neuropsychopharmacology

Physiol Behav

Neurosci Biobehav Rev

Drug holidaysintermittent pharmacology for psychiatric patients

International Drug Therapy Newsletter

Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol

Br J Psychiatry

A 5-year prospective longitundinal study of tardive dyskinesiaFactors predicting appearance of new cases

J Clin Psychopharmacol

Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol

Psychopharmacology

Positron emission tomographic analysis of central D1 and D2 dopamine occupancy in patients treated with classical neuroleptics and clozapineRelation to extrapyramidal side effects

Arch Gen Psychiatry

Effect of drug holidays on tardive dyskinesia.

Extrapyramidal side effects, tardive dykinesia, and the concept of atypicality

J Clin Psychiatry

Persistent vacuous chewing movements in rats following neuroleptic treatmentRelationship with dopaminergic and cholinergic function

Psychopharmacology

Intermittent neuroleptic therapy and tardive dyskinesiaa literature review

Hosp Community Psychiatry

Mixture in the distribution of haloperidol-induced oral dyskinesias in the rat supports an amimal model of tardive dyskinesia

Psychopharmacology

Tardive dyskinesia

Schizophr Bull

Integrating incidence and prevalence of tardive dyskinesia

Psychopharmacol Bull

Original articles
Continuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats