"Breakthrough" Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2007; 27(11):2979-86. DOI: 10.1523/JNEUROSCI.5416-06.2007
Source: PubMed


Antipsychotics often lose efficacy in patients despite chronic continuous treatment. Why this occurs is not known. It is known, however, that withdrawal from chronic antipsychotic treatment induces behavioral dopaminergic supersensitivity in animals. How this emerging supersensitivity might interact with ongoing treatment has never been assessed. Therefore, we asked whether dopamine supersensitivity could overcome the behavioral and neurochemical effects of antipsychotics while they are still in use. Using two models of antipsychotic-like effects in rats, we show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding. Treatment failure occurred despite high levels of dopamine D2 receptor occupancy by the antipsychotic and was at least temporarily reversible by an additional increase in antipsychotic dose. To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system and observed that antipsychotic failure was accompanied by opposing changes across the synapse: tolerance to the ability of haloperidol to increase basal dopamine and dopamine turnover on one side, and 20-40% increases in D2 receptor number and 100-160% increases in the proportion of D2 receptors in the high-affinity state for dopamine (D2(High)) on the other. Thus, the loss of antipsychotic efficacy is linked to an increase in D2 receptor number and sensitivity. These results are the first to demonstrate that "breakthrough" supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy. These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics.

Download full-text


Available from: Philip Seeman, Mar 13, 2015
38 Reads
  • Source
    • "These two phenomena can manifest at multiple levels, including neurotransmitter release, changes in neuroreceptor levels, receptor-mediated second messenger activities, cell electrophysiology, and behaviors, and which can be clinically relevant. For example, haloperidol-induced sensitization has been linked to the gradual development of some extrapyramidal motor side effects (Turrone et al., 2005), increased dopamine supersensitivity (Samaha et al., 2007), and the progressive improvement of psychosis (Agid et al., 2003). One important issue in the field of antipsychotic sensitization and tolerance is to identify the critical factors that determine the specific patterns of the long-term effects of chronic antipsychotic drug treatment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. © The Author(s) 2015.
    Journal of Psychopharmacology 01/2015; 29(4). DOI:10.1177/0269881114565937 · 3.59 Impact Factor
  • Source
    • "). This kind of response has been well documented in other areas of medicine (e. g., Eghøj and Sørensen, 2012; Nauck et al., 2011; Samaha et al., 2007). However, it could also be the case that subsequent depressive episodes are not caused by the same etiological pathway . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Major depressive disorder (MDD) presents with a variety of symptoms and responds to a wide range of treatment interventions. Diagnostic criteria collapse multiple syndromes with distinct etiologies into the same disorder. MDD is typically understood as a malfunction of neurotransmission or brain circuitry regulating mood, pleasure and reward, or executive function. However, research from an evolutionary perspective suggests that the “normal” functioning of adaptations may also generate symptoms meeting diagnostic criteria. Functioning adaptations may be an underappreciated etiological pathway to MDD. Many adaptive functions for depressive symptoms have been suggested: biasing cognition to avoid losses, conserving energy, disengaging from unobtainable goals, signaling submission, soliciting resources, and promoting analytical thinking. We review the potential role of these adaptive functions and how they can lead to specific clusters of depressive symptoms. Understanding MDD from such a perspective reduces the heterogeneity of cases and may help to select the best intervention for each patient. We discuss the implications of different adaptive and maladaptive etiological pathways for the use of antidepressants and various modes of psychotherapy. In particular, instances of MDD caused by functioning adaptations may benefit most from treatments that support the adaptive function, or that target the precipitating causal stressor. We conclude that an evolutionary approach to the study of MDD may be one of the more promising approaches to reduce its heterogeneity and to better match patients and treatment.
    Journal of Affective Disorders 09/2014; 172. DOI:10.1016/j.jad.2014.09.032 · 3.38 Impact Factor
  • Source
    • "This increase in D (2)-high-receptors is a necessary basic requirement for the development of a psychosis that correlates with dopamine supersensitivity (104). This specific increase in D (2)-receptors and dopamine supersensitivity might result in antipsychotic treatment failure (105, 106). Although D (2)-receptor antagonists induce dopamine activity (107), the mechanisms underlying the action of dopamine D (2)-receptor antagonists are not entirely clear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia.The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.
    Frontiers in Psychiatry 05/2014; 5. DOI:10.3389/fpsyt.2014.00047
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.