When antipsychotic medications stop working, and what to do about it: lessons from rodents
Anne-Noël Samaha, Montréal (Canada)
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Anne-Noël Samaha, Montréal (Canada)
Some patients with schizophrenia that initially respond to antipsychotic treatment show a progressive loss of antipsychotic efficacy. Previously effective doses can no longer control psychotic symptoms. This perplexing clinical phenomenon has been modelled in laboratory rats. Just like in patients, rats can show treatment failure despite high levels of dopamine D2 receptor occupancy by antipsychotic, and this is temporarily reversible by increasing the antipsychotic dose. The antipsychotic failure is accompanied by an augmented behavioural response to dopamine agonists, suggesting supersensitivity to dopamine stimulation. At the brain level, there is upregulation of both D2 receptors and D2 receptors in a high-affinity state for dopamine in the striatum, without marked changes in presynaptic dopamine release, synthesis or reuptake. Thus, the brain compensates for continuous D2 receptor blockade by increasing striatal D2 receptor number and function. This could contribute to dopamine supersensitivity, where endogenous dopamine drive is potentiated and compromises the efficacy of the antipsychotic. Using intermittent rather than continuous treatment, and using atypical versus typical antipsychotics can prevent antipsychotic-induced dopamine supersensitivity. Pharmacological modulation of neurobiological systems that modulate dopamine function indirectly, such as neurotensin or 5-HT2A serotonin receptors, can also attenuate the expression of established antipsychotic-induced dopamine supersensitivity. Based on these findings, I propose that an antipsychotic-induced increase in dopamine sensitivity might predispose certain people to psychotic relapse, in the absence of antipsychotic drug discontinuation or dose reduction. Solutions to this problem include using 1) minimal therapeutic doses during maintenance treatment, 2) atypical versus typical antipsychotics, and 3) intermittent versus continuous treatment.