Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine

Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.

Recent discussions on dopamine supersensitivity psychosis: Eight points to consider when diagnosing treatment-resistant schizophrenia

: Dopamine supersensitivity psychosis is a clinical concept characterized by an unstable psychotic state and tardive dyskinesia in schizophrenia patients at the chronic stage. This state is thought to be induced by a compensatory upregulation of dopamine D2 receptors, which is provoked by long-term and/or high-dose medications. Recent clinical data suggest that patients who responded well to medication but later exhibit dopamine supersensitivity develop tolerance to antipsychotics’ effects and eventually transit to treatment-resistant schizophrenia, indicating that dopamine supersensitivity could be an etiology contributing to treatment-resistant schizophrenia. However, any clinicians and researchers consider dopamine supersensitivity psychosis a minor phenomenon during the clinical course and do not make much of it. This opinion is often based on numerous clinical data which indicating that dopamine supersensitivity psychosis is a relatively rare event. This review examines the data dealing with dopamine supersensitivity with the five themes of frequency, severity, withdrawal studies, switching to aripiprazole, and tardive dyskinesia. These themes’ effects on discussions of the clinical meaning of dopamine supersensitivity psychosis are then reviewed. The present review will help clinicians to speculate as to the background of severe psychopathology in a given patient; to make diagnoses of treatment-resistant schizophrenia and dopamine supersensitivity psychosis; and to plan antipsychotic medication regimens with the goal of achieving better long-term prognosis.

Where and how does d-amphetamine act to reveal antipsychotic-induced dopamine supersensitivity in rats?

ABSTRACTAntipsychotic treatment can produce a dopamine supersensitive state. In both schizophrenia patients and rodents, this is linked to antipsychotic treatment failure. In rodents, dopamine supersensitivity is often confirmed by an exaggerated behavioural response to the indirect monoamine agonist, d-amphetamine, after discontinuation of antipsychotic treatment. Here we investigated where and how d-amphetamine acts to trigger behavioural expression of dopamine supersensitivity, as this could uncover pathophysiological mechanisms underlying this supersensitivity. First, we examined the contributions of a central increase in dopamine/monoamine activity. Haloperidol-treated rats showed a potentiated psychomotor response to systemic d-amphetamine, confirming dopamine supersensitivity. However, they showed a normal psychomotor response to an increase in ventral midbrain dopamine impulse flow or to intracerebroventricular injection of d-amphetamine. This suggests that d-amphetamine’s peripheral effects are required for a supersensitive response. Second, we determined the specific contributions of dopamine neurotransmission. The D2 agonist quinpirole, but not the D1 agonist SKF38393 or the dopamine reuptake blocker GBR12783 produced a supersensitive psychomotor response in haloperidol-treated rats. In these rats, the D1 antagonist SCH39166 decreased d-amphetamine-induced psychomotor activity, whereas the D2 antagonist sulpiride enhanced it. Thus, when d-amphetamine triggers a supersensitive response, this involves both D1- and D2-mediated transmission. Finally, we measured d-amphetamine-induced changes in D1- and D2-mediated intracellular signalling pathways in the striatum. In haloperidol-treated rats, a supersensitive response to d-amphetamine was linked to enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens, suggesting increased D2-mediated signalling. These findings provide new insights into the neurobiology of antipsychotic-evoked dopamine supersensitivity.