Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review

Abstract

Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

Clinical Guidance on the Identification and Management of Treatment-Resistant Schizophrenia

“…Current data suggest that there are probably multiple clinical pathways and different potential neurobiological mechanisms involved in the pathophysiology of TRS ( Figure 1). 5,15,16,[20][21][22][23][24][25][26][27][28][29] For example, heterogeneity has been observed in the onset of treatment nonresponse. Approximately 30% of individuals diagnosed with schizophrenia exhibit a partial response or no response to initial treatment, 8 whereas 10%-60% of individuals exhibiting an initial response to ■ Upon recognition of TRS, the treatment plan should be reevaluated and alternative treatments considered.…”

“…Normodopaminergictype schizophrenia 24,25 Dopaminesupersensitive-type schizophrenia [19][20][21][22][23][24]27,29 Other hypotheses [24][25][26][27][28] Initial response but treatment resistance develops over time 15,16 No initial response 5,[15][16] antipsychotic treatment develop treatment resistance over time 5,15,16 and after multiple relapses. 30 There are also multiple hypotheses concerning the underlying neurobiological mechanisms of TRS that account for the 2 main clinical paths to TRS (initial resistance vs resistance that emerges over time).…”

“…[20][21][22][23][24] This supersensitivity may be due to an increase in the number of receptors or an increase in receptor affinity for dopamine. 29 Antipsychotic medications mitigate psychosis by blocking DRD2 receptors. However, prolonged blockade of postsynaptic dopamine receptors may lead to dopamine supersensitivity, resulting in increased psychotic symptoms (breakthrough psychosis) and motor side effects such as abnormal involuntary movements (eg, tardive dyskinesia) in treated patients.…”

“…23,24 However, clinical support for a causal role of dopamine supersensitivity psychosis in TRS is currently lacking. 29,31 An alternative theory for TRS, the "normodopaminergic" hypothesis, is based on evidence indicating that not all individuals with schizophrenia have characteristics of a hyperdopaminergic system. 25,26 In one positron emission tomography study, patients with TRS had lower dopamine synthesis capacity than treatment-responsive patients but a similar capacity to healthy volunteers.…”

What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?

“…The existence of this phenomenon has been controversial and only supported by small studies. Nevertheless, there has been a recent resurgent interest in dopamine supersensitivity as a potential cause of the emergence of treatment resistance. However, a meta‐analysis of RCTs found no differences in relapse rates between abrupt and gradual antipsychotic withdrawal or between different antipsychotic doses prior to discontinuation.…”