Antipsychotic Induced Dopamine Receptor Supersensitivity and It's Clinical Implications

Background : Schizophrenia is a serious mental disorder that requires multi-modal and continuous treatment, mainly with antipsychotic. Along with the increasing life expectancy of schizophrenic patients, various problems due to prolonged blocking of dopamine receptors have emerged, especially dopamin receptor supersensitivity and it's clinical implications.

Aim : This study aims to determine the problems with long-term use of antipsycotics and the clinical implications of dopamine receptor supersensitivity..

Methods : PubMed and Google Scholar were searched using the following keyword: (schizophrenia) AND (long term antipsychotic OR prolonged antipsychotic) AND ( D2 receptor OR dopamine-2 receptor) AND (supersensitivity) using the journal publication filter for the 2000-2019 issue. We also used textbooks published in the last 10 years and were related to writing themes.

Review : Given their chronic nature, it is often necessary to give schizophrenia patient long-term antipsychotics. Prolonged blocking of D2 receptor can results variety of unpleasant effect, including dopamine receptor supersensitivity. This phenomenon can cause problematic implications such as dopamine supersensitivity psychosis, treatment-resistant schizophrenia and tardive dyskinesia. The risk of these side effects arises if antipsychotic use is not done wisely, such as the use of higher-than-recommended doses, antipsychotic polypharmacy, improper indications, and only rely on antipsychotics without maximizing the role of other therapeutic modalities.

Summary : Clinicians need to pay attention to the rationality of the use of antipsychotics and conduct intensive supervision to reduce the risk of any clinical implications of dopamine receptor supersensitivity.

Keywords: schizophrenia, long term antipsychotic, dopamine, receptor D2, supersensitivity.

Introduction

Schizophrenia is a form of serious mental dis- order that requires long-term and comprehen- sive therapy[1]. One of the main modalities in the management of schizophrenia is the admin- istration of antipsychotics from the dopamine receptor antagonist class. As the life expectan- cy of schizophrenic patients increases, several problems related to the long-term effects of an- tipsychotics have begun to emerge. The block of dopamine receptors by antipsychotics in the long term will trigger dopamine receptors to increase their affinity for dopamine, as a compensation mechanism from the body. This phenomenon is called dopamine receptor supersensitivity. This condition can lead to increased physiological re- sponses, behavioral responses, and biochemical responses that are more than usual when the re- ceptors encounter dopamine[1]. When the body is no longer able to compensate, this phenome- non will cause significant clinical implications that have the potential to become a problem for sufferers, such as the occurrence of Dopamine Supersensitivity Psychosis (DSP), tardive dsyki- nesia, and treatment-resistant schizophrenia.[2]. The risk of clinical implications of dopamine re- ceptor supersensitivity increases if the adminis- tration of antipsychotics is not prudent, such as the use of higher than recommended doses[3], inappropriate indications[4], and the increasing use of polypharmacy antipsychotics[5]. Data from WHO also shows that 50% of drug use worldwide is still irrational[6]. Clinicians need to be careful and carry out comprehensive peri- odic supervision in administering long-term anti- psychotics to schizophrenic patients, to minimize the risk of complications that can arise due to the phenomenon of dopamine receptor supersensitiv- ity.

Aims

Given their chronic and relapsing nature, cli- nicians often have to administer antipsychotics, either alone or in combination, over a long pe- riod of time to schizophrenic patients. This pro- longed blockade of dopamine receptors can trig- ger various physiological responses as a form of compensation, one of which is an increase in the

affinity of D2 receptors for dopamine. If the body is no longer able to compensate, various clini- cal implications can arise which can become a problem. This literature review aims to determine more clearly the pathophysiology of long-term antipsychotic-induced dopamine receptor super- sensitivity and its clinical implications, as well as how the factors of antipsychotic use patterns increase the risk of this phenomenon.

Methods

PubMed and Google Scholar were searched us- ing the following keyword: (cognitive function) AND (neurodevelopmental OR neurotoxicity hypothesis) AND (duration of untreated psycho- sis OR dup) AND (schizophrenia OR psychosis OR psychotic) using the journal publication filter for the 2000-2019 issue in any research design. We also used textbooks published in the last 10 years that were related to the writing theme. Our searches are primarily on the pathophysiology of antipsychotic-induced dopamine receptor super- sensitivity and it’s clinical implications. Howev- er, journals about antipsychotic use patterns were also included to determine strategies for rational use of antipsychotics in order to minimize the risk of antipsychotic-induced dopamine receptor supersensitivity.

Review

Schizophrenia is a chronic mental disorder characterized by disharmony in the elements of thought processes, affect, emotions, volition, and psychomotor, which are reinforced by other sec- ondary symptoms[1]. The prevalence of schizo- phrenia in general is estimated at 1%, which means that 1 person in 100 people will experi- ence schizophrenia in their lifetime[1],[7]. It has been postulated that schizophrenics experience hyperactivity in the dopaminergic system in their brain[1],[8], either because more dopamine is released at the synaptic cleft, as well as increased expression and sensitivity of the D2 receptor, the receptor that plays a major role in the pathophys- iology of schizophrenia[9],[10], and known as dopamine theory of schizophrenia. Based on the dopamine theory, the administration of antipsy- chotics from the dopamine receptor antagonist

class has been shown to be useful in relieving the symptoms of schizophrenia. However, man- agement of schizophrenia can not only be done with one modality, but includes many modalities which ideally should be implemented in an inte- grated and proportional way so that it can pro- duce effective results.

Given it’s chronic and recurrence nature, long- term administration of antipsychotics in schizo- phrenic patients is not uncommon. In some cases, antipsychotics are even given for life. Long-term use of antipsychotics can cause dopamine re- ceptor supersensitivity phenomena, namely an increase in physiological responses, behavioral responses, and biochemical responses from do- pamine receptors after binding to dopamine ag- onists[2].

The mechanism for dopamine receptor super- sensitivity is based on the up-regulation of do- pamine D2 receptors due to chronic blockade by antipsychotics, as an attempt to maintain a nor- mal dopaminergic response[2],[7]. This up-reg- ulation includes 2 processes, namely an increase in the affinity and density of the dopamine D2 receptor, as well as an increase in post-synaptic dopaminergic signaling through modification of the proteins and enzymes involved.

The affinity of dopamine receptors, especial- ly D2 receptors, for dopamine agonists plays a major role in the response that occurs. Like oth- er receptors, the D2 dopamine receptors can be available in a high-affinity state, called D2high, and a low-affinity state, called D2low. D2high re- ceptors have a higher affinity for dopamine than D2low receptors. Both types of receptors are in an equilibrium state, to get the normal response desired[11]. The administration of antipsychot- ics will modify the

.....