728428

review-article2017
JOP0010.1177/0269881117728428Journal of PsychopharmacologyNakata et al.

Review

Dopamine supersensitivity psychosis in

schizophrenia: Concepts and implications
in clinical practice Journal of Psychopharmacology
2017, Vol. 31(12) 1511­–1518
© The Author(s) 2017
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DOI: 10.1177/0269881117728428
https://doi.org/10.1177/0269881117728428
Yusuke Nakata1, Nobuhisa Kanahara2 and Masaomi Iyo1 journals.sagepub.com/home/jop

Abstract
Dopamine supersensitivity psychosis (DSP) is observed in patients with schizophrenia under antipsychotic treatment, and it is characterized by
rebound psychosis, an uncontrollable psychotic episode following a stable state and tardive dyskinesia. DSP, first described in patients taking
typical antipsychotics in the late 1970s, sometimes appears even in patients who are treated with current atypical antipsychotics. It was recently
demonstrated that DSP can have a negative impact on the long-term prognosis of schizophrenia patients and that DSP could be involved in the
etiology of some cases of treatment-resistant schizophrenia. Accumulating evidence suggests that an up-regulation of dopamine D2 receptors (DRD2)
in the brain caused by long-term exposure to antipsychotics is related to the DSP phenomenon. The present review describes the clinical characteristics
and the etiology of DSP in the era of second-generation antipsychotics for patients with schizophrenia. Based on the mechanism of DSP, several
potential treatments for patients presenting with a DSP episode or the dopamine supersensitivity state are also discussed.

Keywords
Antipsychotic, dopamine partial agonist, dopamine supersensitivity, schizophrenia, tardive dyskinesia

Introduction psychotic episodes, even among patients in remission (Llorca,

Schizophrenia has shown an approximately 1% lifetime preva-
lence rate worldwide (Tandon et al., 2008). When an individual
suffers from schizophrenia, he or she may be severely affected by
a variety of psychiatric symptoms, including positive symptoms
such as delusions and hallucinations, negative symptoms and
cognitive impairments, all of which may persist for the individu-
al’s lifetime. Pharmacotherapy with antipsychotics has been the
most effective treatment for schizophrenia, providing ameliora-
tive effects on positive symptoms in particular.
The main action mechanism of these antipsychotics has been
considered to be the blockade by the antipsychotic(s) of dopa-
mine D2 receptors (DRD2) in the brain (Seeman et al., 1975,
1976). However, this antagonistic effect on DRD2 can also result
in extrapyramidal symptoms (EPS) such as parkinsonism, and/or
hyperprolactinemia. Although atypical antipsychotics with phar-
macological profiles that provide a lesser risk of EPS have been
the main pharmacotherapy for schizophrenia over the past two
decades, the use of these drugs can also cause adverse metabolic
effects such as hyperglycemia and hyperlipidemia, which are sig-
nificantly negative physical problems for many patients (Mitchell
et al., 2013). Individuals being treated for schizophrenia with one
or more atypical antipsychotics should thus be monitored neuro-
logically and endocrinologically throughout their lifetime.
It has been demonstrated that such a variety of adverse effects
by typical or atypical antipsychotics also have negative impacts
on the disease course itself (Tandon and Jibson, 2002). Patients
experiencing a side effect of an antipsychotic are more likely to
lapse into partial or complete non-adherence to their medication
regimen. Less adherence leads to a higher rate of relapse of
2008; Masand et al., 2009; Valenstein et al., 2002). Generally,
treatment for relapse episodes requires a higher dose of the antip-
sychotic to control the psychosis in the relevant episode com-
pared to the individual’s first-episode psychosis, and the higher
dose could provoke further adverse effects. It is therefore impor-
tant for physicians to continuously treat patients over a long term
in order to prevent the adverse effects of antipsychotics as much
as possible. However, it is a challenge to maintain a maximum
continuous rate of treatment and a minimum level of side effects
in clinical practice, and this difficulty is reflected by the docu-
mented high rate of withdrawal from atypical antipsychotic treat-
ment (Azekawa et al., 2011; Gorwood, 2006).
In this context, an important task in clinical research is to
clarify the reasons why (1) a higher dosage of antipsychotic is
often needed for the treatment of relapse episodes, and (2) why
such higher dosages sometimes no longer provide a treatment
effect, in a phenomenon known in the past as “neuroleptic-
induced supersensitivity psychosis” (Chouinard and Jones, 1980;
Chouinard et al., 1978; Davis and Rosenberg, 1979). Davis and
1Department of Psychiatry, Chiba University Graduate School of
Medicine, Chiba, Japan
2Division of Medical Treatment and Rehabilitation, Chiba University
Center for Forensic Mental Health, Chiba, Japan
Corresponding author:
Nobuhisa Kanahara, Division of Medical Treatment and Rehabilitation,
Chiba University Center for Forensic Mental Health, 1-8-1 Inohana,
Chuou-ku, Chiba-shi, Chiba 260-8670, Japan.
Email: kanahara@faculty.chiba-u.jp
1512 Journal of Psychopharmacology 31(12)
Rosenberg (1979) proposed supersensitivity psychosis as a lim-
bic equivalent to tardive dyskinesia (TD). Essentially, an up-reg-
ulation of DRD2 in a patient’s brain caused by antipsychotic(s)
underlies this supersensitivity psychosis (Iyo et al., 2013), which
has been well studied in the basic research field of psychophar-
macology. That is, chronic administrations of a typical or atypical
antipsychotic to animals cause the up-regulation of DRD2 par-
ticularly in the striatum, and these animals have shown a super-
sensitive profile at the behavioral level (Huang et al., 1997; Inoue
et al., 1997; Köhler, et al., 1994; Samaha et al., 2007; Tadokoro
et al., 2011; Vasconcelos et al., 2003). However, whether or not
the up-regulation of DRD2 actually occurs in a living human’s
brain has not yet been demonstrated, although one PET study
showed that DRD2 of patients taking antipsychotic(s) may be
up-regulated (Silvestri et al., 2000). Thus the mechanisms that
underlie neuroleptic-induced supersensitivity psychosis in
humans continue to be unknown (Oda et al., 2015).
However, advances in neuroimaging and molecular research
techniques have increased our understanding of the mechanisms
of action of antipsychotics on the human brain, and this progress
has provided useful clues to the questions of how the up-regula-
tion of DRD2 caused by antipsychotics affects a patient’s
responsiveness to treatment and how this responsiveness may
change over a long-term treatment course. Herein we review the
clinical characteristics of neuroleptic-induced supersensitivity
psychosis in the era of atypical antipsychotics treatment. We use
the term “dopamine supersensitivity psychosis (DSP)” instead
of neuroleptic-induced supersensitivity psychosis in this review,
because the essence of this phenomenon is dopamine’s stimula-
tion of DRD2 (Iyo et al., 2013). We also discuss the latest find-
ings regarding DSP in schizophrenia patients’ brains. Potential
treatment approaches—both preventive (avoiding the develop-
ment of supersensitivity psychosis) and ameliorative (diminish-
ing the psychosis which has already appeared)—are also
described. The reader is also referred to the recent review by
Chouinard et al. (2017) to explore the relevant knowledge
gained in animal studies and to see newly proposed DSP criteria
that are suitable for the era of atypical antipsychotics. The pre-
sent review aims to explain the important concept of DSP in a
more compact manner in order to help physicians understand a
given patient presenting with DSP.
The concept of dopamine
supersensitivity psychosis
The concept of DSP originated with reports in the 1970s of
patients whose psychotic symptoms worsened immediately upon
cessation of treatment and thereafter higher dosages of drugs
were needed to control the patients’ psychosis, and eventually TD
appeared (Chouinard and Jones, 1980; Chouinard et al., 1978).
Chouinard and colleagues, who had reported on these patients
most extensively at that time, highlighted both TD and high-dose
treatment upon diagnosing DSP. In this context, it seems that they
recognized this state as a pure adverse event caused by neurolep-
tics, which are similar to others such as EPS. This viewpoint is
reflected by the term of “neuroleptic-induced supersensitivity
psychosis” named later by these researchers.
Thereafter Chouinard proposed the following core features
of this state as the research diagnostic criteria (Chouinard,
1991): When a patient with schizophrenia is diagnosed as hav-
ing DSP, he or she should continuously take antipsychotic(s) for
more than 3 months. In addition, one of the following three
criteria must met: (i) the presence of rebound psychosis, i.e., a
psychotic relapse that occurs immediately after the reduction,
cessation, or change of antipsychotics (“immediately” = within
six weeks for oral agents and within three months for depot
injectable antipsychotics) has occurred; (ii) tolerance to the
antipsychotics’ effect is observed: that is, when severe psy-
chotic symptoms and/or other positive symptoms emerge, a
higher dosage of antipsychotics is needed to control the psy-
chotic symptoms compared to the dose(s) for previous treat-
ment, and in some cases even high-dosage treatment cannot
control the psychosis; (iii) the presence or history of TD: TD
appears at the withdrawal of medication, or disappears after a
readministration of antipsychotics. Chouinard proposed that
TD and DSP could be divided into three stages, classified as a
covert or masked state, an overt state, and a persistent state
(Chouinard and Jones, 1980). According to their survey, how-
ever, such DSP were not necessarily linked to poor prognosis in
patients, although a significant number (22–43%) of patients
experienced a DSP episode (Chouinard et al., 1986).
In recent years, as atypical (second-generation) antipsychot-
ics have become the mainstay in treatment, rebound psychosis
has also been reported: abrupt exacerbation of psychosis when
switching from an antipsychotic to a dopamine partial agonist
(e.g., aripiprazole), or when an antipsychotic with lower affin-
ity to DRD2 (e.g., quetiapine or clozapine) is reduced or fully
tapered off, both of which are recognized to result in typical
rebound psychotic episodes (Margolese et al., 2002; Moncrieff,
2006; Seeman and Tallerico, 1999; Takase et al., 2015). These
reports indicate that triggers causing rebound psychosis could
be categorized to several patterns, such as stimulation by dopa-
mine agonistic profile (aripiprazole) and loose binding with
DRD2 (quetiapine), and such worsening patterns appear as
novel situations of rebound psychosis in the era of atypical
antipsychotics.
Several clinical signs indicating DSP and/or its trigger caus-
ing DSP, e.g., hyperprolactinemia and stress (Chouinard, 1991)
or polydipsia (Yamada et al., 2014), have been raised as minor
criteria for dopamine supersensitivity state. Twenty years after
the initial research, Fallon et al. and Iyo et al., working in sepa-
rate research teams, have recently emphasized both required vul-
nerability to stress and overall EPS, including TD, as other
important signs of the dopamine supersensitivity state (Fallon
and Dursun, 2011; Fallon et al., 2012; Iyo et al., 2013). These
viewpoints try to capture broader components of DSP from a
variety of symptoms presented by patients. Thus, the concept of
such DSP in the era of treatment with atypical antipsychotics is a
more complex phenomenon with multiple and continuous epi-
sodes, which can be triggered by various situations as well.
In a given patient showing worsening symptoms, a physician
may be unable to differentiate the symptoms cause from a natural
relapse episode (e.g., due to a simple lack of adherence) versus a
relapse episode by DSP (i.e., due to a rebound psychosis). An
episode of worsening symptoms could also be due to a mixture of
both elements. Even if it is not possible to determine the precise
cause(s) of a relapse, it is valuable to consider the possibility of
DSP as underlying the relapse based on all available information,
in terms of the future treatment plan.
Nakata et al. 1513
Dopamine supersensitivity psychosis
in treatment-resistant schizophrenia
In clinical practice, there is a significant portion of schizophrenia
patients who do not respond to medications at an initial or later
stage. Whether an individual with schizophrenia is diagnosed as
having treatment-resistant schizophrenia (TRS) is determined by
his or her treating physician (Quintero et al., 2011). The essential
feature for the diagnosis of TRS is generally characterized by an
inadequate improvement of a patient’s psychotic symptoms by
the administration of two different chemical classes of antipsy-
chotics, at doses higher than the standard dose (600 mg/day in
chlorpromazine-equivalent [CPeq.] dose) for at least four weeks
(Molina et al., 2012; Peuskens, 1999). According to this defini-
tion, approximately 30–40% of schizophrenia patients meet the
criteria of TRS in clinical practice (Juarez-Reyes et al., 1995).
Although the etiology of TRS is complex and has not been eluci-
dated to date, it is clear that based on clinical observations and
published research, the etiology includes several clinical courses
or types of the disease among patients with TRS (Kane, 1996;
Keefe et al., 1987; Ventura et al., 2010).
Several clinical trials have reported that 12–15% of first-epi-
sode schizophrenia patients respond poorly to pharmacotherapy,
indicating a good response to the first antipsychotic in the major-
ity of patients (Chiliza et al., 2015; Robinson et al., 1999).
However, some patients with a good response to their initial
treatment subsequently need an increased dose of antipsychotic
dosage to control their psychosis over the course of repeated
relapses, eventually progressing to treatment resistance. Relapse
is recognized as related to a lack of adherence to the prescribed
treatment regimen; it has been reported that 42% of schizophre-
nia patients stopped taking their medication within one year fol-
lowing the introduction of treatment (Kahn et al., 2008).
Thus, a significant number of schizophrenia patients are in
only partial adherence to their pharmacotherapy (Masand et al.,
2009). Since insufficient adherence leads to an increase in the rate
of recurrence and may necessitate higher doses of antipsychotics
compared to the dose used at the first-episode, insufficient adher-
ence and the higher rate of subsequent relapse could well affect
the disease course in these patients (Hasan et al., 2012).
It has been suggested that DSP may be involved in the pro-
gression to TRS, that is, DSP may be one of the clinical subsets
of TRS. Both Chouinard and Chouinard (2008) and Iyo et al.
(2013) argued that once dopamine supersensitivity develops in a
patient’s brain, the efficacy of a given dose of antipsychotics that
has been previously effective diminishes, implying that the
patient’s psychotic symptoms become refractory. They catego-
rized this condition as one of the putative subsets of TRS.
The most typical case of a DSP patient progressing to TRS is
an individual who responds well to initial treatment but gradually
develops treatment resistance, showing less response even to a
higher dose of antipsychotic. This process is related to a variety
of clinical situations including a lack of adherence to the treat-
ment regimen and the subsequent relapse, rebound psychosis fol-
lowing the reduction or cessation of an antipsychotic, or a switch
of the antipsychotic for whatever reason. However, it is possible
that a patient who shows a good response at his or her first epi-
sode, but maintains the psychosis under high-dose treatment
(>600 mg in CPeq.) could be in a dopamine supersensitivity
state. In addition, the appearance of EPS could be related to the
dopamine supersensitivity state, which later leads to DSP or TD
(Iyo et al., 2013).
Chouinard and Chouinard (2008) estimated that approxi-
mately half of TRS cases could be etiologically related to DSP,
based on the relatively high ratio of TD reported in numerous
clinical trials with conventional antipsychotics. For example,
Suzuki et al. (2015) reported a high ratio of DSP episodes among
147 TRS patients who had been treated, on average, for more
than 20 years. The study results revealed that rebound psychosis,
tolerance to antipsychotics, and the presence or a history of TD
were observed in 41.5%, 55.7% and 44.3% of the patients,
respectively. In addition, 72% of the studied patients had experi-
enced at least one type of these DSP episodes. Moreover,
Yamanaka et al. (2016) reported that patients who had experi-
enced more than one of the types of DSP episode mentioned
above were closely associated with progression to TRS with 15
times of the odds ratio. These findings strongly suggest the
importance of DSP in considerations of treatment approaches to
TRS. It is thus crucial to clarify the mechanism of DSP and to
elucidate the preventive methodology and treatment of DSP.
The mechanisms underlying the
pathology of DSP
It is well established that the efficacy of antipsychotics against
positive symptoms in patients with schizophrenia is achieved
through the blockade of DRD2 in the brain’s mesolimbic system
(Seeman, 2002). A chronic and excessive blockade of DRD2 by
antipsychotics leads to a reciprocal increase in DRD2 density, a
phenomenon which essentially underlies the etiology of DSP
(Iyo et al., 2013). Numerous basic studies have demonstrated that
a blockade of DRD2 by typical and atypical antipsychotics
increases DRD2 densities and eventually behavioral supersensi-
tivity and TD-like movements (Köhler et al., 1994; Samaha et al.,
2007; Vasconcelos et al., 2003). In clinical practice, it is well
known that DSP frequently occurs particularly in patients under
polypharmacy with high-potency antipsychotics (Chouinard and
Chouinard, 2008). In fact, haloperidol (a prototype of a high-
potency typical neuroleptic) induced a significant increase in
DRD2 densities in rodent models (Samaha et al., 2007; Tadokoro
et al., 2011; Vasconcelos et al., 2003). In addition, a PET study of
patients who had been taking antipsychotics for more than a few
months suggested an increase in the density of striatum DRD2
(Silvestri et al., 2000).
Although the mechanism of DRD2 up-regulation has not yet
been clarified, DRD2 internalizes from the surface of neurons by
a DRD2 agonist such as dopamine, and then one part of DRD2 is
broken down within the neurons and the other part is recycled
again in the membrane of neurons (Beaulieu and Gainetdinov,
2011). It has been suggested that antipsychotics disrupt the inter-
nalization of DRD2, which could be related to the receptor up-
regulation (Figure 1).
Iyo et al. (2013) constructed a mathematical theory regarding
DSP from the viewpoint of the up-regulated level of DRD2 and
the corresponding responsiveness to antipsychotics, they argued
that antipsychotic(s) do not provide a beneficial effect in patients
with increased DRD2 density, which is indeed sometimes
observed in clinical settings. In general, the appropriate occu-
pancy rate of DRD2 in the striatum by an antipsychotic is from
1514 Journal of Psychopharmacology 31(12)

Figure 1.  Schema of relationship between the sensitivity in DRD2 and clinical picture of schizophrenia.
(a) Level of dopamine (DA) neurotransmission: In untreated patients or patients under acute psychosis (both first psychotic episode and relapse episode), dopamine
neurotransmission is activated, whereas in improved patients with few positive symptoms (generally due to appropriate pharmacotherapy) the neurotransmission is
attenuated. (b) Post-DRD2 sensitivity: Numerous animal studies demonstrated that antipsychotic administration causes increased post-DRD2 sensitivity to endogenous
dopamine (supersensitivity), which may be promoted particularly by high-dose treatment. The post-DRD2 up-regulation is presumed to be related to the acquired
supersensitivity. (c) Clinical DSP: The supersensitivity of DRD2 appears as clinical dopamine supersensitivity psychosis (DSP) in patients in this state (i.e., overt DSP).
The clinical DSP may be masked if further higher-dose antipsychotic(s) are continuously administered (covert DSP). On the other hand, patients who have continued to
show a very good clinical course, generally under appropriate dosage (< 600 mg in chlorpromazine-equivalent dose) rarely experience clinical DSP. (d) Clinical course and
disease severity: Clinical DSP is traditionally defined as rebound psychosis, tolerance to the effect of an antipsychotic, and tardive dyskinesia. In addition, these classical
DSP symptoms are tightly connected to further high-dose treatment or an unstable clinical course, progressing to treatment-resistant schizophrenia. The solid square
range indicates high-dose antipsychotics’ effects promoting clinical DSP. The dashed square range indicates the presumed phenomenon at the receptor or synaptic levels,
which cannot be observed clinically.

65 to 78%, based on the measurement by PET studies of drug-
naïve patients (Kapur et al., 2000). The occupancy range, also
called the “therapeutic window”, is the range that would provide
the best balance of a significant amelioration of psychotic symp-
toms and less EPS. Iyo et al. (2013) also calculated that under a
dopamine supersensitivity state with the advent of DRD2 up-reg-
ulation caused by a chronic excessive blockade by antipsychotics,
the therapeutic window was positively related to the DRD2 den-
sity, and when antipsychotics bind with DRD2, the therapeutic
window would shift to a higher and more narrow range compared
to the range under the standard state. That is, a higher dosage of
antipsychotics becomes necessary to achieve the occupancy level
that will provide an amelioration of psychotic symptoms in
patients in a dopamine supersensitivity state. Such a narrow thera-
peutic range also indicates a higher risk of developing EPS.
When antipsychotics dissociate from DRD2, the density
which has already increased due to previous treatment, tapering
off medication or discontinuation by patients themselves, or the
binding of dopamine with available DRD2 stimulates the emer-
gence of a DSP episode. In patients under high-dose treatment,
the occurrence of a DSP episode could provide a larger fluctua-
tion in the blood concentration of the antipsychotic(s). In this
situation, if a greater amount is administered to address the DSP
episode, the concentration could exceed over the upper threshold
of the therapeutic window, but if a sufficient amount of the
antipsychotic is not given, or self-discontinuation by the patient,
or switching to another agent is conducted, the concentration pro-
vided by the dose may be under the lower threshold. This puta-
tive mechanism of DSP theory has been explained in detail in
other literature (Iyo et al., 2013).
DRD2s exist in two physiologically different states: D2High
and D2Low receptors. In studies of mainly animal models, it was
suggested that the number of DRD2s in the functional high-affin-
ity state (D2High) is increased, particularly in the dopamine
supersensitivity state (Seeman, 2011). In humans at the whole-
brain level, this possibility has not been determined. These
notions suggest that physiological and/or structural changes of
DRD2, but not simply its density, are also involved in the devel-
opment of DSP. Moreover, it was recently reported that the acti-
vation of 5-HT2A receptors by antipsychotics was required for
the full expression of neuroleptic-induced DSP in an animal
model (Charron et al., 2015). To date, however, the complete
mechanism at the molecular level underlying the DSP phenome-
non has not been clarified (Oda et al., 2015).
Treatment strategies for DSP
From the viewpoint of the prevention of the development of DSP,
it is important for physicians to recognize from an early point of
management that the higher the dosage of high-potency
Nakata et al. 1515
antipsychotic the higher risk of the up-regulation of DRD2
(namely, the risk of a dopamine supersensitivity state). Thus,
avoiding the excessive blockade of DRD2 is important to prevent
the emergency of DSP. Signs of EPS should be monitored care-
fully, especially in the early phase of treatment, since the appear-
ance of EPS is a risk factor for the development of DSP (Iyo
et al., 2013). Borderline EPS and anhedonia in particular are
warning signs of an initial step toward the development of the
dopamine supersensitivity state. Since the appearance of EPS
implies an excessive blockade of striatum DRD2, physicians
should recognize that EPS is an initiative sign of the development
of a dopamine supersensitivity state, or in latent state. For this
reason, since treatment with atypical antipsychotics result in EPS
less frequently compared to typical antipsychotics (Haddad et al.,
2012; Peluso et al., 2012), the former are more advantageous for
preventing DSP.
Aripiprazole is an atypical antipsychotic with a unique DRD2
partial agonist profile. Several clinical trials demonstrated that
aripiprazole treatment results in significantly less EPS in patients
compared to other atypical antipsychotics (Citrome, 2006; Kane
et al., 2007), suggesting that aripiprazole does not cause an
excessive blockade of DRD2, even at a high dose. Several basic
studies in cell and animal models showed that aripiprazole did
not increase the DRD2 density, which is a clearly different result
from that obtained with typical antipsychotics (Inoue et al., 1997;
Tadokoro et al., 2011). These findings suggest that aripiprazole
treatment does not lead easily to the development of DSP.
Although aripiprazole is theoretically effective as the initial man-
agement to prevent the development of DSP, rebound psychosis
has been reported in DSP patients starting on aripiprazole treat-
ment. Switching to aripiprazole (particularly for patients with
both a history of a DSP episode and over 600mg CPeq. dose
treatment) needs more careful attention, since the switching pro-
cess presents a high risk of the emergence of rebound psychosis
(Takase et al., 2015; Takeuchi et al., 2009). As there is a lack of
clinical evidence regarding aripiprazole for DSP treatment, ari-
piprazole should be used carefully under observation for the
emergence of DSP episodes.
Similarly, the use of an antipsychotic agent with loose binding
to DRD2 (such as quetiapine, but not clozapine) should be avoided
when treating patients with established dopamine supersensitivity,
since the binding of this type of agent could be defeated with
endogenous dopamine in comparative binding to DRD2.
Quetiapine, as well as aripiprazole, may be advantageous in the
prevention of the development of dopamine supersensitivity.
The half-life of the agent must be considered when selecting
an antipsychotic. When two agents with half-lives of differing
length provide the same occupancy level of DRD2, the agent
with the longer half-life will result in a smaller fluctuation of the
blood concentration compared to the other agent (Mannaert et al.,
2005). Under treatment with the agent with the shorter half-life,
there can be a period of time when the drug concentration exceeds
the upper range of the therapeutic window (at the peak level), and
thus an excessive blockade of DRD2 and/or EPS easily occurs.
For the treatment of patients in a dopamine supersensitivity
state that was established during previous treatment, it is crucial
to consider the content of each DSP episode, including its trigger,
causal agent and severity. Iyo et al. (2013) proposed that antipsy-
chotics with a longer half-life and smaller peak-to-trough fluctu-
ation in blood concentration should be used instead of other
agents for the type of dopamine supersensitivity state in which
the therapeutic window is shifted upward and narrowed. This
idea is in opposition to the fact that antipsychotics with a shorter
half-life, high potency, and higher dosages can promote the risk
of the dopamine supersensitivity state. In this context, a long-
acting injectable (LAI) or an osmotic controlled release oral
delivery system (OROS; e.g., paliperidone), both of which have
a smaller peak-to-trough fluctuation compared to classical oral
agents, can provide beneficial effects for patients in a dopamine
supersensitivity state (Kimura et al., 2014, 2016).
This advantageous character of longer half-life for DSP treat-
ment may be true for blonanserine, an atypical antipsychotics,
which has been approved in Japan and Korea. Blonanserine has
higher affinity to DRD2 compared to haloperidol or risperidone,
and furthermore, has high lipophilicity and inhibits P-glycoprotein
(Inoue et al., 2012). These profiles can contribute to the longer
half-life of approximately 70 hours in repetitive administration,
compared to 16 hours in a single administration (Tenjin et al.,
2013), which may be valid as an agent with a smaller peak-trough
fluctuation in blood concentration. Actually, Tachibana et al.
(2016) reported that blonanserine was efficacious for patients
with DSP. In their case series, blonanserine was adjunctively
added to high-dose antipsychotics in eight patients with DSP, and
then the dosage of the patients’ previously administered agents
was gradually and carefully decreased. This one-year treatment
resulted in significant improvements in the patients’ Brief
Psychiatric Rating Scale (BPRS) scores compared to the base-
line; i.e., 80.0 to 57.8 at 1 year.
Since it has been established that clozapine and electrocon-
vulsive therapy (ECT) are both efficacious for significant num-
bers of TRS patients (Kane et al., 1988; Kho et al., 2004),
Clozapine and ECT would be expected to provide positive effects
for patients with DSP. Clozapine is the only antipsychotic for
which efficacy in cases of TRS has been established. It was
reported that 70% of TRS patients respond well to clozapine
(Fakra and Azorin, 2012). Although clozapine’s mechanisms of
action remains unknown, its efficacy for TRS may include supe-
riority to other antipsychotics regarding DSP and/or the dopa-
mine supersensitivity state. Indeed, accumulated findings
demonstrated that the rate of hospitalization and recurrence rate
of psychotic episodes in patients switched to clozapine treatment
from other psychotics was lower (Stroup et al., 2016). Several
studies reported that patients starting clozapine treatment also
show a lower rate of discontinuation of treatment compared to
patients starting treatment with other antipsychotics (McEvoy
et al., 2006), which may be related to the low recurrence rate. In
addition, clozapine’s higher efficacy for TD was observed (Louzã
and Bassitt, 2005; Small et al., 1987). When clozapine treatment
is initiated, the CPeq. dose of clozapine is generally reduced from
the dose of the previous agents (Lewis et al., 2006). All of these
findings indicate that clozapine could become an option for DSP
treatment (Chouinard et al., 1994; Nakata et al., 2016).
As other possible treatment options, there have been several
reports that demonstrated the effectiveness of treatment with an
adjunctive mood stabilizer such as valproate or with asenapine.
Regarding the beneficial effect of sodium valproate, the fluctua-
tion in the blood concentration of an antipsychotic between its
peak and trough could produce the kindling effect in the brain by
non-electrical stimulation, and rarely, this phenomenon could
lower the seizure threshold. Chouinard and Sultan (1990)
1516 Journal of Psychopharmacology 31(12)
hypothesized that antiepileptic agents including sodium valproate
can contribute to the prevention of DSP through an active mecha-
nism against the kindling effect. Compared to other atypical antip-
sychotics, asenapine has shown the tightest binding to 5-HT2A.
The involvement of this receptor-binding profile in treatment of
DSP is not yet known, but a case was reported in which asenapine
improved a patient’s DSP episode that had been caused by ziprasi-
done (Rajkumar, 2014).
Conclusion
DSP induced by long-term exposure to antipsychotics, is an
important considerationa in the pharmacotherapy of patients with
schizophrenia, even in the era of treatment with atypical antipsy-
chotics. This phenomenon is a serious problem, which could
sometimes be misunderstood as a developing process toward dis-
ease refractoriness. Its underlying mechanism is related to the
compensatory up-regulation of DRD2 in the brains of patients.
As regards to treatment for DSP, the preventive viewpoint of
avoiding excessive blockade of DRD2 by high-dose antipsychot-
ics is important. For patients who have already established the
dopamine supersensitivity state, treatment with an agent with a
long half-life, dopamine partial agonist or clozapine can be
potential options in terms of masking additional occurrence of a
DSP episode or lessening the supersensitivity of DRD2.
Declaration of conflicting interest
The author(s) declared the following potential conflicts of interest with respect
to the research, authorship, and/or publication of this article: Dr. Kanahara
reports honoraria from Eli Lilly, Otsuka, Dainippon Sumitomo, Janssen and
Meiji Seika Pharma. Dr. Iyo received consultant fees from Janssen, Eli Lilly,
Otsuka, Meiji Seika Pharma and reports honoraria from Janssen, Eli Lilly,
Otsuka, Meiji Seika Pharma, Astellas, Dainippon Sumitomo, Ono, Mochida,
MSD, Eisai, Daiichi-Sankyo, Novartis, Teijin, Shionogi, Hisamitsu and Asahi
Kasei. Dr. Nakata declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: Funding from
Japan Agency for Medical Research and Development.
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