Behavioural Brain Research 403 (2021) 113126

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Behavioural Brain Research

journal homepage: www.elsevier.com/locate/bbr

Review

Rationale and neurobiological effects of treatment with antipsychotics in

patients with chronic schizophrenia considering dopamine supersensitivity
Hiroshi Kimura a, b, c, *, Nobuhisa Kanahara b, d, Masaomi Iyo b
a
Department of Psychiatry, School of Medicine, International University of Health and Welfare, Chiba, Japan
b
Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
c
Department of Psychiatry, Gakuji-kai Kimura Hospital, Chiba, Japan
d
Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: The long-term treatment of patients with schizophrenia often involves the management of relapses for most
Antipsychotic patients and the development of treatment resistance in some patients. To stabilize the clinical course and allow
Dopamine as many patients as possible to recover, clinicians need to recognize dopamine supersensitivity, which can be
Long-acting injectable antipsychotics (LAI)
provoked by administration of high dosages of antipsychotics, and deal with it properly. However, no treatment
Dopamine partial agonist
Clozapine
guidelines have addressed this issue. The present review summarized the characteristics of long-acting injectable
Relapse antipsychotics, dopamine partial agonists, and clozapine in relation to dopamine supersensitivity from the
viewpoints of receptor profiles and pharmacokinetics. The potential merits and limitations of these medicines are
discussed, as well as the risks of treating patients with established dopamine supersensitivity with these classes of
drugs. Finally, the review discussed the biological influence of antipsychotic treatment on the human brain based
on findings regarding the relationship between the hippocampus and antipsychotics.

1. Introduction emission tomography (PET) studies demonstrated that in the brains of

The long-term outcome for patients with schizophrenia varies in
terms of their symptoms, social function, and quality of life, and it is
affected by diverse factors including genetic, environmental, and
treatment factors. Although the outcomes of long-term studies seem to
be different depending on their follow-up durations (i.e., 2 years, 5
years, or 10 years), most of these studies indicated that the continuation
of pharmacological treatment with antipsychotics is one of the strongest
factors determining the long-term outcomes of schizophrenia patients
[1–4].
Antipsychotic medication has been the mainstay treatment to miti­
gate the symptoms of schizophrenia. The effectiveness of antipsychotics
has been generally measured for every categorical domain such as
positive symptoms (delusions, hallucinations, disorganized speech,
catatonic behavior), negative symptoms (affective flattening, alogia,
abolition) and cognitive dysfunctions. Accumulating evidence suggests
that dopamine dysregulation is caused by the excess release and/or
synthesis of dopamine in the brains of patients with schizophrenia [5],
and antipsychotics with dopamine receptor D2 (DRD2) antagonist
properties can mainly ameliorate positive symptoms [6,7]. Positron
patients treated with antipsychotics, achieving a DRD2 occupancy rate
of > 65 % with an antipsychotic corresponded to clinical effectiveness
but a DRD2 occupancy rate of >80 % elicited extrapyramidal symptoms
(EPS) [8,9]. Moreover, an antipsychotic achieving a DRD2 occupancy
rate of >80 % may be associated with depressive symptoms and/or
negative symptoms [10,11]; that is, antipsychotics have adequate and
optimal DRD2 occupancy ranges. The therapeutic window for the DRD2
occupancy range holds for all antipsychotics except clozapine, although
various types of antipsychotics have been developed since the intro­
duction of the first antipsychotic medication in the 1950s.
Clinical practice guidelines generally recommend that treatment
with second generation antipsychotics (SGAs) having profiles of DRD2
and multiple 5-TH receptors, which contribute to favorable adverse
events be continued after remission, because a high risk of relapse re­
mains [12–17]. Recently, the middle- and long-term benefits of anti­
psychotics have been questioned due to the occurrence of multiple
adverse events such as EPS and metabolic symptoms [18]. More
importantly, some skepticism of the long-term effectiveness of antipsy­
chotics for treating psychosis itself have been raised, whereas accumu­
lating evidence has emphasized the necessity of antipsychotics for

* Corresponding author at: Department of Psychiatry, International University of Health and Welfare, 852 Hatakeda, Narita, Chiba, 286-8520, Japan.
E-mail address: hkimura@iuhw.ac.jp (H. Kimura).

https://doi.org/10.1016/j.bbr.2021.113126
Received 2 October 2020; Received in revised form 29 December 2020; Accepted 4 January 2021
Available online 15 January 2021
0166-4328/© 2021 Elsevier B.V. All rights reserved.
H. Kimura et al.
improving acute psychosis [19–21]. Dopamine supersensitivity (DS) or
dopamine supersensitivity psychosis (DSP) is the representative delete­
rious effect of long-term antipsychotic treatment on patients’ outcomes
[19], which is related to rebound psychosis, withdrawal discontinuation
syndromes and tardive dyskinesia [22]. This phenomenon, derived from
the effects of switching, decreasing and discontinuing antipsychotics,
constitutes a common and serious problem for psychiatric patients and
physicians.
Actually, there are some patients in whom the dose of antipsychotics
is gradually increased over the time [23], whereas low-dose antipsy­
chotics are sufficient to prevent symptoms after remission in other pa­
tients [24,25]. Multiple relapses tend to lead to a gradual increase in the
medication dose during a course of illness [1]. Correll and his colleagues
described that short-term follow-up studies (< 3 years) demonstrated
that continuous treatment with antipsychotics evidently diminishes the
likelihood of relapses, but some long-term longitudinal studies did not
demonstrate a significant difference in symptomatic outcomes between
antipsychotics-treated patients and patients who drop out of treatment
[20], casting some doubt on the long-term efficacy of antipsychotic
treatment. However, the relationship between the continuous adminis­
tration of antipsychotic medication and the long-term prognoses of pa­
tients is difficult to address because most studies had substantial
methodological limitations, including small sample sizes, selection bias
of the studied patients, and uncontrolled treatment in continuous
treatment cohorts. Besides all these limitations, a greater reason for the
difficulty in addressing the concerns regarding the long-term efficacy of
antipsychotics is a scarcity of direct biological evidence showing nega­
tive effects of antipsychotic medication on the human brain. Numerous
magnetic resonance imaging (MRI) studies have been carried out to
examine the possible deleterious effects of antipsychotics on patients’
brains (e.g., volume reduction), but these studies have not yet yielded
robust conclusions [26,27]. Thus, more rigorously designed, long-term
prospective studies are needed to clarify the long-term effects of anti­
psychotic medication in the treatment of patients with schizophrenia
[28].
Based on the accumulating evidence suggesting varying clinical
courses among patients and varying treatment responses to antipsy­
chotic(s) among patients or among disease stages [29–34], in selecting
an appropriate agent from among various types of antipsychotics for a
given patient with schizophrenia in clinical practice, clinicians are al­
ways required to determine the targeted symptom(s), to assess the
severity, and to predict the patient’s responsiveness to the selected agent
at each stage of illness, all the while considering the clinical guidelines
for the treatment of schizophrenia. In particular, to maximize the po­
tential benefit of long-term treatment with antipsychotics and to mini­
mize risks of adverse events including DSP, it is important for clinicians
to repeatedly evaluate the selected agent’s dose in terms of its efficacy
and adverse events, and to carefully balance its merits and demerits.
This article provides a brief overview of the pharmacokinetics and
pharmacodynamics of antipsychotics treatment focused on DSP and its
relevant issues which determine the middle- and long-term prognosis of
schizophrenia patients. We then describe potential roles and limitations
of the candidate antipsychotics (i.e., long-acting injectable (LAI) anti­
psychotic, dopamine partial agonist and clozapine) in treatments of
patient with schizophrenia; while such drugs have been used clinically
to treat mood symptoms in those with mood disorders, we exclude them
from our discussion in order to avoid the complications introduced by
differences in pathophysiological mechanisms. Although many phar­
macological guidelines have become available to provide practical an­
swers in clinical settings, clinicians might still need to make judgements
based on their experience when attempting to address problems for
which insufficient published evidence exists. Thus, understanding well
some different profiles among SGAs may help clinicians to overcome
such difficult treatment situations.
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Behavioural Brain Research 403 (2021) 113126
2. Concept of dopamine supersensitivity psychosis
Antipsychotic medications have proven to be effective for positive
symptoms of patients after relapse and at early stages of antipsychotic
treatment. Even if remission is successfully induced by antipsychotics,
long-term treatment with antipsychotics can elicit a DS state in patients.
DS has been described as a compensatory alteration to chronic
antipsychotic treatment [35,36]. The clinical features of DSP include
rebound psychosis upon the rapid cessation or reduction of antipsy­
chotic therapy, episodes indicating tolerance to the effects of antipsy­
chotics, and/or increased vulnerability to minor stress [37–40].
Additionally, tardive dyskinesia is one of the representative clinical
signs of a DS state [36,37]. Because DSP can develop after long-term
treatment with an excessive dose of antipsychotics and lead to multi­
ple relapses during the course of the illness, understanding DSP is a
pivotal factor in elucidating the vulnerability to relapse in
schizophrenia.
To confirm DSP and related psychosis, it may be necessary to clarify
the existence of brain DRD2 up-regulation following long-term treat­
ment of high dose antipsychotic drugs and its relation with clinical
symptoms, suggested by the results of a preliminary PET study [41].
However, in living human brain and post-mortem brain studies, it has
not been clearly demonstrated that antipsychotics directly induce the
upregulation of DRD2s. Despite this, preclinical studies using animals
have suggested that antipsychotics are associated with the upregulation
of DRD2s in the striatum [42–47]. Indeed, these animal studies have
demonstrated that haloperidol increases DRD2 in the striatum and
evokes behavioral abnormalities related to schizophrenia. The level of
sensitivity in the DS state depends on the properties of the antipsychotics
used, including the affinity for DRD2s and the area under the
concentration-time curves for each of the antipsychotics [48]. Although
all antipsychotics including clozapine may become potential causative
agents of a DS state [48], high dosages of antipsychotics with a high
affinity to DRD2s are most likely to evoke a DS state.
Although it has been well established in animal model studies that
the DS state is a compensatory response to antipsychotics, this has
recently become more controversial due to the lack of evidence on any
direct association between brain alterations and antipsychotics in in vivo
human studies [49,50]. Some of the reasons for the lack of evidence
might include the complexity of identifying the pathophysiological
mechanism underlying the DS and/or DSP state due to the existence of
numerous and unknown confounding factors that affect the alteration of
the human brain during lifelong treatment with antipsychotics. How­
ever, some studies have suggested some candidate mechanisms for the
development of a DS state. As one of the candidate mechanisms, DSP is
assumed to underlie a high-affinity state for dopamine that is elicited by
the coupling of striatal D2-like dopamine receptors to G proteins, the
so-called D2high state [51–53]. The D2high state can elicit greater acti­
vation in the downstream region [54]. In addition, 5-HTergic neuro­
transmission might be related to the development of the DS state
because an animal model study showed that the administration of
5-HT2A agonists or antidepressants was associated with improvement of
the DS state [55]. In addition, considering that the DS state is likely to
persist in young rats relative to adult rats [56], the severity of the DS
state might depend on age at the disease onset or the duration spent
taking the medication. Taken together, these data may suggest that the
DS state is evoked by broadly overlapping effects in neurotransmitter
systems other than the mesolimbic dopamine system and the severity of
the DS state might depend on the antipsychotic regimen and the pa­
tient’s background.
The DS state is generally evoked by the administration of antipsy­
chotics for more than 5 consecutive days in an animal model of
schizophrenia. Although, in humans, the threshold dose and duration of
antipsychotic treatment for developing a DS state are unknown, there
are clinical signs of manifestations associated with the DS state: EPS at
the initial treatment and continuous high dosage treatment with
H. Kimura et al.
antipsychotics (generally a more than 600 mg/day chlorpromazine
equivalent (CPZE) dose) [36,57]. Some researchers include hyper­
prolactinemia and water intoxication syndrome as one of the clinical
phenotypes of a DS state [37,58,59]. In terms of the clinical course prior
to the development of DSP, antipsychotics are effective in some patients
at the beginning of treatment, and the patients then remain in a stable
state with high-dose antipsychotics (more than 600 mg/day CPZE doses)
for a few years. But after this period, the patients present with an overtly
unstable state such as rebound psychosis, which is caused by multiple
triggers or clinical situations (i.e., switching or dose reduction of anti­
psychotics due to side effects or for other reasons).
A recent review suggested that the DS state may reflect etiological
processes of treatment resistant schizophrenia (TRS) [60]. Although the
decision to undergo a retrial or to further increase the dosage of anti­
psychotics is common for rebound psychosis in clinical practice, such
changes do not always contribute to persistent remission in patients who
have developed DS. That is, this state implies the development of
treatment resistance to antipsychotics. These findings have renewed
interest in the question of whether increasing the dosage of antipsy­
chotics leads to substantial clinical improvement. Although there are
findings that long-term antipsychotic treatment and immediate discon­
tinuation of antipsychotics is not likely to provoke rebound psychosis
and DSP [12,61–63], our research has demonstrated that 72 % of the
TRS patients examined had experienced at least one DSP episode pre­
viously in Japan, where very high-dose of antipsychotic use (mean daily
dose 1033.8 mg chlorpromazine equivalent dose) in schizophrenia have
been reported [64,65]. On the other hand, only 21 % of non-TRS pa­
tients experienced a prior DSP episode, indicating that the occurrence of
a DSP episode is strongly linked to TRS [66,67]. However, some skep­
ticism of the DSP theory was recently raised [20,50,68], regardless of
the abundant evidence for it mainly in animal studies, so more clinical
studies are urgently needed.
3. Treatment of dopamine supersensitivity psychosis
It has been suggested that DSP is induced by an excess of DRD2s
occupancy by antipsychotics and that treatment with high doses of an­
tipsychotics with short half-lives is more likely to result in DSP
compared to treatment with antipsychotics with long half-lives such as
LAIs [36]. In this context, LAI antipsychotics, which are antipsychotics
with a longer half-life but not an acute elevation of the drug concen­
tration, play a role in steadily blocking DRD2s. Therefore, the use of LAIs
may prevent the development of DSP in patients.
One of the pharmacokinetics features of LAIs includes a narrow peak-
to-trough fluctuation. The gap between the peak and trough blood
concentrations of risperidone-LAI (RLAI) (i.e., Cmax/Cmin) is 32%–42%
smaller than that of oral risperidone providing they show an equivalent
occupancy level of the brain’s DRD2 [69]. The peak-to-trough fluctua­
tion in plasma concentration over the recommended dosing interval of
oral risperidone and RLAI are 3.30 and 1.70, respectively [70], sug­
gesting that this ratio might be a useful metric in selecting an antipsy­
chotic for patients with DSP.
This indicator is 1.56 for paliperidone LAI, 1.21～1.41 for oral par­
iperidone (half-life time: 25.4 h), 1.13 for blonanserin (half-life time:
67.9 h), and 1.14 for oral aripiprazole (half-life time: 64.59 h) [70–72].
Although this indicator for asenapine is unclear, its half-life time is
relatively longer at 35.5 h, suggesting a less broad fluctuation of the
blood concentration [73]. In addition, blonanserin and asenapine have
profiles with high lipid solubility (i.e., high coefficients of partition),
leading to longer half-life times with repeated administration compared
to that with a single administration. On the other hand, the fluctuation
ratios for quetiapine (half-life time: 3.5 h) and perospirone (half-life
time: 1.7 h) are 10.8 and 11.1, respectively [74], which imply wider
fluctuations of the concentration. The former groups of agents with
smaller fluctuations might contribute to the stabilization of symptoms in
patients with DSP. However, to date, there have been no studies
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Behavioural Brain Research 403 (2021) 113126
prospectively comparing the development of DS among agents with
different half-life times.
We conducted the study to elucidate the effectiveness of an LAI, with
its relatively small peak-trough fluctuations in the blood concentrations
of antipsychotics, for patients with DSP. In this study, RLAI was given as
an adjunctive medication to oral antipsychotics in 108 patients with
TRS: 72 patients with a history of DSP (the DSP group) and 36 patients
without such a history (the non-DSP group). Although both groups
showed significant improvements in the total Brief Psychotic Rating
Scale score in the 2-year follow-up period, greater improvement was
observed in the DSP group compared to the non-DSP group (P < .05).
The total dose of antipsychotics including the dose of RLAI and/or oral
antipsychotics did not change in either group throughout the study
period. It should be noted, however, that the severity of EPS, including
tardive dyskinesia, was significantly improved only in the DSP group.
SGA in long-acting forms, such as RLAI, can provide beneficial effects for
patients with DSP [75,76].
In summary, in the treatment of patients with developed DS and/or
with DSP, LAIs can be a promising option in seeking to avoid further
increases in the dosage of antipsychotics and to prevent further acquired
vulnerability to relapse. This hypothesis is true of oral antipsychotics
with long half-life times. Such antipsychotics include paliperidone,
blonanserin, and asenapine, which have half-life times of over 24 h, but
there is insufficient evidence that they have merit in the treatment of
DSP. Furthermore, there are many patients under treatment with dos­
ages of antipsychotics over a CPZE of 1000 mg, leading to complex
regimens for subsequent treatment. It is uncertain whether these LAIs or
longer half-life time oral agents can downregulate DRD2s in patients
with DSP, and whether these patients will or will not develop further
DSP.
4. Long-acting injectable antipsychotics
4.1. An option to improve adherence
Ever since the arrival of FGA-LAIs in the 1960s, LAIs have been
suggested to improve adherence in patients with chronic schizophrenia.
Widespread non-adherence or partial adherence to prescribed oral
medications among patients with schizophrenia was recognized by
medical staff members and patients’ families at the beginning of psy­
chopharmacological era [77]. A lack of insight into their illness is one of
the most common factors underlying poor adherence to medication in
patients with schizophrenia, which is estimated to affect approximately
50 % of patients [78–80]. LAI formulations have become an alternative
to oral formulations to improve adherence. [81].
However, whether LAIs are superior to oral antipsychotics can
depend on the study design when comparing a variety of clinical pa­
rameters. For instance, the relapse-rated outcomes of LAIs in several
pivotal randomized controlled trials (RCTs), have not been superior to
those of oral antipsychotics, although both groups showed significant
improvements relative to their respective baseline scores [82–85]. It has
been generally speculated that the RCT findings of equal outcomes be­
tween both forms of medication can be explained on the basis of the
different treatment environments in the RCTs and in real clinical prac­
tice. RCT studies on LAIs dilute the possible differences in adherence
between the assigned LAI group and the assigned oral group by raising
the adherence level in the former group, and also possibly in the latter
group [86,87].
A well-designed RCT might, however, lead to some underestimation
of the efficacy of LAIs, because most RCT trials have been of relatively
short duration (< 2 years), but treating physicians generally evaluate
patients’ prognoses over a longer time window in clinical practice. A
variety of findings of nonRCT studies and retrospective surveys reflect­
ing real-world clinical practice have shown that patients treated with
LAIs have significantly lower relapse rates than patients treated with
oral antipsychotics [88–93]. Moreover, LAIs were shown to improve the
H. Kimura et al.
long-term prognoses of patients with schizophrenia [94]. Consequently,
LAIs contribute to a reduction of the cost burden of treatment for pa­
tients with schizophrenia [95]. Although a clinical observational study
showed that the initiation of LAI treatment in patients at an early stage
of schizophrenia led to a significantly higher treatment response and
subsequent better social performance [96], there has been scarce evi­
dence as to the adequate timing of the initiation of LAIs and the adequate
duration of treatment with LAIs. These are critical and urgent issues in
clinical practice, as the role of LAIs in pharmacotherapy for the lifelong
treatment of schizophrenia has not yet been clarified.
Recently, studies on the pharmacokinetics of LAI forms of SGAs have
been increasingly reported. LAIs stored in muscle are slowly and steadily
released to the systematic blood flow and pass the blood-brain barrier
without passing through the liver. Unlike oral antipsychotics, which
undergo first-pass metabolism in the liver after digestion in the gastro­
intestinal tract, LAIs have several possible advantages due to this
pharmacokinetic profile. First, the pharmacokinetics of LAIs relatively
enhance their bioavailability compared to oral antipsychotics [96,97].
Second, LAIs have a longer half-life than oral antipsychotics and yield
more stable blood concentrations, with a narrower difference between
the peak and trough plasma levels compared to that of the oral type of
the same agent [98] (this issue is discussed in detail in the next section).
Third, although there is not sufficient evidence,
LAIs may be able to mitigate the potential risks that are derived from
differences in the functional levels of pharmacokinetic molecules,
including drug-metabolizing enzymes, among individuals (See. 4.2. LAIs
and metabolizing enzymes). Thus treatment with LAIs together with suf­
ficient knowledge of pharmacokinetics might aid in the prediction of
antipsychotic responses including the efficacy and adverse events in a
given patient, although this is true of antipsychotic medication in gen­
eral, and is not limited to LAIs.
4.2. LAIs and metabolizing enzymes
Although the effects of metabolizing enzymes are related to all for­
mations of antipsychotics (not limited to LAIs), the knowledge in this
area is valuable particularly in treatment with LAIs. Most antipsychotic
agents are metabolized extensively by cytochrome P450 (CYP) drug
oxidases including CYP2D6, CYP3A4, and CYP1A2. Patients with poor
metabolism, who lack these enzymes or show poor function of these
enzymes can experience unexpected drug responses due to the higher
bioavailability and higher concentration of the drug compared to pa­
tients with normal enzyme function. In particular, CYP2D6 plays a major
role in the elimination of antipsychotic agents and therefore has been
extensively examined in relation to the association between the genetic
variants and the phenotypes [99]. Poor metabolism of CYP2D6 alleles
with nonfunctional enzyme activity, namely CYP2D6*3,*4,*5,*6, is
found in Caucasians at a relatively high frequency [99,100]. Patients
with poor CYP2D6 metabolism have a higher plasma risperidone con­
centration compared to CYP2D6 Non-poor metabolizers [101–106]. In
addition, patients with poor metabolizing activity have a higher ten­
dency to experience EPS with a possible risk of great severity. Similarly,
lower metabolizing variants of CYP3A4 affect the blood concentration of
aripiprazole, and this can also have some impact on adverse events
during treatment with aripiprazole, which is metabolized by CYP2D6
and CYP3A4 [107]. A recent large-scale retrospective study demon­
strated that the incidence of treatment failure in patients with low
CYP2D6 activity and who were treated with risperidone or aripiprazole
was significantly higher compared to those who have other enzyme
functions [108].
Subjects with homozygotes of variants with slightly weak metabo­
lizing activity such as CYP2D6 *9, *10, and *41 or heterozygotes of
slightly weak variants and wild-type variants (CYP2D6 *1, *2) are
generally classified as extensive metabolizers. However, even extensive
metabolizers can have higher concentrations of the medication, partic­
ularly under treatment with risperidone, although this is dependent on
4
Behavioural Brain Research 403 (2021) 113126
the specific variants. East Asians have one or two alleles of CYP2D6 *10
at a relatively high rate of 35–45 % [109], and such patients must be
monitored carefully when treated with risperidone. Indeed, our study on
patients who were treated with long-term risperidone showed that pa­
tients with one or two alleles of CYP2D6*10 had higher blood concen­
tration of risperidone and had more often DSP episodes compared to
those without the allele [110]. Although literature has noted that ris­
peridone and 9-OH-risperidone were not different in pharmacological
effects [111], the higher emergent rate of adverse events including EPS
in poor metabolizers under treatment with risperidone might imply that
risperidone contributes greatly to adverse events compared to
9-OH-risperidone.
Taken together, the property of LAIs to cross the blood-brain barrier
without passing through the liver may provide specific advantages over
oral antipsychotics in some patients. However, this advantage of LAIs
does not apply to all patients with varying phenotypes of drug-
metabolizing enzymes in the liver. Only a relationship between certain
phenotypes and certain antipsychotics was clearly demonstrated, and
further study of this relationship would surely provide useful informa­
tion for clinicians and patients considering treatment with LAIs.
5. Dopamine partial agonists
Aripiprazole was first approved as dopamine partial agonist by the
FDA in the US in 2002. To date, brexpiprazole and cariprazine have been
available in clinical practice, which has led to the establishment of a
distinctive class (i.e., dopamine partial agonist) of antipsychotic agents.
Dopamine partial agonists have properties of D2 partial agonists and
display a unique mechanism of action among SGAs [112]. Physicians
need to understand their respective pharmacological profiles, which are
different from those of other classes of antipsychotics and from each
other, to maximize the treatment effects of this class.
Dopamine partial agonists function as antagonists when their
endogenous activity as agonists is low, which is similar to how general
antipsychotics antagonize DRD2s, and therefore there are risks of EPS
and hyperprolactinemia. On the other hand, agents in this class function
as agonists when their endogenous activity is high, whereby the po­
tential risks of EPS and hyperprolactinemia are low, but the antipsy­
chotic action is also low [113,114]. In vitro study to examine the degree
of partial agonism assesses the inhibition of cAMP accumulation induced
by folscholine in cells expressing human dopamine D2L receptors. Such
an examination showed that aripiprazole and brexpiprazole inhibited 61
% and 43 % of cAMP accumulation, respectively, compared to dopa­
mine’s ability [115], suggesting that the endogenous activity of brex­
piprazole is two-thirds that of aripiprazole.
It was demonstrated that aripiprazole occupies > 80 % of DRD2s in
human brains in the dose range (>10 mg) used in clinical practice
[116–118]. Aripiprazole has a lower risk of EPS due to its high partial
agonism. These advantages of this drug could help prevent the devel­
opment of DSP. Indeed, in an animal model, aripiprazole did not induce
DSP [47], unlike other types of antipsychotics. Numerous clinical data
indicated that aripiprazole causes little hyperprolactinemia, as it even
further decreases prolactin compared to the level of healthy subjects,
supporting certain clinical advantages for DSP [119,120]. In addition,
metabolic symptoms including body weight gain, hyperlipidemia,
increased glucose level, and diabetes mellitus, are not common,
although these problems are common with SGAs [121]. In a retrospec­
tive cohort study, the time to discontinuation of treatment with aripi­
prazole was significantly longer than those of other second-generation
antipsychotics such as risperidone or olanzapine [122]. Although these
characteristics of aripiprazole can contribute to longer-term continuity
of pharmacotherapy in patients without development of DS, clinical
caution is recommended in the initiation of aripiprazole for patients
with DS.
It has been reported that an acute exacerbation of symptoms can be
provoked when switching from another antipsychotic to aripiprazole or
H. Kimura et al.
when taking aripiprazole as an add-on therapy [123,124]. This phe­
nomenon has been speculated to be associated with the initiation of
dopamine partial agonists in DS state. In patients in a potential DS state,
DSP is likely to be provoked by the adding-on of aripiprazole or
switching to aripiprazole [125], but it may also be attributed to
behavioral toxicity such as increased agitation with antipsychotics in
some patients [126].
Our study [125] showed that patients receiving more than 600
mg/day CPZE of antipsychotic(s) and experienced at least one episode of
DSP failed to switch to aripiprazole due to their symptoms worsening at
a higher rate compared to patients receiving less than 600 mg/day CPZE
and without a past DSP episode (23 % vs. 8%). In addition, 81 % of
patients with a history of DSP episode(s) dropped out due to worsening
symptoms and/or other reasons when switching from another antipsy­
chotic to aripiprazole. On the other hand, 52 % of patients without DSP
episode(s) could successfully continue the aripiprazole treatment after
switching, suggesting that both switching and continuity are reasonably
safe if patients do not develop DSP. Even in the latter group, a few pa­
tients showed worsening symptoms during the switching process or after
switching, but they had been treated with a high dose of an antipsy­
chotic medication, implying that they had developed latent DSP (i.e.,
covert DSP) although there was no evidence of a DSP episode.
Clinicians should pay close attention to the fluctuation of symptoms
when a patient’s treatment is changed to aripiprazole as an add-on or by
switching. If a patient who is taking a high dose of an antipsychotic
develops psychotic worsening after switching to aripiprazole or taking it
as an add-on, this is a sign that the patient may be in a DS state [56]. It is
clinically important for clinicians who prescribe a switch to or add-on of
aripiprazole to gather information on the patient’s medication record
including the history of relapse or the results of switching to antipsy­
chotics. Careless switching to aripiprazole can result in profound psy­
chotic exacerbation, in particular when a patient has had DSP or a latent
DSP state. Likewise, some antipsychotics, such as quetiapine, that have
the property of a low binding affinity for DRD2, may provoke exacer­
bation of psychosis when switching from a high dose of an antipsychotic
having a high binding affinity for DRD2 [36,127]. Regarding the psy­
chotic worsening after the initiation of aripiprazole, two possible clinical
patterns have been proposed: insomnia and/or hyperarousal immedi­
ately after the start of aripiprazole treatment and, as an additional
distinct pattern, acute psychosis a few weeks after aripiprazole initia­
tion. The rebound psychosis caused by the addition of aripiprazole
might be avoided or minimized by a gradual switching procedure
instead of abrupt switching to aripiprazole [128–130].
The initiation of aripiprazole in a once monthly injectable form
(AOM) for patients taking a high dose of antipsychotics would also be a
challenging treatment. It is unknown whether AOM can restore the
upregulation of DRD2 to a normal level or if this form, with its longer-
lasting effect than oral aripiprazole, leads to the worsening of unfavor­
able symptoms. At present, the gradual tapering off of previous anti­
psychotics over a long duration should be encouraged for patients who
under treatment with high doses of antipsychotic drugs [131].
It is possible that brexpiprazole provides a treatment benefit to pa­
tients who would be improved or who are expected to be improved with
aripiprazole, due to its relatively low endogenous activity. The PET
study showed that brexpiprazole with a treatment range of 1− 4 mg
occupied 60–80 % of DRD2/D3s in the human striatum, which was
lower than the occupancy level of aripiprazole [132]. In addition to
these characteristics of brexpiprazole, this agent has a strong binding
affinity to 5HT2A receptors [133], which is related to the benefit of this
medication observed in clinical practice. These characteristics
contribute to a lower risk of EPS and especially akathisia, which is a
serious problem in aripiprazole treatment [134,135].
Furthermore, brexpiprazole was shown to lead to less DSP regardless
of low endogenous activity [136]. Theoretically, rebound psychosis,
which is a serious problem in the case of switching to aripiprazole, might
be lessened when the drug being switched to is brexpiprazole although
5
Behavioural Brain Research 403 (2021) 113126
no data to that point exist because brexpiprazole is relatively new drug
in the market. Since our survey indicated that patients receiving a dose
of over CPeq. 600 mg of medication had high risks of
symptom-worsening with aripiprazole [125], brexpiprazole, due to its
low endogenous activity, might be an efficacious treatment at doses of
CPeq. 600 mg or more, leading to successful switching. A retrospective
study demonstrated that switching to brexpiprazole failed in some pa­
tients receiving doses of 800 mg or greater, whereas patients receiving
doses under CPeq. 800 mg were able to switch successfully [137], sug­
gesting that brexpiprazole can cover patients with treatment under
wider range of dose compared to aripiprazole.
Cariprazine as well as brexpiprazole is a new dopamine D2 receptor
partial agonist. Cariprazine has an approximately 10-times higher af­
finity to DRD3s compared to DRD2s [138], and has lower endogenous
activity compared to aripiprazole [139]. Diddesmethyl-cariprazine, the
main active metabolite of the parent compound, has a longer half-life
time of 2–3 weeks and has at least half of the endogenous activity of
brexpiprazole [140]. Therefore, cariprazine is also less likely to cause
DSP and to have a benefit for more patients receiving a wider range of
dosages of their previous medication, although there are currently not
enough clinical data to conclude that this drug is appropriate in DSP.
To our knowledge, little data has been reported on brexpiprazole and
cariprazine with respect to DSP and relevant topics, and particularly on
switching to these two agents, which are included as an urgent need in
clinical practice.
6. Clozapine
Clozapine was the first antipsychotic to demonstrate efficacy (70 %)
for TRS [141]. Clozapine simultaneously causes multiple neurochemical
actions through various receptors including the dopamine (D1-D5), se­
rotonin (5-HT1A/1D, 5-HT2A/2C, 5-HT3, 5-HT6, and 5-HT7), hista­
minergic (H1-H3), muscarinic (M1-M5), adrenergic (α1 − 2 and β1− 3),
and GABAA receptors [142,143]. However, the detailed action mecha­
nism of the agent that accounts for the higher efficacy of clozapine
compared to all other antipsychotics has not been clarified as yet. In
addition, clozapine has risks of agranulocytosis, myocarditis, diabetes
mellitus, pneumonia, and other illnesses, which can have a lethal effect
[144]. In some countries, it has long been pointed out that clozapine was
underused in patients who should have been candidates for treatment
with this agent, since patients, their families, and even treating physi­
cians have strong reservations about clozapine due to the multiple po­
tential adverse events and the requirement for regular blood monitoring
[145]. These reservations may be related to the unidentified action
mechanism of clozapine.
It was demonstrated that the DRD2 occupancy rate of clozapine in
the striatum in human brains was at the most ~70 %, and the maximum
occupancy level was limited to a very short time period [146]. The high
efficacy of clozapine is unlikely to be attributable to the adequate DRD2
occupancy of the agent, unlike other antipsychotics, possibly except for
quetiapine. Thus it is difficult to explain the main action mechanism of
clozapine simply based on the blockade of DRD2s. However, several
studies reported that the occupancy rate of DRD2/D3s by clozapine
could be higher in the extrastriatum regions than in the striatum
[147–149].
The main mechanism of clozapine action has been proposed to be
either a higher affinity receptor rate of 5-HT2A/DRD2, which is an
atypical profile of the most extreme nature, and/or a faster dissociation
from DRD2s [8,150]. The action of its main active metabolite (norclo­
zapine) and the blockade of DRD4 by clozapine have been also discussed
[151–153]. Despite these extensive studies and discussions, it remains
uncertain whether these factors are involved in the efficacy of clozapine.
The perspective of DSP can partly explain the mechanism of cloza­
pine action. A study reported that clozapine, like aripiprazole, did not
cause DRD2 up-regulation at cell levels [154]. On the other hand,
several animal models showed behavioral supersensitivity caused by
H. Kimura et al.
clozapine [155,156]. Past studies have shown that clozapine greatly
improved tardive dyskinesia which was caused by previous medications
[157]. Clozapine generally causes fewer EPS, with improvements not
limited to the improvement in tardive dyskinesia [158], and that it
greatly improved symptoms of DSP [159,160]. These findings strongly
suggest that clozapine exhibited high efficacy against psychosis and EPS,
at least partly by stabilizing dopamine transmission [161]. However, it
is uncertain whether clozapine down-regulates the supersensitive
DRD2s or normalizes the synthesis/release of dopamine from presyn­
aptic dopaminergic neurons. Thus, it is possible that clozapine partially
mitigates any supersensitivity of DRD2s that has been caused by previ­
ous medications, but this has not been confirmed.
On the other hand, O’Connor’s review of animal studies regarding
the association between clozapine and gamma-aminobutyric acid
(GABA) transmission demonstrated that the rebound psychosis pro­
voked by drug withdrawal after chronic clozapine treatment was due to
the reduction of GABA levels in the ventral tegmental area. [162] This
suggests that clozapine would not normalize the sensitivity of DRD2s.
[163].
Despite some relevant findings of clozapine improving DSP, a full
explanation of clozapine’s high efficacies against diverse symptom do­
mains has not yet been provided. For instance, clozapine was demon­
strated to exhibit high efficacy in treating aggressive symptoms and
suicide-related symptoms [164–167]. These findings suggest the
possible involvement of the action of 5-TH receptors in the positive ef­
fects of clozapine on these behavioral symptoms. Some patients with
TRS have severe negative symptoms and/or cognitive impairments
(including social cognitive impairments). To date, clozapine’s effects on
these two domains have been unclear. Although several trials showed
that negative symptoms were improved to some degree in patients
receiving clozapine treatment [167], some researchers questioned the
true effect of clozapine since it could improve only secondary negative
symptoms via improving positive symptoms or lessening EPS [167].
Similarly, this is true of cognitive impairments: some studies showed
significant improvements in certain cognitive domains [168], but others
failed to show the significant gains [169,170]. However, these studies
had the common limitations of a small number of subjects and
short-term follow-up. The inclusion of patients with severe psychopa­
thology can be likely to lead to heterogeneous results because the factors
that contribute to poor response to antipsychotics are various.
Several recent studies pointed out that delaying the introduction of
clozapine could have negative impacts on patients’ responsiveness to
clozapine [171–173]. These findings imply that the earlier clozapine is
introduced after the patient meets the criteria for TRS, the greater the
improvements brought by clozapine are. Some studies indicated that the
threshold for this delay of clozapine was only 2.8 years [174,175]. These
findings may imply that clozapine contributes more to the aberrant
neuronal network if its administration is started before progressive and
accumulating brain damage is done by the disease. However, there have
been few studies demonstrating clear positive effects of clozapine on
patients’ brain structure.
In this context, glutamatergic and GABAnergic systems have recently
gained much attention as the action mechanisms of clozapine [162].
Several MRS studies demonstrated that glutamine acid (GLU) and
glutamine acid plus glutamine (GLx) may have been altered in patients
with TRS or ultra-TRS, and that clozapine can have some effects on these
compounds [176,177]. The studies that measured the cortical silent
period (CSP), which is an indicator of GABA functions through GABAB
receptors, using transcranial magnetic stimulation (TMS) indicated that
clozapine prolonged the CSP [178–180]. These findings are still far from
being clinically applied, e.g., through the prediction of clozapine
responsiveness, but they suggest that clozapine has several action
mechanisms other than dopamine transmission. In addition, these recent
findings suggest that clozapine should be introduced earlier if at least
two types of SGAs that act mainly through blocking DRD2 are shown not
to sufficiently improve psychotic symptoms in a given patient.
6
Behavioural Brain Research 403 (2021) 113126
7. Future directions
Although accumulating evidence strongly indicates that medication
with antipsychotics provide great benefit for patients with schizo­
phrenia, physicians have to continue to take available measures in order
to maintain and improve quality of living. These efforts attempting to
prevent and overcome a lot of problems which occur in patients’ lives
and medications are necessary to achieve remission and recovery in
patients. In this context, long-term treatment for patients with schizo­
phrenia occasionally contains elements beyond current clinical guide­
lines. Regarding clinical pharmacology, more data connecting basic
pharmacology and long-term prognosis in patients are urgently needed.
The scarcity of this type of knowledge is likely attributable to difficulties
in research methodology and vice versa.
Numerous studies have examined potential brain sites with abnor­
malities that affect the disease process in patients with schizophrenia.
Along with such abnormal alterations that are inherent to schizophrenia
itself, growing evidence has shown that brain alterations could be
attributed to the deleterious actions of antipsychotics [27,37].
Dorph-Petersen et al. suggested that post-mortem brain studies and
longitudinal imaging studies have antipsychotic medications as a con­
founding factor [181]. In vivo identification of antipsychotics-induced
brain alteration over a long illness duration is always difficult
because, in the past few decades, several types of SGAs, including
serotonin-dopamine antagonists, multi-acting receptor targeted anti­
psychotics, and dopamine partial agonists, have been developed, and
the use of LAI and clozapine has been encouraged with changes in
pharmacological guidelines, which become a factor in the complex
treatment histories of individual patients. On the other hand, many basic
studies seem to provide basis for clear merit of short-term treatment. For
instance, it is well-known that antidepressants increase neurogenesis
[182]. It is also suggested that antipsychotics is implicated in cell gen­
esis, although the findings were inconsistent among studies [183,184].
Neurotrophic factors have been examined as one of the vital factors in
the putative mechanism. Brain-derived growth factor (BDNF), a neuro­
trophic factor, plays a pivotal role in neurogenesis including neuronal
proliferation in the hippocampus [185,186]. Although it has been
speculated that antipsychotics as well as antidepressants have positive
effects through the modulation of BDNF, the results of studies on this
process have been inconsistent [187,188]. It has been shown that pa­
tients who were treated with clozapine had higher BDNF levels than
those who were treated with FGAs and that the level of serum BDNF was
positively correlated with the clozapine dose [189]. An animal model of
schizophrenia suggested that long-term administrations of FGAs and
SGAs were differentially related to both changes in serum BDNF and in
the hippocampal volume [190,191]. Heat shock proteins (HSPs) as well
as BDNF are involved in neuroprotective responses to a variety of insults
[192] and are decreased by haloperidol and risperidone [193].
There are previous clinical studies, although there have a few
studies, suggesting that SGAs have neuroprotective effect, which was
observed particularly in the hippocampus region [194,195]. An MRI
study revealed that patients taking SGAs had larger hippocampi than
those taking FGAs at the early stage of schizophrenia [195]. On the other
hand, an imaging study by Zierhut et al. demonstrated that the
morphological changes in the hippocampus were associated with the
doses of antipsychotics [195]. They revealed that higher doses of anti­
psychotics led to a smaller volume of the CA1subfield of hippocampus.
Although a causal relationship between the volume reduction of the CA1
and a high dosage of antipsychotics was not established in this study,
their findings were very important in suggesting an evident association
between antipsychotics and hippocampal alteration. Another study on
first-episode psychosis (FEP) demonstrated an association between
hippocampal alteration and the duration of untreated psychosis (DUP)
[196]. According to this study, patients with FEP showed smaller hip­
pocampus volume compared to healthy controls, and the authors found
that left hippocampus atrophy at the 8-week follow-up point was
H. Kimura et al.
significantly correlated with DUP [196]. These data suggesting benefi­
cial effects of antipsychotics are restricted to studies with short-term
observation period, in particularly in clinical studies. The issue of DS
or DSP is in line with these scarce research situations regardless often
observation in clinical practice. Although antipsychotic medication with
at least low-dose and short-term period provides great merit to patients,
whether there can be a threshold or a bifurcation paint leading to poor
outcome in long-term treatment is great important research issue.
8. Conclusion
To maintain clinical condition for a long time and to overcome
relapse in treatment of patients at chronic stage of schizophrenia, phy­
sicians have to pay attention to the potential development of DS. It is
also important to know the methodology of treating and prevent DS
state. To achieve this goal, antipsychotic should be appropriately
selected from the viewpoints of the fluctuations of blood concentrations
of agents (i.e., pharmacokinetics) and DRD2s occupancy (i.e., pharma­
codynamics). LAIs (including oral agent with long half-life time),
dopamine partial agonists and clozapine can be candidate to treat DSP
and prevent DS state. However, without careful monitor, treatment with
even these agents can give restricted merit to patients.
Funding source
This study was supported by a Grant-in-Aid for Young Scientists (B)
(20K16640) from the Japan Society for the Promotion of Science (JSPS).
CRediT authorship contribution statement
Hiroshi Kimura: Conceptualization, Funding acquisition, Writing -
original draft, Writing - review & editing. Nobuhisa Kanahara: Su­
pervision. Masaomi Iyo: Supervision.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
None.
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