Psychiatry and Clinical Neurosciences 2018; 72: 35–44

doi:10.1111/pcn.12613

Regular Article

Pyridoxamine: A novel treatment for schizophrenia
with enhanced carbonyl stress
Masanari Itokawa, MD, PhD,1,2,3,*,† Mitsuhiro Miyashita, MD, PhD ,1,2,4,† Makoto Arai, PhD,1
Takashi Dan, MD, PhD,5 Katsuyoshi Takahashi, MD, PhD,2 Taro Tokunaga, MD,2
Kayo Ishimoto, MD,2 Kazuya Toriumi, PhD,1 Tomoe Ichikawa, PhD,1 Yasue Horiuchi, PhD,1
Akiko Kobori, MS,1 Satoshi Usami, PhD,6 Takeo Yoshikawa, MD, PhD,3 Naoji Amano, MD, PhD,4
Shinsuke Washizuka, MD, PhD,4 Yuji Okazaki, MD2 and Toshio Miyata, MD, PhD5
1

Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, 2Department of Psychiatry, Tokyo
Metropolitan Matsuzawa Hospital, Tokyo, 3Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako,
4
Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, 5Division of Molecular Medicine andTherapy, Tohoku University Graduate School of Medicine, Sendai, and 6Graduate School of Education, University of Tokyo,
Tokyo, Japan

Aim: The aim of this clinical trial was to obtain
proof of concept for high-dose pyridoxamine as anovel treatment for schizophrenia with enhanced
carbonyl stress.
Methods: Ten Japanese schizophrenia patients withhigh plasma pentosidine, which is a representative
biomarker of enhanced carbonyl stress, were recruitedin a 24-week, open trial in which high-dose pyridoxamine (ranging from 1200 to 2400 mg/day) was
administered using a conventional antipsychotic regimen. Main outcomes were the total change in Positive
and Negative Syndrome Scale score and the Brief Psychiatric Rating Scale score from baseline to end oftreatment at week 24 (or at withdrawal).
Results: Decreased plasma pentosidine levels wereobserved in eight patients. Two patients showedmarked improvement in their psychological symptoms. A patient who harbors a frameshift mutation in the Glyoxalase 1 gene also showed

considerable reduction in psychosis accompaniedwith a moderate decrease in plasma pentosidine
levels. A reduction of greater than 20% in theassessment scale of drug-induced Parkinsonism
occurred in four patients. Although there was nosevere suicide-related ideation or behavior, Wernicke’s encephalopathy-like adverse drug reactions
occurred in two patients and were completely suppressed by thiamine supplementation.

Conclusion: High-dose pyridoxamine add-on treatment was, in part, effective for a subpopulation ofschizophrenia patients with enhanced carbonyl
stress. Further randomized, placebo-controlled trials
with careful monitoring will be required to validate
the efﬁcacy of high-dose pyridoxamine for thesepatients.
Key words: advanced glycation end-products, carbonyl stress, pentosidine, pyridoxamine, schizophrenia.

S*Correspondence: Masanari Itokawa, MD, PhD, Center for Medical
Research Cooperation, Tokyo Metropolitan Institute of Medical Science,
2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Email: itokawa-ms@igakuken.or.jp†
Both authors contributed equally to this manuscript.
Received 11 June 2017; revised 7 September 2017;
accepted 18 October 2017.

CHIZOPHRENIA IS A devastating disorder characterized by positive symptoms, including auditory hallucinations and delusions, and negative
symptoms, including blunted affect, anhedonia, andcognitive deﬁcits. The lifetime prevalence ranges
from approximately 0.3% to 0.7%, and disease
onset frequently occurs during puberty or early adolescence. Adequate psychosocial support as well as© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

35

36

M. Itokawa et al.

psychopharmacologic treatment is needed to achieve
and maintain recovery. Although many studies havebeen conducted to clarify the underlying mechanismof the disease, the main cause and pathophysiology
of schizophrenia still remains elusive since there isconsiderable heterogeneity in symptoms, and longterm clinical courses differ substantially from patientto patient.
Carbonyl stress is an abnormal metabolic state
resulting from either increased production of reactive carbonyl compounds (RCO) or decreased detoxiﬁcation of RCO.1 Advanced glycation end products(AGE) are generated as a consequence of elevatedcarbonyl stress, and numerous experimental studies
in animals and humans implicate increased AGE ina variety of diseases, including diabetes mellitus,2–4
chronic kidney disease,1 cardiovascular diseases5
and cognitive impairment with or without
dementia.6–8 Pyridoxamine, one of the three formsof vitamin B6, is capable of scavenging certain RCO,
thereby inhibiting the formation of AGE and alleviating their unfavorable physiological effects. The
other forms of vitamin B6, pyridoxine and pyridoxal,
lack this therapeutic beneﬁt. However, pyridoxamine
is synthesized from both pyridoxal and pyridoxine
in vivo, so that depleting pyridoxamine to combat
enhanced carbonyl stress eventually leads todecreases in both pyridoxal and pyridoxine.
We previously reported that enhanced carbonyl
stress is associated with a subpopulation of patients
suffering from schizophrenia.9 In addition, a close
relationship between schizophrenia and carbonyl
stress was also found in a larger cohort,10 and adrug-naïve patient with high pentosidine levels has
been reported.11 Clinical features of patients withenhanced carbonyl stress are similar to those withtreatment-resistant schizophrenia, and negative correlations between psychological symptoms ofschizophrenia and serum pyridoxal levels have beenreported.12 Likewise, a recent study suggests thatpyridoxal levels could be a possible biomarker topredict the clinical course in a subset of schizophrenia patients.13 Clozapine is the most effective agent
among various antipsychotics for patients withtreatment-resistant schizophrenia.14,15 However, theuse of clozapine is restricted because of serious andlethal adverse effects, including granulocytopenia,16
which require strict and frequent monitoring ofwhite blood cell counts. Thus, clozapine treatment
causes problems for both patients as well as healthcare providers.

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

In contrast, clinical interventions, such as pyridoxamine supplementation, aimed at reducing carbonyl
stress, may provide a safe and effective treatment for
schizophrenia patients with enhanced carbonyl
stress. To test this hypothesis, we conducted a 24week, open-label clinical trial with high-dose pyridoxamine supplementation in schizophrenia
patients. In this study, two patients showed marked
improvement in clinical symptoms, and one patient
showed considerable improvement in psychologicalsymptoms accompanied by a moderate decrease inplasma pentosidine levels. Additionally, four participants showed improvements in drug-induced Parkinsonism and two patients experienced Wernicke’s
encephalopathy, which was completely alleviatedfollowing thiamine supplementation.

METHODS
Subjects
Inclusion criteria for this clinical trial were patientswith schizophrenia or schizoaffective disorder aged
20–65 years who were hospitalized in Matsuzawa
Metropolitan Hospital. Diagnoses were made by atleast two experienced psychiatrists according to the
DSM-IV-TR. Patients with diabetes mellitus or chronic
kidney disease were excluded, since both diseases
occasionally induce increased plasma pentosidine
levels. Other exclusion criteria included: organic mental diseases, substance dependence, past history of
substance dependence, comorbid malignant tumors,pregnancy, modiﬁed electroconvulsive therapy within
3 months, prescription to theophylline, choline theophylline, aminophylline and levodopa (which arecontraindicated with pyridoxamine), and severe physical conditions that made study participation inappropriate. Eligible patients exhibited enhanced carbonyl
stress deﬁned as elevated plasma pentosidine levels
according to a previous report9 (>55.2 ng/mL; deﬁned
above 2 SD of healthy control subjects). In this study,
serum pyridoxal levels could not be used as an inclusion criterion because the number of patients fulﬁllingboth high pentosidine and low pyridoxal were so few
that sufﬁcient participants could not be recruited.
After patient selection, 10 eligible patients were identiﬁed for this clinical trial.

Study design
A 24-week, open-label design was adopted. Pyridoxamine was initiated with a dose of 1200 mg/day© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

supplementing the existing antipsychotic regimen,with the responsible doctor setting the daily dose(1200, 1800, or 2400 mg/day) during the trial. The
dose was determined according to phase I clinical
trials. To avoid degradation, we stored pyridoxamine
in powder form in a light-blocking box and dissolved it in water and syrup (to reduce sourness) for
three daily oral administrations. Treatment adherence and the general condition of all participants
were carefully monitored throughout the trial
period. All participants provided written informed
consent and study protocols were approved by theInstitutional Review Board of Tokyo Metropolitan
Matsuzawa Hospital. The trial was registered at
the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, number
UMIN000006398.

Efﬁcacy and safety assessment
Clinical efﬁcacy and safety assessment as well as
measurements of plasma pentosidine and the threeforms of vitamin B6 were carried out every 2 weeks
for the ﬁrst month and every 4 weeks for the following 5 months. Primary outcomes were improvements in the Brief Psychiatric Rating Scale (BPRS)
and the Positive and Negative Syndrome Scale(PANSS) from baseline assessments scored by thesame rater during the trial. The Drug-Induced Extrapyramidal
Symptoms Scale(DIEPSS)
and
Columbia-Suicide Severity Rating Scale wereassessed to determine the severity of extrapyramidal
symptoms (EPS) and the occurrence of suiciderelated adverse events. We also recorded bodyweight, blood pressure, and pulse rate, and measured blood count, coagulation, liver and kidney
function, blood sugar, hemoglobin A1c, thyroid hormone, urine test, and electrocardiography at each
visit.

Measurement of pentosidine
Fresh plasma and serum was obtained from participants, and pentosidine was measured using highperformance liquid chromatography (HPLC), as
described previously.17 In brief, plasma samples
were lyophilized, hydrolyzed in 100 μL 6 N hydrochloric acid for 16 h at 110 C under nitrogen, neutralized with 100 μL 5 N sodium hydroxide and200 μL of 0.5 M sodium phosphate buffer (pH 7.4),
ﬁltered through a 0.5-μm ﬁlter, and diluted with

Pyridoxamine treatment for schizophrenia

37

phosphate-buffered saline. A sample (corresponding
to 25 μg of protein) was injected into an HPLC system and fractionated on a C18 reverse-phase column. Eluent was monitored at excitation-emission
wavelengths of 335/385 nm using a ﬂuorescence
detector (RF-10A; Shimadzu, Kyoto, Japan). Synthetic pentosidine was used to obtain a standard
curve. Three forms of vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) were measured in serum
samples by HPLC according to a previously
described method. These measurements were conducted at SRL (Tokyo, Japan) or LSI Medience Corporation (Tokyo, Japan), which are private clinicallaboratory test companies. As serum pyridoxamineand pyridoxine were below detection levels, we used
serum pyridoxal levels to quantify serum vitamin
B6. Other parameters (glycohemoglobin AlC, creatinine) were measured in blood samples. The glomerular ﬁltration rate was estimated using theabbreviated Modiﬁcation of Diet in Renal Diseases
study equation.

Genotype of Glyoxalase 1 gene
Glyoxalase 1 (GLO1) is the key enzyme in thedetoxiﬁcation system of carbonyl compounds anddysfunction of this enzyme, due to genetic mutations, such as frameshift mutations or the
Glu111Ala GLO1 genotype (rs4746), contribute toincreased carbonyl stress and high plasma pentosidine levels. We conducted genotyping of GLO1 for
all patients as described previously.9 GLO1 genotypes are shown in Table 1.

Statistical analysis
All statistical analyses were performed using PRISM(GraphPad Software, San Diego, CA, USA). Comparisons of means and standard errors of data were performed using unpaired t-tests or Mann–Whitney Utests (both two-tailed). Fisher’s exact tests were used
for categorical variables. Signiﬁcance was deﬁned
as P < 0.05.

RESULTSHalf of the patients fulﬁlled the rigid deﬁnition oftreatment-resistant schizophrenia by Kane18 and allparticipants showed poor social function. Baseline
demographic and clinical characteristics of the participants are summarized in Table 1.

© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

M. Itokawa et al.

38

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

Table 1. Demographics of participants
Patients

A

B

C

D

E

F

G

38
F
302.8

61
F
89.8

63
F
185.2

42
F
143.5

62
M
89.0

50
41
33
F
M
F
383.2 139.3 75.8

6.5
5.0
0.89
Never

5.0
5.0
0.57
Never

10.1
4.6
0.48
Never

3.5
6.4
4.6
12.2 7.3
5.2
4.7
4.8
4.9
4.9
0.70 0.51 0.80 0.69 0.49
Never Never Never Never Never

Glu/Glu

Glu/Glu

Glu/Glu

2.5
5.2
0.78
Current
smokerGlu/Glu

Yes

No

No

No

No

Yes

Yes

No

No

Yes

9

12

12

12

12

18

12

12

12

16

Hospitalized Hospitalized Hospitalized Hospitalized Poor
15
19
15
26
16
49
19
46
37
26

Poor
20
42

Poor
28
22

Poor
20
21

Poor Poor
22
24
11
18

5

4

16

14

5

4

5

4

2

11

46

16

20

20

4

3

3

1

1

6

2532

2732

1005

530

2505

441

1255 3214 2552 2636

Age
64
Sex
M
Pentosidine
227.9(ng/mL)
Pyridoxal (ng/mL) 2.1
HbA1C
4.9
Creatinine (mg/dL) 1.01
Smoking status
Current
smokerGLO1 genotype
T 27NfsX15
Clinical variables
Family history ofpsychosis
Educational status(years)Social function†
Onset (years old)
Duration of illness(years)Number ofprevious
hospitalizations
Total duration of
hospitalization(years)Antipsychotics(mg/day, CP
equivalent)

H

I

J
42
F
109.0

Glu/ Glu/ Glu/ Glu/ Glu/
Glu Glu Glu Ala
Glu†‘Poor’ deﬁned as not having continuous work at least 1 year prior to trial.
CP, chlorpromazine.

Trial results are summarized in Table 2. Each letterfrom A to J indicates an individual schizophrenia
patient listed in order of participation. Patient F
dropped out of the trial at day 121 because of worsening physical conditions. Thus nine patients completed the trial. Of the participants, patients C and J
showed marked improvements from baseline assessments of psychotic symptoms demonstrated by
BPRS and the PANSS Negative, General, and Total
subscale scores (Table 2). They also both showedsigniﬁcant improvement in terms of rapport, expressing emotions, and frequency of participation indaily care programs. Although patient C could notwalk alone unless a care-giver supported her at the
beginning of the trial, she became highly motivatedto participate in the walking rehabilitation program

during the trial, ultimately succeeding in walking byherself. Drastic improvements in the daily activitiesof these patients had not been observed in previous
hospitalizations before the start of this trial. Behavioral changes were conﬁrmed by primary care-givers,
including nurses. The effective dose of pyridoxamine
in patients C and J was 1200 mg/day. Patient C
deteriorated immediately after the trial, whereas
patient J maintained an improved psychologicalcondition beyond the study end-point. Improvements in rapport and emotional expressions werealso observed in other patients. Patient A, who harbors a GLO1 frameshift mutation and exhibited low
pyridoxal levels (which indicates a vulnerability tocarbonyl stress), also showed moderate improvement of clinical symptoms assessed by BPRS and© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

total PANSS score accompanied with a considerable
reduction in plasma pentosidine levels (Table 2).
The clinical courses of patients A, C, and J are summarized in Fig. 1. Intriguingly, four patients(patients C, G, I, and J) demonstrated a >20%
reduction in DIEPSS scores from baseline evaluations, indicating improvement of EPS (Table 2).
Patient F also showed a marked reduction in his
DIEPSS score. However, his improvement might
have been caused by discontinuation of antipsychotics due to worsening physical conditions.
Decreases in plasma pentosidine were observed ineight patients, and the overall reduction (including
patient F) was 26.8% (Table S1), a ﬁnding in contrast with a previous report by Katsuta et al., whichfound a reduction of 3.0% in 137 schizophrenia
patients.13 Patient J showed remarkable increase ofplasma pentosidine levels; however, the precise
mechanism of elevated pentosidine concentration
remains to be elucidated. Serum pyridoxal concentrations increased in all patients and the overall rateof increase was 345.3-fold from baseline (Table S1).
In the clinical assessment, the overall reduction rates
for the PANSS Positive, Negative, General, and Total
subscales and the BPRS scores were 6.9%, 5.8%,
9.9%, 8.1%, and 10.8%, respectively, which did notreach statistical signiﬁcance, probably due to thesmall number of participants (Table S1).
All adverse events occurring in this trial are summarized in Table 3. No severe suicide-related ideation or behavior was observed during the trial, asassessed by the Columbia-Suicide Severity Rating
Scale. We decreased the antipsychotic doses inpatients B, D, and H during the trial because of

Pyridoxamine treatment for schizophrenia

39

oversedation or exacerbation of EPS. Unfortunately,
severe adverse drug reactions occurred in twopatients at a dose of 1800 mg/day, where clinicalsymptoms and course were very similar to Wernicke’s encephalopathy (Fig. 2a,b upper panels).
However, the patients recovered completely following thiamine supplementation (Fig. 2a,b lower
panels). After observing these adverse reactions, wemeasured serum thiamine levels and conductedhead magnetic resonance imaging (MRI) of theother participants, but observed no abnormal ﬁndings. We also produced a new consent form explaining these adverse reactions, and obtained consent
from patients and guardians for trial continuation.
Additionally, we conducted a preventive intervention consisting of oral thiamine administration for
all participants. No further adverse events occurred
after preventive administration of thiamine.

DISCUSSION
In this trial, we tested the hypothesis that pyridoxamine treatment improves clinical symptoms in a
subset of schizophrenia patients with increased carbonyl stress. Previously, we found that most schizophrenia patients with high plasma pentosidine areclassiﬁed as having treatment-resistant schizophrenia.9 Of 10 total participants, two patients showedmarked improvements in psychotic symptoms, especially the PANSS Negative and General subscales,
and one patient with a GLO1 frameshift mutation
showed considerable improvement accompanied bya moderate reduction of plasma pentosidine levels.
In addition, four participants exhibited improved

Table 2. Summary of clinical parameters
Patients

A

B

C

D

E

F

G

H

I

J

Pentosidine
PANSS Positive
PANSS Negative
PANSS General
PANSS Total
BPRS
DIEPSS

−24.7
−20.7
−5.6
−5.5
−9.2
−15.0
0.0

−32.8
17.2
20.8
6.1
11.8
13.0
−14.3

−12.1
−33.3
−60.5
−53.6
−51.5
−52.6
−43.8

−15.0
18.8
12.2
13.7
13.9
8.8
14.3

19.6
25.0
−8.3
22.6
17.5
18.4
0.0

−14.3
−57.9
40.0
−3.7
−6.1
−27.9
−100.0

−79.6
12.5
35.0
−4.7
8.9
2.1
−20.0

−5.7
−16.1
−6.7
−5.8
−8.9
−14.5
10.0

−32.8
5.3
−4.4
−15.2
−6.7
2.4
−33.3

135.2
−3.9
−36.4
−26.8
−24.4
−21.3
−85.7

Numeric values represent rates of change (%), which are calculated by (week 24 − baseline) / baseline × 100. Negativevalues indicate decreases in pentosidine levels or improvement in clinical assessments. Boldface is used for variables thatshow >10% improvement. For patient F, values at the time of discontinuation are used instead of week 24.
BPRS, Brief Psychiatric Rating Scale; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; PANSS, Positive and Negative
Syndrome Scale.

© 2017 The Authors
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M. Itokawa et al.

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

PANSS

150
90
125

0

100
16
9

14
1

Da
y

11
3

Da
y

85

Da
y

57

Da
y

Da
y

29

80
1

0

100

Da
y

1200

200

175

15

2400

400

Da
y

3600

110
200

Da
y

4800

120

225
600

Pentosidine (ng/mL)

6000

Pyridoxamine (ng/mL)

Dose of pyridoxamine (mg/day)Patient A
250

800

7200

500

PANSS

75

16
9

14
1

Da
y

11
3

Da
y

85

Da
y

Da
y

80

57

7200

50
Da
y

0
1

0

29

1200

100

Da
y

2400

1000

15

3600

100

Da
y

4800

1500

Da
y

6000

Pentosidine (ng/mL)

7200
Pyridoxamine (ng/mL)

Dose of pyridoxamine (mg/day)Patient C
2000

150
125
50

drug-induced Parkinsonism. Two patients experienced Wernicke’s encephalopathy but completely
recovered following thiamine supplementation.
Since 1973, several clinical studies have been conducted to evaluate the efﬁcacy of vitamin B6

16
9

14
1

Da
y

11
3

Da
y

85

Da
y

Da
y

Da
y

57

105
29

0

1

0

PANSS

175

Da
y

1200

20

100

200

15

2400

40

Da
y

3600

225

Da
y

4800

250
60

Pentosidine (ng/mL)

6000

Pyridoxamine (ng/mL)

Dose of pyridoxamine (mg/day)Patient J
275

Figure 1. Clinical courses ofpatients (a) A, (b) C, and (c) J,
who showed great improvements in their psychologicalsymptoms. () Positive
and Negative Syndrome Scale(PANSS) score, () plasma
pentosidine levels, ()
serum pyridoxamine concentrations, and () dailydose of pyridoxamine areshown in the ﬁgure.

treatment for schizophrenia; however, results havebeen inconclusive.19–25 Previous studies used pyridoxine or pyridoxal as the vitamin B6 therapeutic,
and used dosages much lower than ours. Additionally, the participants in past trials were not as well

© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

Pyridoxamine treatment for schizophrenia

41

Table 3. Summary of adverse events
Adverse events

Incidence

Seriousness

OutcomeCausal relation

Wernicke-like encephalopathy
SeizureSubstupor
Loss of consciousness
Subileus
Pneumonia
Oversedation
Increased urinary white blood cells
Common cold
Elevated creatine kinase
Worsening of EPS
Bradycardia
Elevated lactate dehydrogenase
Eosinophilia
Asthmatic attack
Aggravation of asteatotic dermatitis
Sciatica
Unspeciﬁc T wave abnormality
Inﬂuenza virus infection
Insomnia
Thought disturbanceAgitation
Leukocytosis
Neutrophilia
Monocytosis
Lymphopenia
Hypernatremia
Hyponatremia
Hyperﬁbrinogenemia
Hyperammonemia
Hyperglycemia
Bacteriuria
Increased urinary squamous cells

2
1
1
1
1
1
4
4
3
3
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1

Serious
Serious
Serious
Serious
Serious
Serious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious
Nonserious

Disappearance
Disappearance
Disappearance
Disappearance
Disappearance
Disappearance
Disappearance 3, remission 1
Disappearance 3, remission 1
Disappearance
Disappearance
Disappearance
Disappearance 1, remission 1
Disappearance
Disappearance
Disappearance
Remission
Remission
Continued
Disappearance
Disappearance
Disappearance
Disappearance
Disappearance
Remission
Disappearance
Remission
DisappearanceContinued
DisappearanceContinued
Disappearance
Remission
Disappearance

CausalNone
Not likely
Possible
None
Possible
Not likely = 3, None = 1
None
None
None
Possible = 1, None = 1
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None

EPS, extrapyramidal symptoms.

characterized as the patients in our study, who wereselected based on plasma levels of pentosidine, arepresentative carbonyl stress biomarker. To ourknowledge, this is the ﬁrst clinical trial to test the
hypothesis that a therapeutic strategy aimed at
reducing carbonyl stress yields symptomatic
improvements for schizophrenia patients with highpentosidine. Supporting this hypothesis, we foundthat eight patients showed decreased plasma pentosidine levels, with one patient showing clinicalimprovements associated with a moderate reductionin pentosidine levels, and a second showing signiﬁcant improvements in psychological symptoms anda slight decrease in plasma pentosidine. A third
patient also showed signiﬁcant psychologicalimprovements not associated with deceased plasma
pentosidine, suggesting that pyridoxamine may also
have uncharacterized beneﬁts unrelated to its function in relieving carbonyl stress. Because glutamate
decarboxylase and aromatic-L-amino-acid decarboxylase are pyridoxal-phosphate-dependent enzymes,
high-dose pyridoxamine may affect metabolism andbiosynthesis of neurotransmitters, including dopamine, serotonin, and gamma aminobutyric acid
(GABA). Indeed, pyridoxine treatment increased theprotein levels of glutamic acid decarboxylase (GAD)© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

42

M. Itokawa et al.

(a)

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

T1WI

T2WI

FLAIR

Pyridoxamine

Figure 2. (a) Head magnetic

Pyridoxamine+
thiamine

(b)

T1WI

T2WI

Pyridoxamine

Pyridoxamine+
thiamine

67, an enzyme for GABA synthesis in the mousedentate gyrus.26 This report suggests that pyridoxine
treatment upregulated the GABAergic system in vivo.
Thus, it is speculated that pyridoxine converted fromhigh-dose pyridoxamine augments the GABA function leading to improvement in clinical symptoms.
Changes in dopamine in the central nervous system(CNS) induced by high-dose pyridoxamine may be
associated with improvements in negative symptoms, daily activity, and drug-induced Parkinsonism,
while pyridoxamine-induced alterations in CNS
GABA synthesis may induce sedation in somepatients, reducing the required dosages of antipsychotics. The observed improvements in EPS are also

FLAIR

resonance imaging (MRI) of
patient C. Top: Bilateral medial
thalamus lesions are shown inhorizontal sections of T2weighted image (T2WI) andT1-weighted image (T1WI).
The lesions were also conﬁrmed in a coronal section of
ﬂuid-attenuatedinversion
recovery (FLAIR) image. Yellow
arrows indicate the lesions.
Bottom: After thiamine treatment, the abnormal intensities
almost completely disappeared.
(b) Head MRI of patient F. Top:
MRI image scanned at onset.
Similar to patient C, bilateral
medial thalamic lesions wereobserved in case F. Yellow
arrows indicate the lesions.
Bottom: MRI image scanned
afterthiamine
treatment.
Thiamine administration markedly improved the abnormal
intensities.

consistent with the results of previous trials investigating the effect of vitamin B6 on tardive dyskinesia.27,28 However, precise molecular mechanisms
underlying these clinical changes still remain unclear
and should be addressed in future studies.
As mentioned above, Wernicke’s encephalopathylike reactions occurred in two patients during treatment. A previous study using a rodent model
reported that high-dose pyridoxal caused death due
to convulsions.29 Additionally, clinical studies haveindicated that high doses of pyridoxine caused neurotoxicity related to peripheral neuropathy.30,31
Another study noted that pyridoxine treatment
caused dizziness in a chronic schizophrenia© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2018; 72: 35–44

patient.19 We propose that administration of highdose
pyridoxamine
may
cause
Wernicke’s
encephalopathy-like reactions through conversion ofpyridoxamine to pyridoxal, which entraps amino
compounds, such as thiamine, by carbonyl-amine
chemistry. These adverse drug reactions can be prevented with simultaneous prescription of thiamine,and Wernicke’s encephalopathy was not observed
after thiamine supplementation in our trial.
Our current study had a small sample size andwas not a randomized, placebo-controlled trial.
Thus, although our results suggest that pyridoxamine supplementation is a promising therapy fortreatment-resistant schizophrenia associated withincreased carbonyl stress, a larger randomized,
placebo-controlled study will be required to conﬁrm
the validity of our ﬁndings.

Conclusion
High-dose pyridoxamine was effective in alleviating
psychotic symptoms in a subset of schizophrenia
patients with enhanced carbonyl stress. Thiamine
should be coadministered to prevent Wernicke’s
encephalopathy. Further studies will be needed tovalidate the clinical efﬁcacy and investigate the pharmacological actions of pyridoxamine.

ACKNOWLEDGMENTS
This work was partly supported by JSPS KAKENHI
Grant Number JP16H05380, JP25861040, andJP25253074. The data obtained at this work is utilized for Phase IIb clinical trial partially supported
by 16dm0107088h0001 and 17dm0107088h0002.
We thank Hiroko Yuzawa and Shunya Takizawa formeasurements of plasma pentosidine; Izumi
Nohara, Mayumi Arai, and Nanako Obata for technical assistance; Yuuki Yoshida, Ikuyo Kito, andSachie Kyogoku for technical advice and assistancewith manuscript preparation; Junjirou Horiuchi for
special advice with manuscript arrangement; and Ms
Hiromi Idosawa and Ms Yoshie Matsumoto, at theclinical research ofﬁce in Matsuzawa Hospital. We
also express our appreciation to the staff at Matsuzawa Hospital who supported our trial, and to thepatients and their families.

DISCLOSURE STATEMENT
We state that there is a conﬂict of interest. This work
was supported by PROJECT PM Co., Ltd. The

Pyridoxamine treatment for schizophrenia

43

sponsor had no inﬂuence on design, analysis, interpretation, or writing of the report. Drs M. Itokawa,
M. Arai, M. Miyashita, K. Toriumi, Y. Horiuchi, andA. Kobori report grants from Kowa Company, Ltd.
Drs M. Itokawa and M. Arai report other support
from Renascience Co., Ltd. Drs M. Itokawa, M. Arai,
M. Miyashita, and T. Miyata hold a patent broadly
relevant to the work. The other authors have no conﬂict of interest for this trial.

AUTHOR CONTRIBUTIONS
Drs M.I., M.M., M.A., and T.M. designed the trial.
Drs M.M., M.I., T.T., K.I., and K.T. collected the clinical data. Drs M.I., M.M., M.A., and T.M. conducted
the literature search, designed the ﬁgures and tables,
and analyzed and interpreted the data. Drs T.D., T.I.,
K.T., A.K., Y.H., T.Y., Y.O.N.A., and S.W. interpreted
the data. Dr S.U. provided special advice on statistical analysis. Drs M.I., M.M., M.A., and T.M. revised
the ﬁrst draft and completed the ﬁnal manuscript.
All authors approved the ﬁnal manuscript.

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SUPPORTING INFORMATION
Additional Supporting Information may be found in
the online version of this article at the publisher’s
web-site:
Table S1. Clinical and safety assessments during thetrial.

© 2017 The Authors
Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology