MHGCJ – 2020
Mental Health: Global Challenges Journal
https://mhgcj.org ISSN 2612-2138
The role of metformin hydrochloride in complex
therapy of disorders of carbohydrate metabolism in
patients with paranoid schizophrenia treated with
atypical antipsychotics
Ivan Romash
Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine
Abstract
Introduction. According to the literature, mortality among patients with schizophrenia is 1.5 -2
times higher than in the healthy population. One explanation for this is the complication of
neuroleptic therapy, which, according to various authors, occurs in 2 to 100% of cases.
Purpose. We aimed to study some indicators of carbohydrate metabolism disorders in patients
with paranoid schizophrenia who have been taking neuroleptics for a long time, to correct the
established changes by adding metformin hydrochloride to the standard regimen and to
monitor its effectiveness.
Methodology. The study was conducted based on Municipal non-commercial enterprise
"Precarpathian regional clinical center of mental health of Ivano-Frankivsk regional council. This
study included patients diagnosed with paranoid schizophrenia according to the criteria of ICD-
10 (F20.0). As a result of our studies in 63 patients, we found a violation of carbohydrate
metabolism, which accounted for 52% of all examined. Among them, 55 patients with
prediabetes: 12 (19.04%) patients with impaired glucose tolerance (IGT), 43 (68%) with impaired
fasting glycemia (IFG), and 8 patients (12.7%) with type 2 diabetes mellitus (T2D). Subsequently,
all these 63 patients were prescribed corrective therapy with a drug from the group of
biguanides - metformin hydrochloride at a dose from 500 to 1000 mg/day: in violation of IFG at
a dose of 500 mg/day; in case of IGT - 850 mg/day; in the case of T2D- 1000 mg/day. All studies
were performed before and after 3 months of metformin correction. These included fasting
glucose, postprandial hyperglycemia (PPG) (two hours after a meal), glycosylated hemoglobin
(HbAIc), immunoreactive insulin (IRI), and, if necessary, an oral glucose tolerance test (OGTT).
Fasting plasma glucose (FPG) was measured by the glucose oxidase method. HbAIc values
were determined by ion-exchange high-performance liquid chromatography (HPLC). The
determination of the IRI level was performed by enzyme-linked immunosorbent assay (ELISA)
Results and Discussion. The results of the research showed that 52% of all surveyed found
disorders of carbohydrate metabolism. They were prescribed corrective therapy with a drug
from the group of biguanides - metformin hydrochloride at a dose of 500 to 1000 mg/day. As a
result of the research, we found that in all groups of examined patients revealed a positive
dynamics of carbohydrate metabolism under the influence of this drug. A significantly higher
therapeutic effect of the treatment of carbohydrate metabolism disorders with metformin was
found in patients receiving the latter in combination with haloperidol. The combination of
metformin with risperidone and quetiapine showed a slightly lower clinical effect.
Conclusion. Our own clinical experience gives grounds to recommend metformin
hydrochloride as a medium for the correction of carbohydrate metabolism disorders in patients
with a paranoid form of schizophrenia in the treatment of this category of patients with
neuroleptics.
Keywords
carbohydrate metabolism, paranoid schizophrenia, atypical neuroleptics, metformin
MHGCJ – 2020
Mental Health: Global Challenges Journal
https://mhgcj.org ISSN 2612-2138
Submitted for publication: 11
June 2020
Received: 11 June 2020
Accepted for publication: 17
October 2020
Introduction
According to the literature, mortality among
patients with schizophrenia is 1.5 -2 times higher
than in the healthy population (1,2,3). One
explanation for this is the complication of
neuroleptic therapy, which, according to various
authors, occurs in 2 to 100% of cases (IHME,
2018; Maruta et al., 2015).
Patients with schizophrenia, which is
comorbid, need special attention somatic
pathology, in particular metabolic disorders,
which often go unnoticed by clinicians.
Concomitant metabolic disorders in
schizophrenia not only increase mortality but also
create serious problems, in particular, in providing
psychopharmacological care to this group of
patients. According to scientific data, patients
with paranoid schizophrenia comorbid with
diabetes in 45% of cases in the first place put the
treatment of somatic pathology, neglecting the
treatment of the underlying disease, the other
40% - on the contrary - leave concomitant
metabolic disorders without adequate correction
(Jungsun, 2019; Romash, 2016, a).
The emergence of a new generation of
antipsychotic pharmacotherapy, the so-called
atypical antipsychotics (AA), largely devoid of the
disadvantages of classical neuroleptics, has
certainly been an important step forward in the
treatment of patients with schizophrenia (Siskind
et al., 2016). Several studies have confirmed the
hypothesis of greater efficacy and safety of AA.
Also, comparative studies have identified
additional features of their clinical action: the
ability to reduce secondary and possibly primary
negative symptoms, reduce the severity of
cognitive impairment, reduce comorbid affective
symptoms, some drugs lack or low
hyperprolactinemia and effectiveness in some
cases, resistant to traditional neuroleptics (Siskind
et al., 2018; Freyberg et.al.,2017; Romash, 2016).
However, several large recent studies have
questioned the unconditional superiority of AA
over typical ones. This was due to the
appearance of information about the presence
of many metabolic side effects in AA, which lead
to extremely serious consequences for physical
health. According to the literature, the
prevalence of metabolic syndrome (MS) in
patients with schizophrenia is 37% -40%, which is
higher than in the general population (Siskind et
al., 2018; IHME, 2018; Maruta et al., 2015;
Romash, 2016).
Although "new" - atypical antipsychotic
drugs cause fewer neurological side effects, they
have a significant impact on the development of
metabolic processes (Romash et al., 2016). In our
recent studies were showed that neurological
complications occur significantly more often on
the background of taking a typical neuroleptic
haloperidol than risperidone or quetiapine. In
turn, a comparison of the presented AN showed
that risperidone has a statistically higher
probability of developing neurological
complications compared to quetiapine. These
data are consistent with recent studies by
Spielmans G.I. et all., Oh G.H., who showed that
of the currently known and widely used
neuroleptics, risperidone has the highest level of
akathisia, from 7% to 50%, and the lowest
incidence of akathisia is quetiapine (2 to 13%).
The incidence of akathisia in quetiapine is
significantly lower than that of risperidone from
2% to 13%. Complications from the functioning
of the autonomic nervous system were also more
common in patients of the haloperidol group.
According to the data obtained, it should be
noted that the use of atypical neuroleptics
risperidone or quetiapine has a lower risk of
developing late dyskinesia than with treatment
with haloperidol. The study indicates the benefits
of atypical antipsychotics mainly due to the lower
severity of most neurological symptoms. Only
some neurological symptoms in the examined
patients were more common on the background
of therapy with atypical antipsychotics. These
results are consistent with the data of other
authors who indicated a high probability of
extrapyramidal side effects, including severe
complications such as tardive dyskinesia,
toxicoallergic reactions and neuroleptic
malignant syndrome with haloperidol. Gardner M.
D. and sang. Geddes J. R. et al. noted the
development of tardive dyskinesia in patients
treated with haloperidol for one year 17 times
more often than with risperidone. However,
according to S. Leucht et al., the advantage of
MHGCJ – 2020
Mental Health: Global Challenges Journal
https://mhgcj.org ISSN 2612-2138
modern antipsychotics over drugs of previous
generations is variable.
Therefore, in recent years, in addition to
developing new drugs devoid of such side
effects, more and more scientists from around
the world have begun to look for rational
concomitant corrective therapy. In particular, in
their randomized 24-week double-blind,
placebo-controlled study, Dan Siskind and co-
authors studied the effect of concomitant
metformin on weight change when clozapine
was started. (Siskind et al., 2018) They
demonstrated that co-initiation of metformin with
the initiation of clozapine may reduce the burden
of clozapine on cardiovascular and metabolic
diseases.
Purpose
To investigate the effect of metformin
corrective therapy on insulin resistance (IR) in
patients with paranoid schizophrenia who had
been taking neuroleptics for a long time.
Methodology
The study was conducted based on Municipal
non-commercial enterprise "Precarpathian
regional clinical center of mental health of Ivano-
Frankivsk regional council. This study included
patients diagnosed with paranoid schizophrenia
according to the criteria of ICD-10 (F20.0). The
study was approved by the Bioethics Committee
of Ivano-Frankivsk National Medical University and
conducted following the principles of the Helsinki
Declaration of the World Medical Association
(Helsinki 1964, 2000 ed.). Before the study, all
patients signed voluntary informed consent.
As a result of our studies in 63 patients, we
found a violation of carbohydrate metabolism,
which accounted for 52% of all examined.
Among them, 55 patients with prediabetes: 12
(19.04%) patients with impaired glucose
tolerance (IGT), 43 (68%) with impaired fasting
glycemia (IFG), and 8 patients (12.7%) with type 2
diabetes mellitus (T2D). Subsequently, all these 63
patients were prescribed corrective therapy with
a drug from the group of biguanides - metformin
hydrochloride at a dose from 500 to 1000
mg/day: in violation of IFG at a dose of 500
mg/day; in case of IGT - 850 mg/day; in the case
of T2D- 1000 mg/day. The initial dose in all groups
was 500 mg once daily with meals (breakfast or
dinner), after 5-7 days, in the absence of
gastrointestinal side effects, the dose was
increased to 850-1000 mg after breakfast or
dinner. In case of side effects, the dose was
reduced to the previous one and increased
again after 5-7 days. Depending on the main 3-
month therapy of paranoid schizophrenia
preceding this stage of the study, patients were
divided as follows: the first (I) Group included 15
patients receiving the typical neuroleptic
haloperidol, the second (II) Group - 22 patients
receiving atypical neuroleptic (AN) risperidone, to
Group III - 15 patients who received atypical
neuroleptic quetiapine. The fourth (IV) Group was
a control group, which included 11 patients with
paranoid schizophrenia in remission who did not
receive neuroleptic therapy during the last 6
months. The duration of corrective therapy in
patients of the study groups was 3 months.
It should be noted that the drug for
concomitant corrective therapy was selected
taking into account its mechanisms of action:
reduces insulin resistance at the level of
peripheral tissues (fat, muscle), increases glucose
utilization by anaerobic glycolysis, slows glucose
absorption in the intestinal tract, stops
gluconeogenesis insulin in the liver and numerical
benefits: low risk of hypoglycemia, promotes
normalization and weight loss (anorexigenic
effect), improves lipid profile, reduces the risk of
developing type 2 diabetes in patients with
impaired glucose tolerance, has a potential
cardioprotective effect myocardial infarction in
patients with obesity and type 2 diabetes; a small
number of contraindications: hepatic
insufficiency, GFR <60 ml/min., creatinine ˃130
μmol/l in women and 120 μmol/l in men; and
rare side effects: gastrointestinal phenomena.
Also taken into account the experience of this
drug by scientists such as Batista T., Henderson D.
C. and Allison D. B. In addition, as proof of the
safety of this drug is the fact that it can be used in
children from 6 years. Therefore, it is important to
mention the scientific study of Anagnostou E. et
al. She used metformin hydrochloride to reduce
weight in children with auricular disorders (aged 6
years) who were taking AA. In her study,
metformin was more effective for weight loss with
antipsychotics than placebo in this category of
children (Anagnostou E. et al., 2016).
All studies were performed before and after 3
months of metformin correction. These included
fasting glucose, postprandial hyperglycemia
(PPG) (two hours after a meal), glycosylated
hemoglobin (HbAIc), immunoreactive insulin (IRI),
and, if necessary, an oral glucose tolerance test
(OGTT). Fasting plasma glucose (FPG) was
measured by the glucose oxidase method.
HbAIc values were determined by ion-exchange
high-performance liquid chromatography (HPLC).
The determination of the IRI level was performed
by enzyme-linked immunosorbent assay (ELISA).
We assessed carbohydrate metabolism
according to the criteria of the International
MHGCJ – 2020
Mental Health: Global Challenges Journal
https://mhgcj.org ISSN 2612-2138
Diabetes Federation (IDF) -2005 classifications,
and the metabolic syndrome was diagnosed
according to the IDF-2007 criteria submitted by
the working group of authors in the Adapted
Clinical Regulation to the Unified Clinical
Secondary Protocol care for type 2 diabetes.
(Order of the Ministry of Health of Ukraine № 1118
of 21. 12. 2012. "On approval and
implementation of medical and technological
documents for the standardization of medical
care for type 2 diabetes").
Statistical processing of the obtained results
was performed using the program "STATISTICA
7.0." And the package of statistical functions of
the program "Microsoft Excel, 2016". The reliability
of the obtained results was confirmed based on
the calculation of the Student's ratio. The
arithmetic mean (M) and its error (m) were used
to describe the quantitative features, the mean
values were presented as M ± m.
Results and Discussion
Corrective metformin therapy lasted 3
months. We evaluated the results of the initial and
final data. Under the influence of corrective
therapy, in all studied groups significantly
decreased the rate of blood pressure (BP).
Among men, this figure decreased by an
average of 4.56%, reaching an average of 93.81
cm. Among women, BP decreased by 4.82%,
reaching 86.49 cm.
Due to corrective therapy with metformin for 3
months, a significant decrease in body weight
was found among patients of group I. Among the
studied II and III groups there was a tendency to
decrease body weight, but in comparison with
the control group, it remains higher. We found a
positive effect of biguanide therapy on body
mass index (BMI): it decreased by 5.68% in Group
I (haloperidol); by 3.79% - in Group II (risperidone)
and by 2.29% - in Group III (quetiron). In groups II
and III, BMI after 3 months of correction tended to
decrease but remained probably higher
compared to the Control group
1)a
1)b
Fig.1 a), 1b) Dynamics of changes in waist
circumference under the influence of
corrective therapy
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in
comparison with the indices of the control group
As can be seen from the data in Fig.1 a), 1b),
in all groups studied significantly decreased waist
circumference (WC). Among men, this figure
decreased by an average of 4.56%, reaching an
average of 93.81 cm. Among women, WC
decreased by 4.82%, reaching 86.49 cm
Fig.2 Dynamics of body weight in patients
with paranoid schizophrenia before and after 3
months of correction with metformin
hydrochloride.
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in
comparison with the indices of the control group.
Due to corrective therapy with metformin
for 3 months, we observe a probable decrease in
body weight among patients of group I. Among
the studied Groups II and III we see a tendency to
decrease body weight, but in comparison with
the control group, it is probably higher. We found
a positive effect of biguanide therapy on BMI: this
figure decreased by 5.68% in group I
(haloperidol); by 3.79% - in Group II (risperidone)
and by 2.29% - in Group III (quetiron). In Groups II
and III, BMI after 3 months of correction tended to
decrease but remained probably higher
compared to the control group (Fig. 2).
MHGCJ – 2020
Mental Health: Global Challenges Journal
https://mhgcj.org ISSN 2612-2138
Consider the dynamics of carbohydrate
metabolism in patients with paranoid
schizophrenia who received corrective therapy
with metformin. Fasting plasma glucose levels
(Fig. 3) decreased by an average of 14.86%,
reaching an average of 6.23 ± 1.76 mmol/l in all
groups compared with the initial value of 7.40 ±
0.26 mmol/l, which is statistically significant.
In Group I, fasting blood glucose decreased
from 7.01 ± 0.29 mmol/l to 6.35 ± 0.18 mmol/l
after hypoglycemic therapy.
In Group II, glycemic parameters after
corrective therapy had a significant decrease:
from 8.44 ± 0.23 mmol/l to 6.02 ± 0.22 mmol/l
(p <0.05).
In Group III, the indicators also had a positive
downward trend. Postprandial glycemia
decreased by an average of 27.35%, reaching
an average of 7.03 ± 0.38 mmol/liter
Fig. 3 Dynamics of fasting plasma glucose
levels under the influence of corrective therapy
with metformin.
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in relation
to indicators in patients of the control group.
Statistially significant was the decrease of
PPG in all study groups (Fig. 4)
Fig. 4. Index of PPG in patients with paranoid
schizophrenia before treatment and after 3
months of metformin correction.
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in relation
to indicators in patients of the control group.
The appointment of antidiabetic therapy had
a positive effect on the prognostic value of
HbA1c. (Fig. 5.) This indicator decreased by an
average of 16.01%: from 6.58 ± 0.11% to 5.12
± 0.12% in Group I; from 7.1 ± 0.15% to 5.8 ±
0.25% in Group II (p <0.05). In Group III there
was also a tendency to reduce this indicator from
6.6 ± 0.63% to 6.1 ± 0.63%.
Fig. 5. Dynamics of glycosylated
hemoglobin in patients with paranoid
schizophrenia before treatment and after 3
months of metformin correction.
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in relation
to indicators in patients of the control group.
No less important in the diagnostic value is
the IRI indicator (Fig. 6). According to scientific
data, this indicator is used to assess the degree
of IR and functional activity of ß-cells of the
pancreas. In our case, IRI decreased by an
average of 26.96%: achieving a significant
decrease compared to the baseline of 25.56 ±
0.70 μIU/ml to 13.40 ± 0.35 μIU/ml in patients of
Group I (p <0, 05); from 28.85 ± 1.50 μIU / ml to
15.64 ± 0.33 μIU / ml - Group II (p <0.05); from
26.49 ± 0.69 μIU / ml to 14.56 ± 0.46 μIU / ml -
Group III
Fig. 6. Dynamics of IRI in patients with
paranoid schizophrenia before treatment and
after 3 months of metformin correction
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in relation
to indicators in patients of the control group.
The value of the HOMA-IR index, which
characterizes the IR, decreased by an average
of 49.46%: from 7.96 ± 0.75 to 3.52 ± 0.55 in
the group of patients taking haloperidol (p
MHGCJ – 2020
Mental Health: Global Challenges Journal
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<0.05); from 10.82 ± 0.47 to 5.97 ± 0.5 -
risperidone (p <0.05); from 7.95 ± 0.98 to 4.15
± 0.98 - quetirone (p <0.05)
Fig. 7. Dynamics of the HOMA index in
patients with paranoid schizophrenia before
treatment and after 3 months of metformin
correction
Notes:
1. * - (p <0.05) data are reliable for indicators
before and after treatment.
2. ^ - (p <0,05) data are reliable in relation
to indicators in patients of the control group.
Another, no less important, IP index - Caro.
Under the influence of corrective therapy with
metformin, this indicator increased in all three
groups: in Group I by 74.04% reaching 0.47 ±
0.02 (p <0.05); in Group II by 31.03% and
amounted to 0.38 ± 0.03. In Group III, the Caro
index probably increased by 72% reaching an
average of 0.43 ± 0.04 (p <0.05)
Conclusion
It was found that in all groups of examined
patients revealed a positive dynamics of
carbohydrate metabolism under the influence of
metformin.
A significantly higher therapeutic effect of
the treatment of carbohydrate metabolism
disorders with metformin was found in patients
receiving the latter in combination with
haloperidol. The combination of metformin with
risperidone and quetiapine showed a slightly
lower clinical effect. Our own clinical experience
gives grounds to recommend metformin
hydrochloride as a medium for the correction of
carbohydrate metabolism disorders in patients
with a paranoid form of schizophrenia in the
treatment of this category of patients with
neuroleptics.
Conflict of interest
The Author declares that he has no conflict of
interests
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