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METFORMIN FOR TREATMENT OF ANTIPSYCHOTIC-INDUCED AMENORRHEA AND WEIGHT GAIN

814 ajp.psychiatryonline.org Am J Psychiatry 169:8, August 2012

The diagnosis of schizophrenia was determined by the Struc-

tured Clinical Interview for DSM-IV Axis I Disorders, ClinicianVersion (24). To be eligible for the study, patients had to be rela-tively stable during the screening phase, as indicated by a totalscore


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WU, JIN, GAO, ET AL.

Am J Psychiatry 169:8, August 2012 ajp.psychiatryonline.org 815

monal levels were determined by using the commercially avail-

able Abbott Axsym microparticle enzyme immunoassays (AbbottLaboratories, Abbott Park, Ill.). All of the assays had a within-assayprecision of


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ond Xiangya Hospital. As for medication adherence dur-

ing the study, the patients and their caregivers reported

that 88%100% of patients in both groups took 80% or

more of their medications.

Between-Group Difference in Percentage With

Restored Menstruation

Twenty-eight patients in the metformin group (66.7%)

resumed menstruation, compared with only two in the

placebo group (4.8%; 2=35.05, df=1, p10%of their baseline weight (2=11.012, df=1, p=0.001).

Changes in Metabolic Measures

The mean insulin level and insulin resistance index de-

creased significantly in the metformin group at months

2, 4, and 6 compared with baseline values. In the placebo

group, however, there was no significant change in in-

sulin level or insulin resistance index at any of these as-

sessments (Figure 3; see also Table S1 in the online data

supplement). In the metformin group, the mean insulin

resistance index decreased by 2.04 from baseline to end

of study. The decreases in insulin levels and insulin re-

prolactin, LH, FSH, estradiol, and testosterone; changes in fast-ing insulin and glucose levels, LH/FSH ratio, insulin resistanceindex, and PANSS score; and frequency of adverse events. Insulinresistance index was calculated based on the homeostasis modelassessment: insulin (103 IU/liter) fasting glucose (mmol/li-ter)/22.5 (27).

Statistical Analysis

All analyses were conducted with SPSS, version 11.5 (SPSS,Inc., Chicago) and SAS, version 9.2 (SAS Institute, Inc., Cary, N.C.),using data from all randomized patients with at least 1 follow-up

test (intent-to-treat analysis). The follow-up data (except for theproportion of patients who resumed menstruation) were all re-peated measures. The repeated outcome measures were analyzedusing mixed-models repeated-measures regression analyses. Thesubject was treated as the random effect and month as the fixedeffect during the mixed-models repeated-measures modelingprocess. A compound symmetry matrix was specified as the ap-propriate structure for the variance-covariance matrix used todescribe the relationships among the data points.

Because the outcome of restoring menstruation was a dichoto-mous outcome, binary logistic regression analysis was performed

to examine the relationship between changes in body weight,

BMI from baseline to month 3, and changes in insulin levels, in-sulin resistance index, prolactin levels, LH levels, and LH/FSHratio from baseline to month 4 with restoration of menstruation.

A second analysis was conducted with the independent variablechanges from baseline to month 6 with restoration of menstrua-tion as the dependent variable. Observed associations were ex-pressed as coefficients. All these independent factors were en-tered into the backward likelihood ratio binary logistic equationat a single stage with the probability for entry set at 0.10 and re-moval at 0.15, reporting the coefficient values that were signifi-

cant at a two-tailed p level of 0.05.The sample size calculation was based on the data available

on metformin in obese women with amenorrhea (20, 21). With atotal sample size of 84 subjects, 42 subjects per arm, the power ofthe study was 85%.

Results

Randomization and Patient Characteristics

Of the 84 eligible patients, half were randomly assigned

to receive metformin, and half to receive placebo (Figure

1). A total of 76 patients (90.5%) completed the 6-month

treatments, 39 (92.8%) of whom were in the metformin

group and 37 (88.1%) in the placebo group. The demo-

graphic and clinical characteristics and baseline assess-

ments did not differ significantly between the two groups

(Table 1). At baseline, the patients had taken antipsychotic

medication for a mean of 6.2 months in the metformin

group and 6.5 months in the placebo group. Eight (19.0%)

patients in the metformin group and 10 (23.8%) in the pla-

cebo group had a BMI above the normal range (reference

range: 18.523.9). Overall, 59 (70.2%) patients (31 metfor-

min patients and 28 placebo patients) had gained more

than 10% of their body weight compared to their weight

prior to taking antipsychotics, which is often considered

excessive within the first year of treatment. Change in

body weight was determined by the weight at the study

screening visit and at the first visit (either as an outpatient

or an inpatient) to the Mental Health Institute of the Sec-


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tio in the metformin group were significantly greater than

those in the placebo group at month 6. The estradiol level

did not significantly change in the two groups during the

study period.

Relationship Between Restoration of Menstruation

and Changes in Body Weight and Hormone Levels

The mean time to menstruation restoration in the met-

formin group was 2 months, and all cases occurred in the

first 3 months. We performed binary backward logistic

regression analysis to evaluate the relationship of men-

struation restoration to changes in body weight, BMI from

baseline to month 3, and insulin level, insulin resistanceindex, prolactin level, LH level, and LH/FSH ratio from

baseline to month 4. The results showed that the extent of

decreases in body weight, insulin resistance index, prolac-

tin level, and LH level contributed to a greater probabil-

ity of restoration of menstruation, with values of 1.134

(p


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renal function tests, and ECG results remained normal in

all patients throughout the course of the study, and there

were no episodes of vomiting or lactic acidosis.

Discussion

In this first randomized, double-blind, placebo-con-trolled, 6-month study of metformin compared with pla-

cebo for antipsychotic-induced amenorrhea and weight

gain in female patients with first-episode schizophrenia,

we found that 66.7% of patients in the metformin group

resumed menstruation, whereas only 4.8% in the placebo

group did so. Furthermore, the mean body weight, BMI,

insulin level, and insulin resistance index significantly de-

creased from baseline in the metformin group, whereas

there were significant increases in body weight and BMI

in the placebo group. In our previous studies (15, 16),

we found that metformin could attenuate antipsychot-

ic-induced weight gain and improve insulin resistance.

Similarly, Klein et al. (27) reported that metformin could

reduce weight gain in children and adolescents who were

treated with olanzapine.

In this study, we also observed statistically significant

decreases in mean prolactin, LH, and testosterone levels

and LH/FSH ratio in the metformin group. These findings

suggest that metformin may improve or reverse antipsy-

chotic-induced amenorrhea and endocrine system dys-

function.

Since metformin has numerous central and peripheral

pharmacological effects in humans, the exact mechanism

by which it restores menstruation is unknown; altera-

tions in dopamine tone, reduction in weight, decreased

prolactin levels, and reduced metabolic syndrome may

be potential mechanisms underlying restoration of men-

struation (13, 14). Some studies suggest that antipsychot-

ic-induced menstrual dysfunction is independent of pro-

lactin levels but related to ovarian dysfunction, which can

be exacerbated by insulin resistance (2830). Moreover,

antipsychotic-induced weight gain may be highly related

to abnormal hormone levels, including increased levels of

prolactin, estrogen, and testosterone (31). Prolactin secre-

tion can be modulated by levels of other hormones, such

as estrogen (32), and hyperprolactinemia may be related

probability of restoration of menstruation, with values

of 0.833 (p=0.001), 1.375 (p=0.002), 0.488 (p=0.040), and

0.312 (p=0.033), respectively.

Last-observation-carried-forward analyses, which were

conducted separately, revealed findings similar to those of

the mixed-models repeated-measures analysis and thusare not presented here.

Adverse Events

There were no significant differences in the frequency

and types of adverse events reported between the two

groups. Adverse events that affected more than 5% of

the overall sample are presented in Table 2. There were

three serious adverse events that led to withdrawal from

the trial, one in the metformin group and two in placebo

group. All three events were exacerbation of psychosis and

resulted in hospital admission. No hypoglycemia was re-

ported during the trial. Serum lactic acid levels, liver and

TABLE 2. Adverse Events in a Randomized, Placebo-Controlled Study of Metformin for Treatment of Antipsychotic-InducedAmenorrhea and Weight Gaina

Total (N=84) Metformin Group (N=42) Placebo Group (N=42)

Adverse Event N % N % N %

Nausea 16 19.0 9 21.4 7 16.7

Extrapyramidal symptoms 25 29.8 12 28.5 13 30.9

Insomnia and agitation 16 19.0 9 21.4 7 16.7

Somnolence 11 13.1 5 11.9 6 14.3Headache 12 14.3 5 11.9 7 16.7

Dry mouth 16 19.0 7 16.7 9 21.4aThe table lists adverse events that affected more than 5% of the entire sample. There were no significant differences between groups on any

adverse event.

FIGURE 2. Time to Restoration of Menstruation After Initia-tion of Metformin in Patients With Antipsychotic-InducedAmenorrhea (N=28) Who Resumed Menstruation DuringMetformin Treatmenta

Months Since Initiation ofMetformin Treatment

ProportionofPatientsWhoHave

NotResumedMenstruation

0.0

0.2

0.4

0.6

0.8

1.0

0.50 1.00 1.50 2.00 2.50 3.00

aThe placebo group was not included in the survival curve, as onlytwo placebo patients resumed menstruation during the study pe-riod (one at 2 months and the other at 2.5 months).


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androgen-secreting neoplasms, and nonclassic adrenal

hyperplasia. There is substantial evidence that in polycys-

tic ovarian syndrome, metformin decreases weight gain,

improves insulin resistance, and restores menstruation,

suggesting a possible link between the metabolic ab-

normalities and hyperprolactinemia and amenorrhea in

polycystic ovarian syndrome (1719).

to multiple factors, including weight gain, metabolic syn-

drome, and insulin resistance (33, 34).

Polycystic ovarian syndrome, a common syndrome

occurring in 7% of women, can be characterized by hy-

perandrogenism, ovary dysfunction, polycystic ovarian

morphological abnormalities, chronic ovulation, amenor-

rhea, hirsutism, thyroid dysfunction, hyperprolactinemia,

FIGURE 3. Treatment Outcomes in a Placebo-Controlled Study of Metformin for Treatment of Antipsychotic-InducedAmenorrhea and Weight Gain (N=84)a

Prolactin(g/L)

Bod

yMassIndex

Months

0 1 2 3 4 5 6

W

eight(kg)

60

59

58

57

56

55

54

53

Months

0 1 2 3 4 5 6

28

27

26

25

24

23

22

21

Months

0 1 2 3 4 5 6FastingGlucose(mmol/L)

5.14

5.12

5.10

5.08

5.06

5.04

5.02

5.00

Comparison Group

Metformin Group

InsulinResistanceIndex

Months

0 1 2 3 4 5 6

Insulin(IU/mL)

26

24

22

20

18

16

14

12

Months

0 1 2 3 4 5 6

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

Months

0 1 2 3 4 5 6

260

240

220

200

180

160

140

120

100

80

Follicle-Stimulating

Hormone(FSH)(IU/L)

Months

0 1 2 3 4 5 6LuteinizingHormone(LH)(IU/L)

18

16

14

12

10

8

6

Months

0 1 2 3 4 5 6

8

7

6

5

4

3

Months

0 1 2 3 4 5 6

LH/FSHRatio

4.0

3.5

3.0

2.5

2.0

1.5

1.0

Testosterone(nmoI/L)

Months

0 1 2 3 4 5 6

Estradiol(nmoI/L)

0.8

0.7

0.6

0.5

0.4

0.3

Months

0 1 2 3 4 5 6

2.50

2.25

2.00

1.75

1.50

1.25

1.00

****

***

****

****

*

**** ****

**

*

*

aInteraction effect (derived from mixed-models repeated-measures [MMRM]) of group by time: F values were 32.62 for weight, 32.13 for bodymass index, 20.56 for insulin, 17.78 for insulin resistance index, 9.65 for prolactin, 7.92 for LH, and 4.40 for LH/FSH ratio. Difference for each

time point between the two treatment groups is from estimates of least squares mean using MMRM t test analysis (*p


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cebo group, with similar changes in fasting glucose and

insulin levels, although Western studies do not all show a

large change. Metformin has been used widely for the past

50 years throughout the world for type 2 diabetes and is

considered by many guidelines to be the drug of choice

for this indication because it reduces weight and has a

good safety profile (13). Some consider it the treatment of

choice for polycystic ovarian syndrome-induced amenor-rhea (19). Rarely lactic acidosis can occur, but usually in

the context of either metformin overdose or medical con-

traindications (19). In a study of the accumulated experi-

ence of more than 30,000 patients, no cases of lactic aci-

dosis were reported (36). In the present study, we observed

no adverse effects of metformin on the positive and nega-

tive symptoms of schizophrenia. Long-term therapy with

metformin is associated with decreased intestinal absorp-

tion of vitamin B12and folate, although in adults the re-

ductions in these nutrients are rarely clinically important,

and they are reversed when the drug is discontinued (37).

Our study has some limitations. First, this was a 6-monthtrial, and therefore we do not know whether restoration of

menstruation and reduction of body weight can be sus-

tained after patients stop taking metformin. Second, we

did not monitor serum B12and folate levels, although our

laboratory tests did indicate that there was no decline in

hemoglobin levels in any of the patients. Third, we did not

examine pharmacokinetic interactions between antipsy-

chotics and metformin. However, metformin is unlikely

to have interactions with antipsychotics because it is not

metabolized and does not inhibit the metabolism of other

drugs. Fourth, our sample size was relatively small. Finally,

our patients, as first-episode schizophrenia patients withless than a year of illness, were young, so we do not know

whether metformin would have the same effect in older or

chronic patients with schizophrenia.

Despite these limitations, this study has shown clearly

that the addition of metformin to antipsychotics is a po-

tential treatment to restore antipsychotic-induced amen-

orrhea in female patients with schizophrenia.

Received Sept. 26, 2011; revisions received Dec. 27, 2011,

and March 5, 2012; accepted April 13, 2012 (doi: 10.1176/appi.

ajp.2012.11091432). From the Institute of Mental Health of the Sec-

ond Xiangya Hospital, Central South University, Changsha, China; the

Department of Psychiatry, University of California, San Diego, La Jol-

la; the Department of Psychiatry, Case Western Reserve and Univer-

sity Hospital Case Medical Center, Cleveland; the Center of Excellence

for Stress and Mental Health, VA San Diego Healthcare System, San

Diego; the Department of Psychiatry, University of Illinois at Chicago;

and the Hangzhou Seventh People Hospital, Hangzhou, China. Ad-

dress correspondence to Dr. Wu ([email protected]) or

Dr. Zhao ([email protected]).

Dr. Gao has received research grants from AstraZeneca, NARSAD,

and the Cleveland Foundation. The other authors report no financial

relationships with commercial interests.

Supported by grant 30971052 from the National Natural Science

Foundation of China to Dr. Wu and by grant 201002003 from the

National R&D Special Program for Health Professions to Dr. Zhao.

Dr. Wu is grateful to the World Psychiatric Association for providing

financial support for her fellowship.

Because polycystic ovarian syndrome is a common

disorder, it would be expected to be equally common in

schizophrenia, and it is possible that polycystic ovarian

syndrome or pre-polycystic ovarian syndrome exists in

many of these patients and is involved in antipsychotic-

induced weight gain. There are clearly analogies between

polycystic ovarian syndrome and antipsychotic-induced

weight gain and amenorrhea. Metformin increases dopa-minergic tone in polycystic ovarian syndrome (23), which

would reduce the patients elevated prolactin level. Even

so, the exact mechanism by which metformin restores

menstruation in polycystic ovarian syndrome is not clearly

understood, again because of metformins many actions.

Since most patients with polycystic ovarian syndrome are

obese and have consequent metabolic problems, metfor-

min clearly restores menstruation and decreases weight

in these patients, but it can also restore menstruation in

normal-weight patients with polycystic ovarian syndrome

(35). We found here that the restoration of menstruation

was strongly related to weight loss and that weight losspreceded the normalization of other metabolic distur-

bances such as insulin resistance, which is similar to the

circumstances of restoration of menstruation in women

with polycystic ovarian syndrome (19). The menstrual

determinants in antipsychotic-induced elevated prolac-

tin levels, weight gain, and metabolic changes are disas-

sociated in that the drugs that cause the most weight gain

(olanzapine and clozapine) do not elevate prolactin lev-

els, while sulpiride, amisulpride, and high-potency first-

generation antipsychotics do, but only risperidone causes

moderate weight gain and elevated prolactin levels.

Since the relationship between menstruation restora-tion and weight loss is stronger than the relationships be-

tween menstruation restoration and prolactin decrease

or insulin resistance index normalization, it will require

further research to disentangle the relative roles of these

various changes in menstruation restoration and antipsy-

chotic-induced amenorrhea.

Weight gain, metabolic abnormalities, prolactin eleva-

tion, and amenorrhea are important side effects of anti-

psychotics. Metformin provides a new option for manag-

ing these complications. Indeed, amenorrhea, weight gain,

and metabolic syndrome can occur in the same patient,

so metformin may be a particularly important potential

treatment, especially for those who have a good thera-

peutic response to risperidone. Of course, a patient with

amenorrhea on risperidone could be switched to olan-

zapine or clozapine and have a good clinical response, but

those drugs may induce further weight gain.

We found previously (16) that substantial weight loss

can occur with metformin. Indeed, the average weight loss

with metformin coupled with lifestyle changes was 4.7 kg,

whereas weight increased by 3.1 kg in placebo-treated pa-

tients. The insulin resistance index improved markedly (a

decrease of 3.6) in the metformin-plus-lifestyle-changes

group, but deteriorated (an increase of 0.4) in the pla-


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