Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review Qi-Jing Bo a,b, Zhi-Min Wang a,b, Xian-Bin Li a,b, Xin Ma a, Chuan-Yue Wang a,b,n, Jose de Leon c,d,e a
Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology, Beijing, China c Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA d Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain e Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apóstol Hospital, University of the Basque Country, Vitoria, Spain b
art ic l e i nf o
a b s t r a c t
Article history: Received 19 June 2015 Received in revised form 9 November 2015 Accepted 15 January 2016
This systematic review examines adjunctive metformin therapy for the treatment of antipsychotic-induced hyperprolactinemia. A computerized search of databases in Chinese and the international databases in English provided three trials with a total of 325 patients including one randomized clinical trial (RCT) and two observational studies (single-group, before-after design). A meta-analysis could not be conducted. The quality of evidence ranged from “very low” to “moderate”. Metformin patients had a significant decrease in serum prolactin level with a mean of 54.6 μg/l in the three trials. In the RCT, menstruation restarted in 67% of those with menstrual disturbances versus 5% in placebo. In one observational study, 91% of patients no longer had signs or symptoms of galactorrhea. In the RCT, adverse drug reactions (ADRs) occurred at similar incidence rates among metformin and placebo patients, except that no significant increases in nausea, insomnia and agitation occurred which were not associated with discontinuations. Our systematic review indicated that adjunctive metformin significantly lowered prolactin level and relieved prolactin-related symptoms in patients with antipsychotic-induced hyperprolactinemia. Future higher quality RCTs need to verify the currently available limited evidence based on three trials which suggest that adjunctive metformin may be used effectively and safely for antipsychotic-induced hyperprolactinemia. & 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Metabolic abnormalities Prolactin Weight gain
1. Introduction Use of antipsychotic drugs has been associated with hyperprolactinemia, defined as a prolactin level above the reference interval; this hormonal abnormality can interfere with the functioning of metabolic, endocrine, and reproductive systems (Inder and Castle, 2011). Hyperprolactinemia is one of the most common antipsychotic-induced adverse drug reactions (ADRs), with respective rates in male and female patients of 18–76% and 42–90% (Bushe and Shaw, 2007; Byerly et al., 2007; Bushe et al., 2008; Kim et al., 2012). Hyperprolactinemia has short- and long-term consequences that can seriously affect quality of life: menstrual irregularities, amenorrhea, galactorrhea, sexual dysfunction, gynecomastia, infertility, decreased bone mineral density, even breast n Corresponding author at: Beijing Anding Hospital, Capital Medical University No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing 100088, China. E-mail address: [email protected] (C.-Y. Wang).
cancer, and poor treatment adherence (Halbreich and Kahn, 2003; O'Keane, 2008; Bushe et al., 2009; Kishimoto et al., 2012). Several strategies have been recommended to prevent or alleviate hyperprolactinemia (Bostwick et al., 2009; Nunes et al., 2012). Using the lowest effective antipsychotic dose can minimize hyperprolactinemia risk, but maintenance treatments with reduced doses have higher relapse rates than the full treatment dose (Wang et al., 2010). Switching to an antipsychotic agent with lower hyperprolactinemia risk is not always possible since the alternative agent may not be effective or may be associated with other ADRs (Leucht et al., 2013). Adding a dopamine agonist, such as bromocriptine, amantadine or cabergoline, can compromise antipsychotic efficacy and aggravate abnormal involuntary movements (Marken et al., 1992; Biller et al., 1999; Yuan et al., 2008). Some studies indicate that some herbal medicines can resolve risperidone-induced hyperprolactinemia (Yamada et al., 1999; Yuan et al., 2008). Adding aripiprazole can be effective for hyperprolactinemia (Shim et al., 2007; Hoffer et al., 2009; Kane et al., 2009; Li et al., 2013), but antipsychotic polytherapy is not
http://dx.doi.org/10.1016/j.psychres.2016.01.031 0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
2
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Fig. 1. Flow diagram of study selection.
recommended (Lehman et al., 2004), and can increase other ADRs (Bhattacharjee and El-Sayeh, 2008). Metformin is the most prescribed oral antidiabetic drug for the treatment of type 2 diabetes mellitus, and has been reported to reduce prolactin levels (Velazquez et al., 1994; Billa et al., 2009; Krysiak et al., 2015). It is possible that reducing prolactin levels may also contribute to decreased weight, since Baptista et al. (2001) proposed that prolactin may be involved in antipsychoticinduced weight gain. They found a positive association between prolactin levels and body mass index (BMI) only in males. According to them, several mechanisms may explain this association, since prolactin may: (1) impair the synthesis of the gonadal sex hormones which may influence brain hormones and promote obesity; (2) interfere with synthesis of brain peptides and secondarily with opioid-endorphin rewarding aspects of feeding; (3) induce hyperinsulinemia promoting fat deposit; and (4) stimulate feeding by acting directly at the hypothalamus. The role of metformin on antipsychotic-induced hyperprolactinemia has recently been brought to psychiatrists’ attention (Smith, 2012). There have been a few trials of the addition of metformin for hyperprolactinemia (Liang, 2013; Shi and Ding, 2013), and a randomized controlled trial (RCT) indicated normalization in prolactin levels and patients’ recovery from prolactinrelated symptoms (Wu et al., 2012). As there has been no thorough systematic review on this topic, the aim of this systematic review was to evaluate adjunctive metformin therapy for the treatment of antipsychotic-induced hyperprolactinemia, particularly focusing on efficacy and safety.
2. Methods 2.1. Protocol Before we conducted this systematic review, our protocol of reviewing metformin use for antipsychotic-induced hyperprolactinemia was published online (http://www.crd.york.ac.uk/pros pero/); the registration number was CRD42014013839 at the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PRISMA provides an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses (Moher et al., 2009). 2.2. Types of trials All types of adult trials evaluating the efficacy and safety of adjunctive metformin for antipsychotic-induced hyperprolactinemia were eligible for inclusion. We included studies with welldefined treatment protocols and which reported at least one of the outcome measures mentioned below. We included case series, RCTs, open-label retrospective studies and prospective trials. We excluded meta-analyses and systematic reviews. 2.3. Outcome measures We recorded clinical outcomes according to intent-to-treat (ITT) analyses where available. The primary outcome measures of this systematic review were efficacy of treatment (serum prolactin level and prolactin-related symptoms: oligomenorrhea, amenorrhea, and galactorrhea recovery) and ADRs (nausea, extrapyramidal symptoms, insomnia and agitation, somnolence, headache, and dry mouth), as reported in the studies. The secondary
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
Table 1 Summary of studies. Study
Design
Duration (weeks)
N
Antipsychotic
Wu et al. (2012)
PLA-controlled Double-blind Randomized
36
84 ♀
Liang (2013)
Observational Single group
8
116 ♀
Shi and Ding (2013)
Observational Single group
12
35 ♀/♂
Clozapine Olanzapine Risperidone Sulpiride Chlorpromazine Clozapine Risperidone Sulpiride Chlorpromazine Clozapine Quetiapine Risperidone Sulpiride
MET dose (mg/day)
↓ prolactin level μg/L
Symptoms
1000
MET: 84.2 7 18.1 PLA: 8.4 7 23.9
Regained menses 67% in MET 5% in PLA
1500
MET: 61.8 7 11.5
750
MET: 17.7 725.3
91% regained menses and no galactorrhea 9% no improvement Not applicable
MET: metformin. PLA: placebo.
outcome measures were discontinuation (all reasons for study discontinuation were included) and improvement in psychiatric symptoms (the change of PANSS total score). 2.4. Study selection Two authors, Q-JB and Z-MW, independently searched the PubMed, Embase, SCI, and Cochrane Library databases and the Cochrane Controlled Trials Register, WHO ICTRP, NIH ClinicalTrials. gov, and the Chinese Clinical Trials Register for trials evaluating adjunctive metformin for antipsychotic-induced hyperprolactinemia. We also searched the Chinese databases (CBM, CNKI, and WanFang) using the same key words. The search included all studies from January 1957 to October 2015. Both indexed and free text terms were used, and no language restriction was applied. The keywords included: metformin, hyperprolactinemia, prolactin abnormal, amenorrhea, menstrual irregularities, oligomenorrhea, galactorrhea, and gynecomastia. The keywords were used in combination with the Boolean operators AND, OR, and NOT. We manually searched bibliographies of RCTs, meta-analyses, and systematic reviews for studies that were missed in the initial electronic search (Fig. 1). Authors Q-JB and Z-MW assessed studies that met the inclusion criteria for the meta-analysis independently; the third author was involved in the discussion if any disagreements existed. 2.5. Assessment of the risk of bias in included studies The included studies were assessed for risk of bias using the Cochrane risk of bias assessment tool to assess selection bias (sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessors), attrition bias (completeness of outcome data), reporting bias (selective outcome reporting), and other potential sources of bias. Authors Q-JB and Z-MW assessed the included studies according to these six criteria; any disagreements were resolved by discussion with the third author. Furthermore, we used the grading of recommendations assessment, development, and evaluation (GRADE) system to rate the quality of evidence and strength of recommendations of this systematic review. This was recommended by the Cochrane Collaboration. GRADE included systematic assessments of all included trials across six main domains for each outcome: limitations of the study design and execution, inconsistency, indirectness, and imprecision of results, publication bias, and large effect. Accordingly, we graded the recommendations for outcome measure of metformin for hyperprolactinemia as very low, low, moderate, or high.
2.6. Data extraction Authors Q-JB and Z-MW initially considered all included studies, without seeing comparison data, to judge clinical, methodological and statistical heterogeneity and thereby decide whether each study would be included in the meta-analysis or another data synthesis. Then they extracted data into standard, simple forms. Again, any disagreement was discussed, decisions documented, and, if necessary, authors of studies were contacted for clarification. If any information on trial methodology or any trial data were missing, the study authors were contacted by email in order to obtain missing information or for clarification whenever deemed necessary.
3. Results 3.1. Quality assessment and study design We included three trials in our systematic review (Fig. 1, Tables 1 and 2). Table 1 summarizes the characteristics of the three included studies. Table 2 describes the details of the studies including one RCT (Wu et al., 2012) and two observational studies (Liang, 2013; Shi and Ding, 2013). These studies were published in the last three years, which indicates that metformin for antipsychotic-induced hyperprolactinemia is a new clinically-important topic. All three studies tested the serum prolactin level but only two studies reported prolactin-related ADRs (Table 1). Using the Cochrane risk of bias assessment tool, the RCT demonstrated low risk for selection bias, performance bias, detection bias, attrition bias, reporting bias and other potential sources of bias. Randomization methods were reported as computer-generated in the study. A research pharmacist who was independent of the investigators was assigned to ensure concealment of the randomization. The two observational trials were single group, before-after studies (Liang, 2013; Shi and Ding, 2013). 3.2. Analysis of outcomes Tables 1 and 3 summarize outcomes for the individual trials. It was not possible to conduct a meta-analysis because of the trials’ heterogeneity, which included differences in gender (female vs. either gender), methodology (observational study vs. RCT), followup time (8 weeks, 12 weeks and 6 months) and outcome definition (symptoms vs. serum prolactin level). Furthermore, metformin dosage varied between 750, 1000, and 1500 mg/day. Although meta-analysis is a powerful tool for analyzing data (Leandro, 2008), confounding inter-study variables that cannot be controlled
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
3.3. Treatment efficacy
Table 2 Description of each study.
Metformin patients had a significant decrease in the serum prolactin level with a mean of 54.6 μg/l in the three trials. In the RCT, menstruation restarted in 67% of those with menstrual disturbances. In one of the observational studies, 91% no longer had signs or symptoms of galactorrhea (Table 1).
Wu et al. (2012) Methods: Randomized, double-blind, placebo-controlled study. Subjects: Eighty-four women (ages 18 to 40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned. Patients were excluded from the study if there was evidence of liver or renal dysfunction, cardiovascular disease, or diabetes mellitus; if they were pregnant or lactating; or if they had a psychiatric diagnosis other than schizophrenia or a current history of substance use disorder. Interventions: Participants received 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. Outcomes: Decreases in mean serum prolactin levels, restoration of menstruation, and ADR incidence.
3.4. ADRs and discontinuation rates Table 3 summarizes ADRs and discontinuation rates. ADRs occurred at similar incidence rates among metformin and placebo patients, except for nausea, insomnia and agitation, which were more frequent in the metformin group in the RCT (Wu et al., 2012), but with no significant differences. ADRs were not reported in the two observational studies (Liang, 2013; Shi and Ding, 2013). In the RCT, there was no discontinuation associated with an ADR. One of the observational studies did not describe discontinuation rates (Liang, 2013).
Liang (2013) Methods: Open-label prospective trial. Subjects: All 116 female patients with schizophrenia, ages 18–50 years, with galactorrhea-amenorrhea syndrome lasting for 3 months who had serum prolactin levelsZ 60 mg/L were enrolled. Patients were ineligible if they had high risk for suicide, severe endocrine disease or gynecological disease, drug allergy history, or were pregnant during the trial period. Interventions: Participants received adjunctive metformin 1500 mg daily for 8 weeks. Outcomes: Decreases in mean serum prolactin levels, improvement of menstruation and galactorrhea, and ADR incidence.
4. Discussion
Shi and Ding (2013) Methods: Open-label prospective trial. Subjects: Thirty-five patients during antipsychotic treatment, either gender, ages 18 to 50 years who had serum prolactin levelsZ30 ng/mL were enrolled. Patients were ineligible if they had any medical illness, were pregnant or lactating. Interventions: Participants were assigned to receive metformin treatment of 750 mg/day for 12 weeks. Outcomes: Decreases in mean serum prolactin levels, and ADR incidence.
4.1. Efficacy
ADR: adverse drug reaction.
may violate basic statistical assumptions, making these types of analyses error-prone (Ried, 2006; Leandro, 2008). Therefore, we only extracted data onto standard, simple forms as well as other descriptive statistics. Quality assessment of the included studies according to the GRADE approach showed some limitations of the study design and imprecision, but no obvious indirectness or inconsistency in reporting the results (Table 4). Based on the above assessments, the quality of evidence presented for each outcome ranged from “very low” to “moderate”. We did not conduct a funnel plot analysis to show the presence of risk of publication bias because only three studies were included and asymmetry could not be reliably judged. Nonetheless, we did not identify any unpublished negative studies related to the papers.
This is the first systematic review of metformin for antipsychotic-induced hyperprolactinemia which summarizes its efficacy and safety. Our comprehensive systematic review includes three studies with a total of 235 patients and suggests that metformin may be an effective therapy, safe and well-tolerated. Adjunctive metformin was superior to placebo in prolactin level decrease and prolactin-related symptom recovery. While it is an interesting and potentially important adjunctive treatment, these findings clearly need to be verified in extended studies in this field. Our systematic review indicated that adjunctive metformin significantly lowered prolactin level and relieved prolactin-related symptoms in patients with antipsychotic-induced hyperprolactinemia. Antipsychotic treatment through high D2 occupancy in the tuberoinfundibular system region can lead to a dopamine deficiency, increasing the risk of hyperprolactinemia (Nordstrom and Farde, 1998). Metformin has been shown to increase the endogenous dopaminergic tone in women with polycystic ovary syndrome (Ortega-Gonzalez et al., 2005), and this may be one of its mechanisms of action in the clinical effects (Krysiak et al., 2015). Metformin is an old drug that is now gaining increasing attention in the treatment of antipsychotic ADRs (Linneke et al., 2014). Studies have indicated that metformin can attenuate or
Table 3 ADRs and discontinuation rates. Study
ADRs
Discontinuation Rate
Wu et al. (2012)
Liang (2013) Shi and Ding (2013)
Nausea Extrapyramidal symptoms Insomnia and agitation Somnolence Headaches Dry mouth None None
PLA 17% (7/42) 31% (13/42) 17% (7/42) 14% (6/42) 17% (7/42) 21% (9/42)
MET 21% (9/42) 29% (12/42) 21% (9/42) 12% (5/42) 12% (5/42) 17% (7/42)
PLA 12% (5/42)a,b
MET 7% (3/42)a,b
Not reported 11 patients withdrawn but reason was not reported
MET: metformin. PLA: placebo. a b
Lost to follow-up: 3 on PLA and 2 on MET. Hospitalized: 2 on PLA and 1 on MET.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
5
Table 4 GRADE system analysis. Design Observational Prolactin level Symptom-recoveryd Discontinuation RCT Prolactin level Symptom-recoveryd Discontinuation Nausea EPS Insomnia/agitation Somnolence Headache Dry mouth
N (studies)
Risk of Bias
Inconsistency
Indirectness
Imprecision
Publication bias
Large effect
Overall quality of evidencea
151 (2) 116 (1) 35 (1)
Seriousb Seriousb Seriousb
No No No
No No No
Seriousc Seriouse Seriouse
Undetected Undetected Undetected
No No No
Very low Very low Very low
84 84 84 84 84 84 84 84 84
No No No No No No No No No
No No No No No No No No No
No No No No No No No No No
Seriousc Seriouse Seriouse Seriouse Seriouse Seriouse Seriouse Seriouse Seriouse
Undetected Undetected Undetected Undetected Undetected Undetected Undetected Undetected Undetected
No No No No No No No No No
Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate
(1) (1) (1) (1) (1) (1) (1) (1) (1)
EPS: extrapyramidal symptoms. GRADE: grading of recommendations assessment, development, and evaluation. RCT: randomized clinical trial. a The quality of evidence was rated using the GRADE Working Group system. High quality indicates that further research is very unlikely to change our confidence in the estimate of effect but none of the studies reached that level. Moderate quality indicates that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality indicates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality indicates that we are very uncertain about the estimate. b The two studies included a single group and withdrawal from the study or the reasons for withdrawal were not reported. c For continuous outcomes, N o 400. d Recovery from symptoms associated with hyperprolactinemia. e For dichotomous outcomes, N o300.
reverse some of the weight gain, fasting glucose level, insulin level, insulin resistance, and metabolic abnormalities induced by antipsychotic drugs (Baptista et al., 2008; Ehret et al., 2010; Wang et al., 2010; Wu et al., 2012; Correll et al., 2013; Jarskog et al., 2013). Meta-analyses have shown that four second-generation antipsychotics (amisulpride, clozapine, olanzapine, and risperidone) are more efficacious than others. These four antipsychotics were not associated with increased discontinuation rates (Davis et al., 2003; Leucht et al., 2009, 2013), but clozapine and olanzapine are associated with greater weight gain (Meyer, 2010; Musil et al., 2015) and amisulpride and risperidone are associated with considerably greater increases in prolactin levels (Haddad and Wieck, 2004). Metformin, a low-cost medicine, not only can limit weight gain but may also lower prolactin levels. 4.2. Safety There were no significant differences in ADRs when compared with placebo in the RCT and no obvious ADRs in the observational studies. Gastrointestinal reaction is the most common ADR but may be alleviated by taking metformin after meals. The observational trials were limited by no report of discontinuations or reasons for discontinuation but the RCT showed metformin discontinuation rates similar to placebo. 4.3. Limitations This review is limited for several reasons. First, it was not possible to conduct a meta-analysis because of the studies’ heterogeneity, including differences in their methodology, study design, study size and follow-up duration, patient and treatment selection, and outcome variables. The breadth of these differences may violate basic statistical assumptions and make these analyses error-prone. Therefore, we only extracted data onto standard, simple forms. Secondly, only three articles met the inclusion criteria and were used in the qualitative analysis. Two of them were observational trials; only one RCT was available. The GRADE approach showed the quality of evidence was “very low” for prolactin level, prolactin-related symptoms and discontinuations; the other
outcomes were “moderate” (Table 4). High quality evidence does not necessarily imply strong recommendations, and strong recommendations can arise from low quality evidence, depending on patients with varying values and preferences (Guyatt et al., 2008). In spite of the low quality of the evidence, metformin may be considered for managing antipsychotic-induced hyperprolactinemia, especially for women with irregular menstruation, even amenorrhea. Thirdly, the relationship between metformin dose and the change in prolactin levels was not analyzed. All of the included studies were very recent (from 2012 and 2013), demonstrating that the use of metformin in antipsychotic-induced hyperprolactinemia is a new idea. There was not enough evidence to explore the association between metformin dose and prolactin level when used as adjunctive treatment, which needs to be evaluated in future studies. Fourth, second-generation antipsychotics are now generally accepted as an iatrogenic cause of hyperprolactinemia and metabolic illness but other causes need to be considered. Polycystic ovarian syndrome (PCOS) has been referred to as a women's version of the metabolic syndrome (Matevosyan, 2011; Yum et al., 2014). There is some evidence that metformin may be effective for PCOS (Wu et al., 2012) which can be an indirect way of decreasing prolactin secretion in female patients taking antipsychotics. Other authors do not agree. Krysiak et al. (2015) found no mean change in fasting prolactin after metformin treatment. In this systematic review, patients were ineligible if they had severe endocrine disease, including PCOS. Furthermore, we also included 18 male patients; although the included subjects were almost exclusively females because hyperprolactinemia and its symptoms are more obvious in female patients. Thus, according to the limited studies included in this review, metformin appeared to have direct effects in decreasing prolactin associated with antipsychotic treatment and these effects do not appear to be mediated by improving PCOS. In conclusion, the currently available limited evidence of three trials suggests that adjunctive metformin may be used effectively and safely for antipsychotic-induced hyperprolactinemia. Adjunctive metformin appears to be superior to placebo in prolactin level decrease and prolactin-related symptom recovery.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
6
Adjunctive metformin does not appear to be associated with ADR increases or increased discontinuations. The use of adjunctive metformin to manage hyperprolactinemia and/or weight gain during the early phases of schizophrenia treatment may increase treatment compliance, which could offer long-term benefits in a chronic illness such as schizophrenia. Higher-quality metformin RCTs in hyperprolactinemia are needed.
Contributors As the text describes, Drs. Bo and ZM Wang completed study searches and bias assessments, and extracted data. Drs. Bo and ZM Wang wrote and contributed equally to the first draft. Dr. de Leon adjusted this first daft to the style of this journal. All authors have contributed to and have approved the final manuscript.
Conflict of interest None in the past three years. No pharmaceutical company had any role in the writing of this paper for publication.
Acknowledgments The review was conducted under the auspices of the Cochrane Schizophrenia Group, to which the authors are indebted. The authors thank Lorraine Maw, M.A., for editorial assistance. The study was supported by funding from the National Natural Science Foundation of China (81071083) to Dr. C.Y. Wang. This study was also supported by funding from the Beijing Science and Technology Commission (D101107047810001) and Beijing Hospital Authority clinical development projects "Sail" program (ZYLX201403) to Dr. C.Y. Wang.
References Baptista, T., LaCruz, A., Meza, T., Contreras, Q., Delgado, C., Mejías, M.A., Hernández, L., 2001. Antipsychotic drugs and obesity: Is prolactin involved? Can. J. Psychiatry 46, 829–834. Baptista, T., ElFakih, Y., Uzcátegui, E., Sandia, I., Tálamo, E., Araujo de Baptista, E., Beaulieu, S., 2008. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 22, 477–495. Bhattacharjee, J., El-Sayeh, H.G., 2008. Aripiprazole versus typicals for schizophrenia. Cochrane Database Syst. Rev. 16, CD006617. Billa, E., Kapolla, N., Nicopoulou, S.C., Koukkou, E., Venaki, E., Milingos, S., Antsaklis, A., Adamopoulos, D.A., 2009. Metformin administration was associated with a modification of LH, prolactin and insulin secretion dynamics in women with polycystic ovarian syndrome. Gynecol. Endocrinol. 25, 427–434. Biller, B., Luciano, A., Crosignani, P., Molitch, M., Olive, D., Rebar, R., Sanfilippo, J., Webster, J., Zacur, H., 1999. Guidelines for the diagnosis and treatment of hyperprolactinemia. J. Reprod. Med. 44, 1075–1084. Bostwick, J.R., Guthrie, S.K., Ellingrod, V.L., 2009. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy 29, 64–73. Bushe, C., Shaw, M., 2007. Prevalence of hyperprolactinaemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical antipsychotics. J. Psychopharmacol. 21, 768–773. Bushe, C., Shaw, M., Peveler, R.C., 2008. A review of the association between antipsychotic use and hyperprolactinaemia. J. Psychopharmacol. 22, 46–55. Bushe, C.J., Bradley, A.J., Wildgust, H.J., Hodgson, R.E., 2009. Schizophrenia and breast cancer incidence: a systematic review of clinical studies. Schizophr. Res. 114, 6–16. Byerly, M., Suppes, T., Tran, Q.V., Baker, R.A., 2007. Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives. J. Clin. Psychopharmacol. 27, 639–661. Correll, C.U., Sikich, L., Reeves, G., Riddle, M., 2013. Metformin for antipsychoticrelated weight gain and metabolic abnormalities: when, for whom, and for how long? Am. J. Psychiatry 170, 947–952. Davis, J.M., Chen, N., Glick, I.D., 2003. A meta-analysis of the efficacy of secondgeneration antipsychotics. Arch. Gen. Psychiatry 60, 553–564.
Ehret, M., Goethe, J., Lanosa, M., Coleman, C.I., 2010. The effect of metformin on anthropometrics and insulin resistance in patients receiving atypical antipsychotic agents: a meta-analysis. J. Clin. Psychiatry 71, 1286–1292. Guyatt, G.H., Oxman, A.D., Vist, G.E., Kunz, R., Falck-Ytter., Y., Alonso-Coello, P., Schünemann, H.J., GRADE Working Group, 2008. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br. Med. J. 336, 924–926. Haddad, P.M., Wieck, A., 2004. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 64, 2291–2314. Halbreich, U., Kahn, L.S., 2003. Hyperprolactinemia and schizophrenia: mechanisms and clinical aspects. J. Psychiatr. Pract. 9, 344–353. Hoffer, Z.S., Roth, R.L., Mathews, M., 2009. Evidence for the partial dopamine-receptor agonist aripiprazole as a first-line treatment of psychosis in patients with iatrogenic or tumorogenic hyperprolactinemia. Psychosomatics 50, 317–324. Inder, W.J., Castle, D., 2011. Antipsychotic-induced hyperprolactinaemia. Aust. N.Z J. Psychiatry 45, 830–837. Jarskog, L.F., Hamer, R.M., Catellier, D.J., Stewart, D.D., Lavange, L., Ray, N., Golden, L. H., Lieberman, J.A., Stroup, T.S., METS Investigators, 2013. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am. J. Psychiatry 170, 1032–1040. Kane, J.M., Correll, C.U., Goff, D.C., Kirkpatrick, B., Marder, S.R., Vester-Blokland, E., Sun, W., Carson, W.H., Pikalov, A., Assunção-Talbott, S., 2009. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J. Clin. Psychiatry 70, 1348–1357. Kim, E.Y., Kim, S.H., Lee, N.Y., Jung, D.C., Kim, Y.S., Ahn, Y.M., 2012. Relationship between prolactin levels and subjective endocrine-related adverse effects in patients with schizophrenia receiving long-term treatment with amisulpride. Pharmacopsychiatry 45, 57–63. Kishimoto, T., De Hert, M., Carlson, H.E., Manu, P., Correll, C.U., 2012. Osteoporosis and fracture risk in people with schizophrenia. Curr. Opin. Psychiatry 25, 415–429. Krysiak, R., Okrzesik, J., Okopien, B., 2015. The effect of short-term metformin treatment on plasma prolactin levels in bromocriptine-treated patients with hyperprolactinaemia and impaired glucose tolerance: a pilot study. Endocrine 49, 242–249. Leandro, G. 2008. Meta-analysis in Medical Research: The Handbook for the Understanding and Practice of Meta-analysis. Wiley.com. Available from: 〈http:// www.books.google.com〉 (accessed May 2015). Lehman, A.F., Lieberman, J., Dixon, L., McGlashan, T., Miller, A., Perkins, D.O., Kreyenbuhl, J., American Psychiatric Association, Steering Committee on Practice Guidelines, 2004. Practice guideline for the treatment of patients with schizophrenia. Am. J. Psychiatry 161 (2 Suppl), 1–56. Leucht, S., Komossa, K., Rummel-Kluge, C., Corves, C., Hunger, H., Schmid, F., Asenjo Lobos, C., Schwarz, S., Davis, J.M., 2009. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am. J. Psychiatry 166, 152–163. Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Orey, D., Richter, F., Samara, M., Barbui, C., Engel, R.R., Geddes, J.R., Kissling, W., Stapf, M.P., Lässig, B., Salanti, G., Davis, J.M., 2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951–962. Li, X., Tang, Y., Wang, C., 2013. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One 8, e70179. Liang, C.S., 2013. Effect of metformin on antipsychotic drug-induced galactorrheaamenorrhea syndrome. China Mod. Med. 20, 54–56 [In Chinese]. Linneke, J.L., Jorgensen, G.K., Csillag, C., 2014. Metformin for weight loss and control in patients with mood disorder. J. Clin. Psychiatry 75, e1140–e1141. Marken, P.A., Haykal, R.F., Fisher, J.N., 1992. Management of psychotropic-induced hyperprolactinemia. Clin. Pharm. 11, 851–856. Matevosyan, N.R., 2011. Schizophrenia and Stein-Leventhal syndrome: comorbidity features. Arch. Gynecol. Obstet. 284, 1035–1041. Meyer, J.M., 2010. Antipsychotics and metabolics in the post-CATIE era. Curr. Top. Bevav. Neurosci. 4, 23–42. Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann. Intern. Med. 151, 264–269. Musil, R., Obermeier, M., Russ, P., Hamerle, M., 2015. Weight gain and antipsychotics: a drug safety review. Expert. Opin. Drug. Saf. 14, 73–96. Nordstrom, A.L., Farde, L., 1998. Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients. J. Clin. Psychopharmacol. 18, 305–310. Nunes, L.V., Moreira, H.C., Razzouk, D., Nunes, S.O., Mari, J., de, J., 2012. Strategies for the treatment of antipsychotic-induced sexual dysfunction and/or hyperprolactinemia among patients of the schizophrenia spectrum: a review. J. Sex. Marital. Ther. 38, 281–301. O'Keane, V., 2008. Antipsychotic-induced hyperprolactinaemia, hypogonadism and osteoporosis in the treatment of schizophrenia. J. Psychopharmacol. 22, 70–75. Ortega-Gonzalez, C., Cardoza, L., Coutino, B., Hidalgo, R., Arteaga-Troncoso, G., Parra, A., 2005. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J. Endocrinol. 184, 233–239. Ried, K., 2006. Interpreting and understanding meta-analysis graphs – a practical guide. Aust. Fam. Phys. 35, 635–638. Shi, W., Ding, S.E., 2013. Preliminary observation of the metformin in efficacy for
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎ hyperprolactinemia induced by antipsychotics. J. Clin. Psychiatry 23, 408–409 [In Chinese]. Shim, J.C., Shin, J.G., Kelly, D.L., Jung, D.U., Seo, Y.S., Liu, K.H., Shon, J.H., Conley, R.R., 2007. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am. J. Psychiatry 164, 1404–1410. Smith, R.C., 2012. Metformin as a treatment for antipsychotic drug side effects: special focus on women with schizophrenia. Am. J. Psychiatry 169, 774–776. Velazquez, E.M., Mendoza, S., Hamer, T., Sosa, F., Glueck, C.J., 1994. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43, 647–654. Wang, C.Y., Xiang, Y.T., Cai, Z.J., Weng, Y.Z., Bo, Q.J., Zhao, J.P., Liu, T.Q., Wang, G.H., Weng, S.M., Zhang, H.Y., Chen, D.F., Tang, W.K., Ungvari, G.S., Risperidone Maintenance Treatment in Schizophrenia (RMTS) investigators, 2010. Risperidone maintenance treatment in schizophrenia: a randomized, controlled trial.
7
Am. J. Psychiatry 167, 676–685. Wu, R.R., Jin, H., Gao, K., Twamley, E.W., Ou, J.J., Shao, P., Wang, J., Guo, X.F., Davis, J. M., Chan, P.K., Zhao, J.P., 2012. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. Am. J. Psychiatry 169, 813–821. Yamada, K., Kanba, S., Yagi, G., Asai, M., 1999. Herbal medicine (Shakuyaku-kanzoto) in the treatment of risperidone-induced amenorrhea. J. Clin. Psychopharmacol. 19, 380–381 [In Chinese]. Yuan, H.N., Wang, C.Y., Sze, C.W., Tong, Y., Tan, Q.R., Feng, X.J., Liu, R.M., Zhang, J.Z., Zhang, Y.B., Zhang, Z.J., 2008. A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. J. Clin. Psychopharmacol. 28, 264–370. Yum, S.K., Kim, T., Hwang, M.Y., 2014. Polycystic ovaries is a disproportionate signal in pharmacovigilance data mining of second generation antipsychotics. Schizophr. Res. 158, 275–276.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review Qi-Jing Bo a,b, Zhi-Min Wang a,b, Xian-Bin Li a,b, Xin Ma a, Chuan-Yue Wang a,b,n, Jose de Leon c,d,e a
Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology, Beijing, China c Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA d Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain e Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apóstol Hospital, University of the Basque Country, Vitoria, Spain b
art ic l e i nf o
a b s t r a c t
Article history: Received 19 June 2015 Received in revised form 9 November 2015 Accepted 15 January 2016
This systematic review examines adjunctive metformin therapy for the treatment of antipsychotic-induced hyperprolactinemia. A computerized search of databases in Chinese and the international databases in English provided three trials with a total of 325 patients including one randomized clinical trial (RCT) and two observational studies (single-group, before-after design). A meta-analysis could not be conducted. The quality of evidence ranged from “very low” to “moderate”. Metformin patients had a significant decrease in serum prolactin level with a mean of 54.6 μg/l in the three trials. In the RCT, menstruation restarted in 67% of those with menstrual disturbances versus 5% in placebo. In one observational study, 91% of patients no longer had signs or symptoms of galactorrhea. In the RCT, adverse drug reactions (ADRs) occurred at similar incidence rates among metformin and placebo patients, except that no significant increases in nausea, insomnia and agitation occurred which were not associated with discontinuations. Our systematic review indicated that adjunctive metformin significantly lowered prolactin level and relieved prolactin-related symptoms in patients with antipsychotic-induced hyperprolactinemia. Future higher quality RCTs need to verify the currently available limited evidence based on three trials which suggest that adjunctive metformin may be used effectively and safely for antipsychotic-induced hyperprolactinemia. & 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Metabolic abnormalities Prolactin Weight gain
1. Introduction Use of antipsychotic drugs has been associated with hyperprolactinemia, defined as a prolactin level above the reference interval; this hormonal abnormality can interfere with the functioning of metabolic, endocrine, and reproductive systems (Inder and Castle, 2011). Hyperprolactinemia is one of the most common antipsychotic-induced adverse drug reactions (ADRs), with respective rates in male and female patients of 18–76% and 42–90% (Bushe and Shaw, 2007; Byerly et al., 2007; Bushe et al., 2008; Kim et al., 2012). Hyperprolactinemia has short- and long-term consequences that can seriously affect quality of life: menstrual irregularities, amenorrhea, galactorrhea, sexual dysfunction, gynecomastia, infertility, decreased bone mineral density, even breast n Corresponding author at: Beijing Anding Hospital, Capital Medical University No.5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing 100088, China. E-mail address: [email protected] (C.-Y. Wang).
cancer, and poor treatment adherence (Halbreich and Kahn, 2003; O'Keane, 2008; Bushe et al., 2009; Kishimoto et al., 2012). Several strategies have been recommended to prevent or alleviate hyperprolactinemia (Bostwick et al., 2009; Nunes et al., 2012). Using the lowest effective antipsychotic dose can minimize hyperprolactinemia risk, but maintenance treatments with reduced doses have higher relapse rates than the full treatment dose (Wang et al., 2010). Switching to an antipsychotic agent with lower hyperprolactinemia risk is not always possible since the alternative agent may not be effective or may be associated with other ADRs (Leucht et al., 2013). Adding a dopamine agonist, such as bromocriptine, amantadine or cabergoline, can compromise antipsychotic efficacy and aggravate abnormal involuntary movements (Marken et al., 1992; Biller et al., 1999; Yuan et al., 2008). Some studies indicate that some herbal medicines can resolve risperidone-induced hyperprolactinemia (Yamada et al., 1999; Yuan et al., 2008). Adding aripiprazole can be effective for hyperprolactinemia (Shim et al., 2007; Hoffer et al., 2009; Kane et al., 2009; Li et al., 2013), but antipsychotic polytherapy is not
http://dx.doi.org/10.1016/j.psychres.2016.01.031 0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
2
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Fig. 1. Flow diagram of study selection.
recommended (Lehman et al., 2004), and can increase other ADRs (Bhattacharjee and El-Sayeh, 2008). Metformin is the most prescribed oral antidiabetic drug for the treatment of type 2 diabetes mellitus, and has been reported to reduce prolactin levels (Velazquez et al., 1994; Billa et al., 2009; Krysiak et al., 2015). It is possible that reducing prolactin levels may also contribute to decreased weight, since Baptista et al. (2001) proposed that prolactin may be involved in antipsychoticinduced weight gain. They found a positive association between prolactin levels and body mass index (BMI) only in males. According to them, several mechanisms may explain this association, since prolactin may: (1) impair the synthesis of the gonadal sex hormones which may influence brain hormones and promote obesity; (2) interfere with synthesis of brain peptides and secondarily with opioid-endorphin rewarding aspects of feeding; (3) induce hyperinsulinemia promoting fat deposit; and (4) stimulate feeding by acting directly at the hypothalamus. The role of metformin on antipsychotic-induced hyperprolactinemia has recently been brought to psychiatrists’ attention (Smith, 2012). There have been a few trials of the addition of metformin for hyperprolactinemia (Liang, 2013; Shi and Ding, 2013), and a randomized controlled trial (RCT) indicated normalization in prolactin levels and patients’ recovery from prolactinrelated symptoms (Wu et al., 2012). As there has been no thorough systematic review on this topic, the aim of this systematic review was to evaluate adjunctive metformin therapy for the treatment of antipsychotic-induced hyperprolactinemia, particularly focusing on efficacy and safety.
2. Methods 2.1. Protocol Before we conducted this systematic review, our protocol of reviewing metformin use for antipsychotic-induced hyperprolactinemia was published online (http://www.crd.york.ac.uk/pros pero/); the registration number was CRD42014013839 at the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PRISMA provides an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses (Moher et al., 2009). 2.2. Types of trials All types of adult trials evaluating the efficacy and safety of adjunctive metformin for antipsychotic-induced hyperprolactinemia were eligible for inclusion. We included studies with welldefined treatment protocols and which reported at least one of the outcome measures mentioned below. We included case series, RCTs, open-label retrospective studies and prospective trials. We excluded meta-analyses and systematic reviews. 2.3. Outcome measures We recorded clinical outcomes according to intent-to-treat (ITT) analyses where available. The primary outcome measures of this systematic review were efficacy of treatment (serum prolactin level and prolactin-related symptoms: oligomenorrhea, amenorrhea, and galactorrhea recovery) and ADRs (nausea, extrapyramidal symptoms, insomnia and agitation, somnolence, headache, and dry mouth), as reported in the studies. The secondary
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
Table 1 Summary of studies. Study
Design
Duration (weeks)
N
Antipsychotic
Wu et al. (2012)
PLA-controlled Double-blind Randomized
36
84 ♀
Liang (2013)
Observational Single group
8
116 ♀
Shi and Ding (2013)
Observational Single group
12
35 ♀/♂
Clozapine Olanzapine Risperidone Sulpiride Chlorpromazine Clozapine Risperidone Sulpiride Chlorpromazine Clozapine Quetiapine Risperidone Sulpiride
MET dose (mg/day)
↓ prolactin level μg/L
Symptoms
1000
MET: 84.2 7 18.1 PLA: 8.4 7 23.9
Regained menses 67% in MET 5% in PLA
1500
MET: 61.8 7 11.5
750
MET: 17.7 725.3
91% regained menses and no galactorrhea 9% no improvement Not applicable
MET: metformin. PLA: placebo.
outcome measures were discontinuation (all reasons for study discontinuation were included) and improvement in psychiatric symptoms (the change of PANSS total score). 2.4. Study selection Two authors, Q-JB and Z-MW, independently searched the PubMed, Embase, SCI, and Cochrane Library databases and the Cochrane Controlled Trials Register, WHO ICTRP, NIH ClinicalTrials. gov, and the Chinese Clinical Trials Register for trials evaluating adjunctive metformin for antipsychotic-induced hyperprolactinemia. We also searched the Chinese databases (CBM, CNKI, and WanFang) using the same key words. The search included all studies from January 1957 to October 2015. Both indexed and free text terms were used, and no language restriction was applied. The keywords included: metformin, hyperprolactinemia, prolactin abnormal, amenorrhea, menstrual irregularities, oligomenorrhea, galactorrhea, and gynecomastia. The keywords were used in combination with the Boolean operators AND, OR, and NOT. We manually searched bibliographies of RCTs, meta-analyses, and systematic reviews for studies that were missed in the initial electronic search (Fig. 1). Authors Q-JB and Z-MW assessed studies that met the inclusion criteria for the meta-analysis independently; the third author was involved in the discussion if any disagreements existed. 2.5. Assessment of the risk of bias in included studies The included studies were assessed for risk of bias using the Cochrane risk of bias assessment tool to assess selection bias (sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessors), attrition bias (completeness of outcome data), reporting bias (selective outcome reporting), and other potential sources of bias. Authors Q-JB and Z-MW assessed the included studies according to these six criteria; any disagreements were resolved by discussion with the third author. Furthermore, we used the grading of recommendations assessment, development, and evaluation (GRADE) system to rate the quality of evidence and strength of recommendations of this systematic review. This was recommended by the Cochrane Collaboration. GRADE included systematic assessments of all included trials across six main domains for each outcome: limitations of the study design and execution, inconsistency, indirectness, and imprecision of results, publication bias, and large effect. Accordingly, we graded the recommendations for outcome measure of metformin for hyperprolactinemia as very low, low, moderate, or high.
2.6. Data extraction Authors Q-JB and Z-MW initially considered all included studies, without seeing comparison data, to judge clinical, methodological and statistical heterogeneity and thereby decide whether each study would be included in the meta-analysis or another data synthesis. Then they extracted data into standard, simple forms. Again, any disagreement was discussed, decisions documented, and, if necessary, authors of studies were contacted for clarification. If any information on trial methodology or any trial data were missing, the study authors were contacted by email in order to obtain missing information or for clarification whenever deemed necessary.
3. Results 3.1. Quality assessment and study design We included three trials in our systematic review (Fig. 1, Tables 1 and 2). Table 1 summarizes the characteristics of the three included studies. Table 2 describes the details of the studies including one RCT (Wu et al., 2012) and two observational studies (Liang, 2013; Shi and Ding, 2013). These studies were published in the last three years, which indicates that metformin for antipsychotic-induced hyperprolactinemia is a new clinically-important topic. All three studies tested the serum prolactin level but only two studies reported prolactin-related ADRs (Table 1). Using the Cochrane risk of bias assessment tool, the RCT demonstrated low risk for selection bias, performance bias, detection bias, attrition bias, reporting bias and other potential sources of bias. Randomization methods were reported as computer-generated in the study. A research pharmacist who was independent of the investigators was assigned to ensure concealment of the randomization. The two observational trials were single group, before-after studies (Liang, 2013; Shi and Ding, 2013). 3.2. Analysis of outcomes Tables 1 and 3 summarize outcomes for the individual trials. It was not possible to conduct a meta-analysis because of the trials’ heterogeneity, which included differences in gender (female vs. either gender), methodology (observational study vs. RCT), followup time (8 weeks, 12 weeks and 6 months) and outcome definition (symptoms vs. serum prolactin level). Furthermore, metformin dosage varied between 750, 1000, and 1500 mg/day. Although meta-analysis is a powerful tool for analyzing data (Leandro, 2008), confounding inter-study variables that cannot be controlled
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
3.3. Treatment efficacy
Table 2 Description of each study.
Metformin patients had a significant decrease in the serum prolactin level with a mean of 54.6 μg/l in the three trials. In the RCT, menstruation restarted in 67% of those with menstrual disturbances. In one of the observational studies, 91% no longer had signs or symptoms of galactorrhea (Table 1).
Wu et al. (2012) Methods: Randomized, double-blind, placebo-controlled study. Subjects: Eighty-four women (ages 18 to 40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned. Patients were excluded from the study if there was evidence of liver or renal dysfunction, cardiovascular disease, or diabetes mellitus; if they were pregnant or lactating; or if they had a psychiatric diagnosis other than schizophrenia or a current history of substance use disorder. Interventions: Participants received 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. Outcomes: Decreases in mean serum prolactin levels, restoration of menstruation, and ADR incidence.
3.4. ADRs and discontinuation rates Table 3 summarizes ADRs and discontinuation rates. ADRs occurred at similar incidence rates among metformin and placebo patients, except for nausea, insomnia and agitation, which were more frequent in the metformin group in the RCT (Wu et al., 2012), but with no significant differences. ADRs were not reported in the two observational studies (Liang, 2013; Shi and Ding, 2013). In the RCT, there was no discontinuation associated with an ADR. One of the observational studies did not describe discontinuation rates (Liang, 2013).
Liang (2013) Methods: Open-label prospective trial. Subjects: All 116 female patients with schizophrenia, ages 18–50 years, with galactorrhea-amenorrhea syndrome lasting for 3 months who had serum prolactin levelsZ 60 mg/L were enrolled. Patients were ineligible if they had high risk for suicide, severe endocrine disease or gynecological disease, drug allergy history, or were pregnant during the trial period. Interventions: Participants received adjunctive metformin 1500 mg daily for 8 weeks. Outcomes: Decreases in mean serum prolactin levels, improvement of menstruation and galactorrhea, and ADR incidence.
4. Discussion
Shi and Ding (2013) Methods: Open-label prospective trial. Subjects: Thirty-five patients during antipsychotic treatment, either gender, ages 18 to 50 years who had serum prolactin levelsZ30 ng/mL were enrolled. Patients were ineligible if they had any medical illness, were pregnant or lactating. Interventions: Participants were assigned to receive metformin treatment of 750 mg/day for 12 weeks. Outcomes: Decreases in mean serum prolactin levels, and ADR incidence.
4.1. Efficacy
ADR: adverse drug reaction.
may violate basic statistical assumptions, making these types of analyses error-prone (Ried, 2006; Leandro, 2008). Therefore, we only extracted data onto standard, simple forms as well as other descriptive statistics. Quality assessment of the included studies according to the GRADE approach showed some limitations of the study design and imprecision, but no obvious indirectness or inconsistency in reporting the results (Table 4). Based on the above assessments, the quality of evidence presented for each outcome ranged from “very low” to “moderate”. We did not conduct a funnel plot analysis to show the presence of risk of publication bias because only three studies were included and asymmetry could not be reliably judged. Nonetheless, we did not identify any unpublished negative studies related to the papers.
This is the first systematic review of metformin for antipsychotic-induced hyperprolactinemia which summarizes its efficacy and safety. Our comprehensive systematic review includes three studies with a total of 235 patients and suggests that metformin may be an effective therapy, safe and well-tolerated. Adjunctive metformin was superior to placebo in prolactin level decrease and prolactin-related symptom recovery. While it is an interesting and potentially important adjunctive treatment, these findings clearly need to be verified in extended studies in this field. Our systematic review indicated that adjunctive metformin significantly lowered prolactin level and relieved prolactin-related symptoms in patients with antipsychotic-induced hyperprolactinemia. Antipsychotic treatment through high D2 occupancy in the tuberoinfundibular system region can lead to a dopamine deficiency, increasing the risk of hyperprolactinemia (Nordstrom and Farde, 1998). Metformin has been shown to increase the endogenous dopaminergic tone in women with polycystic ovary syndrome (Ortega-Gonzalez et al., 2005), and this may be one of its mechanisms of action in the clinical effects (Krysiak et al., 2015). Metformin is an old drug that is now gaining increasing attention in the treatment of antipsychotic ADRs (Linneke et al., 2014). Studies have indicated that metformin can attenuate or
Table 3 ADRs and discontinuation rates. Study
ADRs
Discontinuation Rate
Wu et al. (2012)
Liang (2013) Shi and Ding (2013)
Nausea Extrapyramidal symptoms Insomnia and agitation Somnolence Headaches Dry mouth None None
PLA 17% (7/42) 31% (13/42) 17% (7/42) 14% (6/42) 17% (7/42) 21% (9/42)
MET 21% (9/42) 29% (12/42) 21% (9/42) 12% (5/42) 12% (5/42) 17% (7/42)
PLA 12% (5/42)a,b
MET 7% (3/42)a,b
Not reported 11 patients withdrawn but reason was not reported
MET: metformin. PLA: placebo. a b
Lost to follow-up: 3 on PLA and 2 on MET. Hospitalized: 2 on PLA and 1 on MET.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
5
Table 4 GRADE system analysis. Design Observational Prolactin level Symptom-recoveryd Discontinuation RCT Prolactin level Symptom-recoveryd Discontinuation Nausea EPS Insomnia/agitation Somnolence Headache Dry mouth
N (studies)
Risk of Bias
Inconsistency
Indirectness
Imprecision
Publication bias
Large effect
Overall quality of evidencea
151 (2) 116 (1) 35 (1)
Seriousb Seriousb Seriousb
No No No
No No No
Seriousc Seriouse Seriouse
Undetected Undetected Undetected
No No No
Very low Very low Very low
84 84 84 84 84 84 84 84 84
No No No No No No No No No
No No No No No No No No No
No No No No No No No No No
Seriousc Seriouse Seriouse Seriouse Seriouse Seriouse Seriouse Seriouse Seriouse
Undetected Undetected Undetected Undetected Undetected Undetected Undetected Undetected Undetected
No No No No No No No No No
Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate
(1) (1) (1) (1) (1) (1) (1) (1) (1)
EPS: extrapyramidal symptoms. GRADE: grading of recommendations assessment, development, and evaluation. RCT: randomized clinical trial. a The quality of evidence was rated using the GRADE Working Group system. High quality indicates that further research is very unlikely to change our confidence in the estimate of effect but none of the studies reached that level. Moderate quality indicates that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality indicates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality indicates that we are very uncertain about the estimate. b The two studies included a single group and withdrawal from the study or the reasons for withdrawal were not reported. c For continuous outcomes, N o 400. d Recovery from symptoms associated with hyperprolactinemia. e For dichotomous outcomes, N o300.
reverse some of the weight gain, fasting glucose level, insulin level, insulin resistance, and metabolic abnormalities induced by antipsychotic drugs (Baptista et al., 2008; Ehret et al., 2010; Wang et al., 2010; Wu et al., 2012; Correll et al., 2013; Jarskog et al., 2013). Meta-analyses have shown that four second-generation antipsychotics (amisulpride, clozapine, olanzapine, and risperidone) are more efficacious than others. These four antipsychotics were not associated with increased discontinuation rates (Davis et al., 2003; Leucht et al., 2009, 2013), but clozapine and olanzapine are associated with greater weight gain (Meyer, 2010; Musil et al., 2015) and amisulpride and risperidone are associated with considerably greater increases in prolactin levels (Haddad and Wieck, 2004). Metformin, a low-cost medicine, not only can limit weight gain but may also lower prolactin levels. 4.2. Safety There were no significant differences in ADRs when compared with placebo in the RCT and no obvious ADRs in the observational studies. Gastrointestinal reaction is the most common ADR but may be alleviated by taking metformin after meals. The observational trials were limited by no report of discontinuations or reasons for discontinuation but the RCT showed metformin discontinuation rates similar to placebo. 4.3. Limitations This review is limited for several reasons. First, it was not possible to conduct a meta-analysis because of the studies’ heterogeneity, including differences in their methodology, study design, study size and follow-up duration, patient and treatment selection, and outcome variables. The breadth of these differences may violate basic statistical assumptions and make these analyses error-prone. Therefore, we only extracted data onto standard, simple forms. Secondly, only three articles met the inclusion criteria and were used in the qualitative analysis. Two of them were observational trials; only one RCT was available. The GRADE approach showed the quality of evidence was “very low” for prolactin level, prolactin-related symptoms and discontinuations; the other
outcomes were “moderate” (Table 4). High quality evidence does not necessarily imply strong recommendations, and strong recommendations can arise from low quality evidence, depending on patients with varying values and preferences (Guyatt et al., 2008). In spite of the low quality of the evidence, metformin may be considered for managing antipsychotic-induced hyperprolactinemia, especially for women with irregular menstruation, even amenorrhea. Thirdly, the relationship between metformin dose and the change in prolactin levels was not analyzed. All of the included studies were very recent (from 2012 and 2013), demonstrating that the use of metformin in antipsychotic-induced hyperprolactinemia is a new idea. There was not enough evidence to explore the association between metformin dose and prolactin level when used as adjunctive treatment, which needs to be evaluated in future studies. Fourth, second-generation antipsychotics are now generally accepted as an iatrogenic cause of hyperprolactinemia and metabolic illness but other causes need to be considered. Polycystic ovarian syndrome (PCOS) has been referred to as a women's version of the metabolic syndrome (Matevosyan, 2011; Yum et al., 2014). There is some evidence that metformin may be effective for PCOS (Wu et al., 2012) which can be an indirect way of decreasing prolactin secretion in female patients taking antipsychotics. Other authors do not agree. Krysiak et al. (2015) found no mean change in fasting prolactin after metformin treatment. In this systematic review, patients were ineligible if they had severe endocrine disease, including PCOS. Furthermore, we also included 18 male patients; although the included subjects were almost exclusively females because hyperprolactinemia and its symptoms are more obvious in female patients. Thus, according to the limited studies included in this review, metformin appeared to have direct effects in decreasing prolactin associated with antipsychotic treatment and these effects do not appear to be mediated by improving PCOS. In conclusion, the currently available limited evidence of three trials suggests that adjunctive metformin may be used effectively and safely for antipsychotic-induced hyperprolactinemia. Adjunctive metformin appears to be superior to placebo in prolactin level decrease and prolactin-related symptom recovery.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
6
Adjunctive metformin does not appear to be associated with ADR increases or increased discontinuations. The use of adjunctive metformin to manage hyperprolactinemia and/or weight gain during the early phases of schizophrenia treatment may increase treatment compliance, which could offer long-term benefits in a chronic illness such as schizophrenia. Higher-quality metformin RCTs in hyperprolactinemia are needed.
Contributors As the text describes, Drs. Bo and ZM Wang completed study searches and bias assessments, and extracted data. Drs. Bo and ZM Wang wrote and contributed equally to the first draft. Dr. de Leon adjusted this first daft to the style of this journal. All authors have contributed to and have approved the final manuscript.
Conflict of interest None in the past three years. No pharmaceutical company had any role in the writing of this paper for publication.
Acknowledgments The review was conducted under the auspices of the Cochrane Schizophrenia Group, to which the authors are indebted. The authors thank Lorraine Maw, M.A., for editorial assistance. The study was supported by funding from the National Natural Science Foundation of China (81071083) to Dr. C.Y. Wang. This study was also supported by funding from the Beijing Science and Technology Commission (D101107047810001) and Beijing Hospital Authority clinical development projects "Sail" program (ZYLX201403) to Dr. C.Y. Wang.
References Baptista, T., LaCruz, A., Meza, T., Contreras, Q., Delgado, C., Mejías, M.A., Hernández, L., 2001. Antipsychotic drugs and obesity: Is prolactin involved? Can. J. Psychiatry 46, 829–834. Baptista, T., ElFakih, Y., Uzcátegui, E., Sandia, I., Tálamo, E., Araujo de Baptista, E., Beaulieu, S., 2008. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 22, 477–495. Bhattacharjee, J., El-Sayeh, H.G., 2008. Aripiprazole versus typicals for schizophrenia. Cochrane Database Syst. Rev. 16, CD006617. Billa, E., Kapolla, N., Nicopoulou, S.C., Koukkou, E., Venaki, E., Milingos, S., Antsaklis, A., Adamopoulos, D.A., 2009. Metformin administration was associated with a modification of LH, prolactin and insulin secretion dynamics in women with polycystic ovarian syndrome. Gynecol. Endocrinol. 25, 427–434. Biller, B., Luciano, A., Crosignani, P., Molitch, M., Olive, D., Rebar, R., Sanfilippo, J., Webster, J., Zacur, H., 1999. Guidelines for the diagnosis and treatment of hyperprolactinemia. J. Reprod. Med. 44, 1075–1084. Bostwick, J.R., Guthrie, S.K., Ellingrod, V.L., 2009. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy 29, 64–73. Bushe, C., Shaw, M., 2007. Prevalence of hyperprolactinaemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical antipsychotics. J. Psychopharmacol. 21, 768–773. Bushe, C., Shaw, M., Peveler, R.C., 2008. A review of the association between antipsychotic use and hyperprolactinaemia. J. Psychopharmacol. 22, 46–55. Bushe, C.J., Bradley, A.J., Wildgust, H.J., Hodgson, R.E., 2009. Schizophrenia and breast cancer incidence: a systematic review of clinical studies. Schizophr. Res. 114, 6–16. Byerly, M., Suppes, T., Tran, Q.V., Baker, R.A., 2007. Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives. J. Clin. Psychopharmacol. 27, 639–661. Correll, C.U., Sikich, L., Reeves, G., Riddle, M., 2013. Metformin for antipsychoticrelated weight gain and metabolic abnormalities: when, for whom, and for how long? Am. J. Psychiatry 170, 947–952. Davis, J.M., Chen, N., Glick, I.D., 2003. A meta-analysis of the efficacy of secondgeneration antipsychotics. Arch. Gen. Psychiatry 60, 553–564.
Ehret, M., Goethe, J., Lanosa, M., Coleman, C.I., 2010. The effect of metformin on anthropometrics and insulin resistance in patients receiving atypical antipsychotic agents: a meta-analysis. J. Clin. Psychiatry 71, 1286–1292. Guyatt, G.H., Oxman, A.D., Vist, G.E., Kunz, R., Falck-Ytter., Y., Alonso-Coello, P., Schünemann, H.J., GRADE Working Group, 2008. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br. Med. J. 336, 924–926. Haddad, P.M., Wieck, A., 2004. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 64, 2291–2314. Halbreich, U., Kahn, L.S., 2003. Hyperprolactinemia and schizophrenia: mechanisms and clinical aspects. J. Psychiatr. Pract. 9, 344–353. Hoffer, Z.S., Roth, R.L., Mathews, M., 2009. Evidence for the partial dopamine-receptor agonist aripiprazole as a first-line treatment of psychosis in patients with iatrogenic or tumorogenic hyperprolactinemia. Psychosomatics 50, 317–324. Inder, W.J., Castle, D., 2011. Antipsychotic-induced hyperprolactinaemia. Aust. N.Z J. Psychiatry 45, 830–837. Jarskog, L.F., Hamer, R.M., Catellier, D.J., Stewart, D.D., Lavange, L., Ray, N., Golden, L. H., Lieberman, J.A., Stroup, T.S., METS Investigators, 2013. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am. J. Psychiatry 170, 1032–1040. Kane, J.M., Correll, C.U., Goff, D.C., Kirkpatrick, B., Marder, S.R., Vester-Blokland, E., Sun, W., Carson, W.H., Pikalov, A., Assunção-Talbott, S., 2009. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J. Clin. Psychiatry 70, 1348–1357. Kim, E.Y., Kim, S.H., Lee, N.Y., Jung, D.C., Kim, Y.S., Ahn, Y.M., 2012. Relationship between prolactin levels and subjective endocrine-related adverse effects in patients with schizophrenia receiving long-term treatment with amisulpride. Pharmacopsychiatry 45, 57–63. Kishimoto, T., De Hert, M., Carlson, H.E., Manu, P., Correll, C.U., 2012. Osteoporosis and fracture risk in people with schizophrenia. Curr. Opin. Psychiatry 25, 415–429. Krysiak, R., Okrzesik, J., Okopien, B., 2015. The effect of short-term metformin treatment on plasma prolactin levels in bromocriptine-treated patients with hyperprolactinaemia and impaired glucose tolerance: a pilot study. Endocrine 49, 242–249. Leandro, G. 2008. Meta-analysis in Medical Research: The Handbook for the Understanding and Practice of Meta-analysis. Wiley.com. Available from: 〈http:// www.books.google.com〉 (accessed May 2015). Lehman, A.F., Lieberman, J., Dixon, L., McGlashan, T., Miller, A., Perkins, D.O., Kreyenbuhl, J., American Psychiatric Association, Steering Committee on Practice Guidelines, 2004. Practice guideline for the treatment of patients with schizophrenia. Am. J. Psychiatry 161 (2 Suppl), 1–56. Leucht, S., Komossa, K., Rummel-Kluge, C., Corves, C., Hunger, H., Schmid, F., Asenjo Lobos, C., Schwarz, S., Davis, J.M., 2009. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am. J. Psychiatry 166, 152–163. Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Orey, D., Richter, F., Samara, M., Barbui, C., Engel, R.R., Geddes, J.R., Kissling, W., Stapf, M.P., Lässig, B., Salanti, G., Davis, J.M., 2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951–962. Li, X., Tang, Y., Wang, C., 2013. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One 8, e70179. Liang, C.S., 2013. Effect of metformin on antipsychotic drug-induced galactorrheaamenorrhea syndrome. China Mod. Med. 20, 54–56 [In Chinese]. Linneke, J.L., Jorgensen, G.K., Csillag, C., 2014. Metformin for weight loss and control in patients with mood disorder. J. Clin. Psychiatry 75, e1140–e1141. Marken, P.A., Haykal, R.F., Fisher, J.N., 1992. Management of psychotropic-induced hyperprolactinemia. Clin. Pharm. 11, 851–856. Matevosyan, N.R., 2011. Schizophrenia and Stein-Leventhal syndrome: comorbidity features. Arch. Gynecol. Obstet. 284, 1035–1041. Meyer, J.M., 2010. Antipsychotics and metabolics in the post-CATIE era. Curr. Top. Bevav. Neurosci. 4, 23–42. Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann. Intern. Med. 151, 264–269. Musil, R., Obermeier, M., Russ, P., Hamerle, M., 2015. Weight gain and antipsychotics: a drug safety review. Expert. Opin. Drug. Saf. 14, 73–96. Nordstrom, A.L., Farde, L., 1998. Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients. J. Clin. Psychopharmacol. 18, 305–310. Nunes, L.V., Moreira, H.C., Razzouk, D., Nunes, S.O., Mari, J., de, J., 2012. Strategies for the treatment of antipsychotic-induced sexual dysfunction and/or hyperprolactinemia among patients of the schizophrenia spectrum: a review. J. Sex. Marital. Ther. 38, 281–301. O'Keane, V., 2008. Antipsychotic-induced hyperprolactinaemia, hypogonadism and osteoporosis in the treatment of schizophrenia. J. Psychopharmacol. 22, 70–75. Ortega-Gonzalez, C., Cardoza, L., Coutino, B., Hidalgo, R., Arteaga-Troncoso, G., Parra, A., 2005. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J. Endocrinol. 184, 233–239. Ried, K., 2006. Interpreting and understanding meta-analysis graphs – a practical guide. Aust. Fam. Phys. 35, 635–638. Shi, W., Ding, S.E., 2013. Preliminary observation of the metformin in efficacy for
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
Q.-J. Bo et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎ hyperprolactinemia induced by antipsychotics. J. Clin. Psychiatry 23, 408–409 [In Chinese]. Shim, J.C., Shin, J.G., Kelly, D.L., Jung, D.U., Seo, Y.S., Liu, K.H., Shon, J.H., Conley, R.R., 2007. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am. J. Psychiatry 164, 1404–1410. Smith, R.C., 2012. Metformin as a treatment for antipsychotic drug side effects: special focus on women with schizophrenia. Am. J. Psychiatry 169, 774–776. Velazquez, E.M., Mendoza, S., Hamer, T., Sosa, F., Glueck, C.J., 1994. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43, 647–654. Wang, C.Y., Xiang, Y.T., Cai, Z.J., Weng, Y.Z., Bo, Q.J., Zhao, J.P., Liu, T.Q., Wang, G.H., Weng, S.M., Zhang, H.Y., Chen, D.F., Tang, W.K., Ungvari, G.S., Risperidone Maintenance Treatment in Schizophrenia (RMTS) investigators, 2010. Risperidone maintenance treatment in schizophrenia: a randomized, controlled trial.
7
Am. J. Psychiatry 167, 676–685. Wu, R.R., Jin, H., Gao, K., Twamley, E.W., Ou, J.J., Shao, P., Wang, J., Guo, X.F., Davis, J. M., Chan, P.K., Zhao, J.P., 2012. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. Am. J. Psychiatry 169, 813–821. Yamada, K., Kanba, S., Yagi, G., Asai, M., 1999. Herbal medicine (Shakuyaku-kanzoto) in the treatment of risperidone-induced amenorrhea. J. Clin. Psychopharmacol. 19, 380–381 [In Chinese]. Yuan, H.N., Wang, C.Y., Sze, C.W., Tong, Y., Tan, Q.R., Feng, X.J., Liu, R.M., Zhang, J.Z., Zhang, Y.B., Zhang, Z.J., 2008. A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. J. Clin. Psychopharmacol. 28, 264–370. Yum, S.K., Kim, T., Hwang, M.Y., 2014. Polycystic ovaries is a disproportionate signal in pharmacovigilance data mining of second generation antipsychotics. Schizophr. Res. 158, 275–276.
Please cite this article as: Bo, Q.-J., et al., Adjunctive metformin for antipsychotic-induced hyperprolactinemia: A systematic review. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2016.01.031i
