Brief Report
`
`Metformin for Weight Loss in Pediatric Patients
`Taking Psychotropic Drugs
`
`John A. Morrison, Ph.D.
`Elizabeth M. Cottingham, M.D.
`Bruce A. Barton, Ph.D.
`
`seven girls. In a 12-week open-label study, each patient received
`metformin, 500 mg t.i.d. Changes in weight and body mass in-
`dex were evaluated by using repeated measures analysis of
`variance.
`
`Objective: Metformin was assessed as a treatment for weight
`gain in children taking olanzapine, risperidone, quetiapine, or
`valproate.
`
`Results: Of the 19 patients, 15 lost weight, three gained 1.6 kg
`or less, and one had no change. The mean changes in weight
`and body mass index at 12 weeks were highly significant.
`
`Method: The subjects were 19 patients aged 10–18 years; 15
`were white and four were black, and there were 12 boys and
`
`Conclusions: Metformin merits further study as a treatment
`for weight gain in patients taking psychotropic medications.
`
`(Am J Psychiatry 2002; 159:655–657)
`
`Olanzapine, risperidone, quetiapine, and valproate
`
`provide effective treatment of bipolar disorder and psy-
`chosis (1). Their use, however, is associated with weight
`gain in as many as 50% of patients (1–5). Metformin,
`which is prescribed for patients with non-insulin-depen-
`dent diabetes to control blood sugar levels, has been re-
`ported to effect weight loss in several groups of patients
`characterized by insulin resistance. These include women
`with polycystic ovary disease (6, 7) and obese hyperlipi-
`demic men and women with and without non-insulin-de-
`pendent diabetes (8). Metformin has recently been ap-
`proved for use in children. Within this framework, we
`conducted an open-label study of metformin and weight
`loss in pediatric patients who had gained weight while tak-
`ing target drugs. We hypothesized that metformin would
`manage weight gain and lead to weight loss.
`
`Method
`
`Patients taking olanzapine, risperidone, quetiapine, or valpro-
`ate at Children’s Hospital Medical Center, Cincinnati, with weight
`gain over 10% of baseline were given metformin, 500 mg t.i.d. De-
`termination of weight gain was based on hospital records and the
`patient’s weight at enrollment. Weight and height were measured
`to the nearest 0.1 kg and 0.1 cm, respectively, according to a Na-
`tional Institutes of Health protocol (9). The first two patients were
`seen under an 8-week protocol; subsequent patients were seen
`under a 12-week protocol. The patients were instructed not to
`change diet or physical activity during the study. Safety monitor-
`ing tests for lactic acidosis and liver function were conducted at
`all visits. Postmenarchal girls took urine pregnancy tests monthly.
`The study’s primary outcome measures were change in weight
`and body mass index at 12 weeks of metformin treatment. For
`these outcomes, we used paired t tests to assess whether the
`mean changes were significantly different from zero. To control
`for multiple comparisons, we adjusted the critical alpha level by
`using Bonferroni adjustment, testing each outcome at an alpha of
`0.025. We tested changes in weight and body mass index at 4 and
`8 weeks as secondary outcomes, using a more conservative alpha
`of 0.01. All analyses were performed by using SAS version 8.0 (10).
`
`The Children’s Hospital Medical Center institutional review
`board approved the protocol. Written informed assent/consent
`was obtained. The participants were told that we wanted to see
`whether metformin affected weight loss independently of dietary
`changes or physical activity.
`
`Results
`
`Nineteen patients, aged 10–18 years (mean=14.1, SD=
`2.5), were treated. They included 15 white and four black
`subjects; 12 were male, and seven were female. Two pa-
`tients were taking valproate only, four were taking valpro-
`ate plus olanzapine, eight were taking olanzapine only,
`one was taking valproate plus risperidone, three were tak-
`ing risperidone only, and one was taking quetiapine only.
`The length of treatment with these drugs ranged from 1 to
`36 months (mean=10.4, SD=9.5), and weight gain ranged
`from 6.0 to 59.1 kg (mean=28.6, SD=15.3). Follow-up data
`were available for 19 patients at 4 weeks, 16 patients at 8
`weeks, and 12 patients at 12 weeks. Seven patients had less
`than 12 weeks of data. Two patients were seen under an 8-
`week protocol. One patient stopped taking olanzapine af-
`ter 8 weeks of weight loss and was lost to follow-up, al-
`though later admitted to the hospital. One patient moved
`away. One patient, who gained 0.6 kg in 4 weeks, dropped
`out to try a different, dietary approach and was counted as
`gaining weight. Two patients did not complete the 12-
`week protocol before funding and institutional review
`board approval expired. The weight change outcomes
`were based on patients’ results at 4, 8, and 12 weeks, and
`the weight change classification was based on each pa-
`tient’s final visit, whether that was at 4, 8, or 12 weeks.
`Of the 19 patients, 15 lost weight, the weight of one re-
`mained unchanged, and three gained weight. Weight
`gains in these three patients were 0.2 kg (over 3 months),
`0.6 kg (over 1 month), and 1.6 kg (over 3 months). The
`mean changes in weight and body mass index by length of
`follow-up are summarized in Table 1. At 12 weeks, the
`
`Am J Psychiatry 159:4, April 2002
`
`655
`
`

`

`BRIEF REPORTS
`
`TABLE 1. Changes in Weight and Body Mass Index in Patients Aged 10–18 Years Who Took Metformin for 12 Weeks in Ad-
`dition to Psychotropic Drugsa
`
`Weight
`
`Change in Weight
`(kg)
`
`SD
`Mean
`Time
`1.68
`–0.93
`4 weeks (N=19)
`2.45
`–1.05
`8 weeks (N=16)
`3.13
`–2.93
`12 weeks (N=12)
`a Olanzapine, risperidone, quetiapine, or valproate.
`b Two-sided probabilities.
`
`Paired t Testb
`df
`18
`15
`11
`
`t
`–2.41
`–1.71
`–3.24
`
`p
`0.03
`0.11
`0.008
`
`SD
`0.97
`1.52
`1.98
`
`Body Mass Index
`Change in Index
`(kg/m2)
`Mean
`–0.84
`–0.90
`–2.22
`
`Paired t Testb
`df
`18
`15
`11
`
`t
`–3.77
`–2.37
`–3.90
`
`p
`0.001
`0.03
`0.003
`
`mean weight change was –2.93 kg, and the mean change
`in body mass index was –2.22 kg/m2. Thus, both primary
`outcomes yielded highly significant results. Although
`there was weight loss and reduction in body mass index at
`weeks 4 and 8, only the reduction of body mass index at 4
`weeks reached significance at the adjusted alpha level of
`0.01 (Table 1). Four patients followed as private patients
`beyond the 12-week protocol to evaluate longer-term
`weight loss continued to lose weight, achieving losses of
`4.1, 4.6, 8.2, and 13.1 kg.
`The results of the safety tests for lactic acidosis were un-
`remarkable. That is, the readings outside the normal range
`were within laboratory error. Many of the patients with ab-
`normal results on the liver function tests had abnormal
`readings at baseline. One of the two patients with low
`SGOT levels had a low level at baseline. Of the 10 patients
`with high SGOT levels, six had high levels at baseline. Of
`the five patients with low SGPT levels, one had a low base-
`line level. Of the four patients with high SGPT levels, one
`had a high baseline level. Of the three patients with high γ-
`glutamyltransferase levels, two had high levels at baseline.
`All other laboratory results were within normal ranges.
`
`Discussion
`
`In this preliminary evaluation of metformin as a treat-
`ment for weight gain associated with psychotropic drugs,
`the steep increase in weight experienced from these drugs
`was arrested in all patients. In addition, 15 of 19 patients
`lost weight. One patient, experiencing a weight gain of 1.6
`kg, was also receiving intramuscular medroxyprogester-
`one acetate, an agent independently associated with
`weight gain.
`Lustig (11) reported that use of metformin led to weight
`loss in eight obese adolescent girls who had failed to lose
`weight after caloric restriction. The mechanism by which
`metformin effects weight loss is not presently understood,
`but evidence is accumulating that it influences metabo-
`lism. Metformin is known to improve insulin sensitivity.
`Lenhard et al. (12) found that metformin increased mito-
`chondrial metabolism, stimulating aerobic respiration
`and mitochondrial β-oxidation.
`This preliminary study has several limitations. First, it
`was an open-label study, and the open-label treatment of
`obesity is subject to the placebo effect. However, the pat-
`
`tern of sustained, continued weight loss suggests that the
`weight loss was not due to the placebo effect. Second, a
`small number of patients were enrolled, so comparisons
`of weight loss among the target drugs were not possible.
`Different mean levels of weight gain with the various tar-
`get drugs have been reported in previous studies (3, 5).
`Third, different doses of metformin were not evaluated.
`Fourth, data on the occurrence of side effects were not sys-
`tematically collected. Six patients reported diarrhea or wa-
`tery stools at one or more visits. Fifth, although the pa-
`tients reported making no change in energy intake or
`output, as instructed, hard data on dietary intake and
`physical activity were not collected. Sixth, long-term fol-
`low-up to determine the clinical significance of the mean
`weight loss was not conducted. The continued follow up
`of four patients beyond 12 weeks suggests clinically signif-
`icant weight loss.
`In this sample of 19 patients, metformin was well toler-
`ated. One additional patient enrolled in the study but
`withdrew in the first month because of diarrhea. This pa-
`tient was mentally retarded, wore diapers, and required a
`2-hour bus ride each weekday. The patients reporting spo-
`radic diarrhea, consisting of loose stools and/or increased
`frequency, indicated that it was not a cause for discontin-
`uation and resolved with time. The results of safety tests
`were unremarkable.
`We conclude that metformin holds promise as a treat-
`ment for weight gain in pediatric patients taking psycho-
`tropic medications. Further studies, including randomized
`controlled trials and longer follow-up periods, are war-
`ranted and required before a final evaluation is possible.
`
`Received Sept. 27, 2000; revisions received Feb. 7 and Aug. 14,
`2001; accepted Dec. 18, 2001. From the Divisions of Cardiology and
`Psychiatry, Children’s Hospital Medical Center; and the Maryland
`Medical Research Institute, Baltimore. Address reprint requests to Dr.
`Morrison, Division of Cardiology, OSB 4, Children’s Hospital Medical
`Center, 3333 Burnet Ave., Cincinnati, OH 45229; morrj2@chmcc.org
`(e-mail).
`Supported by funding from the Children’s Hospital Medical Center
`Research Foundation.
`The metformin for this study was provided by Bristol-Myers Squibb.
`
`References
`
`1. The Collaborative Working Group on Clinical Trial Evaluations:
`Adverse effects of the atypical antipsychotics. J Clin Psychiatry
`1998; 59:17–22
`
`656
`
`Am J Psychiatry 159:4, April 2002
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`

`

`BRIEF REPORTS
`
`2. Egger J, Brett EM: Effects of sodium valproate in 100 children
`with special reference to weight. Br Med J 1981; 283:577–581
`3. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, In-
`fante MC, Weiden PJ: Antipsychotic-induced weight gain: a
`comprehensive research synthesis. Am J Psychiatry 1999; 156:
`1686–1696
`4. Sachs GS, Guille C: Weight gain associated with use of psycho-
`tropic medications. J Clin Psychiatry 1999; 60(suppl 21):16–19
`5. Sikich L, Williamson K, Malekpour A, Bashford R, Sheitman B,
`Liberman J: Double-blind comparison of haloperidol, risperi-
`done, and olanzapine in psychotic youth, in Scientific Proceed-
`ings of the 46th Annual Meeting of the American Academy of
`Child and Adolescent Psychiatry. Washington, DC, AACAP, 1999,
`p 136
`6. Velazquez EM, Mendoza S, Hammer T, Sosa F, Glueck CJ: Met-
`formin therapy in polycystic ovary syndrome reduces hyperin-
`sulinemia, insulin resistance, hyperandrogenism, and systolic
`blood pressure, while facilitating normal menses and preg-
`nancy. Metabolism 1994; 43:647–654
`7. Velazquez EM, Mendoza SG, Wang P, Glueck CJ: Metformin ther-
`apy is associated with a decrease in plasma plasminogen acti-
`
`vator inhibitor-1, lipoprotein(a), and immunoreactive insulin
`levels in patients with polycystic ovary syndrome. Metabolism
`1997; 46:454–457
`8. Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E,
`Streicher P, Sieve-Smith L, Tracy TM, Lang JE, McCullough P:
`Metformin reduces weight, centripetal obesity, insulin, leptin,
`and low-density lipoprotein cholesterol in nondiabetic, mor-
`bidly obese subjects with body mass index greater than 30.
`Metabolism 2001; 50:856–861
`9. Obesity and cardiovascular disease risk factors in black and
`white girls: the NHLBI Growth and Health Study. Am J Public
`Health 1992; 82:1613–1620
`10. SAS/STAT User’s Guide, version 8. Cary, NC, SAS Institute, 2000
`11. Lustig R: Childhood obesity, in A Current Review of Pediatric
`Endocrinology 1999. Rockland, Mass, Serono Symposia, 1999,
`pp 133–139
`12. Lenhard JM, Liewer SA, Paulik MA, Plunket KD, Lehmann JM,
`Weiel JE: Effects of troglitazone and metformin on glucose and
`lipid metabolism: alteration of two distinct molecular path-
`ways. Biochem Pharmacol 1999; 54:801–808
`
`Brief Report
`
`An Animal Model of Tourette’s Syndrome
`
`Jane R. Taylor, Ph.D.
`Syed A. Morshed, M.D., Ph.D.
`Salina Parveen, M.D.
`Marcos T. Mercadante, M.D., Ph.D.
`Lawrence Scahill, M.S.N., Ph.D.
`Bradley S. Peterson, M.D.
`Robert A. King, M.D.
`James F. Leckman, M.D.
`Paul J. Lombroso, M.D.
`
`Method: Sera from 12 patients with Tourette’s syndrome with
`high levels of antineural or antinuclear antibodies were in-
`fused bilaterally into the ventrolateral striatum of rats. Sera
`from 12 additional Tourette’s syndrome patients and 12 nor-
`mal subjects (both groups with low levels of autoantibodies)
`were infused for comparison. Rates of oral stereotypies were
`recorded by observers who were blind to the origin of the in-
`fused sera.
`
`Results: Oral stereotypies significantly increased in the rats in-
`fused with sera from the patients with high levels of autoanti-
`bodies.
`
`Objective: An animal model was used to investigate an au-
`toimmune etiology for some cases of Tourette’s syndrome.
`
`Conclusions: The results are consistent with an autoimmune
`etiology in a subset of cases of Tourette’s syndrome.
`
`(Am J Psychiatry 2002; 159:657–660)
`
`Tourette’s syndrome is a complex neuropsychiatric dis-
`
`order characterized by fluctuating motor and phonic tics
`that may result in marked impairment (1). An autoimmune
`etiology has been suggested for at least some cases (2–5).
`The presence of tics or obsessive-compulsive symptoms
`has been linked to infection with group A β-hemolytic
`streptococci (2, 3). The molecular mimicry hypothesis pre-
`dicts that genetically vulnerable individuals produce anti-
`bodies against streptococci that recognize self-proteins
`within the central nervous system (CNS). Cross-reactivity
`results in compromised neuronal function.
`
`Several reports have shown that autoantibodies are
`present in a subset of patients with Tourette’s syndrome
`(2–5). However, the presence of autoantibodies does not
`indicate causality. An animal model in which these au-
`toantibodies reproduce symptoms of the disorder is an
`important step. A recent animal model for Tourette’s syn-
`drome reported the induction of stereotypies in rats after
`intrastriatal infusions of serum from Tourette’s syndrome
`patients (6). The present report extends these findings by
`1) infusing sera from patients with Tourette’s syndrome
`into a striatal region associated with oral stereotypy and
`
`Am J Psychiatry 159:4, April 2002
`
`657
`
`