Expert: Ivan Goldberg, M.D. - 5/25/2008

Question
When I was young I was diagnosis with many things the last being bipolar mixed episodes I noticed that it fits the problem is I can not find a medicine that works for me. I have tried lithium and it made me zombie like. I have tried abilify and it didn't really work. I also tried lamictal and it cause my body to shake. What would you recommend taking? And what prescribed weight loss drug would you recommend taking with it because I am having a weight gaining problem that the doctors can not figure out( gained 30lbs in less than 2 months with no change in diet and exercise. It started to level out and stay the same but now it is starting to increase rapidly again)?

Answer
Hi, Nicole . . .

In my practice I get to see many people with stories similar to yours. You will not like what I am about to write, but what usually stops their cycling is a combined LOW DOSE lithium treatment together with LOW DOSE Lamictal.

Weight gain is often a result of an undetected thyroid problem. Your thyroid should be checked if if such testing was done a few months ago. I often prescribe Topamax and/or metformin to help with weight loss. A few abstracts are below.

Best regards . . .

Ivan
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1: JAMA. 2008 Jan 9;299(2):185-93.

Comment in:
   JAMA. 2008 Apr 23;299(16):1898-9; author reply 1899-900.    JAMA. 2008 Apr 23;299(16):1899; author reply 1899-900.

Lifestyle intervention and metformin for treatment of antipsychotic-induced
weight gain: a randomized controlled trial.

Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF, He YQ, Liu YJ, Chen JD, Li LH.

Mental Health Institute of the Second Xiangya Hospital, Central South University,
Changsha, Hunan, China. wurenrong2005@yahoo.com.cn

CONTEXT: Weight gain, a common adverse effect of antipsychotic medications, is
associated with medical comorbidities in psychiatric patients. OBJECTIVE: To test
the efficacy of lifestyle intervention and metformin alone and in combination for
antipsychotic-induced weight gain and abnormalities in insulin sensitivity.
DESIGN, SETTING, AND PATIENTS: A randomized controlled trial (October
2004-December 2006) involving 128 adult patients with schizophrenia in the Mental
Health Institute of the Second Xiangya Hospital, Central South University, China.
Participants who gained more than 10% of their predrug weight were assigned to 1
of 4 treatment groups. INTERVENTIONS: Patients continued their antipsychotic
medication and were randomly assigned to 12 weeks of placebo, 750 mg/d of
metformin alone, 750 mg/d of metformin and lifestyle intervention, or lifestyle
intervention only. MAIN OUTCOME MEASURES: Body mass index, waist circumference,
insulin levels, and insulin resistance index. RESULTS: All 128 first-episode
schizophrenia patients maintained relatively stable psychiatric improvement. The
lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8
(95% confidence interval [CI], 1.3-2.3), insulin resistance index of 3.6 (95% CI,
2.7-4.5), and waist circumference of 2.0 cm (95% CI, 1.5-2.4 cm). The
metformin-alone group had mean decreases in BMI of 1.2 (95% CI, 0.9-1.5), insulin
resistance index of 3.5 (95% CI, 2.7-4.4), and waist circumference of 1.3 cm (95%
CI, 1.1-1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of
0.5 (95% CI, 0.3-0.8) and insulin resistance index of 1.0 (95% CI, 0.5-1.5).
However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9-1.5),
insulin resistance index of 0.4 (95% CI, 0.1-0.7), and waist circumference of 2.2
cm (95% CI, 1.7-2.8 cm). The lifestyle-plus-metformin treatment was significantly
superior to metformin alone and to lifestyle plus placebo for weight, BMI, and
waist circumference reduction. CONCLUSIONS: Lifestyle intervention and metformin
alone and in combination demonstrated efficacy for antipsychotic-induced weight
gain. Lifestyle intervention plus metformin showed the best effect on weight
loss. Metformin alone was more effective in weight loss and improving insulin
sensitivity than lifestyle intervention alone. Trial Registration
clinicaltrials.gov Identifier: NCT00451399.

Publication Types:
   Randomized Controlled Trial
   Research Support, Non-U.S. Gov't

PMID: 18182600 [PubMed - indexed for MEDLINE]

2: J Neurol Neurosurg Psychiatry. 2008 May;79(5):590-3. Epub 2007 Dec 12.

Topiramate, nutrition and weight change: a prospective study.

Klein KM, Theisen F, Knake S, Oertel WH, Hebebrand J, Rosenow F, Hamer HM.

Interdisciplinary Epilepsy-Centre, Department of Neurology, Philipps-University
Marburg, Rudolf-Bultmann-Str 8, 35033 Marburg, Germany.
klein.km@staff.uni-marburg.de

PURPOSE: To evaluate prospectively the relationship between appetite, food
composition, nutritional habits and weight loss following administration of
topiramate (TPM) and to identify predictors for TPM induced weight loss. METHODS:
22 patients with epilepsy who were started on TPM were prospectively followed for
6 months and contacted again after a mean follow-up time of 37.1 months. RESULTS:
Body mass index (BMI) loss occurred in 59% of patients, with a mean weight loss
of 9.5 kg after 6 months while receiving TPM without further weight loss at the
long term follow-up. Weight loss was associated with reduction in appetite
without affecting food composition. Predictors for BMI loss after 6 months were
high initial BMI and body fat. After 3 weeks of treatment with TPM, the recorded
parameters did not predict BMI loss but at 3 months, weight loss, reduction of
appetite and amount of food intake were predictive for the amount of BMI loss
after 6 months.

Publication Types:
   Research Support, Non-U.S. Gov't

PMID: 18077476 [PubMed - indexed for MEDLINE]

3: J Clin Psychopharmacol. 2007 Oct;27(5):475-8.

Influence of topiramate on olanzapine-related weight gain in women: an 18-month
follow-up observation.

Egger C, Muehlbacher M, Schatz M, Nickel M.

Universitätsklinik für Psychiatrie und Psychotherapie, PMU, Salzburg, Austria.
c.egger@salk.at

In a randomized controlled trial, we compared the efficacy of topiramate versus
placebo in women undergoing olanzapine therapy and found that topiramate
effectively contributed to weight loss in short-term treatment and had a positive
effect on health-related quality of life, the patients' actual state of health,
and psychological impairments. The aim of this observational study was to assess
whether topiramate has a sustained benefit in long-term treatment of
olanzapine-associated weight gain in subjects who had participated in the
previous randomized controlled trial comparing topiramate with placebo. The
subjects (topiramate group, n = 25; former placebo group, n = 18) were observed
in an 18-month open-label study. After unblinding, subjects from the former
topiramate group continued treatment with topiramate, whereas subjects from the
former placebo group received neither placebo nor topiramate.The subjects were
seen every 6 months, weighed, and tested with the SF-36 Health Survey, Scale of
Well-Being, and the Adjective Checklist. According to the intent-to-treat
principle, the repeated-measures analysis showed a significant interaction for
the group-by-time effect for change of weight (P < 0.01) on the Scale of
Well-Being (P < 0.01), all scales of the Adjective Checkist (all P < 0.01), and 5
scales (physical functioning, role limitations due to physical health, social
functioning, mental health, and vitality) of the SF-36 Health Survey (all P <
0.01). Topiramate was well tolerated and seems to be effective and safe in the
long-term treatment of olanzapine-related adiposity in women. Furthermore,
positive changes in the patients' state of health, psychological impairments, and
health-related quality of life could be also observed.

Publication Types:
   Randomized Controlled Trial

PMID: 17873679 [PubMed - indexed for MEDLINE]

4: Can J Clin Pharmacol. 2007 Summer;14(2):e234-9. Epub 2007 Jun 12.

Topiramate-induced weight loss in schizophrenia: a retrospective case series
study.

Lévy E, Agbokou C, Ferreri F, Chouinard G, Margolese HC.

Clinical Psychopharmacology Unit, McGill University Health Centre and Department
of Psychiatry, McGill University, Montreal, Quebec, Canada.
psychopharm.unit@staff.mcgill.ca

OBJECTIVE: Atypical antipsychotics have been associated with weight gain. This
study examines the efficacy of adjunctive topiramate in patients with
schizophrenia and schizoaffective disorder with antipsychotic-induced weight
gain. METHODS: A 2-year retrospective case analysis was performed in all 300
patients of the outpatient Special Follow-up Clinic for chronic schizophrenia and
related psychoses at the Allan Memorial Institute, McGill University Health
Centre (Montreal, Canada), a tertiary care University teaching hospital. RESULTS:
10 patients met study inclusion criteria. Mean daily topiramate dose was 197.5 mg
(A+/-77) (range, 125-400 mg). Topiramate produced continued weight loss
throughout the study duration without tolerance. Patients treated for 6 months
and more had significantly higher Body Mass Index (BMI) differences than those
treated for shorter durations (BMI-d6 months=-4.7A+/-2.4; BMI-d2
months=-3.2A+/-2.3; P=0.015). BMI changes were similar across genders.
CONCLUSION: This study supports topiramate use to target weight loss in stable
overweight schizophrenic patients as a potential therapy that requires further
investigation.

PMID: 17565171 [PubMed - indexed for MEDLINE]

5: Schizophr Res. 2007 Jul;93(1-3):99-108. Epub 2007 May 8.

Metformin as an adjunctive treatment to control body weight and metabolic
dysfunction during olanzapine administration: a multicentric, double-blind,
placebo-controlled trial.

Baptista T, Rangel N, Fernández V, Carrizo E, El Fakih Y, Uzcátegui E, Galeazzi
T, Gutiérrez MA, Servigna M, Dávila A, Uzcátegui M, Serrano A, Connell L,
Beaulieu S, de Baptista EA.

Department of Physiology, Los Andes University Medical School, PO Box 93, Mérida,
5101-A, Venezuela. trinbap@yahoo.com

BACKGROUND: Excessive body weight gain (BWG) is a clinically relevant side effect
of olanzapine administration. The primary objective of this study was to assess
whether metformin prevents or reverses BWG in patients with schizophrenia or
bipolar disorder under olanzapine administration. Secondarily we evaluated
diverse metabolic variables. METHODS: Eighty patients taking olanzapine (5-20 mg
daily for more than 4 consecutive months) were randomly allocated to metformin
(n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind
protocol. Waist circumference (WC) body weight (BW), body mass index (BMI)
fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index
(HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth
hormone (GH) were evaluated at baseline and at week 12 of treatment. RESULTS: The
metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin
levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg
(p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not
change after metformin (p=0.8). No ostensible differences were observed in the
other variables, even though metformin did not improve the lipid profile and the
Hb1c levels. CONCLUSIONS: Metformin may safely assist olanzapine-treated patients
in body weight and carbohydrate metabolism control.

Publication Types:
   Multicenter Study
   Randomized Controlled Trial
   Research Support, Non-U.S. Gov't

PMID: 17490862 [PubMed - indexed for MEDLINE]

6: Eat Weight Disord. 2007 Mar;12(1):48-53.

Adjunctive topiramate treatment in refractory obese bipolar patients: a
descriptive open label study.

Gabriel A.

University of Calgary, Calgary, Alberta, Canada. gabriel@ucalgary.ca

OBJECTIVES: To examine efficacy and tolerability of topiramate as an adjunctive
treatment for overweight refractory bipolar patients. METHOD: Patients (n=30)
with Bipolar I or II, were provided with an open label treatment with topiramate
as an add-on therapy. All patients deemed refractory to at least one mood
stabilizer, were overweight, and were treated with topiramate as an adjuvant to
existing medication for at least 12 weeks. The primary effectiveness measure was
the Clinical Global Impression Scale (CGI). Other scales included the Young's
Mania Rating Scale (YMRS), and the Hamilton Depression scale (HAMD21). Measures
prior to adding topiramate were compared to those repeated at 4, 8 and 12 weeks.
Tolerance, and weight changes were monitored. RESULTS: There was significant
reduction in both depressive and manic symptoms with adjunctive treatment. The
mean BMI at 12 weeks of topiramate treatment dropped by 2 points (p<0.0001).
CONCLUSION: Topiramate is an effective adjunctive treatment in bipolar refractory
patients and the significant weight reduction effects may result in important
medical risk reductions, and make topiramate attractive for some obese bipolar
patients.

Publication Types:
   Clinical Trial

PMID: 17384530 [PubMed - indexed for MEDLINE]

7: Am J Psychiatry. 2006 Dec;163(12):2072-9.

Comment in:
   Am J Psychiatry. 2006 Dec;163(12):2034-6.

A randomized, double-blind, placebo-controlled trial of metformin treatment of
weight gain associated with initiation of atypical antipsychotic therapy in
children and adolescents.

Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA.

Division of Endocrinology, Cincinnati Children's Hospital Medical Center, ML
7012, 3333 Burnet Ave., Cincinnati, OH 45229, USA. david.klein@cchmc.org

OBJECTIVE: Second-generation, or atypical, antipsychotics effectively treat
psychiatric illness in children and adolescents. However, weight gain and
abnormalities in insulin sensitivity, including diabetes, complicate this
therapy. METHOD: A 16-week double-blind, placebo-controlled trial was conducted
to evaluate the effectiveness of metformin in managing weight gain in 39
subjects, ages 10-17, whose weight had increased by more than 10% during less
than 1 year of olanzapine, risperidone, or quetiapine therapy. Body weight, body
mass index (kilograms per square meter of height), and waist circumference were
measured regularly, as were fasting insulin and glucose levels. RESULTS: Weight
was stabilized in subjects receiving metformin, while those receiving placebo
continued to gain weight (0.31 kg/week). Because the study was conducted with
growing children, metformin treatment resulted in reduction in z scores for both
weight and body mass index. The homeostasis model assessment, a surrogate
indicator of insulin sensitivity, decreased in treated subjects. Overt diabetes
was diagnosed in two subjects before treatment (elevated baseline fasting glucose
and insulin values) and in two placebo-treated subjects (one at week 12 and the
other after study completion). One subject taking placebo developed impaired
fasting glucose. Placebo treatment was associated with the need to perform oral
glucose tolerance testing upon study completion, by which three additional
subjects were identified with impaired glucose tolerance. No serious adverse
events resulted from metformin treatment. CONCLUSIONS: Metformin therapy is safe
and effective in abrogating weight gain, decreased insulin sensitivity, and
abnormal glucose metabolism resulting from treatment of children and adolescents
with atypicals.

Publication Types:
   Randomized Controlled Trial
   Research Support, Non-U.S. Gov't

PMID: 17151157 [PubMed - indexed for MEDLINE]

8: Clin J Pain. 2006 Jul-Aug;22(6):526-31.

Topiramate in treatment of patients with chronic low back pain: a randomized,
double-blind, placebo-controlled study.

Muehlbacher M, Nickel MK, Kettler C, Tritt K, Lahmann C, Leiberich PK, Nickel C,
Krawczyk J, Mitterlehner FO, Rother WK, Loew TH, Kaplan P.

University Clinic for Psychiatry 1, PMU, Salzburg, Austria.

OBJECTIVE: Chronic low back pain (CLBP) is a widespread ailment. The aim of this
study was to assess the efficacy of topiramate in the treatment of CLBP and the
changes in anger status and processing, body weight, subjective pain-related
disability and health-related quality of life during the course of treatment.
METHODS: We conducted a 10-week, randomized, double-blind, placebo-controlled
study of topiramate in 96 (36 women) patients with CLBP. The subjects were
randomly assigned to topiramate (n=48) or placebo (n=48). Primary outcome
measures were changes on the McGill Pain Questionnaire, State-Trait Anger
Expression Inventory, Oswestry Low Back Pain Disability Questionnaire and SF-36
Health Survey scales, and in body weight. RESULTS: In comparison with the placebo
group (according to the intent-to-treat principle), significant changes on the
pain rating index of McGill Pain Questionnaire (Ps<0.001), State-Trait Anger
Expression Inventory Scales (all Ps<0.001), Oswestry Low Back Pain Disability
Questionnaire (P<0.001), and SF-36 Health Survey scales (all P<0.001, except on
the role-emotional scale) were observed after 10 weeks in the patients treated
with topiramate. Weight loss was also observed and was significantly more
pronounced in the group treated with topiramate than in those treated with
placebo (P<0.001). Most patients tolerated topiramate relatively well but 2
patients dropped out because of side effects. DISCUSSION: Topiramate seems to be
a relatively safe and effective agent in the treatment of CLBP. Significantly
positive changes in pain sensitivity, anger status and processing, subjective
disability, health-related quality of life, and loss of weight were observed.

Publication Types:
   Clinical Trial
   Comparative Study
   Randomized Controlled Trial

PMID: 16788338 [PubMed - indexed for MEDLINE]

9: Int J Obes (Lond). 2007 Jan;31(1):138-46. Epub 2006 May 16.

Efficacy and safety of topiramate in combination with metformin in the treatment
of obese subjects with type 2 diabetes: a randomized, double-blind,
placebo-controlled study.

Toplak H, Hamann A, Moore R, Masson E, Gorska M, Vercruysse F, Sun X, Fitchet M.

Department of Medicine, Institute for Diabetes and Metabolism, Medical
University, Graz, Austria. hermann.toplak@meduni-graz.at

OBJECTIVE: To investigate the efficacy and safety of topiramate in obese subjects
with type 2 diabetes treated with metformin. DESIGN: This was a multicenter,
double-blind, placebo-controlled trial. All subjects received a
non-pharmacological program of diet, exercise and behavioral modification
throughout the study; the assigned diet was 600 kcal/day less than the subject's
individually calculated energy expenditure. After a 6-week single-blind placebo
run-in, subjects were randomized to placebo, topiramate 96 mg/day or topiramate
192 mg/day. Following an 8-week titration period, subjects remained on their
assigned dose for 52 weeks. However, the sponsor ended the study early in order
to develop a new controlled-release formulation with the potential to enhance
tolerability and simplify dosing in this patient population. A total of 646 obese
men and women (age: 18-75 years, body mass index: 27-50 kg/m(2)) with an
established history of type 2 diabetes mellitus controlled by metformin
monotherapy were randomized. Efficacy was assessed in a pre-determined modified
intent-to-treat (MITT) population of 307 subjects whose randomization date would
have allowed them to complete 24 weeks on study medication before the
announcement of study termination. MEASUREMENTS: Joint primary efficacy
parameters were mean percent change in weight and change in glycosylated
hemoglobin (HbA(1c)) from baseline to week 24. RESULTS: Subjects in the placebo,
topiramate 96 mg/day and topiramate 192 mg/day groups lost 1.7%, 4.5% (P<0.001)
and 6.5% (P<0.001), respectively, of their baseline body weight and had absolute
decreases in HbA(1c) of 0.1%, 0.4% (P<0.001) and 0.6% (P<0.001) (MITT, last
observation carried forward). Topiramate-treated subjects also experienced
statistically significant decreases in systolic blood pressure. Most common
adverse events were paresthesia and events related to the central nervous system.
CONCLUSIONS: Topiramate was effective for weight reduction and improvement in
glycemic control in obese subjects with type 2 diabetes treated with metformin
monotherapy. Further study in obese diabetics is warranted.

Publication Types:
   Multicenter Study
   Randomized Controlled Trial
   Research Support, Non-U.S. Gov't

PMID: 16703004 [PubMed - indexed for MEDLINE]