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Bipolar disorder is associated with a high incidence of significant obesity, much of which is likely iatrogenic and caused by mood-stabilizing medications. It is clearly incumbent upon clinicians to minimize the potential for iatrogenic weight gain induced by medications. This review seeks to provide clinically useful information for the practicing psychiatrist by summarizing the literature relating bipolar disorder and obesity, comparing the weight gains associated with different mood stabilizers, and providing options for the treatment of obesity in bipolar patients. Recent studies suggest that obesity occurs at higher rates in patients with bipolar disorder. Medications which are considered mood stabilizing in nature include lithium, a subset of antiepileptic drugs (AEDs), and the range of atypical antipsychotic medications. A similar association was found in studies by Isojarvi and colleagues,21 who observed higher rates of obesity (defined by BMI≥25) in a group of women with epilepsy naturalistically treated with valproate (59%) relative to those treated with carbamazepine (28%) or to controls (12%). A subset of these obese valproate-treated women were subsequently switched to lamotrigine and experienced significant weight loss, with resolution of associated endocrine and metabolic abnormalities. Carbamazepine has demonstrated efficacy in acute mania and maintenance treatment of bipolar disorder.
Lamotrigine has demonstrated efficacy for bipolar depression and rapid-cycling bipolar disorder.
The bipolar literature supports the minimal weight effect observed in the epilepsy literature. Appetite suppression and weight loss have been observed in trials using topiramate for both epilepsy and bipolar disorder.
In a retrospective review34 of naturalistic treatment of bipolar patients, adjunctive use of topiramate was associated with weight loss in half of the patients.
The potential benefits of topiramate for either mood stabilization or weight reduction must be balanced against the potential for troublesome side effects. In summary, weight loss has been associated with topiramate treatment in patients with a variety of disorders when used as either a monotherapy or an adjunctive treatment. The association between early atypical antipsychotics and weight gain in patients with schizophrenia is well known. Multiple studies support the efficacy of olanzapine in the acute and maintenance treatment of bipolar mania. Clinical treatment would benefit from the ability to predict which patients would gain significant weight with olanzapine. Clozapine retains an important role as a treatment for severe, refractory mania or rapid cycling but has been associated with weight gain comparable to, or exceeding,48 that of olanzapine.
As estimated by Allison and colleagues,41 mean 10-week weight gain for risperidone is 2.1 kg.
Overall, ziprasidone has been associated with minimal or no weight gain.41,54 No significant weight gain was observed in a short-term placebo-controlled acute mania study54,55 or in schizophrenia trials. As the data illustrates, significant weight gain is associated with many of the medications we employ for the acute and chronic treatment of bipolar disorder. After the start of treatment, it is critical to monitor weight change closely, particularly for patients who are not as self-observant. If weight gain occurs during the course of treatment, metabolic and endocrine parameters should be reassessed. Phentermine is a sympathomimetic drug, with central nervous system actions similar to dextroamphetamine and other stimulants. Although stimulants are frequently used in the treatment of bipolar disorder (particularly bipolar depression with hypersomnia and anergy), the high rates of comorbid substance abuse with the illness mandate careful evaluation of the potential phentermine patient for stimulant abuse liability. Weight loss was identified as an adverse event in epilepsy clinical trials of zonisamide, a newer AED. Bipolar disorder is complicated by rates of obesity and related medical conditions which are greater than in the general population. E-newsletter Opt-inSent no more than 2–3 times each month, our E-Newsletter brings you recent findings and commentary from the psychiatric literature. This obesity produces a significant psychosocial burden, increases the risk for a range of comorbid medical disorders, and leads to higher rates of medication noncompliance and clinical relapse.
Data derived from the survey3 demonstrated that type 2 diabetes, gallbladder disease, coronary heart disease, hypercholesterolemia, and hypertension all occurred at significantly higher rates in the overweight and obese subgroups of the population. This is particularly true for psychiatrists managing chronic psychotic and affective disorders, where symptoms of the illness (altered appetite, poor impulse control, decreased rates of exercise) may conspire with the effects of medications to produce tremendous weight gain in some patients.
Elmslie and colleagues5 compared bipolar patients to controls from a population database and found higher rates of being overweight in female patients relative to controls (44% versus 25%) and higher rates of obesity in female (20% versus 13%) and male (19% versus 10%) patients relative to controls. Not surprisingly, most of the data relating weight gain to AEDs and antipsychotics have been collected in patients with epilepsy and schizophrenia, respectively. In their review of 12 early lithium studies in bipolar patients, Goodwin and Jamison8 reported that weight gain was a subjective complaint of approximately one in five patients. Dinesen and colleagues17 observed that 57% of 63 epilepsy patients treated with valproate gained more than 4 kg during treatment. In a recent study, Pylvanen and colleagues23 compared valproate-treated epilepsy patients with controls matched by BMI. Similar to valproate, carbamazepine is more effective for periods of mood elevation than depression.
Devinsky and colleagues26 evaluated the weight change in 463 subjects drawn from adjunctive lamotrigine epilepsy trials and found a median weight gain of only 0.1 kg after a mean duration of treatment for 318 days.
A mean loss of 9% of body weight was observed in a naturalistic study of epilepsy patients maintained on topiramate for an average of 2 years.33 In a prospective study, weight loss was evaluated in a sample of epilepsy patients taking adjunctive topiramate for at least 1 year.
For topiramate, side effects most often include parasthesias, somnolence, and cognitive difficulties (including memory, concentration, and word-finding difficulties). The degree of weight loss appears dose dependent, is positively related to baseline weight, and is maintained or improved beyond at least 1 year of treatment.
This extensive literature has been widely reviewed,38-40 and our discussion will therefore be limited to more recent findings.
A retrospective analysis47 of weight gain in 1,189 schizophrenia patients treated with olanzapine (mean=13.2 mg) for 1 year divided patients into rapid and non-rapid weight gain groups based upon whether they gained 7% or more of baseline body weight in the first 6 weeks of treatment.
This data should be used to guide medication selection and factored into the risk:benefit analysis undertaken for any proposed treatment.

Weight monitoring should become part of the regular routine in patients with chronic illnesses, such as bipolar disorder. Some assessments are medication specific (eg, checking for emergent hypothyroidism with lithium) and some are general (eg, monitoring for elevated fasting blood sugar, checking fasting lipids, following blood pressure more closely). Topiramate appears to be a reasonable choice for a weight-reducing medication for bipolar patients due to its potential antimanic efficacy when used as an augmentation agent, the absence of risk for cycle acceleration, and the low potential for the development of tolerance or abuse. It acts by blocking the conversion of triglycerides into free fatty acids and monoglycerides, thereby decreasing the rate of absorption of lipids from the intestine. Based upon the studies cited, iatrogenic weight gain due to mood-stabilizing medication is likely responsible for a significant fraction of this added morbidity. Prevalence of obesity and weight change during treatment in patients with bipolar I disorder.
Fortunately, the range of mood-stabilizing agents is expanding and several of the newer agents have a lower tendency to promote weight gain. It is important to remember that even the relatively modest excess weight found in the overweight group increased risk for these medical comorbidities. Since many psychiatric patients are less likely to adhere to regular medical evaluation by an internist, psychiatrists need to be aware of the causes and consequences of weight gain, monitor weight and metabolic parameters, pursue primary prevention of obesity when possible, and be aware of treatment options for obesity.
An elevated waist-to-hip ratio (indicative of central obesity and increased cardiovascular risk) was more common in patients relative to controls for both women (59% versus 17%) and men (58% versus 35%).
In a study of 100 children with epilepsy treated with valproate,18 44% developed significant weight gain. As noted in a series of studies comparing carbamazepine to lithium16 or valproate,20,21 weight gain is less severe with carbamazepine than with either of lithium or valproate. In a 32-week double-blind, randomized trial of lamotrigine and valproate monotherapy in patients with epilepsy (n=133), Biton and colleagues27 reported that valproate produced a mean weight gain of 12.8 lbs, which had not yet reached a plateau at the end of the study.
In contrast, in the lithium versus lamotrigine bipolar maintenance study previously cited,14 11% of lamotrigine-treated subjects gained 7% of body weight over 18 months.
To some degree, these side effects can be reduced with more gradual titration of the medication. Comparison of weight gain liabilities across the atypical agents is facilitated by a meta-analysis41 of data from 81 published clinical trials. Fifteen percent of the sample fell into the rapid weight gain group, whose members gained 2% or more of body weight in the first 2 weeks (4–7 lbs) and who subsequently reached a plateau of approximately 20 lbs gained by 22 weeks. The rate of weight gain decreased after 12 months but weight did not plateau until approximately month 46. Based upon this recent data, as well as several studies cited by Allison and colleagues,41 it is reasonable to place quetiapine between risperidone and olanzapine in terms of weight-gain liability.
However, there will be times when medications causing weight gain will need to be used due to a poor response to other medications, the need for polypharmacy, or avoidance of other adverse effects.
Weight monitoring should be incorporated into treatment in a fashion analogous to checking blood levels and monitoring liver function tests and other lab values. In addition to the non-pharmacologic strategies listed above, a variety of medications can be employed to facilitate weight loss. Mean weight loss of 4 kg occurred over a 4-week lead-in period, in line with previous short-term clinical trials. When combined with fenfluramine, phentermine was associated with increased rates of valvular heart disease and primary pulmonary hypertension, prompting removal from the market of this combination. There is a pronounced range of weight-gain liability across the spectrum of mood stabilizing agents (Table 3).
Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder: sex differences. Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review.
A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Weight gain in epileptic patients during treatment with valproic acid: a retrospective study. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder.
Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.
Lamotrigine versus valproate monotherapy-associated weight change in adolescents with epilepsy: results from a post hoc analysis of a randomized, double-blind clinical trial.
A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder.
Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.
Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial.
Bodyweight gain associated with atypical antipsychotics: epidemiology and therapeutic implications.
Weight gain and antipsychotic medication: differences between antipsychotic-free and treatment periods. Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: results of the EIRE study. Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study.
Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia.
Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Weight, lipids, glucose, and behavioral measures with ziprasidone treatment in a population with mental retardation.

Weight reduction and long-term maintenance after 18 months treatment with orlistat for obesity. Malaspina is professor of psychiatry, all in the Department of Psychiatry at Columbia University in New York City.
Malaspina is a consultant to Bristol-Myers Squibb and Janssen, and is on the speaker’s bureau for Wyeth. Also, a greater focus on medication-associated weight gain has increased the data available to aid in medication selection.
With the exception of hypercholesterolemia, progressively higher rates were seen with increasing obesity class. Fagiolini and colleagues6 found that 68% of bipolar subjects were either overweight (36%) or obese (32%) and that BMI correlated with number of previous depressive episodes. Corman and colleagues19 retrospectively characterized the weight gain in 70 epilepsy patients treated with valproate for 27 months and found that 71% had gained at least 5% of baseline weight, compared to 43% of patients in a smaller carbamazepine control group. However, insulin levels were higher in both normal weight and obese valproate subjects relative to controls. Weight gain was reported as an adverse event by 12% and 7.9% of subjects in the olanzapine and valproate groups, respectively.
Weight loss at 3 months correlated with reduced caloric intake, suggesting a direct effect of topiramate on appetite.
The predicted mean weight gains at 10 weeks of treatment derived from that analysis are listed in Table 2.
The non-rapid weight gain group, consisting of the other 85% of subjects, gained an average of 4 lbs over the course of the 52-week study.
For drugs with high weight-gain liability, particularly in patients with other risk factors or higher baseline weight, it makes sense to preempt further weight gain with nutritionist consultation, implementation of an appropriate diet, and a regular exercise program.
Although lacking systemic effects, orlistat is associated with gastrointestinal side effects, must be taken three times a day, and requires compliance with a reduced fat diet. The risk of cardiopulmonary disease with phentermine monotherapy cannot be entirely ruled out. This article summarizes epidemiologic data relating obesity to bipolar illness, describe the associations between specific mood stabilizers and weight gain, and provide practical approaches to the management of weight gain in bipolar patients. McElroy and colleagues7 reviewed the data on 644 patients with bipolar disorder treated in a naturalistic fashion. Isojarvi and colleagues21 proposed that valproate-induced weight gain led to insulin resistance and hyperinsulinemia and thereby to increased androgen levels and polycystic ovaries. In a randomized, double-blind comparison of lamotrigine and valproate for adolescents with epilepsy,28 lamotrigine produced no weight gain while valproate treatment resulted in significant weight gain by week 10, with a further increase over the subsequent 22 weeks. However, the literature suggests that there is minimal weight gain associated with lamotrigine. Unfortunately, there was insufficient quetiapine data to include that medication in the analysis.
This study suggests that there may be a subgroup of patients at risk for severe weight gain on olanzapine who can be identified based upon rapid weight gain in the first 2 weeks of treatment.
The rate of new onset diabetes in this group was remarkably high (37% over 5 years) but did not correlate with weight gain. To minimize frustration in both the patient and clinician, the difficulty of implementing such a program (particularly by someone with a chronic psychiatric illness) should be articulated and understood. Most weight loss occurs in the initial treatment period and there is the potential for tolerance or tachyphylaxis. However, pending more extensive data, including studies of bipolar patients, it seems prudent to be cautious in its use. They found that being overweight, obese, or extremely obese occurred in 58%, 21%, and 5% of the sample, respectively. The finding by Pylvanen and colleagues23 provides further evidence of valproate-associated weight gain and its potential association to other medical problems.
In that study, weight gain was identified as an adverse event in 25% of olanzapine patients and 10% of valproate patients. Although providing important comparison data to assist in medication selection, this meta-analysis only estimates short-term weight gain. A recent analysis from extended clinical trials46 in schizophrenia suggest that weight gain plateaus by 39 weeks of treatment.
This finding, also observed in studies of weight gain and diabetes with other atypicals, suggests that different mechanisms are responsible for these two metabolic adverse events. This study reaffirmed the efficacy of sibutramine in acute treatment and suggested that benefits are maintained after discontinuation (ie, there was no marked weight gain during placebo group maintenance) and are extended with continued dosing. Side effects can include sedation, ataxia, dizziness, and difficulty with concentration and memory.
It is incumbent upon the clinician to inform and educate the patient about weight gain, monitor weight and related endocrine and metabolic parameters closely, and be aware of pharmacologic and nonpharmacologic strategies to reduce obesity. Comorbid medical conditions that occurred at higher rates in the overweight or obese bipolar patients included hypertension, diabetes, and arthritis. Higher postprandial insulin levels were also observed in the valproate-treated patients, providing evidence of possible insulin resistance. Body weight appeared to plateau at approximately 28 days for valproate and 42 days for olanzapine. Degree of exposure to psychotropic medications known to cause weight gain correlated positively with current BMI, while frequency of exercise correlated negatively.
Taken together, these studies suggest that valproate produces significant weight gain in a minority of bipolar patients, but that it produces less weight gain than olanzapine. They observed a greater reduction in the topiramate group in binge frequency, binge-eating obsessions, BMI, and body weight. Since sibutramine is a potent serotonin and norepinephrine reuptake inhibitor (similar to venlafaxine) it likely has the potential to induce a switch into mania (which has been reported58) or cause cycle acceleration. These data highlight the elevated rates of obesity and associated medical consequences in bipolar patients.

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