Obesity and Psychotropics

SUMMARY

Weight gain is on the rise in the United States as is the diagnosis and treatment of mental disorders. These two phenomena are distinctly separate but tend to overlap in that most psychotropic agents approved for use in the United States are associated with the potential to induce weight gain. Metabolic disorders such as diabetes, hypercholesterolemia, and hypertension are also on the rise and often associated with weight gain and clearly associated with certain psychotropic medications. This article serves to provide a succinct review regarding the epidemiology, etiology, and treatment options for psychotropic‐induced obesity.

Introduction

Weight gain is a major problem that contributes to patient noncompliance with psychotropic regimens, may lead to symptomatic relapse, and contributes to medical comorbidity, and currently prescribed psychotropics may cause 2–17 kg of weight gain over the course of clinical treatment [1, 2]. The antipsychotics, mood stabilizers [3, 4, 5], and antidepressants [6] are all known to cause weight gain. Comparatively, there are only a very few psychotropics associated with weight loss [7, 8, 9]. This article is not intended to be an exhaustive review, but a brief introduction and overview in regard to the prevalence, etiology, and treatment of psychotropic‐induced, iatrogenic weight gain and obesity. This manuscript should give the reader a sense of the agents involved and provide clinical application for use in psychopharmacological practice.

Weight Gain Due to Psychotropics

Antipsychotics

With the introduction of the newer, atypical, second‐generation antipsychotics (SGAs), the potential to cause remarkable weight gain has been recognized. Nearly every antipsychotic has been reported to cause weight gain. Although comparison is limited by the different designs and recruitment procedures of reviewed studies [10], a MEDLINE search from 1966 to 2010 showed that the amount of body weight gain was highest in patients treated with olanzapine (average body weight gain 2.3 kg/month), quetiapine (1.8 kg/month), and clozapine (1.7 kg/month). Treatment with risperidone showed moderate changes in body weight (average body weight gain 1.0 kg/month), where ziprasidone seemed to induce only slight body weight changes (0.8 kg/month). Asenapine causes up to 0.9 kg weight gain in the first 3 weeks of treatment [11] and its FDA Package Insert discusses a 52‐week regulatory trial causing negligible weight gain over time, suggesting that it may also be less metabolically problematic [12]. A total of 19% of patients treated with asenapine have weight gain as compared to 31% who were treated with olanzapine [13]. Another recently FDA‐approved SGA is iloperidone. It has shown mild to moderate weight gain (1.5–2.1 kg). This appears to be more than that produced by ziprasidone, but more similar to that seen with risperidone [14]. Paliperidone was approved in December 2006, and over both short and long term (52 weeks) has shown no significant metabolic side effects including weight gain [15, 16]. Lurasidone [17] has just been FDA approved for schizophrenia and in acute trials, pooled data from short‐term, placebo‐controlled study suggest that mean weight gain was 0.75 kg for lurasidone‐treated patients compared to 0.26 kg for placebo‐treated patients. A comparative trial with olanzapine revealed that it caused 4.15 kg over the same timeframe. Lurasidone appears to be weight neutral in short‐term trials.

A common comparative finding in the literature suggests that risperdone causes weight gain between 0.3 and 2.6 kg while ziprasidone often causes relatively less weight gain [18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. Olanzapine may be the most significant second‐generation agent causing weight gain from 4.2 to 7.4 kg, and even up to an average gain of 12 kg in 45–90% of patients have significant weight gain [28, 29, 30, 31, 32, 33]. Quetiapine (regular release and extended release) also has been implicated in causing more remarkable weight gain from 4.1 to 5.6 kg [34, 35]. Clozapine is likely to cause remarkable weight gain with highest reports ranging from 2.4 to 31.3 kg, which is often a 10% gain over their baseline [36, 37, 38, 39, 40]. Finally, a short‐term study using aripiprazole showed limited 0.5–0.9 kg weight gain as compared to placebo [41]. Over all, weight gain seems to be greatest for clozapine, olanzapine, risperidone, and quetiapine when compared to the relatively weight‐neutral paliperidone, ziprasidone, aripiprazole, asenapine, and lurasidone (see Table 1).

Table 1.

Weight changes due to psychotropics

Medication	Percentage of patients having weight changes	Duration	Amount of weight gain
Olanzapine	31%, 45–90%		2.3 kg/month average.
			4.2–7.4 kg total up to 12 kg
Quetiapine			4.1–5.6 kg total
			1.8 kg/month
Risperdone			1.0 kg/month
Ziprasidone			0.8 kg/month
Asenapine		3 weeks of treatment	0.9 kg
Ileperidone			1.5–2.1 kg
Palipradone	–	52 weeks	None
Aripiprazole			0.5–0.9 kg weight gain total
Clozapine	Most likely to cause weight gain		2.4–31.3 kg
			1.7 kg/month
Imipramine	10%		3–4 kg
Amitryptiline			2 kg
Trazadone			0.5–1.1 kg
Fluoxetine		Long term	2–2.5 kg
Citalopram		1 year	1–1.5 kg
Fluvoxamine			No change in weight
Duloxetine		8‐month trial	0.61 kg
Escitalopram			1.83 kg
Divalproex	71% of patients		4 kg
			0.9–14 kg
Lamotrigine			−2 kg or 0.6 kg weight gain
Carbamazepine			15 kg
Lithium	20%		10 kg or 6.3 kg
Zonasemide	35%		Weight loss

Antidepressants

The prevalence of weight gain due to antidepressants is more chronic and more common, as prescribing volume is higher. Weight gain here appears to be underrecognized as there are fewer studies emphasizing antidepressant‐induced side effects as the focus has been on the SGAs. As depression and anxiety are more common diagnostically and epidemiologically as compared to psychotic disorders [42] there is greater overall potential for iatrogenic weight gain with this class of medications in our opinion.

Tricyclic antidepressants (TCAs) and perhaps monoamine oxidase inhibitors (MAOIs) may be more likely to cause weight gain than the selective serotonin reuptake inhibitors (SSRIs) or the newer antidepressants in clinical practice. Mirtazapine may be placed between the SSRIs and the TCAs in terms of relative risk of weight gain and is likely the most risky drug for weight gain out of the novel antidepressants that postdate TCAs and MAOIs. Bupropion may be the only modern agent to lower weight [6]. Though the newly release vilazodone will need to be evaluated once it is used clinically in practice.

It is possible that a 1–3 kg average weight gain on antidepressants in 10–20% of the population may be a greater population side effect burden than the 2–10 kg average weight gain previously discussed in the 1% of the population with schizophrenia. Although antipsychotic medication use is escalating, as the SGAs are being used more often now with the FDA approval for bipolar and major depressive disorders, antidepressant prescribing far outweighs SGA prescribing.

Imipramine subjects may gain, on average, 3–4 kg [43] and 13.3% of patients may experience a greater than 10% gain in baseline weight. Amitriptyline‐treated patients may gain an average of 2 kg. In contrast, nortriptyline was shown not to promote weight gain in depressed adult patients over 60 years in age and in children with attention deficit disorder [44, 45]. Some authors [46] suggest that MAOIs are less likely to produce weight gain than TCAs. A literature review [46] suggests that phenelzine is the MAOI most likely to induce weight gain while reports of isocarboxazide or transdermal selegiline‐induced weight gain are less common. Clearly, clinical experience shows at least moderate weight gain with MAOIs.

Regarding the novel antidepressants, trazodone studies show 0.5–1.1 kg weight gain over time [8, 47]. Bupropion is routinely associated with weight loss. Five percent of baseline weight loss or 3–4.4 kg of weight loss has been reported [48, 49, 50]. For the most commonly prescribed antidepressants, the SSRIs, often an initial weight loss is noticed with sometimes a reversal to over all weight gain after a year of treatment. This is a common clinical finding, which was not noted in initial acute SSRI drug trials, which were all short term in nature [51]. SSRI data are controversial in that short‐term anorectic action of fluoxetine has been recognized, but long‐term follow‐up reveals that its weight‐reducing effects are transient, eventually causing a gain in body weight over time [52]. Acute losses of 0.35 kg may be noted, but an average of 2–2.5 kg of weight may be gained [53]. Citalopram may cause 1–1.5 kg weight gain over a year's time [54, 55]. Fluvoxamine [6, 56] has two studies showing no weight gain and no weight loss. Sertraline studies suggest more weight gain than control groups [57]. Paroxetine is the most likely of the SSRIs to cause weight gain. Fava et al. showed that paroxetine promoted more weight gain when compared to fluoxetine and sertraline [57].

These findings suggest a slower iatrogenic weight gain side effect profile compared to the SGAs mentioned above.

Mirtazapine has consistently shown greater weight gain when compared to SSRIs (fluoxetine, paroxetine, citalopram) [58, 59, 60]. In clinical practice it seems to react like an SGA in regard to weight and metabolic issues.

As aripiprazole is now approved for adjunctive treatment in major depressive disorder, we will review its data for this indication and place its more recent info here with the antidepressants. Various studies show that aripiprazole tends to have a low risk of association for metabolic and endocrine alteration [61], but it appears that prescribing serotonergic antidepressants and aripiprazole may increase weight gain potential over the aripiprazole alone [62].

In regard to the SNRI class of antidepressants, a recent 8‐month double‐blind randomized prospective trial with subjects initially on duloxetine, escitalopram, or placebo, the mean change in weight was significantly higher for escitalopram compared with duloxetine (+0.61 kg, duloxetine; +1.83 kg, escitalopram; P < 0.05); however, the incidence of treatment‐emergent abnormal weight gain (> or = 7% increase in weight from baseline) was similar between drugs and was significantly greater for both duloxetine and escitalopram compared with placebo.

Mood Stabilizers

Mood stabilizing agents are used for bipolar disorder and schizoaffective disorder. As with the antipsychotics and antidepressants, weight gain is a common side effect. Mood stabilizers are associated with weight gain of similar magnitude to that of antipsychotics, and often greater than that associated with the antidepressants.

A total of 71% of divalproex patients may gain weight of more than 4 kg [46]. A total of 0.9–14 kg of divalproex‐induced weight gain has been reported in other studies [63, 64] with an incidence of 8–59%. Lamotrigine has a more favorable, weight‐neutral profile and may cause some weight loss of 2 kg and a gain only up to 0.6 kg [65]. Carbamazapine may show a weight change up to 15 kg based on limited studies [66, 67]. Lithium reviews suggest weight gain also as a common side effect. Twenty percent of patients on lithium gained 10 kg or more in one study and a 6.3 kg weight gain in a second [68].

In contrast to the above mood stabilizers zonasimide, albeit off‐label has been shown to cause weight loss instead of weight gain. Zonasimide has been used recently to help reduce weight in some patients. The results of one small controlled study suggest that zonisamide may have efficacy in binge eating disorder with obesity [69].

For example, zonisamide augmentation to individual cognitive behavior therapy can improve the treatment of binge eating disorder patients, reducing body weight and the number of binge eating episodes. These results were maintained 1 year after the end of treatment [70]. About 35% of patients who were treated with zonisamide lost weight, especially who were overweight, but this weight loss was reversible [71].

Cause of Weight Gain

This section will attempt to briefly review the possible causes of iatrogenic weight gain.

Gothelf et al. [33] studied weight gain mechanisms and energy balance in olanzapine‐treated patients and found that an increase in body mass index (BMI) was due to an increase in calorie intake, but also revealed effects on the resting energy expenditure or slowing of metabolism. The simplest explanation for this antipsychotic‐induced weight gain is that olanzapine increased appetite and caloric intake while slowing the basal metabolic rate.

Psychotropics have broad pharmacodynamic profiles, and it is likely that multiple neurotransmitters, receptors, and neurocircuits are responsible for drug‐induced weight gain. Olanzapine has activity at several different receptor sites [72]. Others, like clozapine, may act at even different receptors (i.e., sigma‐opiod receptors) effecting weight gain [73]. Research suggests that serotonin 5‐hydroxytryptamine 2C (5‐HT_2C) receptors play a role in regulating appetite. In rats, activating these receptors decreases eating behavior and mice lacking in 5‐HT_2C (deactivated) receptors become obese [74]. Atypical antipsychotics often block this receptor functionally, which may cause an increase in eating and caloric intake. Many of the antipsychotics (olanzapine, quetiapine, clozapine) and some antidepressants (mirtazapine) have this 5‐HT_2C blocking property. Beta‐3 adrenergic receptors found in adipose tissues play an active role in weight control by converting fat into energy especially in response to norepinepherine [75]. Clinically there are no data to suggest effects on weight gain with alpha‐adrenoceptor antagonists but it is noted that psychotropics with higher affinities (i.e., TCA) for these are associated with weight gain whereas those with low affinities for these receptors(e.g., SSRI) are not [76]. The exact role of histamine‐1 receptors in appetite control is not known. However, psychotropics with greater ability to block H‐1 receptors often show greater weight gain potential [77] possibly through deactivating brain satiety centers and increasing hunger. Another mechanism may be related to blockage of anticholinergic sites, all of which are related to appetite stimulation.

Treatment Weight Gain

Early intervention is the key to preventing significant drug‐related weight gain. Patients should be told about weight gain as a potential adverse effect before they begin treatment and their weight should be monitored routinely as a standard of care, as long as they continue taking drugs that may increase weight. Informed consent about this risk should be the standard of care. Routine blood monitoring for hyperlipidemia, hyperglucosemia, hypertension, and abdominal girth should occur. Metabolic syndrome is now a well‐documented effect of second‐generation antipsychotic use. Ideally, a diet and exercise plan should be initiated to prevent or treat weight gain before medically significant weight gain occurs [78]. A successful weight loss program is one which can produce a loss of 0.5–1% of the patient's initial body weight per week, a rate of loss considered safe and acceptable [79]. Diet and exercise produces maximal benefit, but require considerable commitment and motivation on the part of the patient. This is often difficult or impossible in the mentally ill.

Besides diet and exercise, formal behavior modification techniques involve changing eating habits and reinforcing desired dieting behavior. It is the gradual but consistent change in behavior that leads to healthier eating habits and weight loss. Simple use of “portion control” behaviors can teach patients to eat less at every meal without the complexity of counting fat versus carbohydrate calories and does not require the willpower to follow a bland low‐salt, low‐fat, and low‐sugar diet [80]. Behavior modification alone can generate a weight loss of 0.5–0.7 kg per week [81]. Through formal cognitive therapy patients can achieve satisfaction with body image and acceptance of modest weight loss. In one study, the effects of cognitive‐behavioral therapy on weight gain due to psychotropics were studied in six schizophrenics (mean age 37.3 years). The mean BMI (kg/m²) decreased from 29.6 kg to 25.1 kg in the post‐treatment group [82].

Generally, drug therapy informed consent, active monitoring of weight and early intervention or even prophlyaxis with diet and exercise are the first treatment options. If this fails, or the patient is too ill to comply, then clinical practice suggests that antiobesity drugs may be appropriate. Risks and benefits should be evaluated for each antiobesity agent. Sometimes, prior to trying an antiobesity medication, one may choose to switch the current psychotropic medication to one with same indication but less weight gain potential.

Drugs that reduce caloric intake, suppress hunger, are commonly known as anorectic agents or appetite suppressants. They act centrally by decreasing appetite or increasing satiety. Sympathomimetic agents include phendimetrazine, phentermine, mazindol, diethylpropion (many are controlled substances), amphetamine‐related compounds, and phenylpropanolamine. The amphetamine products are used on label for the treatment of sleep apnea, narcolepsy, and attention deficit/hyperactivity disorders. When these conditions are comorbid with other primary psychiatric disorders a weight loss advantage is often clinically noted. Serotonergic agents, fenfluramine and dexfenfluramine, were withdrawn from the US market in September 1997 over concerns about valvular heart disease [83].

The three most currently prescribed drugs that are FDA approved to treat obesity likely are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2–5 kg over placebo. At least four other types of single‐agent weight loss drugs are in possible late‐stage development: [1] selective central cannabinoid‐1 receptor blockers, [2] selective central 5‐HT_2C serotonin receptor agonists, [3] an intestinal lipase blocker, and [4] central‐acting incretin mimetic drugs [84]. Furthermore, other agents under development that may produce beneficial changes in appetite expression in the obese include glucagon‐like peptide‐1 analogs such as liraglutide, an amylin analog davalintide, the 5‐HT_2C receptor agonist lorcaserin, the monoamine reuptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide [85]. Psychiatrists will recognize some of the above agents as they are FDA approved for other indications but are well known to cause weight loss as an adverse effect.

As an example, in one study, following a 1‐week placebo lead‐in, 244 obese or overweight, nondiabetic subjects received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 microg t.i.d.), pramlintide sc (120 microg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 microg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo [86]. As weight gain is often substantial with psychotropics, combined antiobesity therapy in clinical practice is frequently needed. Psychiatrists are often clinically savvy using rational polypharmacy to achieve remission of the psychiatric disorder at hand, and perhaps may consider polypharmacy in severe cases of psychotropic drug‐induced obesity.

Single sympathomimetic amphetamine agents because of their high potential for abuse, cardiac and psychiatric side effects, are generally not often recommended for treating obesity [83]. Sibutramine is a nonaddictive, mixed serotonergic, and noradrenergic reuptake inhibitor, which recently is being evaluated by the FDA due to cardiac safety concerns. It helps patients achieve a 10–15% loss of body weight [87, 88, 89, 90]. The safety and effectiveness beyond 1 year of use have not been determined. The mechanism by which sibutramine acts is increased satiety. It decreases the levels of triglycerides, total cholesterol and LDL cholesterol, while also increasing the levels of HDL cholesterol (seen in people who lose > 5% of body weight). Sibutramine can increase blood pressure and heart rate. Other common adverse effects of sibutramine are dry mouth, anorexia, insomnia, irritability, and constipation. These studies were conducted in obese individuals who were not taking psychotropics, so outcome may not be generalizable to the mentally ill. This agent when combined with other antidepressants may lead to serotonin syndrome and is often avoided or contraindicated.

Orlistat, a fat or lipase blocker, shows safety and efficacy for up to 2 years. Orlistat may be a better option than sibutramine for patients already taking other drugs because it does not act systemically, so there is less risk of interaction with centrally acting medications. Specifically, it inhibits gastric and pancreatic lipases by binding covalently to the serine residue at the active site of these enzymes [91]. This allows fat not to be absorbed by the GI system when taken with meals [92, 93, 94]. It decreases triglycerides, total cholesterol, and low‐density lipoprotein cholesterol while increasing high‐density lipoprotein cholesterol [91]. The drug also improves glycemic control [91]. The most common adverse effects are gastrointestinal: including increased defecation, soft stools, fatty or oily stools, and vitamin A and E deficiency [93, 94]. Patients take orlistat 120 mg three times daily and must take a multivitamin to avoid deficiencies.

Two large placebo‐controlled trials [95, 96] document the efficacy of orlistat use for up to 2 years. After 1 year, the orlistat group lost 10.2% of body weight in one study and 8.8% in the second study. After 2 years, twice as many patients taking orlistat maintained a weight loss of more than 10%. Patients must take other medications 1 h pre‐ or postorlistat to avoid change in absorption of these medications [97]. One study in the mentally ill reported that 13 consecutive patients with psychotropic induced weight gain lost 34.6% of side effect weight gained [98]. Nine of the 13 subjects suffered from major depressive disorder and were taking serotonergic antidepressants. Patients were deemed obese with a BMI of > 30 kg/m². The average weight gained from psychotropics prior to orlistat initiation was 16.4 kg. The average weight loss within this relatively short time period was 5.6 kg, or 34.6% of the weight gained as a result of psychotropic drug use.

Amantadine has also been studied [99] in 12 patients who had already gained a mean of 7.3 kg during olanzapine treatment. Subjects were started on amantadine at 300 mg per day. Results of the study showed an average weight loss of 3.5 kg over 3–6 months. No adverse effects were reported. Nizatidine, a histamine‐2 receptor antagonist was studied in a 16‐week, randomized, double‐blind, placebo‐controlled study. Dosed at 300 mg twice per day, it allowed patients to gain an average of 2.5 kg compared with the 5.5 kg gained by patients treated without nizatidine [100]. Naltrexone, an opioid antagonist, at a dosage of 50 mg/day, has been shown to decrease weight by reversing the observed hunger and craving for sweet, fatty foods caused by TCAs and lithium. Subjects reported decreased enjoyment ratings of food and also diminished subjective feelings of hunger. No adverse effects of opioid antagonism were seen regarding depressive symptoms. In another study, naltrexone was coadministered with antidepressants to eight female patients who had already gained greater than 6 kg. After 8 weeks, the results of the study showed that weight gain reversed in five patients, stopped in two patients and attenuated in one patient. However, weight increased again by 1.5+/−2.7 kg within 14 weeks after the drug was stopped. Of note, the mean weight loss was small compared to previous drug‐induced weight gain [101].

Preliminary findings suggest that topiramate may serve as a dual purpose agent in the treatment of obese patients with affective disorders. In one case report [102], topiramate was administered to a 29‐year‐old male schizophrenic who had gained weight due to clozapine. Results showed a sustained weight loss for the first time with an improvement of psychotic symptoms. Additionally, topiramate add‐on studies for bipolar disorder have shown 33–55% of patients losing weight ([10, 11, 12, 13, 14, 15] lbs) [103, 104]. Side effects of fatigue, cognitive dulling, ataxia, glaucoma, oligohydrosis, and acidosis are reported at doses of 100–400 mg/day.

Metformin holds promise as a treatment for weight gain in patients taking psychotropic medications. In a 12‐week open‐label study [105] conducted on 19 patients (aged 10–18 years) who had gained over 10% of their baseline weight on antipsychotics, 500 mg three times a day of metformin was given for 12 weeks in addition to psychotropic drugs. The results of the study showed 15 patients lost weight, 3 gained weight, and for 1 weight remained unchanged. Sporadic diarrhea was noted in some patients that resolved with time. The results of the safety tests for lactic acidosis were unremarkable. A recent controlled study by the same group confirmed this open label finding [106]. In a recent review, among 15 different pharmacologic strategies (N = 35, n = 1629), only metformin, fenfluramine, sibutramine, topiramate, and reboxetine were more effective than placebo, with the most evidence being available for metformin, and no head‐to‐head trials comparing individual pharmacologic interventions [107].

Conclusions

The prevalence of obesity in the general population and in patients with mental illness is increasing. The widespread use of psychotropic medications has likely contributed to the increased prevalence. The authors have briefly reviewed the risk, etiology, and potential treatment options in regard to psychotropic‐induced obesity. There are no FDA approved agents for reversing or preventing this weight gain specifically, and all options reported above are considered off‐label. Many studies are uncontrolled and of small scale, limiting our conclusions in the mentally ill population. A combination of diet, exercise, and medications would be the ideal approach for combating the weight gain seen in the mentally ill population. Perhaps the smaller scale studies noted above and the continued pipeline of psychotropics that continue to cause weight side effects will prompt larger, funded studies or more future medications that are weight neutral.

Finally, it may be possible in the future office setting to draw blood, or perform a cheek swab in hopes of determining which patients are at risk for pathologic weight gain and metabolic syndrome due to psychotropics. For example, initial studies have suggested certain risk alleles or genes may predispose certain patients to this iatrogenic weight gain. For example, the X‐linked 5‐HT2C receptor gene (HTR2C) may be the most strongly implicated. Carriers of the −759T allele have been found to gain less weight than those with the wildrype C allele. The T allele is also associated with lower gene expression. This may result in differing levels of circulating leptin as a potential cause of weight side effects [108, 109, 110, 111]. Patients who can be shown to carry little genetic metabolic risk can likely be placed on any psychotropic in the armanetarium, but those with clear risk should then avoid any agent that directly, or indirectly manipulates the 5HT2c receptor.

Conflict of Interest

The authors have no conflict of interest.