Psychotropic-Induced Weight Gain: A Review of Management Strategies
ABSTRACT: Psychotropic-induced weight gain can add to the medical concerns that are inherent risks of severe mental illnesses. Pharmacological features of psychotropics that can cause weight gain include antagonism of histamine-1, serotonin-2C, and dopamine-2 receptors. Psychotropics with the greatest propensity to cause weight gain include various antidepressants (eg, amitriptyline, mirtazapine), antipsychotics (eg, olanzapine, clozapine), and mood stabilizers (eg, lithium, valproate). Clinicians can potentially avoid psychotropic-induced weight gain by carefully selecting medications with a lower propensity to cause weight gain. Management strategies to deal with psychotropic-induced weight gain include switching medications, using non-pharmacologic interventions, or treating with various medications, such as topiramate or metformin.
Key words: psychotropic, antidepressant, antipsychotic, mood stabilizer, overweight, obesity, adverse drug effect
There is an epidemic of overweight (body mass index [BMI] of 25 kg/m2 or higher) and obesity (BMI of 30 kg/m2 or higher); however, patients with severe mental illnesses (eg, schizophrenia, bipolar disorder) have an even greater risk of weight gain and obesity than the general population.1,2 In fact, this risk may approach two-fold1,3; up to 60% of patients with severe mental illnesses may be obese.4
Given that excessive weight leads to an increased risk of various medical conditions, including most notably dyslipidemias, metabolic syndrome, hypertension, and type 2 diabetes mellitus, it is not surprising that the prevalence of such conditions is particularly high (69%, 63%, 58%, and 15%, respectively) among those with severe mental illnesses.5 The net result of these various factors is that patients with severe mental illnesses have shorter life spans and increased mortality from medical causes.3,4 Specifically, the severely mentally ill are significantly more likely than those in the general population to die of cardiovascular disease1,5 and, indeed, cardiovascular disease is the most common cause of death in this population.3,4
The reason for increased rates of weight gain and obesity as well as consequent medical complications in the severely mentally ill is multifactorial, and includes genetic and lifestyle factors plus treatment-related factors.3,4,6 Certain genes that add risk of severe mental illness might also predispose to the co-occurrence of metabolic and cardiovascular disorders.4,6 Mentally ill patients exhibit higher rates of smoking, physical inactivity, and poor dietary habits relative to the general population.1,6,7 In addition, mentally ill patients may have limited access to healthcare for the prevention and treatment of medical conditions.3 Unfortunately, many psychotropic medications can cause weight gain as an adverse effect. Examples include various antidepressants, antipsychotics, and mood stabilizers.2,4.8,9
Aside from adding to the medical concerns described above, psychotropic-induced weight gain can contribute to psychological consequences of excessive weight in mentally ill patients, including impaired self-image, low self-esteem, and reduced social interactions.2,9 Importantly, psychotropic-induced weight gain is a common cause of medication nonadherence, which can lead to illness relapse, hospitalization, and worsened outcomes.2,8,9 Therefore, it is imperative to have a thorough understanding of psychotropic-induced weight gain, including the relative incidence between psychotropic agents, the pharmacological basis for the adverse effect, and different clinical strategies to avoid or manage the adverse effect.
RELATIVE INCIDENCE OF WEIGHT GAIN
Antidepressants. A meta-analysis10 reviewed studies reporting body weight changes during treatment with antidepressants. According to the findings of the meta-analysis, amitriptyline, mirtazapine, and paroxetine were associated with the greatest risk of weight gain. The mean weight gain seen in acute (ie, 4 to 12 weeks) and maintenance (ie, 4 months or longer) treatment periods with amitriptyline was 1.52 kg and 2.24 kg, respectively. Mirtazapine maintained significant weight changes from the acute to maintenance phase of treatment (1.74 kg and 2.59 kg, respectively). Paroxetine had little effect on weight during acute treatment, but resulted in weight gain similar to that of amitriptyline and mirtazapine during maintenance treatment. Conversely, other selective serotonin reuptake inhibitors, including citalopram, escitalopram, fluoxetine, and sertraline, showed only minimal effects on weight. Serotonin-norepinephrine reuptake inhibitors, such as duloxetine and venlafaxine, also had little effect on weight.10 Bupropion is the antidepressant with the lowest risk of weight gain, and it can even cause weight loss in many patients.10,11
Antipsychotics. Low-potency typical antipsychotics (eg, chlorpromazine) pose a moderate risk of weight gain,12-14 whereas high-potency typical antipsychotics (eg, haloperidol) have not been shown to cause significant weight gain.2,12,15 Overall, weight gain and obesity are more problematic with atypical antipsychotics than with typical antipsychotics. Of the atypical antipsychotics, clozapine and olanzapine have the most significant effect on weight.12,15-18 The incidence of weight gain with clozapine is considered to be the most significant at 4% to 31%,19 and one study indicated almost half of patients gained 20% or more of their initial body weight.2,20 The amount of weight gain with clozapine can be related to duration of treatment and patients not being overweight at baseline.21 Olanzapine follows clozapine in significant weight gain with an incidence of 5% to 40%.22 A meta-analysis by Allison and colleagues23 suggested that olanzapine was associated with a mean weight gain of 4.15 kg, while the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial indicated 30% of patients taking olanzapine experienced a weight gain of more than 7% from baseline (mean increase of 9.4 kg).24
Quetiapine and risperidone pose a moderate risk of weight gain with incidences of 3% to 23% and 9% to 21%, respectively.12-14,25,26 The CATIE trial reported a weight gain of more than 7% from baseline in 16% of patients taking quetiapine (mean increase, 1.1 kg) and 14% of patients taking risperidone (mean increase, 0.8 kg).24 Ziprasidone and aripiprazole have the lowest incidence of weight gain.2,12-14 Data from the CATIE trial showed that ziprasidone use actually resulted in an average weight loss of 1.6 kg,24 and the meta-analysis by Allison and associates23 estimated a mean weight gain of 0.04 kg. Aripiprazole treatment resulted in a mean weight gain of approximately 1 kg in a 52-week trial, but actually resulted in mean weight loss of 0.9 to 1.37 kg in several 26-week trials.16 Weight effects of aripiprazole appear to be influenced by patients’ baseline weights; patients with lower BMIs (less than 23 kg/m2) are more likely to gain weight, whereas those with higher BMIs (more than 27 kg/m2) are more likely to lose weight.16,27
Mood stabilizers. Two mood stabilizers in particular carry the risk of weight gain: lithium and valproate.28,29 The exact incidence of weight gain with valproate is difficult to pinpoint, but many of the recently published studies that examined metabolic effects of valproate in adult patients found that approximately 45% to 55% of patients gained weight.30 Torrent and colleagues2 estimated that weight gain with valproate ranges from 3 to 10 kg over a period of 3 to 12 months, but can possibly be up to 20 kg. Another study suggested that weight gain occurs more frequently in female patients taking valproate compared to males.31 Approximately 25% of patients taking lithium experience weight gain,2 and clinically significant weight gain (more than 7%) occurs more frequently with lithium compared to placebo.32 Lithium-induced weight gain has been estimated to range between 4.5 and 12 kg.2 Weight gain with lithium is likely a dose-dependent effect and is less likely to occur at serum concentrations lower than 0.8 mmol/L.2 In contrast, lamotrigine and carbamazepine have relatively low incidences of weight gain, although data evaluating weight gain with these two agents are scarce in this patient population.2,17,28
Table 1 depicts the relative incidence of weight gain with antidepressants, antipsychotics, and mood stabilizers as discussed in this section.2,10,12-14,28-29
PHARMACOLOGICAL BASIS OF PSYCHOTROPIC-INDUCED WEIGHT GAIN
Weight gain due to psychotropic agents is very complex and may involve several different mechanisms. Table 2 depicts differences in binding constants of some of the most commonly prescribed psychotropic agents on various receptors that are involved in psychotropic-induced weight gain.33-36 Table 3 describes the mechanisms by which these receptors are involved in the weight effects of psychotropic medications.37-39
Antidepressants. Antidepressants appear to cause weight gain through their interactions at histamine-1, serotonin-2C, and perhaps muscarinic cholinergic receptors. Amitriptyline has potent anticholinergic and antihistamine effects in addition to potency at the serotonin-2C receptor, and mirtazapine displays significant antagonism of both histamine-1 and serotonin-2C receptors. Of the selective serotonin reuptake inhibitors, the agent most commonly associated with weight gain is paroxetine.10 One key difference between paroxetine and the other selective serotonin reuptake inhibitors is its affinity for muscarinic cholinergic receptors. In contrast, bupropion exhibits extremely low binding at these receptors, and it is not associated with weight gain.
Antipsychotics. Dopamine-2 receptor antagonism may be a common factor behind antipsychotic-induced weight gain, but other receptors certainly play a major role in determining the relative risks of weight gain caused by antipsychotic medications.37-39 The capability of antipsychotics to cause weight gain roughly correlates with their affinity for histamine-1 and serotonin-2C receptors.37 For example, both clozapine and olanzapine are potent antagonists of these receptors, and these agents are associated with the most weight gain. Quetiapine has high affinity for histamine-1 receptors, but much lower affinities for dopamine-2 and serotonin-2C receptors, and it causes moderate weight gain. Haloperidol has low affinity for histamine-1 and serotonin-2C receptors, and it is less likely to cause weight gain. Still, other receptors (eg, serotonin-1A) or mechanisms must be involved in the weight effects of these medications, as some atypical antipsychotics (eg, aripiprazole, asenapine, ziprasidone) have moderate to high affinity at histamine-1 and/or serotonin-2C receptors yet have little weight gain associated with their use.
Mood stabilizers. Many of the mood stabilizers utilized in the treatment of bipolar disorder are associated with weight changes, though quite variable and with poorly understood mechanisms. Since lithium is linked to hypothyroidism and subclinical hypothyroidism, concomitant weight gain associated with lithium may result in part from a slowed metabolic rate.2,32 In addition, lithium can directly stimulate appetite at the hypothalamus, cause fluid retention, and increase thirst (which might be quenched by high-calorie beverages).2,32,40 Valproate has been associated with increased appetite, including carbohydrate craving, and increased thirst; these effects are thought to be caused by a poorly understood mechanism in the hypothalamus. In addition, valproate may have the ability to enhance secretion of insulin from pancreatic beta cells and to reduce insulin clearance by the liver, both resulting in hyperinsulinemia and associated weight gain.30
PREVENTION AND MANAGEMENT
Several clinical strategies have been proposed to limit the possibility or extent of psychotropic-induced weight gain. None of these strategies are inherently better than the others, rather clinicians should consider patient-specific factors when selecting a particular strategy for a particular patient. Advantages and disadvantages of the various strategies are outlined in Table 4.
Avoidance. Appropriate selection of the first psychotropic agent can significantly reduce initial weight gain. Particularly in cases involving patients who are already overweight or obese, or patients who have expressed concerns about the possibility of gaining weight due to medication therapy, it is imperative for the clinician to choose agents with lower propensities for causing weight gain. For instance, bupropion would be preferable to mirtazapine or paroxetine, aripiprazole or ziprasidone would be preferable to olanzapine, and lamotrigine would be preferable to valproate or lithium.
Switching medications. Patients who experience significant weight gain while taking one psychotropic may benefit from a switch to an alternative. For example, in patients receiving olanzapine or risperidone, switching to ziprasidone has produced weight loss, and in patients receiving olanzapine, switching to aripiprazole has produced weight loss.41 Selection of appropriate candidates for switching is critical, and factors to consider include the following41:
•A clear relationship between psychotropic exposure and weight gain.
•A new-onset health risk (obesity, diabetes, etc).
•Nonadherence due to weight gain.
•Abuse of other medications to offset the weight gain.41
Switching medications will not reverse obesity that existed prior to the psychotropic medication use or obesity caused by a medication other than the psychotropic.41 Various strategies may be used to switch patients from one psychotropic medication to another, and the clinician should take into account the risk of withdrawal effects, relapse, drug interactions, and additive adverse effects when selecting a strategy for a particular patient.
Non-pharmacologic interventions. Non-pharmacologic interventions including cognitive-behavioral therapy, nutrition counseling, and combined nutritional and exercise programs delivered to individuals and groups have been shown to reduce body weight in patients taking psychotropic medications and in patients with preexisting psychotropic-induced weight gain. Data suggest that weight loss benefits may be maintained for up to 2 to 3 months post-intervention and that weight may be further reduced despite cessation of the intervention.15
Adjunctive therapy. Pharmacologic treatment of psychotropic-induced weight gain may be considered after non-pharmacologic strategies have failed. Many adjunctive therapies have been examined in regards to treatment of psychotropic-induced weight gain,39,42-44 albeit published studies focus on the treatment of antipsychotic- and mood stabilizer-induced weight gain, and there is a dearth of information about the use of adjunctive agents for treatment of antidepressant-induced weight gain. Positive findings have been reported in double-blind, placebo-controlled trials involving amantadine, metformin, nizatidine, and topiramate.39,42-44 Reboxetine, sibutramine, and dexfenfluramine have also shown efficacy39,42-44; however, the former medication is unavailable in the United States and the latter two medications have been withdrawn from the US market because of safety concerns.
Metformin has been studied more thoroughly than the other agents.39,42-43 Results from meta-analyses conducted by Fiedorowicz and colleagues42 and Maayan and associates43 revealed mean weight losses of 2.93 kg and 2.94 kg, respectively, in patients treated with metformin. Topiramate has produced positive results in several trials and is considered a promising agent for this indication.39,42,44 The aforementioned meta-analyses by Fiedorowicz and colleagues42 and Maayan and associates43 revealed mean weight losses of 3.95 kg and 2.52 kg, respectively, in patients treated with topiramate. However, the weight loss effects of topiramate are often accompanied by various adverse effects, and there are risks associated with its use.39
Various histamine-2 antagonists (ie, famotidine, nizatidine, ranitidine) have received attention in the treatment of psychotropic-induced weight gain, but nizatidine has been studied the most. Unfortunately, nizatidine treatment has yielded mixed results.39,42,44 Moreover, mean weight loss for histamine-2 antagonists in the meta-analysis by Fiedorowicz and colleagues42 was only 1.78 kg, which failed to differ significantly from placebo. Amantadine significantly decreased weight gain compared to placebo in two trials involving olanzapine-treated patients, with one trial showing a large benefit (loss of 0.4 kg versus gain of 4.0 kg) and the other trial showing a more modest benefit (loss of 0.2 kg versus gain of 1.3 kg).42,44 These agents are further described in Table 5.39,42-44
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