SPECIAL REPORT: ADDRESSING SIDE EFFECTS
Obesity is a prevalent global problem that affects patients with major mental illness disproportionately.1 It is associated with cardiovascular risk factors, including hypertension, dyslipidemia, and impaired glucose tolerance. Not surprisingly, the prevalence of these conditions is also high in patients with major mental illness. In fact, patients with major mental illness have a lifespan 10 to 15 years shorter than the general population, with cardiovascular mortality largely accounts for this difference.2
Several biological, psychological, behavioral, and social factors predispose patients with major mental illness to obesity. One well-established risk factor is the weight gain-inducing side effect of antipsychotic drugs.3-8 Two features of this risk factor make it stand out: It is modifiable, and it is under the control of the prescriber.
Weight Gain-Inducing Risk of Antipsychotic Drugs
Most early antipsychotic drugs caused acute and chronic motor side effects. Clozapine was different because it was not haloperidol-like or a high-potency dopamine-2 full antagonist, but its routine use was prevented by the risk of agranulocytosis. Several safer atypical antipsychotic drugs have become available, and they are now standard treatment for schizophrenia and other approved indications. Despite this progress, an important side effect of clozapine—weight gain—has remained an issue with later-generation antipsychotics.
Researchers use 2 measures to determine the weight gain-inducing side effects of psychotropic drugs3: how many patients exposed to a given drug gain weight and how much weight is gained by patients. The latter can be measured as a crude number, or it can be standardized as a proportion of weight gain from baseline. Generally, weight gain greater than 7% from baseline is considered significant.
We now have extensive research on the weight gain-inducing and metabolic risks of antipsychotic drugs, including meta-analyses of the data.3-8 If we leave subtle differences and academic discussions aside, the common antipsychotic drugs can be grouped into 3 categories of weight gain-inducing potential (Table 1).
There are a few important things to remember when contending with weight gain-inducing risk. First, weight gain is an individual-specific phenomenon; therefore, each patient must be monitored individually. Second, young patients who were not previously exposed to an antipsychotic drug (ie, drug-naive patients) are at a much higher risk of weight gain than older individuals who are not drug-naïve.8 Third, there is some evidence that metabolic complications (dyslipidemia and/or glucose intolerance) may result from these drugs independent of significant weight gain.9 Lastly, antipsychotic drug use is associated with weight gain irrespective of the diagnosis.
Limiting and Managing Drug-Induced Weight Gain
A preventive approach. Losing excess weight is tough for anyone and even tougher for individuals with major mental illness.1 Obesity might not receive much clinical attention because it is not acutely distressing or life-threatening. In the long term, however, it contributes to morbidity and mortality. In addition, young, nonobese, drug-naive patients can gain significant weight within a matter of months when exposed to antipsychotic drugs with a high risk of weight gain.8 Once they have gained that weight, many of them will never be able to lose it.
Also in this Special Report
Differences in the efficacy of commonly used antipsychotics are marginal, but differences in their weight gain-inducing potential are huge.7 There is little justification for prescribing an antipsychotic drug that has a high potential to induce weight gain when there are safer alternatives. A more reasonable approach would be to start with a low-risk medication and switch to another medication in case of inefficacy or intolerance.
Despite limited evidence, second-generation antipsychotics are used for several off-label conditions.10 Psychiatric conditions generally have a high placebo response, which may be what off-label antipsychotic use offers, but at a much higher side-effect burden than placebo. It is quite concerning that off-label antipsychotic use is prevalent in children and adolescents, who are particularly prone to these weight gain-inducing and metabolic side effects. The Choosing Wisely recommendations by the American Psychiatric Association (APA) provide more information.11
Baseline assessment and ongoing monitoring. In 2004, the APA along with other associations issued a consensus statement on baseline assessment and monitoring of patients who are prescribed an antipsychotic drug for any indication (Table 2).12 Measurement of waist circumference may not be practical in some cases, but tracking body mass index should not be a problem. Inquiring about family history of antipsychotic drug use, including response and side effects, could also provide useful information.
According to the guidelines, several factors contribute to nonadherence. These include clinicians’ lack of knowledge, psychiatrists’ limited training in monitoring patients’ physical health, limited resources, time constraints, diffusion of roles, and patient nonadherence.13 If an abnormality is detected that warrants further assessment or treatment, it should be communicated to the patient’s general physician with clarity about role designation for further assessment and management. Poor physical health care of patients with major mental illness is a systemic problem. Psychiatrists should use their social influence to shift health care culture, clinical prompts, and monitoring tools to promote an integrated or coordinated health care approach.14
Prioritizing discussions of weight gain, its complications, and healthy lifestyle. Clinical encounters are often too brief to tackle all important matters. In the hierarchy of priorities, discussion of weight and healthy lifestyle are often at the bottom of the list. However, patients with major mental illness are prone to obesity even without an iatrogenic contribution. Furthermore, personal and socioeconomic factors often make it more difficult for individuals with mental illness to adopt healthy lifestyles.1 Obesity is associated with stigma and poor self-esteem; presenting weight issues as a medical problem can help destigmatize it. Discussions about obesity and its complications would automatically become a focus of clinical attention if the aforementioned APA guidance (Table 2)12,15 were incorporated into clinical practice.
Involvement of other experts for healthy lifestyle interventions. Healthy lifestyle interventions are most effective in helping obese patients lose weight and offer the best long-term outcome.16,17 They should be offered to all suitable patients irrespective of other offered interventions.
For a healthy lifestyle intervention to be effective, it should include individualized counseling on diet and exercise, cognitive and behavioral interventions, setting well-defined, attainable goals, objective monitoring of progress, and expertise to plan and implement the interventions.16,17 Most psychiatrists do not have the time or expertise to take on these tasks, so involving relevant professionals (eg, dieticians, psychologists, occupational therapists, and case managers for obese patients) is a good idea. Patients who are already obese or who are gaining unhealthy amounts of weight should be referred to these professionals after appropriate counseling. In addition to monitoring measures of obesity, the 6-minute walk test can be used to monitor general physical fitness.18 Adopting a healthy lifestyle is very difficult for patients with major mental illness due to several factors, many of which are not in their control.1 High failure rates in the form of nonadherence and drop-outs are normal and should not be taken as a disappointment in the intervention or the patient.
Nonacademic medical centers may not have access to healthy lifestyle intervention professionals who have experience working with patients with major mental illness. In such situations, psychiatrists who are knowledgeable about the interventions can guide their colleagues on matters specific to this patient population.
Another efficient approach is to offer them in a group setting. A group setting validates the widespread nature of the problem, and patients can draw encouragement from each other. However, only psychiatrically stable patients would be suitable candidates for a group intervention and, in some cases, patient advocacy, staff capacity building, leadership engagement, and change in organizational policy may be needed.16
Switching antipsychotic drugs. Switching out a higher-risk antipsychotic drug for one that has a lower risk of inducing weight gain can help some patients. The Figure summarizes the main elements of drug switching.19
Switching antipsychotic medications must take into account various factors, including therapeutic response to the current medication, the patient’s comfort with the switch, and pharmacokinetic and pharmacodynamic properties of both drugs. Furthermore, sufficient time must be allowed to clinically document the process of the switch and its effects. The aim should be to completely replace one drug with another, but in rare cases, combination therapy may be justified based on clinical outcome.
Add-on drug treatment for weight loss. Numerous drugs have been studied as adjunctive treatment to counter antipsychotic medication-induced weight gain.20 For this purpose, metformin and topiramate have the best evidence of efficacy and safety.21-23
The metformin studies in patients with major mental illness are heterogeneous in terms of the patient population, duration of current exposure to an antipsychotic drug, and history of chronic exposure to antipsychotic drugs. Review of individual studies shows that metformin is most effective as an add-on treatment for antipsychotic drug-induced weight gain when it is introduced early in the course of treatment of patients who are young, have not been exposed to antipsychotic drugs chronically, and who have gained significant amounts of weight over a short period of time.23 Metformin may also help diminish insulin resistance associated with obesity. The beneficial effect of metformin is likely to diminish over the long term compared with healthy lifestyle interventions.
Topiramate add-on treatment to prevent or reverse antipsychotic drug-induced weight gain has been studied in several trials as well.21 Overall, topiramate was shown to be superior to placebo, with modest weight loss comparable to that observed in the trials with metformin (a mean weight loss of approximately 3 kilograms versus placebo over the course of 16 to 24 weeks).20,21 As with metformin, the greatest benefit is likely to happen in young, previously drug-naive individuals who gained significant weight over a short period of time. An added benefit of topiramate therapy is that it might address some of the mental illness symptoms as well.24 Long-term benefits of topiramate add-on therapy are less well known than those of metformin.
Weight gain associated with the use of atypical antipsychotic drugs is akin to tardive dyskinesia resulting from high-potency, typical antipsychotics. It evolves over time, leads to chronic complications, and is very difficult to reverse. Pharmacologic interventions used to tackle weight gain, namely switching from a higher-risk antipsychotic to one with a lower risk and adding an adjunct medication to counter weight gain, are modestly effective and worth considering in suitable cases. Healthy lifestyle interventions offer the best long-term outcomes, but their availability is limited by a host of factors.
There are 2 important things that need to be done. First, the iatrogenic burden of obesity should be minimized by using low-risk antipsychotics preferentially over those with higher risk for weight gain whenever possible. Second, patients should be monitored for obesity and its complications, and counseled to improve awareness about obesity and the importance of a healthy lifestyle. Efforts to develop antipsychotic drugs with a neutral affect on weight are ongoing. A few have already become available, but a shift in clinical practice for their preferential use will take its due time.
Dr Hasnain recently retired as an associate professor of psychiatry at Memorial University of Newfoundland, Canada. He was the head of the divisions of Geriatric and Consultation & Liaison Psychiatry at Eastern Health St. John’s, Newfoundland and Labrador. Currently he is a freelance health care activist focusing on public health education and health care reform.
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