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Prevention of obesity Rohan Ganguli Prevention of obesity, and its attendant co-morbidities in serious mental illness

Author: Rohan Ganguli, M.D., F.R.C.P Affiliations: University of Toronto, Department of Psychiatry Professor of Psychiatry & Canada research Chair & Center for Addiction and Mental Health, Toronto Executive Vice President for Clinical Programs Address: 901 King Street West, Suite 530 Toronto, ON M5V 3H5 Email: rohan_ganguli@camh.net

Prevention of obesity Rohan Ganguli Declaration of potential conflicts of interest: Over the past 10 years, Dr. Ganguli has received research grants from Janssen, Lilly, Pfizer, and Bristol Myers-Squibb. He has also received honoraria for educational activities from Janssen, Lilly, Bristol Myers-Squibb, and Astra Zeneca. He has not had any grants, honoraria, or other financial compensation from any pharmaceutical or other commercial entity, in the past three years. He does not have any financial investments in pharmaceutical or other health care entities.

Prevention of obesity Rohan Ganguli

The old adage prevention is better than cure seems particularly attractive in the context of obesity, since it is so difficult to lose excess body weight, as discussed in some of the other articles in this issue. The prevalence of obesity is 2-3 times higher in individuals suffering from serious mental illness (1) and many psychotropic medications carry significant risk of causing weight gain (2). Moreover, serious mental illness is associated with a shocking 20-25 year reduction in life span, primarily from premature coronary heart disease, and cerebrovascular disease (3). Since obesity is one of the leading risk factors for heart disease, prevention of obesity is an important goal in the efforts to reduce the mortality gap between those with serious mental illness and the general population. This article will first review the principles of prevention for cardiovascular disease and diabetes. The evidence for success in prevention of weight gain in patients with psychiatric illnesses will then be reviewed. Finally areas for further research in this poorly investigated field will be suggested.

In public health and preventative medicine it has been customary to distinguish between primary, secondary and tertiary prevention. To review the concepts briefly, primary prevention applies to interventions which reduce the risk of a disease occurring, vaccinations being a prime example of primary prevention. At one time a significant proportion of patients in mental hospitals suffered from pellagra. The recognition that this condition resulted from niacin deficiency resulted in remediation of the diets provided to patients and this was followed by the virtual elimination of pellagra in institutional settings (4, 5). In the area of obesity, primary prevention seems to be logically possible, since many of the risk factors are potentially modifiable (quantity

Prevention of obesity Rohan Ganguli and composition of food intake, and physical activity), but the efforts so far, in the general population, have met with limited success (6).

Secondary prevention refers to the early detection of illness and treatment at the very earliest stages so as to limit progression to full blown disease and complications. In psychiatry early intervention programs for several disorders including schizophrenia and bipolar disorder fall into this category. The recommendations for metabolic monitoring of persons on antipsychotics, might be considered an example of secondary prevention with regard to obesity and metabolic syndrome in people with psychiatric illnesses (7).

Tertiary prevention is conceptualized in terms of interventions initiated after disease onset, and with the goal of preventing damage and disablement, preventing or limiting complications, and restoring health to the greatest extent possible. The efforts to assist patients in losing weight, described in accompanying articles, fall mainly into this tertiary prevention category.

Primary prevention of obesity: In the context of the treatment of psychiatric disorders, the choice of medication with the lowest potential for causing weight gain, dyslipidemia, insulin resistance, and diabetes, represents one of the rare opportunities to exercise primary prevention.

Almost all antipsychotics carry some risk of causing weight gain. However, as consistently found, there are marked differences in the risk across different classes of medication (8,2). Clozapine and olanzapine have been consistently found to cause weight gain in the largest

Prevention of obesity Rohan Ganguli proportion of users, as well as to cause the greatest mean weight gain, in comparison to other available antipsychotics. Aripiprazole, ziprasidone, and molindone, on the other hand, have the lowest risk of associated weight gain. The rest of the antipsychotic class of medications fall between these two extremes (8). The practice most consistent with a primary preventative approach would be to offer medications with the least weight gain potential as first line agents, when initiating treatment. Medications with greater potential for causing weight gain, and its attendant comorbidities could be reserved for non-response to low risk agents and other special circumstances.

Behavioral and dietary (lifestyle) strategies, in prevention of obesity As mentioned above, some individuals might be at risk for weight gain even on what are regarded as low risk medications (7). Furthermore, many individuals may not respond to lowrisk medication and it may be necessary for them to try more high-risk medication. Behavioral and dietary strategies have been used to evaluate whether weight gain can be prevented or alleviated. Evans et al. (9) adopted a dietary intervention delivered by a trained dietician in a randomized controlled clinical trial involving patients starting olanzapine. In this study, patients were randomized to either six dietician-delivered nutrition sessions or to usual care. At six months after initiation of olanzapine, both groups had gained weight, but there was significantly less weight gain in the group which received dietary counseling (9). Our group, in a pilot stepped behavioral strategy, combined self monitoring with other behavioral and cognitive strategies to decrease food intake, and increase physical activity, for subjects starting on novel antipsychotics. We found that subjects randomized to the stepped intervention experienced less weight gain and a larger percentage of them experienced no weight gain than individuals

Prevention of obesity Rohan Ganguli randomized to treatment as usual (10). Skouraliakou et al., (11) employed an individualized nutritional approach in obese patients, who were taking olanzapine (mean BMI 33.12). This latter study did not have a control group, but reported that after three months there was a significant decrease in body mass and waist circumference (11).

Use of adjunctive medications to prevent weight gain

There have also been a number of attempts to investigate whether administration of concomitant medications can counteract anti-psychotic induced weight gain. Most studies of this approach involve olanzapine, which is not surprising, since olanzapine is associated with the most weight gain among antipsychotics. Cavazzoni et al (12) reported that co-administration of nizatidine with olanzapine was associated with less early weight gain than placebo, but the results were not statistically significant after 6 weeks of treatment. A second study investigating nizatidine, given concurrently with olanzapine, was unable to find any benefit over placebo (13). It is worth noting that the first study, which was positive, in favor of nizatidine (Cavazzoni et.al,) was funded by Lilly, which manufactures both nizatidine and olanzapine, while the second, negative, study was funded by Bristol Myers-Squibb (which manufactures aripiprazole). A study without these potential conflicts of interest would be desirable, but is currently unavailable.

In a small study (n=21) Graham et al. (14) found that in comparison to placebo, administration of amantadine resulted in no further weight gain in patients taking olanzapine, while patients receiving placebo gained a mean 1.24Kg of weight. Perhaps this is a potential agent for

Prevention of obesity Rohan Ganguli secondary prevention, but more research is necessary before this could be considered a sound clinical recommendation.

The medication with the best evidence for success in preventing olanzapine-associated weight gain is probably metformin, an insulin-sensitizing biguanide. For example Wu et al. in 2008, (15), randomized 40 patients starting olanzapine to either concomitant metformin (750mg) or placebo, in double blind fashion. At the end of 12 weeks there was less mean weight gain and a smaller proportion of individuals with clinically significant weight gain in the metformin group, as compared to those who received placebo.

A recent systematic review and meta-analysis of all trials of concomitant medications to avoid or attenuate antipsychotic-related weight gain and metabolic abnormalities (a total of 32 studies involving 15 medications were included), concluded that the data was most robust for metformin (16). Other drugs with some evidence for ability to attenuate weight gain were D-fenfluramine, sibutramine, topiramate, and reboxetine. It should be noted that, of these latter adjunctive medications, first fenfluramine and then sibutramine have been withdrawn in the US and Canada, due to safety concerns. This review also concludes that the greatest benefits in terms of weight loss or prevention of weight gain have been demonstrated in those studies which combined behavioral weight loss treatment with adjunctive medication (16).

Switching Antipsychotic Medication.

Prevention of obesity Rohan Ganguli Patients who gain weight, or develop dyslipidemias, or increase in blood glucose, in the course of treatment, present opportunities for secondary prevention, of metabolic syndrome, and lowering of the risk of developing heart disease and diabetes. Since there are well established differences in the weight gain liability of the different antipsychotics, patients who gain weight on one of the agents, known to be associated with a high risk of weight gain, might be candidates for a switch to an agent with a lower risk. Several recent studies have indeed shown that a significant proportion of patients might show improvement in metabolic syndrome components following such a switch. Several clinical trials show reductions in body weight when patients are switched to ziprasidone from olanzapine or risperidone (17), olanzapine to aripiprazole (18), or aripiprazole vs usual care (19). Effect sizes of weight loss and metabolic improvements, following switching, are in line with what can be expected from prescribing a weight loss medication such as sibutramine (note: sibutramine is currently withdrawn from the market). In suggesting a switch of medication to reverse or prevent further worsening of weight gain, considerations of relative efficacy and side effects need to be carefully balanced (20), because some of the antipsychotics with the greatest efficacy might also be associated with the greatest metabolic side effects (21,22). Thus, for some patients the risk of illness exacerbation due to loss of efficacy may outweigh the benefits of switching. These decisions are best approached in collaboration with the patient and his/her caregivers, with whom a full discussion of the pros and cons of the contemplated switch ought to be discussed.

Tertiary prevention: treatment of metabolic side effects and complications of drug-induced obesity.

Prevention of obesity Rohan Ganguli Given the high rates of obesity in the population of individuals with serious mental illness, it is not surprising that high rates of obesity-related disorders such as hypertension, diabetes, and hypertension are also found in these same populations. For example, in the CATIE trial, involving approximately 1450 subjects, Nasrallah et al. (23), reported that the point prevalence of hypertension was 33.2%, of diabetes 10,9%, and of dyslipidemia 47.3% . Shockingly, 30% of those with diabetes, 62% of those with hypertension, and 88% of those with abnormal lipids, were not receiving treatment for these abnormalities (23). Clearly, since these were all patients under the care of a physician, and attending treatment in some psychiatric setting, an opportunity for prevention of complications was being lost. A Canadian study of re-hospitalization after a cardiac event found that those with schizophrenia were significantly more likely, than those with no mental illness, to be re-hospitalized (adjusted hazard ratio =1.43, 95% CI, 1.221.69) for a cardiac event in the following four years (24). These differences in outcome for heart disease treatment suggest that there are problems with access or delivery of care to people with severe mental illnesses, and that it is likely that this difference in the quality of care contributes to worse non-psychiatric medical outcomes. Thus it has been proposed that a system which integrates the practitioners of both psychiatric and non-psychiatric care might result in improved health outcomes for the seriously mentally ill (25). In a recent study by Druss et al. (26) testing the benefits of a medical case management model, using nurse case managers, at the end of a year, the intervention group, as compared to the controls, were found to have received significantly more recommended preventive services (58.7% versus 21.8%); have received more evidencebased services for cardiometabolic conditions (34.9% versus 27.7%); were more likely to have a PCP (71.2% versus 51.9%). A subset of subjects had sufficient data to calculate Framingham Cardiovascular Risk Index, and the scores were significantly lower for those with medical case

Prevention of obesity Rohan Ganguli managers (26). Kilbourne et al., (27) studied a self management program for patients with bipolar disorder in a randomized controlled clinical trial of persons recruited from a VA hospital. The psychoeducational program (BCM) addressed symptom management and behavior change related to both mood disorder and risk factors for cardiovascular disease. They found that the controls showed worsening of both the mental and physical components of the SF-12, while those randomized to BCM showed some improvement in both components. These studies demonstrate the tantalizing possibility that a variety of non-pharmacologic approaches could actually prevent some of the non-psychiatric comorbidity, prevalent in those with serious mental illness. It is disappointing that there has not been more funding for studies to systematically study these approaches. To determine whether there is an effect on actual cardiovascular disease outcomes will also require funding of long-term studies, since such outcomes take years to develop. Persons with serious mental illness have also been systematically excluded from large trials involving prevention of cardiovascular disease and diabetes, thus preventing collection of data on the efficacy of those interventions, in these highly vulnerable individuals.

Conclusions Obesity and its myriad serious medical complications are highly prevalent in persons suffering from serious mental illness, and this undoubtedly accounts for a large proportion of premature mortality and morbidity for these individuals. Some of these complications, and obesity itself appear to be associated with the prescribed psychotropic medication. Within a preventative framework, choosing low-risk medication first seems prudent and logical. Regular monitoring of the development of new risk factors should allow for intervention, before co-morbidities become manifest. If monitoring detects the development or worsening of any components of metabolic

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Prevention of obesity Rohan Ganguli syndrome, lifestyle management to reduce weight and increase physical activity and fitness is the initial intervention recommended. These interventions should be available wherever persons with serious mental illness receive psychiatric services. If behavioral measures fail, switching antipsychotic medication should be considered and discussed with patients and their caregivers. If the prior measures fail, specific pharmacological interventions, such as statins, antihypertensives, antidiabetics, etc. will need to be considered in collaboration with a primary care practitioner. Given the high risk of developing diabetes and cardiovascular disease, in persons with serious mental illness, psychiatrists who treat these individuals need to ensure they are familiar with these risks, monitor metabolic parameters in their patients, and educate their patients (and caregivers) about these risks, and how to prevent them. The NIH and other national agencies, responsible for studying innovations in health care need to ensure that persons with serious mental illness are included in trials of interventions aimed at heart disease and diabetes, and also fund interventions specifically for the mentally ill. Most importantly, practitioners need to be aware of the risks of obesity and metabolic syndrome developing, and take what steps they can, including enlisting the help of primary care and other specialties.

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