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Transcript of Prevention of Obesity and It's Attendant Medical Complications_Ganguli_EDITS
8/3/2019 Prevention of Obesity and It's Attendant Medical Complications_Ganguli_EDITS
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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: [email protected]
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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.
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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
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Prevention of obesity
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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
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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 low-
risk 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
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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
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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.
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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.
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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, 1.22–1.69) 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 “evidence-
based 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
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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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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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