Bipolar Disorder and the Metabolic Syndrome

Transcription

CNS Drugs 2008; 22 (8): 655-669
1172-7047/08/0008-0655/$48.00/0
REVIEW ARTICLE
© 2008 Adis Data Information BV. All rights reserved.
Bipolar Disorder and the
Metabolic Syndrome
Causal Factors, Psychiatric Outcomes and Economic Burden
Andrea Fagiolini,1 K.N. Roy Chengappa,1 Isabella Soreca1 and Jane Chang2
1
2
Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric
Institute and Clinic, Pittsburgh, Pennsylvania, USA
Health Economics and Outcomes Research, Novartis Pharmaceuticals Corporation,
East Hanover, New Jersey, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
1. Factors Contributing to the Development of the Metabolic Syndrome in Bipolar Disorder . . . . . . . . 658
1.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
1.2 Lifestyle and Behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
1.3 Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
2. Healthcare and Economic Implications of Metabolic Illness in Bipolar Disorder . . . . . . . . . . . . . . . . . 661
2.1 Increased Morbidity and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
2.2 Economic Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
Abstract
Overweight and obesity are highly prevalent in patients with bipolar disorder,
and metabolic disorders also affect a significant portion of this population.
Obesity and metabolic disorders cause significant economic burden and impair
quality of life in both the general population and patients with bipolar disorder.
This review examines the relationship between bipolar disorder and the metabolic
syndrome, and the associated economic impact.
The metabolic syndrome and bipolar disorder appear to share common risk
factors, including endocrine disturbances, dysregulation of the sympathetic nervous system, and behaviour patterns, such as physical inactivity and overeating. In
addition, many of the commonly used pharmacological treatments for bipolar
disorder may intensify the medical burden in bipolar patients by causing weight
gain and metabolic disturbances, including alterations in lipid and glucose metabolism, which can result in an increased risk for diabetes mellitus, hypertension,
dyslipidaemia, cardiovascular disease and the metabolic syndrome. These
medical co-morbidities and obesity have been associated with a worse disease
course and likely contribute to the premature mortality observed in bipolar
patients. Weight gain is also a major cause of treatment noncompliance, increased
use of outpatient and inpatient services and, consequently, higher healthcare costs.
Prevention of weight gain and metabolic disturbances or early intervention when
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Fagiolini et al.
these are present in bipolar disorder could result in significant health and economic benefits.
Excess weight poses a significant and growing
health crisis in developed countries and even in the
developing world.[1] Body mass index (BMI), calculated as bodyweight (kg) divided by the square of
height (m), is the most widely accepted measure of
obesity.[2] The WHO considers a BMI of ≥25 kg/m2
as overweight and a BMI of ≥30 kg/m2 as obese, and
estimates that worldwide 1.6 billion adults were
overweight and 400 million adults were obese in
2005[3] (thresholds are lower in Asia). Excess
weight gain has severe health consequences; it ranks
among the top ten risk factors contributing to the
overall burden of disease worldwide.[4] Central or
abdominal obesity, in particular, is a significant risk
factor for cardiovascular disease[5] and for the metabolic syndrome.[6] The metabolic syndrome is a
complex and multifactorial condition that has been
associated with an increased risk of diabetes mellitus, heart disease, myocardial infarction and
stroke.[7-9] Moreover, the metabolic syndrome has
been linked to increased cardiovascular and allcause mortality.[9-11] Table I shows the different
definitions that have been proposed for metabolic
syndrome; the most commonly used definitions are
those developed by the WHO[12] and the National
Cholesterol Education Program Adult Treatment
Panel III (NCEP ATP III).[6]
Not surprisingly, in view of the escalating prevalence of obesity in the US, the prevalence of the
metabolic syndrome in US adults has also increased,
from 24% in 1988–94 to 27% in 1999–2000.[16]
In addition to health consequences, excessive
weight gain is associated with substantial economic
burden. Increases in BMI have been linked to significant increases in total lifetime medical care costs
for the treatment of hypertension, hypercholesterolaemia, diabetes, coronary heart disease and
stroke.[17] In the developed world, 2–7% of total
healthcare costs are attributable to obesity.[18] In the
US alone, the combined direct and indirect costs of
obesity were estimated to be $US123 billion in
2001,[18] equivalent to $US144.4 billion in 2007
values. Health-related quality of life (QOL) has also
been found to decrease with an increasing level of
obesity.[19,20]
Overweight and obesity have been related to
mood disorders, particularly bipolar disorder.[21] Evidence indicates that individuals with bipolar disorder are at greater risk than the general population for
overweight and obesity,[21] and there is also increasing evidence of an association between bipolar disorder and the metabolic syndrome and its components. In the general US population, the prevalence of
obesity has increased from 22.9%, as shown by the
Third National Health and Nutrition Examination
Survey (NHANES III; 1988–94), to 30.5% according to the NHANES 1999–2000.[22] In patients with
bipolar disorder, McElroy et al.[23] reported a prevalence rate of 25% for American patients recruited
between 1995 and 2001, whereas in an earlier study,
a prevalence rate of 35% was reported for 175
patients recruited in the period between 1991 and
2000.[24] A later study showed a prevalence rate of
45% for 171 patients recruited from 2003 to
2004.[25]
The rates of the metabolic syndrome have been
reported to be 30% and 42% in patients with bipolar
disorder and schizoaffective disorder-bipolar subtype, respectively.[25,26] Bipolar disorder has been
associated with an increased risk of diabetes,[27]
hypertension[28] and dyslipidaemia.[29]
In a study of 89 euthymic outpatients with bipolar
disorder and a reference group of 445 age- and sexmatched control subjects, Elmslie et al.[30] found that
female patients were more often overweight (44%
vs 25%) and obese (20% vs 13%) than female
reference subjects, and male patients were more
likely to be obese (19% vs 10%) than male reference
subjects. Moreover, the excess fat in the bipolar
patients was centrally distributed, with 59% of female patients versus 17% of female reference subjects having waist : hip ratios >0.8 (p < 0.001) and
CNS Drugs 2008; 22 (8)
58% of male patients versus 35% of male reference
subjects having waist : hip ratios >0.9 (p = 0.003).
This central obesity, which is associated with visceral fat, places patients with bipolar disorder at increased risk of cardiovascular disease, type 2 diabetes and dyslipidaemia.[30]
A study by Fagiolini et al.[25] found high rates of
the metabolic syndrome and its components in a
group of 171 patients with bipolar disorder. Thirty
percent met the NCEP ATP III criteria[6] for the
metabolic syndrome, and 74% were either obese
657
(45%) or overweight (29%). In addition, 49% of
patients met the criterion for abdominal obesity,
41% met the criterion for hypertriglyceridaemia,
48% met the criterion for hypertriglyceridaemia or
were receiving cholesterol-lowering medication,
23% met the criterion for low levels of high-density
lipoprotein-cholesterol (HDL-C), 39% met the criterion for hypertension and 8% met the criterion for
high fasting glucose or antidiabetic medication use.
In this article, the possible pathophysiological
mechanisms leading to the development of the meta-
Table I. Definitions of the metabolic syndrome
NCEP ATP III definition[6]
Any three or more of the following criteria:
1.
Central obesity: waist circumference >102 cm for men and >88 cm for women
2.
Serum triglycerides ≥1.7 mmol/L (≥150 mg/dL)
3.
Blood pressure ≥130/85 mmHg
4.
HDL-C <1.03 mmol/L (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women
5.
Fasting glucose ≥6.1 mmol/L (≥110 mg/dL)
American Heart Association/National Heart, Lung, and Blood Institute-modified NCEP ATP III criteria[13]
Any three or more of the following criteria:
1.
Central obesity: waist circumference ≥102 cm in men and ≥88 cm in women
2.
Serum triglycerides ≥1.7 mmol/L (150 mg/dL) or drug treatment for elevated triglycerides
3.
HDL-C <1.03 mmol/L (40 mg/dL) in men and <1.3 mmol/L (50 mg/dL) in women, or drug treatment for reduced HDL-C
4.
Blood pressure ≥130/85 mmHg or drug treatment for hypertension
5.
Fasting serum glucose ≥5.6 mmol/L (≥100 mg/dL) or drug treatment for elevated glucose
WHO definition[12]
Glucose intolerance, impaired glucose tolerance or diabetes mellitus, and/or insulin resistance, together with at least two of the
following:
1.
Central obesity: waist-to-hip ratio >0.90 in men or >0.85 in women and/or body mass index >30 kg/m2
2.
Serum triglycerides ≥1.7 mmol/L (150 mg/dL) and/or HDL-C <0.9 mmol/L (35 mg/dL) in men and <1.0 mmol/L (39 mg/dL) in
women
3.
Blood pressure ≥140/90 mmHg
4.
Urinary albumin excretion rate >20 µg/min or albumin to creatinine ratio >30 mg/g
European Group for study of Insulin Resistance definition[14]
Insulin resistance (defined as hyperinsulinaemia – top 25% of fasting insulin values among the nondiabetic population) and at least two
of the following criteria:
1.
Central obesity: waist circumference ≥94 cm for men or ≥80 cm for women
2.
Serum triglycerides ≥2.0 mmol/L and/or low HDL-C (<1.0 mmol/L), or treatment
3.
Blood pressure ≥140/90 mmHg, or treatment
4.
Fasting/2 h plasma glucose ≥6.1/7.8 mmol/L but <7.0/11.1 mmol/L
International Diabetes Federation definition[15]
Central obesity (waist circumference ≥94 cm for men and ≥80 cm for women) and at least two of the following criteria:
1.
Serum triglycerides ≥1.7 mmol/L, or treatment
2.
Blood pressure ≥130/85 mmHg, or treatment
3.
Fasting plasma glucose ≥5.6 mmol/L or previous diagnosed type 2 diabetes
HDL-C = high-density lipoprotein-cholesterol; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III.
CNS Drugs 2008; 22 (8)
658
Fagiolini et al.
bolic syndrome in bipolar patients are examined,
together with the healthcare and economic implications resulting from the development of metabolic
disorders in bipolar patients. The findings are based
on clinical experience and a comprehensive literature search combining the phrase ‘bipolar disorder’
or synonyms with terms describing metabolic illness
(e.g. ‘diabetes’, ‘hyperlipidaemia’, ‘obesity’, ‘metabolic syndrome’) and terms related to healthcare
costs and pharmacoeconomics.
1. Factors Contributing to the
Development of the Metabolic
Syndrome in Bipolar Disorder
1.1 Pathophysiology
There appears to be an association between mood
disorders and individual components of the metabolic syndrome, and perhaps the syndrome as a
whole.[31] A number of the physical symptoms
found in bipolar disorder are components of the
metabolic syndrome, and the diseases have common
physiological risk factors, including not only obesity
but also disturbances in glucose and insulin regulation, the hypothalamic-pituitary-adrenal (HPA) and
the hypothalamic-pituitary-thyroid (HPT) axes, and
regulation of haemostasis and the sympathetic nervous system.[32]
Impaired glucose tolerance and insulin resistance
occur more frequently in people with bipolar disorder than in the general population.[32] Cassidy et
al.[27] found a nearly 3-fold higher prevalence of
diabetes in hospitalized patients with bipolar disorder than in the general US population (9.9% vs
3.4%). There is also evidence that impaired glucose
tolerance and insulin resistance in bipolar disorder
are just as common as in schizophrenia,[33] which is
now considered to be an independent risk factor for
diabetes.[32] Furthermore, Regenold et al.[34] found
the rate of diabetes in bipolar disorder to be even
higher than that for schizophrenia (26% vs 13%;
p < 0.006), and the increased prevalence of diabetes
among both groups of mental disorders was independent of the effects of BMI and psychotropic
medication use. Bipolar patients with co-morbid
diabetes have also been found to have a more severe
psychiatric disease course, with a more chronic versus episodic disease pattern,[35] significantly more
rapid cycling[35] and significantly more lifetime psychiatric hospitalizations than nondiabetic patients.[27]
The connections among bipolar disorder, insulin
resistance, abdominal obesity and dyslipidaemia
may be mediated by abnormalities in cortisol regulation. During physiological or psychological stress,
the HPA axis is activated, leading to the production
and release of cortisol. Hypercortisolism may be a
key factor in the pathogenesis of depressive symptoms and cognitive defects, and manic episodes may
be preceded by increases in adrenocorticotropic hormone and cortisol levels, resulting in cognitive
problems and functional impairments.[36] Elevated
cortisol levels have been found in remitted bipolar
patients as well, suggesting that HPA dysfunction
may be a trait abnormality in bipolar disorder.[37]
Persistently elevated glucocorticoid levels also impair the ability of insulin to promote glucose uptake,
which results in increased deposition of body fat and
in the formation of atherosclerotic plaques in coronary arteries.[38] Furthermore, HPA hyperactivity
has been directly linked with obesity and elevated
levels of leptin, a satiety hormone,[39] and increased
visceral fat.[32] Therefore, the disturbances in cortisol regulation seen in bipolar disorder may play a
key role in the development of common aspects of
the metabolic syndrome, including insulin resistance, abdominal obesity and dyslipidaemia.
Abnormalities in the HPT axis are more prevalent in patients with mood disorders than in the
general population.[40] Mood states and affective
stability are closely linked with the proper functioning of the HPT axis; hypothyroidism has been frequently associated with depression, and there is
some evidence of an association between hyperthyroidism and euphoric states, including full manic
reactions.[40] Thyroid hormones also have extensive
metabolic effects in the body, and thyroid dysfunction may, thus, be involved in the development of
the metabolic syndrome in bipolar patients. Hypothyroidism is the most common manifestation of
CNS Drugs 2008; 22 (8)
thyroid dysfunction,[40] and both overt and subclinical hypothyroidism have been associated with metabolic risk factors, including cardiovascular disease
and dyslipidaemia.[41-44] Thyroid dysfunction has
also been linked to slower response to acute treatment and poorer quality of long-term remission in
bipolar patients.[45] The abnormalities in thyroid
function in bipolar disorder have been largely attributed to lithium treatment.[46] Lithium interferes with
thyroid metabolism and increases the incidence of
overt and subclinical hypothyroidism, primarily by
inhibiting thyroid hormone release, which results in
a compensatory elevation of thyroid-stimulating
hormone levels.[47] However, whether lithium is the
only cause of thyroid dysfunction in patients with
bipolar disorder has not yet been established. The
effect of thyroid supplementation in patients with
lithium-associated hypothyroidism has not been systematically studied. Although the risk : benefit ratio
of thyroxine supplementation is usually favourable,
the possibility of adverse events such as angina or
arrhythmias (most commonly atrial fibrillation), or
the development of symptoms such as anxiety, insomnia, tachycardia and sweating should be considered. Also, the risk of a manic switch has been
reported.[42]
Individuals with bipolar disorder have increased
mortality due to cardiovascular disease compared
with the general population.[48-50] This may be partly
attributable to coagulation disturbances that are central to the development and prognosis of cardiovascular disease.[32] There may also be disturbances
in sympathetic nervous system regulation.[51,52] Individuals with bipolar disorder also have higher systolic blood pressure when experiencing manic
events[48] and increased risk of hypertension in general.[28] Dysregulation of the sympathetic nervous
system has also been postulated as an underlying
mechanism of the metabolic syndrome; insulin-mediated glucose uptake in the CNS regulates sympathetic nervous system activity in response to dietary
intake, and increasing evidence points to a correlation between this insulin-mediated sympathetic
stimulation and the pathogenesis of hypertension.[53]
Indicators of elevated activity of the sympathetic
659
nervous system are more tightly linked with elevated HPA activity than with insulin, which suggests
that the sympathetic nervous system and the HPA
axis are activated in parallel.[54] The increased activity of the sympathetic nervous system and HPA
axis observed in individuals with bipolar disorder
may be partly responsible for the common symptoms found in both bipolar disorder and the metabolic syndrome.
1.2 Lifestyle and Behaviour
The lifestyle and behavioural patterns of individuals with bipolar disorder also play important roles
in the prevalence of the metabolic syndrome in this
population. Cigarette smoking, which is not only a
major risk factor for cardiovascular disease but has
also been found to impair insulin action and has,
thus, been implicated as an important risk factor for
the metabolic syndrome,[55] is highly prevalent
among individuals with bipolar disorder. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) assessed the co-morbidity
of nicotine dependence and substance abuse disorders with mood and anxiety disorders in a nationally
representative sample of 43 093 respondents, and
found that 35.3% of individuals with a history of
mania and 33.4% of individuals with a history of
hypomania met the criteria for nicotine dependence
compared with 12.8% of the general population.[56]
Co-morbid substance use disorders are also common among individuals with bipolar disorder,[57]
and substance abuse has been associated with the
likelihood of developing the metabolic syndrome.[58]
Pancreatitis from alcohol and/or other toxins can
increase the risk of diabetes.[59] The NESARC
study[60] estimated the 12-month prevalence of substance use disorders to be 27.9% and 26.6% among
individuals with a history of mania and hypomania,
respectively, whereas the rate of substance use disorders was 9.4% in the general population.
Physical inactivity and overeating are major factors in the development of weight gain and obesity
in bipolar disorder and in the metabolic syndrome.[16,31,61,62] Elmslie et al.[63] found that total
energy intake, total daily sucrose intake, percentage
CNS Drugs 2008; 22 (8)
660
of energy from carbohydrates, total fluid intake and
intake of sweetened drinks were all higher in bipolar
disorder patients than in control patients, but bipolar
patients reported fewer episodes of low to moderateor high-intensity physical activity than controls. Results from a recent study by Soreca et al.[64] also
suggest that patients with bipolar disorder may have
lower basal metabolic rates than individuals without
mood disorders. In addition, there is substantial
overlap between abnormal eating patterns and emotional/mood dysregulation that is evident either at
the symptom level or at a neurobiological/genetic
level. Results from recent studies suggest that there
may be several ‘reward’ or ‘reward-like’ systems
that control food seeking, with food serving to reinforce habits and as a reward or goal for actions.[65]
Dopamine is believed to mediate the rewarding
properties of food in the brain,[66,67] and central
dopamine dysfunction has been linked to increased
feeding behaviour and obesity.[68] It has been hypothesized that individuals with low intrinsic dopamine activity in brain reward pathways, known as
the ‘reward deficiency syndrome’, try to compensate by turning to a variety of reinforcing behaviours, including increased food consumption.[69] A
strong correlation has been found between the presence of the 7-repeat allele of the dopamine-4 receptor gene, a variant associated with decreased affinity
for dopamine, and binge-eating behaviour in women
with seasonal affective disorder.[70] Binge eating is
another prevalent co-morbidity in patients with bipolar disorder. Ramacciotti et al.[71] found that
27.5% of a sample of 51 bipolar patients met the
criteria for a current or lifetime diagnosis of bingeeating disorder or bulimia nervosa. In a sample of 61
patients with bipolar disorder, Kruger et al.[72] found
that 38% had recurrent episodes of binge eating and
13% met the diagnostic criteria for binge-eating
disorder.
Patients with bipolar disorder can also be reluctant to seek healthcare for their medical illnesses
when needed. Despite the high rates of co-morbidity
in patients with bipolar disorder, medical illnesses
often go undetected and are inadequately treated in
this population.[73] A study by Cradock-O’Leary et
Fagiolini et al.
al.[74] examined the use of medical services by
175 633 patients in a central Veterans Affairs (VA)
database during the 2000 fiscal year and identified
3694 veterans with a primary diagnosis of bipolar
disorder. The authors compared the medical services
used by the bipolar veterans with that of all veterans
and found that among all veterans with diabetes and
hypertension, those with a co-morbid diagnosis of
bipolar disorder were at an especially high risk of
not receiving general medical services.
1.3 Pharmacotherapy
Weight gain as a consequence of psychotropic
medications is a significant concern in bipolar disorder. Studies have found BMI to be positively correlated with the number, as well as the specific types,
of weight-gain-inducing medications to which a patient has been exposed.[23,30] However, psychotropic
medications have varied effects on appetite and
weight. Adrenergic antidepressants, such as TCAs,
promote hyperglycaemia and insulin resistance,
while antidepressants that primarily function by
serotonergic mechanisms, such as SSRIs, appear to
have opposite effects (e.g. favourable effect on glycaemic control, insulin resistance and food intake).[75] The TCAs and possibly MAOIs may be
more likely to cause weight gain than SSRIs or some
of the newer antidepressants, except for mirtazapine, which falls between the SSRIs and TCAs in the
risk for weight gain.[76]
Mood-stabilizing agents, such as lithium and valproic acid derivatives, have been associated with
significant weight gain. In a study of maintenance
monotherapy for bipolar disorder, Bowden et al.[77]
found that the rates of weight gain reported as medication adverse effects at 1 year were 13% with
lithium and 21% with divalproex versus 7% with
placebo. Lithium has demonstrated an insulin-like
influence on carbohydrate metabolism, leading to
increased glucose absorption into adipocytes and
stimulation of appetite in some patients.[78-80] The
weight gain associated with valproate may be a
result of impaired fatty acid metabolism.[81] Valproate and lithium may also increase thirst and the
consumption of high-calorie beverages, and have
CNS Drugs 2008; 22 (8)
direct appetite-stimulating effects on the hypothalamus.[21] However, other mood-stabilizing agents
have been shown to be more weight neutral. A
recent retrospective analysis by Sachs et al.[82] found
that lamotrigine monotherapy in bipolar patients
over 1 year was associated with stable weight. Ketter et al.[83] also found carbamazepine to be associated with stable weight in a 6-month, open-label
study of carbamazepine monotherapy in bipolar patients.
Considerable attention has recently been focused
on the relationship between the metabolic syndrome
and atypical antipsychotic treatment. The atypical
antipsychotics have fewer or none of the extrapyramidal adverse effects that have been associated
with first-generation antipsychotics and have, therefore, generally taken the place of the older antipsychotics in the treatment of bipolar disorder.[84,85]
However, several of the atypicals are associated
with metabolic adverse effects, including significant
weight gain as well as alterations in lipid and glucose metabolism.[85] Clozapine and olanzapine are
associated with the most weight gain and higher
occurrence of diabetes and dyslipidaemia, whereas
risperidone and quetiapine appear to have intermediate effects.[84] In mice, clozapine has recently
been found to function through the histamine receptor to quadruple the activity of adenosine monophosphate-activated protein kinase, an enzyme that
controls appetite in mice and presumably humans,
resulting in increased food intake.[86] Little or no
significant weight gain, diabetes or dyslipidaemia
have been observed with aripiprazole and ziprasidone, but limited long-term data are available for
these agents.[84]
Insulin resistance linked with atypical antipsychotics may be the result of weight gain or change in
body fat distribution, or by a direct effect on insulinsensitive target tissues.[84] The metabolic profile resulting from treatment with atypical antipsychotics
has been suggested to resemble type 2 diabetes.[87]
Results from a study by Ader et al.[88] in a canine
model indicate that olanzapine, but not risperidone,
causes preferential deposition of energy into adipose
tissue and induces hepatic insulin resistance. Olan© 2008 Adis Data Information BV. All rights reserved.
661
zapine has also been found to increase weight more
significantly than lithium (mean weight gain 1.8 vs
–1.4 kg; p ≤ 001) or valproate (mean weight gain 2.8
vs 1.2 kg; p < 0.001) in 1-year and 47-week clinical
trials, respectively.[89,90] The currently available, albeit limited, evidence indicates that changes in serum lipids are linked to changes in bodyweight[91]
and, correspondingly, olanzapine and clozapine
have been linked to increases in total cholesterol,
low-density lipoprotein-cholesterol and triglycerides, and with decreases in HDL-C cholesterol,
whereas risperidone and quetiapine appear to have
intermediate effects on lipids, and aripiprazole and
ziprasidone do not seem to worsen serum lipid
levels.[84]
2. Healthcare and Economic
Implications of Metabolic Illness
in Bipolar Disorder
2.1 Increased Morbidity and Mortality
Bipolar disorder is associated with premature
mortality. The burden of bipolar disorder is not
limited to the psychiatric symptoms and dysfunction
related to the disease;[92] medical disease and
medical risk factors are also common in bipolar
disorder, affecting the course and severity of bipolar
disorder and its treatment,[24,25,93-96] leading to even
greater morbidity, mortality and disability.[97]
Patients with bipolar disorder die earlier than
those without mood disorders as a result of cardiovascular, gastrointestinal, respiratory, urogenital, infection, metabolic and specific malignant conditions.[32] The occurrence of metabolic syndrome
confers substantial additional risk above and beyond
the individual risk factors.[11] In fact, the syndrome
has very severe health implications, including a 6fold risk of developing type 2 diabetes[7,98-102] and a
3- to 6-fold increased risk of mortality due to coronary heart disease.[11,103,104] Once type 2 diabetes
emerges, cardiovascular risk increases even more.
Moreover, the metabolic syndrome is also associated with a variety of other conditions, including
fatty liver, polycystic ovary syndrome, cholesterol
gallstones, sleep apnoea and lipodystrophies.[13] A
CNS Drugs 2008; 22 (8)
662
recent review of the literature on medical co-morbidities in bipolar disorder concluded that to ensure
appropriate intervention while avoiding iatrogenic
complications, the clinician must evaluate and monitor patients with bipolar disorder for the presence
and development of co-morbid medical conditions.[105] A Swedish population-based study of patients with unipolar depression or bipolar disorder
from 1973 to 1995 conducted by Osby et al.[50]
found standardized mortality ratios (observed
deaths/unexpected deaths) for all natural causes of
death were 1.9 for males and 2.1 for females with
bipolar disorder. Most of the excess deaths in bipolar disorder were due to natural causes, including
cardiovascular, endocrine and cerebrovascular disease. The most frequent cause of death in bipolar
patients was cardiovascular disease. In comparison
with the general population, the rates of death in
bipolar patients from cardiovascular and cerebrovascular causes were approximately doubled and the
rate of death from endocrine causes was tripled.
Similarly, in a study of 4310 VA patients diagnosed
with bipolar disorder, Kilbourne et al.[106] found that
the most prevalent medical conditions in this population included cardiovascular (e.g. hypertension,
35%) and endocrine disorders (e.g. hyperlipidaemia,
23%; diabetes, 17%).
Weight gain has also been found to impact QOL
in bipolar patients.[107] In a study[107] using the validated Impact of Weight on Quality of Life-Lite
(IWQOL-Lite) questionnaire that included 100 patients with bipolar disorder, the total score, as well
as IWQOL-Lite subscale (physical function, selfesteem, sexual life, public distress and work) scores
and BMI were significantly correlated with poorer
QOL. Furthermore, obesity has been associated with
a worse disease course in bipolar disorder. Fagiolini
et al.[108] examined the prevalence of overweight and
obesity in 50 consecutive patients with bipolar disorder participating in the Pittsburgh MTBD (Maintenance Treatment in Bipolar Disorder) study, and
found that 68% of study patients were overweight or
obese, whereas only 30% of patients were normal
weight and 2% were underweight. The number of
previous depressive episodes was associated with
Fagiolini et al.
the probability of being overweight or obese at study
entry; patients who were overweight or obese at the
initial evaluation had significantly more depressive
episodes compared with patients who were normal
weight or underweight (9.2 vs 2.8; p < 0.03).[108]
A subsequent publication about a larger sample
of subjects from the MTBD study, reporting data
from 175 patients with bipolar disorder who were
treated for an acute episode and followed through a
period of maintenance treatment, also showed that
obesity was correlated with a worse disease course
and poorer treatment outcome.[24] Thirty-five percent of the patients in this study were obese and
were found to have significantly more previous manic episodes (9.6 vs 7.0; p < 0.05), previous depressive episodes (15.0 vs 10.5; p < 0.002) and higher
baseline scores on both the 17-item[109] and 25item[110] Hamilton Rating Scale for Depression
(HAM-D) [17.4 vs 14.5; p < 0.02, and 22.3 vs 18.2;
p < 0.009, respectively] than non-obese subjects. A
Kaplan-Meier survival analysis also found that time
to depressive recurrence was significantly shorter in
the obese group (p < 0.007), and the number of
patients experiencing a depressive recurrence was
significantly higher in the obese than non-obese
group (54.3% vs 35.4%; p < 0.04). In the previously
mentioned study examining the prevalence of the
metabolic syndrome in a group of patients with
bipolar disorder,[25] it was also discovered that those
patients who were obese and/or had the metabolic
syndrome were more likely (p = 0.004 and p = 0.05,
respectively) to report a lifetime history of suicide
attempts.
Finally, the MTBD study also examined the relationship between the number of medical co-morbidities in patients with bipolar disorder and the clinical
characteristics of the disease, and found that medical
illness was correlated with several indicators of
poorer prognosis and outcome.[111] Patients who had
a high number of medical co-morbidities experienced longer durations of both lifetime depression
(p = 0.02) and lifetime inpatient treatment for depression (p = 0.04), as well as slower improvements
in HAM-D scores, even after controlling for baseline HAM-D scores.
CNS Drugs 2008; 22 (8)
663
2.2 Economic Burden
Bipolar disorder is associated with substantial
costs; in 1991, Wyatt and Henter[112] estimated that
the costs for bipolar disorder in the US totalled
$US45 billion, with direct costs (e.g. expenditures
for inpatient and outpatient care) accounting for
$US7.6 billion and indirect costs (e.g. lost productivity) accounting for $US38 billion. In 2007 values,
this represents $US11.6 billion in direct costs and
$US58 billion in indirect costs, for a total of almost
$US70 billion. Costs from general medical conditions contribute greatly to the economic burden
of bipolar disorder. In a 2002 study of healthcare
utilization and direct healthcare costs by BryantComstock et al.,[113] bipolar patients were found to
use three to four times the healthcare resources and
incur 4-fold greater costs per patient than nonbipolar
patients ($US7663 vs $US1962 over 1 year; equivalent to $US8856 vs $US2268 in 2007 values). Most
of the increase in costs for bipolar versus nonbipolar
patients was attributable to inpatient care ($US2779
vs $US398, respectively, or $US3212 vs $US460 in
2007 values), which was the single most expensive
resource in the bipolar group. However, while
mental healthcare accounted for 22% of total perpatient costs in the bipolar group (vs 6% in the
nonbipolar group), nonmental healthcare accounted
for 70% of per-patient costs (table II), suggesting
that general medical conditions contribute prominently to the overall healthcare costs in bipolar
patients.
Gardner et al.[114] directly examined the healthcare costs due to co-morbid physical conditions
among bipolar patients, using data from an employer health insurance claims database over a 2-year
period (2001–2). Overall, annual costs were
$US6836 higher for employees with bipolar disorder than for those without ($US9983 vs $US3147;
p < 0.05, equivalent to $US11 538 vs $US3637 in
2007 values). Comparison of costs for co-morbid
conditions found that for most of the diagnostic
categories examined, employees with bipolar disorder incurred higher average annual costs than employees without bipolar disorder, including endo-
Table II. Mental and nonmental healthcare mean per-patient use (Fx) and costsa ($US; 1997 values) for adult patients treated for bipolar
disorder and for age- and sex-matched comparison group (n = 2883 in each group)[113]
Healthcare
Bipolar group
Fx
Nonbipolar group
$US (% of total)
Fx
$US (% of total)
Mental
Medical encounters
2.6
729 (43)
0.4
inpatient
0.1
432 (26)
<0.1
4 (3)
outpatient hospital
0.4
123 (7)
<0.1
4 (3)
physician’s office
1.9
121 (7)
0.4
26 (22)
emergency room
0.1
14 (1)
<0.1
<0.1
38 (2)
<0.1
2 (2)
18.3
964 (57)
1.9
83 (70)
other
Dispensing
Subtotal
1693 (100)
36 (30)
0.2 (0.2)
118 (100)
Nonmental
Medical encounters
14.3
4893 (92)
3.6
inpatient
0.3
2347 (44)
<0.1
393 (24)
outpatient hospital
2.5
1120 (21)
0.6
469 (29)
physician’s office
10.4
1014 (19)
2.7
367 (22)
emergency room
0.9
93 (2)
0.2
23 (1)
<0.1
321 (6)
<0.1
111 (7)
449 (8)
6.3
other
Dispensing
11.0
1363 (83)
280 (17)
Subtotal
5342 (100)
1642 (100)
Total per-patient cost
7035
1760
a
Excludes laboratory/diagnostic services, as data by type of care (mental health vs nonmental health) were unavailable.
CNS Drugs 2008; 22 (8)
664
crine, nutritional and metabolic diseases, and immunity disorders ($US143 vs $US72, or $US165 vs
$US83 in 2007 values) and circulatory system diseases ($US490 vs $US205, or $US566 vs $US237 in
2007 values). Annual costs for several of the physical health conditions examined were also substantially higher among employees with bipolar disorder, including acute myocardial infarction ($US147
vs $US16, or $US170 vs $US18 in 2007 values),
coronary atherosclerosis ($US101 vs $US47, or
$US117 vs $US54 in 2007 values), nutritional/endocrine/metabolic disorders ($US50 vs $US24, or
$US58 vs $US28 in 2007 values) and hyperlipidaemia ($US21 vs $US10, or $US24 vs $US12
in 2007 values).
The cohort of employees with bipolar disorder
was then stratified according to their annual mean
benefit costs.[115] Those in the highest cost quintile
incurred a mean cost of $US70 616, while those in
the lowest quintile incurred a mean cost of only
$US3385 ($US81 613 and $US3912 in 2007 values,
respectively). Almost all of the difference lay in the
medical costs of treating concurrent conditions
($US52 365 in the highest quintile vs $US870 in the
lowest quintile, p ≤ 0.05, equivalent to $US60 520
vs $US1005 in 2007 values).
By extension, costs are likely to be reduced by
preventing the development of metabolic disorders.
For example, co-morbid diabetes adds to the monthly cost of managing patients with schizophrenia and,
hence, the use of medications that increase the risk
of diabetes may significantly add to the economic
burden of schizophrenia care[116] and probably add
to the burden of care for bipolar disorder as well.
Also, weight gain is a major cause of poor compliance,[117,118] which has been associated with not
only worse outcomes but also increased use of outpatient and inpatient services and, consequently,
with higher direct healthcare costs.[119,120] Thus, although the efficacy of a medication in the treatment
of an underlying psychiatric disorder is the prevailing concern, the metabolic adverse effects of the
medication must also be taken into consideration.
Although the relationship of compliance to medication cost has not been specifically studied in
Fagiolini et al.
bipolar patients, it can be assumed that high costs
are an additional barrier to filling prescriptions, especially for individuals without health insurance.
The monthly costs of standard bipolar therapies are
compared in table III.
3. Conclusions
Metabolic symptoms affect a significant proportion of patients with psychiatric disorders, including
bipolar disorder, and there is a growing awareness of
the potential years of life lost as a result of the
increased medical co-morbidity in these patients.
However, the pathophysiology of the development
of metabolic symptoms is not completely understood. Although research has revealed potential
pathophysiological links between metabolic symptoms and bipolar disorder, it remains unclear whether these medical conditions exacerbate bipolar disorder or vice versa, or whether both can be attributed
to genetic factors. At least one study[122] has found
that weight gain occurs after the onset of bipolar
disorder in overweight bipolar patients, suggesting
that aspects of the illness or its treatment may be
responsible for the increased risk of weight gain in
this population. Additional studies examining the
timing of the development of obesity and the onset
of the metabolic syndrome in bipolar patients are
needed.
The metabolic syndrome remains underdiagnosed and undertreated among patients with bipolar
disorder. The lack of adequate treatment can lead to
adverse medical outcomes, such as increased risk of
Table III. Average US wholesale price of 1 month’s treatment with
selected bipolar disorder drugs[121]
Drug
Aripiprazole
Dosage
(mg/day)
Monthly cost
($US; 2007
costings)
30
555.74
Carbamazepine
1000
124.03
Lithium
1200
78.22
Olanzapine
20
775.44
Quetiapine
600
551.99
6
413.62
1500
267.67
160
436.16
Risperidone
Valproate semisodium
Ziprasidone
CNS Drugs 2008; 22 (8)
diabetes and cardiovascular conditions, which, in
turn, can lead to increased direct and indirect costs.
Medical co-morbidities can also complicate the
treatment of bipolar disorder.[73] In view of the evidence indicating that patients with bipolar disorder
underutilize general medical services, interventions
to improve medical care should be tailored to meet
the needs of this population. There is also a need to
educate physicians regarding the key criteria for
diagnosing the metabolic syndrome. Preventing and
treating medical co-morbidities in patients with bipolar disorder would not only help decrease the
mortality related to somatic illnesses in this population but also has the potential to improve both psychological well-being and the course of bipolar illness.
Long-term treatment strategies that reduce expensive hospitalizations are an important consideration in the management of bipolar disorder. Preventing the development of medical co-morbidities
could also result in overall cost savings. Treatment
approaches for patients with bipolar disorder should
include the use of pharmacotherapies with minimal
adverse events in order to improve adherence, as
well as decrease the risk of developing metabolic
disorders. Medications that have good efficacy and
are least likely to induce serious weight gain or
metabolic/endocrine dysfunction are preferable as
maintenance agents in bipolar disorder. However, it
must be recognized that bipolar disorder is rarely
treated with monotherapy, and medications with
adverse effects, including weight gain, must often be
used to optimize outcome. In some individual cases,
an attempt to simplify the treatment and to reduce
the adverse effect burden is warranted, and this may
result in destabilization of the psychiatric illness.
Although we do not advocate efforts to treat or
prevent metabolic illness at the price of loss of
symptom control, the severe burden of co-morbidities in patients with bipolar disorder should not be
overlooked, given its impact on physical health,
functioning and QOL. Moreover, such co-morbidity
also has an impact on the outcome of bipolar disorder.[24,25,93-96] Ongoing collaboration between the
clinician and the patient is needed to find drug
665
combinations that are safe and tolerable over the
long term, using medications with fewer adverse
effects and drug-drug interactions if possible. Educational and lifestyle interventions also play an important role in minimizing medical risk. As issues
with individual agents become better clarified, some
agents may be used as treatments for acute episodes
but less commonly for long-term treatment, whereas
other agents may be preferred for both acute and
long-term use and others for long-term use only.
Weight and BMI should be checked routinely
during the evaluation of patients with bipolar disorder, in addition to regular assessments of medical,
metabolic and behavioural factors associated with
overweight and obesity, including vital signs, medical history, family history of obesity, blood lipid and
glucose profiles, and eating and physical activity
patterns. An individualized approach to diet and
lifestyle interventions to decrease the risk of obesity
and to recognize metabolic health risks should be
implemented as early as possible.
Although there is substantial research investigating the incidence and aetiology of metabolic symptoms in patients with bipolar disorder, literature
directly addressing related healthcare costs in patients with these co-morbidities is sparse. Quantitative studies assessing health-related and economic
outcomes in bipolar patients with co-morbid metabolic disorders are needed. However, it is clear that
bipolar disorder is associated with a significant economic burden and nonmental healthcare appears to
comprise a substantial portion of these costs. Therefore, preventing weight gain and the development of
metabolic symptoms in bipolar patients will not only
provide positive health benefits but may also reduce
healthcare expenditures in this population.
Acknowledgements
Funding for this article was provided by Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover,
NJ 07936, USA. Editorial assistance for this article was
provided by Strategic Implications International, a business
of Advogent, 1800 Valley Rd, Wayne, NJ 07470, USA.
Dr Fagiolini is a consultant and/or speaker for BristolMyers Squibb, Eli Lilly Italy, Novartis Pharmaceuticals Corporation, Pfizer Inc. and Solvay Pharmaceuticals Inc.
CNS Drugs 2008; 22 (8)
666
Fagiolini et al.
Dr Chengappa is a consultant for AstraZeneca Pharmaceuticals LP, Janssen Pharmaceutical Inc., and Eli Lilly and
Company; has received grant and/or research support from
Janssen Pharmaceutical Inc.; is a speaker on advisory boards
for AstraZeneca Pharmaceuticals LP, and Eli Lilly and Company; and has received honoraria from AstraZeneca Pharmaceuticals LP, and Eli Lilly and Company.
Dr Soreca has received honoraria from Novartis Pharmaceuticals Corporation.
During the preparation of this review, Ms Chang was an
employee and owned stock options in Novartis Pharmaceuticals Corporation.
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Correspondence: Dr Andrea Fagiolini, University of Pittsburgh, WPIC 3811, O’Hara Street, Pittsburgh, PA 15213,
USA.
E-mail: [email protected]
CNS Drugs 2008; 22 (8)

Bipolar Disorder and the Metabolic Syndrome

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