ELS EVl ER
`
`Weight Gain from Novel Antipsychotic Drugs:
`Need for Action
`
`Alan I. Green, M.D., Iayendra K. Patel, M.D., Robert M. Goisman, M.D.,
`David B. Allison, Ph.D., and George Blackburn, M.D., PhD.
`
`Abstract: Obesity is common in schizophrenia, and people
`will: schizophrenia appear to be at increased risk for certain
`obesity-related conditions, such as type 2 diabetes and cardio-
`vascular disease. Antipsychoiic drugs, used chronically to con~
`trot symptoms of schizophrenia, are associated with often-
`substantial weight gain, a side gfi‘ect that is a special concern
`with the latest generation of ltiglily gflectioe “novel" agents.
`Tliat the most efectioe {'e.g., novel) antipsychotic medications
`lead to substaan weight gain presents thefield with a critical
`public health problem. Although preliminary data have been
`reported regarding the beneficial use of behavior therapy pro
`grams fin short-term weight control in patients with schizo-
`phrenia, the available data are quite limited, and there are no
`data regarding the long-term beneficial gfi‘ects of these pro-
`grams in this population. The obesityfield recently has devel-
`oped programs emphasizing "lifestyle changes” (eg, diet, ex—
`ercise, and problem-soloing skills)
`to successfully manage
`weight in patients without schizophrenia. Such programs can
`be adaptedfor patients with schizophrenia through the use of
`highly structured and operationalized modules emphasizing
`medication compliance, social skills development, and partici-
`pation in outpatient programs. Moreover, these programs can
`potentially be combined with the use ofadjunclioe pharmaco—
`therapy to maximize and maintain weight loss. The field must
`solve the paradox that some of our most ofectioe medications
`for schizophrenia produce substantial weight gain and its as-
`sociated troubling health risks. © 2000 Elseoier Science Inc.
`
`
`
`Commonwealth Research Center {A153, and the Massachu—
`setts Mental Health Center (A.I.G., I.K.P., HMS), Harvard
`Medical School Department of Psychiatry (A.I.G., I.K.P., RMEJ
`Boston, Massachusetts; the Division of Nutrition, Beth Israel
`Deaconess Medical Center (6.13.), Harvard Medical School De-
`partment of Surgery (0.3.) Boston, Massachusetls; and the ObLL
`city Research Center, St. Lakes!Roosevelt Hospital, Columbia
`University College of Physicians and Surgeons (D.B.A.] New
`York, New York.
`Address reprint reguests to: Dr. Alan 1. Green, Common—
`wealth Research Center, 74 Fenwood Road, Boston, MA 02115.
`
`Introduction
`
`Sclfizophrenia is a tragic and devastating mental
`illness that usually marfifests in young people on
`the threshold of adulthood [1]. The disease, which
`has a lifetime prevalence of 1% worldwide, extracts
`a high toll in morbidity (60% of patients receive
`disability benefits within the first year after onset)
`[2] and mortality (the suicide rate is 10%) [3,4].
`Antipsycbotlc medications are an integral part of
`the therapeutic program for most individuals with
`schizophrenia, and the new generation of ”novel"
`antlpsychotics are particularly helpful for many pa-
`tients with this and other psychotic disorders. To
`derive maximum benefit from these anfipsychotic
`agents, however, patients must be able to tolerate
`their side effects and take them as prescribed.
`One untoward side effect of many antipsychotic
`drugs, especially the newer ”nova " or “atypic ”
`antlpsychotlcs,
`is often-substantial weight gain
`[5—9]. Studies suggest that 40% to 80% of patients
`taking antipsychotic medication experience weight
`gain that exceeds ideal body weight by 20% or
`greater [10,11]. This noticeable and unwanted side
`effect may undermine compliance and thus predis-
`pose patients to relapse, in addition to increasing
`obesity-related comorbidifies and health risks
`[5,11—13].
`That the most effective (e.g., novel) anfipsycbotlc
`medications lead to substantial weight gain presents
`the field with a critical public health problem. This
`article will initially provide an overview of the topic
`of weight gain in patients treated with the novel an-
`tipsychotic agents. Then, after reviewing the limited
`data regarding approaches to the prevention of such
`weight gain, we will present one possible strategy for
`an approach to treatment in this area.
`
`224
`I$N 0163-3343/00/Hee front miter
`PlI somewmmmmvs
`
`General Hospital Psychiatly 22, 224—235, 2000
`© 2000 Elsevier Scimoe Inc. All rights med.
`655 Avenue of the Americas, New York, NY 10010
`
`DEF-LU RAS-000592'1
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`Exhibit 2022
`
`Slayback v. Sumitomo
`|PR2020-01053
`
`1
`
`Exhibit 2022
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Schizophrenia
`
`Schizophrenia is considered a disease of neural con—
`nectivity caused by multiple factors that affect brain
`develoPment [14—16]. Symptom onset typically is
`seen during the late teens and early 203, when brain
`maturation is reaching completion [17]. Its course is
`characterized by florid symptoms and frequent ex-
`acerbations early in the illness, followed by a
`chronic and often downhill progression over time
`that leads to severe social disability [18,19]. Patients
`with schizophrenia also have impairments in neu-
`rocognition, with deficits in memory, attention, and
`executive function [2042], which are thought to be
`key components of the functional disability caused
`by the illness [23,24]. Nearly 50% of patients suffer
`from comorbid substance abuse, leading to poor
`outcomes in these individuals [25,26]. People with
`schizophrenia have an overall mortality rate of
`about twice that of the general population, a rate
`comparable to that of individuals with diabetes
`mellitus [27]. The rate of completed suicide, most
`often seen in the early years of the illness, is 10%—
`comparable to that for depression [28,29].
`
`Treatment of Schizophrenia
`
`Treatment of schizophrenia usually involves the
`use of antipsychotic medications, first introduced in
`the 19505, which are prescribed in the context of an
`overall psychotherapeutic program. The availabil-
`ity of the standard or "typical” antipsychotic agents
`(e.g., chlorpromazine and haloperidol), all potent
`antagonists at dopamine D2 receptors, heralded a
`major therapeutic advance [30] and allowed many
`patients with schizophrenia to be discharged from
`hospital settings [31]. Although these drugs control
`positive symptoms of schizophrenia, they offer no
`”Cure," and have many shortcomings. Only SOme
`patients respond symptomatically to treatment,
`whereas others respond poorly if at all. Some pa-
`tients improve but quickly relapse, while others,
`who might show improvement, cannot tolerate the
`drugs because of severe neurolog‘c side effects (e.g.,
`dystonia, Parkinsonism, akathesia, or tardive dys-
`kinesia) [32—34].
`Within the past 10 years, a new generation of
`”atypical” or “novel” antlpsychotic drugs (e.g., clo-
`zapine, risperidone, olanzapine, quetiapine) has
`been introduced into ciinical practice [35—38]. These
`new medications have important advantages over
`the older "typical" agents and are gradually sup-
`planfing them in clinical use. Whereas "typical"
`
`Novel Anfipsychotic Drugs and Weight Gain
`
`antipsychotics are primarily dopamine D2 antago-
`nists, the ”novel” drugs have more broad-spectrum
`pharmacological activity at other receptor sites, in-
`cluding dopamine D1 and D4, adrenergic alpha]
`and alphaz, serotonin 5HT23 and SHTZC, and hista-
`minic and muscarinic receptors [36,39].
`From a clinical perspective, these new agents ap-
`pear to be more effective than the older ones for
`control of positive and (at least some) negative
`symptoms of schizophrenia [32,40]. They may also
`prevent relapses [41], improve some cognitive def-
`icits [42,43], and produce a higher level of functiow
`ing of patients with schizophrenia in the commu-
`nity [44,455]. One of the newer agents, clozapine,
`also appears to limit comorbid substance abuse
`[46,47] and suicidality [29] in patients with schizo-
`phrenia.
`In addition to these beneficial effects,
`nevel agents are less likely to produce severe neu—
`rological side effects [48], and are, in general, more
`acceptable to patients than the older, "typical" an—
`tipsychotics [49,50]. The availability of these novel
`antlpsychotics has ushered in a new era of opti—
`mism in the field, including considerable work on
`preventive intervention strategies to dramatically
`improve the outcome of patients with Schizophre-
`nia [51].
`
`Antipsychotics and Weight Gain
`
`Weight fluctuations in patients with schizophrenia
`were well documented in the pre—antipsychotic
`drug era [52]. Since the advent of antipsychotic
`medications, however, weight gain has become an
`enduring health concern [6,8,53—55]. Data from the
`mental health supplement of the 1989 National
`Health Interview Survey (NHIS) [56] indicate that
`body mass index (BMI) distributions of individuals
`with schizophrenia are generally similar to or
`higher than the general population and, thus, a
`substantial proportion were obese even before the
`widespread use of novel antipsychotic drugs [6].
`The reported prevalence of overweight and obesity
`in patients with schizophrenia has been found to
`range from 40% to 62% [657—60], and may be es-
`pecially high for women with schizophrenia. Obe-
`sity is a complicating factor in many medical ill«
`nesses
`commonly
`seen
`in
`patients with
`schizophrenia, e.g., type 2 diabetes, hypertension,
`dyslipidemia,
`sleep
`apnea, and osteoarthritis
`[11,61].
`It appears that novel antipsychotics produce an
`even greater weight gain than the typical agents
`[7,9—11,62—66]. A recent meta-analysis of over 80
`
`225
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`Al. Green et a1.
`
`studies on weight change during antipsychotic
`treatment showed a mean weight gain after 10
`weeks of treatment of 9.8 lb. (4.45 kg) with cloza-
`pine, 9.1 lb (4.15 kg) with olanzapine, and 4.6 lb.
`(2.10 kg) with risperidone compared to 2.4 lb. (1.08
`kg) with the typical antipsychotic haloperidol [67].
`Patients taking 15 mg / day of olanzapine have been
`found to gain a mean of 26 lb. (11.8 kg) after a year
`of treatment
`[7']. In short-term trials of patients
`treated with quetiapine, 23% Were reported to have
`had a 7% or more weight gain. In studies involving
`1 year of treatment with quetiapine, the mean
`weight gain was 4.8 lb. (2.2 kg) [68]. Interestingly,
`some but not all investigators have suggested that
`weight gain with these novel agents may be related
`to therapeutic response [10,62,69,70]. While two
`studies suggest that weight gain may be most dra-
`matic in patients with a low baseline weight [10,65],
`others have failed to find such an association
`
`[62,71]. Weight gain from these agents may be a
`particular problem for children and adolescents
`who are treated with them [72,73].
`Compliance with antipsychotic therapy, which is
`often a problem for patients with schizophrenia,
`may be further undermined by weight gain [11,74].
`This is a particularly difficult problem for the treat-
`ment of patients with schizophrenia because stop—
`ping pharmacological treatment dramatically in-
`creases relapse rates for these patients (by as much
`as 5-fold [75]). Moreover, since there is evidence
`that relapse and continued psychosis may be bio-
`logically “toxic” [41,76,717], such non—compliance
`with treatment may worsen the outcome of the
`disorder. Medication side effects are thought to be
`the cause of non-compliance in up to one—third of
`patients, and although specific data are not avail-
`able, a general perception in the field is that weight
`gain is an important
`factor determining non-
`compliance for many patients [11].
`Many theories (including increased food intake
`[66,78]) have been advanced to explain the
`antipsychotic-induced weight gain in schizophre-
`nia [8,55]. Recently, serotonin (e.g., SHTZC), dopa-
`mine {D2), and histamine (H1) receptor blockade
`have been implicated [5,71,79]. Some have also sug-
`gested that changes in neurohormones and neu-
`ropeptides may underlie weight gain.
`
`Obesity
`
`Beyond any possible effect of weight gain from
`antipsychotic drugs on non-compliance with
`treatment, weight gain occurs and is associated
`
`226
`
`with a disturbing array of increased health risks
`in patients with schizophrenia. In some ways, the
`weight gain from "novel" antipsychotics in pa-
`tients with schizophrenia mirrors the general
`population, in which the prevalence of obesity
`has increased dramatically over the past 10 years.
`Over 50% of adult Americans are now either
`
`overweight (BMI > 25 kg/mz) or obese (BMI > 30
`kg/mz) [80]. Obese individuals experience nu-
`merous adverse health consequences, including
`increased risk for cardiovascular disease, diabe-
`
`tes, stroke, some cancers, osteoarthritis, sleep ap-
`nea, gallbladder disease, and higher mortality
`rates from all causes compared to normal-weight
`individuals [81]. The most common comorbidity
`of obesity, hypertension, affects more than 50
`million people [82], and an estimated 33% of the
`cases of hypertension are obesity related [83].
`As noted above, obesity is a common concomi-
`tant of schizophrenia [6], and schizophrenic indi-
`viduals appear to be at increased risk for certain
`obesity-related conditions, such as type 2 diabetes
`and cardiovascular disease [84- 87]. EpideIIuologi-
`cal studies show that specific stages of life, includ-
`ing early adulthood (the time of onset of schizo-
`phrenic symptoms), confer high risk for
`the
`development of obesity in susceptible individuals
`[88]. This risk will only be further increased when
`patients with schizophrenia are treated with anti-
`psychotic drugs [89}.
`The NIH’s recently released clinical guidelines on
`obesity [81] cite research showing significant in-
`creases in morbidity beyond a BMI of 25 kg/m2 and
`mortality beyond a BMI of 30 kg/m2 [12,90,91], and
`rising incidences of diabetes, coronary heart dis-
`ease, and hypertension well before that point
`[92,93]. Numerous studies consistently have shown
`that short-term reduction in body weight improves
`obesity-related insulin resistance and cardiovascu-
`lar risk factors—hyperglycemia, hyperlipidemia,
`hypertension, and hyperinsulinemia [94,95]. Clini-
`cal and laboratory evidence also show that weight
`losses as low as 5% to 10% of body weight reduce
`obesity-related disorders [96,97] and improve se-
`rum glucose levels, glucose tolerance, and blood
`pressure [92,98]. These findings, coupled with the
`well-documented adverse health effects of weight
`gain and obesity, indicate that the often-substantial
`weight gain observed with antipsychotic medica-
`tions [67] is an important clinical as well as a public
`health concern [6].
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`Obesity, Insulin Resistance,
`Cardiovascular, and Neurological Risk
`Factors
`
`Fifty percent of obese individuals (compared to
`10% of non-obese individuals) [99—101] develop
`Syndrome X {also known as the metabolic or pri-
`mary insulin resistance syndrome) that includes a
`cluster of coexisting clinical conditions: glucose in-
`tolerance or diabetes; hypertension; and hyperlip—
`idemia with hyperinsulinemia and insulin resis—
`tance. Other laboratory abnormalities commonly
`found with Syndrome X include microalbuminuria,
`hyperuricemia, elevated free fatty acids, and the
`presence of Factor VII (with increased levels of
`fibrinogen and/ or PM 1 [plasminogen activator
`inhibitor 1], and thus with defective fibrinolysis
`and increased blood viscosity) [94,102].
`A recent epidemiological study shows that clini-
`cally significant weight gain from early adulthood
`to middle age is strongly associated with increased
`risk for developing the metabolic risk factors of
`Syndrome X [103]. In fact, each 5% increase in body
`weight——-independent of age, height, smoking,
`physical activity, education, and family history—is
`associated with a 200% greater risk of developing
`the insulin resistance syndrome by middle age
`[103]. The cluster of metabolic risk factors associ-
`ated with both insulin resistance and obesity may
`also underlie the well-documented increase in
`
`cardiovascular—related mortality found in type 2
`diabetics (a rate that is similar to that found in
`nondiabetic subjects with prior myocardial infarc-
`tions) [104].
`According to the NIH Guidelines for the treat-
`ment of obesity {81], weight loss is recommended in
`overweight and obese peeple with dyslipidemia to
`raise low levels of high-density lipoprotein (HDL)
`cholesterol and to lower elevated levels of total
`
`cholesterol, low-density lipoprotein (LDL) choles-
`terol, and triglycerides. This recommendation is
`based on randomized control trial data showing
`that 5% to 13% reductions in body weight produced
`impressive improvements in lipid profiles [81]. In
`response to the mounting evidence about the rela-
`tionship of adiposity to coronary heart disease
`(CHD), the American Heart Association recently
`classified obesity as a major, modifiable risk factor
`for CHD and issued a nine-point "call to action"
`that urged legislators, insurers, health care provid-
`ers, and the public to sharply escalate the war
`against obesity [105].
`Relevant to schizophrenia, a recent report [1061
`
`Novel Anfipsychotic Drugs and Weight Gain
`
`suggests that hyperinsulinemia and hyperglycemia
`associated with insulin resistance in patients
`treated with antipsychotic drugs are related to the
`severity of abnormal involuntary movements sec-
`ondary to the use of these drugs. Weight gain from
`novel antipsychotic drugs only makes this condi-
`tion worse.
`
`Efficacy of Weight Loss Programs
`Emphasizing Lifestyle Change
`
`Obesity research has yet to develop completely suc-
`cessful methods for achieving long-term weight
`loss, but a recent review of maintenance strategies
`(none of which was designed for patients with psy-
`chosis) shows that some approaches are more
`promising than others [107}. A weight-focus ”life-
`style” orientation, where individuals learn diet, ex»
`ercise, and problem-solving skills in weekly inten-
`sive intervention sessions for a number of months,
`followed by monthly maintenance treatment meet-
`ings [108], is one such method (with demonstrated
`losses of 5%—13% of body weight [81]). The use of
`formula diet preparations, such as commercial
`weight loss beverages that supplement a portion of
`daily energy intake, is another [109].
`Whatever the method used for weight loss exer-
`cise is an essential component for maintenance
`[110]. Jeffery and colleagues [111] describe an inten-
`sive exercise intervention that increases cues for
`
`activity, makes use of a personal trainer, and rein-
`forces attendance at exercise sessions with small
`
`financial incentives. In that study, subjects who ex-
`ercised at a level that increased energy output to
`2,500 heal/week demonstrated substantial
`long-
`term weight loss.
`Weight loss programs that aim to change lifestyle
`must be appropriate for
`the population being
`treated. For example, Blackburn and colleagues
`[112] recently have described a multifaceted, cultur-
`ally sensitive weightless intervention that they de-
`signed for use with obese African~American
`women (adapting the intervention for this popula-
`tion from existing lifestyle interventions) specifi-
`cally emphasizing the development of new skills in
`four main areas, each of which support healthy
`lifestyles, that were deemed relevant to this pepu-
`lation [113—115]: cogrutive/behavioral techniques;
`exercise; nutrition/ education; and gender/ethnic
`issues.
`
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`Al. Green et a1.
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`Lifestyle Intervention in Schizophrenia
`
`It is reasonable to presume that lifestyle interven-
`tions for individuals with schizophrenia must be
`adapted to be effective in this population. Many
`patients with schizophrenia have cognitive deficits
`[21,43], including attention [22], executive function,
`learning, memory, verbal
`intelligence, and lan-
`guage function skills [20] that may prevent the ac-
`quisition of social skills [24]. Nonetheless, programs
`that use concrete models, simple directions, and
`reinforcement (to compensate for the cognitive def-
`icits) appear to facilitate participation of patients
`with cognitive difficulties and psychosis in weight
`loss programs [116}. Treating patients with schizo—
`phrenia living in a residential program, Rotatori et
`al. [116] assessed a modified behavioral self-control
`14—week weight loss program involving 14 patients;
`those in the active program (11:?) had a mean
`weight loss of 7.28 lbs while those in the control
`group (IF?) had a mean weight gain of 5.6 lbs. In
`this program, however, on follow-up 16 weeks after
`the completion of treatment, those available from
`the active program (n=4) had a mean weight loss of
`1.81 lbs while in the controls (n=5) the average
`weight gained was 2.8 lbs. While these results are
`encouraging, the long-term outcome remains un-
`clear. Other reports of weight loss in carefully con-
`trolled small programs for inpatients with schizo-
`phrenia (or in individual case reports) have also
`been published [117—120]. Taken together, the ex-
`isting data suggest that short-term weight loss is
`achievable in this population, but that careful atten-
`tion to design of the program is essential, and new
`innovative approaches to achieve long-term weight
`loss are necessary.
`The experience of a number of investigators over
`the past 15 years [e.g., {121—1251} has demonstrated
`that highly structmed and operationalized "mod-
`ule” programs (e.g., [l26,127]) lead to improvement
`in medication compliance, social skills develop—
`ment, and participation with outpatient programs,
`and they potentiate the functional gains that pa-
`tients with schizophrenia obtain from the use of
`novel antipsychotics alone [124]. These programs
`emphasize skill acquisition, use of social reinforce-
`ments, incremental approaches to complex behav-
`ioral change, and redundancy of presentation using
`multiple educational modalities [128]. Hence. they
`represent a more sophisticated application of the
`same principles used in the simpler, early behaw
`ioral interventions described above. Any weight
`loss lifestyle intervention designed for patients with
`
`schizophrenia should follow the same principles of
`these ”module” programs to help the patients ac-
`quire, strengthen and generalize knowledge and
`skills in the areas of nutrition and lifestyle modifi—
`cation.
`
`Effect of Physical Activity on Glucose
`Intolerance in Obesity
`
`Epidemiological data show that exercise, and exer—
`cise combined with weight lass intervention, can
`prevent and/or slow the transition from impaired
`glucose tolerance to type 2 diabetes
`[82,129].
`Intervention-based randomized controlled trials
`
`also consistently indicate that physical activity im—
`proves insulin action in obesity. Findings in over-
`weight patients with type 2 diabetes, though more
`ambiguous, indicate a positive effect on insulin sen—
`sitivity [130], which does not always translate, how-
`ever, into improved glucose control. This lack of
`effect on glucose control reflects, in part, the inabil-
`ity of many patients with type 2 diabetes to engage
`in regular high—intensity exercise, as well as the
`strong and persistent nature of insulin secretory
`defects. Data on the physiological effects of exercise
`on insulin sensitivity and glucose tolerance consis-
`tently indicate that the positive effects are relatively
`short—lived, lasting 2 to 3 days after each exercise
`session—a finding that underscores the need for a
`regular program of exercise to sustain health bene-
`fits [131]. Thus, any lifestyle program aimed at
`weight control
`for patients with schizophrenia
`should include a moderate-level exercise program.
`Fortunately, this type of program should be appro-
`priate to the capabilities and dispositions of indi-
`viduals with schizophrenia [132,133]. Indeed, above
`and beyond weight loss, exercise may have benefi-
`cial effects in this population [134].
`
`The Potential Role of Adjunctive
`Pharmacotherapy
`
`The effect of pharmacotherapy on weight loss has
`been evaluated in over 41 randomized controlled
`
`trials (none of which have been performed in pa
`tients with schizophrenia) [135]. Studies of single-
`drug and combination therapy have shown that,
`although mean weight losses with pharmacother-
`apy are modest (2—10 kg); those who take the active
`drug are more likely to achieve a clinically signifi-
`cant weight loss (5°/u—10% of initial body weight)
`[96,136] than those who take placebo [135,137,138].
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`Response to treatment, however, has been inconsis~
`tent. Some patients have shown little response to
`drug therapy, while others have responded with
`clinically significant weight loss [136,139—141].
`If those most likely to benefit could be identified,
`the appropriate use of pharmacotherapy in selected
`patients would improve. More research is needed
`to determine which individuals are likely to re-
`spond to a given medication or class of medica-
`tions, and whether factors such as race, ethnicity,
`sex, percentage above ideal body weight, age of
`onset of obesity, or eating style (such as binge eat«
`ing) can predict response to given medications
`[134,136,139—141].
`Pharmacotherapy is often given to patients in
`conjunction with a program of lifestyle intervention
`[135], with good results over periods of 6 months to
`1 year. A few clinical trials have been described in
`which adjunctive pharmacotherapy has been pro-
`vided after an initial period of lifestyle intervention
`aione. In such studies, the pharmacotherapy has
`successfully potentiated the effect of the lifestyle
`intervention [135]. Smce weight loss programs em-
`phasizing lifestyle intervention for patients with
`schizophrenia have noted that long-term mainte-
`nance of weight reduction can be a problem, life-
`style interventions for patients with schizophrenia
`may well benefit from adjunctive phannacotherapy
`either in conjunction with the lifestyle intervention
`or following an initial period of lifestyle interven-
`tion alone in an attempt to maintain (or improve
`upon) the gains of the initial period of lifestyle
`intervention.
`
`Use of Weight Loss Drugs in Patients
`With Schizophrenia
`
`One concern about using weight loss medications
`in patients with schizophrenia involves their poten-
`tial for negatively impacting on patient symptoms,
`or interfering with the efficacy of on—going antipsy-
`chotic treatment. Antipsychotic medications typi-
`cally achieve their effects by blocking dopamine,
`norepinephrine, and serotonin receptors. However,
`all currently available, centrally-acting weight con-
`trol drugs increase noradrenergic, dopaminergic,
`and/ or serotonergic activity in the central nervous
`system [135], and thus, theoretically, could counter-
`act
`the effects of antipsychotic treatment and
`worsen symptoms of psychosis. For example, nu-
`merous case reports suggest that psychotic symp-
`toms have been either induced or exacerbated by
`
`Novel Anfipsychotic Drugs and Weight Gain
`
`centrally acting weight loss drugs, including fenflu—
`ran-line and/or phentermine [142—145]; diethylpro-
`prion [I46], and phenylpropanoiamine [147,148].
`The use of centrally acting weight control agents in
`schizophrenic individuals clearly presents potential
`challenges.
`While there are no data to suggest whether the
`unique serotonergic—noradrenergic
`(and dopa-
`mine) reuptake inhibitor, sibutramine, that recently
`has been introduced as a treatment for obesity and
`is thought to have relatively few side effects [149—
`151], will also exacerbate psychosis, sibutrainine is
`centrally acting and has a mechanism of action that
`makes it potentiaily risky in this population. None-
`theless, it is an effective anti-obesity agent that ex-
`erts its effect by enhancing satiety and possibly by
`increasing thermogenesis—both contributing to-
`ward weight reduction [1521 and the maintenance
`of weight loss over the long term [153]. Side effects
`of the drug most commonly reported are dry
`mouth, anorexia, insomnia, and constipation; other
`side effects reported are tachycardia,
`increased
`blood pressure, palpitation, dizziness, somnolence,
`CNS stimulation, and emotional lability. Clearly,
`further investigations of the effects of sibutramine
`in patients with schizophrenia and obesity are im-
`portant to determine whether this new agent could
`safely facilitate weight loss in such patients without
`exacerbating psychosis and interacting with anti«
`psychotics. The recommended starting dose of sib-
`utrarnine is 10 mg once daily with or without food
`and the dose can be titrated upwards to 15 mg/day.
`Doses higher than 15 mg/ day are not recom-
`mended.
`
`Orlistat, the first non-centrally acting drug ap-
`proved in Europe, Latin America, and Asia for the
`treatment of obesity [154], recently was approved
`for use in the United States. Since orlistat does not
`
`act systemically, there is little risk of interaction
`with centrally acting medications. A chemically
`synthesized derivative of lipstatin (a natural prod-
`uct of Streptomyces toxytricim), it selectively limits
`the intestinal absorption of approximately one-
`third of dietary fat [155]. Specifically, it inhibits
`gastric and pancreatic lipases [154] and prevents
`triglycerides from being broken down into their
`constituent particles.
`trials (none of
`In placebo-controlled clinical
`which took place in patients with schizophrenia),
`orlistat produced a statistically significant weight
`loss [140,156-158], and like sibutramine [141], its
`use is associated with decreases in triglycerides,
`total cholesterol, and LDL-choiesterol, and in—
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`Al. Green et al.
`
`creases in HDchholestc-rol [157]. These drugs are
`both also associated with improved glycernic con-
`trol 1139.151159]. Unlike sibutramine, however, or-
`listat does not significantly interact with thyroid
`hormones, or catecholan‘lines
`[158]. Given the
`mechanism of action of orlistat in the GI tract, it is
`unlikely to interfere with the absorption of the
`novel antipsychotics. However, data addressing
`this issue are urgently needed. The most common
`adverse effects of orlistat (including increased def-
`ecation, soft stools, fatty or 0in stools, stomach
`pain, and gas with discharge) can be decreased by
`eating a low-fat diet [160,161], which can be encour-
`aged within an overall iifestyle intervention pro-
`gram.
`
`Summary
`
`Obesity is a common concomitant of schizophrenia
`[6,59,162], and people with the illness appear to be
`at increased risk for certain obesity—related condi»
`tions, such as type 2 diabetes and cardiovascular
`disease [84*87]. Antipsychotic drugs, an important
`therapeutic option for people with schizophrenia,
`are associated with often-substantiai weight gain, a
`side effect that occurs with older medications but
`
`even more so with the latest generation of highly
`effective ”novei" agents [5,67].
`Weight gain associated with the use of antipsy-
`chotic medications can lead to important medical
`complications in patients with schizoPhrenia and to
`their treatment noncompliance. These facts, cou-
`pied with the well-documented adverse health con-
`sequences of weight gain and obesity, underscore
`the need to address the often-substantial weight
`gain observed in patients with schizophrenia who
`take antipsychotic drugs (specifically,
`the newer
`highly effective "move ” agents).
`The few preliminary studies done on behavioral
`treatment of obesity in psychiatric patients {in con-
`trolled settings) have shown substantial weight loss
`over brief periods of time [116,118,163—165]; how-
`ever, there have been no trials for overweight pa-
`tients treated with the novel antipsychotics. Con-
`siderations for weight control programs for patients
`with schizophrenia include the use of lifestyle in-
`tervention programs aimed at diet, exercise and
`problem-solving skills that can be adapted for pa-
`tients with schizophrenia to compensate for the
`known cognitive deficits in these patients. In addi-
`tion, the possible use of adjunctive pharmacologic
`approaches such as the non-centrally acting drug
`
`230
`
`orlistat, or possibly sibutramine, can be considered
`as part of the overall program
`Clearly, weight gain in patients with schizophre-
`nia, especially those treated with the novel antipsy—
`chotic drugs, is an important public health problem
`that must be addressed by the field. Carefully con-
`structed programs (including randomized trials)
`aimed at preventing this weight gain will be impor-
`tant to design, implement and evaluate in these
`patients. We must solve the paradox that some of
`our most effective medications for schizophrenia
`produce weight gain and its associated troubiing
`health risks.
`
`References
`
`1. Andreasen NC: Understanding the causes of schizo-
`phrenia. N Eng J Med 34D(8}:645—647, 1999
`2. Ho BC, Andreasen N, Flaum M:
`dence on
`public financial support early in the course of
`schizuphrenia. Psychiatr Serv 48948350, 1997
`3. Cohen L}, Test MA, Brown RL: Suicide and
`schizophrenia: data from a prospective community
`treatment study. Am] Psychiatry 14?:602—607, 1990
`4. Axelsson R, Lagerkvist—Briggs M: Factors predicting
`suicide in psychotic patients.