low cardiorespiratory fitness and physical functional capacity in obese patients with schizophrenia

Low cardiorespiratory fitness and physical functional capacity inobese patients with schizophrenia

Martin Strassnigab Jaspreet S Brarc and Rohan GanguliabcRohan Ganguli Rohan_Gangulicamhneta University of Torontob Center for Addiction and Mental Health Toronto Ontario Canadac Department of Psychiatry University of Pittsburgh Pittsburgh Pennsylvania USA

AbstractBackgroundmdashLow cardiorespiratory fitness is a prominent behavioral risk factor forcardiovascular disease (CVD) morbidity and mortality as cardiorespiratory fitness is stronglyassociated with CVD outcomes High rates of CVD have been observed in the schizophreniapopulation translating into a markedly reduced life expectancy as compared to healthy controlsSurprisingly however while cardiorespiratory fitness is an eminent indicator for overallcardiovascular health as well as eminently modifiable risk factor for CVD no studies havesystematically assessed cardiorespiratory fitness in schizophrenia

MethodsmdashCommunity-dwelling schizophrenia patients underwent graded-exercise tests toascertain maximal oxygen uptake (MaxVo2) considered to be the gold standard for the evaluationof cardiorespiratory fitness and physical functional capacity The modified Bruce-protocol wasused to ascertain cardiorespiratory fitness and physical functional capacity data was normalizedand compared to population standards derived from the ACLS (Aerobics Center LongitudinalStudy) and the National Health and Nutrition Examination Surveys (NHANES) Cycle III and IV

ResultsmdashData for n=117 participants (41 male 46 white) was analyzed Mean age (y) was432plusmn99 and mean BMI was 372plusmn73 Peak HR attained during exercise was 1456plusmn196 after805plusmn36 min achieving 1112plusmn442 watts MaxVo2 was 172plusmn66 lmin MaxVCo2 185plusmn72 lmin and minute ventilation (VE) was 556 plusmn219 mlsec PANSS Positive subscores (133plusmn44 r=minus021 p=0024) were inversely correlated with Max Vo2 mlminus1minminus1kgminus1 Neither PANSS Total(563plusmn123 r=minus0105 p=072) PANSS Negative (14plusmn51 r=minus052 p=057) nor PANSS GeneralPsychopathology (284plusmn74 r=minus028 p=076) scores were correlated with Max Vo2

Corresponding author Center for Addiction and Mental Health (CAMH) 901 King Street West Suite 500 Toronto Ontario M5V3H5 Canada Tel +1 416 535 8501x2102 fax +1 416 583 3485Conflict of InterestDr Ganguli has no current relevant conflicts of interest to report In the past he has received research grant funding from BristolMyers-Squibb Janssen Pfizer and Lilly In the past he has also served as a consultant or received honoraria from Bristol Myers-Squibb Janssen Pfizer and LillyDrs Strassnig and Brar have no relevant conflicts of interest to reportContributorsDr Rohan Ganguli obtained funding for the study and as Principal Investigator over saw the conduct of the research Dr Ganguli andDr Jaspreet Brar designed the study and wrote the protocol Dr Martin Strassnig supervised the graded exercise tests undertook thestatistical analysis and wrote the first draft of the report All authors contributed to and have approved the final manuscriptPublishers Disclaimer This is a PDF file of an unedited manuscript that has been accepted for publication As a service to ourcustomers we are providing this early version of the manuscript The manuscript will undergo copyediting typesetting and review ofthe resulting proof before it is published in its final citable form Please note that during the production process errors may bediscovered which could affect the content and all legal disclaimers that apply to the journal pertain

NIH Public AccessAuthor ManuscriptSchizophr Res Author manuscript available in PMC 2012 March 1

Published in final edited form asSchizophr Res 2011 March 126(1-3) 103ndash109 doi101016jschres201010025

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-PA Author Manuscript

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mlminus1minminus1kgminus1 Peak heart rate and duration of exercise were not correlated with PANSS scoresCompared to healthy controls derived from the ACLS and NHANES respectively 115participants achieved lsquolow levelslsquo of fitness only as well as highly significantly reduced MaxVo2across all age-groups

ConclusionmdashThe test was generally well received and tolerated by those who elected toparticipate and adherence to the protocol was good Among participants with schizophrenia mostof whom were obese and across all age groups cardiorespiratory fitness was exceedingly poorOnly two participants in our entire sample fit the categorization of lsquomoderate fitness levellsquo that isa fitness level at or above the 20thp ercentile of ACLS-derived population comparisonsConversely this left 983 of participants with schizophrenia below population standards Lowcardiorespiratory fitness emerges as an eminent modifiable risk factor for CVD mortality andmorbidity in schizophrenia complicated by obesity

Keywordsschizophrenia obesity fitness cardiovascular disease cardiorespiratory fitness

IntroductionHigh rates of cardiovascular disease (CVD) have been observed in the schizophreniapopulation translating into a life expectancy that is reduced by as much as 20ndash25 incomparison with mentally healthy controls (Hennekens 2007) The reasons are complex andinclude unhealthy lifestyles poor diet little exercise and cigarette smoking (Brown et al1999 Strassnig et al 2005) in addition to treatment with antipsychotic medication whichcan add deleterious metabolic consequences by themselves (Newcomer 2005)

This has lead to the untenable situation that despite improved outcomes with respect topsychiatric symptoms social functioning and quality of life the mortality gap for patientshas not narrowed but may actually be worsening (Saha Chant amp McGrath 2007) Atherapeutically unsustainable situation it coincides with a relative lack of research intolifestyle-related adverse sequelae that would in all likelihood identify causative mechanismsand risk factors that could represent targets of intervention to mitigate close or even reversethat gap (Koivukangas et al 2010)

One lifestyle factor low cardiorespiratory fitness has been recognized as prominentbehavioral risk factor for cardiovascular disease (CVD) morbidity and an independent riskfactor for all-cause mortality in adults (Blair et al 1989 Kampert et al 1996) Highercardiorespiratory fitness decreases overall mortality rates and morbidity and mortality dueto CVD in a dose-response fashion (CDC 1996) These associations are quite robust andhave been demonstrated to be largely independent from other major risk factors (Ekelund etal 1988 Blair et al 1989 Blair et al 1996) Together with anecdotal observations ofsedentary behavior and lack of exercise in schizophrenia patients that may far exceedpopulation standards (Faulkner et al 2006 Lindamer et al 2008 Sharpe et al 2006)cardiorespiratory fitness in schizophrenia emerges as major modifiable risk factor for CVDand overall morbidity- and mortality (Vancampfort et al 2010)

At the same time the literature regarding cardiorespiratory fitness in schizophrenia remainsinsufficient No studies have systematically assessed cardiorespiratory fitness in patientstreated for schizophrenia facing known deleterious lifestyles and chronic treatment withantipsychotic medication Moreover to our knowledge neither the response to structuredphysical exercise nor its tolerability has been systematically examined in patients withschizophrenia This would aid in the development of targeted interventions to improvecardiorespiratory fitness and physical health in patients with schizophrenia and identify

Strassnig et al Page 2

Schizophr Res Author manuscript available in PMC 2012 March 1

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specific subgroups that may be at especially high risk for CVD due to low cardiorespiratoryfitness

MethodsStudy population

Between 2005 and 2008 overweight and obese community-dwelling patients with a DSM-IV diagnosis of schizophrenia schizoaffective disorder and psychotic disorder NOS wererecruited from the outpatient clinic and partial hospital at the Schizophrenia Treatment andResearch Center at Western Psychiatric Institute and Clinic University of PittsburghMedical Center Pittsburgh PA for a clinical trial on weight loss The subjects in the parentstudy were asked if they were willing to participate in graded-exercise tests (GXT) but thiswas not a requirement for continuing in the parent protocol Less than half of the individualsin the clinical trial agreed to undergo GXT Reasons for accepting or declining were nottracked GXT is considered to be the gold standard for the evaluation of cardiovascularfitness and overall physical functional capacity and a standardized GXT protocol at theUniversity of Pittsburgh Medical Centerlsquos ONRC (Obesity and Nutrition Research Center)using the Bruce protocol (Myers et al 1991) was used

The University of Pittsburgh IRB approved the study all of the participants gave writtenconsent prior to the GXT The GXT was completed at baseline before any behavioral weightloss intervention took place Each individual was asked to verify demographic clinical andmedication information with regard to history of chronic disease current medications andcigarette smoking habits Information was verified by chart review Subjects received aphysical examination and baseline electrocardiogram (ECG) and those deemed to have amedically unstable condition or ECG abnormalities were excluded from the GXT Bodyweight and height were recorded BMI was calculated

Graded Exercise Test (GXT) procedureParticipants dressed lightly completed the GXT on a stationary cycle ergometer and thosedeemed to exceed the ergometer safety weight limits (gt400 lbs n=2) were asked tocomplete the GXT on a treadmill Preparation was as follows The subjects were asked to sitdown comfortably on the ergometer after removing excess clothing were then connected toa 12 lead ECG and an automatic sphygmomanometer and had a rubber face mask fitted tocomfortably enclose their mouth and nose The facemask was then connected via flexibletubes to an open-circuit spirometer for the measurement of gas exchange Prior to each testsession the gas analyzers were calibrated with certified gases of known standardconcentration

After a brief rest period to get familiarized with the setup and adjusted to the facemask theexercise test was initiated speed remained constant throughout each subsequent 2 minutetesting stage while resistance was increased During the last 10 seconds of each exercisestage and at the point of test termination heart rate was measured from a 12 lead ECGblood pressure was measured by an automatically inflating sphygmomanometer and ratingof perceived exertion (RPE) was obtained using the 6ndash20 category Borg Scale (Borg 1974)For safety blood pressure was measured during the last 45 seconds of each even minuteexercise stage (ie stages 2 4 6 etc) and for a defined period after test termination using amanual sphygmomanometer Using standard test termination criteria of the AmericanCollege of Sports Medicine (ACSM 2005 Gibbons et al 2002) the test was terminated atvoluntary exhaustion or if the patient reported signs or symptoms of exercise intolerance (iemuscular fatigue significant ST depression and ischemia or complex arrhythmias)



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Cardiorespiratory fitness was expressed as maximal oxygen uptake (Vo2max mlminus1minminus1

kgminus1) Peak exercise time was recorded in minutes peak exercise capacity was estimated asmetabolic equivalents (METs) One MET is defined as the energy expended at rest which isequivalent to an oxygen consumption of 35 ml kgminus1 of body weight per minute and peakexercise capacity as MET (metabolic equivalent) was estimated from speed and resistanceusing standardized quotations where V02 (ml kgminus1 minminus1) [01 ml kgminus1 meterminus1 s(mminminus1)] + [18 ml kgminus1 meterminus1 s(m minminus1)G] + 35 mL kgminus1 minminus1 s = speed and r =resistance in percent METS= Vo2 (ml kgminus1minminus1)35 ml kg minminus1 Predicted Vo2max wascalculated as follows for males VO2 max = 1476 minus (1379 times time) + (0451 times time2) minus(0012 times time3) and for females VO2 max= (438 times time) minus 390 whereas time = max timePredicted maximum heart rate was calculated as follows 220-age

Results were compared to reference data derived from US population surveys that employedsimilar methodologies to ascertain cardiovascular fitness and exercise capacity includingthe Aerobics Center Longitudinal Study (ACLS Blair et al 1989) and the National Healthand Nutrition Examination Survey categorized by age and gender (Duncan et al 2005Wang et al 2010 Sanders et al 2006)

The Borg Scale is a 15-point linear Likert scale and measures subjective ie perceivedexertionexercise intensity (including heart rate respiration effort soreness and fatigue)Exertion is rated on a scale of 6ndash20 between 7 and 8 is lsquovery lightlsquo exertion Eleven is alight level of exertion Fifteen would be consistent with a level of heavy resistance A levelof 20 cannot be sustained

StatisticsThe NHANES survey design is a stratified probability sample of the US population Detailsof the NHANES protocol and testing procedures are available elsewhere(httpwwwcdcgovnchsabutmajronhanesdatalinkhtm199920Current20NHANES )All individuals aged 12ndash49 years were eligible to participate in the cardiovascular fitnesscomponent of NHANES The final sample consisted of 1978 adults who had complete dataavailable for the analysis (Duncan et al 2005)

The ACLS (Blair et al 1989 Mahler et al 1995) stratifies data according to fitness levelsLow cardiovascular fitness is defined as MET below the 20th percentile of the same sex-and age group a moderate fitness levels is a value between the 20th and 59th percentile anda high fitness level is at or above the 60th percentile (also see Table 2 later)

SPSS (for windows) software was employed for data analysis Descriptive analysisincluding mean range and standard deviation for continuous variables was carried out todetermine whether the variables were normally distributed and frequency counts forcategorical data (for example gender race etc) were done to examine the proportions ofGXT were examined for the whole group for males and females and for Caucasians andAfrican Americans Individual GXT values such as max Vo2 METs were categorizedaccording to standard fitness-level cut-offs derived corresponding values observed in theNational Health and Nutrition Examination Survey Cycle III (NHANES III Alaimo et al1994 McDowell et al 1994) Student t-tests and where appropriate Fisherlsquos exact tests chi-square tests and ANOVA were employed to look for statistical differences between themeans of 2 variables Confidence interval was 95 throughout



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ResultsExercise capacity

From among n=260 subjects who were recruited to participate in the behavioral weight losstrial n=117 subjects (41 male 46 white) elected to participate in the GXT Mean age(y) of those subjects was 451plusmn101 and mean BMI was 367plusmn75 Antipsychoticmedications included clozapine (n=21) olanzapine (n=15) risperidone (n=28) quetiapine(n=10) ziprasidone (n=7) aripiprazole (n=19) and antipsychotic polypharmacy (n=19)Psychopathology was measured with the Positive and Negative Symptom Rating Scale(PANSS Kay Fiszbain and Opler 1987) and scores were as follows PANSS Positivesubscores were 133plusmn44 PANSS Negative subscores 14plusmn51 PANSS GeneralPsychopathology subscores were 284plusmn74 and PANSS Total scores were 563plusmn123

Resting BP was 124 (11)80(10) and resting HR was 88plusmn14 Peak HR attained duringexercise was 142plusmn21 after 77plusmn34 min Peak BP was 161plusmn21 and 82plusmn9 Maximal wattattained was 1034plusmn452 corresponding to a Vo2max of 1635plusmn687 mlmin VCo2 max of1741plusmn 731 lmin and minute ventilation (VE) max 49plusmn199 mlsec This equates to a maxMET of 44plusmn175 The anaerobic threshold (AT) amongst all participants was surpassed at106plusmn05 Rate of perceived exertion was 15(plusmn2) indicating lsquohard to very hard worklsquo (Table1)

Compared to individual age-predicted maximal values (ACLS derived) study subjectsachieved 38plusmn16 of maximal MET 12plusmn3 83 of maximal predicted heart rate (171plusmn7)and 42plusmn11 of maximal V02 uptake 2648plusmn916 mlmin One hundred and fifteen (n=115983 ) out of the total participant number of 117 fell in the age-adjusted ACLS lsquolow fitnesscategorylsquo Two participants fell in the lsquomoderate fitness categorylsquo No participant reachedthe ACLS lsquohigh fitness categorylsquo (Table 2)

Age was inversely correlated with Max Vo2 mlminus1minminus1kgminus1 (r= minus0184 p=0047) maxwatt attained (r= minus0215 p=0021) duration of exercise (r= minus0315 p=0001) peak heartrate (r= minus0261 p=0024) but not with RPE (r=0151 p=0104) BMI was inverselycorrelated with Max Vo2 mlminus1minminus1kgminus1 (r= minus0207 p=0025) but not with max minutes(exercise time r= 0038 p=0691) or RPE (r= minus054 p=0561) PANSS Positive subscores(133plusmn44 r=minus021 p=0024) were inversely correlated with Max Vo2 mlminus1minminus1kgminus1Neither PANSS total scores (563plusmn123 r=minus0105 p=072) PANSS Negative (14plusmn51 r=minus052 p=057) PANSS General Psychopathology (284plusmn74 r=minus028 p=076) subscoreswere correlated with Max Vo2 mlminus1minminus1kgminus1 Peak heart rate duration of exercise andRPE were not correlated with PANSS total scores PANSS Positive- Negative and GeneralPsychopathology subscores

There was no difference across antipsychotic medications in Max Vo2 mlminus1minminus1kgminus1

(F=0942 p=047) max VE (F=0427 p=086) RQ (F=028 p=094) Max Watt attained(F=091 p=049) max minutes (F=125 p=029) or RPE (F=054 p=078)

Males (n=46) had higher Max Vo2 mlminus1minminus1kgminus1 than females (n=71 187plusmn68 vs 134plusmn46 p=0017 t=245) maximum MET (54plusmn19 vs 38plusmn13 p=0017 t= 243) but notmaximum minutes (89plusmn39 vs 7plusmn28 p=0104 t=165) peak heart rate (144plusmn20 vs140plusmn21 p=05 t=068) RPE (156plusmn 17 vs145plusmn2 p=096 t=minus046)

There were no differences in BMI (271plusmn7 vs 374plusmn69 p=092 t minus0106) Max Vo2mlminus1minminus1kgminus1 (191plusmn 73 vs 179plusmn 57 p=06 t=0527) and RPE (156plusmn18 vs 158plusmn17p=069 t=minus04) between white (n=32) and black males (n=14) White males exercisedlonger (max minutes 97plusmn42 vs 71plusmn32 p=0039 t=212) Among females white females



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(n=23) had significantly lower BMI (338plusmn 98 vs 377plusmn64 p= 0049 t=minus2) than blackfemales (n=48) and significantly higher Max Vo2 mlminus1minminus1kgminus1 (153plusmn55 vs 126plusmn 39p=0017 t 245) There was no difference in maximum minutes spent exercising (78plusmn31vs 65plusmn26 p=01 t=165) or RPE (144plusmn23 vs 145plusmn19 p=096 t=minus046)

TolerabilityTermination reason was muscular soreness (n=52 445) shortness of breath (n=10 85) physical fatigue n=32 273 dry mouth (n=3 26 ) medical (n=1 08) and other(n=21 18) Nineteen subjects developed ECG changes during the GXT (162 ) elevenof which (94 ) showed ST-wave changes (10 nonspecific 1 terminated) and ten of whichshowed rhythm abnormalities (ie extrasystoles PVCs) No subject had to be terminated dueto GXT-induced rhythm abnormalities but one subject presented to the GXT lab with apreviously undetected baseline sinus arrhythmia and had to be referred to emergency careafter ECG leads were placed and before the protocol was started

ConclusionsThe graded exercise test considered the lsquogold standardlsquo for examination of cardiorespiratoryfitness was generally well received and tolerated by those who elected to participate andtheir adherence to the rather demanding protocol was good Among the study participantsall of whom were suffering from schizophrenia of various illness durations cardiovascularfitness was exceedingly poor All but two participants met ACLS criteria for lsquolowfitnesslsquo levels referring to the lowest quintile of age and sex adjusted fitness levelsaccording to a standardized US population sample Looking more closely there was a highlysignificant difference in Vo2max ndash hallmark of cardiorespiratory fitness ndash between subjectsand population comparisons Even more worrisome yet the lack of cardiorespiratory fitnessamong participants was not confined to older age groups but was present in the youngestage group as well These findings are consistent with those of a handful of recent studies thathave investigated fitness levels in early psychosis patients reporting poor cardiorespiratoryfitness and little habitual physical activity (Koivukangas et al 2010) and amonghospitalized patients with schizophrenia showing low physical activity and fitness levels(Chamove et al 1986)

High rates of subjectively perceived exertion (RPE) together with a Respiratory Quotientthat indicates the participants had on average reached the anaerobic threshold (Wassermanet al 1973) during the GXT ie had exceeded their sustainable exercise performancecapabilities indicate that most participants exerted themselves up to close to theirphysiological limitations In the subset of participants who gave no physical terminationreasons (18) motivational and self-efficacy issues may have imparted limitations on theirexercise capacity that is they may have been able to continue longer with the GXT beforeterminating Overall however because the average cardiovascular fitness among participantsis so low functional capacity ie the physical lsquofunctional reservelsquo is reached quickly andindicates a state of marked physical deconditioning mostly observed in chronic medical- asopposed to psychiatric illness (Fleg et al 2000)

The subjects in this study were all overweight or obese and questions may arise as towhether obesity itself explains the lowered fitness of the schizophrenia subjects In generaloverweight and obese subjects may not have an impaired Vo2max (Leger 1996) Thelimiting factor in aerobic activities of the obese individual is not usually thecardiorespiratory system but rather a limitation in their sub-maximal aerobic capacity asindicated by higher sub-maximal heart and respiratory exchange rates and a shorter time toexhaustion (Goran et al 2000) Stated differently maximal oxygen consumption of fat free



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tissue (predominantly muscle) is mostly independent of body fat mass Thus we suspect thatobesity by itself does not explain the poor physical fitness of our subjects

Health implications are profound Low cardiorespiratory fitness predicts an 8 to 9 foldincreased risk of cardiovascular death over a follow-up period of 82 years (Blair et al1989) Physical activity is inversely correlated with morbidity and mortality from severalchronic diseases including CVD (Harrington et al 2009) Strong evidence supports thatincreased cardiorespiratory fitness improves several parameters of physical health includingbody weight- and composition (Rippe et al 1998) glucose control (Boule et al 2001) bloodpressure (Kokkinos et al 2009) and lipid profile (Kelley et al 2005) These associations ofsedentary habits to health risk are independent of confounding by other well-established riskfactors such as smoking diet or socioeconomic status (Blair et al 1989)

At least two important conclusions can be drawn relevant for obese patients withschizophrenia 1) Low cardiorespiratory fitness is an eminently modifiable risk factor as itclosely correlates with habitual physical activity Because maximal aerobic capacity (ieVo2max) at any given time is inversely related to the initial level of fitness (Astrand 1976)a previously sedentary person may experience a highly relevant - as much as a 25 -increase in VO2 max after as little as 8 weeks of structured training (Wilmore et al 2001)that is receive substantial health benefits from only a short period of physical exercise Datafrom the ACLS indicate that moderately fit men and women have approximately half therisk (eg 50 lower) of all-cause mortality compared with their low fit counterpartsBecause the level of cardiorespiratory fitness may be extremely low in patients withschizophrenia amounting to a state of deconditioning and a very low capacity for sustainedphysical activity that is high in intensity activities promoting low- to moderate activitylevels may serve the population well and lead to highly relevant improvements in healthprospects

2) On a more fundamental level cardiorespiratory fitness translates directly into the abilityto engage in aerobic ie oxygen-using work and as such is a requirement for all activitiesof daily living (Levinger et al 2009 Fleg et al 2000) Cardiorespiratory fitness in thiscontext becomes an important predeterminant for health-related quality of life andincreases in cardiorespiratory fitness commensurately increase functional capacity (Fleg etal 2000) In addition several studies point to a relationship of physical activity and mentalhealth that is they have shown how physical activity improves mental health status in avariety of domains including depression anxiety and overall mental well-being (Moses etal 1989 Babyak et al 2000 Mather et al 2002 Dogan et al 2004 Schmitz et al 2004)Regular physical exercise to improve cardiorespiratory fitness practiced by patients withschizophrenia can be a useful non-pharmacological application to improve their mentalstates quality of life and functional capacity (Faulkner and Biddle 1999 Speck 2002) Ahandful of small studies confirm positive outcomes in these domains most notably in thephysical fitness of residents (Fogarty and Happel 2005) overall however physical exerciseprescription remains a neglected intervention in schizophrenia

There are several limitations of this study The subjects were all overweight or obese withthe mean BMI for the group in the moderate to severe range This was not a random sampledrawn from the population nor a random sample from a defined clinic population but asubset of individuals who had initially volunteered to take part in a weight loss studyAccordingly caution is recommended in generalizing the results to all or most persons withschizophrenia The results are most likely to be applicable to obese individuals withschizophrenia which does however represent a large proportion of people suffering fromthis disorder Unfortunately neither NHANES nor ACLS provide BMI stratified exercisedata limiting our ability to draw conclusions from our own data which is derived from



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overweight and obese patients On the other hand most of the exercise capacityphysicalfitness literature available reports Max Vo2 mlminus1minminus1kgminus1 that is uses Vo2Max datarelative to body weight This is an accepted method when analyzing and reporting exercisecomparisons between exercise performance of normal weight- and obese subjects (Goran etal 2000)

AcknowledgmentsFunding for this study was provided by NIMH R01 MH66068 (PI Ganguli) 5M01RR00056 (General ClinicalResearch Center) and 1P30DK46204 (Obesity and Nutrition Research Center) at the University of PittsburghMedical Center We appreciate the skill of the staff at the General Clinical Research and Obesity and NutritionResearch centers for their expert technical and analytical support The authors wish to acknowledge the valuableinput of Dr David A Kelley MD and Dr Bret Goodpaster PhD with design and implementation of the exercisetests We also thank the staff of the Following programs at Western Psychiatric Institute and Clinic University ofPittsburgh Medical Center for their assistance with recruitment Services and Research for Recovery in SeriousMental Illness and the Schizophrenia Treatment and Research Center

Role of funding source

Funding for this study was provided by NIMH grant R01 MH66068 (PI Ganguli) as well as by NIH grants5M01RR00056 (General Clinical Research Center) and 1P30DK46204 (Obesity and Nutrition Research Center) atthe University of Pittsburgh (PI David Kelley) The funding agencies had no further role in study design in thecollection analysis and interpretation of data in the writing of the report and in the decision to submit the paperfor publication

LiteratureAcil AA Dogan S Dogan O The effects of physical exercises to mental state and quality of life in

patients with schizophrenia J Psychiatr Ment Health Nurs 200815(10)808ndash815 [PubMed19012672]

American College of Sports Medicine American College of Sports Medicine Guidelines of ExerciseTesting and Prescription 7 Baltimore Williams amp Wilkins 2005 p 93-114

Astrand PO Quantification of exercise capability and evaluation of physical capacity in man ProgCardiovasc Dis 197619(1)51ndash67 [PubMed 785542]

Blair SN Kohl HW III Paffenbarger RS et al Physical fitness and all-cause mortality A prospectivestudy of healthy men and women JAMA 1989262(17)2395ndash2401 [PubMed 2795824]

Blair SN Kampert JB Kohl HW III et al Influences of cardiorespiratory fitness and other precursorson cardiovascular disease and all-cause mortality in men and women JAMA 1996276(3)205ndash210[PubMed 8667564]

Borg GA Perceived exertion Exerc Sport Sci Rev 19742131ndash151 [PubMed 4466663]Bouchard C Blair SN Haskell W Physical Activity and Health 1 Human Kinetics 2006 Sep 13

p 1512006Bouleacute NG Haddad E Kenny GP et al Effects of exercise on glycemic control and body mass in type

2 diabetes mellitus a meta-analysis of controlled clinical trials JAMA 2001286(10)1218ndash1227[PubMed 11559268]

Callaghan P Exercise a neglected intervention in mental health care J Psychiatr Ment Health Nurs200411(4)476ndash83 [PubMed 15255923]

Centers for Disease Control and Prevention Prevalence of physical activity including lifestyleactivites among adults United States 2000ndash2001 MMWR 200352764ndash769 [PubMed12917582]

Chamove AS Positive short-term effects of activity on behaviour in chronic schizophrenic patients BrJ Clin Psychol 198625(2)125ndash132 [PubMed 3730648]

Duncan GE Li SM Zhou XH Cardiovascular fitness among US adults NHANES 1999ndash2000 and2001ndash2002 Med Sci Sports Exerc 200537(8)1324ndash1328 [PubMed 16118579]



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Elekund LG Haskell WL Johnson JL et al Physical fitness as a predictor of cardiovascular mortalityin asymptomatic North American men The Lipid Research Clinics Mortality Follow-up Study NEngl J Med 1988319(21)1379ndash1384 [PubMed 3185648]

Faulkner G Biddle S Exercise as an adjunct treatment for schizophrenia a review of the literature JMental Health 19998441ndash457

Fleg JL Pina IL Balady GJ et al Assessment of Functional Capacity in Clinical and ResearchApplications Circulation 20001021591ndash1597 [PubMed 11004153]

Fogarty M Happell B Pinikahana J The benefits of an exercise program for people withschizophrenia a pilot study Psychiatr Rehabil J 200428(2)173ndash176 [PubMed 15605754]

Fogarty M Happell B Exploring the benefits of an exercise program for people with schizophrenia aqualitative study Issues Ment Health Nurs 200526(3)341ndash351 [PubMed 16020051]

Gibbons RJ Balady GJ Bricker JT et al ACCAHA 2002 Guidelines Update for Exercise TestingSummary Article A report of the American College of CardiologyAmerican heart AssociationTask Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines)Circulation 20021061883ndash1892 [PubMed 12356646]

Goran M Fields DA Hunter GR Herd SL Weinsier RL Total body fat does not influence maximalaerobic capacity Int J Obes 200024841ndash848

Harrington M Gibson S Cottrell RC A review and meta-analysis of the effect of weight loss on all-cause mortality risk Nutr Res Rev 200922(1)93ndash108 [PubMed 19555520]

Kampert JB Blair SN Barlow et al Physical activity physical fitness and all-cause cancer mortalitya prospective study of men and women Ann Epidemiol 19966(5)452ndash457 [PubMed 8915477]

Kay SR Fiszbein A Opler LA The positive and negative syndrome scale (PANSS)for schizophreniaSchizophr Bull 198713(2)261ndash76 [PubMed 3616518]

Kelley GA Kelley KS Vu Tran Z Aerobic exercise lipids and lipoproteins in overweight and obeseadults a meta-analysis of randomized controlled trials Int J Obesity 200529(8)881ndash893

Koivukangas J Tammelin T Kaakinen M et al Physical activity and fitness in adolescents at risk forpsychosis within the Northern Finland 1986 Birth Cohort Schizophr Res 2010116152ndash158[PubMed 19942409]

Kokkinos P Manolis A Pittaras A et al Exercise Capacity and Mortality in Hypertensive Men withand Without additional Risk Factors Hypertension 200953494ndash499 [PubMed 19171789]

Leger L Aerobic performance In Docherty D editor Measurement in pediatric exercise scienceVol 16 Human Kinetics Champaign 1996 p 183-223

Levinger C Goodman D Hare G et al Functional capacity and quality of life in middle-age men andwomen with high and low number of metabolic risk factors Int J Cardiol 2009133(2)281ndash283[PubMed 18190990]

Lindenmayer JP Khan A Wance D et al Outcome Evaluation of a Structured Educational WellnessProgram in Patients With Severe Mental Illness J Clin Psychiatry 200970(10)1385ndash1396[PubMed 19778494]

Mahler DA Froelicher VF Miller NH et al ACSMlsquos Guidelines for Exercise Testing andPrescription 5 Media PA Williams amp Wilkins 1995 p 113-118

Menza M Vreeland B Minsky S et al Managing Atypical Antipsychotic-Associated Weight Gain12-Month Data on a Multimodal Weight Control Program J Clin Psychiatry 200465471ndash477[PubMed 15119908]

Myers J Buchanan N Walsh D et al Comparison of the ramp versus standard exercise protocols JAm Coll Cardiol 1991171334ndash1342 [PubMed 2016451]

Newcomer JW Metabolic risk during antipsychotic treatment Clin Ther 200526(12)1936ndash1946[PubMed 15823759]

Rippe JM Hess S The role of physical activity in the prevention and management of obesity J AmDiet Assoc 199898(10 Suppl 2)S31ndash38 [PubMed 9787734]

Sanders LF Duncan GE Population-based reference standards for cardiovascular fitness among USadults NHANES 1999ndash2000 and 2001ndash2002 Med Sci Sports Exerc 200638(4)701ndash707[PubMed 16679986]



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US Department of Health and Human Services Physical Activity and Health A Report of the SurgeonGeneral Atlanta GA National Center for Chronic Disease Prevention and Health PromotionCenters for Disease Control and Prevention US Department of Health and Human Services 1996

Vancampfort D Knapen J Probst M et al Considering a frame of reference for physiclal activityresearch related to the cardiometabolic risk profile in schizophrenia Psychiatr Res 2010177271ndash279

Wang CY Haskell WL Farrell SW et al Cardiorespiratory fitness levels among US adults 20ndash49years of age findings from the 1999ndash2004 National Health and Nutrition Examination SurveyAm J Epidemiol 2010171(4)426ndash435 [PubMed 20080809]

Wasserman K Whipp BJ Koyal SN et al Anaerobic threshold and respiratory gas exchange duringexercise J Appl Physiol 197335(2)236ndash243 [PubMed 4723033]

Wilmore JH Green JS Stanforth PR et al Relationship of changes in maximal and submaximalaerobic fitness to changes in cardiovascular disease and non-insulin-dependent diabetes mellitusrisk factors with endurance training the HERITAGE Family Study Metabolism 200150(11)1255ndash1263 [PubMed 11699041]

Strassnig et al 0


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Table 1

Population Distribution Cardiorespiratory Fitness

Cardiovascular Fitness Level Population Males Population Females

(age) 20ndash39

Low lt108 lt86

Moderate 109ndash133 87ndash108

High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72

Moderate 90ndash113+ 73ndash89

High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81

Maximal MET cutoff points for low moderate and high cardiovascular fitness adapted from the Aerobics Center Longitudinal Study (2002)

+One male study participant each in the 40ndash49 year group (n=1) and 50ndash59 year group (n=1) respectively reached moderate levels of fitness

respectively all other participants (n=115) male and female age-adjusted only reached low levels of fitness


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Table 2

Study Participants Cardiorespiratory Fitness

Schizophrenia Healthy Controls

Males Females Males Females

(age) 20ndash29 20ndash29

n=5 n=7 n=675 n=576

BMI 441 plusmn3 9 395 plusmn95

Vo2 mlminus1minminus1kgminus1 185 plusmn59 149plusmn43 445 plusmn04plt00001t=959

365 plusmn04plt00001t=837

Minute Ventilation (VE) 623 plusmn26 44 plusmn17

Watt 150 plusmn66 107plusmn31

Minutes 12 plusmn42 86 plusmn3

MET 53 plusmn17 42 plusmn12

PredMaxHR 824plusmn 11 80 plusmn10

PredMaxVo2+ 65 plusmn81 445 plusmn45

30ndash39 30ndash39

n=10 n=14 n=574 n=542

BMI 42 plusmn78 389plusmn 86

Vo2 mlminus1minminus1kgminus1 223 plusmn62 156 plusmn52 428 plusmn05plt00001t=636


VE 64 plusmn13 476 plusmn108

Watt 138 plusmn32 96 plusmn35


MaxMet 64 plusmn18 45 plusmn15

PredMaxHR 87 plusmn14 78 plusmn8

PredMaxVo2 665 plusmn18 69 plusmn216

40ndash49 40ndash49

n=19 n=29 n=458 n=425

BMI 376 plusmn6 358 plusmn53









50ndash59 50ndash59

n=21 n=23

BMI 338 plusmn43 34 plusmn8 9

Vo2 mlminus1minminus1kgminus1 171 plusmn65 12 plusmn37



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n=5 n=7 n=675 n=576






PredMaxHR = Percentage of expected maximal heart rate

+PredMaxVo2 = Percentage of expected maximal Vo2 mlminus1minminus1kgminus1

NHANES population GXT data available until age 49 (Duncan et al 2006)


mlminus1minminus1kgminus1 Peak heart rate and duration of exercise were not correlated with PANSS scoresCompared to healthy controls derived from the ACLS and NHANES respectively 115participants achieved lsquolow levelslsquo of fitness only as well as highly significantly reduced MaxVo2across all age-groups

ConclusionmdashThe test was generally well received and tolerated by those who elected toparticipate and adherence to the protocol was good Among participants with schizophrenia mostof whom were obese and across all age groups cardiorespiratory fitness was exceedingly poorOnly two participants in our entire sample fit the categorization of lsquomoderate fitness levellsquo that isa fitness level at or above the 20thp ercentile of ACLS-derived population comparisonsConversely this left 983 of participants with schizophrenia below population standards Lowcardiorespiratory fitness emerges as an eminent modifiable risk factor for CVD mortality andmorbidity in schizophrenia complicated by obesity

Keywordsschizophrenia obesity fitness cardiovascular disease cardiorespiratory fitness

IntroductionHigh rates of cardiovascular disease (CVD) have been observed in the schizophreniapopulation translating into a life expectancy that is reduced by as much as 20ndash25 incomparison with mentally healthy controls (Hennekens 2007) The reasons are complex andinclude unhealthy lifestyles poor diet little exercise and cigarette smoking (Brown et al1999 Strassnig et al 2005) in addition to treatment with antipsychotic medication whichcan add deleterious metabolic consequences by themselves (Newcomer 2005)

This has lead to the untenable situation that despite improved outcomes with respect topsychiatric symptoms social functioning and quality of life the mortality gap for patientshas not narrowed but may actually be worsening (Saha Chant amp McGrath 2007) Atherapeutically unsustainable situation it coincides with a relative lack of research intolifestyle-related adverse sequelae that would in all likelihood identify causative mechanismsand risk factors that could represent targets of intervention to mitigate close or even reversethat gap (Koivukangas et al 2010)

One lifestyle factor low cardiorespiratory fitness has been recognized as prominentbehavioral risk factor for cardiovascular disease (CVD) morbidity and an independent riskfactor for all-cause mortality in adults (Blair et al 1989 Kampert et al 1996) Highercardiorespiratory fitness decreases overall mortality rates and morbidity and mortality dueto CVD in a dose-response fashion (CDC 1996) These associations are quite robust andhave been demonstrated to be largely independent from other major risk factors (Ekelund etal 1988 Blair et al 1989 Blair et al 1996) Together with anecdotal observations ofsedentary behavior and lack of exercise in schizophrenia patients that may far exceedpopulation standards (Faulkner et al 2006 Lindamer et al 2008 Sharpe et al 2006)cardiorespiratory fitness in schizophrenia emerges as major modifiable risk factor for CVDand overall morbidity- and mortality (Vancampfort et al 2010)

At the same time the literature regarding cardiorespiratory fitness in schizophrenia remainsinsufficient No studies have systematically assessed cardiorespiratory fitness in patientstreated for schizophrenia facing known deleterious lifestyles and chronic treatment withantipsychotic medication Moreover to our knowledge neither the response to structuredphysical exercise nor its tolerability has been systematically examined in patients withschizophrenia This would aid in the development of targeted interventions to improvecardiorespiratory fitness and physical health in patients with schizophrenia and identify

Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





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NIH






n=5 n=7 n=675 n=576
















Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


NIH


NIH



Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


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n=5 n=7 n=675 n=576

















Strassnig et al


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NIH


NIH


NIH



Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


NIH


NIH



Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


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NIH






n=5 n=7 n=675 n=576



















Strassnig et al


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NIH



Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


NIH


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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





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n=5 n=7 n=675 n=576















Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


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n=5 n=7 n=675 n=576















Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


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n=5 n=7 n=675 n=576



























Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


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NIH






n=5 n=7 n=675 n=576
































Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





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n=5 n=7 n=675 n=576















Strassnig et al


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Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


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Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


NIH


NIH






n=5 n=7 n=675 n=576










NIH


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NIH


Strassnig et al

Table 1



(age) 20ndash39

Low lt108 lt86


High gt133 gt108

40ndash49

Low lt99 lt81


High gt124 gt99

50ndash59

Low lt89 lt72


High gt113 gt89

60+

Low lt81 lt63


High gt103 gt81





NIH


NIH


NIH



Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


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n=5 n=7 n=675 n=576










NIH


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NIH


Strassnig et al

Table 2





n=5 n=7 n=675 n=576










30ndash39 30ndash39

n=10 n=14 n=574 n=542










40ndash49 40ndash49

n=19 n=29 n=458 n=425










50ndash59 50ndash59

n=21 n=23





NIH


NIH


NIH






n=5 n=7 n=675 n=576










NIH


NIH


NIH


Strassnig et al




n=5 n=7 n=675 n=576










low cardiorespiratory fitness and physical functional capacity in obese patients with schizophrenia

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