EDITORIAL doi: 10.1111/j.1559-4572.2008.00049.x

When the Heart and the Mind Collide: Cardiovascular RiskFactors and Antipsychotic Use in the Schizophrenic Population

From Thorazine to Abilify:The Role of Pharmacotherapyin the Treatment ofSchizophreniaFor millions of people, 1954 was theyear voices stopped. It was during thisyear that the pharmaceutical companySmith Kline & French (known today asGlaxoSmithKline) began US distribu-tion of the first antipsychotic, chlor-promazine, better known by its tradename, Thorazine. For many, chlor-promazine was a wonder drug—a quickfix for the debilitating and frighteningsymptoms of schizophrenia. Indeed,more than 100 million patients weretreated with chlorpromazine and otherdrugs in the phenothiazine class beforethese drugs fell out of favor due to theirpronounced adverse effects. Theseadverse effects, often referred to asextrapyramidal symptoms (EPSs),included movement abnormalities,ranging from mild tremor to severeinvoluntary facial grimacing and eyerolling, and tardive dyskinesia. Chlor-promazine and other similar drugs thatplayed on the subtleties of the dopami-nergic system, are now known as first-generation, or typical, antipsychotics.This nomenclature came into use in thedecades that followed with the intro-duction of novel antipsychotic drugs,known as atypicals, that tinkered notonly with dopamine but with its sisterneurotransmitter, serotonin, in whatseemed to be a successful effort toavoid the untoward effects of the earlierdrugs. Clozapine, the first of these atyp-ical or second-generation antipsychotics(SGAs), was used in Europe as early asthe mid 1970s. While it was initiallywelcomed as an alternative to the EPS-inducing typicals, reports of fatal agran-ulocytosis associated with its use quicklydampened this initial excitement. Ulti-mately, clozapine was approved in theUnited States, but not until 1989 andwith the US Food and Drug Adminis-

tration’s (FDA’s) stipulation that it beused only to treat ‘‘refractory schizo-phrenia’’ (for which it had been shownto be particularly efficacious).

Clozapine aside, the true heyday ofthe atypicals began in the mid 1990swith the introduction of olanzapine.Olanzapine and other atypical anti-psychotics like quetiapine, aripiprazole,risperidone, and ziprasidone, now inwidespread use, have transformedthe pharmacotherapy of schizophrenicpatients. But at what cost? In recentyears, this question has received a lot ofattention. Both in the lay press and inthe medical literature, one theme hasemerged as dominant: The patient pop-ulation using these drugs has beenshown to have abnormally high rates ofobesity, diabetes, dyslipidemia, andcardiovascular disease (CVD).

Antipsychotic-Induced WeightGain and CVDEven a cursory glance through the med-ical literature reveals a growing body ofevidence supporting the idea that anti-psychotic medication leads to a host ofmedical complications. Weight gain,and the tendency toward obesity, is per-haps the most well-known side effect ofantipsychotic use. In 1999, Allison andcolleagues1 published a meta-analysis ofmore than 80 articles on the treatmentof schizophrenia highlighting the asso-ciation between atypical antipsychotics

and weight gain. According to theresults of the analysis, among the SGAsit was reported that clozapine resultedin the greatest degree of weight gain,and a newer drug, ziprasidone, was asso-ciated with the least weight gain(Table). Subsequent studies, in particu-lar, the findings reported by Marderand coworkers2 in 2004, supportedthese findings and highlighted the dif-ferences among the various drugs withregard to their weight gain liability.

Weight gain is not an issue that canbe ignored. Obesity, the epidemicof the ‘‘can-you-supersize-those-fries-please’’ generation, has been repeatedlyshown to result in significant increasesin morbidity and mortality, in particu-lar, with regard to CVD.3 Alarming sta-tistics include the oft-quoted 100%increase in mortality assigned to obeseindividuals as compared to their thinnercounterparts. While the details regard-ing the pathophysiologic link betweenobesity and CVD are continually beingmodified based on new studies, the cur-rent understanding is that obesityaffects a cascade of metabolic derange-ments that culminates in CVD. Specifi-cally, researchers have posited thatadipose tissue releases certain factorsthat serve to adversely affect glucose andlipid regulation, most likely viaderangements produced in the insulinpathway (Figure).4 What results is anobese individual who now also has

Sari Halpert, MD; Samy I. McFarlane, MD, MPH

From the Division of Endocrinology, Department of Medicine, SUNY-Downstate and

Kings County Hospital Center, Brooklyn, NY

Address for correspondence:

Samy I. McFarlane, MD, MPH, Division of Endocrinology, Medical Director of Clinical

Research, College of Medicine, SUNY-Downstate and Kings County Hospital Center,

450 Clarkson Avenue, Box 50, Brooklyn, NY 11203

E-mail: smcfarlane@downstate.edu

cardiovascular risk factors and antipsychotic use JCMS winter 2009 1

diabetes, dyslipidemia, and hyperten-sion—all of which are independent riskfactors for CVD! 4 To add insult toinjury, individuals with schizophreniaseem to have a propensity to store thisadditional weight in a central distribu-tion,5 saddling them with the additionalhandicap of visceral adiposity, which isassociated with a greater CVD risk thanother distributions of weight.4

It is no surprise, therefore, thatalongside the literature on antipsy-chotic use and weight gain are numer-ous articles implicating these drugs inthe emergence of insulin resistance,overt diabetes, and dyslipidemia. 6–8 Astudy published in 2004 examininglipid parameters in a group of 606 in-patients treated with antipsychotics

identified approximately 67% as meet-ing criteria for dyslipidemia.9 Withregard to diabetes, one study, drawingon an impressively large health caredatabase of 2.5 million people, founda significantly greater risk of diabetesdeveloping after 12 months of treat-ment with clozapine or olanzapine.This diabetogenic effect was not seenwith risperidone.10 That clozapine andolanzapine are the worst offendersseems to be a trend in the literature, asidentified in an excellent review byNewcomer.11 Indeed, as Newcomerstates, clozapine and olanzapine arethe 2 SGAs most commonly associatedwith diabetes; the data regarding ris-peridone, ziprasidone, and aripiprazoleare less convincing.

Given the increased incidence ofthe above-mentioned cardiometabolicderangements, it is quite expected thatwe find a high rate of the cardiometa-bolic syndrome in this population. Thecardiometabolic syndrome is a termthat was originally coined to describethe presence of a constellation of CVDfactors within one individual includingabdominal obesity, abnormal lipidlevels, hypertension, impaired fastingglucose concentrations, and a pro-thrombotic tendency.12 This syndromehas been identified as increasing the riskof congestive heart failure and stroke by3-fold.13 According to the recent land-mark Clinical Antipsychotic Trials ofIntervention Effectiveness (CATIE)study, 36.6% of male schizophrenicpatients and 54.2% of female schizo-phrenic patients met criteria for themetabolic syndrome. Compared with asample of matched controls, this placesmale schizophrenic patients at an 85%greater risk and female schizophrenicsat a 137% greater risk for the cardio-metabolic syndrome.14

While the literature seems at firstglance to be quite incriminating, severalimportant issues must be kept in mind.First, is schizophrenia itself an indepen-dent risk factor for metabolic abnormal-ities and hence CVD? Put another way,what role does genetics play in thisequation? Granted, this population ismore obese and has a greater prevalenceof diabetes, but to what degree can anti-psychotic use be deemed the primaryculprit? Indeed, long before the adventof SGAs, there were whispers in themedical community about an associa-tion between metabolic disturbancesand mental illness.15 In addition, litera-ture exists documenting an increasedincidence of diabetes in first-degreefamily members of schizophrenicpatients, suggesting that genetic factorsmay play a greater role in this equationthan previously thought.16 The issuebecomes even more complicated whenone considers recent studies demon-strating metabolic derangements inantipsychotic-naive patients. Moreover,schizophrenia itself may act as indepen-dent risk factor not only in terms ofgenetic predisposition but also with

Table. Effect of Antipsychotic Medications on Body Weight After 10 Weeksof Administration

Medication

Mean Weight

Change (kg)

95% Confidence

Interval

Placebo )0.74 )1.6 to 0.12

Nonpharmacologic control 1.33 0.84 to 1.82Conventional agents

Molindone )0.39 )2.4 to 1.65Fluphenazine 0.43 )0.65 to 1.51

Haloperidol 1.08 0.35 to 4.25Chlorpromazine 2.58 0.91 to 4.25Thoridazine 3.19 1.39 to 4.99

Novel agentsZiprasidone 0.04 )0.49 to 0.57Risperidone 2.1 1.69 to 2.51

Sertindole 2.92 1.76 to 4.08Olanzapine 4.15 3.82 to 5.88Clozapine 4.45 3.02 to 5.88

aBased on data from Allison et al, 1999.1

Figure. Potential mechanisms of hyperglycemia with antipshychotic drugs. Interference of glucosetransporters in the insulin signaling pathway.

cardiovascular risk factors and antipsychotic use JCMS winter 20092

regard to lifestyle choices. This popula-tion has been found to have increasedrates of smoking, poor diet, lack ofexercise, and subpar medical care, all ofwhich put them at greater risk forobesity, diabetes, and CVD. It is likely,therefore, that the observed meta-bolic abnormalities are the result ofsome complex, ill-defined interactionamong genetic vulnerability, lifestylefactors, and the actual side effects ofthese drugs.

Another issue to keep in mind whenassessing the validity of the associationbetween SGAs and CVD risk factors isthe strength of the evidence presentedin these studies. In particular, it is rele-vant that few to none of the studies suc-cessfully controlled for body weight,diet, level of physical activity, race, thepresence of diabetogenic medications,and other potentially confounding vari-ables. In addition, while there is admit-tedly a wealth of literature on this topic,the majority of the studies cited areeither case studies or retrospectiveanalyses; prospective studies are nearlyabsent from the literature.

Finally, it is important to realize thateven if one accepts the notion that SGAsmay cause diabetes and other CVD riskfactors, there remain many unansweredquestions regarding the mechanismresponsible for this observation. Forexample, as olanzapine has been associ-ated with both weight gain and diabe-tes, there is an inclination to attributeits diabetogenic effect to its weight gainliability, as the 2 conditions havebeen independently demonstrated to belinked. Such neat answers, however,may prove to be inadequate in the faceof advancing research. Several articles,for example, have pointed out the exis-tence of a significant minority ofpatients receiving antipsychotics inwhom diabetes developed in theabsence of weight gain, suggesting thatthese medications may have a heretoforeunrecognized direct effect on insulinregulation.17 Hypotheses abound as tothe mechanism underlying this effect.In a recently published article, forexample, researchers using a rat modeldemonstrated that clozapine andolanzapine, but not risperidone, results

in acute insulin resistance prior to anymeasurable effects on body weight orcomposition.18

FutureResearchOpportunities:Unanswered QuestionsAs is quite evident from the discussionabove, the issues surrounding antipsy-chotic use, metabolic derangements,and CVD risk are complex and call forfurther investigations to address severalunanswered questions. Among these arethe following:

Race. For the US clinician, the dearthof information on the metabolic effectsof antipsychotics as they relate tominorities is astounding. The majorityof the studies cited above were con-ducted in European settings where thestudy population was nearly alwaysupward of 98% Caucasian. What doesthat say for the clinician practicing inurban centers like New York City,where minorities represent a significantproportion of the population? Further-more, when one considers that minori-ties have a baseline risk for diabetes andCVD that is significantly higher than inthe Caucasian population and that theygenerally have CVD risk factors that aremore difficult to control,19 it becomesclear that it is on this group in particularthat researchers and clinicians should befocusing their attention.

Children and Adolescents. The recentUS FDA approval of risperidone use inchildren with schizophrenia and bipolardisorder raises several questions aboutthe metabolic consequences of thesedrugs in this vulnerable population.Can our children afford the weight lia-bility posed by these medications? Thenumbers suggest not. US children(aged 6–11) and adolescents and youngadults (aged 12–19) have been growingin more ways than one: The prevalenceof overweight (body mass index >95thpercentile) in children jumped from 4%in 1965 to 13% in 1999, and in adoles-cents the numbers rose from 5% in1970 to 14% in 1999. While there areas of yet no controlled studies of treat-ment-induced metabolic changes inchildren, the data that are available

suggest that the issue of antipsychotic-induced weight gain may be evenmore pronounced among childrenthan in adults.20 This is an area thatrequires further investigation, as it raisestremendous concerns regarding theconsequences of such treatments andthe development of the best preven-tion strategies.

Polypharmacy. In recent years, therehas been a noticeable shift away fromthe ‘‘1-pill panacea’’ treatment modelamong clinicians treating psychotic ill-ness. Instead, we find an increasingnumber of patients receiving more thanone antipsychotic; polypharmacy hasbecome the only tenable option forcertain patients. In light of this trend, itis obvious that future studies must takeinto account the potential effects ofpolypharmacy with regard to metabolicrisk and CVD. Few if any studies haveaccounted for this trend, and it hasobvious implications for decision mak-ing within the treatment construct.

Future Directions: NovelTherapeutic ModalitiesPharmacotherapy. With the advent ofnovel drugs to treat psychosis, clinicianscan expect to decide on efficacy vs safetywith increasing frequency. Consider,for example, bifeprunox, a new drugthat is in the process of US FDAapproval. What has been demonstratedso far, and what is indeed the focus ofan advertising campaign, is that thedrug has a potentially more favorablemetabolic profile compared with itscompetitors.21 What is less certain,however, is how this newer drug mea-sures up with regard to efficacy. For theclinician treating the psychotic patient,this brings to the fore the common butuncomfortable decision regarding themerits of possibly compromising effi-cacy for what may or may not be a bettersafety profile.

Behavioral Modification. In additionto optimizing pharmacotherapy, clini-cians should consider placing more ofan emphasis on the more establishedCVD risk factors that are so prevalentin the schizophrenic population, such as

cardiovascular risk factors and antipsychotic use JCMS winter 2009 3

smoking, sedentary lifestyle, and poordiet. While effecting such change is notwithout its own challenges, there isaccumulating evidence that such inter-ventions may be successful. For exam-ple, a recent study involving a cohort ofschizophrenic patients in Santander,Spain, demonstrated that early behav-ioral intervention, a technique aimed atnutritional, exercise, and behavioralmodification at the start of antipsy-chotic therapy, was successful in attenu-ating the weight gain associated withthese medications.22

Finally, as information evolvesfrom ongoing studies, various scien-tific communities periodically updatetheir guidelines and monitoringrecommendations regarding antipsy-chotic use and cardiometabolic risk.The American Diabetes Association,the American Psychiatric Association,and other groups issued a set ofguidelines regarding the monitoringof patients using antipsychotic medi-cations that included specific recom-mendations regarding glucose, lipid,and other metabolic parameters.23

However, there is little evidence that

these guidelines have been translatedinto clinical practice. In fact, arecent study of psychiatrists indicatedthat only 1 out of every 2 psychia-trists is aware of the increased riskof diabetes associated with antipsy-chotic use, and worse, the percentageof psychiatrists identifying the meta-bolic syndrome as a cause for con-cern in this population was adisgraceful 3%.24 Physician educa-tion, therefore, remains an issue thatmust be properly addressed beforethere can be any true hope of effec-tively treating the cardiometaboliccomplications of antipsychotic use.

In addition, the psychiatrist mustbe kept up to date on the emergingtreatment options for these patients.Recent data, for example, demonstratea possible benefit of the use of metfor-min, the popular antidiabetic drug, asa means of offsetting the weight gaininduced by antipsychotic use.25 Met-formin is a drug that for years hasbeen widely prescribed in the generalpopulation to treat diabetes. The drughas been shown to be particularly effi-cacious in diabetics with comorbid

obesity because it decreases insulinresistance and results in weight loss.26

Researchers are now claiming that theweight loss benefit observed in thegeneral population may extend toschizophrenic patients for whom anti-psychotic use has proven to be aweight liability. It is precisely suchemerging data that must be allowed toflow freely between the medical andpsychiatric health care providers inorder to optimize patient care.

ConclusionsAs is the case in most areas of pharma-cotherapy, in the final analysis the phy-sician is charged with reconciling theoften conflicting goals of safety and effi-cacy and deciding on the best option forher or his patient. In the case of antipsy-chotic medications and CVD risk, qui-eting the voices is a commendable goal,but physicians must keep in mind thatCVD remains the most common causeof death among patients with schizo-phrenia. The takeaway point, in sound-bite format, is this: A sound mind is ofno use in a body whose heart has ceasedto beat.

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