Untitled

ONLINE FIRST
Systematic Review of Early Cardiometabolic
Outcomes of the First Treated Episode of Psychosis
Debra L. Foley, PhD; Katherine I. Morley, PhD Context: The increased mortality associated with schizo-
scribing 53 independent studies; 25 studies met inclu- phrenia is largely due to cardiovascular disease. Treat- sion criteria and were retained for detailed review.
ment with antipsychotics is associated with weight gainand changes in other cardiovascular risk factors. Early Data Synthesis: Consolidated Standards of Reporting
identification of modifiable cardiovascular risk factors is Trials and Strengthening the Reporting of Observa- a clinical imperative but prospective longitudinal stud- tional Studies in Epidemiology checklists were used to ies of the early cardiometabolic adverse effects of anti- assess the methods and reporting of studies. A qualita- psychotic drug treatment other than weight gain have not tive review of findings was conducted.
been previously reviewed.
Conclusions: Two key hypotheses were identified based
on this review: (1) in general, there is no difference in car-
Objectives: To assess the methods and reporting of car-
diovascular risk assessed by weight or metabolic indices diometabolic outcome studies of the first treated epi- between individuals with an untreated first episode of psy- sode of psychosis, review key findings, and suggest di- chosis and healthy controls and (2) cardiovascular risk in- rections for future research.
creases after first exposure to any antipsychotic drug. Arank order of drugs can be derived but there is no evi- Data Sources: PsycINFO, MEDLINE, and Scopus from
dence of significant class differences. Recommended di- January 1990 to June 2010.
rections for future research include assessing the effect oncardiometabolic outcomes of medication adherence and Study Selection: Subjects were experiencing their first
dosage effects, determining the therapeutic window for an- treated episode of psychosis. Subjects were antipsy- tipsychotic use in adults and youth, and testing for mod- chotic naive or had been exposed to antipsychotics for a eration of outcomes by demographic factors, including sex short known period at the beginning of the study. Car- and age, and clinical and genetic factors.
diometabolic indices were assessed. Studies used a lon-gitudinal design.
Arch Gen Psychiatry.
Published online February 7, 2011. Data Extraction: Sixty-four articles were identified de-
Author Affiliations: Applied
Genetics and Biostatistics,
Orygen Youth Health Research
Centre (Dr Foley), and Centres
agnosis, individuals with and glucose abnormalities.7 The risk for schizophrenia have a mor- cardiovascular disease appears to be in- tality risk that is 3 times creasing among individuals with schizo- that of the general popula- phrenia,1 creating an ever-widening gap be- tion.1 Although risk of suicide is in- tween the life expectancy of the seriously for Youth Mental Health creased 18-fold over 25 years,1 the very low mentally ill and the broader commu- (Dr Foley) and Molecular, base rate for suicide in the wider commu- nity.8 Determining if antipsychotic drugs Environmental, Genetic, and nity means that the major cause of mor- reduce or increase overall mortality asso- Analytic Epidemiology, School tality and morbidity among individuals ciated with schizophrenia or other psy- of Population Health with schizophrenia is actually natural choses is therefore a pressing issue9,10 and (Dr Morley), the University of causes, predominantly cardiovascular dis- the identification of, and intervention di- Melbourne, Parkville, Victoria, ease.1,2 Antipsychotic drugs, such as cloza- rected at, modifiable risk factors for car- Australia; and Wellcome Trust pine, can save lives by reducing the im- diovascular disease among the seriously Sanger Institute, Wellcome pulsiveness and aggression that can lead mentally ill, a clinical imperative.
Trust Genome Campus,Hinxton, Cambridge, England to suicide3,4 but they can also alter risk for Research is needed to understand the (Dr Morley).
cardiovascular disease by causing weight nature and magnitude of the cardiovas- (REPRINTED) ARCH GEN PSYCHIATRY PUBLISHED ONLINE FEBRUARY 7, 2011 2011 American Medical Association. All rights reserved.
Table. Cardiometabolic Indices Assessed by the Studies Reviewed Herein and Their Association With Cardiovascular Outcomes
Risk Factor
Total body weight; 7%/4-kg increase in body Central obesity promotes insulin resistance, dyslipidemia, endothelial weight; BMI; intra-abdominal, subcutaneous, dysfunction and hypertension; outcomes include type 2 diabetes, the and total body fat; waist circumference; waist metabolic syndrome, and cardiovascular disease. Genes encoding to hip ratio; adiponectin level; ghrelin level; bioactive substances such as cytokines (eg, IL-6, visfatin) and protein IL-6/IL-12 level; leptin level; resistin level; hormones (eg, adiponectin and leptin) are all abundantly expressed in visceral fat. IL-6 may exert a direct inflammatory effect on the heartand peripheral circulation. Adiponectin and leptin are inverselyassociated with visceral fat accumulation. Adiponectin hasantidiabetic, antihypertensive, antiatherogenic, and anti-inflammatoryfunctions. Leptin regulates satiety and thereby appetite and weight.
Ghrelin is thought to be an appetite stimulant. Some argue centralobesity is a better discriminator of cardiovascular risk than BMI ortotal body weight; others argue there is no consensus regarding whatis clinically more meaningful.
Blood glucose level C peptide level; fasting, random, postprandial C peptide is made when proinsulin is split into insulin and C peptide and plasma glucose level; fasting insulin level; is used to gauge how much insulin is being produced by the body.
insulin resistance; diabetes Elevated blood glucose level (hyperglycemia) and insulin level(hyperinsulinemia) are associated with the development of insulinresistance, type 2 diabetes, hypertension, the metabolic syndrome,and cardiovascular disease.
Elevated blood pressure is a risk factor for atherosclerosis and VCAM-1 level; E-selectin level; IL-12 level; heart Cell adhesion molecules, including VCAM-1 and the selectins (P, E, and rate; creatine kinase level L), are inflammatory markers found in atherosclerotic plaques andimplicated in the initiation and development of atherosclerosis andtherefore the metabolic syndrome and cardiovascular disease.
Adhesion molecules might add information for clinical risk predictionand as therapeutic targets. Increased heart rate may accompanyincreased inflammation and increases mechanical strain on the heart.
An elevated creatine kinase level can indicate inflammation of the heartmuscle (myocarditis).
Fasting total cholesterol level; fasting LDL Plasma concentrations of total cholesterol, LDL cholesterol, HDL cholesterol level; fasting HDL cholesterol cholesterol, and triglycerides are all risk factors for cardiovascular level; fasting triglyceride level; dietary fat disease and targets for therapeutic intervention.
Stress elevates cortisol levels, which affects glucose metabolism, insulin release, blood pressure, and inflammatory response.
Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; IL, interleukin; LDL, low-density lipoprotein; VCAM-1, vascular adhesion molecule 1.
cular risk factors associated with schizophrenia and other perglycemia and hyperinsulinemia, dyslipidemia, hyper- psychoses in the early phase of illness to track the ef- tension, and inflammatory markers (Table).
fects of different drug treatments for psychosis on key 2. Summarize the methods and quality of reporting risk factors for cardiovascular disease. Distinguishing pre- of identified studies.
treatment status from treatment effects is important for 3. Conduct a review of the early cardiometabolic out- understanding the source of cardiovascular disease as- comes of treated psychosis and report key findings.
sociated with psychosis and to inform decisions regard- 4. Suggest directions for future research.
ing medication review and other interventions. This dis-tinction can only be made at the very beginning of treatment in patients with a first episode of psychosis whohave not previously been exposed to antipsychotic drugs DATA SOURCES
or who have been exposed for a short known period.11First-episode psychosis is an intermediate diagnosis used Two search strings were used to identify studies: ["first epi- in the early phase of psychotic illness until the clinical sode psychosis" AND metabolism] and [psychosis AND naive picture stabilizes.12 Most first episodes of psychosis will AND "glucose OR insulin OR cholesterol OR triglycerides OR eventually be diagnosed as schizophrenia in younger co- blood pressure OR weight"]. The search was limited to English- horts, or as schizophrenia, bipolar disorder, or major de- language publications and was conducted using MEDLINE (via pression with psychotic features in samples unselected PubMed), PsycINFO, and Scopus for the period from January for age at onset.13 1, 1990, through June 15, 2010. The reference lists of identi- The aims of this report are to: fied articles were also hand searched.
1. Identify prospective longitudinal treatment stud- ies of the first episode of psychosis that include assess-ment of cardiometabolic outcomes. These include body Studies were included if (1) subjects had a first episode of psy- weight and central obesity and associated biomarkers, hy- chosis; (2) subjects were antipsychotic drug naive or only re- (REPRINTED) ARCH GEN PSYCHIATRY PUBLISHED ONLINE FEBRUARY 7, 2011 2011 American Medical Association. All rights reserved.
cently exposed to antipsychotics for a short known period at trial, and 4 cohort studies excluded subjects who used rec- the initiation of the study; and (3) a prospective longitudinal reational drugs,28 had recent alcohol or drug abuse,37 or a study design was implemented. File audits, cohort studies, and substance use disorder.18-20,25,33,36,38 The drugs were not drug trials (blind or open) were all eligible. Medical record file specified. Six studies excluded individuals with any car- audits were considered only if they used data from clinics that diometabolic abnormality at baseline.18,19,25,28,30,31 Only 2 conducted routine monitoring of all patients.
studies reported the number of potential subjects who meteligibility criteria. Four studies reported the percentage of eligible individuals approached who subsequently con-sented to participate in the study (eTable 1) (for Adding- Items from the Consolidated Standards of Reporting Trials ton et al,27 no participation rate is recorded because it was (CONSORT)14,15 and Strengthening the Reporting of Observa- a retrospective medical file audit study). All others re- tional Studies in Epidemiology (STROBE)16,17 checklists were ported that their sample consisted of all consecutive ad- used to assess the methods and quality of reporting (eTable 1, missions at 1 or more treatment centers.
http://www.archgenpsychiatry.com). We added 4 additionalfields—industry sponsorship, assessment of medication com- Drug-Naive Status and Medication
pliance, follow-up psychiatric diagnosis, and if tests for differ-ences in cardiometabolic outcomes across different antipsy- Patients were either antipsychotic naive or had been ex- chotics were conducted.
posed to antipsychotics for between 9 days and 16 weeks.
All studies described the medication administered, but only 4 formally assessed medication compliance, using pillcounts,35,39 prescription counts,20 or patient report.40 PROSPECTIVE LONGITUDINAL TREATMENT
STUDIES OF THE FIRST EPISODE OF PSYCHOSIS
Selection of Control Subjects
Sixty-four articles were identified describing 53 inde- Eight studies included controls (eTable 1). Controls were pendent studies; 25 studies met inclusion criteria and were recruited from hospital staff,19,24 universities, and the gen- retained for detailed review (eTable 1). Studies were ex- eral community21,24 and an anonymous workplace health cluded because they did not consist solely of patients with screening program.18 The other studies provided no infor- first-episode psychosis (n = 21), patients were not anti- mation on how controls were recruited. No study pro- psychotic drug naive at entry to the study and recent brief vided any information on how many controls were ini- exposure was not explicitly specified (n = 5), or expo- tially approached or any differences between control sure was not brief (ie, at least 6 months) (n = 2).
participants and nonparticipants in the study. All but 1study21 attempted to match controls to cases on at least some METHODS AND QUALITY OF REPORTING
pertinent characteristics such as age, sex, and ethnicity.
Sample Size and Follow-up
Ten studies received support from the pharmaceutical Sample size varied (n=9-555) but most studies were small.
industry (eTable 1).
Only 4 studies ascertained more than 200 patients. Onestudy provided an explicit description of how subjects Study Design and Hypotheses
were followed up for postbaseline assessments.28 For 3studies, it could be inferred that follow-up of subjects was Studies reviewed comprised 10 randomized trials, 5 non- routinely conducted because subjects appeared to have randomized trials, and 10 observational cohort studies been inpatients for the duration of the study.30,31,39 Oth- (eTable 1). One randomized trial, 1 nonrandomized trial, ers did not provide any information on how subjects were and 4 cohort studies included healthy controls to con- tracked through the course of the study, how and where duct a cross-sectional case-control comparison of base- follow-up assessments were conducted, and methods used line cardiometabolic indices.18-24 Cardiometabolic out- to try to find subjects lost to follow-up. Nine studies pro- comes (predominantly weight) were a primary outcome vided information about the reasons that follow-up as- measure in 16 studies18-21,23-34; the primary outcome was sessments could not be conducted21,23,30,31,35,36,40-42 (sim- treatment efficacy or all-cause medication discontinua- ply stating that patients were discharged from the hospital tion, with cardiometabolic measures a secondary out- or dropped out of the study was not considered suffi- come, in the remaining studies (eTable 2).
cient). The average follow-up time across studies was 31.7weeks (median, 52 weeks) but ranged from 4 weeks34 to 2.5 years23 (3 years including the additional follow-up and Subject Participation
study by Addington et al43).
Two studies described in detail the population from which Analytical Methods Including
subjects were ascertained and both appear to have ascer- Missing Data Handling
tained samples representative of the broader populationof patients.35,36 All studies provided information on eligi- Subgroup analyses or tests of interaction were generally bility criteria. Four randomized trials, 1 nonrandomized not well described or justified. The methods used for han- (REPRINTED) ARCH GEN PSYCHIATRY PUBLISHED ONLINE FEBRUARY 7, 2011 2011 American Medical Association. All rights reserved.
dling missing data were described in only 6 studies. For independent of weight or low-density lipoprotein (LDL) 3 others, it could be inferred that a complete case analy- cholesterol given that the relevant controls were signifi- sis was conducted.27,29,40 cantly more likely to have elevated LDL cholesterol lev-els and to be overweight or obese (52% vs 27%, in their corrected Table 1) compared with patients. Patients didnot differ from controls on trigylceride21; total, LDL,22 or Four studies did not provide information on diag- high-density lipoprotein (HDL) cholesterol21,22; insu- noses,21,26,27,33 and 1 provided incomplete information.29 lin21; adiponectin; leptin; interleukin 6; vascular cell ad- All studies provided some demographic information on hesion molecule 1; or E-selectin21 levels. One study found subjects, such as proportion of males and females, aver- an elevated waist to hip ratio and elevated fasting insu- age age, socioeconomic status, and ethnicity. Most stud- lin level relative to controls only in female patients.19 ies did not tabulate the number of participants with miss- Two studies used controls to test if change over time ing data for each variable, making it difficult to determine was due to factors other than treatment.20,46 One study numbers of subjects in different analyses.
matched hospitalized cases and controls by sex, age, ex-ercise and diet (basal metabolic rate), race, and socio- Tested for Drug Differences
economic status to match for possible confounders ofnatural weight gain over time.46 Concomitant drugs that Nineteen studies administered multiple antipsychot- could potentially affect weight were not permitted. Pa- ics.* Nine studies analyzed data for all drugs com- tients had significantly elevated weight (4 kg) and BMI bined.19,21,23,27,29,32-34,44 Ten studies tested for drug differ- (2 kg) after 6 weeks of double-blind, randomized treat- ences in cardiometabolic outcomes.† Six studies ment with haloperidol, risperidone, or olanzapine com- administered a single antipsychotic25,26,30,31,37,45; 5 admin- pared with controls after 6 weeks of unmedicated follow- istered olanzapine,25,26,30,31,45 some to test if the mode of up. After 12 months of treatment with haloperidol, administration45 or adjunct treatments minimized weight risperidone, olanzapine, or perphenazine, cases had a sig- nificantly greater increase in BMI (2 kg) than controlsmatched only for age.20 To control for progressive weight gain in cases over time, independent of medication, 1 study included a sec- Seven studies tested if patients were different from con- ond control group of patients (n = 7) who refused anti- trols at baseline with regard to weight and fat distribu- psychotic drug treatment for longitudinal comparison with tion and diet; indices of diabetes risk; and biochemical treated patients and healthy controls.20 The mean weight indices such as triglyceride, cholesterol, and cortisol lev- gain was 17 kg across 1 year for olanzapine, 8 kg for ris- els (eTable 1). Four studies recruited patients who were peridone, 4 kg for haloperidol, 1 kg for perphenazine, 1 antipsychotic naive18,19,24,46: 1 included patients within 72 kg for patients who refused antipsychotics, and 1 kg for hours of first exposure,22 1 included patients with up to age- and sex-matched controls with no history of psy- 2 weeks' lifetime exposure but no more than 3 doses in the month prior to recruitment,20 and another recruitedpatients with up to 16 weeks of recent exposure.21 Change in Cardiometabolic Risk Factors
After Treatment With Antipsychotics
Studies that administered multiple antipsychotics but ana- lyzed data for all drugs combined19,21,23,27,29,32-34,44 foundthat changes in weight, BMI, and waist circumference were At baseline, patients had a higher waist to hip ratio than evident after 1 month.34 There was a significant increase controls in 3 studies,18,19,24 a higher saturated fat in- in interleukin 12 after 6 weeks47 and a significant in- take,24 and, in a study that matched on body mass index crease in subcutaneous and intra-abdominal fat, a 3-fold (BMI), 3 times more intra-abdominal fat,24 but there was increase in leptin level, and a significant increase in total no elevation of intra-abdominal fat in another study that and LDL cholesterol, triglyceride, and nonfasting glu- did not report matching.19 There were no other signifi- cose levels after 10 weeks.19 Total body weight in- cant weight-related differences. At baseline, patients did creased by 10% to 12% after 6 to 12 months.27,29 Most of not have more total body fat,24 abdominal subcutaneous that weight change occurred in the first 6 months. At base- fat,19,24 unsaturated fat intake,24 or a higher weight,19,21,46 line, 36% to 42% were overweight or obese21,27 (like the BMI,19-21,24,46 or waist circumference46 than controls.
broader community); after 6 months, 58% to 71% were Patients had a higher prevalence of prediabetes (el- overweight or obese.21,27 evated fasting glucose21 or insulin19 level) than controls There was a significant change in total,21,29,44 LDL,21,44 in 2 studies but 1 of these included patients exposed to and HDL cholesterol,29 triglyceride,29,44 fasting insulin and antipsychotics for up to 16 weeks.21 Another study re- glucose, leptin, E-selectin, and adiponectin levels by 6 ported a 10-fold higher prevalence of diabetes in pa- months.21 Weight gain continued for at least 3 years.43 tients (5%) than controls (0.5%),22 which may be largely Those who had taken antipsychotics continuously over2.5 years had nonsignificantly more weight gain (13 kg) *References 18-21, 23, 24, 27-29, 32-36, 38, 40-42, 44. than those who had not (7 kg).23 Genotype may also play †References 18, 20, 24, 28, 35, 36, 38, 40-42. a role. The wild-type variant of the 5HT2C receptor gene (REPRINTED) ARCH GEN PSYCHIATRY PUBLISHED ONLINE FEBRUARY 7, 2011 2011 American Medical Association. All rights reserved.
regulatory region was associated with significantly more This ranking of antipsychotics was reflected in other weight gain after 10 weeks taking risperidone or chlor- weight-related changes, such as 4-kg or more weight in- promazine than the −759 C/T polymorphism in a Han crease,36 7% or more weight increase,42,46 increasing Chinese cohort.32 This finding was replicated in a Span- BMI,41,48 and the incidence of metabolic syndrome,49 but ish cohort treated with a different combination of anti- not for intra-abdominal fat.24 Orally disintegrating tab- psychotics and in the subset of those given olanzapine.33 lets of olanzapine were associated with significantly less In studies that administered multiple antipsychotics weight gain than standard tablets,45 as was adjunctive re- and tested for differences in cardiometabolic outcomes boxetine31 but not fluoxetine.30 across drugs,‡ the combination of drugs studied and the At 12 months, there was a significant increase in in- follow-up interval varied (eTable 1), which is important sulin level, insulin resistance, and total and LDL choles- because the trajectory of weight gain varies across dif- terol, triglyceride, leptin, and ghrelin levels,40,50,51 an el- ferent drugs. We therefore summarize results by fol- evation in fasting glucose level in 1 study40 but not in 2 low-up point to better show the pattern of findings that others,35,50 and weight gain significantly correlated with emerges across studies.
insulin and leptin levels.51 No significant differences werefound across haloperidol, olanzapine, or risperdione.51 By 6 to 8 Weeks. Weight gain was significant. The av-
No significant differences were found across haloperi- erage weight gain after 6 to 8 weeks taking olanzapine dol, amisulpride, olanzapine, quetiapine, or ziprasi- was 5 to 6 kg,18,26,45 which was significantly higher than done.40 A comparison of olanzapine, risperidone, and the average weight gained while taking risperidone (4 kg) quetiapine in another of the larger samples did find sig- or haloperidol (3 kg).18 In another study, means were not nificant differences at 12 months: olanzapine and queti- reported but the rank order of weight gain by drug ad- apine were associated with a greater elevation in triglyc- ministered was the same.36 There was a significant in- eride level and systolic blood pressure than risperidone; crease in fasting and postprandial blood glucose levels olanzapine was associated with a greater elevation in dia- and the incidence of diabetes after 6 weeks in male pa- stolic blood pressure than risperidone; quetiapine was tients.39 The largest effects were seen for olanzapine, then associated with a greater elevation in cholesterol level than risperidone and haloperidol. At 8 weeks, there was a sig- risperidone; and olanzapine was associated with a greater nificant increase in insulin level, insulin resistance, and reduction in HDL cholesterol level than quetiapine or ris- glucose, cholesterol, triglyceride, and C peptide levels peridone.42 This is consistent with the earlier- across clozapine, olanzapine, risperidone, and sulpiride mentioned ranking for weight, with olanzapine over queti- combined but no significant difference between drugs.28 apine over risperidone.
By 3 to 4 Months. Olanzapine was associated with sig-
nificantly more weight gain (7-9 kg)26,41,48 than haloperi- of Cardiometabolic Outcomes
dol (3-4 kg)41,48 but not risperidone (6 kg).48 Risperi-done was associated with significantly more weight gain Lower pretreatment BMI,20,44,46 younger age,20,44 triglyc- than haloperidol (5 kg vs 3 kg).38 Other results were less eride level,44 more negative symptoms,20 and more co- consistent. A significant increase in cholesterol and fast- medications and antidepressants20 predicted weight gain ing insulin levels was found after 3 to 4 months taking after antipsychotic treatment. In 1 study, women (but not olanzapine in 1 study26 but not another.25 No significant men) starting with a normal BMI gained a significantly increase was found in fasting triglyceride, glucose,26 or higher percentage of body weight (mean, 18%) than those leptin25 levels but there was a significant increase in ab- starting with an overweight BMI (mean, 2%).27 solute fat mass; percentage of body fat and waist to hipratio, suggesting central deposition of body fat; and C pep-tide level while taking olanzapine.25 By 6 Months. Gain in intra-abdominal fat was nonsig-
Drawing definitive conclusions about the impact of an- nificantly higher with risperidone (27 cm2) than olanza- tipsychotics on cardiovascular risk factors in patients with a first episode of treated psychosis is not currently pos-sible. Some drug comparisons are entirely lacking, and By 1 Year. There was no significant difference in weight
others appear underpowered. Sample sizes varied widely gain across different antipsychotics.20,35,38,40,48 Two stud- but most were small. Only 4 studies ascertained more than ies did not report pairwise drug comparisons, just 4- and 200 patients. Most studies do not describe their patient 5-way comparisons.20,40 The rank and range of average or control samples well enough to gauge representative- weight gain reported after 1 year taking antipsychotics for ness. Medication compliance is rarely assessed and never each drug across informative studies is olanzapine, 11 to explicitly factored into analyses, even in formal treat- 14 to 17 kg20,40,48; amisulpride, 10 kg40; clozapine, 10 kg35; ment trials. Dropout rates in the longer trials were as high quetiapine fumarate, 10 kg40; risperidone, 8 to 9 kg20,48 and as 80% to 90%,41,52 which limits conclusions about longer- at 2 years, 7 kg38; haloperidol, 4 to 7 to 11 kg20,40,48 and at term outcomes. Given the sparseness of cardiometa- 2 years, 6 kg38; chlorpromazine, 6 kg35; ziprasidone hy- bolic outcome data beyond 1 year, a commonly used drochloride, 5 kg40; and perphenazine, 1 kg.20 method for handling missing data (last observation car-ried forward) may underestimate weight gain and asso- ‡References 18, 20, 24, 28, 35, 36, 38, 40-42. ciated parameters in patients compliant with antipsy- (REPRINTED) ARCH GEN PSYCHIATRY PUBLISHED ONLINE FEBRUARY 7, 2011 2011 American Medical Association. All rights reserved.
chotic use for much longer than average periods by as crease risk for cardiovascular disease,58,59 but we do not know if they moderate cardiovascular risk during treat- The results of the studies reviewed herein point to- ment with antipsychotics.
ward 2 important hypotheses that need further re- The age distribution in cohorts of patients with a first treated episode of psychosis varies by sex because of sexdifferences in the age at onset of psychosis.13 Patients with 1. In general, there is no difference in cardiometa- first-episode psychosis are composed of younger men and bolic indices between patients and controls prior to treat- older women unless artificially constrained to ascertain ment with antipsychotic drugs. Caveat: Prior to first ex- a specific age range via a youth service. This means that posure to antipsychotics, patients may have a higher waist the prevalence of schizophrenia in first-episode cohorts to hip ratio and more intra-abdominal fat relative to BMI will be much higher in youth and young adults than in than controls but adequate control matching may be re- those unselected for age.13 Tests for sex differences should quired to detect these early differences.
therefore control for age effects60 and all studies should 2. Risk for cardiovascular disease, indexed by weight report any age limits on ascertainment and intake/ and other metabolic indices, increases after first expo- outcome diagnosis. Diagnosis is important because large sure to any antipsychotic. Caveat: After 1 year of anti- population-based studies have shown that different psy- psychotic drug treatment, a rank order of drugs can be chosis subtypes index partly distinct risk factors,61 which derived across all studies reviewed herein but there is no may prove to be related to comorbidity with physical dis- evidence of significant differences between first- and sec- ease. There is no a priori reason to assume that treat- ond-generation antipsychotics. Weight gain after 1 year ment effects are unrelated to risk factors for psychosis taking risperidone, for example, was very similar to weight or cardiovascular disease.
gain after 1 year taking haloperidol or chlorpromazine.
Women may be more sensitive to the effects of anti- Variance in adverse cardiometabolic effects within each psychotics60 and their increased risk for central obesity class indexes the most meaningful source of variance.
may be evident early.19 After 3 to 6 months of treatment, Weight gain while taking olanzapine, for example, was women had waist circumference measures in the high- much higher than weight gain while taking ziprasidone.
risk range.29 Hypoadiponectinemia induced by visceralfat accumulation may be a strong risk factor for meta- SUGGESTIONS FOR FUTURE DIRECTIONS
bolic and cardiovascular diseases and some cancers.62 Cen-tral obesity early in the course of treated illness may there- Weight gain may be the most visible of the adverse car- fore predict later physical disease. Efforts to evaluate diometabolic effects of antipsychotic drugs but tracking interventions that target emerging central obesity, espe- less visible risk factors is just as important. Elevated LDL cially in women, should be a clinical research priority.
cholesterol level is the main target for primary preven- Adoption of both the CONSORT guidelines for ran- tion of heart disease2 but it is not clear whether changes domized controlled trials and the STROBE guidelines for in LDL or HDL cholesterol, triglyceride, or serum glu- observational (cohort) studies will increase the accu- cose levels or insulin resistance in the first treated epi- racy of reporting and interpretation of future studies of sode of psychosis are independent of weight changes. More cardiometabolic outcomes of the first treated episode of research in this area is needed to determine which car- psychosis. Beyond the implementation of these guide- diometabolic indices are most strongly affected by which lines we recommend future studies: antipsychotics and what the long-term consequences of 1. Provide a more detailed characterization of the pri- mary exposure—medication—by assessing and analyz- As many as 39% of patients are nonadherent and 20% ing medication compliance by identifying the therapeu- inadequately adherent53 in their first year of antipsy- tic window for antipsychotic drugs in adults and youth chotic drug treatment but many studies do not assess or and by evaluating dosage effects.
analyze medication compliance. Assessment of serum lev- 2. Undertake a comprehensive assessment of cardio- els of antipsychotics is important because compliance with metabolic risk factors following, at the very least, rec- a prescription does not ensure a therapeutic dose and that ommended monitoring guidelines.63 Long-term fol- is ultimately the point of tracking adherence with pre- low-up will be required to accurately document the scribed medication in relation to outcomes. Some anti- emergence of some outcomes, such as diabetes.
psychotics do not even have a known therapeutic win- 3. Examine whether cardiovascular outcomes are mod- dow, especially for youth.54 This is an important unsolved erated by (1) demographic characteristics (sex and age problem. Dosage effects on the efficacy of antipsychot- at a minimum); (2) clinical characteristics; and (3) ge- ics for psychotic symptom reduction and the emergence netic factors.
or exacerbation of cardiometabolic risk factors, and theirrelationship, should be tested.
Comorbidity, sex, age, and genetic makeup may all affect treatment efficacy and adverse effects. Exclusioncriteria in drug trials often include substance abuse and Individuals treated with antipsychotics should be as- depression or other medical conditions, even minor car- sessed before (or very soon after) first exposure to anti- diometabolic abnormalities. Recreational drug use, drug psychotics to determine baseline cardiovascular risk.
abuse, and depression are all common in cohorts of pa- Regular monitoring is then recommended using consen- tients with a first treated episode of psychosis55-57 and in- sus guidelines.63 Any clinically significant changes should (REPRINTED) ARCH GEN PSYCHIATRY PUBLISHED ONLINE FEBRUARY 7, 2011 2011 American Medical Association. All rights reserved.
be dealt with following recommended protocols and re- Correspondence: Debra L. Foley, PhD, Orygen Youth
ferral to a primary care physician or appropriate special- Health Research Centre, 35 Poplar Rd, Parkville, VIC ist.64 Information from monitoring should guide the se- 3052, Australia ([email protected]).
lection (and switching) of antipsychotic agents,63 but in Financial Disclosure: None reported.
practice, regular monitoring is rarely conducted.65 We have Funding/Support: Dr Foley was supported by the Colo-
found that general nurses can conduct monitoring in a nial Foundation (Australia) and is a recipient of grant first-episode psychosis service,66 but in other settings, and G09M4402 from the Heart Foundation (Australia). Dr outside of the rigorous protocols of research studies, car- Morley was supported by Public Health Fellowship diometabolic monitoring is still not routinely imple- 520452 from the Australian National Health and Medi- mented.67 This is an important failure of care.
cal Research Council.
Online-Only Materials: The eTables are available at http:
There are many unresolved issues. Contrary to expecta- tions, in all but 1 of the largest studies,42 cardiometabolicoutcomes were not significantly different across different 1. Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a commu- antipsychotics at study end points. This may reflect low nity cohort with schizophrenia. Br J Psychiatry. 2010;196(2):116-121.
power to detect true differences given currently attain- 2. Hennekens CH. Increasing global burden of cardiovascular disease in general populations and patients with schizophrenia. J Clin Psychiatry. 2007;68(suppl able sample sizes relative to the number of antipsychotics administered. A recent meta-analysis of weight gain fol- 3. Saunders KEHK, Hawton K. The role of psychopharmacology in suicide prevention.
lowing first exposure to antipsychotics in the absence of Epidemiol Psichiatr Soc. 2009;18(3):172-178.
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