THE PRIMARY CARE COMPANION ron CNS Drsonosas
`
`Prim Care Companion CNS Drsord. 2011, 13(6) PCC.11|01174
`do:
`19 ‘Qfllflg 11521114
`
`PMCID PMC3304588
`PMID 225m
`
`OIanzapine-Induced Weight Gain in Patients Vlfith Bipolar | Disorder: A Meta-Analysis
`
`Mina G Nashed BSc, Maria R. Restivo. BSc, and Valerie H. TayM, MD, PhD, FRCPCM
`MINDS Neuroscience Graduaa Progam. McMaster Unlversty. Hamilton (Mr Mashed and Ms Restlvo). and Women‘s College Hospital. Department 0' Psychiatry. University at Toronto (Dr
`Taylor). Ontario. Canada
`orresponding author.
`Compondlng euthanVaiene H Taylor, MD. PhD. FRCPC. Departments! Psychiatry University at Toronto. Women's College Hospital 76 Grenville St. Twonto. Ontario. M58 182 Canada
`(valenetaymwchospfialcs).
`Received 2011 Feb 25; Accepted 2011 Jun 13.
`Cogyflgmo 2011. Physicians Postgraduate Press, Inc.
`
`Abstract
`
`Go to:
`
`Objective: The weight impact pmduced by the atypical antipsychotic olanzapine has been explored in meta-analyses focusing on patients with
`schizophrenia. However. outcomes identified for schizophrenia patients cannot always be generalized to patients with bipolar disorder. This study
`aims to quantitatively estimate the impact of olanmpine on the weight of patients with bipolar disorder.
`
`Data Sam-cm: EMBASE. Medline, and PsycINFO were searched using the keywords olanzapine AND (bipolar OR acute maria) in conjunction
`with (weight gain OR weight increase) (last search: October 2010, with no restrictions on dates of publication). English language was used as a
`restriction.
`
`Study Selection: The search identified 110 articles for review. The inclusion criteria for the chosen studies were a diagnosis of bipolar disorder. the
`presence of an olanzapine monotherapy group. a comparator placebo or monotherapy group. and mean weight gain andlor incidences of weight
`gain data. This process identified 13 studies for inclusion.
`
`Data Extraction: The primary outcome measure was the mean weight change between olanzapine monotherapy and comparator monotlrerapy.
`reported in kilograms. Standard deviation was extracted directly from studies when possible and imputed for 3 studies. The secondary outcome
`measure was the reported incidences 013 7% weight gain.
`
`Data Synthesis: The mean difference in weight gain was calculated for the continuous data of the primary outcome. Olanzapinc monothcrapy was
`associated with more weight gain when compared to placebo (mean difference : 2.10 kg: 95% CI, 1.16—3.05: P ~22 .001) and other bipolar
`monothcrapy (mean difference — 1.34 kg; 95% CI, 0.95—1.72: P <1 .001). Odds ratio analysis of the dichotomous secondary outcome also showed
`more weight gain with olanzapine monotherspy compared to placebo (odds ratio [OR] = 10.12: 95% Cl. 193—53. 14; P = .006) and other bipolar
`monotherapy (OR = 2.09; 95% CI. 1.27—3.44; P = .004).
`
`Conclusions: Cunently available data suggest that olanzapinc is associated with significant weight gain in bipolar patients. Issues related to side
`effect profiles and their impact on treatment compliance and physical health outcomes need to be considered when selecting phannacotherapy.
`
`
`Bipolar disorder. a chronic mental illness that impacts 1% of the population. is defined clinically by a wide range of symptoms: a depressed or
`euphoric mood. lack of activity paralleled at times with energized behavior. and a decreased need for sleep and social interaction that can manifest
`as either the desire for complete isolation or extreme extroversion that can become problematic.l To further complicate the picture. individuals in
`either the manic or depressed phases of bipolar disorder can experience psychotic symptoms as well.l As a consequence. the pharrnacologic
`management of bipolar disorder involves a myriad of options from a variety of drug categories: mood stabilizers, antidepressants, and atypical
`antipsychotics are all recommended as first-line agents, either as monotherapy or in combination.1 Of these options, the most recent class of
`medications to become first line for acute and maintenance treatment of bipolar disorder is the second-generation atypical antipsychotics (SGAs).
`While these agents are heterogeneous in their efficacy and tolerability. studies suggest that SGAs, either alone or in combination with mood
`stabilizers. are currently an cfficacrous treatment strategy in the management of both the dcprcssrve and manic stages of bipolar disorder.= Added
`benefits in favor of the use of SGAs include reduced extrapyramidal side effects and the absence of depressive symptom exacerbation}- There are
`concems associated with the use of this medication class. however: and the adverse metabolic profile associated with SGAs needs to be considered
`when making treatment recommendations.
`
`In temis of market share. the most commonly prescribed atypical antipsychotic worldwide is olanzapine.‘1 In 2003. olanzapine was approved for
`the treatment of bipolar depressive episodes in combination with fluoxetine,é and in 2004 it was approved for long-tenn maintenance treatment of
`bipolar disorder.é Since then, olanzapine has become the best-studied SGA in this patient population, but while significant weight gain has been
`consistently reported with the use of olanzapine in the treatment of bipolar disorder. there has not been a meta-analysis to comprehensively
`investigate the problem in this population. The bulk of work examining the weight gain side effects associated with olanzapine has focused on
`schizophrenia. and a 2009 meta-analysis by Leucht et all concluded that olanzapine was associated with 3.3-kg more weight gain when compared
`with haloperidol monotherapy (95% CI. 2.2 4.4. P '41 .001) in 9 studies on patients with schizophrenia. In 2 other meta—analyses, olanzapine was
`shown to cause more weight gain than any other SGA. with the exception ofclozapine. in patients in schizophrenia.£2
`
`1
`
`Exhibit 2047
`Slayback v. Sumitomo
`|PR2020—01053
`
`Exhibit 2047
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Results from schizophrenia studies are not always generalizable to other patient populations: therefore. a meta-analysis on the weight gain effects
`of olanzapine on patients with bipolar disorder is warranted. The aim of this study was to compare weight gain outcomes of olanzapine
`monothcrapy to placebo and other monothcrapies in patients with bipolar disorder.
`
`Cllnlcal Polnts
`
`()latlzapine monotherapy is associated with significantly more weight gain than placebo and other bipolar disorder medications that are
`known to cause moderate weight gain
`-Weight gain may exacerbate other health risks associated with bipolar disorder, such as compromised neurocognitive function.
`Clinician awareness regarding the adverse metabolic side effects of antipsychotics, such as olanzapine. will ensure that patients are able
`to safely choose the best medication to manage their complicated illness and improve medication compliance.
`
`
`
`METHOD Go to:
`
`Database Search
`
`The OVID search engine was used to perfonn a combined search of 3 databases: EMBASE. MEDLINE, and PsycINFO. The last search was
`conducted in October of 2010. and there were no restrictions on date of publication. English language was used as a restriction. Abstracts. titles.
`and indexed terms of studies were searched using the keywords olanzapine AND (bipolar OR acute mania) in conjunction with (weight gain OR
`weight increase). After duplicates and articles with no abstracts were filtered out. 784 results remained (figure I). Studies that did not investigate
`weight gain with olanzapine monotherapy were excluded. This process identified 1 10 articles for full-text investigation. Of these. studies that did
`not include at least 1 comparator to olanzapine monotherapy were excluded. along with studies that did not investigate bipolar patients. Studies on
`adolescent bipolar patients were not included in the analysis due to limitations in comparing weight gain between adults and adolescents. Open-
`label and naturalistic studies were included since physical measures. such as weight gain. are not susceptible to placebo effect.
`
`Further screening of the 110 retrieved articles and their references identified 12 double-blind. randomized controlled studies and 1 naturalistic
`observational study to be included in this analysis. Four of the total 13 studies were placebo controlled, and the remaining tested olanzapine
`monotherapy against an alternative monotherapy. The coauthors of the present analysis (M.G.N. and M.R.R.) performed the search and extracted
`data from the studies independently, and disagreements were discussed until a consensus was reached. The inclusion criteria for the final studies
`were a diagnosis of bipolar disorder. the presence of an olanzapine monotherapy group. a comparator placebo or monothcrapy group. and mean
`weight gain andt‘or incidences of weight gain data.
`
`It is worth noting that 2 studies that initially passed all phases of screening were later excluded. The first is a maintenance study by Tohen et alm
`in which subjects were randomized to receive either olanzapine or lithium after 6 to 12 weeks of open-label cotherapy. Consequently. the subjects
`were not olanzapine naive at randomization. having gained a mean of2.7 kg during cotherapy. The second study was also a maintenance study by
`Tohen ct al.fl and. similarly. this study randomized subjects to receive either olanzapine or placebo after 6 to 12 weeks of open-label olanzapine
`treatment. Thus. the placebo group had gained weight due to olanzapine treatment prior to randomization. Both studies show significantly more
`weight gain with olanzapine monotherapy at endpoint but were excluded from the present analysis due to their experimental design.
`
`The clinical trials registry glinjgglmalggoy was searched for unpublished results using the keywords almrzapine AND bipolar AND weight. This
`search yielded 30 trials, of which 2 were completed with results. Ofthese, 1 compared placebo to olanzapine combination therapy with divalpmex
`and was therefore excluded on the basis of not having an olanzapine monotherapy group. The other study included schizophrenia and
`schizoaffective subjects, along with bipolar subjects, and reported the weight gain results for all subjects combined. The investigators of this trial
`were contacted via email. requesting the separate weight gain results of the bipolar subject but no response was obtained.
`
`Outcome Parameters and Data Extraction
`
`The primary outcome of interest for this analysis was the mean weight gain in the olanzapine monotherapy and comparator monotherapy groups.
`For the primary outcome. we needed to extract mean weight gain. standard deviation (SD). and sample size from each study. When reported. the
`last observation carried forward (LOCF) was used as the sample size in the analysis. For studies that did not report a LOCF. the randomized
`sample size was used. For 10 of the 13 articles. the SDs were extracted directly from the article, and for the remaining 3 studies that did not
`disclose SDs. the SDs were imputed using the pooled SDs from all the other articles matched appropriately for intervention group. This method
`was used because borrowing SDs from other studies to impute data has been empirically shown to be an appropriate remedy for missing SDs in
`meta-analyses.Q
`
`The secondary outcome of interest was the incidence of weight gain. that is. the number of patients in each group who gained weight during the
`intervention. Clinically significant weight gain was defined as 7% or more of initial body weight. While it would have been preferable to use body
`mass index or waist circumference as a surrogate marker of weight gain, only 4 of the 13 studies included in this meta-analysis had information on
`body mass index and of these 4 studies, 3 reported baseline body mass index but not change over time. No data on change in waist circumference
`were available.
`
`Analytic Methods
`
`The meta-analysis was conducted using the software Review Manager Version 5.0 (Clicktimecom. Inc, San Francisco, California) with statistical
`significance set at P c. .05. As the primary outcome examined continuous data the mean difference in weight gain (change in kilograms) was
`calculated with a 95% confidence interval (CI). For the dichotomous data of the secondary measure incidence of weight gain. an odds ratio (OR)
`analysis was performed This method allows for the inclusion of more types of studies and is less prone to outliers than relative risk analysisl-‘Mi
`
`

`

`A random-effects model was used in both primary and secondary outcome analyses. with heterogeneity among studies investigated using both )8
`(P <- . 01 ) and 12 tests.
`RESULTS Go to:
`
`
`
`Study Characteristics
`
`Table 1 summarizes the characteristics of the 13 studies included in the meta-analysis.”‘21 The duration for most of the studies was between 3
`and 12 weeks, with 3 studies each investigating 3-week and 4-week intervals.l‘i‘m‘m‘n‘Ji‘Z‘é 2 studies investigating a 6-week period, 3% 1 study
`The remaining study looked at side effects
`.
`.
`’3
`investigating an 8-week follow-up.fl and 4 studies investigating weight gain over 12 weeksfl—E’fi
`over a longer maintenance phase of 47 weeks.“—1
`
`With respect to study type, 4 of the 13 studies in the present analysis were placebo controlled,E E while the remaining studies compared
`olanzapine monotherapy to various comparators namely haloperidol.fl divalproextvalpromefl‘E—Q lithiumg‘z—4 risperidone,3E and
`asenapinefi Tohen ct alu conducted a 3-branch examination on olanzapine monotherapy versus placebo versus divalprocx rrtonothcrapy. while
`Kim ct a1g conducted a 3-branch monotherapy examination of olanzapine versus lithium versus valproate, so data from both studies were
`included in 2 comparisons. The study comparing olanzapine monotherapy with haloperidol monotherapyu was grouped with the placebo-
`controlled studies. as haloperidol has not been associated with significant weight gain and for the purpose of the present analysis behaves as a
`placebofi’z—9 Thus. “olanzapine monotherapy versus placebo or haloperidol" constituted the first comparison. Studies with other comparators
`were grouped together under the second comparison, “olanzapine versus other bipolar disorder medication known to cause moderate weight gain."
`As this comparison suggests. studies with nonplacebo. nonhaloperidol comparators were grouped together due to their documented comparable
`effects on weight gain. 0n the basis of the literature, divalproex, lithium, risperidone. and asenapine have all been associated with weight gain that
`is significantly greater than placebo, but less than olanzapineziL”—l
`
`Prlmary Outcome: Mean Welght Galn
`
`Olanzapine versus placebo/haloperidol. The 5 studies in the first analysis compared olanzapi rte monotherapy versus placebo or haloperidol. In
`this comparison, olanzapine was associated with significantly more weight gain than placebo or haloperidol (LEM)- The pooled mean
`difference of this comparison was 2.10 kg (95% CI. 1.162105; P .: .001). The results showed significant heterogeneity among the 5 studies (I2 '-
`90%, x2 = 38.32, P < .001). Sequential removal of single studies from the analysis was performed to test for a possible outlier. but no single
`removal was found to render heterogeneity nonsignificant.
`
`Olanzapine versus other bipolar disorder medication. The 10 studies in the second comparison investigated olanzapine monotherapy versus
`other bipolar disorder medications that are known to cause moderate weight gain. The outcome of this comparison showed greater weight gain
`associated with olanzapine versus other bipolar disorder medication. As expected, the effect size was smaller than that observed in the first
`comparison. The pooled mean difference of this cotnparison was 1.34 kg (95% CI, 0.95—1.72: P .001). The heterogeneity of the 10 studies was
`not significant (12 = 27%, x2 = 12.30, P = .20 ).
`
`Separated analyses. To test the belief that the divalproex, lithium, risperidone. and asenapine trials can justifiably be combined into 1
`comparison and that the haloperidol trial can be combined with the placebo-controlled comparison, a second analysis was perfomred with all
`comparators separated (Egrfl) Results from this analysis showed little change in the placebo group's pooled effect size and heterogeneity when
`the haloperidol triallg was separated, and, so. this combination may be justifiable.
`
`Effect sizes from the lithium and risperidone groups were similar (mean differences of 0.88 to 0.64 kg, respectively), suggesting justifiable
`combination. However, the divalprocx and asenapine groups showed varied effect sizes (mean differences of l .42 and 2.20 kg, respectively). Only
`the divalproex mean difference of l .42 kg was similar to the combined mean difference of I .34 kg. Furthennore, all groups in the separated
`analysis showed less heterogeneity. when applicable. than the combined analysis. On the basis of these results, it is unclear whether the combined
`analyses are justifiable: therefore. both the combined and separated analyses are presented.
`
`Secondary Outcome: Incidence of Welgl'rt Galn
`
`Olanzapine versus placebo/haloperidol. When incidences of reported weight gain were investigated olanzapine was again associated with
`significantly more weight gain than was placebo or haloperidol (EgM). The pooled OR of this comparison was 10.12 (95% Cl. 193—53. 14:. P =
`.006). The results for these trials were heterogeneous (I2 = 78%, x2 = 13.68, P = .003). The heterogeneity was rendered nonsignificant with the
`removal of2 studies by Tohen et a1: Tohen et alu (I2 = 0%. x2 = 1.12, P = .57) and Tohen et 8112 (I2 = 51%, x2 = 4.10. P = .13), and it is possible
`that at least 1 of these studies is an outlier. It is worth noting that exclusion of the Tohen et a1 studyl2 increased the pooled OR to 17.35 (95% C1,
`3.20~94 .01 ), and exclusion of the Tohen et a1 studyfl decreased the OR to 3.68 (95% CI. 2.39—5.67). However, exclusion of these studies did not
`affect the conclusion of the results as they remained significant in all cases.
`
`Second comparison: olanzapine versus other bipolar disorder medication. Analysis on incidences of weight gain for the second comparison
`showed more people gaining weight with olanzapine versus other bipolar disorder medication, with an effect size smaller than that observed in the
`first comparison. The pooled OR of this comparison was 2.09 (95% CI. 1.27—3.44: P — .004). The results for these trials were heterogeneous (I2 —
`669-0. 1,2 = 17.51. P = .008), but heterogeneity was rendered nonsignifrcant with the removal of the study by Novick et {112—6 (I2 = 389/6. 12 = 8.00. P
`= .16), indicating that it may be an outlier. Removal of this study had little effect on the pooled OR. however, and did not affect the conclusion of
`the analysis.
`
`Separated analyses. As with the primary outcome, 2: second analysis was performed with all comparators separated (figure 5). For this outcome,
`separation of the haloperidol study from the placebo-controlled group caused an increase in the pooled OR of the placebo group (from 10.12 to
`17.42). In addition, heterogeneity of the results decreased. indicating the combined analysis may not be justifiable.
`3
`
`

`

`Effect sizes from the divalproex. lithium, ascnapine, and risperidone groups were relatively similar (ORs ranging from 1.68 to 6.45 ). Individually.
`the divalproex group showed less heterogeneity (I2 = 11%) when separated, whereas the risperidone group showed more hetemgeneity (I2 = 92%),
`possibly owing to the previously discussed outlier effect of the study by Novick et alm As with the primary outcome. it is unclear whether a
`combined analysis is justifiable; therefore. both the combined and separated analyses are presented.
`
`Possible covariates. Linear regression analysis failed to show a significant relationship between study duration and mean weight gain when all of
`the studies were included (R — 0.39: F1,12 — 2.10; P — .17). However. when the maintenance study by Tohen et a12—l was removed from the
`analysis. a significant relationship was observed between study duration and mean weight gain (R — 0.781171,” — 17.42: P — .0015). The same
`pattem with nearly identical statistics was observed when incidences of weight gain were used in place of mean weight gain. suggesting a possible
`plateau effect on weight gain between 12 and 47 weeks. A second linear regression was performed to assess the effect of mean olanzapine dosage
`on mean weight gain. This analysis found no significant effect (R = 4125; 171.10 = 0.62; P = .45). Additionally, no significant effect of mean
`olanzapine dosage on incidences of weight gain was found (R = 70.182141] = 0.24; P = .64).
`
`D_ISCUSSIO_N
`
`
`Go to:
`
`To our knowledge. this is the first meta-analysis investigating the extent of weight gain associated with olanzapine monotherapy in the treatment
`of patients with bipolar disorder. The results clearly show that olanzapine monotherapy is associated with significantly more weight gain than
`placebo and other bipolar disorder medications that are known to cause moderate weight gain. These medications include other SGAs (risperidone
`and asenapine). a first-generation antipsychotic (halopen'dol), a mood stabilizer (lithium). and an anticonvulsant (divalproexvvalproate). These
`results held when investigating mean weight gained during monotherapy. as well as incidences of reported weight gain.
`
`Our results are consistent with meta-analyses investigating the weight gain effects of olanzapine on schizophrenia subjects that have also focused
`on comparisons between different SGAs. In an analysis of 16 studies by Rummel-Klugc et 31.2 for example, the mean difference in weight gain
`between olanzapine and risperidone was 2.44 kg (95% CI, 161—3 .27) in favor of risperidone. while in a l3-study analysis by Komossa et a1.§ the
`mean difference between olan7api ne and risperidone was 2.61 kg (95% CI. 1.48—3.74) in favor of risperidone. The results fmm the present
`analysis, in comparison. show a mean difference of 0.64 kg (95% CI. $.12 to 1.40) in favor of risperidone. although the results are based on only
`2 studies. A 9-study meta-analysis by Leacht et alZ investigated the weight gain effects of olanzapine versus haloperidol on schizophrenia subjects
`and suggests a mean difference of 3.3 kg (95% CI. 2.2—4.4) in favor of haloperidol. similar to the present analysis that suggests a mean difference
`of2.80 kg (95% Cl, 1.90—3 .70) in favor of haloperidol the basis of 1 study only. Due to the low power of the olanzapine versus risperidone and
`olanzapine versus haloperidol comparisons in this analysis. it is still difficult to draw strong conclusions. Our findings are supported by a study by
`Treuer et a1g in which olanzapine monotherapy was examined in both schizophrenia and bipolar subgroups. In this study. both groups gained
`weight, with the schizophrenia patients gaining a larger proportion of weight earlier than the bipolar subgroup (25% vs 11%. respectively).
`
`A limitation of this analysis is the small number of studies available. \Mthout active exclusion of possible outliers, the combined analyses for both
`outcomes showed significant heterogeneity, with the exception of the combined mean differences for bipolar disorder medications known to cause
`moderate weight gain (primary outcome. second comparison). Performing separate analyses (with all comparators separated) helped remedy this
`problem in most cases but also decreased the number of trials and total number of subjects in each comparison. resulting in a decrease in the
`power of the individual analyses.
`
`Another point of caution stems from the conclusions of the individual studies. While all placebry'haloperidol trials reported more weight gain in
`their olanzapine monothcrapy group. this was not the case for the other comparators. The naturalistic study by Kim et al3 reported greater mean
`weight gain with lithium monotherapy when compared to olanzapine monotherapy. while a study by Novick et a]:é found no difference in the
`mean weight gain between the olanzapine group and the risperidone group. but reported more incidences of weight gain in the risperidone group.
`This trial, however. was targeted as a possible outlier in our analysis. Another limitation of our results is a confoundcr that impacts many reviews
`on medication use: only 2 trials in our analysisg22 did not receive funding from Eli Lilly. the maker of olanzapine. Weight gain was not the
`primary endpoint of the trials included. however. and weight gain was reported in all studies.
`
`The results of this analysis highlight the significant weight gain associated with olanzapine in the treatment of bipolar disorder and illustrate the
`need to focus on this side effect. Olanzapine was the most effective SGA in the Clinical Antipsychotic Trials of Intervention Effectiveness
`schizophrenia trialQ and has proven effectiveness in bipolar disorder as well.l Issues related to weight gain have a significant impact on treatment
`compliance, and a consensus statement by clinical and research experts lists SGA-associatcd weight gain as 1 of the main risk factors for
`34
`‘
`medication adherence in both patients with bipolar disorder and patients with schizophrenia— putting patients at risk for relapse};
`
`Weight gain may also exacerbate other health risks associated with bipolar disorder. as both obesity and mood disorders are chronic low-grade
`proinflammatoq states, and the 2 conditions existing together may be associated with problems such as compromised neurocognitive ftutctionf-ii
`Rates of obesity-related medical illness, such as cardiovascular disease. type 2 diabetes and metabolic syndrome are also increased in patients
`with bipolar disorder and may increase the risk of premature mortality in this populationsLbfl Therefore. continued research on the metabolically
`adverse effects of SGAs is warranted in order to counter these effects. increase treatment compliance, and confer better patient care to individuals
`with bipolar disorder.
`
`Side effect profiles of medications need to be considered when making treatment decisions. as does the use of interventions to counteract these
`side effects. Current literature suggests that most of the weight gain associated with olanzapine occurs within the first 12 weeks of treatmenL3—8
`with a plateau usually reached between 36 and 39 weeks.3—8'3j These results may have little to do with the pharmacologic properties ofthe
`medication. however. and instead may be related to interventions and lifestyle changes that are put in place once weight changes are observed. A
`number of trials examining the effects of medication.flfl cognitive-behavioral therapy?‘2 and lifestylei‘l- changes have been able to successfully
`impact weight gain and cause weight loss in patients taking olanzapine. As clinicians. we need to be more aware of medication side effects and
`better able to educate patients on how to minimize these outcomes. This awareness will ensure that patients are able to safely choose the best
`medication to manage their complicated illness.
`
`

`

`Drug names: asenapine (Saphris). clozapine (Cloznril, FazaClo. and others). divalproex sodium (Dcpakote and others), fluoxctine (Prozac and
`others). haloperidol (Haldol and others). lithium (Lithobid and others), Olanzapine (Zyprexa), risperidone (Risperdal and others).
`
`Potential conflicts ofinterwt: None reported.
`
`Funding/support: None reported.
`
`Acknowledgments
`
`Go to:
`
`Acknmvledgnumts: The authors would like to thank David Streiner, PhD (Department of Psychiatry and Behavioural Neurosciences, McMaster
`University. Hamilton. and Department of Psychiatry. University of Toronto. Ontario. Canada). for his help and direction regarding the meta-
`analytical techniques. Dr Streiner reports no conflicts of interest related to the subject of this article.
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