Antidepressant Drug Effects and Depression

Severity
A Patient-Level Meta-analysis
Jay C Fournier, MA;
2 #obert J De#ubeis, PhD;
3 $teven D Hollon, PhD;
4 $ona Dimidjian, PhD;
5 Jay D Amsterdam, MD;
6 #ichard C $helton, MD;
7 Jan Fawcett, MD
|| Author AIIiliations
Author Affiliations: Departments of Psychology (Mr Fournier and Dr DeRubeis) and
Psychiatry (Dr Amsterdam), University of Pennsylvania, Philadelphia, Departments of
Psychology (Dr Hollon) and Psychiatry (Dr Shelton), Janderbilt University, Nashville,
Tennessee, Department of Psychology, University of Colorado at Boulder (Dr
Dimidfian), and Department of Psychiatry, University of New Mexico School of
Medicine, Albuquerque (Dr Fawcett)
orresponding Author: Jay C Fournier, MA, Department oI Psychology, University oI
Pennsylvania, 3720 Walnut $t, Philadelphia, PA 04 (jcIsasupennedu)
More author inIormation

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Abstract
ontext Antidepressant medications represent the best established treatment Ior major
depressive disorder, but there is little evidence that they have a speciIic pharmacological eIIect
relative to pill placebo Ior patients with less severe depression
Objective To estimate the relative beneIit oI medication vs placebo across a wide range oI initial
symptom severity in patients diagnosed with depression
Data Sources PubMed, PsycINFO, and the Cochrane Library databases were searched Irom
January 0 through March 200, along with reIerences Irom meta-analyses and reviews
Study Selection #andomized placebo-controlled trials oI antidepressants approved by the Food
and Drug Administration in the treatment oI major or minor depressive disorder were selected
$tudies were included iI their authors provided the requisite original data, they comprised adult
outpatients, they included a medication vs placebo comparison Ior at least 6 weeks, they did not
exclude patients on the basis oI a placebo washout period, and they used the Hamilton
Depression #ating $cale (HD#$) Data Irom 6 studies (7 patients) were included
Data Extraction Individual patient-level data were obtained Irom study authors
Results Medication vs placebo diIIerences varied substantially as a Iunction oI baseline severity
Among patients with HD#$ scores below 23, Cohen d eIIect sizes Ior the diIIerence between
medication and placebo were estimated to be less than 020 (a standard deIinition oI a small
eIIect) Estimates oI the magnitude oI the superiority oI medication over placebo increased with
increases in baseline depression severity and crossed the threshold deIined by the National
Institute Ior Clinical Excellence Ior a clinically signiIicant diIIerence at a baseline HD#$ score
oI 25
onclusions The magnitude oI beneIit oI antidepressant medication compared with placebo
increases with severity oI depression symptoms and may be minimal or nonexistent, on average,
in patients with mild or moderate symptoms For patients with very severe depression, the
beneIit oI medications over placebo is substantial
KEYWO#D$
O ANTIDEP#E$$IVE AGENT$,
O DEP#E$$ION,
O DEP#E$$IVE DI$O#DE#, MAJO#,
O D#UG THE#APY,
O IMIP#AMINE,
O META-ANALY$I$,
O PA#OXETINE,
O PHA#MACOLOGICAL P#OCE$$E$,
O PLACEBO$,
O $EVE#ITY OF ILLNE$$ INDEX
Antidepressant medication (ADM) represents the current standard oI treatment Ior major
depressive disorder (MDD)

Antidepressant medication has been shown to be superior to

placebo in thousands oI controlled clinical trials over the past 5 decades
2,3
The extent to which
ADM outperIorms placebo (which controls Ior nonpharmacological aspects oI ADM) can be
used to index the 'true pharmacological eIIect oI ADM in clinical settings
The randomized, double-blind, placebo-controlled trial is the gold standard Ior testing treatment
eIIicacy and aIIords the opportunity to identiIy patient characteristics that predict diIIerential
pharmacological response Baseline symptom severity is one dimension that may aIIect
treatment outcome Kirsch et al
4
and Khan et al
5
presented independent meta-analyses oI
randomized placebo-controlled trials based on data Irom the Food and Drug Administration
(FDA) clinical trial database Using mean scores and standard deviations on the Hamilton
Depression #ating $cale (HD#$)
6
Irom each study, they examined the eIIect oI baseline
symptom severity on the relative eIIicacy oI ADM vs placebo Kirsch et al Iound that as the
mean baseline HD#$ score increased, the magnitude oI HD#$ change decreased Ior placebo but
remained unchanged Ior ADM Khan et al did not Iind a signiIicant relationship between
baseline scores and symptom change Ior the placebo condition but Iound greater symptom
change in ADM as baseline HD#$ scores increased Thus, both studies Iound that the greater the
baseline symptom severity, the greater the magnitude oI the diIIerence Iavoring ADM over
placebo Kirsch et al inIerred Irom their Iindings that the minimum baseline HD#$ score needed
to achieve a clinically meaningIul ADM/placebo diIIerence is approximately 2 and that
diIIerences are negligible Ior lower baseline HD#$ scores
One limitation to these meta-analyses is the restricted range oI baseline severity scores included
in their constituent studies In the analysis by Kirsch et al,
4
only oI 35 studies comprised
samples with mean baseline HD#$ scores lower than 23 As the authors noted, a score oI 23 is
characteristic oI 'very severe depression according to the American Psychiatric Association's
Handbook of Psychiatric Measures (which deIines mild depression as HD#$ scores Irom -3,
moderate depression Irom 4-, severe depression Irom -22, and very severe depression as
_23)
7
$imilarly, each oI the studies included by Khan et al
5
required a minimum entry score oI
20 on the HD#$, meaning that all patients could be classiIied as severe or very severe It is likely
that a sizable proportion oI depressed individuals who start ADM in the community present with
severity levels well below this value In Iact, a recent survey oI depressed, treatment-seeking
outpatients Iound that 7 oI the 503 patients assessed had HD#$ scores less than 22

There
has been a paucity oI systematic investigations oI the true eIIect oI ADM in patients with less
severe depression $uch data are scarce in the FDA database and in the published literature This
is partly the result oI the inclusion criteria used Ior many FDA registration trials in which cutoII
scores are imposed at baseline expressly to increase the sensitivity oI ADM/placebo
comparisons
A second limitation oI the Kirsch et al and Khan et al meta-analyses is that each included studies
that used a placebo washout period Typically, placebo washouts last Irom several days to 2
weeks, during which patients are administered a pill placebo in single-blind Iashion At the end
oI this period, patients who demonstrate an improvement oI a particular magnitude (typically
_20 on the HD#$) are excluded Irom the trial prior to randomization The goal oI this
procedure is to increase the power to detect diIIerences in eIIicacy between ADM and placebo
by removing known placebo responders at the outset Although it is not clear that placebo
washouts actually enhance the statistical power oI ADM/placebo comparisons,
,0
this design
Ieature severely limits the ability to generate accurate estimates oI the placebo response rate
Because early placebo responders are removed Irom the trial beIore they can contribute data, the
true rate oI placebo response may be underestimated in trials that use this Ieature
In the present study, we combined data Irom 6 large-scale, placebo-controlled trials that
comprised patients with a broad range oI baseline symptom severity
,2,3,4,5,6
Because most
MDD studies incorporate a minimum baseline depressive severity score as an inclusion criterion,
studies oI minor depressive disorder (which do not typically have such strict thresholds) were
included in this analysis as well The entry criteria allowed patients to enter these studies with
HD#$ scores that ranged Irom the low teens to the upper 30s
,2,3,4,5,6
Unlike the data
analyzed by Kirsch et al and Khan et al, which contained inIormation only at the level oI
treatment group and thus could support only standard meta-analytic procedures, the databases
Irom the 6 studies included in the present investigation provided data Ior a patient-level meta-
analysis, also known as a mega-analysis This approach is more appropriate and more powerIul
than a standard meta-analysis when original data are available and a Iine-grained multivariate
analysis is desired
7
Based on the Iindings oI Kirsch et al and Khan et al, we hypothesized that
ADM/placebo diIIerences would become larger as baseline severity increased
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METHODS
English-language articles Irom January 0 through March 200 were searched in the
electronic databases PubMed and PsycINFO using the Iollowing search criteria antidepres* and
randomi:* and placebo and depression and (treatment or trial) The Cochrane Library was
searched using the Iollowing terms as key words antidepres* and placebo and depression No
Iurther restrictions were imposed on either search We also examined the reIerence sections oI
meta-analyses and reviews to identiIy relevant randomized controlled trials
The criteria Ior inclusion required studies to be randomized placebo-controlled trials oI an FDA-
approved antidepressant in the treatment oI the Iull range oI patients with major or minor
depressive disorder (ie, studies that exclusively examined special populations or subtypes were
excluded as were studies that exclusively examined patients diagnosed solely with dysthymia)
The studies were restricted to adult outpatient samples; those that included children or
adolescents below the age oI years were excluded In addition, the studies had to include an
ADM/placebo comparison oI at least 6 weeks' duration and HD#$ scores at intake and at the end
oI treatment $tudies were excluded iI they excluded patients on the basis oI a placebo washout
period The Iinal inclusion criterion was that individual patient-level data had to be available Ior
analysis
Article Selection and Data Acquisition
The initial screening oI the search results was supervised ($D and JCF) and reviewed (JCF)
to ensure accuracy All selected articles were read by 2 authors (JCF and either $D or $DH)
to determine whether they met inclusion criteria (with an average k oI 02) Discrepancies were
resolved by consensus
The corresponding authors oI studies meeting the inclusion criteria were contacted to veriIy that
the study did not exclude patients on the basis oI a placebo washout period and to ascertain
whether individual patient-level data were available Authors were initially asked to respond
within 3 weeks, and additional time was provided to allow those making a positive response the
opportunity to provide the requested data Figure displays the results oI the search and data
acquisition strategies

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igure 1. $tudy $election and Data Acquisition
#easons Ior exclusion describe the Iirst reason Ior exclusion that was encountered during the
review process $everal articles had multiple reasons Ior exclusion #CTs indicates randomized
controlled trials; FDA, U$ Food and Drug Administration; ADM, antidepressant medication;
HD#$, Hamilton Depression #ating $cale
Participants
The sample consisted oI participants Irom the ADM and pill-placebo conditions oI 5 MDD
trialsDe#ubeis et al,
2
Dimidjian et al,
3
Elkin et al,
4
Philipp et al,
5
Wichers et al
6
and
minor depression trial, Barrett et al

Full descriptions oI the study designs, sample

characteristics, treatment protocols, and primary outcome Iindings have been reported
elsewhere
,2,3,4,5,6
Three studies used the tricyclic antidepressant imipramine
4,5,6
and 3
used the selective serotonin reuptake inhibitor paroxetine
,2,3
Table lists characteristics that
diIIer among the 6 studies The pooled sample used in the current analyses included 434 patients
in the ADM group and 24 patients in the placebo group Individual baseline HD#$ depression
severity levels ranged Irom 0 to 3 In comparison with the 7 identiIied studies Ior which data
were not available, the 6 included studies tended to have Jadad quality scores at the higher end oI
the range, to use Ilexible (as opposed to Iixed) medication doses, and to provide more
inIormation about the samples in the original report (eTable)
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Table 1. DiIIerences Between 6 $tudies oI Medications and Placebo Ior Depressed Outpatients
Statistical Analyses
Our primary statistical analysis investigated the relationship between baseline symptom severity
and subsequent symptom change Irom intake to the end oI acute treatment We used a modiIied
intent-to-treat approach whereby we used the most inclusive sample analyzed in the original
publication oI each oI the 6 studies (Table ) To investigate the association between initial
severity and symptom change scores in ADM vs placebo, we conducted analyses oI covariance
that controlled Ior the eIIect oI the study Irom which the data originated For individuals who
dropped out oI treatment, we used the patient's last score prior to dropout (last observation
carried Iorward) to calculate the change score Continuous variables were centered at their grand
means, and nonsigniIicant higher-order interaction terms were removed Irom the models Level
oI signiIicance was set at P 05
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RESULTS
Study haracteristics
Mean baseline depression severity scores and attrition rates Ior the 6 studies are displayed in
Table 2 A 2 6 (treatment study) analysis oI variance was conducted to examine diIIerences
in levels oI intake depression severity The study treatment interaction was not signiIicant and
was removed Irom the model Mean intake severity did not diIIer as a Iunction oI treatment
condition (F
,7
005, P 2), but the 6 studies did show diIIerent mean intake severity
levels, reIlecting diIIerences in inclusion criteria (F
5,7
756, P 00) Attrition rates were
compared in a logistic regression model examining the eIIects oI study, treatment, and the
study treatment interaction The study treatment interaction term was not signiIicant and was
removed Irom the model Attrition rates did not diIIer signiIicantly as a Iunction oI treatment
condition ( 047, P 4), but diIIerences did emerge in the rates oI attrition among the 6
studies ( 3034, P 00) (Table 2)
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Table 2. $ample $ize, Dropout #ates, and Baseline Depression $everity in 6 $tudies That
Compared Active Antidepressant Medications With Pill Placebo
Baseline Severity and Symptom hange in ADM and Placebo
Pooling the data across the 6 studies, the severity treatment interaction (the statistic oI primary
interest in this investigation) was signiIicant in a model that predicted depression change scores
controlling Ior study oI origin (F
,70
3, P 002) The main eIIects oI baseline severity
(F
,70
554, P 00) and treatment (F
,70
25, P 00) were also signiIicant
As displayed in Figure 2, the regression coeIIicient (ie, the slope representing the relation
between initial severity and change in symptoms) was positive Ior both ADM (b 070,
t
70
4, P 00) and placebo (b 036, t
70
37, P 00) The diIIerence in the slopes oI
the 2 regression lines, b 034, represents the interaction eIIect described earlier in this section
The 2 regression lines converged near the lower end oI the range oI baseline severity scores and
the magnitude oI the diIIerence between the treatments increased with increasing baseline
depression severity To illustrate the magnitude oI the diIIerence between the 2 treatments as a
Iunction oI initial depression severity, we divided the sample into 3 groups based on the
characterizations oI the HD#$ scores oIIered by the American Psychiatric Association mild to
moderate, HD#$ score oI or less (n 0); severe, HD#$ score oI to 22 (n 255); and
very severe, HD#$ score oI 23 or greater (n 23)
7
For patients in the mild to moderate range,
the Cohen d eIIect size was d 0 (5 conIidence interval, |CI|, 0 to 04) and Ior
patients in the severe range, d 07 (5 CI, 00 to 043) Both values were below the
standard description oI a small eIIect (d 020)

For patients in the very severe group, d 047

(5 CI, 022 to 07) This value was just below 050, the accepted cutoII Ior a medium eIIect
size We also converted these d eIIect sizes into estimates oI the number oI patients needed to
treat (NNT) to increase by the number oI patients in the treatment group who would have a
better outcome than a randomly selected patient Irom the control group

Number-needed-to-
treat values were estimated to be 6, , and 4 Ior the mild to moderate, severe, and very severe
subgroups, respectively

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igure 2. Observed and Estimated Change in HD#$ $cores Following Treatment With ADM
and Placebo
Circles represent observed (raw) mean change in depressive symptoms Irom intake to the end oI
treatment at each initial Hamilton Depression #ating $cale (HD#$) score Ior both the
antidepressant medication (ADM) and placebo conditions The size (area) oI the circles is
proportional to the number oI data points that contributed to each mean #egression lines
represent estimates oI change in depression symptoms Irom intake to end oI treatment Ior ADM
and placebo conditions as a Iunction oI baseline symptom severity These regression lines were
estimated Irom a model oI the baseline severity treatment interaction, controlling Ior the
eIIects oI the study Irom which the data originated The National Institute Ior Clinical Excellence
threshold Ior clinical signiIicance (an HD#$ point diIIerence _3) was met Ior intake HD#$
scores oI 25 or greater, indicated by the blue line
The National Institute Ior Clinical Excellence (NICE) oI the National Health $ervice in England
has deIined a threshold Ior clinical signiIicance as an eIIect size oI 050 or a drug/placebo
diIIerence oI 3 points on the HD#$
20
Using least-squares means Irom the primary model
described earlier in this section, we estimated that this threshold was met Ior intake HD#$ scores
oI 25 or greater, using the more liberal oI the 2 criteria (a diIIerence in HD#$ scores oI _3
points) To examine the more conservative threshold deIined by d 050, we estimated Cohen d
eIIect sizes, again using least-squares means estimates Irom the primary model Drug/placebo
diIIerences were estimated to cross this threshold at an initial HD#$ score oI 27 (NNT 4)
When we divided the sample into subgroups using these 2 thresholds, the superiority oI
medications over placebo was associated with a medium-sized eIIect Ior patients with HD#$
scores oI 25 or greater (d 053; 5 CI, 0 to 06) and a large eIIect Ior patients with HD#$
oI 27 or greater (d 0; 5 CI, 030 to 32)
Baseline Severity and Symptom hange for Patients With MDD
To determine whether the pattern oI results reported was evident in patients diagnosed with
MDD, data Irom the Barrett et al

study oI minor depressive disorder were removed and the

models were rerun The severity treatment interaction was again signiIicant (F
,633
63,
P 00) As beIore, the ADM/placebo diIIerence was estimated to cross the NICE criteria at an
initial baseline HD#$ score oI 25
Baseline Severity and Symptom hange for ompleters
To assess whether attrition might have biased the results, the primary analyses were repeated in a
completers-only sample Again the severity treatment interaction was signiIicant (F
,57
562,
P 02) Among completers, the diIIerence between ADM and placebo was estimated to cross
the NICE threshold at an initial HD#$ score oI 24 ( point lower than that observed Ior the
entire sample) We also repeated the primary analysis using data only Irom the 3 studies with the
lowest dropout rates
2,3,5
Again, the interaction oI interest was signiIicant (F
,452
6,
P 0)
Drug lass
Three oI the studies used the selective serotonin reuptake inhibitor paroxetine as the active
ADM, whereas the other 3 studies used the tricyclic antidepressant imipramine To investigate
whether baseline severity moderates treatment response in both drug classes, we conducted a
secondary analysis in which we replaced the term representing ADM/placebo with a categorical
variable representing medication type As in the primary analysis, the severity drug class
interaction was signiIicant (F
2,707
44, P 0) $peciIic contrasts revealed that the regression
coeIIicient (ie, the slope representing the relationship between initial severity and change in
symptoms) was more positive Ior each medication class relative to placebo imipramine,
F
,707
560, P 02, and paroxetine, F
,707
5, P 02
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OMMENT
The present Iindings indicate that the eIIicacy oI ADM treatment Ior depression varies
considerably as a Iunction oI symptom severity True drug eIIects (an advantage oI ADM over
placebo) were nonexistent to negligible among depressed patients with mild, moderate, and even
severe baseline symptoms, whereas they were large Ior patients with very severe symptoms For
baseline severity scores on the HD#$ less than 25, estimates oI the magnitudes oI drug/placebo
diIIerences did not meet either oI the 2 thresholds Ior clinical signiIicance proposed by NICE
20

Conversely, Ior patients with the highest levels oI baseline depression severity, ADM was
markedly superior to placebo
As documented in the analysis by Zimmerman et al

oI published eIIicacy trials, as well as in the

analyses by Kirsch et al
4
and Khan et al
5
oI studies submitted to the FDA, evidence concerning
the eIIects oI ADM in patients with mild and moderate MDD has been sparse Our Iindings add
substantially to knowledge oI the eIIects oI ADM across the Iull range oI symptom severity in
patients diagnosed with depression These Iindings are consistent with an understanding that has
inIormed the entry criteria used in ADM registration trials, in which cutoII scores oI or
greater typically have been imposed As noted by Zimmerman et al, using such cutoIIs can be
expected to exclude nearly halI oI all patients who meet diagnostic criteria Ior MDD
We note several limitations oI the present inquiry First, all oI the studies used in the current
investigation imposed a minimum baseline severity criterion Because only a small proportion oI
the patients registered baseline HD#$ scores oI 3 or lower, the results oI the current
investigation may not generalize to such individuals $econd, when a minimum score at intake is
required Ior study entry, study diagnosticians sometimes inadvertently inIlate the scores oI
patients whose true score is just below the cutoII
2
We have no evidence that this occurred in the
current data sets, but iI it did, it should have worked against the hypothesis that severity
moderates outcome Moreover, the inclusion oI studies with diIIerent minimum severity levels
should have mitigated any bias that such rater inIlation might have caused Third, scores on the
HD#$ were used as the primary outcome measure Ior all analyses The HD#$ has been the most
commonly used measure oI depression symptom severity in clinical trials oI ADM, but the
measure's psychometric properties have been criticized
22,23
Future eIIorts might use alternative
symptom measures to examine the eIIects oI baseline severity on treatment outcome Fourth,
because Iew studies in the literature report the magnitude oI the baseline severity treatment
interaction eIIect, it is diIIicult to assess the role oI publication bias in this report For a detailed
account oI publication bias regarding the main eIIect oI ADM, see Turner et al
24
Finally, the
results reported herein apply to acute treatment only and not to continuation or maintenance
treatment
Despite diIIerences in methods, our Iindings are consistent with those oI both Kirsch et al
4
and
Khan et al
5
that ADM/placebo diIIerences increase as initial severity increases We used
individual patient data and included patients with less severe depression, whereas both Kirsch et
al and Khan et al analyzed group means that largely excluded patients with HD#$ scores below
20 Moreover, both Kirsch et al and Khan et al included studies that screened out pill-placebo
responders prior to randomization, whereas the studies Irom which our data were drawn did not
Given these diIIerences, the consistency oI the primary Iinding across the 3 reviews is striking
However, there also were subtle diIIerences in the pattern oI Iindings across the 3 investigations
that likely reIlect additional diIIerences in methodology For example, using within-group eIIect
sizes, Kirsch et al Iound that initial severity was unrelated to outcome among patients treated
with ADM but negatively related to outcome among placebo patients, whereas using between-
group comparisons, Khan et al Iound that initial severity predicted greater symptom change
among ADM patients (as did we using individual patient data) but was unrelated with respect to
placebo patients (whereas we Iound a small positive relationship) Given these inconsistencies, it
would be premature to speculate regarding whether the increasing superiority oI ADM relative to
placebo as severity increases is due to an increasing eIIicacy oI ADM or a declining eIIicacy oI
placebo $uch a distinction depends, in part, on the index oI change that is chosen
$everal studies have demonstrated that ADM is superior to placebo Ior patients diagnosed with
dysthymia, a condition partly deIined by lower symptom levels relative to MDD
25,26
The
dysthymia studies indicate that ADM can produce a true drug eIIect in patients with mild or
moderate depressive symptoms However, dysthymia is by deIinition a chronic condition, and
chronicity is known to be associated with poor response to placebo
27,2
Thus, it may be the
chronic nature oI dysthymia that explains the advantage oI ADM over placebo in this condition
Future work should examine whether chronicity moderates ADM/placebo diIIerences across the
range oI baseline severity
The general pattern oI results reported in this work is not surprising As early as the 50s,
researchers conducting controlled investigations oI treatments Ior a wide variety oI medical and
psychiatric conditions described a phenomenon whereby patients with higher levels oI severity
showed greater diIIerential (ie, speciIic) beneIit Irom the active treatments
2,30
What makes our
Iindings surprising is the high level oI depression symptom severity that appears to be required
Ior clinically meaningIul drug/placebo diIIerences to emerge, particularly given the evidence that
the majority oI patients receiving ADM in clinical practice present with scores below these
levels
Prescribers, policy makers, and consumers may not be aware that the eIIicacy oI medications
largely has been established on the basis oI studies that have included only those individuals with
more severe Iorms oI depression This important Ieature oI the evidence base is not reIlected in
the implicit messages present in the marketing oI these medications to clinicians and the public
There is little mention oI the Iact that eIIicacy data oIten come Irom studies that exclude
precisely those MDD patients who derive little speciIic pharmacological beneIit Irom taking
medications Pending Iindings contrary to those reported here and those obtained by Kirsch et al
and Khan et al, eIIorts should be made to clariIy to clinicians and prospective patients that
whereas ADM can have a substantial eIIect with more severe depressions, there is little evidence
to suggest that they produce speciIic pharmacological beneIit Ior the majority oI patients with
less severe acute depressions
Previous $ectionNext $ection
Author Information
Author Affiliations: Departments of Psychology (Mr Fournier and Dr DeRubeis) and
Psychiatry (Dr Amsterdam), University of Pennsylvania, Philadelphia, Departments of
Psychology (Dr Hollon) and Psychiatry (Dr Shelton), Janderbilt University, Nashville,
Tennessee, Department of Psychology, University of Colorado at Boulder (Dr
Dimidfian), and Department of Psychiatry, University of New Mexico School of
Medicine, Albuquerque (Dr Fawcett)
orresponding Author: Jay C Fournier, MA, Department oI Psychology, University oI
Pennsylvania, 3720 Walnut $t, Philadelphia, PA 04 (jcIsasupennedu)
Author ontributions: Mr Fournier had Iull access to all oI the data in the study and takes
responsibility Ior the integrity oI the data and the accuracy oI the data analysis
Study concept and design Fournier, De#ubeis, Hollon, Dimidjian, Amsterdam, $helton,
Fawcett
Acquisition of data Fournier, De#ubeis, Hollon, Dimidjian, Amsterdam, $helton, Fawcett
Analysis and interpretation of data Fournier, De#ubeis, Hollon, Dimidjian, Amsterdam,
$helton, Fawcett
Drafting of the manuscript Fournier, De#ubeis, Hollon
Critical revision of the manuscript for important intellectual content Fournier, De#ubeis,
Hollon, Dimidjian, Amsterdam, $helton, Fawcett
Statistical analysis Fournier, De#ubeis
Obtained funding De#ubeis, Hollon, Amsterdam
Administrative, technical, or material support Fournier, De#ubeis, Hollon, Dimidjian,
Amsterdam, $helton, Fawcett
inancial Disclosures: Dr Amsterdam reported serving on the speakers' bureau oI Wyeth
Pharmaceuticals and Bristol Myers $quibb; receiving research support Irom Novartis, Eli Lilly,
$anoIi, Cephalon, and Forest Laboratories; and serving as a consultant Ior Bristol Myers $quibb
Dr $helton reported serving as a consultant to AstraZeneca, Eli Lilly, Evotec, Forest
Pharmaceuticals, Gideon #ichter, Janssen Pharmaceuticals, Merck, Novartis Pharmaceuticals,
Ostuka Pharmaceuticals, Pamlab, PIizer, #epligen, $ierra Neuropharmaceuticals, and Wyeth;
receiving speaking honoraria Irom AstraZeneca, Eli Lilly, Forest Pharmaceuticals,
Glaxo$mithKline, Pamlab, PIizer, and Wyeth; and receiving research and/or grant support Irom
Bristol Myers $quibb, Eli Lilly, Evotec, Forest Pharmaceuticals, Glaxo$mithKline, Janssen
Pharmaceuticals, Novartis Pharmaceuticals, Ostuka Pharmaceuticals, Pamlab, PIizer, #epligen,
and Wyeth Dr Fawcett reported serving as a consultant to Abbott Laboratories, Merck, and
$lack; receiving speaking honoraria Irom Eli Lilly; and serving as a board member Ior the
Berman Center and on the scientiIic advisory boards Ior the nonproIit advocacy organizations
NA#$AD and the Depression and Bipolar $upport Alliance Dr Fawcett also reported providing
expert testimony on cases involving pharmaceutical companies including Banner Health and
Alphapharm and currently chairing the Mood Disorders Work Group Ior the Iorthcoming
revision oI the Diagnostic and Statistical Manual of Mental Disorders (FiIth Edition) No other
disclosures were reported
unding/Support: This research was supported by grants MH502 (#0), MH5575 (#0),
MH067 (K02), MH074 (K24), and MH060 (#0) Irom the National Institute oI Mental
Health, Bethesda, Maryland
Role of the Sponsor: The Iunding sources had no role in the design and conduct oI the study; in
the collection, analysis, and interpretation oI the data; or in the preparation, review, or approval
oI the manuscript
Additional ontributions: We thank the authors who shared their data with us Ior this project,
with special thanks to Marieke Wichers, PhD, Maastricht University, $chool Ior Mental Health
and Neuroscience; John Cornell, PhD, University oI Texas Health $cience Center; and Karl-O
Hiller, PhD, $teiner Arzneimittel, Ior providing us with the raw data Irom their respective
studies Finally, we thank all those who responded to our inquiries, even iI data Irom their
studies could not be made available None were compensated Ior their contributions












Northeast monsoon to bring rain over
Northern, entral Luzon-Pagasa
8y lrances Mangoslng
lnCul8L8neL
830 am | Wednesday november 23rd 2011

MT$AT ENHANCED I# $atellite Image Ior am, 23 November 20
MANILA, Philippines A northeast monsoon prevailing over Northern and Central Luzon is
expected to bring scattered rains and isolated thunderstorms in these regions, the Philippine
Atmospheric Geophysical and Astronomical $ervices Administration said Wednesday
'Northern and Central Luzon will experience mostly cloudy skies with scattered rainshowers and
isolated thunderstorms becoming cloudy with widespread rains over the eastern section which
may trigger IlashIloods and landslides, while the rest oI the country will have partly cloudy to
cloudy skies with isolated rainshowers or thunderstorms, it also said
Moderate to strong winds blowing Irom the Northeast will prevail over Luzon and Visayas and
the coastal waters along these areas will be moderate to rough, the state weather bureau said
Elsewhere, winds will be light to moderate coming Irom the northeast with slight to moderate
seas, Pagasa said




uinness: Smallest Man in the World 2011 - ilipino man, 23.5 inches (Video)
are
18

In our article written last June , Junrey Balawing, Filipino, is expected to be crowned on his
th birthday in $indangan, Zamboanga del Norte the title "The $mallest Man in the World" We
also reported that Junrey will not only be the shortest living man on earth but he will also hold
the title oI "$hortest Living Man in History"

Pls lnlLlal elgL before Cra|g G|enday edlLorlnclef of Le Culnness 8ook of World 8ecords measured
8alawlngs was 22 lnces !usL recenLly Loday LaL Clenday Lold AssoclaLed ress and [ournallsLs LaL
!unrey 8alawlng ls Le worlds sorLesL man

Pls offlclal record ls 3993 cenLlmeLers or 233 lnces

A loL of wlses as e celebraLed ls blrLday Loday !une 12 came ouL from commenLs of readers from
Lousands of webslLes Wlsers wls lm good luck good ealL and long llfe

!unrey wlll soon Lravel Lo oLer counLrles lncludlng Luropeans and Le unlLed LaLes and make some
speclal 1v appearances

ource LLp//wwwbazlcsneL/2011/06/gulnnesssmallesLmanlnworld2011Lml#lxzz1ee9v79zC