Affective temperamental profiles are associated with white matter hyperintensity and suicidal risk in patients with mood disorders

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Affective temperamental profiles are associated with white matter hyperintensity and suicidal risk in patients with mood disorders
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  Research report Affective temperamental pro fi les are associated with white matterhyperintensity and suicidal risk in patients with mood disorders Gianluca Sera fi ni a, ⁎ , Maurizio Pompili a,b , Marco Innamorati c , Paolo Fusar-Poli d ,Hagop S. Akiskal e , Zoltan Rihmer f ,k , David Lester g , Andrea Romano h , Irismar Reis de Oliveira i ,Leonardo Strusi  j , Stefano Ferracuti a , Paolo Girardi a , Roberto Tatarelli a a Department of Neuroscience, Mental Health and Sensory Functions  –  Sant'Andrea Hospital, Sapienza University of Rome, Italy b McLean Hospital  –  Harvard Medical School, USA c Università Europea di Roma, Italy d Psychosis Clinical Academic Group, Institute of Psychiatry, King's Health Partners, King's College London, UK  e International Mood Center at the University of California at San Diego and V.A. Hospital, USA f  Department of Clinical and Theoretical Mental Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary g The Richard Stockton College of New Jersey, USA h Department of Neuroradiology  –  Sant'Andrea Hospital, Sapienza University of Rome, Italy i Department of Neurosciences and Mental Health, Federal University of Bahia, Brazil  j Casa di Cura  “  Samadi ”  , Italy k International Mood Center, USA a r t i c l e i n f o a b s t r a c t  Article history: Received 3 June 2010Accepted 17 July 2010Available online 12 August 2010 Background:  Patients with white matter hyperintensities (WMH) may be at higher risk foraffective disorders and suicide. Affective temperaments may play a signi fi cant role in mooddisorders. This study aimed to evaluate the eventual association between WMH, affectivetemperaments and suicidal behaviour in major affective disorder. Methods:  A total of 318 patients with major affective disorders were consecutively admitted aspsychiatric inpatient. A total of 247 were included and given, brain magnetic resonance imaging(MRI) and assessed with the Mini International Neuropsychiatric Interview (MINI), the BeckHopelessness Scale (BHS), the Hamilton Depression Rating Scale (HDRS 17 ), the Young ManiaRating Scale (YMRS) and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego(TEMPS-A). Results:  A total of 48% of patients had periventricular WMH (PWMH) and 39% of them had deepWMH (DWMH). Patients with higher dysthymia and lower hyperthymia (H-DCIA group) weremorelikelytohavehigherBHSscores(BHS ≥ 9=77%vs.52%;  p N 0.001),moreWMH(46%vs.29%; χ  2 n =3 =9.90;  p b 0.05),higherMINI suicidalrisk (54%vs. 42%;  p b 0.05), and more recent suicideattempts(24%vs.14%;  p b 0.05),thanpatientswithhigherhyperthymiaandlowerdysthymia(H-H group). Limitations:  The small sample size did not allow the generalization of the present  fi ndings. Conclusions: DifferencesamongtemperamentgroupsmeasuredbytheTEMPS-Aareassociatedwithdifferences in their MRIs, indicating that different temperament pro fi les are associated withdifferencesinthesubcorticalstructuresofthebrain.Theimplicationsoftheresultswerediscussed.© 2010 Elsevier B.V. All rights reserved. Keywords: MRIMood disordersSuicidal riskAffective temperamentsPWMHDWMH 1. Introduction White matter hyperintensities (WMH) appear as hyper-intense signals on T2-weighted magnetic resonance images  Journal of Affective Disorders 129 (2011) 47 – 55 ⁎  Corresponding author. Department of Neuroscience, Mental Health andSensoryFunctions,UniversityofRome,Sant'AndreaHospital,ViaGrottarossa1037, Rome 00189, Italy. Tel.: +39 0633775675; fax: +39 0633775342. E-mail address:  gianluca.sera fi ni@uniroma1.it (G. Sera fi ni).0165-0327/$  –  see front matter © 2010 Elsevier B.V. All rights reserved.doi:10.1016/j.jad.2010.07.020 Contents lists available at ScienceDirect  Journal of Affective Disorders  journal homepage: www.elsevier.com/locate/jad  (MRI) and represent ependymal loss and differing degrees of myelination in the brain (Thomas et al., 2002a,b). WMHs,depending on the localization, are commonly classi fi ed asperiventricular white matter hyperintensities (PWMH) anddeepwhitematterhyperintensities(DWMH)havingmainlyavascular aetiology. WMH are reported to be commonlyassociated with older age and cardiovascular risk factorssuch as hypertension and diabetes (Ovbiagele and Saver,2006; Steffens and Krishnan, 1998; Videbech, 1997). Degen-erative changes in brain WM have been reported to beassociated with mood disorders and suicidal behaviour bothin children and young adults (Ehrlich et al., 2004, 2005;Pompilietal.,2007)whiletheyarenotspeci fi cto fi rstepisodepsychotic disorders (Zanetti et al., 2008). Taylor andcolleagues hypothesized that patients with WMHs may beat higher risk for developing mood disorders and suicidebecause of possible disruption of neuroanatomic pathways(Taylor et al., 2001). Mood regulation depends on the com-plex extensive connections between the prefrontal cortex,amygdala – hippocampus complex, thalamus and basal gan-glia (Soares and Mann, 1997).Those brain structures linked to mood regulation may beinvestigated and measured with MRI. Also, mood disordersrange from subthreshold affective temperament traits mea-sured by the TEMPS-A (Akiskal and Akiskal, 2005) throughminorandmajormooddisorderstosevereaffectivepsychosis(Akiskal et al., 1979; Akiskal and Mallya, 1987; Parker, 2003;Rihmer et al., 2010; Oedegaard et al., 2009). Affectivetemperaments are also conceptualized and measured bymoretraditionalpsychometricmeasuressuchastheNEOFiveFactor Inventory (McCrae and John, 1992; Costa and Mccrae,1992, 1995) and the MMPI (Trull et al., 1995) and may play a signi fi cant role in the psychopathological characteristics of mood disorders including the clinical evolution of minor/ major mood episodes, the direction of polarity, the clinicalsymptomatology, the long-term course, suicidality and evenmedication adherence (Akiskal et al., 1979; Akiskal andMallya,1987;Rihmeretal.,2010;Oedegaardetal.,2009;Laraet al., 2006; Sayin and Aslan, 2005; Akdeniz et al., 2004;Liraud and Verdoux, 2001).Individuals with a hyperthymic temperament are oftenseen as strong, energetic, productive, and well-respected,whereas the cyclothymic temperament is a pattern of alternation between hypomanic or irritable moods, anddepressive moods, cognitions, and behaviours. The associa-tion between affective temperament, suicidal behaviour andMRI abnormalities is complex and largely unclear.Rihmer et al. (2009) investigated the role of affectivetemperaments in suicidal behaviour using the TEMP-A andcompared the affective temperament pro fi les of 150 consecu-tively non-violent suicide attempters and 302 age, sex andeducation matched normal controls. They found that, com-pared to controls, both female and male suicide attemptersscored signi fi cantly higher in the more frequent depressive,cyclothymic,irritableandanxiousaffectivetemperaments.Thehyperthymictemperament,characteristicforbipolarIdisorder,was not signi fi cantly less common among suicide attempters,whereas the cyclothymic temperament is characteristic forbipolar II disorder and the depressivetemperament prevailsinunipolar majordepression.Additionally,degenerative changesin brain WM have been reported to be associated both indepressed young adults and in children and adolescents withmajor affective disorders and suicidal behaviour (Ehrlich et al.,2004, 2005; Pompili et al., 2007). Pompili et al. (2007) have shown, after logistic regression analysis in 99 inpatients withmajor affective disorders, that the presence of PWMH isrobustly associated with suicidal behaviour.Based on previous evidence, we hypothesized that sometemperamental traits, like depressive, cyclothymic, irritableand anxious temperaments eventually linked withWMH,mayplay a more signi fi cant role as endophenotypes than thehyperthymic temperament in the context of mood disordersand suicidality. The present study  fi rst aimed to evaluatewhether the presence of WMH is associated with affectivetemperaments and suicidal behaviour in patients with majoraffective disorders and then whether WMH in addition tospeci fi c temperament pro fi les might be a useful biologicalpredictor of suicidal behaviour. To our current knowledge,there are no data linking white matter abnormalities, affectivetemperaments and suicidal behaviour in mood disorders. 2. Methods  2.1. Participants and study design From September 2007 to September 2009, a total of 318white Italian patients were consecutively admitted to thepsychiatric inpatient units of Sant'Andrea Hospital and the “ Samadi Clinic ”  in Rome. The inclusion criterion was a DSM-IV-TR diagnosis of major affective disorders (unipolar majordepressive disorder, bipolar disorder type I, bipolar disordertype II) (American Psychiatric Association, 1994). Of the 318subjectswhowereeligibleforthestudy,45werenotincludedin the  fi nal sample because they had other psychiatricdiagnoses; 84% of them were excluded because they werediagnosed with schizophrenia and 16% with personalitydisorders. 26 patients were excluded because 53.8% refusedto undergo the MRI scans (they could not complete the scanas a result of claustrophobic reactions) and 46.2% becausethey decided not to participate in research or complete thetemperament measures. Patients excluded from the studyhad similar demographic characteristics and did not differsigni fi cantly from the patients included in the  fi nal samplewith respect to clinical variables, diagnosis or history of suicide attempts. The  fi nal sample consisted of 247 patients(118 men, 129 women). Demographic and clinical character-istics of the sample are presented in Table 1.Clinical and socio-demographic information was takenfrom medical records by two researchers independently. Incases of disagreement, a third party was consulted. Bloodpressure, glycemia, triglycerides, and total cholesterol wereretrieved from of  fi cial medical records. Hypertension wasde fi ned as the presence of more than 140 mm Hg for systolicblood pressure, and 90 mm Hg for diastolic blood pressureand/or current use of antihypertensive medication ( JointNational Committee on Detection E, and Treatment of highblood pressure, 1997).Current severity of affective symptomatology was evalu-ated using the YMRS (Young et al., 1978) and the HDRS(Hamilton, 1960). Participants were additionally adminis-tered the MINI (Sheehan et al., 1998), the BHS (Beck et al., 48  G. Sera  fi ni et al. / Journal of Affective Disorders 129 (2011) 47  – 55  1974; Beck and Steer, 1989) and the TEMPS-A (Akiskal andAkiskal, 2005).Exclusion criteria were: presence of neurological disorder(e.g., epilepsy, multiple sclerosis, and Alzheimer's Disease,dementia), diagnosis of other major psychiatric disorders byDSM-IV criteria; family history of dementia; presence of structural MRI  fi ndings compatible with stroke or other grossbrain lesions or malformations; and history of electroconvul-sive therapy in the past 6 months. Subjects participatedvoluntarily in the study, and each subject provided writteninformed consent. The study protocol received ethics ap-proval from the local research ethics review board.  2.2. Magnetic resonance image acquisition and rating of whitematter hyperintensities Brain MRIs were performed using a Siemens Sonata,Erlangen,Germany(1.5 T).TheFLAIRscansequencewasusedfor WMH measurement (ax: TR 10000; TE 125; thickness5 mm; matrix 144×256). Proton density and T2-weightedimages were obtained (PD and T2 ax: TR 2870; TE 13/107;thickness 5 mm; matrix 147×256) in the axial and thecoronal planes. Axial and sagittal T1-weighted images werealso obtained (T1 ax: TR 647; TE 17; thickness 5 mm; matrix128×192 T1 sag: TR 552; TE 17; thickness 5 mm; matrix231×192). The presence of WMH was assessed by aneuroradiologist blind to all clinical information, using themodi fi ed Fazekasfour-pointratingscale whichdescribes MRIhyperintensities on an ascending scale of intensity andfrequency (Coffey et al., 1993). A second neuroradiologist,blind to all clinical information and previous ratings,reviewed all MRI  fi lms. The mean  k  value for interraterreliability for both PWMH and DWMH was 0.90.  2.3. Measures: clinical assessment  2.3.1. MINI  TheMINIisaclinicallyadministeredtoolinuseinourunit,soon after the admission. One section of this instrument isdeveloped to assess suicidal risk, with questions about pastand current suicidality (Sheehan et al., 1998). The MINI is ashort structured interview with high validity and reliabilitydeveloped to explore 17 disorders according to DSM-III-R (Amorim et al., 1998). Although the MINI should not be asubstitute for a psychiatric clinical interview, validationstudies con fi rm the validity of this instrument as a reliabletoolinpsychiatry(Sheehanetal.,1998).MINIdiagnoseswerecon fi rmed by clinical DSM-IV-TR diagnoses. Clinical diagno-ses were assigned by a staff psychiatrist and an attendingphysician who were blind to the results of MINI and MRI.  2.3.2. TEMPS-A The TEMPS-A is a new self report measure of the affectivetemperament with 110 items that de fi nes the bipolarspectrum,with depressive (D),cyclothymic (C), hyperthymic(H), irritable (I), and anxious (A) subscales (Akiskal andAkiskal, 2005). The scale is different from most othertemperament scales in that it taps subaffective trait expres-sions as they were conceptualized in Greek psychologicalmedicine and, in more modern times, German psychiatry.Additionally, the TEMPS-A is not affected by current moodstate (e.g., depressive  vs.  manic) and is able to identifytemperament pro fi les reliably in psychiatric inpatients with  Table 1 Sociodemographic characteristics of the two groups (higher dysthymia, cyclothymia, irritability, and anxiety and lower hyperthymia — H-DCIA; and higherhyperthymia, and lower dysthymia, anxiety, and cyclothymia — H-H). The 2-group solution (BIC change= − 127.70; ratio of distance measures=2.23) wasindicated by the Two Step Cluster Analysis procedure. Only TEMPS-A Hyperthymic trait contributed negatively to the composition of the  fi rst group compared toother traits, whereas the most signi fi cant positive trait in the composition of the group was the TEMPS-A Dysthymic trait. Conversely, TEMPS-A Hyperthymic traitcontributed signi fi cantly in the positive way in the composition of the second group, while TEMPS-A Dysthymia, Anxiety, and Cyclothymia signi fi cantlycontributed in a negative way the composition of the group (H-H — high hyperthymia).H-DCIA group( n =140)H-H group( n =107)Test Signi fi cance OR Log-OR 95% con fi denceinterval  p -valueVariables (Referencecategory is:H-H group)LowerboundUpperboundMen 50.0% 44.9% 0.25Age — mean (SD) 48.28 (15.05) 48.09 (15.90)  t  =0.09 0.93BD (BD 1) 72.9% (59.3%) 77.6% (56.1%) 0.24Substance misuse  χ  2 n =3 =0.67 0.88Alcohol 15.7% 16.8%Illicit drugs 17.9% 16.8%Alcohol+Illicit drugs 1.4% 2.8%Recent suicide attempts 23.6% 14.0% 0.05 1.92 0.65  − 0.06 1368.00 0.07Lifetime suicide attempts 42.1% 42.1% 0.55Lifetime suicidal ideation 52.1% 53.3% 0.48PWMH  χ  2 n =3 =2.82 0.421 31.4% 34.6%2 17.9% 10.3%3 0.7% 0.9%DWMH  χ  2 n =3 =9.90 0.051 39.3% 21.5% 2.48 0.91 0.29 1520.00 0.0012 5.0% 6.5% 1.06 0.06  − 1.10 1221.00 0.923 2.1% 0.9% 2.73 1.00  − 1.31 3318.00 0.40Loglinear model statistics: likelihood ratio  χ  2 n =25 =12.49;  p =0.98.49 G. Sera  fi ni et al. / Journal of Affective Disorders 129 (2011) 47  – 55  severe Axis-I psychopathology presumably combined withlife crises leading to hospitalization (Akiskal et al., 2005).  2.3.3. BHS  The BHS is a 20-item scale for measuring negativeattitudes about the future (Beck et al., 1974). This powerfulpredictorofeventualsuicideaddressedthreemajoraspectsof hopelessness: feelings about the future, loss of motivationand expectations. Research consistently supports a positiverelationshipbetweenBHSscoresandmeasuresofdepression,suicidal intent and current suicidal ideation (Beck et al.,1990).TheBHSmay,therefore,beusedasaproxyindicatorof suicide potential. In the series reported in 1985 91 of peoplewho died by suicide had a score  ≥ 10 while only 9% had ascore  ≤ 9, so the BHS cutoff score as 9 or higher (Beck et al.,1985).  2.3.4. HDRS  17   and YMRS  The HDRS 17  (Hamilton, 1960), a 17-item clinician-ratedscale, was used to evaluate depressive symptom severity. TheYMRS is an 11-item rating scale for mania that explores manicsymptoms and is considered the gold standard for evaluatingthe concurrent validity of bipolar mania with newer scales(Young et al., 1978). HAMD 17  and YMRS were given primarilyto assess the severity of mood symptoms (Table 2). 3. Statistical analysis In order to reveal temperament groupings (or clusters)within the data set, we used a Two Step Cluster Analysisprocedure. This procedure can handle categorical andcontinuous variables, using a likelihood distance measurewhich assumes that variables in the cluster model areindependent. Continuous variables are assumed to have anormal (Gaussian) distribution and categorical variables areassumed to have a multinomial distribution. Empiricalinternal testing indicates that the procedure is fairly robustto violations of both the assumption of independence anddistributional assumptions. The two steps of the Two StepCluster Analysis procedure's algorithm can be summarized asfollows: 1) the procedure begins with the construction of aCluster Features (CF)Tree. The tree beginsby placing the fi rstcaseattherootofthetreeinaleafnodethatcontainsvariableinformation about that case. Each successive case is thenadded to an existing node or forms a new node, based uponits similarity to existing nodes and using the distancemeasure as the similarity criterion. A node that containsmultiple cases contains a summary of variable informationabout those cases. Thus, the CF tree provides a capsulesummary of the data  fi le. 2) The leaf nodes of the CF tree arethen grouped using an agglomerative clustering algorithm.The agglomerative clustering can be used to produce a rangeof solutions. To determine which number of clusters is  “ best ” ,each of these cluster solutions is compared using Schwarz'sBayesian Criterion (BIC) or the Akaike Information Criterion(AIC) as the clustering criterion. For the analysis, we let theprocedure automatically determine the number of clusters,and we selected the log-likelihood distance measure and theSchwarz's Bayesian Criterion (BIC) as clustering criteria.One-way Fisher exact tests, chi-squared tests ( χ  2 ),ANOVAs, and  t   tests were used for bivariate analyses. Allvariables which were signi fi cantly associated with thetemperament groups were entered in a logit loglinearmodel analysis as independent variables, with the tempera-ment groups as dependent variables, to measure themultivariate associations. Odds ratio (OR) and log-OR withtheir 95% con fi dence intervals (CI) were used as measures of association. If not otherwise indicated, statistical tests aretwo-tailed with  p ≤ 0.05. All analyses were performed withthe SPSS 13.0 statistical package. 4. Results 4.1. Clinical characteristics of the sample Patientswere185BD(75%;143BDI, and42BDII),and62MDD (25%). Sixteen percent of the patients reported currentalcohol misuse, 17% reported current use of illicit drugs, and2% reported current alcohol misuse and illicit drugs use asassessed by the MINI.All the patients had a HDRS 17  of 14 or higher indicatingmoderate to severe depression ( M  =29.1; SD=6.2). Patientshadanaveragescoreof10.9(SD=6.9;11.4±7.3fortheBDvs.9.3±5.5 for the MDD;  t  245 =2.12;  p b 0.05) on the YMRS.  Table 2 Psychometric characteristics of the two groups (high dysthymia, cyclothymia, irritability, and anxiety and low hyperthymia — H-DCIA; and high hyperthymia, andlow dysthymia, anxiety, and cyclothymia — H-H).H-DCIA group( n =140)H-H group( n =107)Test Signi fi cance OR Log-OR 95% con fi denceinterval  p -valueVariables (Referencecategory is:H-H group)LowerboundUpperboundTEMPS-A Dysthymia — mean (SD) 17.11 (2.97) 9.27 (4.29)  – – TEMPS-A Cyclothymia — mean (SD) 13.98 (4.24) 10.80 (4.58)  – – TEMPS-A Hyperthymia — mean (SD) 3.88 (2.82) 12.00 (4.94)  – – TEMPS-A Irritability — mean (SD) 10.78 (3.64) 8.95 (4.82)  – – TEMPS-A Anxiety — mean (SD) 17.44 (4.83) 12.10 (5.149)  – – Higher MINI suicidal risk 53.6% 42.1% 0.05 1.67 0.52  − 0.04 1064.00 0.07BHS ≥ 9 77.1% 52.3% 0.001** 2.88 1.06 0.49 1625.00 0.001BHS — mean (SD) 11.50 (4.63) 8.48 (4.49)  – HAMD 17 — mean (SD) 29.60 (5.67) 28.34 (6.75) 0.12YMRS — mean (SD) 10.21 (5.89) 11.76 (8.06) 0.08Loglinear model statistics: likelihood ratio  χ  2 n =25 =12.49;  p =0.98.50  G. Sera  fi ni et al. / Journal of Affective Disorders 129 (2011) 47  – 55  Patients had a mean score of 10.2 (SD=4.8) on the BHS with66% of the sample reporting scores of 9 or higher. 4.2. Suicide risk A total of 49% of the patients were at higher risk of suicideon the MINI interview among all patients with mooddisorders; 42% reported lifetime suicide attempts and 53%lifetime suicidal ideation. 4.3. MRI results The MRI indicated that 48% of patients had PWMH (morethan 15% had PWMH of 2 or higher on the modi fi ed Fazekasscale),and39%ofthemhadDWMH(morethan7%hadDWMHof 2 or higher on the modi fi ed Fazekas scale). We calculatedSpearman's rho indices for the correlations between PWMH,DWMH, hypertension,diabetes, total cholesterol, triglycerides,and number of daily cigarettes in this sample of patients; theanalysesindicatedthattheseverityofPWMHisassociatedonlywith the blood level of triglycerides (Spearman rho=0.26;  p b 0.05). All other indices were not signi fi cant. 4.4. Temperament pro  fi les and groups composition Subjects with BD type I were more likely to be cyclothymiccomparedtosubjectswithMDD(13.3vs.11.42  p =0.05)whilesubjects with BD type I and II were more likely to behyperthymic compared to subjects with MDD (7.54 vs. 9.60vs.5.58  p =0.001).Therewerenosigni fi cantassociationsinthedescriptiveanalysesandmultiplecomparisonsbetweenWMHsand affective temperaments (data not shown).The Two Step Cluster Analysis procedure indicated a 2-group solution (BIC change= − 127.70; ratio of distancemeasures=2.23).Temperamentcharacteristics ofthegroupsare listed in Table 1 and Figs. 1 and 2. TEMPS-A Hyperthymic trait contributed negatively to the composition of the  fi rstgroup, while other traits contributed positively to itscomposition (H-DCIA — High dysthymic, cyclothymic, irrita-bility, and anxiety;  n =140); however, the most signi fi cantpositivetrait in the composition of the groupwasthe TEMPS-Adysthymictrait.Conversely,theTEMPS-Ahyperthymictraitcontributed signi fi cantly in a positive way to the compositionof the second group,whilethe TEMPS-Adysthymia, TEMPS-Aanxiety, and TEMPS-A cyclothymia contributed signi fi cantlyto the composition of the group but in a negative way (H-H — High hyperthymia;  n =107). Thus, the H-H group is mostlycharacterizedbypatientswithhigherhyperthymiaandlowerdysthymia, while the H-DCIA group is mostly characterizedby patients with higher dysthymia and lower hyperthymia.Furthermore, differences among the groups were con- fi rmed by 4 (out of 13) differences on clinical and radio-graphic variables (see Table 1). Patients in the H-DCIA groupwere more likely to have higher BHS (BHS ≥ 9=77% vs. 52%;  p N 0.001),moreDWMH(46%vs.29%; χ  2 n =3 =9.90;  p b 0.05),higher MINI suicidal risk (54% vs. 42%;  p b 0.05), and morerecent suicide attempts (24% vs. 14%;  p b 0.05), than patientsintheH-Hgroup.EvenwhendichotomizingthewhitematterintensitiesusingFazekasscoresintoabsencevs.presence,thepattern of associations did not change (not reported in the Fig. 1.  Relative contribution of temperamental traits in the formation of the H-DCIA group (higher dysthymia, anxiety, cyclothymia, and irritability, and lowerhyperthymia) — bars indicate contribution of each temperamental trait; the dashed vertical lines mark the critical values for determining the signi fi cance of eachvariable (for a variable to be considered signi fi cant, its  t   statistic must exceed the dashed line in either a positive or negative direction).51 G. Sera  fi ni et al. / Journal of Affective Disorders 129 (2011) 47  – 55
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