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Brain White-Matter Hyperintensities and Treatment Outcome in Major BRITISH JOURNAL OF PSYCHIATRY (2006),(2006),188,180^185 188, 180^185 AUTHOR’ S P ROOF Brain white-matter hyperintensities and treatment Participants were required to have a score of 16 or over on the 17-item Hamilton Rating outcome in major depressive disorder Scale for Depression (HRSD; Hamilton, 1967) at the screening visit. We excluded people who failed to respond during the DAN V. IOSIFESCU, PERRY F. RENSHAW, IN KYOON LYOO, HO KYU LEE, current episode of depression to at least ROY H. PERLIS, GEORGE I. PAPAKOSTAS, ANDERW A. NIERENBERG one adequate antidepressant trial. and MAURIZIO FAVA Treatment-resistant major depressive disorder Nineteen participants (mean age 39.6 years, s.d.s.d.¼9.8), of whom 10 (52.6%) were womenwomen,, were recruited at the Depression Background An increased incidence The association between major depressive Clinical and Research Program at Massa- of brain white-matter hyperintensities has disorder and increased prevalence of brain chusetts General Hospital for a clinical trial white-matter hyperintensities has been re- in people with treatment-resistant depres- been describedinmajordepressive ported in elderly people (Krishnan et aletal,, sion, beginning with open-label nortripty- disorder, butthebuttheimpactof impactof such 1997; de Groot et aletal, 2000), but studies in line (Nierenberg et aletal, 2003). Patients hyperintensities on treatment outcome is younger patients have been inconclusive eligible for inclusion were men and women still controversial. (Coffey(Coffey et aletal, 1993; Lenze et aletal, 1999; Lyoo aged 18–70 years with major depressive et aletal, 2002). In samples of elderly people disorder diagnosed using the SCID–P and Aims ToinvestigateTo investigate the relationship of with depression, such hyperintensities were a score on the HRSD of at least 18. brain white-matter hyperintensities with associated with lower rates of response to Treatment resistance was defined as non- cardiovascular risk factors and with antidepressant treatment (Hickie et aletal,, response to at least one, but no more than 1997; Simpson et aletal, 1998; Steffens et aletal,, five, adequate antidepressant trials during treatmenttreatmentoutcome outcome ininyounger younger people 2002) as well as higher rates of relapse dur- the current depressive episode. with major depressive disorder. ing follow-up (O’Brien et aletal, 1998; Yanai etet alal, 1998). The study reported here is, to our Exclusion criteria MethodMethod We assessed brain white- knowledge, the first to explore the impact For both the depressive disorder samples, matter hyperintensities and cardiovascular of white-matter hyperintensities on anti- exclusion criteria were bipolar disorder, risk factorsin 84 people with major depressant treatment outcome and the psychotic disorder, a history of organic depressive disorder prior to initiating relationship between such hyperintensities mental or seizure disorder, serious or un- and cardiovascular risk factors in younger stable medical illness, substance misuse or antidepressanttreatment.We also people with depression. We predicted that dependence disorder active within the past assessed hyperintensitiesin 35 matched the presence of brain white-matter hyper- 12 months, acute suicidal risk, pregnancy, controls. intensities would correlate with cardiovas- lactation, history of adverse reaction or al- cular risk factors and with lower rates of lergy to the study medications, concomitant ResultsResults We found no significant treatment response. use of psychotropic medications, clinical or difference in the prevalence of white- laboratory evidence of thyroid abnormal- matter hyperintensities betweenbetweenthe the METHOD ities, an existing diagnosis of dementia or a score below 27 on the Mini-Mental State depression and the control groups.Left- Participants Examination (Folstein et aletal, 1975), and any hemisphere subcorticalsubcorticalhyperintensities hyperintensities All study participants signed consent forms, contraindication to magnetic resonance correlated withlowerwith lower rates oftreatmentof treatment approved by the institutional review board, imaging, including metallic implants or response.We found no correlation prior to the initial study visit. severe claustrophobia. between globalhyperintensitymeasuresglobalhyperintensity measures Non-treatment-resistant major depressive Controls and clinical outcome.Brain white-matter disorder We also recruited through advertisements hyperintensities correlated with The study group with non-treatment- 35 healthy volunteers, matched for age hypertension and age and withtotal resistant major depressive disorder com- and gender (40% females; mean age 39.3 cardiovascular risk score. prised 65 people aged 18–65 years (mean years, s.d.years,s.d.¼9.8). These volunteers under- age 40.7, s.d.¼10.2), recruited through went the physician-administered SCID–P Conclusions SubcorticalSubcorticalwhite-matter white-matter advertisements and clinical referrals for a to rule out any Axis I psychopathology. hyperintensities in the left hemisphere (but clinical trial beginning with open-label fluoxetine treatment (Fava et aletal, 2002).,2002). Tests and procedures notin other brain areas) may be associated All participants, 24 (37%) of whom were We assessed cardiovascular risk factors in with poor response to antidepressant women, met criteria for major depressive all participants with major depressive dis- treatmentin major depression. disorder, diagnosed by the physician- order following the National Institutes of administered Structured Clinical Interview Health Adult Treatment Panel III guide- Declaration of interest None. for DSM–III–R Axis I Disorders – Patient lines, based on the Framingham Heart Funding detailed in Acknowledgements. edition (SCID–P; Spitzer et aletal, 1989).,1989). Study (Wilson et aletal, 1998; Expert Panel 180180 Downloaded from https://www.cambridge.org/core. 28 Sep 2021 at 17:13:13, subject to the Cambridge Core terms of use. WHITE MATTER HYPERINTENSITIES AND TREATMENT OUTCOME IN DEPRESSION AUTHOR’SAUTHOR’ S PROOFP ROOF on Detection, Evaluation and Treatment of and fluid-attenuated inversion recovery The differences in the severity of white- High Blood Cholesterol in Adults, 2001). (FLAIR) axial images (TE¼133133ms,ms, matter hyperintensities between partici- We recorded, for each person in the two TRTR¼9002 ms, inversion time TI¼22002200ms,ms, pants in the two depression groups and depression groups, age, gender, smoking 25625666192 matrix; field of view 22 cm, the healthy comparison sample were ana- status, family history of cardiovascular 5 mm thick slices, 2 mm skip). Voxel dimen- lysedlysedusingusing ww22-tests. We used multiple ordi- disease, total serum cholesterol,personal sions were 0.975 mm660.9750.975mmmm663.03.0mm.mm. nal logistic regression to test the association history of arterial hypertension and diabetes,diabetes, Analysis of the images was performed off- between hyperintensity scores and cardio- and concomitant medications. We calcu- line using a SUN Microsystems (Mountain- vascular risk factors. Analysis of variance lated a cumulated cardiovascular risk score view, California, USA) Sparc2 workstation was used to test the association between (range 0–6) by assigning a point for each of and the radiological film. Lesions were clas- hyperintensity scores and the total cardio- the following six factors: sified according to the Fazekas classification vascular risk score (sum of the six (a)(a)age:age: male 45 years old or more, female system (Fazekas etetalal, 1987), which pro- cardiovascular risk factors). Since age is 55 years old or more; vides an assessment of severity of the one of the cardiovascular risk factors, these white-matter hyperintensities, rated sepa- analyses were not adjusted for age. Correla- (b)(b)activeactive smoking status within the past 12 rately for the subcortical white matter tions between clinical outcome variables months;months; (range 0–3) and the periventricular white (response and remission) and hyper- (c)(c)familyfamily history of premature vascular matter (range 0–3). The total white-matter intensity scores were tested using logistic disease (e.g. myocardial infarction, hyperintensity score was considered to be regression, adjusted for age. Statistical stroke) in male first-degree relatives the higher of the subcortical score and the significance was defined as PP550.05,0.05, under 55 years old, and in female periventricular score, following previous two-tailed.two-tailed. first-degree relatives under 65 years old; classifications of white-matter hyperinten- (d)(d)totaltotal cholesterol level greater than sity in people with major depressive dis- 55mmol/lmmol/l;; order (Krishnan etetalal, 1997). All ratings of RREESUSULLTTSS (e)(e)arterialarterial hypertension (blood pressure white-matter hyperintensities were done by over 140/90 mmHg, or use of anti- an experienced neuroradiologist (H.K.L.), The demographic and clinical characteris- hypertensive medication); who was unaware of participant identity tics of the three study groups are presented in Table 1. The initial HRSD scores for (f)(f)diabetesdiabetes mellitus. and clinical status. Another investigator in the study (D.V.I.) assessed independently a depression severity were not statistically After the initial evaluation the non- selection of 111 magnetic resonance images different between the two depression treatment-resistant sample entered 8 weeks using the same rating criteria, for measure- groups: 21.6 v.v. 20.2; unpaired tt-test,-test, of
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