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Doi:10.1016/j.psychres.2007.04.01

Psychiatry Research xx (2007) xxx – xxx Predicting therapeutic response to secondary treatment with bupropion: Dichotic listening tests of functional brain asymmetry Gerard E. Bruder ⁎, Jonathan W. Stewart, Jennifer D. Schaller, Patrick J. McGrath Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, United States Received 5 October 2006; received in revised form 9 March 2007; accepted 7 April 2007 Studies using neuroimaging, electrophysiologic and cognitive measures have raised hopes for developing predictors of therapeutic response to antidepressants. Pretreatment measures of functional brain asymmetry have been found to be related toresponse to the selective serotonin reuptake inhibitor fluoxetine. This report examines the extent to which dichotic listening testsalso predict clinical response to an antidepressant with a different mechanism of action, i.e., bupropion. Dichotic listening datawere obtained for 17 unmedicated depressed patients who were subsequently treated with bupropion. Right-handed outpatientswere tested on dichotic fused-words and complex-tones tests. Seven patients who responded to bupropion and 10 nonrespondersdid not differ in gender, age or education. Bupropion responders had significantly larger left-hemisphere advantage for perceivingwords when compared to nonresponders, but there was no difference in their right-hemisphere advantage for tones. All patientshaving a left-hemisphere advantage above the normal mean responded to bupropion, whereas only 9% of patients below the normalmean responded to treatment. These findings should encourage further study of the clinical value of dichotic listening and othermeasures of functional brain asymmetry for identifying depressed patients who most benefit from treatment with different classesof antidepressants.
2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Depression; Bupropion; Treatment response; Dichotic listening; Hemispheric asymmetry Although a variety of antidepressants with different mechanisms of action are available for treatment of de- pression, clinicians have no way of knowing in advance whether or not a given patient will benefit from treat- ment with a specific agent. Patients often must endure a brain function suggest that pretreatment differences prolonged “trial and error” period before finding an among depressed patients are associated with respon- effective antidepressant, and they may become increas- siveness to antidepressants, raising hopes for identifying ingly hopeless if they fail to benefit and discontinue predictors of clinical response to antidepressants. It isnot, however, known whether these findings are asso- ciated with a specific class of antidepressants, e.g., se- Corresponding author. Tel.: +1 212 543 5468; fax: +1 212 543 6540.
lective serotonin reuptake inhibitors (SSRIs), or are 0165-1781/$ - see front matter 2007 Elsevier Ireland Ltd. All rights reserved.
doi: Please cite this article as: Bruder, G.E. et al. Predicting therapeutic response to secondary treatment with bupropion: Dichotic listening tests offunctional brain asymmetry. Psychiatry Research (2007), do G.E. Bruder et al. / Psychiatry Research xx (2007) xxx–xxx common to antidepressants with different mechanisms mental disorder, history of head trauma, or other neurological disorder. They were also excluded if they Studies using dichotic listening tests indicate that had a hearing loss greater than 30 dB in either ear at 500, pretreatment measures of functional asymmetry of the 1000 or 2000 Hz or if they had an ear difference greater right–left brain are related to subsequent responsiveness than 10 dB. All participants gave written informed consent before participating in the study. Diagnostic assessment was by Structured Interview for Clinical dichotic listening tests, different stimuli (e.g., words or tones) are simultaneously presented to the left and right conducted by research psychiatrists before dichotic ears and the advantage for hearing items in the right or listening tests. Patients met DSM-IV criteria for major left ear, referred to as perceptual asymmetry (PA), depressive disorder or, in one case, dysthymia. All find- provides a measure of the advantage of the contralateral ings reported below for the full sample were confirmed hemisphere for processing verbal or tonal information.
after excluding the one dysthymic patient.
Unmedicated depressed patients at two clinical centers Before being treated with bupropion, the patients who subsequently responded favorably to fluoxetine participated in a fluoxetine treatment study (n = 14) or differed from nonresponders in showing greater left- were treated openly with fluoxetine (n = 3). Their daily hemisphere advantage for perceiving dichotic words and fluoxetine dose was titrated to a maximum of 40–80 mg less right-hemisphere advantage for perceiving complex over a period of up to 12 weeks. All but 4 of these patients were judged to be fluoxetine nonresponders listening between fluoxetine responders and nonrespon- using Clinical Global Impression Improvement (CGI-I) ders was replicated in two additional studies, and was criteria of minimal or no improvement. The remaining 4 found to be dependent on gender in both studies patients responded to fluoxetine treatment but relapsed ). The heightened left-hemisphere advantage or had side effects. These patients were subsequently for words in fluoxetine responders was present among treated with the SR formulation of bupropion. Twelve women but not men, whereas reduced right-hemisphere patients received bupropion within an 8 week open label advantage for tones in responders was present among study and 5 patients received open clinical treatment, beginning with a daily dose of 100 or 150 mg and The clinical value of dichotic listening or other tests titrating to a maximum dose of 400 mg (except for one for predicting treatment response would be strengthened patient who received 600 mg). Only patients who if they also indicated whether an alternative treatment received a minimum of 6 weeks of bupropion treatment would benefit patients who are not likely to respond to an SSRI, the usual initial treatment. This report presents A research psychiatrist blind to dichotic listening dichotic listening data for patients who were treated with data reviewed each patient's chart to determine bupropion after, in most cases, unsuccessful treatment treatment response independent of knowledge of the with the SSRI fluoxetine. We examined whether dichotic dichotic listening results. To be considered a “respond- listening tests obtained before treatment would pre- er” (R) the chart had to document a marked clinical dict clinical response to bupropion and, if so, whether improvement in the patient's depression, as indicated by differences between bupropion responders and nonre- chart notes such as “depression much improved”, sponders are similar to or different from those seen for “remitted”, “no longer depressed”, “feeling well” or similar assessments within four weeks of the patientstarting on their maximal dose. In addition, improve- ment had to be sustained for at least 4 weeks. In fourcases where there was not 4 weeks follow-up after their initial benefit, their response was determined to be asindicated in their last chart note. Patients judged to be a Patients were right-handed depressed outpatients “nonresponder” (NR) had descriptors indicating mini- between the ages of 20 and 64 who were attending a mal or no clinical improvement, including “no benefit”, university-affiliated research clinic. Patients were ex- “no change”, “minimal improvement” or “much worse”.
cluded for any of the following reasons: serious suicide In most cases, a treatment call was based on outcome at risk, substance abuse disorders (including alcohol the end of 8th week of treatment or in four patients who abuse) within the last 6 months, psychotic disorders, stopped treatment at the 7th week, the last available visit antisocial personality disorder, seizure disorder, organic Please cite this article as: Bruder, G.E. et al. Predicting therapeutic response to secondary treatment with bupropion: Dichotic listening tests offunctional brain asymmetry. Psychiatry Research (2007), doi G.E. Bruder et al. / Psychiatry Research xx (2007) xxx–xxx scores were used to compute an index of perceptualasymmetry, PA = 100 (Right Correct − Left Correct) / Dichotic listening tests were administered during a (Right Correct + Left Correct). A 2 by 2 repeated mea- pretreatment session before patients received treatment sures ANOVA was performed using one between- with fluoxetine and then bupropion. Patients were subject variable of Bupropion Response (R, NR) and unmedicated a minimum of 7 days before dichotic one repeated-measure variable of Test (words, tones), listening testing, although most patients were drug-free with PA scores being the dependent variable. If a sig- for a considerably longer period or were not previously nificant interaction of Bupropion Response and Test was treated with an antidepressant. No patient was tested present, separate t-tests were planned to evaluate wheth- within 6 weeks of receiving fluoxetine or 1 week of er responders and nonresponders differed on the indi- receiving other antidepressants and no patient had received a monoamine oxidase inhibitor. All patients The potential value of PA scores for predicting thera- and controls were tested on the dichotic fused-words peutic response to bupropion was examined using a χ2 and complex-tones tests described below, with the order test to compare response rates of patients with PA scores of the tests counterbalanced across subjects.
above versus below the mean for healthy adults. Sensi- tivity, specificity, positive predictive value and negative consists of 15 different single-syllable word pairs, in predictive value were also computed.
which each member of every pair differs from the otheronly in the initial consonant (e.g., coat, goat). All words begin with one of six stop consonants (b, d, p, t, g, k) andare natural speech spoken by a male voice. When di- There were 7 bupropion responders (5 men) who did chotically presented, the members of each pair fuse into a not differ significantly from the 10 nonresponders (6 men) single percept. Participants indicate what word they heard in gender, age (R mean = 43.3 yrs, S.D. = 12.1; NR by marking a line through it on a prepared answer sheet mean = 40.5 yrs, S.D. = 9.7; t = 0.53, df = 15, ns), education that has four possible responses, both members of the (R mean = 16.7 yrs, S.D. = 3.2; NR mean = 14.9 yrs, S.D. = dichotic pair and two other words differing from the 2.3; t = 1.36, df = 15, ns) or handedness laterality quotient dichotic stimuli only in the initial consonant. Following (R mean = 84.4, S.D. = 21.0; NR mean = 84.7, S.D. = 18.2; practice trials, each participant received four 30-item t = 0.03, df = 15, ns) on the Edinburgh Inventory ( blocks for a total of 120 trials. Orientation of headphones ). The responder and nonresponder groups also had was reversed after the first and third quarters to control for comparable diagnoses. All met DSM-IV criteria for channel differences and ear of presentation. The words MDD, except for one nonresponder who met criteria for were presented via a matched pair of TDH-49 headphones dysthymia. Two responders also had a panic disorder and at a comfortable level of 75 dB sound pressure level (SPL).
three nonresponders had comorbid anxiety disorders (panic disorder, social phobia or obsessive–compulsive cipants to compare the pitch of a binaural complex tone disorder). Two patients in each group met DSM-IV with the pitches of a dichotic pair of complex tones pre- criteria for atypical depression and an additional two sented 1 s earlier. Subjects point to a response card labeled responders and three nonresponders showed the essential Yes when the probe tone is the same as either member of feature of reactivity of mood and one of four associated the previous dichotic pair or to a card labeled No when it differs from both. The complex tones are square waves The responders and nonresponders also did not differ in with fundamental frequencies corresponding to eight pretreatment severity of depression on the Beck Depres- notes in the octave between C4 and C5. After 16 binaural and 16 dichotic practice trails, participants were tested on session, when dichotic listening tests were performed four blocks of 28 trials in which half of the probe tones (R mean = 19.4, S.D. = 8.0; NR mean = 25.8, S.D. = 9.1; matched a member of the dichotic pair and half did not.
t = 1.49, df = 15, ns). Also, pretreatment BDI scores were Orientation of headphones was reversed after the first and not related to PA for either words (r = −0.05, ns) or tones third blocks. The tones were presented at 74 dB SPL.
gives the PA scores for bupropion responders and nonresponders on the dichotic word and tone tests.
Dashed lines show the mean left-hemisphere advantage Correct responses in the words and tones tests were for words (i.e., positive PA scores) and right-hemisphere computed for right- and left-ear presentations. These advantage for tones (i.e., negative PA scores) for 101 Please cite this article as: Bruder, G.E. et al. Predicting therapeutic response to secondary treatment with bupropion: Dichotic listening tests offunctional brain asymmetry. Psychiatry Research (2007), do G.E. Bruder et al. / Psychiatry Research xx (2007) xxx–xxx Fig. 1. PA scores for individual bupropion responders and nonresponders, and mean PA score for 101 normals on the fused-words and complex-tones tests.
responded to bupropion had a marked left-hemisphere The patients also showed the expected difference advantage for words that was greater than the normal mean in PA for words and tones (main effect of Test: F = 31.17, (dashed line). In contrast, all those who did not respond to df = 1,15, P b 0.001). There was also a significant inter- bupropion had little or no left-hemisphere advantage, i.e., action between Bupropion Response and Test (F = 6.99, their PA scores were less than the normal mean. Patients df = 1,15, P = 0.018). Separate analyses of PA scores for who failed to respond to fluoxetine tended to show a normal each test showed that responders had markedly larger right-hemisphere advantage for tones, which did not differ left-hemisphere advantage for words when compared to between bupropion responders and nonresponders.
nonresponders (t = 4.06, df = 15, P = 0.001), but there Given the marked difference between bupropion was no group difference in right-hemisphere advantage responders and nonresponders in PA scores for words, for tones (t = 0.36, df = 15, ns), which accounts for this we further evaluated their potential value for predicting interaction. Although gender was not included as a outcome of treatment. As in our prior studies ( variable in the ANOVA because cell sizes would be too small, inspection of the data for individual men (closed (dashed line in as a cutoff score for dividing points) and women (open points) in suggests that patients into those with relatively large versus small left- gender was not a factor. The 5 male responders had hemisphere advantage and a comparison was made significantly larger left-hemisphere advantage for words of their treatment response. All 6 of the patients with a when compared to the 6 male nonresponders (t = 2.62, left-hemisphere advantage above the normal mean re- df = 9, P b 0.05) and the same difference was seen be- sponded to bupropion, whereas only one of 11 patients tween 2 female responders and 4 female nonresponders with a left-hemisphere advantage less than the normal mean responded to bupropion (χ2 = 13.25, P b 0.001).
Among patients who previously failed to benefit from Thus, using this cutoff score to predict bupropion re- fluoxetine (circles in ), all those who subsequently sponse, the words test had high sensitivity (85.7%), Please cite this article as: Bruder, G.E. et al. Predicting therapeutic response to secondary treatment with bupropion: Dichotic listening tests offunctional brain asymmetry. Psychiatry Research (2007), doi G.E. Bruder et al. / Psychiatry Research xx (2007) xxx–xxx specificity (100%), positive predictive value (100%), and The difference in asymmetry for perceiving dichotic words between patients who do or do not respond fa- We also examined whether or not there were differ- vorably to bupropion is in general similar to that pre- ences between bupropion responders and nonresponders in absolute accuracy scores for perceiving tones pre- sented to the left and right ear. A 2 (Bupropion Reponse) pathophysiology of patients who respond to these by 2 (Ear) ANOVA revealed the expected left ear (right different classes of antidepressant. In this regard, an hemisphere) advantage for tones (F = 9.49, df = 1,15, extensive STAR⁎D clinical trial found that depressed P b 0.01), but there was no significant difference in patients who had unsuccessful treatment with an SSRI accuracy between groups (F = 1.04, df = 1,15, ns). There showed about the same remission of symptoms after was also no Bupropion Response by Ear interaction switching to a different SSRI, bupropion or venlafaxine (F = 0.35, df = 1,15, ns), which supports the lack of a group difference in right-hemisphere advantage for The gender differences for predicting response to tones. Since words on the Fused Rhymed Words Test fuse to form a single percept and subjects report only a hold for bupropion. Our prior studies showed that single word on each trial, they are close to 100% correct heightened left-hemisphere advantage for dichotic for reporting the word heard in either ear and therefore words predicted positive fluoxetine response for women the above analysis was not performed for the word test.
but not men. In the current study, 3 of the 4 patients with a There was no difference in the number of errors made by left-hemisphere advantage greater than normal who responders (mean = 1.7, S.D. = 2.3) and nonresponders nevertheless failed to respond to fluoxetine were men (mean = 2.2, S.D. = 2.7; t = 0.38, df = 15, ns).
(see Although sample sizes were small, men whoresponded to bupropion had significantly larger left- hemisphere advantage for words when compared tononresponders and this difference was also apparent for This study presents the first evidence that pretreatment women. Also, men who responded to fluoxetine differed asymmetry on a dichotic words test predicts who will or from nonresponders in showing reduced right-hemisphere will not benefit from secondary treatment with the antidepressant bupropion. Among depressed patients, this difference was not found between bupropion most of whom failed to respond to fluoxetine, those who responders and nonresponders. Given that most of the subsequently responded to bupropion had markedly patients who were treated with bupropion had previously larger left-hemisphere advantage for words when com- failed to respond to fluoxetine, their normal right- pared to nonresponders. All patients having above normal hemisphere advantage is understandable. Thus, men left-hemisphere advantage for words responded well to who have both larger than normal left-hemisphere treatment with bupropion, whereas those having less than advantage for words and right-hemisphere advantage for normal or no left-hemisphere advantage had only a 9% tones may benefit more from treatment with bupropion response rate to bupropion. The words test showed both than fluoxetine. Women who have a larger than normal high sensitivity (87.5%) and specificity (100%) for left-hemisphere advantage for words would be expected predicting response to bupropion. The value of dichotic to respond well to fluoxetine, but if they fail to respond, listening tests for predicting clinical response to the SSRI they should nonetheless benefit from treatment with fluoxetine was demonstrated in our prior studies ( bupropion, whereas those with little or no left-hemisphere advantage may have a poor response to either antidepres- words test showed moderately high sensitivity (76.3%) sant. Although increased left-hemisphere advantage for and specificity (85.7%) for predicting response to words appeared to be present for both men and women fluoxetine in women, but not in men. Examination of who responded to bupropion, a study in a larger sample the treatment response for patients with less than normal is needed to more adequately evaluate gender effects for left-hemisphere advantage () indicates that the word test has high negative predictive value (i.e., nonresponder An important question that needs further research is rate for patients predicted to be nonresponders) for both why hemispheric asymmetry for perceiving dichotic bupropion (90.9%) and fluoxetine (81.8%). Thus, the words is related to outcome of treatment with anti- dichotic word test may prove to be particularly useful as a depressants. Pretreatment differences in dichotic listen- clinical predictor of patients who are likely to be treatment ing asymmetry between fluoxetine responders and nonresponders did not change following treatment, Please cite this article as: Bruder, G.E. et al. Predicting therapeutic response to secondary treatment with bupropion: Dichotic listening tests offunctional brain asymmetry. Psychiatry Research (2007), do G.E. Bruder et al. / Psychiatry Research xx (2007) xxx–xxx which suggests that they represent stable, trait char- randomly assigned to treatment with either bupropion or an SSRI, is clearly needed to confirm the value of the characteristic tendency for relatively greater left than dichotic word test for predicting response to treatment right-hemisphere activation is associated with better with these different antidepressants.
treatment response. This hypothesis is supported by electrophysiologic evidence of differences in hemi- promise of the STAR⁎D trial may be in the identifica- spheric asymmetry between fluoxetine responders and tion of predictors of antidepressant response, which would permit more individualized treatment of de- maging studies have found that differences in hemi- pressed patients. Our findings should encourage further spheric activity in left frontal or temporal lobe regions study of the clinical value of dichotic listening and other are related to response to SSRI or other antidepressants measures of functional brain asymmetry for identifying depressed patients who will most benefit from treatment One possible explanation for these findings with different classes of antidepressants.
is that neurotransmitter systems affected by antidepres-sants may have an asymmetric distribution in the brain or may be asymmetrically disturbed in treatment respon-sive or nonresponsive subtypes of depression.
This research was supported in part by a National Some limitations of this study should also be dis- Institute of Mental Health grant MH36295.
cussed. First, the patients in this study were participantsin an open label study or received open clinical treat- ment. Although they received systematic treatment withbupropion, there was no active control (e.g., an SSRI) or Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbaugh, J., 1961.
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laterality to therapeutic response. Neuropsychopharmnacology 15, This limits the generalizability of the findings to patients receiving secondary treatment with bupropion. Third, Bruder, G.E., Stewart, J.W., Tenke, C.E., McGrath, P.J., Leite, P., Bhattacharya, N., Quitkin, F.M., 2001. Electroencephalographic the categorization of the patients’ treatment response and perceptual asymmetry differences between responders and was based on chart review. A psychiatrist, who was nonresponders to an SSRI antidepressant. Biological Psychiatrty blind to the dichotic listening data, gave a treatment response call on the basis of the patient's global clinical Bruder, G.E., Stewart, J.W., McGrath, P.J., Deliyannides, D., Quitkin, improvement. Although we did not use a predetermined F.M., 2004. Dichotic listening tests of functional brain asymmetrypredict response to fluoxetine in depressed women and men.
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