© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Bipolar Disorders 2015: 17: 444–449
BIPOLAR DISORDERS
Brief Report
Neurofunctional effects of quetiapine in patients with bipolar mania Davis AK, DelBello MP, Eliassen J, Welge J, Blom TJ, Fleck DE, Weber WA, Jarvis KB, Rummelhoff E, Strakowski SM, Adler CM. Neurofunctional effects of quetiapine in patients with bipolar mania. Bipolar Disord 2015: 17: 444–449. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood. Methods: Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans. Results: At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003). Conclusions: These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex —restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.
Although the neuropathophysiology of bipolar disorder remains poorly understood, recent research has strongly implicated dysfunction within frontalsubcortical networks involved in emotional expression and regulation; in particular, several lines of evidence suggest that subjects with bipolar disorder demonstrate abnormalities in brain activity centered on portions of the prefrontal cortex, as
444
Andrew K Davisa, Melissa P DelBelloa, James Eliassena,b, Jeffrey Welgea, Thomas J Bloma, David E Flecka,b, Wade A Webera, Kelly B Jarvisa, Emily Rummelhoffa, Stephen M Strakowskia,b and Caleb M Adlera,b a
Department of Psychiatry and Behavioral Neuroscience, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, bCenter for Imaging Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
doi: 10.1111/bdi.12274 Key words: bipolar disorder – fMRI – functional magnetic resonance imaging – mania – prefrontal cortex – quetiapine Received 6 July 2014, revised and accepted for publication 23 September 2014 Corresponding author: Caleb M. Adler, M.D. Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine 260 Stetson Street, Suite 3200 Cincinnati, OH 45219-0516 USA Fax: 513-558-3399 E-mail: [email protected]
well as linked subcortical and medial temporal structures (1–7). Portions of the prefrontal cortex including Brodmann areas (BA) 11 and 12 have been widely observed to modulate the response to affective stimuli by limbic structures associated with emotional expression, leading to speculation that loss of activity in these regions may be related to the deficits in affective regulation that
Quetiapine effects in bipolar mania characterize bipolar mania (8, 9). Consistent with this suggestion, acutely manic individuals show evidence of relatively decreased prefrontal activity with concomitant increases in activation of the amygdala (9–12). Symptomatic resolution has in turn been linked with normalization of functional activity in the prefrontal cortex, and improvement in mania ratings have been correlated with activation changes in other regions of the expanded limbic network (13, 14, 15). Since olanzapine became the first of six secondgeneration antipsychotic medications to be Food and Drug Administration (FDA) -approved for mania, these therapeutics have become a mainstay of bipolar disorder treatment (16, 17). Data addressing their mechanism of action, however, remain at best tentative. While measures of direct medication effects on functional activation suggest that mood stabilizers generally normalize functional activation, the vast majority of these studies have been cross-sectional in nature—longitudinal studies of symptomatic patients with bipolar disorder remain quite limited in number (14). Furthermore, few of these studies examined the relationship between changes in neuronal activity and treatment response (14, 18). Nonetheless, several studies have reported evidence of treatment-related changes in functional activity in portions of the prefrontal cortex and subcortical structures involved in affective regulation—for the most part following administration of lamotrigine or divalproex (14). Atypical antipsychotics including quetiapine have been linked to prefrontal neurochemical changes that include evidence of increased metabolism, with several of these studies observing that neurochemical findings differentiated treatment-responders from non-responders (19, 20). In this report, we describe a prospective longitudinal study examining the effects of quetiapine on brain activity in response to an affective stimulus in a group of adults with bipolar mania. Based on previous findings, we hypothesized that symptomatic improvement with quetiapine treatment would be associated with increased prefrontal activation and concomitantly decreased activation of the amygdala.
Patients and methods Participants
Adult subjects aged 18–55 years experiencing an episode of bipolar mania were recruited from inpatient and outpatient facilities at the University of Cincinnati (Cincinnati, OH, USA). Subjects with bipolar disorder were free of comorbid Axis I
disorders. A group of healthy subjects with no DSM-IV Axis I condition in themselves or any first-degree relatives was recruited from the community. All subjects were medically healthy, and no subjects had a history of head trauma resulting in loss of consciousness for longer than 10 min. No subjects met criteria for a current or remitted substance use disorder. Diagnostic assessments were performed in subjects with bipolar disorder and in healthy subjects using the Structured Clinical Interview for DSMIV Axis I Disorders–Patient Edition (SCID-IV); affective symptoms were rated using the Young Mania Rating Scale (YMRS) (21, 22). All instruments were administered by interviewers with good diagnostic reliabilities (kappa > 0.9). All but four patients had discontinued psychotropic medications for at least two weeks prior to enrollment in this study; four patients were taking low doses of quetiapine on entry [mean standard deviation (SD): 188 118 mg]. This study was approved by the Institutional Review Board of the University of Cincinnati, and all subjects consented to participation. Treatment
Subjects with bipolar disorder were treated with open-label quetiapine, administered by a boardcertified psychiatrist (CMA). Dosing was initiated at 100 mg daily and increased as clinically indicated to a maximum of 1,000 mg daily (mean SD: 563 180 mg). Patients were seen weekly for the first four weeks, and then at least biweekly for the remainder of the eight-week study. Subjects participated in functional magnetic resonance imaging (fMRI) at baseline and eight weeks after starting treatment. Thirty-one subjects with bipolar disorder signed consent but only 22 of these subjects were ultimately enrolled in the study —nine subjects were excluded for technical reasons or because they no longer met mania severity criteria on the day of the baseline evaluation and scan. Excluded subjects with bipolar disorder did not significantly differ from the remainder in age (p = 0.94), or baseline YMRS scores (p = 0.98). More men than women were in the excluded group (p = 0.05). Three subjects discontinued participation after their baseline scans and were lost to follow-up (two women) (mean age SD: 35 11 years). fMRI
During the fMRI scan, subjects performed a continuous performance task with emotional and
445
Davis et al. neutral distractors (CPT-END) (23, 24). Seventy percent of the cues were simple squares, 10% simple circles, 10% emotionally neutral pictures, and 10% negatively valenced pictures. Neutral and negative pictures were taken from the International Affective Picture System (University of Florida, Gainesville, FL, USA) based upon the rating criteria used by Yamasaki and colleagues (23). Each visual cue required a response; subjects were instructed to press a single button (Button 1) in response to squares and pictures, and to press a second button (Button 2) in response to circles (targets). Each imaging session consisted of two runs, with 158 visual cues per run, presented pseudorandomly for two seconds each at three-second intervals. Subjects were scanned at the University of Cincinnati Center for Imaging Research (CIR) using a 4.0 Tesla Varian, Unity INOVA Whole Body MRI/MRS System (Varian, Inc., Palo Alto, CA, USA). Visual stimuli were presented using high-resolution video goggles (Resonance Technologies, Inc., Northridge, CA, USA). To provide anatomical localization, a high-resolution, T1weighted, three-dimensional brain scan was obtained (25). A midsagittal localizer scan was acquired to place 40 contiguous 4-mm axial slices to encompass the entire brain. Next, a multiecho reference scan was obtained to correct for ghost and geometric distortions (26). Subjects then completed two fMRI scans in which whole-brain images (volumes) were acquired coronally every three seconds using a T2*-weighted gradient-echo echo-planar imaging pulse sequence (repetition time/echo time = 3,000/29 msec, field of view = 20.8 9 20.8 cm, matrix 64 9 64 pixels, slice thickness = 5 mm, flip angle = 75°) while performing the CPT-END. fMRI data were analyzed using Analysis of Functional NeuroImages (AFNI; National Institutes of Health, Bethesda, MD, USA; http://afni. nimh.nih.gove/afni). Structural and functional images were co-registered, and functional images corrected for motion using a six-parameter rigid body transformation (27). Each volume was inspected for signal artifacts using a semiautomated algorithm in AFNI. Subjects were excluded from further analysis if uncorrectable head movement occurred; no scans were included with head movement >2 mm (28). Anatomical and functional maps were normalized to Talairach space. Motion correction parameters were included as regressors of no interest and low-frequency components of the signal removed. We applied 3D Hamming filtering at imaging reconstruction, which introduces smoothing of 1.8 times the
446
original voxel size. Individual voxel-wise eventrelated activation maps were created following standard AFNI procedures using an algorithm that compares the actual hemodynamic response to a canonical hemodynamic response function (29, 30). All events were modeled in the analysis of the fMRI time series, and event-related response functions derived for negatively valenced pictures, as per our a priori hypothesis. Orbitofrontal cortex (OFC) (BA 11/12) and amygdala, as well as other exploratory regions of interest (ROIs) previously identified to be active in affective expression and regulation, including the globus pallidus, thalamus, and putamen, were identified using the automatic anatomical labeling atlas in AFNI (23, 31, 32). Using SPSS (IBM SPSS Statistics for Windows, Version 22.0; Armonk, NY, USA), baseline comparisons of non-zero mean percent signal change extracted from each ROI were compared between subjects with bipolar disorder and healthy subjects, and baseline versus Week 8 comparisons made for subjects with bipolar disorder. Baseline versus Week 8 comparisons were made in a subset of healthy subjects in regions for which a significant finding in subjects with bipolar disorder was observed. A linear mixed model was used to examine the relationship between changes in YMRS scores and regional brain activation. Significance was defined for all analyses as p ≤ 0.05. Results
Twenty-two subjects with bipolar I disorder (11 women) ranging in age from 18 to 48 years (mean SD: 30 8 years) participated in baseline evaluations including fMRI scanning. Nineteen of these subjects with bipolar disorder completed the eight-week scan and assessment (nine women) (mean age SD: 29 8 years). Twenty-six healthy subjects (16 women) ranging in age from 11 to 41 years (28 7 years) also participated in fMRI scans. Subjects with bipolar disorder and healthy subjects did not differ in gender (p = 0.42) or age (p = 0.36). At entry, all subjects with bipolar disorder had a YMRS score ≥20 (mean SD: 25 5). At baseline, subjects with bipolar disorder did not significantly differ from healthy subjects in activation of any of the regions measured. Subjects with bipolar disorder demonstrated a significant increase in activation from baseline in the right OFC (BAs 11/12) during exposure to negatively valenced stimuli (p = 0.002) after eight weeks of quetiapine treatment. No other regions showed a significant change in activation from baseline
Quetiapine effects in bipolar mania Table 1. Functional activation in healthy subjects and in subjects with bipolar disorder Baseline ROI
Scan
OFC (BA 11/12)
L R L R L R L R L R
Amygdala Thalamus Globus pallidus Putamen
Healthy subjects 0.049 0.046 0.187 0.181 0.101 0.112 0.048 0.057 0.057 0.052
0.477 0.678 0.234 0.329 0.142 0.137 0.123 0.149 0.119 0.174
Week 8 Bipolar disorder 0.168 0.116 0.297 0.066 0.130 0.107 0.126 0.002 0.104 0.009
0.326 0.446 0.341 0.376 0.148 0.176 0.225 0.256 0.195 0.163
Bipolar disorder 0.268 0.204 0.212 0.024 0.122 0.074 0.028 0.095 0.065 0.017
0.437 0.751a 0.310 0.346 0.238 0.225 0.239 0.340 0.128 0.196
BA = Brodmann area; L = left; OFC = orbitofrontal cortex; R = right; ROI = region of interest. p = 0.002.
a
(Table 1). Over the eight weeks of treatment, YMRS scores of subjects with bipolar disorder decreased from 25 5 to 11 7 (p < 0.001). A subset of 14 healthy subjects (seven women), ranging in age from 19 to 41 years (27 7 years), were scanned a second time eight weeks after the baseline MRI. No significant change in activation of the right OFC (BAs 11/12) between the two scans was observed (p = 0.67). We observed a significant association between decreases in mania ratings and increasing functional activity in the right (p = 0.003), but not left (p = 0.85) OFC. No other significant associations between changes in functional activation and YMRS scores were observed. However, there was a large but non-significant association between decreases in mania ratings and nonsignificantly increasing functional activity in the left (p = 0.07), but not right (p = 0.16) amygdala. Discussion
In this study, we found that patients with bipolar mania who received quetiapine showed treatment-related increases in activation of the right OFC that were not observed in healthy subjects rescanned after eight weeks. These results are consistent with previous studies that have demonstrated increased prefrontal activation in euthymic patients with bipolar disorder, suggesting that mania is associated with a loss of modulatory control normally exerted over limbic regions by the prefrontal cortex (33). While right OFC activation was non-significantly greater in manic than healthy subjects, treatment was correlated with a further increase in activity. Further, improvement in YMRS scores showed a significant interaction with
increased OFC activity—while the improvement in mania symptoms cannot be unambiguously ascribed to changes in prefrontal activation, the observed relationship suggests that increased activity in BAs 11 and 12 is related to relative normalization of affective symptoms indicative of improved affective modulation. There was a similar, albeit non-significant, association between increased left amygdala activity and decreased ratings on the YMRS. The left amygdala, however, did not show a main effect for time, and changes in activation over the eight weeks of this study were not large. Although we have hypothesized that amygdala activity decreases with resolution of manic symptoms, increased amygdala activity has been previously observed in patients with bipolar disorder with even non-affective cognitive stimuli, including attention; observations of increased amygdala activity may be an artifact of disparate effects of treatment on response to attention and negatively valenced stimuli (34). This suggestion is buttressed by a previous study utilizing the CPT-END, in which we similarly observed increased amygdala activity in manic patients (8). We did not see baseline activation differences between manic and healthy subjects in any of the brain regions examined. This finding is not entirely consistent with previous studies showing significant differences in functional activation between manic subjects with bipolar disorder and healthy subjects during administration of similar tasks. Furthermore, the majority of these subjects were medication free at baseline—which would typically enhance rather than diminish differences (14). Potential findings may have been vitiated by the nature of the task, which included a cognitive baseline component; we have previously observed
447
© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Bipolar Disorders 2015: 17: 444–449
BIPOLAR DISORDERS
Brief Report
Neurofunctional effects of quetiapine in patients with bipolar mania Davis AK, DelBello MP, Eliassen J, Welge J, Blom TJ, Fleck DE, Weber WA, Jarvis KB, Rummelhoff E, Strakowski SM, Adler CM. Neurofunctional effects of quetiapine in patients with bipolar mania. Bipolar Disord 2015: 17: 444–449. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood. Methods: Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans. Results: At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003). Conclusions: These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex —restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.
Although the neuropathophysiology of bipolar disorder remains poorly understood, recent research has strongly implicated dysfunction within frontalsubcortical networks involved in emotional expression and regulation; in particular, several lines of evidence suggest that subjects with bipolar disorder demonstrate abnormalities in brain activity centered on portions of the prefrontal cortex, as
444
Andrew K Davisa, Melissa P DelBelloa, James Eliassena,b, Jeffrey Welgea, Thomas J Bloma, David E Flecka,b, Wade A Webera, Kelly B Jarvisa, Emily Rummelhoffa, Stephen M Strakowskia,b and Caleb M Adlera,b a
Department of Psychiatry and Behavioral Neuroscience, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, bCenter for Imaging Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
doi: 10.1111/bdi.12274 Key words: bipolar disorder – fMRI – functional magnetic resonance imaging – mania – prefrontal cortex – quetiapine Received 6 July 2014, revised and accepted for publication 23 September 2014 Corresponding author: Caleb M. Adler, M.D. Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine 260 Stetson Street, Suite 3200 Cincinnati, OH 45219-0516 USA Fax: 513-558-3399 E-mail: [email protected]
well as linked subcortical and medial temporal structures (1–7). Portions of the prefrontal cortex including Brodmann areas (BA) 11 and 12 have been widely observed to modulate the response to affective stimuli by limbic structures associated with emotional expression, leading to speculation that loss of activity in these regions may be related to the deficits in affective regulation that
Quetiapine effects in bipolar mania
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26.
proton magnetic resonance spectroscopy study. J Clin Psychopharmacol 2013; 33: 528–532. DelBello MP, Cecil KM, Adler CM, Daniels JP, Strakowski SM. Neurochemical effects of olanzapine in first-hospitalization manic adolescents: a proton magnetic resonance spectroscopy study. Neuropsychopharmacology 2006; 31: 1264–1273. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York, NY: Biometrics Research Department, New York State Psychiatric Institute, 2002. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–435. Yamasaki H, LaBar KS, McCarthy G. Dissociable prefrontal brain systems for attention and emotion. Proc Natl Acad Sci USA 2002; 99: 11447–11451. Strawn JR, Bitter SM, Weber WA et al. Neurocircuitry of generalized anxiety disorder in adolescents: a pilot functional neuroimaging and functional connectivity study. Depress Anxiety 2012; 29: 939–947. Lee JH, Garwood M, Menon R et al. High contrast and fast three-dimensional magnetic resonance imaging at high fields. Magn Reson Med 1995; 34: 308–312. Schmithorst VJ, Dardzinski BJ, Holland SK. Simultaneous correction of ghost and geometric distortion artifacts in EPI using a multiecho reference scan. IEEE Trans Med Imaging 2001; 20: 535–539.
27. Cox RW, Jesmanowicz A. Real-time 3D image registration for functional MRI. Magn Reson Med 1999; 42: 1014– 1018. 28. Page SJ, Harnish SM, Lamy M, Eliassen JC, Szaflarski JP. Affected arm use and cortical change in stroke patients exhibiting minimal hand movement. Neurorehabil Neural Repair 2010; 24: 195–203. 29. Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 1996; 29: 162–173. 30. Cox RW, Hyde JS. Software tools for analysis and visualization of fMRI data. NMR Biomed 1997; 10: 171–178. 31. Tzourio-Mazoyer N, Landeau B, Papathanassiou D et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002; 15: 273–289. 32. Jha AP, McCarthy G. The influence of memory load upon delay-interval activity in a working-memory task: an event-related functional MRI study. J Cogn Neurosci 2000; 12: 90–105. 33. Adler CM, Holland SK, Schmithorst V, Tuchfarber MJ, Strakowski SM. Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task. Bipolar Disord 2004; 6: 540–549. 34. Strakowski SM, Adler CM, Holland SK, Mills N, DelBello MP. A preliminary fMRI study of sustained attention in euthymic, unmedicated bipolar disorder. Neuropsychopharmacology 2004; 29: 1734–1740.
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Bipolar Disorders 2015: 17: 444–449
BIPOLAR DISORDERS
Brief Report
Neurofunctional effects of quetiapine in patients with bipolar mania Davis AK, DelBello MP, Eliassen J, Welge J, Blom TJ, Fleck DE, Weber WA, Jarvis KB, Rummelhoff E, Strakowski SM, Adler CM. Neurofunctional effects of quetiapine in patients with bipolar mania. Bipolar Disord 2015: 17: 444–449. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood. Methods: Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans. Results: At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003). Conclusions: These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex —restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.
Although the neuropathophysiology of bipolar disorder remains poorly understood, recent research has strongly implicated dysfunction within frontalsubcortical networks involved in emotional expression and regulation; in particular, several lines of evidence suggest that subjects with bipolar disorder demonstrate abnormalities in brain activity centered on portions of the prefrontal cortex, as
444
Andrew K Davisa, Melissa P DelBelloa, James Eliassena,b, Jeffrey Welgea, Thomas J Bloma, David E Flecka,b, Wade A Webera, Kelly B Jarvisa, Emily Rummelhoffa, Stephen M Strakowskia,b and Caleb M Adlera,b a
Department of Psychiatry and Behavioral Neuroscience, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, bCenter for Imaging Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
doi: 10.1111/bdi.12274 Key words: bipolar disorder – fMRI – functional magnetic resonance imaging – mania – prefrontal cortex – quetiapine Received 6 July 2014, revised and accepted for publication 23 September 2014 Corresponding author: Caleb M. Adler, M.D. Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine 260 Stetson Street, Suite 3200 Cincinnati, OH 45219-0516 USA Fax: 513-558-3399 E-mail: [email protected]
well as linked subcortical and medial temporal structures (1–7). Portions of the prefrontal cortex including Brodmann areas (BA) 11 and 12 have been widely observed to modulate the response to affective stimuli by limbic structures associated with emotional expression, leading to speculation that loss of activity in these regions may be related to the deficits in affective regulation that
Quetiapine effects in bipolar mania characterize bipolar mania (8, 9). Consistent with this suggestion, acutely manic individuals show evidence of relatively decreased prefrontal activity with concomitant increases in activation of the amygdala (9–12). Symptomatic resolution has in turn been linked with normalization of functional activity in the prefrontal cortex, and improvement in mania ratings have been correlated with activation changes in other regions of the expanded limbic network (13, 14, 15). Since olanzapine became the first of six secondgeneration antipsychotic medications to be Food and Drug Administration (FDA) -approved for mania, these therapeutics have become a mainstay of bipolar disorder treatment (16, 17). Data addressing their mechanism of action, however, remain at best tentative. While measures of direct medication effects on functional activation suggest that mood stabilizers generally normalize functional activation, the vast majority of these studies have been cross-sectional in nature—longitudinal studies of symptomatic patients with bipolar disorder remain quite limited in number (14). Furthermore, few of these studies examined the relationship between changes in neuronal activity and treatment response (14, 18). Nonetheless, several studies have reported evidence of treatment-related changes in functional activity in portions of the prefrontal cortex and subcortical structures involved in affective regulation—for the most part following administration of lamotrigine or divalproex (14). Atypical antipsychotics including quetiapine have been linked to prefrontal neurochemical changes that include evidence of increased metabolism, with several of these studies observing that neurochemical findings differentiated treatment-responders from non-responders (19, 20). In this report, we describe a prospective longitudinal study examining the effects of quetiapine on brain activity in response to an affective stimulus in a group of adults with bipolar mania. Based on previous findings, we hypothesized that symptomatic improvement with quetiapine treatment would be associated with increased prefrontal activation and concomitantly decreased activation of the amygdala.
Patients and methods Participants
Adult subjects aged 18–55 years experiencing an episode of bipolar mania were recruited from inpatient and outpatient facilities at the University of Cincinnati (Cincinnati, OH, USA). Subjects with bipolar disorder were free of comorbid Axis I
disorders. A group of healthy subjects with no DSM-IV Axis I condition in themselves or any first-degree relatives was recruited from the community. All subjects were medically healthy, and no subjects had a history of head trauma resulting in loss of consciousness for longer than 10 min. No subjects met criteria for a current or remitted substance use disorder. Diagnostic assessments were performed in subjects with bipolar disorder and in healthy subjects using the Structured Clinical Interview for DSMIV Axis I Disorders–Patient Edition (SCID-IV); affective symptoms were rated using the Young Mania Rating Scale (YMRS) (21, 22). All instruments were administered by interviewers with good diagnostic reliabilities (kappa > 0.9). All but four patients had discontinued psychotropic medications for at least two weeks prior to enrollment in this study; four patients were taking low doses of quetiapine on entry [mean standard deviation (SD): 188 118 mg]. This study was approved by the Institutional Review Board of the University of Cincinnati, and all subjects consented to participation. Treatment
Subjects with bipolar disorder were treated with open-label quetiapine, administered by a boardcertified psychiatrist (CMA). Dosing was initiated at 100 mg daily and increased as clinically indicated to a maximum of 1,000 mg daily (mean SD: 563 180 mg). Patients were seen weekly for the first four weeks, and then at least biweekly for the remainder of the eight-week study. Subjects participated in functional magnetic resonance imaging (fMRI) at baseline and eight weeks after starting treatment. Thirty-one subjects with bipolar disorder signed consent but only 22 of these subjects were ultimately enrolled in the study —nine subjects were excluded for technical reasons or because they no longer met mania severity criteria on the day of the baseline evaluation and scan. Excluded subjects with bipolar disorder did not significantly differ from the remainder in age (p = 0.94), or baseline YMRS scores (p = 0.98). More men than women were in the excluded group (p = 0.05). Three subjects discontinued participation after their baseline scans and were lost to follow-up (two women) (mean age SD: 35 11 years). fMRI
During the fMRI scan, subjects performed a continuous performance task with emotional and
445
Davis et al. neutral distractors (CPT-END) (23, 24). Seventy percent of the cues were simple squares, 10% simple circles, 10% emotionally neutral pictures, and 10% negatively valenced pictures. Neutral and negative pictures were taken from the International Affective Picture System (University of Florida, Gainesville, FL, USA) based upon the rating criteria used by Yamasaki and colleagues (23). Each visual cue required a response; subjects were instructed to press a single button (Button 1) in response to squares and pictures, and to press a second button (Button 2) in response to circles (targets). Each imaging session consisted of two runs, with 158 visual cues per run, presented pseudorandomly for two seconds each at three-second intervals. Subjects were scanned at the University of Cincinnati Center for Imaging Research (CIR) using a 4.0 Tesla Varian, Unity INOVA Whole Body MRI/MRS System (Varian, Inc., Palo Alto, CA, USA). Visual stimuli were presented using high-resolution video goggles (Resonance Technologies, Inc., Northridge, CA, USA). To provide anatomical localization, a high-resolution, T1weighted, three-dimensional brain scan was obtained (25). A midsagittal localizer scan was acquired to place 40 contiguous 4-mm axial slices to encompass the entire brain. Next, a multiecho reference scan was obtained to correct for ghost and geometric distortions (26). Subjects then completed two fMRI scans in which whole-brain images (volumes) were acquired coronally every three seconds using a T2*-weighted gradient-echo echo-planar imaging pulse sequence (repetition time/echo time = 3,000/29 msec, field of view = 20.8 9 20.8 cm, matrix 64 9 64 pixels, slice thickness = 5 mm, flip angle = 75°) while performing the CPT-END. fMRI data were analyzed using Analysis of Functional NeuroImages (AFNI; National Institutes of Health, Bethesda, MD, USA; http://afni. nimh.nih.gove/afni). Structural and functional images were co-registered, and functional images corrected for motion using a six-parameter rigid body transformation (27). Each volume was inspected for signal artifacts using a semiautomated algorithm in AFNI. Subjects were excluded from further analysis if uncorrectable head movement occurred; no scans were included with head movement >2 mm (28). Anatomical and functional maps were normalized to Talairach space. Motion correction parameters were included as regressors of no interest and low-frequency components of the signal removed. We applied 3D Hamming filtering at imaging reconstruction, which introduces smoothing of 1.8 times the
446
original voxel size. Individual voxel-wise eventrelated activation maps were created following standard AFNI procedures using an algorithm that compares the actual hemodynamic response to a canonical hemodynamic response function (29, 30). All events were modeled in the analysis of the fMRI time series, and event-related response functions derived for negatively valenced pictures, as per our a priori hypothesis. Orbitofrontal cortex (OFC) (BA 11/12) and amygdala, as well as other exploratory regions of interest (ROIs) previously identified to be active in affective expression and regulation, including the globus pallidus, thalamus, and putamen, were identified using the automatic anatomical labeling atlas in AFNI (23, 31, 32). Using SPSS (IBM SPSS Statistics for Windows, Version 22.0; Armonk, NY, USA), baseline comparisons of non-zero mean percent signal change extracted from each ROI were compared between subjects with bipolar disorder and healthy subjects, and baseline versus Week 8 comparisons made for subjects with bipolar disorder. Baseline versus Week 8 comparisons were made in a subset of healthy subjects in regions for which a significant finding in subjects with bipolar disorder was observed. A linear mixed model was used to examine the relationship between changes in YMRS scores and regional brain activation. Significance was defined for all analyses as p ≤ 0.05. Results
Twenty-two subjects with bipolar I disorder (11 women) ranging in age from 18 to 48 years (mean SD: 30 8 years) participated in baseline evaluations including fMRI scanning. Nineteen of these subjects with bipolar disorder completed the eight-week scan and assessment (nine women) (mean age SD: 29 8 years). Twenty-six healthy subjects (16 women) ranging in age from 11 to 41 years (28 7 years) also participated in fMRI scans. Subjects with bipolar disorder and healthy subjects did not differ in gender (p = 0.42) or age (p = 0.36). At entry, all subjects with bipolar disorder had a YMRS score ≥20 (mean SD: 25 5). At baseline, subjects with bipolar disorder did not significantly differ from healthy subjects in activation of any of the regions measured. Subjects with bipolar disorder demonstrated a significant increase in activation from baseline in the right OFC (BAs 11/12) during exposure to negatively valenced stimuli (p = 0.002) after eight weeks of quetiapine treatment. No other regions showed a significant change in activation from baseline
Quetiapine effects in bipolar mania Table 1. Functional activation in healthy subjects and in subjects with bipolar disorder Baseline ROI
Scan
OFC (BA 11/12)
L R L R L R L R L R
Amygdala Thalamus Globus pallidus Putamen
Healthy subjects 0.049 0.046 0.187 0.181 0.101 0.112 0.048 0.057 0.057 0.052
0.477 0.678 0.234 0.329 0.142 0.137 0.123 0.149 0.119 0.174
Week 8 Bipolar disorder 0.168 0.116 0.297 0.066 0.130 0.107 0.126 0.002 0.104 0.009
0.326 0.446 0.341 0.376 0.148 0.176 0.225 0.256 0.195 0.163
Bipolar disorder 0.268 0.204 0.212 0.024 0.122 0.074 0.028 0.095 0.065 0.017
0.437 0.751a 0.310 0.346 0.238 0.225 0.239 0.340 0.128 0.196
BA = Brodmann area; L = left; OFC = orbitofrontal cortex; R = right; ROI = region of interest. p = 0.002.
a
(Table 1). Over the eight weeks of treatment, YMRS scores of subjects with bipolar disorder decreased from 25 5 to 11 7 (p < 0.001). A subset of 14 healthy subjects (seven women), ranging in age from 19 to 41 years (27 7 years), were scanned a second time eight weeks after the baseline MRI. No significant change in activation of the right OFC (BAs 11/12) between the two scans was observed (p = 0.67). We observed a significant association between decreases in mania ratings and increasing functional activity in the right (p = 0.003), but not left (p = 0.85) OFC. No other significant associations between changes in functional activation and YMRS scores were observed. However, there was a large but non-significant association between decreases in mania ratings and nonsignificantly increasing functional activity in the left (p = 0.07), but not right (p = 0.16) amygdala. Discussion
In this study, we found that patients with bipolar mania who received quetiapine showed treatment-related increases in activation of the right OFC that were not observed in healthy subjects rescanned after eight weeks. These results are consistent with previous studies that have demonstrated increased prefrontal activation in euthymic patients with bipolar disorder, suggesting that mania is associated with a loss of modulatory control normally exerted over limbic regions by the prefrontal cortex (33). While right OFC activation was non-significantly greater in manic than healthy subjects, treatment was correlated with a further increase in activity. Further, improvement in YMRS scores showed a significant interaction with
increased OFC activity—while the improvement in mania symptoms cannot be unambiguously ascribed to changes in prefrontal activation, the observed relationship suggests that increased activity in BAs 11 and 12 is related to relative normalization of affective symptoms indicative of improved affective modulation. There was a similar, albeit non-significant, association between increased left amygdala activity and decreased ratings on the YMRS. The left amygdala, however, did not show a main effect for time, and changes in activation over the eight weeks of this study were not large. Although we have hypothesized that amygdala activity decreases with resolution of manic symptoms, increased amygdala activity has been previously observed in patients with bipolar disorder with even non-affective cognitive stimuli, including attention; observations of increased amygdala activity may be an artifact of disparate effects of treatment on response to attention and negatively valenced stimuli (34). This suggestion is buttressed by a previous study utilizing the CPT-END, in which we similarly observed increased amygdala activity in manic patients (8). We did not see baseline activation differences between manic and healthy subjects in any of the brain regions examined. This finding is not entirely consistent with previous studies showing significant differences in functional activation between manic subjects with bipolar disorder and healthy subjects during administration of similar tasks. Furthermore, the majority of these subjects were medication free at baseline—which would typically enhance rather than diminish differences (14). Potential findings may have been vitiated by the nature of the task, which included a cognitive baseline component; we have previously observed
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© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Bipolar Disorders 2015: 17: 444–449
BIPOLAR DISORDERS
Brief Report
Neurofunctional effects of quetiapine in patients with bipolar mania Davis AK, DelBello MP, Eliassen J, Welge J, Blom TJ, Fleck DE, Weber WA, Jarvis KB, Rummelhoff E, Strakowski SM, Adler CM. Neurofunctional effects of quetiapine in patients with bipolar mania. Bipolar Disord 2015: 17: 444–449. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood. Methods: Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans. Results: At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003). Conclusions: These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex —restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.
Although the neuropathophysiology of bipolar disorder remains poorly understood, recent research has strongly implicated dysfunction within frontalsubcortical networks involved in emotional expression and regulation; in particular, several lines of evidence suggest that subjects with bipolar disorder demonstrate abnormalities in brain activity centered on portions of the prefrontal cortex, as
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Andrew K Davisa, Melissa P DelBelloa, James Eliassena,b, Jeffrey Welgea, Thomas J Bloma, David E Flecka,b, Wade A Webera, Kelly B Jarvisa, Emily Rummelhoffa, Stephen M Strakowskia,b and Caleb M Adlera,b a
Department of Psychiatry and Behavioral Neuroscience, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, bCenter for Imaging Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
doi: 10.1111/bdi.12274 Key words: bipolar disorder – fMRI – functional magnetic resonance imaging – mania – prefrontal cortex – quetiapine Received 6 July 2014, revised and accepted for publication 23 September 2014 Corresponding author: Caleb M. Adler, M.D. Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine 260 Stetson Street, Suite 3200 Cincinnati, OH 45219-0516 USA Fax: 513-558-3399 E-mail: [email protected]
well as linked subcortical and medial temporal structures (1–7). Portions of the prefrontal cortex including Brodmann areas (BA) 11 and 12 have been widely observed to modulate the response to affective stimuli by limbic structures associated with emotional expression, leading to speculation that loss of activity in these regions may be related to the deficits in affective regulation that
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