- Email: [email protected]
Visual contrast sensitivity in major depressive disorder
Journal of Psychosomatic Research 75 (2013) 83–86
Contents lists available at SciVerse ScienceDirect
Journal of Psychosomatic Research
Visual contrast sensitivity in major depressive disorder Johnson Fam a,⁎, A John Rush b, Benjamin Haaland b, Sylvaine Barbier b, Chi Luu c, d a
Department of Psychiatry, Singapore General Hospital, Singapore Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore c Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia d Singapore Eye Research Institute, Singapore b
a r t i c l e
i n f o
Article history: Received 28 November 2012 Received in revised form 12 March 2013 Accepted 15 March 2013 Keywords: Depression Vision Electroretinography
a b s t r a c t Objective: Through the eyes of those depressed, the world may appear dull and gray. Visual contrast sensitivity has recently been reported to be lower in depressed patients compared to healthy controls. We aimed to examine the consistency of this finding and to explore the underlying retinal electrophysiology. Methods: Twenty subjects with major depressive disorder and 20 matched healthy controls were studied. Pattern electroretinogram (PERG) and subjective visual contrast test were used to assess visual contrast sensitivity. Full-field electroretinography (ffERG) was additionally used to assess retinal neurophysiology. Depression was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and depression severity was measured using standard psychometric scales. Results: Visual contrast sensitivity was significantly lower in depressed patients compared to controls based on the Landolt C visual contrast test, but no difference was found between groups using PERG and ffERG. Greater severity of depressive symptoms correlated (r = 0.49, p = 0.001) with poorer visual contrast sensitivity. Conclusions: Depressed subjects had reduced visual contrast discrimination performance, but this finding could not be consistently determined using PERG. The neurobiological link between major depressive disorder and visual contrast sensitivity warrants further investigation. © 2013 Elsevier Inc. All rights reserved.
Introduction Depressed individuals may sometimes describe a world that appears generally duller. Altered retinal sensitivity has been reported in seasonal affective disorder (SAD) based on electroretinography (ERG) [1–3]. In major depressive disorder (MDD), recent reports by Bubl et al. described reduced contrast discrimination performance in patients with symptomatic, non-psychotic MDD using both subjective visual contrast test [4] and objective pattern ERG (PERG) [5]. These findings, if replicable, could potentially suggest retinal function as a biomarker for depression. Visual contrast sensitivity and MDD may be linked through dopamine and melatonin. Dysfunction in central dopaminergic neurotransmission has been reported in both animal and human studies of depression [6]. Dopamine, as a neurotransmitter in the retina, acts through amacrine and interplexiform cells to modulate visual information [7–9]. Visual contrast changes can be seen in diseases that affect central dopaminergic neurotransmission, as exemplified by altered PERG measurements in Parkinson's disease [10–13]. Melatonin on the other hand has been reported to modulate retinal sensitivity [14,15], through photoreceptors and ganglion cells with high melatonin receptor densities [16]. The role ⁎ Corresponding author. Tel.: +65 63214344; fax: +65 63214015. E-mail address: [email protected] (J. Fam). 0022-3999/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2013.03.008
of melatonin in depression has been highlighted by the development of Agomelatine, a melatonergic-based antidepressant [17]. This study aimed to examine the consistency of visual contrast change in MDD and to explore the underlying retinal pathophysiology. We used both subjective visual tests and objective PERG to examine visual contrast sensitivity. In addition, full-field ERG (ffERG) was conducted to characterize retinal electrophysiological differences in MDD. We hypothesized that visual contrast sensitivity would be reduced in depressed subjects compared to healthy controls, and that greater depressive symptom severity would be associated with poorer visual contrast sensitivity.
Methods Methods are fully described in Supplementary data. In brief, 20 depressed participants and 20 matched controls without depression were recruited. Depression was diagnosed using the Mini International Neuropsychiatric Interview and depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale and Beck's Depression Inventory. The Freiburg visual acuity and contrast test (FrACT) was used for subjective visual contrast assessment. PERG and ffERG were recorded using an Espion system (E2, Diagnosys LLC, Lowell, MA, USA).
84
J. Fam et al. / Journal of Psychosomatic Research 75 (2013) 83–86
Results All eligible subjects completed the assessments. Visual and psychiatric assessments were on average conducted within 2 days of each other. Depressed and control subjects were frequency matched on age, race and gender. MDD patients had moderate to severe depression, while controls were clearly not depressed (Table 1). Five of the MDD patients had more than 1 major depressive episode. 80% of depressed subjects were on antidepressants, and for an average duration of 18.4 weeks. Median doses of fluoxetine 20 mg/day, fluvoxamine 50 mg/day, escitalopram 7.5 mg/day and mirtazapine 15 mg/day were prescribed. All subjects were not on any over-the-counter drugs that could adversely affect vision. The visual acuity of those depressed did not differ significantly from healthy volunteers (Table 1). The linear slopes and distributions of PERG contrast gain for both depressed and control groups are shown in Fig. 1. The t-test showed no significant difference in mean PERG-based contrast gain between the depressed and controls [0.057 ± 0.012(SD) vs. 0.056 ± 0.022(SD); p = 0.88]. In addition, there was no mean difference in PERG contrast gain between controls and depressed patients with or without antidepressants (ANOVA, p = 0.98). There was also no difference in PERG contrast gain between unmedicated depressed patients and patients on either selective serotonin reuptake inhibitors or dual channel antidepressants (ANOVA, p = 0.86). The correlations between PERG-contrast gain and BDI as well as MADRS depression scores were r = 0.014 (p = 0.93) and r = −0.005 (p = 0.98) respectively. None of the ffERG responses were significantly different between the depressed and controls (Table 2). Subjective visual contrast tests using FrACT measured higher mean values in the depressed group than controls for the Michelson contrast (%) [1.15 ± 0.97(SD) vs. 0.60 ± 0.33(SD); p = 0.03] and Weber contrast (%) [2.25 ± 1.84(SD) vs. 1.20 ± 0.64(SD); p = 0.02]; which implied reduced contrast sensitivity in the depressed group. Stepwise regression analyses of factors associated with increased Michelson and Weber measurements found high BDI to be a significant covariate (p = 0.001). The correlation coefficients for BDI-Michelson and BDI-Weber were both r = 0.49 (p = 0.001).
Discussion In this study subjective visual contrast discrimination was significantly reduced in patients with non-psychotic MDD, as in a previous report [4]. However, we found no difference in PERG visual contrast sensitivity between depressed subjects and healthy controls. The ERG amplitude of maximal a-wave reflects the function of the outer retina (photoreceptors), while that of b-wave reflects mid retina (bipolar cells) function [18]. The PERG response is derived from inner retinal activity (retinal ganglion cells). In Bubl et al.'s PERG study of patients with MDD [5], separation in contrast gain function between the depressed and controls was found from as low as 16% contrast level. In this study, a difference in contrast gain function was not found at even much higher contrast levels. Bubl et al. also reported PERG modulation after successful antidepressant therapy [19]. Though we did not perform a longitudinal assessment in view of our negative PERG finding, we did examine for antidepressant effects on PERG contrast gain, but did not find any significant effect. We further assessed the outer retina with ffERG as outer retinal dysfunction could affect PERG response due to upstream effects, but did not find altered outer retinal function in our depressed patients.
Table 1 Baseline characteristics of subjects
Age (years) mean (SD) Race (%) Chinese Malay Indian Female (%) Visual acuity (logMAR) mean (SD) MADRS score mean (SD) BDI score mean (SD) a
t-Test.
Depressed n = 20
Controls n = 20
p-Valuea
44.5 (9.8)
43.7 (9.7)
0.78
80 15 5 85 −0.03 (0.18)
80 15 5 85 −0.08 (0.10)
– 0.25
30.6 (7.3)
0.5 (1.1)
b0.001
25.7 (9.2)
1.5 (3.3)
b0.001
–
Low rod and cone photoreceptor sensitivities reported in winter SAD [2,20] could normalize during summer and after bright light therapy [21]. Seasonal differences in light may affect melatonin regulation of retinal sensitivity [14,15], and this sensitivity could be further altered by serotonin dysfunction [22–24]. Bubl's study sample [5] was subject to seasonal variations, where MDD patients with seasonal patterns were not explicitly excluded. PERG findings in that study might possibly be modulated by seasons, but not in this study as our participants live in an equatorial region with no distinct seasons. For the subjective visual test, one difference between our study and the previous study [4] was that we used the Landolt C instead of the Gabor target. Our finding of reduced subjective visual contrast perception in those depressed was nevertheless consistent with the previous report. In addition, we found that greater severity of depressive symptoms correlated with poorer contrast discrimination. Cognitive deficits in depression affect domains such as attention, memory and cognitive inhibition [25]. Subjective responses could be influenced by cognitive deficits, especially in tests that are long and complex. The visual tests used in this study were brief and no time limits were imposed. Therefore, we believe that any response bias due to cognitive deficits in those depressed would have been minimal. Subjective contrast sensitivity may arguably be “reduced” in depression because behaviorally, they could be less likely to “come forward” when they felt unsure about a response. But this seems unlikely because a “forced choice” paradigm was used in this study. At each stimulus presentation, the subject had to select one of the four possible responses, even if unsure, in order to progress to the next stimulus presentation. The difference in subjective visual contrast may be due to altered higher visual processing in depression. Using functional magnetic resonance imaging (fMRI), the prefrontal cortex has been identified to exert top-down modulation in visual processing [26]. Through fMRI, impaired functional connectivity was observed between the frontoparietal networks and visual cortices when patients with depression were presented with visual stimuli [27]. Depressed individuals had counterproductive recruitment of attentional areas in the brain in response to varying visual input loads, which meant that their visual processing network was less effective in filtering relevant from irrelevant visual stimuli [28]. A limitation of this study was that visual evoked potentials (VEPs) were not measured. VEPs based on electrical recordings from the visual cortex, together with ERGs, could test the integrity of the whole visual pathway. P100 response implicit times of pattern reversal VEPs are decreased in atypical and increased in melancholic subtypes of depression [29], while VEP amplitude and reversal of VEP polarity are reduced in depressed patients compared to healthy controls [30]. These findings suggest that higher visual pathways could be affected in depression. Combined assessments using both ERG and VEP will help determine whether these changes are at the retinal or higher processing levels. If reduced visual contrast sensitivity proves to be a consistent finding in depressed individuals, then this simple visual contrast test could well become a surrogate biomarker of depression; a window to the dysfunction circuits of the depressed mind. Future studies could examine whether the remission of depression restores function to the cortico-limbic networks that influence higher visual processing, and whether this in turn could be detected by visual contrast sensitivity testing. Studies should examine whether impaired visual contrast sensitivity is a consistent phenomenon in other psychiatric illnesses as well. Sources of funding J. Fam has received research support from the National Medical Research Council and Duke-NUS, Singapore. A.J. Rush has received consulting fees from Advanced Neuromodulation Systems, Best
J. Fam et al. / Journal of Psychosomatic Research 75 (2013) 83–86
A
85
PERG Amplitude vs Stimulus Contrast
Stimulus Contrast (%)
B
Fig. 1. A) PERG amplitudes at various contrast levels. Linear model-based slopes shown. B) Individual PERG amplitude by stimulus contrast level shown for both depressed and control groups. Pointwise 95% confidence intervals shown in solid bars and model-based fit lines shown in dashed black.
Practice Project Management, Otsuka, University of Michigan and Brain Resource; has received consultant/speaker fees from Forest Pharmaceuticals and Singapore College of Family Physicians; has received consultant fees and is a stockholder of Pfizer; has received author royalties from Guilford Publications, Healthcare Technology Systems and the University of Texas Southwestern Medical Center, meeting travel grant from CINP and has received research support from the National Institute of Mental Health, USA. C. Luu has received
Operational Infrastructure Support from the Victorian Government, Australia. B. Haaland has received research support from the National Medical Research Council, National University of Singapore and Ministry of Health, Singapore. All authors report no biomedical financial interest or potential conflicts of interest.
Table 2 ffERG parameters
Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.jpsychores.2013.03.008. Depressed n = 20 mean (SD)
Scotopic b-wave Amplitude (μV) Implicit time (ms) Maximal a-wave Amplitude (μV) Implicit time (ms) Maximal b-wave Amplitude (μV) Implicit time (ms) a
t-Test.
Controls n = 20 mean (SD)
Appendix A. Supplementary data
p-Valuea
References
184.3 (32.0) 100.8 (9.8)
171.1 (33.1) 102.4 (9.9)
0.21 0.62
194.0 (35.1) 12.9 (1.0)
189.3 (28.1) 13.3 (1.1)
0.64 0.18
279.0 (56.0) 51.5 (4.0)
286.6 (65.4) 50.6 (1.9)
0.70 0.38
[1] Lam R, Beattie C, Buchanan A, Mador J. Electroretinography in seasonal affective disorder. Psychiatry Res 1992;43:55–63. [2] Hébert M, Beattie C, Tam E, Yatham L, Lam R. Electroretinography in patients with winter seasonal affective disorder. Psychiatry Res 2004;127:27–34. [3] Gagné AM, Hébert M. Atypical pattern of rod electroretinogram modulation by recent light history: a possible biomarker of seasonal affective disorder. Psychiatry Res 2011;187:370–4. [4] Bubl E, Tebartz Van Elst L, Gondan M, Ebert D, Greenlee MW. Vision in depressive disorder. World J Biol Psychiatry 2009;10:377–84. [5] Bubl E, Kern E, Ebert D, Bach M, Tebartz van Elst L. Seeing gray when feeling blue? Depression can be measured in the eye of the diseased. Biol Psychiatry 2010;68: 205–8.
86
J. Fam et al. / Journal of Psychosomatic Research 75 (2013) 83–86
[6] Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 2007;64:327–37. [7] Djamgoz MBA, Hankins MW, Hirano J, Archer SN. Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Res 1997;37:3509–29. [8] Frederick JM, Rayborn ME, Laties AM. Dopaminergic neurons in the human retina. J Comp Neurol 1982;210:65–79. [9] Masson G, Mestre D, Blin O. Dopaminergic modulation of visual sensitivity in man. Fundam Clin Pharmacol 1993;7:449–63. [10] Gottlob I, Schneider E, Heider W, Skrandies W. Alteration of visual evoked potentials and electroretinograms in Parkinson's disease. Electroencephalogr Clin Neurophysiol 1987;66:349–57. [11] Langheinrich T, Tebartz van Elst L, Lagreze WA, Bach M, Lucking CH, Greenlee MW. Visual contrast response functions in Parkinson's disease: evidence from electroretinograms, visually evoked potentials and psychophysics. Clin Neurophysiol 2000;111:66–74. [12] Nightingale S, Mitchell KW, Howe JW. Visual evoked cortical potentials and pattern electroretinograms in Parkinson's disease and control subjects. J Neurol Neurosurg Psychiatry 1986;49:1280–7. [13] Peppe A, Stanzione P, Pierelli F, De Angelis D, Pierantozzi M, Bernardi G. Visual alterations in de novo Parkinson's disease: pattern electroretinogram latencies are more delayed and more reversible by levodopa than are visual evoked potentials. Neurology 1995;45:1144–8. [14] Baba K, Pozdeyev N, Mazzoni F, Contreras-Alcantara S, Liu C, Kasamatsu M, et al. Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor. Proc Natl Acad Sci U S A 2009;106:15043–8. [15] Wiechmann AF, Vrieze MJ, Dighe R, Hu Y. Direct modulation of rod photoreceptor responsiveness through a Mel(1c) melatonin receptor in transgenic Xenopus laevis retina. Invest Ophthalmol Vis Sci 2003;44:4522–31. [16] Meyer P, Pache M, Loeffler KU, Brydon L, Jockers R, Flammer J, et al. Melatonin MT-1-receptor immunoreactivity in the human eye. Br J Ophthalmol 2002;86: 1053–7. [17] de Bodinat C, Guardiola-Lemaitre B, Mocaër E, Renard P, Muñoz C, Millan MJ. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov 2010;9:628–42. [18] Graham SL, Klistorner A. Electrophysiology: a review of signal origins and applications to investigating glaucoma. Aust N Z J Ophthalmol 1998;26:71–85.
[19] Bubl E, Ebert D, Kern E, van Elst LT, Bach M. Effect of antidepressive therapy on retinal contrast processing in depressive disorder. Br J Psychiatry 2012;201: 151–8. [20] Hébert M, Dumont M, Lachapelle P. Electrophysiological evidence suggesting a seasonal modulation of retinal sensitivity in subsyndromal winter depression. J Affect Disord 2002;68:191–202. [21] Lavoie MP, Lam RW, Bouchard G, Sasseville A, Charron MC, Gagné AM, et al. Evidence of a biological effect of light therapy on the retina of patients with seasonal affective disorder. Biol Psychiatry 2009;66:253–8. [22] Lambert GW, Reid C, Kaye DM, Jennings GL, Esler MD. Effect of sunlight and season on serotonin turnover in the brain. Lancet 2002;360:1840–2. [23] Praschak-Rieder N, Willeit M, Wilson AA, Houle S, Meyer JH. Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry 2008;65: 1072–8. [24] Willeit M, Sitte HH, Thierry N, Michalek K, Praschak-Rieder N, Zill P, et al. Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology 2008;33:1503–13. [25] Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry 2001;178:200–6. [26] Zanto TP, Rubens MT, Thangavel A, Gazzaley A. Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory. Nat Neurosci 2001;14:656–61. [27] Desseilles M, Balteau E, Sterpenich V, Dang-Vu TT, Darsaud A, Vandewalle G, et al. Abnormal neural filtering of irrelevant visual information in depression. J Neurosci 2009;29:1395–403. [28] Desseilles M, Schwartz S, Dang-Vu TT, Sterpenich V, Ansseau M, Maquet P, et al. Depression alters “top-down” visual attention: a dynamic causal modeling comparison between depressed and healthy subjects. Neuroimage 2011;54:1662–8. [29] Fotiou F, Fountoulakis KN, Iacovides A, Kaprinis G. Pattern-reversed visual evoked potentials in subtypes of major depression. Psychiatry Res 2003;118:259–71. [30] Normann C, Schmitz D, Fürmaier A, Döing C, Bach M. Long-term plasticity of visually evoked potentials in humans is altered in major depression. Biol Psychiatry 2007;62:373–80.
Contents lists available at SciVerse ScienceDirect
Journal of Psychosomatic Research
Visual contrast sensitivity in major depressive disorder Johnson Fam a,⁎, A John Rush b, Benjamin Haaland b, Sylvaine Barbier b, Chi Luu c, d a
Department of Psychiatry, Singapore General Hospital, Singapore Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore c Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia d Singapore Eye Research Institute, Singapore b
a r t i c l e
i n f o
Article history: Received 28 November 2012 Received in revised form 12 March 2013 Accepted 15 March 2013 Keywords: Depression Vision Electroretinography
a b s t r a c t Objective: Through the eyes of those depressed, the world may appear dull and gray. Visual contrast sensitivity has recently been reported to be lower in depressed patients compared to healthy controls. We aimed to examine the consistency of this finding and to explore the underlying retinal electrophysiology. Methods: Twenty subjects with major depressive disorder and 20 matched healthy controls were studied. Pattern electroretinogram (PERG) and subjective visual contrast test were used to assess visual contrast sensitivity. Full-field electroretinography (ffERG) was additionally used to assess retinal neurophysiology. Depression was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and depression severity was measured using standard psychometric scales. Results: Visual contrast sensitivity was significantly lower in depressed patients compared to controls based on the Landolt C visual contrast test, but no difference was found between groups using PERG and ffERG. Greater severity of depressive symptoms correlated (r = 0.49, p = 0.001) with poorer visual contrast sensitivity. Conclusions: Depressed subjects had reduced visual contrast discrimination performance, but this finding could not be consistently determined using PERG. The neurobiological link between major depressive disorder and visual contrast sensitivity warrants further investigation. © 2013 Elsevier Inc. All rights reserved.
Introduction Depressed individuals may sometimes describe a world that appears generally duller. Altered retinal sensitivity has been reported in seasonal affective disorder (SAD) based on electroretinography (ERG) [1–3]. In major depressive disorder (MDD), recent reports by Bubl et al. described reduced contrast discrimination performance in patients with symptomatic, non-psychotic MDD using both subjective visual contrast test [4] and objective pattern ERG (PERG) [5]. These findings, if replicable, could potentially suggest retinal function as a biomarker for depression. Visual contrast sensitivity and MDD may be linked through dopamine and melatonin. Dysfunction in central dopaminergic neurotransmission has been reported in both animal and human studies of depression [6]. Dopamine, as a neurotransmitter in the retina, acts through amacrine and interplexiform cells to modulate visual information [7–9]. Visual contrast changes can be seen in diseases that affect central dopaminergic neurotransmission, as exemplified by altered PERG measurements in Parkinson's disease [10–13]. Melatonin on the other hand has been reported to modulate retinal sensitivity [14,15], through photoreceptors and ganglion cells with high melatonin receptor densities [16]. The role ⁎ Corresponding author. Tel.: +65 63214344; fax: +65 63214015. E-mail address: [email protected] (J. Fam). 0022-3999/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2013.03.008
of melatonin in depression has been highlighted by the development of Agomelatine, a melatonergic-based antidepressant [17]. This study aimed to examine the consistency of visual contrast change in MDD and to explore the underlying retinal pathophysiology. We used both subjective visual tests and objective PERG to examine visual contrast sensitivity. In addition, full-field ERG (ffERG) was conducted to characterize retinal electrophysiological differences in MDD. We hypothesized that visual contrast sensitivity would be reduced in depressed subjects compared to healthy controls, and that greater depressive symptom severity would be associated with poorer visual contrast sensitivity.
Methods Methods are fully described in Supplementary data. In brief, 20 depressed participants and 20 matched controls without depression were recruited. Depression was diagnosed using the Mini International Neuropsychiatric Interview and depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale and Beck's Depression Inventory. The Freiburg visual acuity and contrast test (FrACT) was used for subjective visual contrast assessment. PERG and ffERG were recorded using an Espion system (E2, Diagnosys LLC, Lowell, MA, USA).
84
J. Fam et al. / Journal of Psychosomatic Research 75 (2013) 83–86
Results All eligible subjects completed the assessments. Visual and psychiatric assessments were on average conducted within 2 days of each other. Depressed and control subjects were frequency matched on age, race and gender. MDD patients had moderate to severe depression, while controls were clearly not depressed (Table 1). Five of the MDD patients had more than 1 major depressive episode. 80% of depressed subjects were on antidepressants, and for an average duration of 18.4 weeks. Median doses of fluoxetine 20 mg/day, fluvoxamine 50 mg/day, escitalopram 7.5 mg/day and mirtazapine 15 mg/day were prescribed. All subjects were not on any over-the-counter drugs that could adversely affect vision. The visual acuity of those depressed did not differ significantly from healthy volunteers (Table 1). The linear slopes and distributions of PERG contrast gain for both depressed and control groups are shown in Fig. 1. The t-test showed no significant difference in mean PERG-based contrast gain between the depressed and controls [0.057 ± 0.012(SD) vs. 0.056 ± 0.022(SD); p = 0.88]. In addition, there was no mean difference in PERG contrast gain between controls and depressed patients with or without antidepressants (ANOVA, p = 0.98). There was also no difference in PERG contrast gain between unmedicated depressed patients and patients on either selective serotonin reuptake inhibitors or dual channel antidepressants (ANOVA, p = 0.86). The correlations between PERG-contrast gain and BDI as well as MADRS depression scores were r = 0.014 (p = 0.93) and r = −0.005 (p = 0.98) respectively. None of the ffERG responses were significantly different between the depressed and controls (Table 2). Subjective visual contrast tests using FrACT measured higher mean values in the depressed group than controls for the Michelson contrast (%) [1.15 ± 0.97(SD) vs. 0.60 ± 0.33(SD); p = 0.03] and Weber contrast (%) [2.25 ± 1.84(SD) vs. 1.20 ± 0.64(SD); p = 0.02]; which implied reduced contrast sensitivity in the depressed group. Stepwise regression analyses of factors associated with increased Michelson and Weber measurements found high BDI to be a significant covariate (p = 0.001). The correlation coefficients for BDI-Michelson and BDI-Weber were both r = 0.49 (p = 0.001).
Discussion In this study subjective visual contrast discrimination was significantly reduced in patients with non-psychotic MDD, as in a previous report [4]. However, we found no difference in PERG visual contrast sensitivity between depressed subjects and healthy controls. The ERG amplitude of maximal a-wave reflects the function of the outer retina (photoreceptors), while that of b-wave reflects mid retina (bipolar cells) function [18]. The PERG response is derived from inner retinal activity (retinal ganglion cells). In Bubl et al.'s PERG study of patients with MDD [5], separation in contrast gain function between the depressed and controls was found from as low as 16% contrast level. In this study, a difference in contrast gain function was not found at even much higher contrast levels. Bubl et al. also reported PERG modulation after successful antidepressant therapy [19]. Though we did not perform a longitudinal assessment in view of our negative PERG finding, we did examine for antidepressant effects on PERG contrast gain, but did not find any significant effect. We further assessed the outer retina with ffERG as outer retinal dysfunction could affect PERG response due to upstream effects, but did not find altered outer retinal function in our depressed patients.
Table 1 Baseline characteristics of subjects
Age (years) mean (SD) Race (%) Chinese Malay Indian Female (%) Visual acuity (logMAR) mean (SD) MADRS score mean (SD) BDI score mean (SD) a
t-Test.
Depressed n = 20
Controls n = 20
p-Valuea
44.5 (9.8)
43.7 (9.7)
0.78
80 15 5 85 −0.03 (0.18)
80 15 5 85 −0.08 (0.10)
– 0.25
30.6 (7.3)
0.5 (1.1)
b0.001
25.7 (9.2)
1.5 (3.3)
b0.001
–
Low rod and cone photoreceptor sensitivities reported in winter SAD [2,20] could normalize during summer and after bright light therapy [21]. Seasonal differences in light may affect melatonin regulation of retinal sensitivity [14,15], and this sensitivity could be further altered by serotonin dysfunction [22–24]. Bubl's study sample [5] was subject to seasonal variations, where MDD patients with seasonal patterns were not explicitly excluded. PERG findings in that study might possibly be modulated by seasons, but not in this study as our participants live in an equatorial region with no distinct seasons. For the subjective visual test, one difference between our study and the previous study [4] was that we used the Landolt C instead of the Gabor target. Our finding of reduced subjective visual contrast perception in those depressed was nevertheless consistent with the previous report. In addition, we found that greater severity of depressive symptoms correlated with poorer contrast discrimination. Cognitive deficits in depression affect domains such as attention, memory and cognitive inhibition [25]. Subjective responses could be influenced by cognitive deficits, especially in tests that are long and complex. The visual tests used in this study were brief and no time limits were imposed. Therefore, we believe that any response bias due to cognitive deficits in those depressed would have been minimal. Subjective contrast sensitivity may arguably be “reduced” in depression because behaviorally, they could be less likely to “come forward” when they felt unsure about a response. But this seems unlikely because a “forced choice” paradigm was used in this study. At each stimulus presentation, the subject had to select one of the four possible responses, even if unsure, in order to progress to the next stimulus presentation. The difference in subjective visual contrast may be due to altered higher visual processing in depression. Using functional magnetic resonance imaging (fMRI), the prefrontal cortex has been identified to exert top-down modulation in visual processing [26]. Through fMRI, impaired functional connectivity was observed between the frontoparietal networks and visual cortices when patients with depression were presented with visual stimuli [27]. Depressed individuals had counterproductive recruitment of attentional areas in the brain in response to varying visual input loads, which meant that their visual processing network was less effective in filtering relevant from irrelevant visual stimuli [28]. A limitation of this study was that visual evoked potentials (VEPs) were not measured. VEPs based on electrical recordings from the visual cortex, together with ERGs, could test the integrity of the whole visual pathway. P100 response implicit times of pattern reversal VEPs are decreased in atypical and increased in melancholic subtypes of depression [29], while VEP amplitude and reversal of VEP polarity are reduced in depressed patients compared to healthy controls [30]. These findings suggest that higher visual pathways could be affected in depression. Combined assessments using both ERG and VEP will help determine whether these changes are at the retinal or higher processing levels. If reduced visual contrast sensitivity proves to be a consistent finding in depressed individuals, then this simple visual contrast test could well become a surrogate biomarker of depression; a window to the dysfunction circuits of the depressed mind. Future studies could examine whether the remission of depression restores function to the cortico-limbic networks that influence higher visual processing, and whether this in turn could be detected by visual contrast sensitivity testing. Studies should examine whether impaired visual contrast sensitivity is a consistent phenomenon in other psychiatric illnesses as well. Sources of funding J. Fam has received research support from the National Medical Research Council and Duke-NUS, Singapore. A.J. Rush has received consulting fees from Advanced Neuromodulation Systems, Best
J. Fam et al. / Journal of Psychosomatic Research 75 (2013) 83–86
A
85
PERG Amplitude vs Stimulus Contrast
Stimulus Contrast (%)
B
Fig. 1. A) PERG amplitudes at various contrast levels. Linear model-based slopes shown. B) Individual PERG amplitude by stimulus contrast level shown for both depressed and control groups. Pointwise 95% confidence intervals shown in solid bars and model-based fit lines shown in dashed black.
Practice Project Management, Otsuka, University of Michigan and Brain Resource; has received consultant/speaker fees from Forest Pharmaceuticals and Singapore College of Family Physicians; has received consultant fees and is a stockholder of Pfizer; has received author royalties from Guilford Publications, Healthcare Technology Systems and the University of Texas Southwestern Medical Center, meeting travel grant from CINP and has received research support from the National Institute of Mental Health, USA. C. Luu has received
Operational Infrastructure Support from the Victorian Government, Australia. B. Haaland has received research support from the National Medical Research Council, National University of Singapore and Ministry of Health, Singapore. All authors report no biomedical financial interest or potential conflicts of interest.
Table 2 ffERG parameters
Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.jpsychores.2013.03.008. Depressed n = 20 mean (SD)
Scotopic b-wave Amplitude (μV) Implicit time (ms) Maximal a-wave Amplitude (μV) Implicit time (ms) Maximal b-wave Amplitude (μV) Implicit time (ms) a
t-Test.
Controls n = 20 mean (SD)
Appendix A. Supplementary data
p-Valuea
References
184.3 (32.0) 100.8 (9.8)
171.1 (33.1) 102.4 (9.9)
0.21 0.62
194.0 (35.1) 12.9 (1.0)
189.3 (28.1) 13.3 (1.1)
0.64 0.18
279.0 (56.0) 51.5 (4.0)
286.6 (65.4) 50.6 (1.9)
0.70 0.38
[1] Lam R, Beattie C, Buchanan A, Mador J. Electroretinography in seasonal affective disorder. Psychiatry Res 1992;43:55–63. [2] Hébert M, Beattie C, Tam E, Yatham L, Lam R. Electroretinography in patients with winter seasonal affective disorder. Psychiatry Res 2004;127:27–34. [3] Gagné AM, Hébert M. Atypical pattern of rod electroretinogram modulation by recent light history: a possible biomarker of seasonal affective disorder. Psychiatry Res 2011;187:370–4. [4] Bubl E, Tebartz Van Elst L, Gondan M, Ebert D, Greenlee MW. Vision in depressive disorder. World J Biol Psychiatry 2009;10:377–84. [5] Bubl E, Kern E, Ebert D, Bach M, Tebartz van Elst L. Seeing gray when feeling blue? Depression can be measured in the eye of the diseased. Biol Psychiatry 2010;68: 205–8.
86
J. Fam et al. / Journal of Psychosomatic Research 75 (2013) 83–86
[6] Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 2007;64:327–37. [7] Djamgoz MBA, Hankins MW, Hirano J, Archer SN. Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Res 1997;37:3509–29. [8] Frederick JM, Rayborn ME, Laties AM. Dopaminergic neurons in the human retina. J Comp Neurol 1982;210:65–79. [9] Masson G, Mestre D, Blin O. Dopaminergic modulation of visual sensitivity in man. Fundam Clin Pharmacol 1993;7:449–63. [10] Gottlob I, Schneider E, Heider W, Skrandies W. Alteration of visual evoked potentials and electroretinograms in Parkinson's disease. Electroencephalogr Clin Neurophysiol 1987;66:349–57. [11] Langheinrich T, Tebartz van Elst L, Lagreze WA, Bach M, Lucking CH, Greenlee MW. Visual contrast response functions in Parkinson's disease: evidence from electroretinograms, visually evoked potentials and psychophysics. Clin Neurophysiol 2000;111:66–74. [12] Nightingale S, Mitchell KW, Howe JW. Visual evoked cortical potentials and pattern electroretinograms in Parkinson's disease and control subjects. J Neurol Neurosurg Psychiatry 1986;49:1280–7. [13] Peppe A, Stanzione P, Pierelli F, De Angelis D, Pierantozzi M, Bernardi G. Visual alterations in de novo Parkinson's disease: pattern electroretinogram latencies are more delayed and more reversible by levodopa than are visual evoked potentials. Neurology 1995;45:1144–8. [14] Baba K, Pozdeyev N, Mazzoni F, Contreras-Alcantara S, Liu C, Kasamatsu M, et al. Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor. Proc Natl Acad Sci U S A 2009;106:15043–8. [15] Wiechmann AF, Vrieze MJ, Dighe R, Hu Y. Direct modulation of rod photoreceptor responsiveness through a Mel(1c) melatonin receptor in transgenic Xenopus laevis retina. Invest Ophthalmol Vis Sci 2003;44:4522–31. [16] Meyer P, Pache M, Loeffler KU, Brydon L, Jockers R, Flammer J, et al. Melatonin MT-1-receptor immunoreactivity in the human eye. Br J Ophthalmol 2002;86: 1053–7. [17] de Bodinat C, Guardiola-Lemaitre B, Mocaër E, Renard P, Muñoz C, Millan MJ. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov 2010;9:628–42. [18] Graham SL, Klistorner A. Electrophysiology: a review of signal origins and applications to investigating glaucoma. Aust N Z J Ophthalmol 1998;26:71–85.
[19] Bubl E, Ebert D, Kern E, van Elst LT, Bach M. Effect of antidepressive therapy on retinal contrast processing in depressive disorder. Br J Psychiatry 2012;201: 151–8. [20] Hébert M, Dumont M, Lachapelle P. Electrophysiological evidence suggesting a seasonal modulation of retinal sensitivity in subsyndromal winter depression. J Affect Disord 2002;68:191–202. [21] Lavoie MP, Lam RW, Bouchard G, Sasseville A, Charron MC, Gagné AM, et al. Evidence of a biological effect of light therapy on the retina of patients with seasonal affective disorder. Biol Psychiatry 2009;66:253–8. [22] Lambert GW, Reid C, Kaye DM, Jennings GL, Esler MD. Effect of sunlight and season on serotonin turnover in the brain. Lancet 2002;360:1840–2. [23] Praschak-Rieder N, Willeit M, Wilson AA, Houle S, Meyer JH. Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry 2008;65: 1072–8. [24] Willeit M, Sitte HH, Thierry N, Michalek K, Praschak-Rieder N, Zill P, et al. Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology 2008;33:1503–13. [25] Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry 2001;178:200–6. [26] Zanto TP, Rubens MT, Thangavel A, Gazzaley A. Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory. Nat Neurosci 2001;14:656–61. [27] Desseilles M, Balteau E, Sterpenich V, Dang-Vu TT, Darsaud A, Vandewalle G, et al. Abnormal neural filtering of irrelevant visual information in depression. J Neurosci 2009;29:1395–403. [28] Desseilles M, Schwartz S, Dang-Vu TT, Sterpenich V, Ansseau M, Maquet P, et al. Depression alters “top-down” visual attention: a dynamic causal modeling comparison between depressed and healthy subjects. Neuroimage 2011;54:1662–8. [29] Fotiou F, Fountoulakis KN, Iacovides A, Kaprinis G. Pattern-reversed visual evoked potentials in subtypes of major depression. Psychiatry Res 2003;118:259–71. [30] Normann C, Schmitz D, Fürmaier A, Döing C, Bach M. Long-term plasticity of visually evoked potentials in humans is altered in major depression. Biol Psychiatry 2007;62:373–80.