Mean HRSD scores for depressed and healthy participants were 24.42 (SD = 4.87) and .3 (SD = .5), respectively [t(16) = 16.68, p < .001]. Depressed patients were not on lithium prior to the study. Only participants who were not medicated at the time of the intake assessments were recruited and included in this study. There was no protocol to change or discontinue medications for enrolled participants. All included depressed patients were experiencing a recurrent major depressive episode. Mean duration of the current major depressive episode was 50.73 weeks (SD = 41.25 weeks; range = 1 to 124). On average, patients had 4.22 prior major depressive episodes (SD = 1.92; range 1 to 6). None of the healthy subjects presented with diurnal mood variation, as rated on the HRSD. One of the 12 depressed patients demonstrated obvious changes in mood across time of day on the HRSD, as determined by a score of 2 on the diurnal variability item of the HRSD. Five depressed patients were rated as showing mild and infrequent changes in mood variation (HRSD item score = 1), and six presented no diurnal variation in mood on the HRSD (HRSD item score = 0). Also based on HRSD, five depressed patients showed no current melancholic features (HRSD item score = 0), five showed some current melancholic feature (HRSD item score = 1), and one showed definite current melancholic features (HRSD item score = 2). This information was not available for the remaining patient.
Self-reported diurnal variation in subjective mood ratings improved in the evening relative to morning ratings in six patients, remained unchanged in five patients, and worsened in one patient. Data from the morningness subscale of the Circadian Type Questionnaire (Folkard et al. 1979
) were available for 11 healthy subjects and 9 depressed subjects. The mean morningness score for healthy subjects was 57.27 ± 13.85 (range = 37–90), and the mean morningness score for depressed patients was 57.11 ± 13.34 (range = 27–73). Mean scores did not differ between the two groups, t
(18) = .26, ns. The Spearman correlation between the score on the HRSD item on diurnal variation and the morningness subscale of the CTQ in depressed patients did not reach statistical significance (rho = .61, p
The repeated measure ANOVA revealed a significant group × time of day interaction for the mood scale [F(1,21) = 11.56, p = .003]. Depressed patients showed improvements in mood ratings in the evening relative to morning, whereas healthy participants showed lower mood ratings in the evening compared with the morning (). There was no group (healthy vs. depressed) × time of day (morning vs. evening) interaction on alertness ratings [F(1,21) = .12, ns], no main effect of group [F(1,21) = 4.07, ns), and no main effect of time of day [F(1,21) = .04, ns; ).
Z-score changes in morning and evening ratings for the mood (A) and alertness (B) scales in healthy and depressed subjects.
Absolute glucose metabolism data were complete and available for 11 depressed patients and 8 healthy subjects. There was no correlation between changes in absolute glucose metabolism and changes in mood scores in depressed patients (Spearman rho = .08, ns). Similarly, there was no significant correlation between these measures in healthy subjects (Spearman rho = .06, ns).
Electroencephalographic studies showed that depressed participants remained awake for a mean time of 18.58 minutes (SD = 2.20) during the morning uptake period and 19.64 minutes (SD = .96) during the evening uptake period. Healthy subjects remained awake for a mean of 19.42 minutes (SD = 1.34) of the 20-minute [18F]-FDG uptake period during the morning study and for a mean of 19.73 minutes (SD = 0.66) during the evening study. Time spent awake during morning and evening scans did not differ between groups or time of day [i.e., no significant group × time of day interaction; F(1,20) = .49, p = .49], confirming that the PET scans represent brain metabolic activity during wakefulness rather than sleep in both groups.
Evening-Morning Differences in rCMRglc in Depressed Patients
In depressed patients, relative rCMRglc was significantly greater during evening wakefulness compared with morning wakefulness in two areas (). The first area (Tailarach coordinates x, y, z of voxel of maximum = 28, 36, 8; extent: 4829 contiguous voxels; z = 4.27, p = .001) included midline medial prefrontal cortex, dorsal anterior and pregenual cingulate cortices, basal ganglia (striatum and globus pallidus), thalamus, and hypothalamus and extended into the left medial temporal regions including hippocampus, parahippocampal cortex, amygdala, uncal gyrus, fusiform gyrus, and the cerebellum. The second area was composed of 1282 voxels (voxel of maximum significance = 34, 0, -16; z = 4.48, p < .001). This area included the right superior temporal gyrus and extended into the fusiform and parahippocampal gyrus, hippocampus, and cerebellum.
Figure 2 Areas with greater relative glucose metabolism during evening wakefulness than morning wakefulness in the depressed sample only (p < .05 at the corrected cluster level), projected onto a glass brain (A) and transverse sections (B). The volumes (more ...)
Volume-of-interest analyses confirmed that rCMRglc was greater during evening wakefulness compared with morning wakefulness in the left amygdala (z = 3.20, p = .001; ), left anterior cingulate gyrus (z = 3.22, p = .02; ), and posterior hypothalamus (z = 2.93, p = .006; ).
Group × Time of Day Interaction Analyses
Depressed patients showed a statistically significant smaller morning-to-evening increase in relative rCMRglc compared with healthy subjects in one cluster. This cluster was composed of 1647 contiguous pixels (voxel of maximal significance at Taila-rach coordinates x, y, z = -20, -76, -4; z = 3.97, p < .001) and included bilaterally the lingual and fusiform gyri. depict this area onto glass brains and rendered images. Two volumes of interest also achieved statistical significance: the right midbrain reticular formation (; z = 2.26, p = .02), and the left locus coeruleus (; z = 2.07, p = .03). None of the other volumes of interest showed smaller increases in rCMRglc during evening relative to morning wakefulness in depressed compared with healthy subjects.
Figure 3 Areas where depressed patients significantly differed from healthy subjects during evening relative to morning wakefulness projected onto glass brains (A) and (E) and rendered images (B) and (F). The color scale depicts t values for the morning-evening (more ...)
One area of 726 contiguous voxels reached statistical significance (voxel of maximal significance at Tailarach coordinates x, y, z = 42, -26, 36; z = 3.13, p = .04) for the interaction analysis conducted to investigate areas where depressed patients showed greater increase in rCMRglc during evening wakefulness relative to morning wakefulness compared with healthy subjects (). This area included the central postcentral gyrus and superior and inferior parietal cortices and extended into the superior temporal gyrus. Small volume correction analyses revealed that rCMRglc was significantly greater in depressed patients during evening wakefulness relative to morning wakefulness compared with healthy subjects in the right inferior parietal cortex only (z = 2.72, p = .01; ).
Post Hoc Group Differences During Morning and Evening Wakefulness
Post hoc analyses were conducted to identify between-group differences during each time of day (). During morning wakefulness, depressed patients showed lower rCMRglc than healthy subjects bilaterally in the superior and middle frontal gyrus, medial frontal gyrus, and left central and superior parietal gyri and precuneus (3238 voxels; voxel of maximal significance at coordinates x, y, z = 34, 8, 44; z
= 3.79; p
< .001; ). The volume of interest corresponding to the right dorsolateral prefrontal cortex also showed significantly lower rCMRglc during morning wakefulness in depressed patients compared with healthy subjects (z
= 3.44, p
= .03). None of the other volumes of interest showed significantly reduced rCMRglc during morning wakefulness in depressed compared with healthy subjects. A similar pattern persisted during evening wakefulness. Specifically, depressed patients showed lower rCMRglc bilaterally in the medial dorsal anterior cingulate cortex, medial frontal cortex, and middle and superior frontal gyri during evening wakefulness compared with healthy subjects (Germain et al. 2004
) (). Additionally, relative rCMRglc did not differ between groups during evening wakefulness in any of the volumes of interest.
Figure 4 Between-group differences during morning and evening wakefulness. Areas where rCMRglc is greater or smaller in depressed patients compared with healthy subjects during morning wakefulness presented onto rendered images. Blue lines in the lower two images (more ...)
Depressed patients showed greater rCMRglc in two regions compared with healthy subjects () during morning wakefulness. The first area (5347 contiguous pixels) included the right inferior occipital gyrus; parahippocampal, lingual, and fusiform gyri; hippocampus; thalamus; and striatum (voxel of maximal significance at coordinates x, y, z = 32, -86, 0; z = 4.22, p < .001). The second cluster included the left parahippocampal and lingual gyri, striatum, thalamus, insula, uncus, and amygdala (1836 contiguous voxels; coordinates x, y, z for voxel of maximum significance = -14, -38, 4; z = 3.54, p = .02). Volume-of-interest analyses also revealed that depressed patients showed greater rCMRglc than healthy participants in morning wakefulness in left amygdala (z = 2.46, p = .01), left (z = 2.92, p = .04) and right (z = 2.35, p = .03) subgenual cingulate cortex, right (z = 2.19, p = .01) and left (z = 2.72, p = .002) mid-anterior insula, and left (z = 3.36, p = .006) and right (z = 2.96, p = .005) locus coeruleus. During evening wakefulness, relative rCMRglc was greater in depressed compared with healthy subjects in a large area composed of 5235 contiguous pixels (voxel of maximum significance at x, y, z coordinates = -26, -20, -16; z = 4.22, p < .001) that included bilaterally the cerebellum, fusiform and parahippocampal gyri, and hippocampus and extended into the uncus, striatum, and pulvinar (). None of the volumes of interest showed greater rCMRglc in depressed patients compared with healthy participants during evening wakefulness.