MRI study of the pituitary gland in adolescent depression

Frank P. MacMastera,b,*, Vivek Kusumakarc
aInstitute for Biodiagnostics (Atlantic), National Research Council, 5909 Veterans Memorial Lane, 9th Floor – Psychiatry, Abbie J Lane Memorial Building, QE II Health Sciences Centre, Halifax, Nova Scotia, Canada B3H 2E2 bDepartment of Anatomy and Neurobiology, Dalhousie University, Halifax, NS, Canada cDepartment of Psychiatry, Dalhousie University, Halifax, NS, Canada
Received 3 July 2003; received in revised form 25 August 2003; accepted 3 November 2003
Abstract
Abnormalities in pituitary function have been described in major depressive disorder (MDD) and may re?ect neurodevelopmental abnormalities. We hypothesized alterations in the pituitary in early onset MDD. We measured the volume of the pituitary gland in 17 MDD (mean
S.D.=16.67
1.83 years; 8M, 9F) patients and 17 age and sex matched healthy controls (mean
S.D.=16.23
1.61 years; 8M, 9F) using 1.45 mm thick T1-weighted coronal MRI images. A trained rater blind to diagnosis did all measurements. ANCOVA covarying for age, sex and intracranial volume (ICV) revealed a signi?cant di?erence between the two groups (F=6.43, df=1, 29, P=0.02; MDD subjects demonstrated a 25% increase in pituitary gland volume). Age was signi?cantly correlated with pituitary volume in the healthy controls (r=0.62, P=0.008) but not the MDD group. No signi?cant relationships between pituitary size and clinical severity were found in the MDD patients. To our knowledge, this is the ?rst study that reports larger pituitary volumes in early onset major depression. These ?ndings provide new evidence of abnormalities of the pituitary in early onset MDD, possibly related to neuroendocrine dysfunction. # 2003 Elsevier Ltd. All rights reserved.
Keywords: Adolescent; Depression; Development; Pituitary gland; Magnetic resonance imaging
1. Introduction
The pituitary gland has a central role in endocrine function. It is bulbous at birth, but shifts to a ?atter superior surface after 2 months of age (Tien et al., 1992). MRI studies of pituitary volume have demonstrated a sudden growth during puberty (Takano et al., 1999), and a gradual decrease with age over adulthood (Lurie et al., 1990; Schwartz et al., 1997). Previous studies have demonstrated that endocrine abnormalities are associated with changes in the morphology of the pituitary (Gonzalez et al., 1988; Chakeres et al., 1989). There are sex di?erences in the size of the pituitary; women tend to have larger pituitaries than men (Takano et al., 1999), with additional transient increases during pregnancy and early post-partum period (Dinc et al., 1998).
Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been noted in depression. Sustained hypercortisolemia and failure to suppress serum cortisol after administration of dexamethasone have been noted in MDD patients (Carroll et al., 1981; Krishnan et al., 1985). However, subsequent reports have challenged the selectivity of the dexamethasone suppression test (DST) to a?ective disorders (Volsan & Berzewski, 1985; Lammers et al., 1995; Schreiber et al., 1996). In adolescents with MDD, the evidence of cortisol abnormalities is less compelling. One study failed to note any di?erences in the cortisol measures (Dahl et al., 1989), while two studies noted an increase in cortisol after sleep onset in depressed adolescents (Dahl et al., 1991; Kutcher et al., 1991). After sleep onset, cortisol levels are usually low. It has been hypothesized, therefore, that these results re?ect more the diurnal variation of cortisol level than a robust increase in overall cortisol activity (Dahl et al., 1991; Kutcher et al., 1991). Classic cortisol hypersecretion is thought to be rare in depressed children and adolescents. Alterations in cortisol concentrations
0022-3956/$ – see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2003.11.001
Journal of Psychiatric Research 38 (2004) 231–236
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* Corresponding author. Tel.: +1-902-473-4571; fax: +1-902-4734596. E-mail address: frank.macmaster@nrc.ca (F.P. MacMaster).
appear to be more of a dysregulation of cortisol than hyperactivity per se. To date only four studies have assessed in vivo pituitary sizes with neuroimaging techniques in mood disorders (Krishnan et al., 1991; Axelson et al., 1992; Schwartz et al., 1997; Sassi et al., 2001). Considering the evidence of HPA dysfunction in adult MDD and HPA dysregulation in adolescent depression, we hypothesized that MDD is associated with an increase in pituitary volume that possibly re?ects these changes in HPA activity. Thus, we performed an MRI study in early onset MDD patients focusing on the size of the pituitary. To our knowledge, this is the ?rst study of pituitary size in a pediatric sample of mood disorder patients.
2. Methods
2.1. Subjects
Thirty-four subjects were studied (mean age
S.D.= 16.45
1.71 years), of which 17 were DSM-IV MDD patients [mean age
S.D.=16.67
1.83 years; 8 male (M), 9 female (F)] and 17 were age and sex matched healthy controls (mean age
S.D.=16.23
1.61 years; 8M, 9F). See Table 1. Patients were recruited after being referred to the IWK Health Centre’s Department of Psychiatry. Controls were recruited through advertisement. Mean (
S.D.) age of onset of the ?rst clinical presentation in the patients with MDD was 14.06
1.98 years. Duration of illness in the MDD subjects was 2.89
1.71 years. All case-control pairs were matched for age (
12 months) and sex. Patients and controls were paid a small honorarium for their participation in the study. All subjects and parents/guardians provided signed informed consent. The IWK Health Centre Research Ethics Board (REB) approved the protocol for human subjects. The inclusion criteria were a diagnosis of MDD, with age between 7 and 20 years. All patients met the DSM-IV diagnostic criteria for MDD
as determined by the Kiddie-Schedule for A?ective Disorders and Schizophrenia–Present and Lifetime Version (K-SADS-PL; Kaufman et al., 1997), and con?rmed in a clinical evaluation conducted by an attending psychiatrist. Exclusion criteria for participation in this study were a history of neurological illness, serious medical illness, claustrophobia, age greater than 18 years, or the presence of a ferrous implant or pacemaker. Depression symptom severity was assessed using the Childhood Depression Rating Scale (CDRS; mean
S.D. score, 65.35
13.87; Poznanski et al., 1985). All depressed subjects had a CDRS score above 42, indicative of signi?cant dysfunction. Nine of the 17 MDD subjects had a family history of a mood disorder. Two subjects had a comorbid diagnosis of Substance Abuse and one subject had comorbid diagnosis of Oppositional De?ant Disorder. Three MDD subjects had recently (within 2 weeks) started medication (sertraline, methylphenidate and zopiclone, respectively). The remainder of MDD subjects was treatment nai¨ve (N=14). Controls did not have any psychiatric illness. Controls were also screened for depression with the CDRS (mean
S.D. score, 40.35
13.69).
2.2. MRI data acquisition
MRI scans were conducted on a 1.5 Tesla Seimens Vision system (Erlingen, Germany) at the Queen Elizabeth II Health Sciences Centre. Patients were provided with earphones and video goggles to reduce acoustic noise and alleviate possible boredom during the scan. A 3-plane scout series was ?rst obtained to verify patient position and image quality, to locate a midline sagittal image and for graphic prescription of the coronal and axial images. High-resolution anatomical coronal fast low angle shot (FLASH) sequence parameters were as follows: TE=25 ms, TE=5.40 ms, FliP=40, Slice thickness=1.45 mm, 124 slices, matrix=256  256 pixels. Additionally, a dual echo spin echo sequence was used to obtain T2 and proton density images in the axial plane to screen for unexpected structural lesions. Anatomical measurements were conducted on a MAC workstation (Macintosh G4, G4 processor) using the semi-automated software NIH Image 1.62 (NIH, Bethesda, MD).
2.3. Image analysis
Boundaries of the pituitary gland were determined by reference to standard neuroanatomical atlases (Daniels et al., 1987; Talairach & Tournoux, 1988), and measurement methods were adapted from previously published neuroimaging studies of the pituitary (Doraiswamy et al., 1990, 1991a, b; Krishnan et al., 1991; Tien et al., 1992; MacMaster et al., 1999; Sassi et al., 2001). The entire pituitary was measured, and no
Table 1 Summary of variables Variable Mean
S.D. Control MDD Age (years) 16.23
1.61 16.67
1.83 N 17 17 Male 8 8 Female 9 9 Race caucasian 16 15 Race other 1 2 Duration of illness (years) – 2.89
1.71 Age of onset (years) – 14.06
1.98 CDRS 40.35
13.69 65.35
13.87 Pituitary gland 0.60
0.14 0.74
0.13 ICV 1233.50
114.431150.22
136.28
232 F.P. MacMaster, V. Kusumakar/Journal of Psychiatric Research 38 (2004) 231–236
attempt was made to separate it into the anterior and posterior lobes. The superior border of the pituitary was de?ned as the optic chiasm and infundibular recess of the third ventricle. The sphenoid sinus was used to mark the inferior border of the pituitary. Serial coronal slices (each slice 1.45 mm thick) were used for measuring the pituitary (Fig. 1). The serial measures of pituitary area were summed and multiplied by the slice thickness. An average of 7.38
1.19 slices were used. As the volume was acquired in a 3D mode, sagittal views were also used to guide measurements, when the boundary was unclear in the coronal view. A single trained rater made all measurements, blind to any identifying information. The boundaries of the pituitary are fairly well de?ned, and previously reported inter-rater and intra-rater reliabilities were very high for pituitary measurements. Reliability for this study was high as well (intraclass r=0.92 and 0.98). No empty or partially empty sellas were noted in this sample. Intracranial volumes (ICV) were also measured using every second slice of the same coronal scan. The measure included all gray and white matter in the brain and the cerebellum was excluded. Reliability was very high for this measure (r=0.99).
2.4. Data analyses
An ANCOVA was performed to compare the values of the pituitary volumes among the two age and sex
matched groups with sex, age and ICV used as covariates. ICV’s were used as a covariate in the ANCOVA as they demonstrated a correlation with pituitary volume in MDD patients (r=0.536, P=0.026). ICV also demonstrated a trend for signi?cant di?erence between groups (F=3.93, df=1, 31, P=0.06) with MDD patients ICV’s being smaller than control participants. Age was used as a covariate as well as a strong correlation between pituitary volume and age was noted in the control group (r=0.62, P=0.008). Sex was also used as a covariate as a sex di?erence in pituitary morphology has been noted previously (Takano et al., 1999). The planned comparison contrasted MDD subjects (1) against control participants (1). Pearson’s correlation coe?cients were used to examine the e?ects of age and speci?c clinical variables on the anatomical volumes.
3. Results
Using an ANCOVA (age/sex/ICV), we found that MDD patients had larger pituitary volumes when compared to healthy controls (F=6.43, df=1, 29, P=0.02). The mean
SE pituitary volumes for the two groups were as follows: MDD=0.74
0.03 cc and healthy control=0.60
0.03 cc. See Table 1 and Fig. 2. As only one previous study used ICV as a covariate, we also examined pituitary volume by group using an ANCOVA with age and sex as covariates that revealed an increase in pituitary gland volume in depressed subjects as compared to controls (F=10.55, df=1, 30, P=0.003). We examined the potential e?ects of medication on pituitary volumes in the MDD sample (14 drug-free, three on psychotropic medication). Excluding the treated MDD patient – control pairs from the group did not change the ANCOVA results for the group comparisons, with MDD patients still having signi?cantly
Fig. 1. An example of a coronal magnetic resonance imaging (MRI) scan showing the manual tracing procedure of the pituitary gland. (A) Full image of the head. (B) A section of the image shown at twice magni?cation showing a close up of the pituitary gland in that slice. (C) The pituitary traced (white outline).
Fig. 2. Scattergram of pituitary gland volume (cc) by diagnostic group (the control group as triangles and the depressed group as circles).
F.P. MacMaster, V. Kusumakar/Journal of Psychiatric Research 38 (2004) 231–236 233
larger pituitary volumes when compared to the healthy control (F=4.95, df=1, 23, P=0.04). When considering all subjects, regardless of diagnosis, we found signi?cant e?ects of age on pituitary volumes (Pearson’s correlation=0.43, P=0.01). No signi?cant e?ects of age on pituitary volumes were found when examining the patient group (Pearson’s correlation= 0.08, P=0.75). However, a strong correlation between pituitary volume and age was noted in the healthy controls (Pearson’s correlation=0.62, P=0.008, Fig. 3). In the MDD sample, pituitary volumes did not correlate with CDRS scores (r=0.21, P=0.49) but did demonstrate a trend for a positive relationship with age of onset (r=0.48, P=0.08). There was a trend for sex di?erences in the pituitary volumes when analyzing all 34 subjects (16 M, mean
SE 0.62
0.03 cc; 18F, mean
SE 0.71
0.04 cc; ANOVA, F=3.98; df=1, 15; P=0.06). Among MDD patients, no signi?cant sex di?erences were noted (ANOVA, F=0.96; df=1, 15; P=0.35). A trend for signi?cant sex di?erences was found in healthy controls (ANCOVA, F=3.29; df=1, 15; P=0.09), with women showing larger pituitary volumes. To further evaluate the sex di?erences, we separated the groups and performed further analysis. MDD males (n=8) had signi?cantly larger pituitary volumes than healthy men (n=8), using a paired t-test (t=3.14, df=7, P=0.02). MDD females (n=9) presented a trend to larger pituitaries when compared to healthy women (t=1.96, df=8, P=0.09).
4. Discussion
The main ?ndings of the present study are as follows: an increase in pituitary volume in depressed adolescents compared with age and sex matched healthy controls
was noted. A robust correlation between pituitary volume and age was noted in the healthy controls, consistent with a previous ?nding of an increase in pituitary volume with puberty (Takano et al., 1999). A trend for a sex di?erence in healthy subjects was also noted, similar to past ?ndings (Takano et al., 1999). Interestingly, these two ?ndings were not noted in the MDD subjects, who already have larger pituitaries. MDD subjects did demonstrate a trend for a relationship with age of onset, however. The di?erence in volume was also more prominent when comparing MDD males with healthy male controls than in MDD females as compared to female controls. It would appear that pathological enlargement of the pituitary masks or overwhelms physiological patterns of enlargement. As for the trend towards a signi?cant di?erence with regards to ICV, this may be due to decreases in frontal cortex volume noted in depressed subjects (Soares and Mann, 1997). The reduction in ICV did not a?ect the di?erence noted in pituitary volumes between MDD subjects and controls. Only four MRI studies have evaluated pituitary volumes in major depressive patients. Krishnan et al. (1991) found enlarged pituitary volumes in acutely depressed adult patients as compared to healthy controls. Axelson et al. (1992) found a positive correlation between post-dexamethasone plasma cortisol concentration and pituitary volumes in a group of psychiatric inpatients, which consisted mainly of MDD patients. More recently, Schwartz et al. (1997) did not ?nd any di?erences in pituitary volumes between seasonally a?ective disorder patients and healthy controls. Sassi et al. (2001) did ?nd a signi?cant decrease in pituitary volume in bipolar adults compared to controls but not in their unipolar sample. To our knowledge, this study is the ?rst direct comparison of in vivo pituitary volumes between early onset adolescent MDD patients and age and sex matched healthy controls, indicating anatomical abnormalities in the pituitaries of these patients. Our ?ndings for MDD are in contrast with the studies by Schwartz et al. (1997) and Sassi et al. (2001), who found no di?erences between unipolar depressed adult patients and healthy controls. However, our ?ndings are consistent with the ?ndings by Krishnan et al. (1991), who reported enlargement of the pituitary gland in adult unipolar depression. A few methodological di?erences between our study and the ones by Schwartz et al. (1997) and Sassi et al. (2001) may explain the discrepant ?ndings. First, our sample of MDD patients is much younger than any previously reported, and it is possible that the normal increase in pituitary volume during puberty might mask depression-related changes in older patients. This is supported by our ?nding of a robust correlation between age and pituitary volume in controls. An interesting possibility is that as the elderly age range is reached, the decrease noted in pituitary size in healthy
Fig. 3. Correlations of pituitary gland volume (cc) with age. Pituitary gland volume (y-axis) is related to age (x-axis) in the control group (triangles and dotted line; r=0.62, P=0.008) but not in the depressed group (circles and line; r=0.08, P=0.75).
234 F.P. MacMaster, V. Kusumakar/Journal of Psychiatric Research 38 (2004) 231–236
people previously (Lurie et al., 1990) might again reveal the larger pituitary volumes in MDD subjects. Second, the unipolar sample studied by Sassi et al. (2001) was composed mostly of women, which could have in?uenced their results, since we found a much less robust e?ect in the size of the pituitary in the female MDD subjects as compared to the healthy females. Third, half of the unipolar samples in Sassi et al. (2001) were euthymic at the time of the MRI scan, whereas in our study all patients were acutely depressed. Changes in cortisol tend to resolve with remission of the depression and may a?ect pituitary gland volume. This may be less important as Schwartz et al. (1997) did not show any in?uence of a?ective status on pituitary size. It is unlikely that the discrepancy is due to di?erences in the technique utilized to measure the volume of the pituitary. In our study and in Sassi et al. (2001) and Schwartz et al. (1997), contiguous coronal images were utilized to measure the area of the gland in all slices where it could be identi?ed, and the total area was multiplied by the slice thickness to obtain the volume. The reliability of this method is well established. Our ?ndings of enlarged pituitary volumes in adolescent MDD patients would be expected, as abnormal levels of serum cortisol would only occur with a hyperactive pituitary. However, as the hypercortisolemia noted in adults with MDD is rare in children and adolescents with MDD, the increase may re?ect the changes in the diurnal variation of pituitary controlled hormones noted in adolescents as opposed to an increase in cortisol per se. However, these explanations should be regarded as speculation, as we did not perform endocrinological measurements in our patients. This limits our ability to attempt to directly link the anatomical pituitary ?ndings to possible neuroendocrine abnormalities. To date, only eight MRI studies have previously examined pituitary volumes in psychiatric illness (Doraiswamy et al., 1990; Doraiswamy et al., 1991; Krishnan et al., 1991b; Axelson et al., 1992; Schwartz et al., 1997; MacMaster et al., 1999; Beresford et al., 1999; Sassi et al., 2001). Beresford et al. (1999) reported a trend towards enlarged pituitary in subjects with alcohol dependence. As only two of our subjects reported any substance abuse, the e?ect noted here is unlikely to be due to that. Decreased pituitary volumes have been noted in bulimic patients (Doraiswamy et al., 1990, 1991a) and in treatment-nai¨ve pediatric obsessivecompulsive disorder (MacMaster et al., 1999). Our ?ndings have a few potential methodological limitations, which would need to be addressed in future studies of the pituitary gland in MDD. Our MDD patients were all acutely depressed. Hence, further studies of euthymic patients are needed in order to determine if this is state-related or a trait of depressive disorders in youth. A larger confound is the fact that
one cannot reliably delineate the anterior from the posterior pituitary, even with high resolution MRI. Therefore we cannot specify the region of hypertrophy with any degree of certainty. This is important, as the function of the anterior and posterior lobes is markedly di?erent. In summary, we report for the ?rst time evidence of increased pituitary volume in early onset MDD patients. This change in volume may re?ect an adaptation to chronically high plasma cortisol levels or a change in the diurnal variation more typically seen in adolescents. Future studies with larger patient samples and direct endocrine measures will be needed to further evaluate these speculations.
Acknowledgements
The authors would like to acknowledge the support of the Nova Scotia Health Research Foundation and the Theodore and Vada Stanley Foundation.
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