Decreased pituitary volume in patients with bipolar disorder

Decreased Pituitary Volume in Patients with Bipolar Disorder Roberto B. Sassi, Mark Nicoletti, Paolo Brambilla, Keith Harenski, Alan G. Mallinger, Ellen Frank, David J. Kupfer, Matcheri S. Keshavan, and Jair C. Soares Background: Neuroendocrinologic investigations in bipolar disorder have suggested abnormalities in pituitary function. However, few imaging studies have evaluated possible anatomical differences in this brain structure in mood disorder patients. Our aim was to examine potential abnormalities in pituitary volume in patients with bipolar and in a comparison group of patients with unipolar disorder. Methods: We measured the volumes of the pituitary gland in 23 patients with bipolar disorder (mean ⫾ s.d. ⫽ 34.3 ⫾ 9.9 years) and 13 patients with unipolar disorder (41.2 ⫾ 9.6 years), and 34 healthy control subjects (36.6 ⫾ 9.6 years) using 1.5 mm thick T1-weighted coronal 1.5 T MRI images. All measurements were done blindly by a trained rater. Results: Patients with bipolar disorder had significantly smaller pituitary volumes than healthy control subjects (mean volume ⫾ s.d. ⫽ 0.55 ⫾ 0.15 ml and 0.68 ⫾ 0.20 ml, respectively; ANCOVA, F ⫽ 8.66, p ⫽ 0.005), and than patients with unipolar disorder (0.70 ⫾ 0.12 ml, F ⫽ 5.98, p ⫽ 0.02). No differences were found between patients with unipolar disorder and healthy control subjects (F ⫽ 0.01, p ⫽ 0.91). Conclusions: To our knowledge, this is the first study that reports smaller pituitary volumes in bipolar disorder. Our findings suggest that detectable abnormalities in pituitary size are present in patients with bipolar disorder, which may reflect a dysfunctional HPA axis. Biol Psychiatry 2001;50: 271–280 © 2001 Society of Biological Psychiatry Key Words: Neuroimaging, pituitary, mood disorders, bipolar disorders, MRI, HPA axis

From the Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (RBS, MN, PB, KH, AGM, EF, DJK, MSK, JCS); Department of Psychiatry, Institute of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil (RBS); Department of Psychiatry, University of Pavia School of Medicine, Pavia, Italy (PB), Department of Pharmacology (AGM), Department of Psychology (EF), University of Pittsburgh, Pittsburgh, Pennsylvania, Department of Neuroscience (DK), University of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to Jair C. Soares, M.D., Neurochemical Brain Imaging Laboratory, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara St., Pittsburgh, PA 15213. Received October 20, 2000; revised January 2, 2001; accepted January 4, 2001.

© 2001 Society of Biological Psychiatry

Introduction

T

he pituitary gland plays a key role in the neuroendocrine regulation of a large array of body functions. The production and release of hormones by the anterior and posterior pituitary are under the influence of feedback loops, involving target organs such as adrenal, thyroid, gonads, and discrete brain regions such as the hypothalamus (Wilson et al 1998). The volume of the pituitary gland changes during life, and these anatomic changes are believed to reflect the functional status of the gland. Accordingly, magnetic resonance imaging (MRI) studies of pituitary volume have demonstrated a sudden growth during puberty (Takano et al 1999) and a decrease with age (Lurie et al 1990; Schwartz et al 1997). Healthy women tend to have larger pituitaries than men (Takano et al 1999), with transient increases during pregnancy and early postpartum period (Dinc et al 1998). Abnormalities in some of the neuroendocrine loops involving the pituitary have been reported in affective disorders. Dysfunction in the hypothalamic-pituitaryadrenal axis (HPA) has been postulated to play a role in affective disorders since Strokes et al (1975) demonstrated an increased proportion of nonsuppressors at the dexamethasone suppression test (DST) in depressed subjects compared with healthy control subjects. Subsequent reports have challenged the specificity of the DST to affective syndromes and have demonstrated abnormalities of the HPA axis in other psychiatric disorders as well (Lammers et al 1995; Schreiber et al 1996; Volsan and Berzewski 1985). Although there is still some controversy in the literature, it appears that DST nonsuppression is more frequent in patients with bipolar than in patients with unipolar disorder, even during remission (Rush et al 1997; Rybakowski and Twardowska 1999; Schmider et al 1995). Abnormalities in the hypothalamus-pituitary-thyroid axis (HPT) have also been reported in affective patients. Lower basal thyrotropin (TSH) levels have been reported in depressed subjects (Golstein et al 1980; Kjellman et al 1984; Poirier et al 1995; Rubin et al 1987), with a trend to even lower levels in patients with bipolar disorder com0006-3223/01/$20.00 PII S0006-3223(01)01086-1

272

BIOL PSYCHIATRY 2001;50:271–280

pared with unipolar depressed patients (Poirier et al 1995). In addition, it has been found that 30% to 40% of major depressive unipolar and bipolar patients have a blunted TSH response to thyrotropin-releasing hormone (TRH) stimulation (Extein et al 1982; Hubain et al 1994; Kirkegaard and Bjorum 1980; Linkowski et al 1981; Poirier et al 1995), with a possibly higher prevalence in patients with bipolar disorder (Rush et al 1997). Few studies have assessed pituitary hormones that do not participate in the HPA or HPT axes, and the results are less clear. Abnormalities on the hypothalamic-pituitarygonadal axis (HPG) have been suggested in affective syndromes related to the female reproductive cycle, such as premenopausal depression (Baischer et al 1995), premenstrual syndrome (PMS) (Halbreich et al 1988), or in patients with bipolar disorder whose symptoms fluctuate accordingly with the menstrual cycle (Matsunaga and Sarai 1993). Concerning growth hormone (GH) levels, there are some reports of blunted GH release after stimulation in manic (Ansseau 1992; Thakore and Dinan 1996) and depressed patients (Dinan and Barry 1990; Lesch et al 1988; Pitchot et al 1995; Ryan et al 1994; Valdivieso et al 1996), although not in all studies (Gann et al 1995; Krishnan et al 1988). Differences in the circadian prolactin levels were also reported between patients with bipolar and unipolar disorder (Joyce et al 1988; Mendlewicz et al 1980), although there were also negative reports (Kuruvilla et al 1991). Neuroimaging techniques may have a role as a complementary approach to evaluate neuroendocrine pathways in mood disorders. However, only three MRI studies have assessed in vivo pituitary volumes in patients with affective disorders, mostly unipolar depressive patients (Axelson et al 1992; Krishnan et al 1991; Schwartz et al 1997). Although controversial, the literature suggests that hormonal abnormalities are more frequently found in patients with bipolar disorder than in unipolar subjects, which may represent a distinct pattern of neuroendocrine involvement between the two disorders. It is not clear, however, if these postulated endocrine abnormalities are state or trait dependent. In our study we examined the volume of the pituitary gland in patients with bipolar and unipolar disorder and healthy control subjects using MRI images. To our knowledge, this is the first study to directly examine pituitary volumes in patients with bipolar disorder.

Methods and Materials Subjects Seventy-four subjects were studied (mean age ⫾ SD ⫽ 37.1 ⫾ 9.9 years), of which 24 were DSM-IV patients with bipolar disorder (mean age ⫾ SD ⫽ 34.7 ⫾ 9.9 years; 16 men, 8 women; all Caucasians), 14 were DSM-IV patients with unipolar disorder

R.B. Sassi et al

(mean age ⫾ SD ⫽ 42 ⫾ 9.8 years; 1 man, 13 women; all Caucasians), and 36 were healthy control subjects (mean age ⫾ SD ⫽ 36.7 ⫾ 9.6 years; 22 men, 14 women; 32 Caucasians, 3 African Americans, 1 Hispanic). All subjects provided signed informed consent after having understood all issues involved in participation in the study protocol. This research study was approved by the University of Pittsburgh Biomedical Internal Review Board. The patients were recruited at the outpatient facilities of the University of Pittsburgh Medical Center or through advertisements in the local media. The inclusion criteria were a diagnosis of either bipolar or unipolar disorder, with age between 18 and 65 years, and without any psychotropic drug use other than lithium (or off all psychotropic medications) for at least 2 weeks before the scan. All patients met the DSM-IV diagnostic criteria for bipolar or unipolar disorder as determined by the Structured Clinical Interview for DSM IV (SCID-IV; Spitzer et al 1994) and confirmed in a clinical evaluation conducted by an attending psychiatrist. The diagnosis was subsequently reviewed in a consensus meeting with the clinician who completed the SCID, the clinic research coordinator, and a senior investigator. The Bech-Rafaelsen Mania Scale (BRMS; Bech et al 1979) and the Hamilton Depression Rating Scales (HRDS), 17 and 25 items, (Hamilton 1960) were used to rate the clinical symptoms, and were administered within a week of the MRI study. At the time of participation in the study, nine patients with bipolar disorder (mean age ⫾ SD ⫽ 37.8 ⫾ 9.9 years; 4 bipolar I [BP I], 5 bipolar II [BP II]; 6 men, 3 women) were off all psychotropic drugs for at least 2 weeks and off lithium for at least 1 month; and 15 patients (mean age ⫾ SD ⫽ 32.8 ⫾ 9.7 years; 14 BP I, 1 BP II; 10 men, 5 women) were on lithium monotherapy and off all other psychotropic medications for at least 1 month. All patients with unipolar disorder were off psychotropic medications for at least 4 weeks. All subjects had normal physical exams and had no history of neurologic problems. Patients with any comorbid psychiatric disorder, current medical problems, or alcohol or substance abuse within the 6 months preceding the study were excluded. Information about family history of psychiatric disorders, age at onset of illness, length of illness, number of previous affective episodes defined according to DSM-IV criteria, number of weeks on lithium treatment, current lithium dose, and medication history was retrieved from patients’ psychiatric interviews and medical charts. Healthy control subjects had no DSM-IV axis I disorders, as determined by the SCID-IV nonpatient version (SCID-NP), no current medical problems, and no history of psychiatric disorders among first-degree relatives. The three groups did not differ significantly regarding their educational level (chi square ⫽ 13.25, df ⫽ 10, p ⫽ .21) or age (F ⫽ 2.1, df ⫽ 2, p ⫽ .1). There were no significant differences in gender distribution between the bipolar and control groups (chi square ⫽ 0.7, df ⫽ 1, p ⫽ .8). The unipolar group, however, was composed mostly of women (12 women, 1 man) and had a significantly larger number of women than the control (chi square ⫽ 11.04, df ⫽ 1, p ⫽ .001) or bipolar (chi square ⫽ 11.31, df ⫽ 1, p ⫽ .001) groups.

Decreased Pituitary Volume in Patients with Bipolar Disorder

BIOL PSYCHIATRY 2001;50:271–280

273

Magnetic Resonance Imaging Procedure We acquired MRI scans with a 1.5T GE Signa Imaging System running version Signa 5.4.3 software (General Electric Medical Systems, Milwaukee, WI, USA). Patients were provided with earplugs to reduce noise disturbances. A sagittal scout series was first obtained to verify patient position, image quality, and locate a midline sagittal image. A T1 weighted sagittal scout image was obtained for graphic prescription of the coronal and axial images. Three-dimensional gradient echo imaging (spoiled gradient recalled acquisition, SPGR) was performed in the coronal plane (TR ⫽ 25 m/sec, TE ⫽ 5 m/sec, nutation angle ⫽ 40°, FOV ⫽ 24 cm, slice thickness ⫽ 1.5 mm, NEX ⫽ 1, matrix size ⫽ 256 ⫻ 192) to obtain 124 images covering the entire brain. Additionally, a double echo-spin echo sequence was used to obtain T2 and proton density images in the axial plane to screen for neuroradiologic abnormalities. Anatomic measurements were conducted on a personal computer workstation (Dell Dimension, Pentium III 550 MHz, Windows NT 4.0) using the semiautomated software Scion Image Beta-3b for Windows (Scion Corporation, Frederick, MD, USA). Volumetric measurements of the pituitary were obtained by a trained evaluator blind to group assignment and to subjects’ identity, who traced the pituitary glands in the MRIs in reference to standard brain atlases (Jackson and Duncan 1996; Patel and Friedman 1997). The interrater reliability, established by two evaluators tracing 10 training scans, was 0.95 (intraclass correlation coefficient). The volumes of this brain structure were calculated by multiplying the measured areas by the slice thickness (0.15 cm). All volumes were reported in cm3. The intracranial volumes (ICV) were traced manually, also by two evaluators blind to subject’s identity and diagnosis. The interrater reliability for the ICV measures was r ⫽ .97 (intraclass correlation coefficient). For the ICV measurements, the even slices were deleted, and the volumes were calculated by multiplying the final area by 0.3 cm.

Pituitary Measurements All coronal slices where the pituitary could be visualized at the sella turcica were utilized. The number of coronal slices traced per case varied from 5 to 11 (mean ⫾ SD ⫽ 8.0 ⫾ 1 slices). We traced around the usually well-defined borders of anterior and posterior pituitary, excluding the infundibular stalk (see Figure 1). The bright posterior pituitary, one of the most common normal variations in brain MRI (Patel and Friedman 1997), was included in the measurements because it is considered to represent hyperintense signals from the neurosecretory vesicles or intracellular lipids in the posterior pituitary cells (Holder and Elster 1997; Kucharczyk et al 1989). In four cases, the pituitary could not be measured, and these cases were excluded from the final analysis: one healthy control subject had an empty sella (which is considered a normal anatomic variation, rarely presenting symptoms), and there were three cases of extremely flattened pituitary, with no clinical symptoms, in one healthy control subject, one unipolar subject, and one bipolar subject. Therefore, the statistical analysis for the pituitary volumes was performed in 23 bipolar disorder patients (mean ⫾ SD ⫽ 34.3 ⫾ 9.9 years; 15

Figure 1. The tracing of the pituitary gland is illustrated in a coronal MRI slice, as marked by the white lines, indicating the pituitary boundaries. The pituitary stalk was not included in the tracings. men, 8 women), 13 unipolar patients (mean ⫾ SD ⫽ 41.2 ⫾ 9.6 years; 1 man, 12 women), and 34 healthy control subjects (mean ⫾ SD ⫽ 36.6 ⫾ 9.6 years; 21 men, 13 women; see Table 1).

Statistical Analyses All analyses were conducted using the SPSS for Windows software, version 8.0 (SPSS, Chicago), and two-tailed statistical significance level was set at p ⬍ .05. All the MRI volumetric measures were ICV corrected and were found to be normally distributed as determined by the Shapiro-Wilks test. We performed MANCOVA with age, gender, and ICV as covariates to compare the values of the pituitary volumes among the groups. The nonparametric Mann–Whitney U test was used to perform comparisons between patients’ subgroups because the sample sizes involved were relatively small. Pearson’s correlation coefficients were used to examine the effects of age and specific clinical variables on the anatomical volumes. The clinical variables that did not follow a normal distribution (length of illness, age at onset, number of prior affective episodes, HRDS scores, and uninterrupted weeks on lithium before the MRI) were transformed in normally distributed ones by using square root transformation (SQRT). We performed ANCOVA with Scheffe as a post hoc test to evaluate the effects of gender and episode type on anatomic measures.

Results The 3 subject groups were different concerning ICV measures (mean ⫾ SD ⫽ 1476.17 ⫾ 117.55, 1515.26 ⫾

274

R.B. Sassi et al

BIOL PSYCHIATRY 2001;50:271–280

Table 1. Demographic and Clinical Information for the Bipolar and Unipolar Disorder Groups Subject

Psychiatric diagnosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar

disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder, disorder,

1 2 3 4 5 6 7 8 9 10 11 12 13

Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar Unipolar

disorder disorder disorder disorder disorder disorder disorder disorder disorder disorder disorder disorder disorder

type type type type type type type type type type type type type type type type type type type type type type type

I I I I I I I I I I I I I I I I I I II II II II II

Gender

Age

Mood status at time of scan

F M M M F M M M F M F M M F F M M M M M M F F

41 55 30 36 40 42 40 26 19 24 29 29 44 28 36 37 21 30 25 23 41 37 56

Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Depressed Depressed Depressed Depressed Depressed Depressed Depressed Euthymic Euthymic Depressed Depressed Depressed

Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Lithium only, Drug free Drug free Lithium only, Drug free Lithium only, Lithium only, Drug free Lithium only, Drug free Drug free Drug free Drug free

F F F F F F F F M F F F F

59 41 40 24 51 48 41 26 42 32 45 40 47

Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Euthymic Depressed Depressed Depressed Depressed Depressed Depressed

Drug Drug Drug Drug Drug Drug Drug Drug Drug Drug Drug Drug Drug

158.70, and 1381.91 ⫾ 108.69 cm3 for control subjects, bipolar subjects, and unipolar subjects, respectively; F ⫽ 4.33, df ⫽ 2, p ⫽ .01). The unipolar group had significantly smaller intracranial volumes when compared with the control (F ⫽ 0.058, df ⫽ 45, p ⫽ .01) or the bipolar (F ⫽ 2.4, df ⫽ 34, p ⫽ .01) groups. There were no significant differences in ICV between bipolar and control groups (F ⫽ 3.2, df ⫽ 55, p ⫽ .3). The volumetric analyses for the pituitary measurements included ICV as a covariate to correct for these differences. The mean ⫾ SD pituitary volumes for the three groups were: bipolar ⫽ 0.55 ⫾ 0.15 cm3, unipolar ⫽ 0.70 ⫾ 0.12 cm3, healthy control subjects ⫽ 0.68 ⫾ 0.20 cm3. Using independent samples t test, we found that patients with bipolar disorder had smaller pituitary volumes when compared with healthy control subjects (p ⫽ .01) and unipolar patients (p ⫽ .003). Patients with unipolar disorder and

Psychotropic medication before the scan (at least 2 weeks) 750 mg/day 1500 mg/day 1200 mg/day 1200 mg/day 900 mg/day 1500 mg/day 900 mg/day 1650 mg/day 900 mg/day 2100 mg/day 900 mg/day

750 mg/day 1200 mg/day 900 mg/day 900 mg/day

free free free free free free free free free free free free free

healthy control subjects had no significant difference in pituitary volume (p ⫽ .7). The same differences persisted when using ANCOVA, with age, gender, and ICV as covariates: patients with bipolar disorder still had smaller pituitary volumes than control subjects (F ⫽ 8.66; df ⫽ 1, 52; p ⫽ .005) and than patients with unipolar disorder (F ⫽ 5.98; df ⫽ 1, 31; p ⫽ .02). Again, no significant differences were found between patients with unipolar disorder and healthy control subjects (F ⫽ 0.01; df ⫽ 1, 42; p ⫽ .91; see Figure 2). One of the control subjects had an unexpectedly high pituitary volume (see Figure 2), but excluding this subject did not change the final results (F ⫽ 9.58; df ⫽ 1, 51; p ⫽ .003 and F ⫽ 0.07; df ⫽ 1, 41; p ⫽ .8 when comparing healthy control subjects with patients with bipolar disorder and unipolar disorder, respectively). When considering all subjects, regardless of diagnosis, we did not find significant effects of age on ICV-corrected

Decreased Pituitary Volume in Patients with Bipolar Disorder

Figure 2. This figure illustrates the individual measures of pituitary volumes in patients with bipolar disorder, patients with unipolar disorder, and healthy control subjects. The patients with bipolar disorder had significantly lower volumes compared to healthy control subjects or patients with unipolar disorder.

pituitary volumes (Pearson’s correlation ⫽ ⫺0.45, p ⫽ .71). No significant effects of age on pituitary volumes were found when examining the individual subject groups (Pearson’s correlation ⫽ ⫺0.18, p ⫽ .41 for patients with bipolar disorder; Pearson’s correlation ⫽ 0.17, p ⫽ .58 for patients with unipolar disorder; Pearson’s correlation ⫽ ⫺0.21, p ⫽ .23 for healthy control subjects). There were significant gender differences in the pituitary volumes when analyzing all 70 subjects (37 men, 0.59 ⫾ 0.21 cm3; 33 women, 0.69 ⫾ 0.13 cm3; ANCOVA, F ⫽ 6.24; df ⫽ 1, 66; p ⫽ .015), with women showing larger pituitary volumes. Nevertheless, when covarying for gender alone, the differences observed between patients with bipolar disorder and control subjects persisted (F ⫽ 6.97; df ⫽ 1, 54; p ⫽ .012). The significant difference in pituitary volume between the patients with bipolar and unipolar disorder became a trend when covarying only for gender (F ⫽ 3.34; df ⫽ 1, 33; p ⫽ .07). We believe that the differences in ICV between the groups could explain this discrepancy. Still, no differences were found comparing healthy control and unipolar subjects with gender as the single covariate (F ⫽ 0.09; df ⫽ 1, 44; p ⫽ .7). Among patients with bipolar disorder, women had larger pituitary volumes than men (ANCOVA, age and ICV as covariates, F ⫽ 5.23; df ⫽ 1, 19; p ⫽ .03). No significant gender differences were found in healthy control subjects (ANCOVA, F ⫽ 1.07; df ⫽ 1, 30; p ⫽ .31). In the unipolar sample, the unequal number of women and men (12 of 13 subjects were women) did not allow a statistical analysis. To further evaluate the gender differ-

BIOL PSYCHIATRY 2001;50:271–280

275

ences, we separated the groups to perform further analysis. Men with bipolar disorder (n ⫽ 15) had significant smaller pituitary volumes than healthy men (n ⫽ 21), using ANCOVA with age and ICV as covariates (F ⫽ 4.75; df ⫽ 1, 32; p ⫽ .04). Women with bipolar disorder (n ⫽ 8) presented a trend to smaller pituitaries when compared with healthy women (n ⫽ 13; ANCOVA, F ⫽ 4.04; df ⫽ 1, 17; p ⫽ .06). Similar findings were observed comparing the women in the unipolar (n ⫽ 12) and bipolar groups (ANCOVA, F ⫽ 3.84; df ⫽ 1, 16; p ⫽ .07). Women with unipolar disorder and healthy women did not differ in pituitary volumes (ANCOVA, F ⫽ 0.15; df ⫽ 1, 21; p ⫽ .71). The unipolar sample had only one man, therefore we could not compare it with the other subgroups. Because all patients with unipolar disorder were free of medication, we examined the potential effects of current medication use on pituitary volumes only in the bipolar sample (8 drug free, 15 on lithium monotherapy). There was no evidence of significant effects of lithium treatment on pituitary volumes (ANCOVA with age, gender, and ICV as covariates, F ⫽ 1.47; df ⫽ 1, 18; p ⫽ .24; Mann–Whitney, p ⫽ .10). Among those receiving lithium, there were no significant effects of the lithium dosage at the time of the MRI scan (r ⫽ .39, p ⫽ .16) or length of use of lithium preceding the MRI scan (r ⫽ .06, p ⫽ .83) on pituitary volumes. Also, no evidence of effects of bipolar subtype was detected (18 bipolar I, 5 bipolar II; ANCOVA with age, gender, and ICV as covariates, F ⫽ 0.52; df ⫽ 1, 18; p ⫽ .48; Mann–Whitney U test, p ⫽ .49). Excluding the bipolar II patients from the bipolar group did not change the results for the group comparisons, and bipolar I patients were still found to have significantly smaller pituitary volumes when compared with the healthy control subjects (ANCOVA, age, gender, and ICV as covariates; F ⫽ 6.55; df ⫽ 1, 47; p ⫽ .01) or patients with unipolar disorder (F ⫽ 5.85; df ⫽ 1, 26; p ⫽ .02). Five of thirteen unipolar and 11 of 23 patients with bipolar disorder had a positive familial history of affective disorders. There were no significant differences on pituitary volumes between patients with and without a positive family history of mood disorders (ANCOVA with age, gender, and ICV as covariates; F ⫽ 0.41; df ⫽ 1, 31; p ⫽ .53 for all patients; F ⫽ 0.19; df ⫽ 1, 18; p ⫽ .67 for bipolar patients; F ⫽ 0.30, df ⫽ 1, 8; p ⫽ .60 for unipolar patients). The bipolar group was composed by 10 acutely depressed and 13 euthymic patients. In the unipolar group, we had six acutely depressed and seven remmitted patients. There was no evidence of significant effects of current affective symptoms on measures of pituitary volumes (ANCOVA, gender, age, and ICV as covariates: F ⫽ 0.68; df ⫽ 1, 31; p ⫽ .42 for the total patient sample; F ⫽

276

BIOL PSYCHIATRY 2001;50:271–280

0.99; df ⫽ 1, 18; p ⫽ .33 for the bipolar group; F ⫽ 0.39; df ⫽ 1, 8; p ⫽ .55 for the unipolar group). Pearson’s correlation coefficients were calculated to examine the relationship between pituitary volumes and length of illness (total patient sample: r ⫽ ⫺.20, p ⫽ .24; bipolar: r ⫽ ⫺.11, p ⫽ .62; unipolar: r ⫽ .24, p ⫽ .44), age at onset of illness (total patient sample: r ⫽ .24, p ⫽ .16; bipolar: r ⫽ ⫺.52, p ⫽ .81; unipolar: r ⫽ ⫺.12, p ⫽ .68), number of previous affective episodes (total patient sample: r ⫽ ⫺.13, p ⫽ .5; bipolar: r ⫽ .04, p ⫽ .87; unipolar: r ⫽ .18, p ⫽ .55), Hamilton-17 scores (total patient sample: r ⫽ ⫺.21, p ⫽ .9; bipolar: r ⫽ ⫺.13, p ⫽ .5; unipolar: r ⫽ .24, p ⫽ .4), and Hamilton-25 scores (total patient sample: r ⫽ ⫺.37, p ⫽ .83; bipolar: r ⫽ ⫺.13, p ⫽ .5; unipolar: r ⫽ .19, p ⫽ .5). No significant effects of these variables on pituitary volumes were found. These variables were normally transformed so that the Pearson’s correlation coefficients could be utilized.

Discussion Nonsuppression of DST is one of the most replicated neuroendocrine findings in affective disorders. The exact pathophysiologic mechanisms involved in the DST nonsuppression are not known, but they are supposed to reflect abnormally elevated levels of cortisol. Indeed, some investigators have found elevated basal plasma level of cortisol in depressed (Linkowski et al 1987) and manic patients (Whalley et al 1989). One recent study has shown higher cortisol levels in bipolar compared with unipolar patients, during acute depressive episodes or while in remission (Rybakowski and Twardowska 1999). Concerning pituitary function, the available findings on basal corticotropin are conflicting, with reports of increased levels (Winokur et al 1985) or no difference (Goodwin et al 1992; Linkowski et al 1985) between affective disorder patients and control subjects. Nonetheless, there is strong evidence of decreased corticotropin levels following stimulation of corticotropin releasing hormone (CRH) in unipolar and bipolar depressed subjects (Gold et al 1986; Kathol et al 1989; Thalen et al 1993), with possible return to normal levels during remission in unipolar patients (Holsboer et al 1985). In euthymic patients with bipolar disorder, there are persistent endocrinologic abnormalities, as suggested by a decreased corticotropin response to tryptophan stimulation (Nurnberger et al 1990). Not all studies, however, supported these findings (Schmider et al 1995). Interestingly, a blunted corticotropin response to CRH stimulation in depression can be abolished with pretreatment with metyrapone, a substance that blocks the production of cortisol, and eventually reverts the hypercortisolemia present in depressed subjects (Young et al 1995). Therefore, it seems that the elevated plasma corti-

R.B. Sassi et al

sol levels in depression may lead to pituitary inhibition and lower release of corticotropin after CRH stimulation, instead of that being caused by a specific subsensitivity of receptors to CRH in the pituitary. In consonance with these findings, some investigators have found increased adrenal sensitivity to corticotropin in depressed subjects, that is, smaller amounts of exogenous (Amsterdam et al 1983; Gerken and Holsboer 1986; Jaeckle et al 1987) or endogenous (Kathol et al 1989; Lopez et al 1987; Meller et al 1987) corticotropin can lead to augmented cortisol response. This might explain why depressed patients still have higher cortisol levels even with a putative decrease in stimulation from pituitary hormones. A possible explanation for the blunted TSH release after stimulation in affective disorders also could be related to increased cortisol levels. Although some studies did not find a correlation between cortisol levels and TSH suppression (Barry and Dinan 1990; Targum et al 1982), other studies reported a relative overlap of TSH suppression and DST nonsuppression (Aggernaes et al 1983; Rush et al 1997), that is, depressed patients with a blunted TSH response to TRH stimulation have a greater chance to present DST nonsuppression and vice versa. Therefore, the available evidence from several neuroendocrinologic studies points to functional abnormalities in the anterior pituitary in patients suffering from affective disorder. Although a considerable part of the studies had some methodologic limitations, such as including unipolar and bipolar depression in a single group, it appears that endocrinologic abnormalities may be more frequent in paitents with bipolar disorder than patients with unipolar disorder. Moreover, in a considerable fraction of these patients, there is a decreased pituitary response to stimulation at the HPA and HPT axes, and perhaps also a decrease in GH and prolactin release. The exact mechanism to explain this “hypofunction” of the anterior pituitary remains to be fully elucidated but is likely to be related to a chronic hyperactivation of the HPA axis and thus higher plasma cortisol levels. Anatomic brain imaging techniques can provide a complementary approach to evaluate some of the key structures involved on neuroendocrine pathways; however, there is a dearth of studies specifically designed to evaluate these structures (e.g., hypothalamus, pituitary, and hippocampus in patients with bipolar and unipolar disorder). Reliable methods to measure area or volume of the hypothalamus are not available, even with highresolution MRIs, because of difficulties in defining the exact boundaries of this anatomic structure. A few MRI studies have evaluated hippocampal volume in affective disorders. Although some studies have not found hippocampal volumetric abnormalities in unipolar (Vakili et al 2000) or bipolar individuals (Hauser et al 2000), other MRI investigations reported smaller hippocampus in

Decreased Pituitary Volume in Patients with Bipolar Disorder

unipolar (Bremner et al 2000; Mervaala et al 2000; Sheline et al 1999) and bipolar (Swayze et al 1992) patients. Because the neurons in the hippocampus are particularly sensitive to higher glucocorticoid concentrations (Wilson et al 1998), the findings of hippocampal atrophy reported by other authors are in consonance with the hypercortisolemia frequently found in affective disorders. The pituitary gland is a structure that has been measured with in vivo imaging techniques in a few studies. To our knowledge, seven MRI studies have examined pituitary volumes in selected groups of psychiatric patients (Axelson et al 1992; Beresford et al 1999; Doraiswamy et al 1990, 1991; Krishnan et al 1991; MacMaster et al 1999; Schwartz et al 1997). A recent report by Beresford et al (1999) reported a trend toward enlarged pituitary in subjects with alcohol dependence. Two MRI studies (Doraiswamy et al 1990, 1991) have demonstrated decreased pituitary volumes in anorexic and bulimic patients. It is not clear if these differences are related to nutritional and metabolic deficits in these patients or if the hypercortisolemia frequently found in eating disorders (Gwirtsman et al 1989) could be responsible for a decrease in pituitary size. Indeed, some studies (Katzman et al 1996) have found a negative correlation between cortisol levels and gray matter brain content, suggesting a possible role for high cortisol levels in brain atrophy. Interestingly, decreased pituitary area was also reported in a preliminary study in treatment-naı¨ve pediatric obsessive-compulsive disorder (MacMaster et al 1999). There were only three MRI studies that evaluated pituitary volumes in major depressive patients. Krishnan et al (Krishnan et al 1991) found enlarged pituitary volumes in acutely depressed patients (16 had unipolar and 3 bipolar depression) compared with healthy control subjects. In another study (Axelson et al 1992), this same group of investigators found a positive correlation between postdexamethasone plasma cortisol concentration and pituitary volumes in a group of psychiatric inpatients (20 of 24 were unipolar depressed patients). Although there was no control group in this study, it suggests that cortisol can influence pituitary volume. A recent study (Schwartz et al 1997), however, did not find any differences in pituitary volumes between patients suffering from seasonal depression and healthy control subjects. In their report, the subjects were initially scanned while acutely depressed and then after symptom remission; no abnormalities in pituitary size were found. To our knowledge, our study is the first to directly compare in vivo pituitary volumes in patients with bipolar disorder and healthy control subjects, indicating that anatomic abnormalities in the pituitary gland are present in these patients. Furthermore, our findings suggest that these abnormalities may be present in bipolar and not in unipolar disorder. Our findings for unipolar disorder are in

BIOL PSYCHIATRY 2001;50:271–280

277

consonance with the study by Schwartz et al (1997), in which no differences were found between unipolar depressed patients and healthy control subjects; however, they are in contrast with the findings of Krishnan et al (1991), in which enlargement of the pituitary gland in unipolar depression was reported. A few methodologic differences between our study and the one by Krishnan et al (1991) may explain the discrepant findings. First, our sample of patients with unipolar disorder has a narrower age range and was younger (24 –59 years, mean ⫾ SD ⫽ 41.2 ⫾ 9.6 years) than theirs (23– 80 years, mean ⫾ SD ⫽ 54.7 ⫾ 19 years). This could be relevant because the elderly depressed subjects in their sample had a significantly larger pituitary area and volume than age-matched control subjects. In their sample, 53% of the depressed patients (10 of 19) were at least 50 years old, whereas this same subpopulation represented only 15% of our patients with unipolar disorder (2 of 13). Second, our unipolar sample was composed mostly of women, which could have influenced our results because we found a gender effect on pituitary sites. Third, half of our unipolar sample (7 of 13) was euthymic at the moment of the MRI scan, whereas in their study all patients were acutely depressed. Nonetheless, the study of Schwartz et al (1997), however, did not show influence of affective status on pituitary size. Last, the technique utilized to measure the volume of the pituitary differed between the studies. In our study and in Schwartz et al (1997), contiguous coronal images were utilized to measure the area of the gland in all slices where it could be identified, and the total area was multiplied by the slice thickness to obtain the volume. Krishnan et al (1991) measured cross-sectional area, maximum length, and central height of the gland in a single midsagittal image, and the maximum width in a single coronal slice through the pituitary stalk. The formula area ⫻ width was used to estimate the volume. Therefore, important methodologic differences among the studies may have contributed to the conflicting findings. Our findings of smaller pituitary volumes in patients with bipolar disorder may appear counterintuitive, if high levels of serum cortisol would only occur with a hyperactive pituitary; however, as discussed above, there is evidence suggesting that decreased anterior pituitary function (e.g., blunted stimulated-release of ACTH, TSH, and perhaps GH and prolactin) may also occur in the presence of a hyperactive HPA axis. Indeed, hyperactivation of the HPA axis may occur even with lower levels of corticotropin because the chronically high cortisol levels could be another factor responsible for a tonic inhibition of corticotropin (and maybe TRH, GH, and prolactin) release through its inhibitory action on pituitary corticotrophs, leading eventually to a decrease in the gland size. Considering that bipolar disorder may be related to higher rates,

278

R.B. Sassi et al

BIOL PSYCHIATRY 2001;50:271–280

and perhaps also to more severe abnormalities of the HPA and HPT axes than unipolar depression, it is possible that more severe neuroendocrinologic abnormalities are present in bipolar disorder and that it would lead to a differential pattern of pituitary anatomic involvement between patients with unipolar and bipolar disorder. These potential explanations should be regarded as tentative, however, because we did not perform endocrinologic measurements in our patients, which limited our ability to attempt to directly link the anatomic pituitary findings to possible neuroendocrine abnormalities. Our findings have a few potential methodologic limitations. First, our unipolar sample was primarily composed of women. Although we attempted to account for this potential bias by using gender as a covariate and by performing statistical analysis within gender-specific groups, the results for the comparisons involving the unipolar group should be seen with caution and considered preliminary. Further replication of these findings in unipolar samples that are properly matched for gender will be needed. Also, we did not find any significant influence of affective state in pituitary volumes, in concordance with Schwartz et al (1997). Our affective disorder patients were all either acutely depressed or euthymic, and for this reason studies involving patients in manic, hypomanic, or mixed states, as well as follow-up studies of the same patients in different affective states, will be necessary to clarify whether identified pituitary abnormalities might be state related. Furthermore, the inclusion of a few bipolar II patients among our predominantly bipolar I sample should be seen with caution, because it is possible that these disorders involve distinct underlying neuropathology. Nonetheless, we did not find volumetric differences in the pituitary size between bipolar type I and II subjects, and the exclusion of bipolar II patients from our sample did not change the results. Another limitation in our study is the fact that it is not possible to accurately separate the anterior and posterior portions of the pituitary gland with available MRI methods. Therefore, we cannot tell with certainty whether the decreased pituitary volume found in the patients with bipolar disorder is related to the anterior, posterior, or both parts of the pituitary, and this distinction would be important as the hystologic characteristics and function of anterior and posterior pituitary are strikingly different. Last, we set relatively stringent inclusion criteria for our patients, which could have generated an atypical patient sample, especially concerning the bipolar group. Our studied sample consisted exclusively of outpatients, nonrapid cyclers, who had no Axis I psychiatric comorbidities, and who had mostly been maintained on lithium monotherapy, or were drug free for more than 2 weeks at the time they were enrolled in the study. They may not

accurately represent a large proportion of the patients with bipolar disorder, who are often maintained on a combination of various medications, but we did so to be able to account for other potential confounding factors, such as medication effects, possible brain effects of alcohol and drug abuse, and potential brain abnormalities that could be related to other psychiatric comorbidities. In summary, we report for the first time evidence of decreased pituitary volume in patients with bipolar disorder. Our findings are in consonance with reports of a blunted response of pituitary hormones under various stimulation paradigms in affective disorders, and may represent an adaptation to chronically high plasma cortisol levels. Our results also suggest that abnormalities in pituitary size may be restricted to bipolar disorder and not be present in unipolar disorder. Future studies with larger patient samples will be needed to further evaluate these hypotheses and to attempt to independently replicate our findings.

This work was partially supported by Grant Nos. MH 01736, MH 29618, and MH 30915; the Theodore and Vada Stanley Foundation; the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD); and CAPES Foundation (Brazil). Dr. Soares was the 1999 –2000 Selo NARSAD Investigator. The authors thank Patty Houck for advice on the statistical analyses.

References Aggernaes H, Kirkegaard C, Krog-Meyer I, et al (1983): Dexamethasone suppression test and TRH test in endogenous depression. Acta Psychiatr Scand 67:258 – 64. Amsterdam JD, Winokur A, Abelman E, Lucki I, Rickels K (1983): Cosyntropin (ACTH alpha 1–24) stimulation test in depressed patients and healthy subjects. Am J Psychiatry 140:907–909. Ansseau M (1992): Blunting of clonidine-stimulated growth hormone release in mania. Am J Psychiatry 149:584. Axelson DA, Doraiswamy PM, Boyko OB, et al (1992): In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: Relationship to dexamethasone suppression test results in patients. Psychiatry Res 44:63–70. Baischer W, Koinig G, Hartmann B, Huber J, Langer G (1995): Hypothalamic-pituitary-gonadal axis in depressed premenopausal women: Elevated blood testosterone concentrations compared to normal controls. Psychoneuroendocrinology 20: 553–559. Barry S, Dinan TG (1990): Neuroendocrine challenge tests in depression: A study of growth hormone, TRH and cortisol release. J Affect Disord 18:229 –234. Bech P, Bolwig TG, Kramp P, Rafaelsen OJ (1979): The Bech-Rafaelsen Mania Scale and the Hamilton Depression Scale. Acta Psychiatr Scand 59:420 – 430. Beresford T, Arciniegas D, Rojas D, et al (1999): Hippocampal to pituitary volume ratio: A specific measure of reciprocal

Decreased Pituitary Volume in Patients with Bipolar Disorder

neuroendocrine alterations in alcohol dependence. J Stud Alcohol 60:586 – 8. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000): Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–118. Dinan TG, Barry S (1990): Responses of growth hormone to desipramine in endogenous and non-endogenous depression. Br J Psychiatry 156:680 – 684. Dinc H, Esen F, Demirci A, Sari A, Resit Gumele H (1998): Pituitary dimensions and volume measurements in pregnancy and post partum. MR assessment. Acta Radiol 39:64 – 69. Doraiswamy PM, Krishnan KR, Boyko OB, et al (1991): Pituitary abnormalities in eating disorders: Further evidence from MRI studies. Prog Neuropsychopharmacol Biol Psychiatry 15:351–356. Doraiswamy PM, Krishnan KR, Figiel GS, et al (1990): A brain magnetic resonance imaging study of pituitary gland morphology in anorexia nervosa and bulimia. Biol Psychiatry 28:110 –116. Extein I, Pottash AL, Gold MS, Silver JM (1982): Thyroidstimulating hormone response to thyrotropin-releasing hormone in unipolar depression before and after clinical improvement. Psychiatry Res 6:161–169. Gann H, Riemann D, Stoll S, Berger M, Muller WE (1995): Growth hormone response to growth hormone-releasing hormone and clonidine in depression. Biol Psychiatry 38:325– 329. Gerken A, Holsboer F (1986): Cortisol and corticosterone response after syn-corticotropin in relationship to dexamethasone suppressibility of cortisol. Psychoneuroendocrinology 11:185–194. Gold PW, Calabrese JR, Kling MA, et al (1986): Abnormal ACTH and cortisol responses to ovine corticotropin releasing factor in patients with primary affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 10:57– 65. Golstein J, Van Cauter E, Linkowski P, Vanhaelst L, Mendlewicz J (1980): Thyrotropin nyctohemeral pattern in primary depression: Differences between unipolar and bipolar women. Life Sci 27:1695–1703. Goodwin GM, Muir WJ, Seckl JR, et al (1992): The effects of cortisol infusion upon hormone secretion from the anterior pituitary and subjective mood in depressive illness and in controls. J Affect Disord 26:73– 83. Gwirtsman HE, Kaye WH, George DT, Jimerson DC, Ebert MH, Gold PW (1989): Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia. Arch Gen Psychiatry 46:61– 69. Halbreich U, Alt IH, Paul L (1988): Premenstrual changes. Impaired hormonal homeostasis. Endocrinol Metab Clin North Am 17:173–194. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 – 62. Hauser P, Matochik J, Altshuler LL, et al (2000): MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders J Affect Disord 60:25–32. Holder CA, Elster AD (1997): Magnetization transfer imaging of the pituitary: Further insights into the nature of the posterior “bright spot.” J Comput Assist Tomogr 21:171–174.

BIOL PSYCHIATRY 2001;50:271–280

279

Holsboer F, Gerken A, Stalla GK, Muller OA (1985): ACTH, cortisol, and corticosterone output after ovine corticotropinreleasing factor challenge during depression and after recovery. Biol Psychiatry 20:276 –286. Hubain PP, Staner L, Dramaix M, et al (1994): TSH response to TRH and EEG sleep in non-bipolar major depression: A multivariate approach. Eur Neuropsychopharmacol 4:517– 525. Jackson GD, Duncan JS (1996): MRI neuronanatomy: A new angle on the brain. New York: Churchill Livingstone. Jaeckle RS, Kathol RG, Lopez JF, Meller WH, Krummel SJ (1987): Enhanced adrenal sensitivity to exogenous cosyntropin (ACTH alpha 1–24) stimulation in major depression. Relationship to dexamethasone suppression test results. Arch Gen Psychiatry 44:233–240. Joyce PR, Sellman JD, Donald RA, Livesey JH, Elder PA (1988): The unipolar-bipolar depressive dichotomy and the relationship between afternoon prolactin and cortisol levels. J Affect Disord 14:189 –193. Kathol RG, Jaeckle RS, Lopez JF, Meller WH (1989): Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with major depression. Br J Psychiatry 155:468 – 478. Katzman DK, Lambe EK, Mikulis DJ, Ridgley JN, Goldbloom DS, Zipursky RB (1996): Cerebral gray matter and white matter volume deficits in adolescent girls with anorexia nervosa. J Pediatr 129:794 – 803. Kirkegaard C, Bjorum N (1980): TSH responses to TRH in endogenous depression [letter]. Lancet 1:152. Kjellman BF, Beck-Friis J, Ljunggren JG, Wetterberg L (1984): Twenty-four-hour serum levels of TSH in affective disorders. Acta Psychiatr Scand 69:491–502. Krishnan KR, Doraiswamy PM, Lurie SN, et al (1991): Pituitary size in depression. J Clin Endocrinol Metab 72:256 –259. Krishnan KR, Manepalli AN, Ritchie JC, et al (1988): Growth hormone-releasing factor stimulation test in depression. Am J Psychiatry 145:90 –92. Kucharczyk J, Kucharczyk W, Berry I, et al (1989): Histochemical characterization and functional significance of the hyperintense signal on MR images of the posterior pituitary. AJR Am J Roentgenol 152:153–157. Kuruvilla A, Srikrishna G, Peedicayil J, Kuruvilla K, Kanagasabapathy AS (1991): Serum prolactin levels in manic patients. Biol Psychiatry 30:421– 423. Lammers CH, Garcia-Borreguero D, Schmider J, et al (1995): Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II. Biol Psychiatry 38:803– 807. Lesch KP, Laux G, Erb A, Pfuller H, Beckmann H (1988): Growth hormone (GH) responses to GH-releasing hormone in depression: Correlation with GH release following clonidine. Psychiatry Res 25:301–310. Linkowski P, Brauman H, Mendlewicz J (1981): Thyrotrophin response to thyrotrophin-releasing hormone in unipolar and bipolar affective illness. J Affect Disord 3:9 –16. Linkowski P, Mendlewicz J, Kerkhofs M, et al (1987): 24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: Effect of antidepressant treatment. J Clin Endocrinol Metab 65:141–152.

280

BIOL PSYCHIATRY 2001;50:271–280

Linkowski P, Van Cauter E, Leclercq R, et al (1985): ACTH, cortisol and growth hormone 24-hour profiles in major depressive illness. Acta Psychiatr Belg 85:615– 623. Lopez JF, Kathol RG, Jaeckle RS, Meller W (1987): The HPA axis response to insulin hypoglycemia in depression. Biol Psychiatry 22:153–166. Lurie SN, Doraiswamy PM, Husain MM, et al (1990): In vivo assessment of pituitary gland volume with magnetic resonance imaging: The effect of age. J Clin Endocrinol Metab 71:505–508. MacMaster FP, Keshavan MS, Rosenberg DR (1999): Pituitary morphology in treatment-naive pediatric OCD. Presented at the Annual Meeting of the Society for Biological Psychiatry, Washington, DC, USA, May 1999. Matsunaga H, Sarai M (1993): Elevated serum LH and androgens in affective disorder related to the menstrual cycle: With reference to polycystic ovary syndrome. Jpn J Psychiatry Neurol 47:825– 842. Meller WH, Kathol RC, Jaeckle RS, Lopez JF (1987): Stimulation of the pituitary-adrenal axis with arginine vasopressin in patients with depression. J Psychiatr Res 21:269 –277. Mendlewicz J, Van Cauter E, Linkowski P, L’Hermite M, Robyn C (1980): Current concepts: I. The 24-hour profile of prolactin in depression. Life Sci 27:2015–2024. Mervaala E, Fohr J, Kononen M, et al (2000): Quantitative MRI of the hippocampus and amygdala in severe depression Psychol Med 30:117–125. Nurnberger JI Jr, Berrettini W, Simmons-Alling S, Lawrence D, Brittain H (1990): Blunted ACTH and cortisol response to afternoon tryptophan infusion in euthymic bipolar patients. Psychiatry Res 31:57– 67. Patel VH, Friedman L (1997): MRI of the brain: Normal anatomy and normal variants. Philadelphia: W. B.Saunders. Pitchot W, Hansenne M, Gonzalez Moreno A, Ansseau M (1995): Effect of previous antidepressant therapy on the growth hormone response to apomorphine. Neuropsychobiology 32:19 –22. Poirier MF, Loo H, Galinowski A, et al (1995): Sensitive assay of thyroid stimulating hormone in depressed patients. Psychiatry Res 57:41– 48. Rubin RT, Poland RE, Lesser IM, Martin DJ (1987): Neuroendocrine aspects of primary endogenous depression–IV. Pituitary-thyroid axis activity in patients and matched control subjects. Psychoneuroendocrinology 12:333–347. Rush AJ, Giles DE, Schlesser MA, et al (1997): Dexamethasone response, thyrotropin-releasing hormone stimulation, rapid eye movement latency, and subtypes of depression. Biol Psychiatry 41:915–928. Ryan ND, Dahl RE, Birmaher B, et al (1994): Stimulatory tests of growth hormone secretion in prepubertal major depression: Depressed versus normal children. J Am Acad Child Adolesc Psychiatry 33:824 – 833. Rybakowski JK, Twardowska K (1999): The dexamethasone/ corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. J Psychiatr Res 33:363–370. Schmider J, Lammers CH, Gotthardt U, Dettling M, Holsboer F, Heuser IJ (1995): Combined dexamethasone/corticotropinreleasing hormone test in acute and remitted manic patients,

R.B. Sassi et al

in acute depression, and in normal controls: I. Biol Psychiatry 38:797– 802. Schreiber W, Lauer CJ, Krumrey K, Holsboer F, Krieg JC (1996): Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder. Neuropsychopharmacology 15:7–15. Schwartz PJ, Loe JA, Bash CN, et al (1997): Seasonality and pituitary volume. Psychiatry Res 74:151–157. Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999): Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034 –5043. Spitzer RL, Williams JBW, Gibbon M, First MB (1994): Structured clinical interview for DSM-IV (SCID-IV). Washington, DC: American Psychiatric Press. Strokes PE, Pick GR, Stoll PM, Nunn WD (1975): Pituitaryadrenal function in depressed patients: Resistance to dexamethasone suppression. J Psychiatr Res 12:271–281. Swayze VW, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC (1992): Subcortical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging study. Biol Psychiatry 31:221–240. Takano K, Utsunomiya H, Ono H, Ohfu M, Okazaki M (1999): Normal development of the pituitary gland: Assessment with three-dimensional MR volumetry. AJNR Am J Neuroradiol 20:312–315. Targum SD, Sullivan AC, Byrnes SM (1982): Neuroendocrine interrelationships in major depressive disorder. Am J Psychiatry 139:282–286. Thakore JH, Dinan TG (1996): Blunted dexamethasone-induced growth hormone responses in acute mania. Psychoneuroendocrinology 21:695–701. Thalen BE, Kjellman BF, Ljunggren JG, et al (1993): Release of corticotropin after administration of corticotropin-releasing hormone in depressed patients in relation to the dexamethasone suppression test. Acta Psychiatr Scand 87:133–140. Vakili K, Pillay SS, Lafer B, et al (2000): Hippocampal volume in primary unipolar major depression: A magnetic resonance imaging study. Biol Psychiatry 47:1087–1090. Valdivieso S, Duval F, Mokrani MC, et al (1996): Growth hormone response to clonidine and the cortisol response to dexamethasone in depressive patients. Psychiatry Res 60:23–32. Volsan O, Berzewski H (1985): Baseline plasma cortisol and dexamethasone test in unselected psychiatric inpatients. Psychopathology 18:186 –197. Whalley LJ, Christie JE, Blackwood DH, et al (1989): Disturbed endocrine function in the psychoses. I: Disordered homeostasis or disease process? Br J Psychiatry 155:455– 461. Wilson JD, Foster JW, Kronenberg HM, Larsen PR (1998): Williams Textbook of Endocrinology, 9th ed. Philadelphia: W. B. Saunders. Winokur G, Pfohl B, Sherman B (1985): The relationships of historically defined subtypes of depression to ACTH and cortisol levels in depression: Preliminary study. Biol Psychiatry 20:751–757. Young EA, Akil H, Haskett RF, Watson SJ (1995): Evidence against changes in corticotroph CRF receptors in depressed patients. Biol Psychiatry 37:355–363.