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Keywords:

  • magnetic resonance imaging;
  • obsessive–compulsive disorder;
  • pituitary;
  • volume

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Aims:  Another structure in the obsessive–compulsive disorder (OCD) circuit may be the pituitary gland because of the fact that limbic–hypothalamic–pituitary–adrenal (LHPA) axis abnormality has been reported in patients with OCD. There has been only one prior study, however, concerning pituitary volumetry, in which the sample was a pediatric group. The purpose of the present study was therefore to investigate this in an adult OCD patient group using magnetic resonance imaging (MRI).

Methods:  Pituitary volume was measured in 23 OCD patients and the same number of healthy control subjects. Volumetric measurements were made on T1-weighted coronal MRI, with 2.40-mm-thick slices, at 1.5 T, and were done blindly.

Results:  A statistically significantly smaller pituitary volume was found in OCD patients compared to healthy controls (age and intracranial volume as covariates). With regard to gender and diagnosis, there was a significant difference in pituitary gland volume (F = 4.18, P < 0.05). In addition, post-hoc analysis indicated near-significant difference in men with OCD as compared with women with OCD (P = 0.07) and significant difference between control men and control women (F = 10.96, P < 0.001).

Conclusions:  Taking into consideration that the prior study found decreases in pituitary volume in pediatric patients with OCD as compared with healthy control subjects, future large MRI studies should investigate pituitary size longitudinally, with a careful characterization of hypothalamo-pituitary-adrenal (HPA) function in conjunction with anatomic MRI evaluation.

OBSESSIVE–COMPULSIVE DISORDER (OCD) is a chronic and often disabling anxiety disorder and is characterized by intrusive unwanted thoughts, ideas, or images that are distressing (obsessions) and urges to perform ritualistic behaviors or mental acts (compulsions) to reduce this distress. Data from the Epidemiological Catchment Area survey and other epidemiological studies showed that the lifetime prevalence of OCD was between 2% and 3% in the general population.1

Structural and functional imaging studies suggest a model for the pathophysiology of OCD that includes volumetric abnormalities and hyperactivity in the fronto-subcortical neuronal pathway of the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC) and the caudate nucleus, sometimes called the ‘OCD circuit’.2 The findings regarding key brain regions from structural imaging studies have been inconsistent, with reports of increases in caudate nucleus,3 decreases in caudate nucleus, OFC and amygdala,4,5 or no differences in ACC, caudate nucleus and thalamus volumes.6–8 Recently Kang et al. measured the volumes of the OFC, ACC, thalamus, and caudate nucleus, which are the main components of the frontal subcortical circuitry in patients with OCD and in normal subjects.9 Other candidate structures, however, have been described. One of these structures may be the pituitary gland because of the fact that limbic–hypothalamic–pituitary–adrenal (LHPA) axis abnormality has been reported in patients with OCD.10–12 An increased activity of the HPA axis in OCD has been reported both indirectly (corticotropin-releasing hormone [CRH] levels in cerebrospinal fluid [CSF] were significantly higher in patients with OCD than in healthy controls10) and directly (Kluge et al. examined the blood of patients and controls every 20 min between 23.00 h and 7.00 h during sleep using a long catheter for later adrenocorticotropic hormone (ACTH) and cortisol analysis13). There has been only one study evaluating pituitary volumes in OCD patients.14 In that study the authors found that pituitary volume was significantly smaller in pediatric patients with OCD as compared with healthy control subjects (11% smaller). No study regarding pituitary volumes has been done in adult OCD patients, however. With this in mind, we therefore evaluated pituitary volume in adult patients with OCD and healthy controls and to determine whether smaller pituitary volume in patients with OCD might also be an epiphenomenon of the underlying psychopathology of the illness, as suggested by MacMaster et al.14

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects and clinical evaluations

Twenty-three patients (mean age ± SD, 29.8 ± 4.4 years; nine male, 14 female) who fulfilled the DSM-IV diagnostic criteria for OCD based on the Structured Clinical Interview for DSM-IV (SCID)15 and who were admitted to Firat University School of Medicine Department of Psychiatry were studied. OCD symptoms were rated using the Yale–Brown Obsession–Compulsion Scale (Y-BOCS).16

Patients with current or lifetime neurologic, current medical problems, history of head trauma, and alcohol/substance abuse within the 6 months preceding the study were excluded. All patients were off OCD medication for at least 2 weeks prior to the study. Of the patients, nine had never been treated with any medication. While seven patients had taken serotonin re-uptake inhibitor (SRI) at any period in their disorder (clomipramine, n = 7; sertraline, n = 4; paroxetine, n = 4; citalopram, n = 3; fluvoxamine, n = 2), at the time of the study they were on SRI treatment with clomipramine (n = 4), sertraline (n = 2) and fluvoxamine (n = 1). Six were on the SRI plus combination treatment (lithium carbonate in four patients, quetiapine in one patient and risperidone in one). Additional comorbid current Axis I psychiatric diagnoses were social phobia (n = 1), generalized anxiety disorder (n = 1), and panic disorder (n = 1). Lifetime Axis I psychiatric diagnoses were major depressive disorder (n = 2), panic disorder (n = 1), and conversion disorder (n = 1). Twenty-three gender-matched healthy controls (mean age ± SD, 32.2 ± 5.7 years; nine male, 14 female) were evaluated by a senior psychiatrist. Healthy controls were excluded if they had any current DSM-IV axis I disorders, any first-degree relatives with a history of psychiatric disorders or any current major medical problems.

There were no significant group differences in age, years of education, lifetime weeks of alcohol intoxication, or sex and handedness ratio.

The study protocol was approved by Local Ethics Committee. The subjects gave informed consent and patient anonymity was preserved. The procedures were in accordance with the Helsinki Declaration of 1975, as revised in 1983.

Magnetic resonance imaging

All magnetic resonance imaging (MRI) was performed at Firat University School of Medicine on a 1.5-T GE Signa Excite high speed scanner (General Electric, Milwaukee, WI, USA). Comfortable head positioning was provided. All MRI scans were reviewed to exclude any clinically significant morphological abnormalities. A high-resolution structural image of the entire brain was obtained using sagittally acquired 2-D spiral fast spin echo high-resolution images (repetition time [TR], 2000 ms; echo time [TE], 15.6 ms; field of view [FOV], 240 mm; flip angle, 20°; bandwidth, 20.8; slice thickness, 2.4 mm; echo spacing, 15.6 ms, 8 echoes; resolution, 0.9375 × 0.9375 × 2.4 mm).

Anatomic measurements were obtained on a computer workstation with GE Volume Viewer Voxtool 4.2 (General Electric, Milwaukee, WI, USA). Tracing was performed by one researcher (H.Y.) blind to subject diagnosis, and independently verified by a second blinded investigator (M.K.). Measured brain structures included the whole brain, total gray and white matter volume, and the pituitary. Boundary definition and tracing of the pituitary were done using standard neuroanatomical atlases17,18 with methods and definitions adapted from neuroimaging studies on the pituitary,19–22 and following MacMaster et al.:14 the superior border of the structure was described as the optic chiasm and infundibular recess of the third ventricle, while the inferior border was the sphenoid sinus. An example of the structure is presented in Fig. 1. All volumes are reported in cubic millimeters. The interrater reliability (intraclass correlation coefficient), established on tracing by two different evaluators, was r = 0.90 for pituitary.

image

Figure 1. Anatomic landmarks for the tracing of the structure evaluated.

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Statistical analysis

Analysis of covariance (ancova), t-test, χ2 test and partial correlation analyses were conducted using SPSS for Windows, version 10.0 (SPSS, Chicago, IL, USA). In ancova analyses, age, gender and intracranial volume (ICV) were covariates. For the measure of age and ICV volume, independent t-test was used. χ2 test was used for the categorical variables. Correlation analysis was done using Pearson's test to evaluate the interaction between pituitary volume and duration of illness, age of onset, or severity of illness. Statistical significance was defined as P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There were no significant differences between the groups on comparisons for age (mean age ± SD: patients, 29.8 ± 4.4 years; controls, 32.2 ± 5.7 years), education, gender (exactly same number men and women in each group) and ICV (patients, 1422.9 ± 111.4 mm3; controls, 1440.4 ± 123.6; P < 0.05). In the patient group, mean Y-BOCS score was 16.8 ± 3.1 (Table 1).

Table 1.  Subject details
ItemPatient group (n = 23)Control group (n = 23)P
  1. Y-BOCS, Yale–Brown Obsession–Compulsion Scale.

Age (years)26.9 ± 5.128.7 ± 3.7>0.05
Gender (F/M)14/914/9>0.05
Education  >0.05
 High school1316 
 Elementary school53 
 First school54 
Handedness (right)2323>0.05
Length of illness (years)4.6 ± 3.4 
Total Y-BOCS score16.8 ± 3.1 
Gray matter volume (cm3)761.5 ± 67.3779.3 ± 78.8>0.05
White matter volume (cm3)459.7 ± 31.7475.6 ± 48.8>0.05
Pituitary volume (cm3)0.691 ± 0.0620.846 ± 0.073<0.001
 Male0.673 ± 0.0590.773 ± 0.081<0.01
 Female0.719 ± 0.0770.959 ± 0.089<0.001

Table 1 lists the unadjusted mean volumes of measured structures for OCD patients and healthy controls. We found significantly smaller pituitary volume in the whole group of OCD patients compared to healthy controls (age and ICV as covariates). With regard to gender and diagnosis, there was a significant difference in pituitary gland volume (F = 4.18, d.f. = 1, 42; P < 0.05). Post-hoc analysis indicated near-significant difference in men with OCD as compared with women with OCD (P = 0.07), and significant difference between control men and control women (F = 10.96, d.f. = 1, 24; P < 0.001).

We found a significant negative correlation between smaller pituitary volume and both duration of illness (r = −0.47, P < 0.05) and onset age (r = −0.44, P < 0.05) in the patient group. There was no correlation, however, between pituitary volume and severity of illness, as determined on Y-BOCS score (r = 0.17, P > 0.05).

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The present study found statistically significantly smaller pituitary volume in patients with OCD compared to healthy controls and a significant negative correlation between smaller pituitary volume and both duration of illness and onset age. In addition, post-hoc analysis demonstrated that both men with OCD and control men had smaller pituitary volume compared to women with OCD and control women, respectively. The pituitary gland is a central part of the neuroendocrine system. Increased activity of the HPA axis in OCD is indicated by the finding that CRH levels in CSF were significantly higher in patients with OCD than in healthy controls.11 In contrast, Chappelli et al. found similar CRH levels in both groups.23 A non-suppression of cortisol secretion in the dexamethasone suppression test (DST) in patients with OCD also points to HPA hyperactivity.11,24 In the pathophysiology of OCD, abnormalities in the HPA axis have been reported due to cortisol non-suppression in the DST in patients with OCD,11,24 and due to the finding that CRH levels in CSF were found to be significantly higher in patients with OCD than in healthy controls,2 but these results were not confirmed in other studies.25–27 There was only one prior study on OCD patients with DST non-suppression13 and it found decreases in pituitary volume in patients with OCD as compared with healthy control subjects (11% smaller), as well as an association between decrease in pituitary volume and increased compulsive but not obsessive symptom severity. The present volumetric findings are in accordance with those of MacMaster et al.14 They speculated that this abnormality might be an early marker of the illness that might be related to the developmental pathophysiology of OCD and concluded that their findings were not consistent with a progressive process in OCD because they did not find any correlation between illness duration and age of onset of OCD. In the present study, however, we also found a significant association between smaller pituitary volumes and both the duration of illness and onset age in the patient group. Therefore, although the present study was also a cross-sectional one, as was the MacMaster et al. study, the aforementioned association suggests that this difference might be a degenerative and progressive process. Meanwhile although all patients did not take OCD medication for at least 2 weeks prior to the study, they took a variety of medications for their OCD including serotonin re-uptake inhibitors, lithium, antipsychotic drugs and so on. It is worth noting that these agents might have affected pituitary volume. For example, it has been demonstrated that antipsychotics may interact with the HPA axis by decreasing cortisol levels28,29 and that changes in endocrine function can affect pituitary morphology.30,31

Several points need to be considered when interpreting these results. First, the present sample, relatively small, may limit the generalizability of our findings, and replication of the results using larger samples is necessary. Second, the present study did not involve a longitudinal follow up. Third, because the sample size was small, it was not possible to determine whether there was an interaction between symptom dimensions and volumes. Finally, the use of 2.4-mm-thick slices should be acknowledged as a limitation.

In conclusion, the present study found significant smaller pituitary volume in adult OCD patients compared to healthy controls. Taking into consideration that a prior study found decreases in pituitary volume in pediatric patients with OCD as compared with healthy control subjects,14 future large MRI studies should investigate pituitary size longitudinally with a careful characterization of HPA function in conjunction with anatomical MRI evaluation.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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