Faculty Bibliography

Attempts to identify biological response predictors generally have met with limited success, particularly where the goal is to develop clinically useful indices. This article reviews the biological approaches to predicting treatment response, beginning with neuroendocrine studies and electroencephalogram analysis and concluding with structural and functional neuroimaging. The article describes the designs of typical studies to aid in interpreting their results and concludes by addressing some of the problems and limitations associated with these approaches and suggesting future directions for this research.

A number of naturalistic studies have found that medical co-morbidity conveys a worse long-term prognosis in the treatment of major depressive disorder (MDD). The purpose of this study was to test whether the presence of co-morbid medical conditions can predict clinical response in patients with treatment-resistant MDD (TRD) treated with open-label nortriptyline (NT). Ninety-two patients with TRD entered a 6-week open trial of NT. The presence of co-morbid medical disorders was assessed during the screen visit. The degree of medical co-morbidity during the screen visit was then quantified with the use of the Cumulative Illness Rating Scale-Geriatric Version (CIRS(G)). We tested whether CIRS(G) scores predicted clinical response or depression severity at endpoint. CIRS scores at baseline did not significantly predict treatment response. The results of this study fail to confirm the relationship between co-morbid medical conditions and poor outcome in the treatment of MDD for patients with TRD. Patients with TRD and co-morbid medical conditions can be expected to respond to antidepressants as well as their counterparts without concurrent axis III co-morbidity. The CIRS(G) scores for this TRD sample were lower than those reported for geriatric depression, or for depressed patients with severe medical illness, common in medical and surgical wards and in most specialty clinics of large academic centers. Thus, the present results cannot be generalized to such populations.

In this paper we review studies of brain cellular high-energy phosphate metabolism, as measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS), in subjects with major depressive disorder (MDD). We also review the literature on the role of thyroid hormones on the cellular high-energy phosphate metabolism in multiple organs. Finally, we review data on the efficacy of thyroid hormones as adjuvant treatment in MDD. The framework established by these findings enables us to hypothesize that dysfunction of brain cellular energy metabolism is a vulnerability factor for MDD, and that correcting cellular energy metabolism (e.g., with thyroid hormones) is a valid therapeutic strategy for improving the symptoms of MDD. We discuss our hypothesis in the context of other current theories on the mechanism of thyroid hormones in MDD.

OBJECTIVE: Patients with major depressive disorder (MDD) may have significant differences in cholesterol levels compared with healthy controls. A previous study by our group reported that depressed patients with elevated cholesterol levels (>or=200 mg/dl) were significantly more likely to be nonresponders to fluoxetine treatment than depressed patients with nonelevated cholesterol levels. However, very little is known regarding cholesterol in patients with treatment-resistant depression (TRD). The purpose of this study was to compare cholesterol levels at baseline between depressed patients with and without TRD and to test whether cholesterol levels at baseline can predict clinical response in patients with TRD treated with open-label nortriptyline (NT). METHODS: Ninety-two patients with TRD entered a 6-week open trial of NT. Baseline cholesterol levels were randomly collected for 59 of these patients. Controlling for age and gender, we compared baseline cholesterol and triglyceride levels for 35 patients with TRD who did not respond to NT with 205 non-TRD patients who responded to an 8-week open trial of fluoxetine. Furthermore, with the use of logistic regression, we tested whether baseline cholesterol levels predicted clinical response to NT in the patients with TRD. RESULTS: Patients with TRD had higher triglyceride levels at baseline compared with depressed patients without TRD. Cholesterol defined as a dichotomous variable being elevated if equal to or greater than 200 mg/dl, predicted poor response to a 6-week open trial of NT in patients with TRD. CONCLUSIONS: The results of this study confirm the relationship between hypercholesterolemia and poor outcome in the treatment of MDD for patients with TRD.

OBJECTIVE: We examined the correlation between the basal triiodothyronine resin uptake (T3-RU) levels in depressed subjects and the response to anti-depressant treatment. METHOD: We treated with fluoxetine 235 outpatients meeting DSM-IV criteria for major depression. We measured T3 resin uptake (T3-RU) levels before the onset of treatment. The 17-item Hamilton Rating Scale for Depression (Ham-D-17) was administered before, during and after the eight weeks of treatment to assess changes in depressive symptoms. RESULTS: 16 patients (6.8 percent) had low T3-RU levels (range 16.5-21), and 7 patients (3.0 percent) had high T3-RU levels (range 36-38). No relationship was found between T3-RU levels and clinical improvement, defined as either total Ham-D-17 score change or Ham-D-17 score < or = 7 in the last 3 weeks of treatment, even after adjusting for baseline severity of depression. CONCLUSION: Abnormal T3-RU levels are rather uncommon in outpatient depression and do not correlate with the response to antidepressant treatment or lack thereof.

OBJECTIVE: Few studies have evaluated the parietal lobe in schizophrenia despite the fact that it has an important role in attention, memory, and language-all functions that have been reported to be abnormal in schizophrenia. The inferior parietal lobule, in particular, is of interest because it is not only part of the heteromodal association cortex but also is part of the semantic-lexical network, which also includes the planum temporale. Both the inferior parietal lobule, particularly the angular gyrus of the inferior parietal lobule, and the planum temporale are brain regions that play a critical role as biological substrates of language and thought. The authors compared volume and asymmetry measures of the individual gyri of the parietal lobe by means of magnetic resonance imaging (MRI) scans. METHOD: MRI scans with a 1. 5-Tesla magnet were obtained from 15 male chronic schizophrenic and 15 comparison subjects matched for age, gender, and parental socioeconomic status. RESULTS: Inferior parietal lobule volumes showed a leftward asymmetry (left 7.0% larger than right) in comparison subjects and a reversed asymmetry (left 6.3% smaller than right) in schizophrenic subjects. The angular gyrus accounted for this difference in asymmetry, with the left angular gyrus being significantly larger (18.7%) than the right in comparison subjects, a finding that was not observed in schizophrenic patients. A further test of angular gyrus asymmetry showed a reversal of the normal left-greater-than-right asymmetry in the schizophrenic patients. CONCLUSIONS: Patients with schizophrenia showed a reversed asymmetry in the inferior parietal lobule that was localized to the angular gyrus, a structure belonging to the heteromodal association cortex as well as being part of the semantic-lexical network. This finding contributes to a more comprehensive understanding of the neural substrates of language and thought disorder in schizophrenia.

A methodology was developed for dividing prefrontal cortical gray matter into insular, orbital, inferior, middle, superior, cingulate, and frontal pole regions using anatomical criteria. This methodology was developed as a follow-up to one that measured whole prefrontal gray and white matter volumes in schizophrenic and control subjects. This study showed no overall volume differences in prefrontal cortex between schizophrenic and control subjects. The parcellation of prefrontal cortex was done to increase the probability of detecting abnormalities that were circumscribed to a particular portion of the region. A 1.5 Tesla magnet was used to acquire contiguous 1.5-mm coronal slices of the entire brain. Volumes were then measured in a group of right-handed male (n = 15) subjects. Gray matter was parcellated using criteria that were mainly based on gross anatomy, as visualized in 3-dimensional renderings of the brain. Reliability of the parcellation scheme was very high (r(i) = 0.80 and above). This methodology should be useful in the study of cortical pathology in a number of neurological disorders, including schizophrenia.

An automated registration algorithm was used to elastically match an anatomical magnetic resonance (MR) atlas onto individual brain MR images. Our goal was to evaluate the accuracy of this procedure for measuring the volume of MRI brain structures. We applied two successive algorithms to a series of 28 MR brain images, from 14 schizophrenia patients and 14 normal controls. First, we used an automated segmentation program to differentiate between white matter, cortical and subcortical gray matter, and cerebrospinal fluid. Next, we elastically deformed the atlas segmentation to fit the subject's brain, by matching the white matter and subcortical gray matter surfaces. To assess the accuracy of these measurements, we compared, on all 28 images, 11 brain structures, measured with elastic matching, with the same structures traced manually on MRI scans. The similarity between the measurements (the relative difference between the manual and the automated volume) was 97% for whole white matter, 92% for whole gray matter, and on average 89% for subcortical structures. The relative spatial overlap between the manual and the automated volumes was 97% for whole white matter, 92% for whole gray matter, and on average 75% for subcortical structures. For all pairs of structures rendered with the automated and the manual method, Pearson correlations were between r = 0.78 and r = 0.98 (P < 0.01, N = 28), except for globus pallidus, where r = 0.55 (left) and r = 0. 44 (right) (P < 0.01, N = 28). In the schizophrenia group, compared to the controls, we found a 16.7% increase in MRI volume for the basal ganglia (i.e., caudate nucleus, putamen, and globus pallidus), but no difference in total gray/white matter volume or in thalamic MR volume. This finding reproduces previously reported results, obtained in the same patient population with manually drawn structures, and suggests the utility/efficacy of our automated registration algorithm over more labor-intensive manual tracings.