Christopher F. Murphy

Executive Dysfunction and the Course of Geriatric Depression

BACKGROUND Executive dysfunction is common in geriatric depression and persists after improvement of depressive symptoms. This study examined the relationship of executive impairment to the course of depressive symptoms among elderly patients with major depression. METHODS A total of 112 nondemented elderly patients with major depression participated in an 8-week citalopram trial at a target daily dose of 40 mg. Executive functions were assessed with the initiation/perseveration subscale of the Dementia Rating Scale and the Stroop Color-Word test. Medical burden was rated with the Cumulative Illness Rating Scale. RESULTS Both abnormal initiation/perseveration and abnormal Stroop Color-Word scores were associated with an unfavorable response of geriatric depression to citalopram. In particular, initiation/perseveration scores below the median (< or =35) and Stroop scores at the lowest quartile (< or =22) predicted limited change in depressive symptoms. Impairment in other Dementia Rating Scale cognitive domains did not significantly influence the outcome of depression. CONCLUSIONS Executive dysfunction increases the risk for poor response of geriatric depression to citalopram. Because executive functions require frontostriatal-limbic integrity, this observation provides the rationale for investigation of the role of specific frontostriatal-limbic pathways in perpetuating geriatric depression. Depressed elderly patients with executive dysfunction require vigilant clinical attention because they might be at risk to fail treatment with a selective serotonin reuptake inhibiting antidepressant.

Microstructural White Matter Abnormalities and Remission of Geriatric Depression

OBJECTIVE White matter abnormalities may interfere with limbic cortical balance and lead to chronic depressive syndromes. The authors used diffusion tensor imaging to test the hypothesis that depressed elders who fail to achieve remission have microstructural white matter abnormalities in cortico-striato-limbic networks implicated in geriatric depression. METHOD The subjects were nondemented individuals with nonpsychotic major depression. After a 2-week placebo period, those subjects who had a Hamilton Depression Rating Scale (HAM-D) score of 18 or greater received escitalopram, 10 mg daily, for 12 weeks. Remission was defined as a HAM-D score of 7 or below for 2 consecutive weeks. Diffusion tensor imaging was performed at a 1.5 Tesla scanner, and voxel-based analysis of fractional anisotropy was conducted using age as the covariate. RESULTS Subjects who failed to achieve remission (N=23) had lower fractional anisotropy in multiple frontal limbic brain areas, including the rostral and dorsal anterior cingulate, dorsolateral prefrontal cortex, genu of the corpus callosum, white matter adjacent to the hippocampus, multiple posterior cingulate cortex regions, and insular white matter, relative to those who achieved remission (N=25). In addition, lower fractional anisotropy was detected in the neostriatum and midbrain as well as select temporal and parietal regions. CONCLUSIONS Lower fractional anisotropy in distributed cerebral networks is associated with poor antidepressant response of geriatric depression and may represent a neuroanatomical substrate that predisposes to this disorder.

WHITE MATTER INTEGRITY PREDICTS STROOP PERFORMANCE IN PATIENTS WITH GERIATRIC DEPRESSION

BACKGROUND This study tested the hypothesis that microstructural white matter abnormalities in frontostriatal-limbic tracts are associated with poor response inhibition on the Stroop task in depressed elders. METHOD Fifty-one elders with major depression participated in a 12-week escitalopram trial. Diffusion tensor imaging was used to determine fractional anisotropy (FA) in white matter regions. Executive function (response inhibition) was assessed with the Stroop task. Voxelwise correlational analysis was used to examine the relationship between Stroop performance and fractional anisotropy. RESULTS Significant associations between FA and Stroop color word interference were evident in multiple frontostriatal-limbic regions, including white matter lateral to the anterior and posterior cingulate cortex and white matter in prefrontal, insular, and parahippocampal regions. CONCLUSIONS These findings suggest that microstructural white matter abnormalities of frontostriatal-limbic networks are associated with executive dysfunction of late-life depression. This observation provides the rationale for examination of specific frontostriatal-limbic pathways in the pathophysiology of geriatric depression.

Macromolecular White Matter Abnormalities in Geriatric Depression : A Magnetization Transfer Imaging Study

Objective Geriatric depression consists of complex and heterogeneous behaviors unlikely to be caused by a single brain lesion. However, abnormalities in specific brain structures and their interconnections may confer vulnerability to the development of late-life depression. The objective of this study was to identify subtle white matter abnormalities in late-life depression. Design The authors used magnetization transfer ratio (MTR) imaging, a technique that is thought primarily to reflect myelin integrity, to examine the hypothesis that individuals with late-life depression would exhibit white matter abnormalities in frontostriatal and limbic regions. Setting The study was conducted in a university-based, geriatric psychiatry clinic. Participants Fifty-five older patients with major depression and 24 elderly comparison subjects were assessed. Measurement Voxel-based analysis of MTR data were conducted with a general linear model using age as a covariate. Results Relative to comparison subjects, patients demonstrated lower MTR in multiple left hemisphere frontostriatal and limbic regions, including white matter lateral to the lentiform nuclei, dorsolateral and dorsomedial prefrontal, dorsal anterior cingulate, subcallosal, periamygdalar, insular, and posterior cingulate regions. Depressed patients had lower MTR in additional left hemisphere locales including the thalamus, splenium of the corpus callosum, inferior parietal, precuneus, and middle occipital white matter regions. Conclusion These findings suggest that geriatric depression may be characterized by reduced myelin integrity in specific aspects of frontostriatal and limbic networks, and complement diffusion tensor studies of geriatric depression that indicate decreased organization of white matter fibers in specific frontal and temporal regions.

Longitudinal Association of Initiation/Perseveration and Severity of Geriatric Depression

OBJECTIVE Many older adults with major depression (MDD) present with impairment in initiation and perseveration (IP) tests. However, it remains unclear how these abnormalities change during the course of depression. METHODS The authors studied the longitudinal covariation of depression severity and IP functioning in 157 depressed older adults with MDD. Patients with and without baseline IP impairment were studied on three occasions over 1 year. RESULTS Depression severity was associated with concurrent IP scores; however, despite IP improvement, those with impaired baseline IP functioning did not reach the level of their non-impaired counterparts. CONCLUSION The persistence of IP abnormalities suggests that these patients require careful treatment planning and follow-up, given that earlier studies noted an association of abnormal IP with disability and poor outcomes of depression treatment.

Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression

OBJECTIVE This study compared microstructural abnormalities in depressed elders and controls and studied the association of the serotonin transporter gene status to white matter abnormalities and to remission of depression. METHODS The subjects were Caucasians with non-psychotic major depression and normal elders. Depressed subjects received escitalopram 10 mg daily for 12 weeks. Remission was defined as a HDRS score of 7 or below for 2 consecutive weeks. Diffusion tensor imaging was performed and voxel-based analysis of fractional anisotropy (FA) was conducted using age and mean diffusivity as covariates. RESULTS Depressed elders (N=27) had lower FA than controls (N=27) in several frontolimbic areas. Depressed elderly S-allele carriers also had lower FA than L homozygotes in frontolimbic brain areas, including the dorsal and rostral anterior cingulate, posterior cingulate, dorsolateral prefrontal and medial prefrontal regions, thalamus, and in other regions. S-allele carriers had a lower remission rate than L homozygotes. LIMITATIONS Small number of subjects, lack of random sampling, fixed antidepressant dose, short follow-up. CONCLUSIONS Lower FA was observed in several frontolimbic and other regions in depressed elders compared to controls. Depressed S-allele carriers had both microstructural white matter abnormalities in frontolimbic networks and a low remission rate. It remains unclear whether the risk for chronicity of geriatric depression in S-allele carriers is mediated by frontolimbic compromise. However, these observations set the stage for studies aiming to identify the relationship of S allele to impairment in specific frontolimbic functions interfering with response of geriatric depression to antidepressants.

Anterior Cingulate Cortical Volumes and Treatment Remission of Geriatric Depression

Structural abnormalities of the anterior cingulate cortex (ACC) may interfere with the interaction of cortical and limbic networks involved in emotional regulation and contribute to chronic depressive syndromes in the elderly. This study examined the relationship of regional anterior cingulate cortical volumes with treatment remission of elderly depressed patients. We hypothesized that patients who failed to remit during a 12‐week controlled treatment trial of escitalopram would exhibit smaller anterior cingulate gray matter volumes than patients who remitted.

BDNF Val66met Polymorphism, White Matter Abnormalities and Remission of Geriatric Depression

OBJECTIVE The polymorphism BDNF val66met of the brain derived neurotrophic factor (BDNF) is common, may increase the risk for depression, and affects BDNF secretion, critical for neuronal survival, plasticity, neurogenesis, and synaptic connectivity. Our objectives were: 1) to test the hypothesis that BDNF(val/met) status influences the remission rate of geriatric depression; 2) to explore whether the relationship between BDNF allelic status to remission is influenced by the presence of microstructural white matter abnormalities. METHOD Non-demented older subjects with major depression had a 2-week placebo period, after which those with a Hamilton Depression Rating Scale (HDRS) of 18 or greater received escitalopram 10 mg daily for 12 weeks. Fractional anisotropy was determined in specific regions using the Reproducible Object Quantification Scheme (ROQS) software that operates on non-normalized data. RESULTS BDNF(met) carriers were more likely to achieve remission than BDNF(val/val) homozygotes after 12 weeks of treatment with escitalopram 10 mg daily. Microstructural abnormalities in the corpus callosum, left superior corona radiata, and right inferior longitudinal fasciculum were also associated with lower remission rate. However, there were no significant interactions between BDNF(val66met) status and microstructural abnormalities in predicting remission. LIMITATIONS Small number of subjects, focus on a single BDNF polymorphism, fixed antidepressant dose. CONCLUSIONS Depressed older BDNF(met) carriers had a higher remission rate than BDNF(val/val) homozygotes. This effect was not related to microstructural white matter abnormalities, which predicted remission independently. We speculate that the relationship between BDNF(val66met) and remission is due to different effects of BDNF in brain structures related to mood regulation.

Population projection of US adults with lifetime experience of depressive disorder by age and sex from year 2005 to 2050

To estimate the projected population of US adults aged 18 years or older with lifetime experience of doctor‐diagnosed depressive disorder from 2005–2050.

Attention Network Dysfunction and Treatment Response of Geriatric Depression

The Attention Network Test was used to assess the efficiency of the executive, orienting and vigilance attention networks and their association to treatment response in older patients with major depression. There were no significant performance differences between depressives and controls. However, within the depressed group, executive-related performance, but not orienting- or vigilance-related performance was correlated with time to remission. The association of executive-attention network efficiency and antidepressant response provides the background for focused structural and functional neuroimaging studies aimed at identifying the functional neuroanatomy of antidepressant response.