Sibel Klimstra

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.

Patients' depression treatment preferences and initiation, adherence, and outcome: a randomized primary care study.

OBJECTIVE The authors examined the association of treatment preferences with treatment initiation, adherence, and clinical outcome among nonsenior adult and senior primary care patients with depression. METHODS Sixty primary care participants meeting DSM-IV criteria for major depression were randomly assigned to receive treatment congruent or incongruent with their primary stated preference. Participants received either 20 weeks of escitalopram, with monitoring by a care manager, or 12 weekly sessions of interpersonal psychotherapy followed by two monthly booster sessions. Adherence to treatment and depression severity were reassessed at weeks 4, 8, 12, and 24. RESULTS Participants expressed stronger preferences for psychotherapy than for antidepressant medication. Preference strength was a more sensitive measure of outcome than was congruence versus incongruence of preference with the assigned treatment. Across age groups, preference strength was significantly associated with treatment initiation and 12-week adherence rate but not with depression severity or remission. CONCLUSIONS A continuous measure of preference strength may be a more useful measure in clinical practice than preferences per se. Future research should focus on whether and how greater facilitation of the treatment decision-making process between patient and clinician influences clinical outcome.

Executive Dysfunction and Disability in Elderly Patients With Major Depression

The authors studied 126 elderly patients without dementia and with unipolar major depression. Impairment in instrumental activities of daily living (IADLs) was significantly associated with age (P<0.0001), gender (P<0.001), medical burden (P=0.013), severity of depression (P=0.01), initiation/perseveration (IP; P=0.035), and IP x depression (P=0.029). Depression was associated with IADL impairment mainly in patients with impaired IP. Among the cognitive impairments, IP-only contributed significantly to IADL impairment, whereas attention, construction, conceptualization, and memory did not. Attention to executive function and disability may guide clinical management and lead to development of innovative pharmacological and behavioral interventions.

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.

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.

Continuation treatment of delusional depression in older adults.

Delusional depression responds poorly to acute antidepressant monotherapy but appears to respond to intensive combination pharmacotherapy, however with poor short-term outcomes after initial improvement, particularly in later life. The authors compared the efficacy and safety of continuation combination therapy to monotherapy among older patients after remission from a delusional depression. Twenty-nine older adults with SCID-diagnosed major depression with delusions received continuation treatment with nortriptyline-plus-perphenazine or nortriptyline-plus-placebo under randomized double-blind conditions after achieving remission after ECT. Of the 28 subjects included in efficacy analyses, 25% suffered relapses. The relapse frequency was nonsignificantly greater in combination therapy than in monotherapy subjects. However, combination subjects had significantly more extrapyramidal symptoms, an increased incidence of tardive dyskinesia, and a greater number of falls. Continuation treatment with a conventional antipsychotic does not decrease relapse rates but is associated with significant untoward adverse events in older persons after recovery from a delusional depression.

Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response.

BACKGROUND Apathy is a prominent feature of geriatric depression that predicts poor clinical outcomes and hinders depression treatment. Yet little is known about the neurobiology and treatment of apathy in late-life depression. This study examined apathy prevalence in a clinical sample of depressed elderly, response of apathy to selective serotonin reuptake inhibitor (SSRI) treatment, and neuroanatomical correlates that distinguished responders from non-responders and healthy controls. METHODS Participants included 45 non-demented, elderly with major depression and 43 elderly comparison individuals. After a 2-week single-blind placebo period, depressed participants received escitalopram 10mg daily for 12 weeks. The Apathy Evaluation Scale (AES) and 24-item Hamilton Depression Rating Scale (HDRS) were administered at baseline and 12 weeks. MRI scans were acquired at baseline for concurrent structural and diffusion tensor imaging of anterior cingulate gray matter and associated white matter tracts. RESULTS 35.5% of depressed patients suffered from apathy. This declined to 15.6% (p<0.1) following treatment, but 43% of initial sufferers continued to report significant apathy. Improvement of apathy with SSRI was independent of change in depression but correlated with larger left posterior subgenual cingulate volumes and greater fractional anisotropy of left uncinate fasciculi. LIMITATIONS Modest sample size, no placebo control, post-hoc secondary analysis, use of 1.5T MRI scanner CONCLUSIONS While prevalent in geriatric depression, apathy is separable from depression with regards to medication response. Structural abnormalities of the posterior subgenual cingulate and uncinate fasciculus may perpetuate apathetic states by interfering with prefrontal cortical recruitment of limbic activity essential to motivated behavior.

Semantic organizational strategy predicts verbal memory and remission rate of geriatric depression

This study tests the hypothesis that the use of semantic organizational strategy during the free‐recall phase of a verbal memory task predicts remission of geriatric depression.

Apathy in Late-Life Depression: Common, Persistent, and Disabling

OBJECTIVE The aims of this study were to examine: (1) the relationship between apathy and disability in late-life depression, and (2) the functional significance of improvement in apathy following escitalopram treatment in terms of its relationship to disability. METHODS Subjects were 71 non-demented elderly with non-psychotic major depression. After a 2-week single-blind placebo period, subjects who had Hamilton Depression Rating Scale (HDRS) ≥ 18 received escitalopram 10 mg daily for 12 weeks. Apathy and disability were assessed with the Apathy Evaluation Scale (AES) and the World Health Organization Disability Assessment Scale II (WHODAS), respectively. These measures and the HDRS were administered at baseline and again following 12 weeks of treatment. RESULTS At baseline, 38% of depressed subjects had significant apathy (AES ≥ 36.5). Severity of apathy at baseline significantly correlated with severity of disability. In a multivariate regression model, baseline severity of apathy, but not the overall depressive syndrome (HDRS), significantly correlated with baseline disability. Following escitalopram treatment, improvement in apathy significantly correlated with improvement in disability measures, while change in the rest of the depressive syndrome did not. The overall change in apathy and disability in response to escitalopram treatment was significant but small. CONCLUSION Apathy is common in late-life depression and is associated with disability above and beyond the influence of other depressive symptoms. Given the strong relationship between apathy and disability, understanding the neurobiology of apathy and developing treatments for apathy may improve the functional outcomes of late-life depression.