Molecular imaging for depressive disorders.

Molecular imaging is the visualization, characterization, and measurement of biologic processes at the molecular and cellular levels in humans and other living systems. Molecular imaging techniques such as MR spectroscopy and PET have been used to explore the molecular pathophysiology of depression and assess treatment responses. MR spectroscopy is a noninvasive technique that assesses the levels of biochemical metabolites in the brain, while PET uses radioligands injected in the bloodstream that have high binding affinity for target molecules. MR spectroscopy findings suggest a role for glutamate/glutamine and gamma-aminobutyric acid in depression. PET has generally failed to find a correlation between radioligand binding potential and depression severity or treatment response, though it may offer promise in distinguishing responders and nonresponders to treatment. A major challenge for both modalities is that depression is a heterogeneous, multifactorial disorder, while MR spectroscopy and PET are limited to examining a few metabolites or a single radioligand at a time. This difference makes a comprehensive evaluation of neurochemical changes in the brain difficult.

Impact of BDNF Val66Met and 5-HTTLPR polymorphism variants on neural substrates related to sadness and executive function.

The brain-derived neurotrophic factor (BDNF) Val(66) Met allelic variation is linked to both the occurrence of mood disorders and antidepressant response. These findings are not universally observed, and the mechanism by which this variation results in increased risk for mood disorders is unclear. One possible explanation is an epistatic relationship with other neurotransmitter genes associated with depression risk, such as the serotonin-transporter-linked promotor region (5-HTTLPR). Further, it is unclear how the coexistence of the BDNF Met and 5-HTTLPR S variants affects the function of the affective and cognitive control systems. To address this question, we conducted a functional magnetic resonance imaging (fMRI) study in 38 older adults (20 healthy and 18 remitted from major depressive disorder). Subjects performed an emotional oddball task during the fMRI scan and provided blood samples for genotyping. Our analyses examined the relationship between genotypes and brain activation to sad distractors and attentional targets. We found that 5-HTTLPR S allele carriers exhibited stronger activation in the amygdala in response to sad distractors, whereas BDNF Met carriers exhibited increased activation to sad stimuli but decreased activation to attentional targets in the dorsolateral prefrontal and dorsomedial prefrontal cortices. In addition, subjects with both the S allele and Met allele genes exhibited increased activation to sad stimuli in the subgenual cingulate and posterior cingulate. Our results indicate that the Met allele alone or in combination with 5-HTTLPR S allele may increase reactivity to sad stimuli, which might represent a neural mechanism underlying increased depression vulnerability.

A functional alternative splicing mutation in human tryptophan hydroxylase-2.

The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.

Angiotensin receptor gene polymorphisms and 2-year change in hyperintense lesion volume in men.

This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A, respectively. 137 depressed and 94 non-depressed participants aged >or=60 years were enrolled. Standard clinical evaluations were performed on all participants and blood samples obtained for genotyping. 1.5-T MRI (magnetic resonance imaging) data were obtained at baseline and approximately 2 years later. These scans were processed using a semi-automated segmentation process, which allowed for the calculation of WML volume at each time point. Statistical models were tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension (HTN) with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without HTN. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene-gene or gene-depression interactions were observed. Our results parallel earlier observed gender differences of the relationship between other renin-angiotensin system polymorphisms and HTN. Further work is needed to determine whether these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and whether antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.

The COMT Val158Met polymorphism and cognition in depressed and nondepressed older adults.

OBJECTIVE: The objective of the current study was to examine the relationship between the COMT Val(158)Met polymorphism and neuropsychological performance in depressed and nondepressed older adults. METHODS: One hundred and twenty-six clinically depressed older adults and 105 nondepressed comparison participants were compared on neuropsychological performance and COMT Val(158)Met (Val/Val, Val/Met, Met/Met). RESULTS: Based on multivariate regression models, the COMT Val(158)Met polymorphism was not associated with cognitive performance among depressed or nondepressed individuals, nor did this polymorphism account for the fact that depressed individuals performed worse than nondepressed individuals on several neuropsychological tests that are typically affected by depression. There was also no difference in frequency of the COMT Val(158)Met alleles between depressed and nondepressed individuals. CONCLUSIONS: Although the current study found no association between COMT Val(158)Met polymorphism on a number of clinical neuropsychological tests that are typically found to be sensitive to depression, differential effects of the COMT Val(158)Met polymorphism on dopamine transmission in psychiatric and non-psychiatric populations may be further clarified by clinical research with neuroscience-based paradigms that segregate cognitive tasks into component processes with precise neural substrates, particularly with respect to the complex functions of the prefrontal cortex. Negative results can be important to narrowing down target processes and understanding the influence of clinical and demographic characteristics in studies of psychiatric genetics.

Neuropsychological correlates of magnetic resonance imaging-defined subcortical ischemic depression.

OBJECTIVE: The goal of the current study was to examine the neuropsychological profile of magnetic resonance imaging (MRI)-defined subcortical ischemic depression (SID). METHODS: Clinically depressed older adults with MRI-defined SID (n = 70) and depressed elders without SID (n = 75) were compared on neuropsychological performance, depression symptoms, and medical burden. RESULTS: Group comparisons revealed that the SID was associated with worse performance on all neuropsychological measures, but also with greater age, higher cardiac illness burden, and greater deficits in the depression symptoms of self-initiation and concentration. In multivariate regression models, auditory working memory and nonverbal memory remained worse among the SID group after controlling for contributions of age, cardiovascular risk, and depression symptoms. CONCLUSIONS: Although auditory working memory span and nonverbal memory appear to be specifically associated with the ischemic pathology that defines SID, the typical individual with SID is also likely to have a broader profile of neuropsychological deficits than those without SID because they are typically older and have specific depression symptoms that predispose them to compromised neurocognitive performance.

Metabolomic mapping of atypical antipsychotic effects in schizophrenia.

Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform 'lipidomics' that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2-3 weeks with olanzapine (n=20), risperidone (n=14) or aripiprazole (n=16). Patients were recruited in two cohorts (study I, n=27 and study II, n=23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.

Prefrontal white matter lesions and prefrontal task impersistence in depressed and nondepressed elders.

Poor task persistence is often observed among depressed individuals, and may be associated with some of the same frontal regions that are involved in depression. The current study explored the association between white-matter lesion volume in prefrontal cortex and noncompletion rates on a complex neurocognitive task among older adults in a treatment study for depression. Older adults in treatment for depression (n=83) and nondepressed (n=47) elders were administered the Stockings of Cambridge subtest (SoC) of the Cambridge Automated Neuropsychological Testing Battery (CANTAB) and completed a brain magnetic resonance imaging scan as part of an ongoing research study. Noncompletion of the SoC occurred in approximately 19% of depressed participants (16/83) and only 2% of nondepressed participants (1/47), which was statistically significant. In multivariate models, failure to complete the SoC was consistently and significantly associated with greater volume of white matter lesions in the anterior-most region of prefrontal cortex, particularly in the left hemisphere, and with greater age. Although SoC completion was not significantly associated with depression severity, noncompletion rates were significantly higher among unremitted individuals and those with comorbid anxiety at study entry. The inability to initiate behavior sufficient to sustain a complex neurocognitive task is a characteristic of geriatric depression which may be associated with integrity of left-prefrontal regions. Future research should investigate whether task impersistence is a construct that generalizes to other neurocognitive tasks, and if it is associated with other adverse outcomes in geriatric depression related to cerebrovascular pathology, such as poor treatment response.

Psychiatric disease in the genomic era: rational approach.

Although the introduction of explicit diagnostic criteria and rule-based classifications, such as Research Diagnostic Criteria, Diagnostic and Statistical Manual Ed 3 and Ed 4, has dramatically influenced teaching and research psychiatric practice, it has significant limitations. As new knowledge is developed with genetic, imaging and metabolomic technologies, a method to incorporate this research in a systematic manner with current classification systems is needed. The current approach, which is essentially nominalist in character, has to be developed where new data and new concepts of disease can be integrated and tested. Examples of how this could happen is shown in the context of Alzheimer's disease and subcortical ischemic disease. It is likely that a standardized approach that can develop and modify classification systems in a timely manner, based on science and free of societal and political influence, can enhance research, teaching and clinical practice.

A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil.

OBJECTIVE: To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. METHODS AND MATERIALS: Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. RESULTS: 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. CONCLUSION: Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia.

Quality of life in patients with spinal cord injury--basic issues, assessment, and recommendations.

INTRODUCTION: Spinal cord injury (SCI) often causes severe disabilities. The degree of functional impairment strongly depends on the level and completeness of lesion (tetraplegic, paraplegic). But evaluation of outcomes also needs to consider the broader concept of health-related quality of the life (HRQL) for SCI patients. A multinational group of clinicians and researchers assessed this concept and reviewed the available instruments for measurement of quality of life in this group of patients. TIME POINTS: Phase I is in the acute clinic; phase II during rehabilitation; phase III after discharge home. Annual follow-up investigations should be maintained. The phase of initial care (phase 0) is important for prognosis and should, therefore, be part of the documentation. INSTRUMENTS: Criteria used to evaluate current QoL measures: reliability, validity, responsiveness, availability of translations, application in SCI patients, existing population norms. Several specific instruments or subscales exist for the following domains: physical and psychological functioning, pain, and handicap. Well-known generic measures of HRQL also have been applied to SCI patients, and a disease-specific instrument has been developed (SCIQL-23). A variety of subjective quality of life measures were evaluated as well. GROUP CONSENSUS/GUIDELINE: Prior to discharge from rehabilitation, the group suggested the use of the Functional Independence Measure, the Hospital Anxiety and Depression Scale and a Visual Analogue Scale for pain. Following discharge from the acute clinic, the SF-36, the Craig Handicap Assessment and Reporting Technique, the Quality of Well-being Scale, or the Life Satisfaction questionnaire were proposed. However, the evidence supporting the use of these instruments is sparse.

Performance feedback deficit in geriatric depression.

BACKGROUND: The orbital frontal cortex is involved with processing of performance feedback. This study tests the hypothesis that older depressed subjects, compared with elderly control subjects, commit more subsequent errors after receiving feedback from an initial error. METHODS: We administered 116 older depressed patients and 139 control subjects the Trail Making Test Part B (TRAILS-B). Subjects who committed an error on TRAILS-B were immediately given feedback on performance. We then measured the frequency of making an error on the subsequent three tries. The likelihood of making any subsequent error was examined. RESULTS: After controlling for the overall initial error rate, more depressed patients than control subjects made subsequent errors. This association remained significant in later regression models. When the depressed group was examined in additional models, severity of depression was not associated with increased subsequent errors. CONCLUSIONS: These results extend previous findings suggesting a performance feedback deficit in geriatric depression. The findings support previous studies linking the orbital frontal cortex and depression.

A controlled study of MRI signal hyperintensities in older depressed patients with and without hypertension.

OBJECTIVES: To compare the frequency/severity of signal hyperintensities--likely markers of cerebrovascular disease--in the subcortical gray and deep white matter on magnetic resonance imaging (MRI) scans of brains of hypertensive and normotensive older depressed and nondepressed comparison subjects. DESIGN: Between-groups comparison of cross-sectional MRI data employing analyses of covariance controlling for the effects of age, gender, and height. SETTING: A comprehensive inpatient-outpatient geriatric psychiatry service in a university hospital. PARTICIPANTS: Nondemented older depressed (n = 81) and nondepressed comparison (n = 70) subjects divided into four groups (hypertensive depressed (n = 40), hypertensive normals (n = 21), normotensive depressed (n = 41), normotensive normals (n = 49)). MEASUREMENTS: Signal hyperintensities were rated on T-2 weighted MRI scans blind to patient diagnoses employing two standardized hyperintensity rating systems (Fazekas, Boyko). RESULTS: Hypertensive depressives had significantly more- severe hyperintensity ratings in both subcortical gray and deep white matter than did normotensive depressives and controls (P < .05) and significantly more-severe hyperintensity ratings only in subcortical gray matter (P < .05) than did hypertensive controls. Hypertensive controls had significantly more-severe ratings in deep white matter than either normotensive group (P < .05). CONCLUSIONS: Findings suggest a relationship between deep white matter hyperintensities and hypertension (regardless of depressive state), and a particular role of subcortical gray matter hyperintensities (possibly interacting with more-severe deep white matter lesions) in older depressed hypertensives, as compared with older depressed normotensives of similar ages and severity of depression. These data support possible heterogeneous pathogenic contributions in late-life depression subgroups, one of which appears to be influenced by cerebrovascular disease.

Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women.

OBJECTIVE: On the basis of the clinical observations that bupropion facilitated weight loss, we investigated the efficacy and tolerability of this drug in overweight and obese adult women. RESEARCH METHODS AND PROCEDURES: A total of 50 overweight and obese (body mass index: 28.0 to 52.6 kg/m(2)) women were included. The core component of the study was a randomized, double-blind, placebo-controlled comparison for 8 weeks. Bupropion or placebo was started at 100 mg/d with gradual dose increase to a maximum of 200 mg twice daily. All subjects were prescribed a 1600 kcal/d balanced diet and compliance was monitored with food diaries. Responders continued the same treatment in a double-blind manner for an additional 16 weeks to a total of 24 weeks. There was additional single-blind follow-up treatment for a total of 2 years. RESULTS: Subjects receiving bupropion achieved greater mean weight loss (last-observation-carried-forward analysis) over the first 8 weeks of the study (p = 0.0001): 4.9% +/- 3.4% (n = 25) for bupropion treatment compared with 1.3% +/- 2.4% (n = 25) for placebo treatment. For those who completed the 8 weeks, the comparison was 6.2% +/- 3.1% (n = 18) vs. 1.6% +/- 2.9% (n = 13), respectively(p = 0.0002), with 12 of 18 of the bupropion subjects (67%) losing over 5% of baseline body weight compared with 2 of 13 in the placebo group (15%; p = 0.0094). In the continuation phase, 14 bupropion responders who completed 24 weeks achieved weight loss of 12.9% +/- 5.6% with fat accounting for 73.5% +/- 3.7% of the weight lost and no change in bone mineral density as assessed by DXA. Bupropion was generally well-tolerated in this sample. DISCUSSION: Bupropion was more effective than placebo in achieving weight loss at 8 weeks in overweight and obese adult women in this preliminary study. Initial responders to bupropion benefited further in the continuation phase.

Evidence of white matter tract disruption in MRI hyperintensities.

BACKGROUND: Diffusion tensor imaging (DTI) of brain tissue measures the apparent diffusion coefficient (ADC), or isotropic diffusion, and anisotropy, or diffusion as influenced by tissue structure. We hypothesized that hyperintensities, when compared with normal tissue by DTI, would show evidence of damage through an increased ADC and decreased anisotropy. We also hypothesized that DTI changes in hyperintensities would be similar between depressed subjects and control subjects. METHODS: Fourteen depressed geriatric patients and nineteen control subjects received DTI. The ADC and aniso-tropy of normal tissue from standard regions were compared with hyperintensities from these regions. The Students' t test compared individual regions and averaged white matter results. RESULTS: Hyperintensities showed higher ADC and lower anisotropy than normal regions. Gray matter exhibited similar trends. There was no significant difference in diffusion characteristics of hyperintensities between subjects and control subjects. CONCLUSIONS: Hyperintensities damage the structure of brain tissue, and do so comparably in depressed subjects and control subjects.

MRI correlates of suicide attempt history in unipolar depression.

BACKGROUND: Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS: In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS: Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS: Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Medial orbital frontal lesions in late-onset depression.

BACKGROUND: Early studies using magnetic resonance (MR) imaging suggested that subcortical vascular changes are more prevalent in late-life depression and that they may play a role in the pathophysiology of depression. Studying the location of the lesion relative to the occurrence of depression could be critical in delineating the neuroanatomic substrates of depression. Our purpose was to characterize these lesions in terms of location by development of statistical parametric maps of lesions that differentiate patients from control subjects. METHODS: Magnetic resonance images were acquired on 88 elderly depressed subjects ("patients," unipolar major depression assessed using the Duke Depression Evaluation Schedule, age range 63-80 years) enrolled in the Duke University Clinical Research Center for the Study of Late-Life Depression and 47 age- and gender-matched nondepressed subjects ("control subjects"). The MR protocol includes a volumetric, dual-contrast fast spin-echo pulse sequence. A statistical parametric map was formed from a two-group t test to test for differences in lesion density between patients and control subjects. Additional testing was performed to evaluate whether there were regions that correlated with the severity of depression using the 17-item Hamilton Depression rating. RESULTS: The statistical parametric mapping analysis between groups showed two major regions of increased lesion density in the patients in the medial orbital prefrontal white matter. Severity of depression among depressed patients was correlated with lesions in the medial orbital region. CONCLUSIONS: This study supports recent evidence implicating the medial orbital frontal cortex in depression.

Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline.

1. The safety and efficacy of sertraline in the treatment of moderate-to-severe major depression in elderly outpatients, aged 60 years and older, with comorbid vascular disease was evaluated. 2. An analysis of the pooled results for the sertraline treatment group drawn from two prospective, randomized, double-blind studies (sertraline vs. fluoxetine, and sertraline vs. nortriptyline) was done. Patients were retrospectively categorized into one of 3 clinical groups: 1) patients with a current diagnosis of hypertension but no other past or present cardiovascular illness (HTN), 2) patients reporting a current or past history of cardiovascular illness, but excluding hypertension (VASC), and 3) patients with no hypertension, and no other comorbid vascular illness (NoVASC). Patients received 12-3. weeks of double-blind treatment with sertraline in flexible daily doses in the range of 50 - 150 mg (in the nortriptyline comparator trial) or 50 - 100 mg (in the fluoxetine comparator trial). 4. Sertraline treatment yielded comparable levels of response in all 3 groups (response criterion: CGI-much or very much improved) at treatment endpoint on both a completer analysis (HTN, 86%; VASC, 89%; NoVASC, 77%) and significantly higher response rates on a 12-week endpoint analysis (HTN, 74%; VASC, 69%; NoVASC, 58%; p < 0.05). Sertraline treatment was well-tolerated, with no between-group differences in rates of adverse events, or in discontinuation due to adverse events. Patients taking 5 or more concomitant medications showed no difference, when compared with patients taking none-or-one concomitant medication, either in rates of adverse events, or in discontinuation due to adverse events. 5. Sertraline was found to be a safe, well-tolerated, and effective as an antidepressant in elderly patients suffering from hypertension and other forms of vascular comorbidity.