Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale.

Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HTExt). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HTExt beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HTExt beyond the SERT inhibitor effect in humans; however, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhancing the pharmacological action and transforming 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here, we review the clinical and preclinical evidence for this treatment.

Suicidal ideation and sex differences in relation to 18 major psychiatric disorders in college and university students: anonymous web-based assessment.

College/university students are at high risk for psychiatric disorder and suicide secondary to age, campus stressors, and social pressures. We therefore report frequencies of 18 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision disorders and suicidal ideation (SI) acquired anonymously from a Web site receiving 113,181 visits from more than 1,500 predominantly US colleges/universities. Depression was foremost, followed by social phobia and eating disorders. Substance-related disorders were less frequent than expected. SI occurred in 47.1% of students, with women evidencing somewhat stronger findings than men. SI was more associated with substance, bipolar, and panic disorders than depression. Self-reported emotional volatility exceeded thoughts of self-harm for all disorders. The results support two subtypes of suicide risk: dysphoric premeditators and those primarily angry and/or impulsive. Clinicians and researchers should therefore consider suicide as an independent psychopathological phenomenon that includes emotional volatility as a risk factor and thoroughly evaluate psychiatric disorders potentially conferring greater suicidal propensity than depression.

Development of a virtual reality assessment of everyday living skills.

Cognitive impairments affect the majority of patients with schizophrenia and these impairments predict poor long term psychosocial outcomes.  Treatment studies aimed at cognitive impairment in patients with schizophrenia not only require demonstration of improvements on cognitive tests, but also evidence that any cognitive changes lead to clinically meaningful improvements.  Measures of "functional capacity" index the extent to which individuals have the potential to perform skills required for real world functioning.  Current data do not support the recommendation of any single instrument for measurement of functional capacity.  The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a novel, interactive gaming based measure of functional capacity that uses a realistic simulated environment to recreate routine activities of daily living. Studies are currently underway to evaluate and establish the VRFCAT's sensitivity, reliability, validity, and practicality. This new measure of functional capacity is practical, relevant, easy to use, and has several features that improve validity and sensitivity of measurement of function in clinical trials of patients with CNS disorders.

Associations between elevated homocysteine, cognitive impairment, and reduced white matter volume in healthy old adults.

OBJECTIVES: Elevated homocysteine has emerged as a risk factor for cognitive impairment even in healthy elderly persons. Reduced brain volume and white matter hyperintensities also occur in healthy elderly as well, but the interrelationships between these have not been well studied. We report these interrelationships in non demented, relatively healthy, community-dwelling older adults from a single East Asian population. METHODS: Two hundred twenty-eight right-handed participants age 55 years and above were evaluated. Persons with medical conditions or neurological diseases other than well-controlled diabetes mellitus and hypertension were excluded. Participants underwent quantitative magnetic resonance imaging of the brain using a standardized protocol and neuropsychological evaluation. Plasma homocysteine, folate, vitamin B(12), and markers for cardiovascular risk: blood pressure, body mass index, fasting blood glucose, and lipid profile were measured. RESULTS: Elevated homocysteine was associated with reduced global cerebral volume, larger ventricles, reduced cerebral white matter volume, and lower cognitive performance in several domains. Elevated homocysteine was associated with reduced white matter volume (ß = -20.80, t = -2.9, df = 223, p = 0.004) and lower speed of processing (ß = -0.38, t = -2.1, df = 223, p = 0.03), even after controlling for age, gender, and education. However, the association between homocysteine and lower speed of processing disappeared after controlling for white matter volume. Elevated homocysteine was not associated with white matter hyperintensity volume or with hippocampal volume. Although homocysteine and folate levels were correlated, their effects on white matter volume were dissociated. CONCLUSION: In non demented, relatively healthy adults, elevated homocysteine is associated with lower cognitive scores and reduced cerebral white matter volume. These effects can be dissociated from those related to white matter hyperintensities or reduced folate level.

Morphometric analysis of vascular pathology in the orbitofrontal cortex of older subjects with major depression.

OBJECTIVE: Late-life depression has been associated with risk for cerebrovascular pathology, as demonstrated in neuroimaging studies of older depressed patients, as well as mood disorder following cerebrovascular accidents. However, more research is needed on neuroanatomical changes in late-life depression, where there has been no clearly documented link to brain injury. Such studies should examine morphological changes in medium and small sized vessels that supply the cortical gray and white matter. METHODS: The present study used a non-specific histological Nissl staining and a more vessel-specific immunolabeling with endothelial marker von Willebrand Factor (vWF) to estimate density and size of blood vessel segments in the orbitofrontal cortex of 16 older subjects with major depressive disorder (MDD) and 9 non-psychiatric comparison subjects. RESULTS: The density of Nissl-stained vessel segments and of segments with perivascular spaces was higher in subjects with MDD than in comparison subjects in gray (GM) and white matter (WM). In GM, the density of vWF-immunoreactive segments with cross-sectional areas greater than 800 µm2 was higher in MDD. In WM, only the density of vWF-immunoreactive segments with patent perivascular spaces and diameters larger than 60 µm was higher in subjects with MDD. Also in the WM, only subjects with late-onset MDD presented a significantly higher density of vWF-positive segments than comparison subjects. CONCLUSIONS: In older subjects with MDD, there appear to be morphological changes that increase visibility of medium-sized vessel segments with some labeling techniques, and this increased visibility may be related to increased patency of perivascular spaces around arterioles.

Reduction of dorsolateral prefrontal cortex gray matter in late-life depression.

Postmortem studies have documented abnormalities in the dorsolateral prefrontal cortex (dlPFC) in depressed subjects. In this study we used magnetic resonance imaging to test for dlPFC volume differences between older depressed and non-depressed individuals. Eighty-eight subjects meeting DSM IV criteria for major depressive disorder and thirty-five control subjects completed clinical evaluations and cranial 3T magnetic resonance imaging. After tissue types were identified using an automated segmentation process, the dlPFC was measured in both hemispheres using manual delineation based on anatomical landmarks. Depressed subjects had significantly lower gray matter in the left and right dorsolateral prefrontal cortex (standardized to cerebral parenchyma) after controlling for age and sex. Our study confirmed the reduction of dorsolateral prefrontal cortex in elderly depressed subjects, especially in the gray matter. These regional abnormalities may be associated with psychopathological changes in late-life depression.

Metabolomic differences in heart failure patients with and without major depression.

Metabolomics is an emerging technology that allows researchers to characterize hundreds of small molecules that comprise the metabolome. We sought to determine metabolic differences in depressed and nondepressed participants. The sample consisted of a depressed group of patients with heart failure enrolled in an NIMH-supported clinical trial of sertraline versus placebo in depressed heart failure patients, and a nondepressed comparator group of heart failure patients. Plasma was obtained from blood samples provided by participants at baseline, and samples were profiled on GC-MS and LC-MS metabolomics platforms for biochemical content. A number of biochemicals were significantly different between groups, with depressed participants showing higher concentrations of several amino acids and dicarboxylic fatty acids. These results are consistent with prior findings where changes in neurotransmitter systems and fatty acid metabolism were shown to associate with the depressed state. It is unclear what role heart failure may have played in these differing concentrations.

Gray and white matter brain volumes in older adults with bipolar disorder.

OBJECTIVES: Structural magnetic resonance imaging (MRI) studies have been inconsistent in demonstrating volumetric differences in subjects with bipolar disorder. Most studies have not found difference in total gray or white matter in bipolar patients compared with controls, but there have been several studies suggesting that regional abnormalities are present. These have predominately been located in the frontal and temporal lobes. Since age has been inversely correlated with total gray matter in patients, analyses of gray matter changes in older adults or in studies that have included older subjects have been difficult. This study assessed the presence of gray matter volume, and the potential for regional volumetric differences in older adults with bipolar disorder. METHODS: Fifty-six older adults with DSM-IV bipolar disorder (mean age 60.5) and 43 non-psychiatrically ill controls (mean age 58.1) had structured interviews and MRI scanning on a 1.5T GE Scanner. Image parcellation divided the cerebrum into 16 units. Volumetric differences were examined using the multivariate linear regression models with alpha = 0.05. RESULTS: Relative to controls, the older adults with bipolar disorder had significantly smaller gray matter volumes bilaterally in the inferior frontal areas. White matter volume was also reduced in these same areas but did not reach statistical significance when controlled for gender and age. No significant difference was noted in total gray or white matter volumes. CONCLUSIONS: Older adults with bipolar disorder showed gray matter volumetric deficits in inferior frontal lobe regions which include structures identified as contributing to the anterior limbic network.

APOE related hippocampal shape alteration in geriatric depression.

Late-onset depression often precedes the onset of dementia associated with the hippocampal degeneration. Using large deformation diffeomorphic metric mapping (LDDMM), we evaluated apolipoprotein E epsilon-4 allele (apoE E4) effects on hippocampal volume and shape in 38 depressed patients without the apoE E4, 14 depressed patients with one apoE E4, and 31 healthy comparison subjects without the apoE E4. The hippocampal volumes were manually assessed. We applied a diffeomorphic template generation procedure for creating the hippocampal templates based on a subset of the population. The LDDMM mappings were used to generate the hippocampal shape of each subject and characterize the surface deformation of each hippocampus relative to the template. Such deformation was modeled as random field characterized by the Laplace-Beltrami basis functions in the template coordinates. Linear regression was used to examine group differences in the hippocampal volume and shape. We found that there were significant hippocampal shape alternations in both depressed groups while the groups of depressed patients and the group of healthy subjects did not differ in the hippocampal volume. The depressed patients with one apoE E4 show more pronounced shape inward-compression in the anterior CA1 than the depressed patients without the apoE E4 when compared with the healthy controls without the apoE E4. Thus, hippocampal shape abnormalities in late-onset depressed patients with one apoE E4 may indicate future conversion of this group to AD at higher risk than depressed patients without the apoE E4.

Temporal lobe volume in bipolar disorder: relationship with diagnosis and antipsychotic medication use.

BACKGROUND: We tested for differences in temporal lobe volume in bipolar disorder and the relationship between these volumes and psychotropic medication use. METHODS: 125 subjects with bipolar disorder and 87 comparison subjects with no psychiatric illness completed clinical interviews and 1.5T MRI brain scans. Temporal lobe volumes were manually traced and segmented into gray matter and white matter volumes using an automated process. General linear models examined the relationship between these volumes and diagnosis as the primary predictor with age, sex, education, and race as copredictors. Secondary analyses incorporated the use of psychotropic medication into the linear models, and parsimonious models developed through backwards regression. RESULTS: In initial models, subjects with bipolar disorder exhibited larger temporal lobe white matter bilaterally (left: F(1,211)=2.86, p=0.0047; right: F(1,211)=3.25, p=0.0014). Current antipsychotic use was significantly associated with larger bilateral temporal lobe white matter volumes (left: F(2,211)=9.45, p=0.0001; right: F(2,211)=10.79, p<0.0001), wherein bipolar subjects taking antipsychotics had larger volumes than bipolar subjects not taking antipsychotics or healthy comparison subjects. Temporal lobe gray matter volume was not significantly associated with diagnosis or medication use. LIMITATIONS: Excluding subjects with substance use disorders may limit the study's generalizability. CONCLUSIONS: These findings indicate that differences in temporal lobe white matter are associated with bipolar disorder and use of antipsychotic medications.

Hyperintense MRI lesions in bipolar disorder: A meta-analysis and review.

BACKGROUND: Cortical and subcortical hyperintensities in magnetic resonance imaging (MRI) scans are thought to represent areas of ischemic damage to brain tissue. Researchers have focused on the possible role these lesions may have in psychiatric disorders, including bipolar disorder. In 1997, the proposed 'vascular mania' diagnosis suggested utilizing not only the presence of strokes, but also confluent hyperintensities in its diagnostic criteria. This study was conducted to use meta-analytic techniques to investigate the association of hyperintensities and bipolar illness and to evaluate the current state of the literature. METHODS: Using the PubMed and MEDLINE databases, we conducted a systematic literature search of studies investigating hyperintensities in subjects with bipolar disorder and controls or other psychiatric illnesses. We identified 44 publications from which 35 studies were included for review and 27 were selected for meta-analysis. Summary statistics of the prevalence were estimated through odds-ratios and confidence interval. Heterogeneity of the results across studies was tested using Q-statistics. RESULTS: Meta-analysis identified an odds ratio of 2.5 (95% CI 1.9, 3.3) for hyperintensities in bipolar subjects compared to controls; however, there was significant heterogeneity among the studies (Q-statistics = 32; p = 0.04). This finding was most prominent for adolescents and children where the odds ratio was 5.7 (95% CI 2.3, 13.7). Deep white matter hyperintensities (odd ratio 3.2; 95% CI 2.2, 4.5) and subcortical grey matter hyperintensities (odds ratio 2.7; 95% CI 1.3, 2.9) were more strongly associated with bipolar subjects. There were no differences between bipolar subjects and controls for perivascular hyperintensities (odds ratio 1.3; 95% CI 0.8, 1.9). Though hyperintensities were numerically greater in bipolar subjects, meta-analysis did not demonstrate any significant differences between bipolar subjects and unipolar depression subjects (OR 1.6; 95% CI 0.9, 2.7) nor subjects with schizophrenia (OR 1.5; 95% CI 0.9, 2.7). CONCLUSIONS: This meta-analysis continues to support the association of bipolar disorder and hyperintensities, especially in the deep white matter and subcortical grey matter. It also highlights the increased incidence in children and adolescence with bipolar disorder. However, hyperintensities are not specific to bipolar disorder, but appear at similar rates in unipolar depression and schizophrenia. Thus, the role of hyperintensities in the pathogenesis, pathophysiology, and treatment of bipolar disorder remains unclear. Further studies are required that are large enough to decrease the heterogeneity of the samples and MRI techniques, assess size and location of hyperintensities, and the impact on treatment response. Coordination with newer imaging techniques, such as diffusion tensor imaging (DTI) may be especially helpful in understanding the pathology of these lesions.

Stressful life events in older bipolar patients.

OBJECTIVE: Theories about the impact of stressful life events (SLE) in bipolar disorder have focused on their role early in the disease. Few studies have examined SLE in older bipolar patients. We wanted to assess the impact of SLE in late life bipolar disorder METHODS: We evaluated negative SLE experienced by older bipolar subjects compared with younger bipolar subjects and older controls for number, type, and their association with phase of illness, age of onset, and previous episodes. RESULTS: Both younger and older bipolar subjects have more SLE than similarly aged controls. There was no significant difference in the number of stressors that younger and older bipolar subjects experienced, based on mood state, previous episodes, or age-of-onset. Both older and younger depressed bipolar subjects reported more SLE in the previous 12 months compared with those in a manic state. CONCLUSIONS: Negative SLE are much more prevalent in bipolar patients compared with age-matched controls, and continue to be frequent in later life.

Social support in older individuals: the role of the BDNF Val66Met polymorphism.

Although often viewed as a purely environmental construct, perception of social support may be influenced by genetic factors. This study examined the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and social support measures in older subjects. The sample consisted of 243 depressed and 115 nondepressed older subjects, age 60 years or older; 233 were Val66 allele homozygotes, while 125 were Met66 allele carriers. All subjects completed clinical assessments, including a self-report questionnaire assessing four social support domains, and provided blood for genotyping. Statistical models examined the relationship between scale scores of social support and BDNF Val66Met genotype, while controlling for presence or absence of major depressive disorder and other demographic factors significantly associated with social support. As social support measures were not normally distributed, log-transformed scores were examined. After controlling for diagnosis and education level, the Met66 allele was associated with lower levels of subjective social support (F(1,357) = 5.33, P = 0.0216) and a trend for fewer social interactions (F(1,357) = 3.66, P = 0.0567). To our knowledge, this is the first report associating a measure of social support with a genetic polymorphism. This supports previous work that genetic factors may influence social support perception. Further work is needed to determine the generalizability of this finding to the broader population, as well as its significance for clinical outcomes.

Age-dependent reduction of amygdala volume in bipolar disorder.

The amygdala is hypothesized to play a critical role in mood regulation, yet its involvement in bipolar disorder remains unclear. The aim of the present study was to compare measurements of amygdala volumes in a relatively large sample of bipolar disorder patients and healthy controls ranging in age from 18 to 49 years. Subjects comprised 54 adult patients meeting DSM-IV criteria for bipolar disorder and 41 healthy controls matched for age, sex, and education. Magnetic resonance imaging (1.5 T) was performed to obtain volumetric measurements of the amygdala using a manual region-of-interest tracing method with software that allowed simultaneous visualization of the amygdala in three orthogonal planes. The anterior head of the hippocampus was removed in the sagittal plane prior to amygdala volumetry measurement. Multiple regression analysis was computed on amygdala volume measurements as a function of diagnosis, age, sex, and cerebral volume. Bipolar patients showed an age-related reduction of amygdala volume, but controls did not. Among bipolar subjects, amygdala volume was unrelated to medication history. There were no significant hemispheric or sex interactions with the main effects. Results support a role for amygdala dysfunction in bipolar disorder which appears most robustly in older relative to younger adult patients. Differential aging effects in bipolar disorder may compromise amygdala integrity and contribute to mood dysregulation.

Hippocampus shape analysis and late-life depression.

Major depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F(1,103) = 5.26; p = 0.0240) but not right hippocampus volume (F(1,103) = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.

The brain-derived neurotrophic factor VAL66MET polymorphism and cerebral white matter hyperintensities in late-life depression.

OBJECTIVE: In animal models, brain-derived neurotrophic factor (BDNF) appears to protect against cerebral ischemia. The authors examined whether the BDNF Val66Met polymorphism, which affects BDNF distribution, was associated with greater volumes of hyperintense lesions as detected on magnetic resonance imaging in a cohort of depressed and nondepressed elders. DESIGN: Subjects completed cross-sectional assessments, including clinical evaluation and a brain magnetic resonance imaging scan, and provided blood samples for Val66Met genotyping. SETTING: The study was conducted at a university-based academic hospital. PARTICIPANTS: Participants included 199 depressed and 113 nondepressed subjects aged 60 years or older. MEASUREMENT: Hyperintensity lesion volumes were measured using a semiautomated segmentation procedure. Statistical models examined the relationship between genotype and lesion volume while controlling for depression, presence of hypertension, age, and sex. RESULTS: After controlling for covariates, Met66 allele carriers exhibited significantly greater white matter hyperintensity volumes (F(1,311) = 4.09, p = 0.0442). This effect was independent of a diagnosis of depression or report of hypertension. Genotype was not significantly related to gray matter hyperintensity volume (F(1,311) = 1.14, p = 0.2871). CONCLUSIONS: The BDNF Met66 allele is associated with greater white matter hyperintensity volumes in older individuals. Further work is needed to determine how this may be associated with other clinically relevant findings in late-life depression.

Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.

BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants. METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables. RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95% CI 1.07 to 2.94). CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.

Short/long heterozygotes at 5HTTLPR and white matter lesions in geriatric depression.

OBJECTIVE: We examined the relationship between 5HTTLPR genotype and volume of magnetic resonance imaging (MRI) brain lesions. METHOD: We studied 217 older depressed patients and 141 individuals in the comparison group using a standard brain MRI protocol to calculate lesion volumes. Genotype at 5HTTLPR was determined for each subject. RESULTS: In age-adjusted models, the l/s genotype was associated with increased volume of total and white-matter lesions among depressed patients. This relationship lost significance in models controlling for reported hypertension. CONCLUSIONS: The finding that 5HTTLPR heterozygotes have higher vascular lesion volumes may be related to development of hypertension.

Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression.

OBJECTIVE: The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with cognitive and neuroimaging changes. The authors examined the relationship between this polymorphism and depression in an elderly sample, hypothesizing that the Met66 allele would be associated with late-life depression. METHODS: A total of 245 elderly depressed white subjects and 94 elderly comparison white subjects completed clinical assessments and provided a blood sample for genotyping. Subjects were dichotomized as either homozygous for the Val66 allele or Met66 allele carriers. Gene frequencies were compared between groups, with separate analyses examining for differences in gene frequencies based on age of depression onset, family history, and depression history. Logistic regression models examined the relationship between genotype and depression after controlling for age, sex, and race. RESULTS: Depressed subjects were more likely to be Met66 allele carriers than were comparison subjects (38.8% versus 24.4%; chi(2) = 6.13, 1 df, p = 0.0133). This relationship remained significant after controlling for covariates (Wald chi(2) = 5.10, 1 df, p = 0.024; odds ratio: 1.92, 95% confidence interval: 1.09-3.38). There were no significant relationships between genotype and age of onset, number of episodes, or family history of depression. CONCLUSION: Met66 allele carriers have almost double the odds of having geriatric depression than do Val66 allele homozygotes. This polymorphism was unrelated to other clinical characteristics of depression in later life.

The COMT Val158Met polymorphism and temporal lobe morphometry in healthy adults.

We examined the relationship between COMT Val158Met genotype and temporal lobe volumes, including the caudate as a control region. Thirty-one healthy subjects completed 1.5T brain MRI and genotyping. After controlling for demographics, Val158 allele homozygotes exhibited significantly smaller temporal lobe and hippocampal volumes, with a trend for smaller amygdala volumes.