Russell T. Joffe

Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness

Altered hippocampal volume, the brain‐derived neurotrophic factor (BDNF) Val66Met polymorphism, and neuroticism have each been implicated in the etiology of psychiatric disorders, especially depression. However, the relationship between these variables is not well understood. Here, we determined the effects of the BDNF Val66met polymorphism on the five‐factor personality dimensions (assessed using the NEO‐FFI), trait depression (assessed with the DASS‐21) in a cross‐sectional cohort of 467 healthy volunteers. A large matched subset of this cohort was also assessed for grey matter volume of the hippocampus and contiguous temporal cortical regions using magnetic resonance imaging. In Met carriers, elevations in neuroticism and trait depression and stress were associated with lower mean hippocampal volume, but there were no such associations in Val homozygotes. Trait depression, in particular, was found to moderate the effects of BDNF genotypes on hippocampal volume. Met carriers with high trait depression showed a reduction in grey matter volume of the mean hippocampus compared with Val homozygotes. These findings suggest that even in otherwise healthy subjects, trait depression may contribute to the susceptibility of Met carriers to hippocampal grey matter loss. Hum Brain Mapp 2009.

Association between BDNF Val66Met polymorphism and trait depression is mediated via resting EEG alpha band activity

A functional polymorphism of the brain-derived neurotrophic factor, BDNF Val66Met, is associated with risk for major depression alongside impairments in memory and selective attention. This study aims to identify the mediating neural mechanisms in links between BDNF and depression using highly heritable electroencephalographic (EEG) recordings. In 305 healthy subjects, BDNF Val66Met genotypes were compared in terms of trait depression, neural function (EEG during a resting state) and cognitive performance. The mediating effects of the EEG brain imaging endophenotypes were also examined using structural equation (path) modeling. A genotype-endophenotype-phenotype path model showed that Met homozygosity predicted elevated working memory commission errors and altered EEG activity; that is elevated relative theta and delta power coupled with reduced alpha power. In turn, reduced EEG alpha activity mediated the relationship between the Met/Met genotype and trait depression. These findings demonstrate the utility of an integrative endophenotype approach. They suggest that the BDNF Met/Met homozygote has a direct impact on memory systems, but impacts trait depression via the secondary effects of neural changes.

Subclinical hypothyroidism, mood, and cognition in older adults: a review.

To perform a critical review of the literature on the mood and cognitive changes associated with subclinical hypothyroidism (SCH), with an emphasis on older adults. To evaluate these data against the Consensus Statement on the management of SCH from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society.

One-year outcome with antidepressant – treatment of bipolar depression

Objective:  To examine the risk of relapse into mania or depression with varying duration of antidepressant treatment in a cohort of 59 patients with bipolar disorder.

Increased subgenual prefrontal cortex size in remitted patients with major depressive disorder

Bilateral reductions in the volume of the anterior cingulate cortex have been reported in patients with major depressive disorder (MDD) when compared with findings in healthy controls. We compared regional brain volumes in the subgenual prefrontal cortex (SGPFC; Brodmann area (BA) 24(sg)), subcallosal gyrus (BA25) and paracingulate gyrus (BA32) in healthy control subjects and a large and well-characterized sample of patients with recurrent MDD, all of whom had received extensive antidepressant therapy. Patients with a remitted episode of MDD had SGPFC volumes larger than those of healthy controls, while those in an active illness episode did not differ from controls. There were no differences in subcallosal gyrus and paracingulate gyrus volumes between patients with MDD and healthy controls, with the exception that women with MDD had smaller paracingulate volumes than their sex-matched controls. This effect was not related to duration of illness, number of previous episodes, age at illness onset, or age at the time of scanning. Our findings demonstrate SGPFC volume increases in association with long-term antidepressant therapy and suggest that this result may be linked to positive clinical response.

A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response

The aim was to evaluate whether adjunctive T3 can help accelerate the antidepressant response and improve overall outcomes when used under naturalistic conditions. Fifty consecutive psychiatric outpatients diagnosed with major depressive disorder who were initiated on antidepressant therapy were randomized to receive adjunctive T3 or placebo in a double-blind manner over the course of 6 wk. There were no restrictions placed on the selection of antidepressant agent, dosing, ancillary medications, or psychotherapy, and there were few exclusion criteria. A positive response was defined as a > or = 50% reduction in Montgomery-Asberg Depression Rating Scale scores. Response rates were higher for the adjunctive T3 cohort compared to the adjunctive placebo cohort after 1 wk (45% vs. 24%) and 2 wk (57% vs. 33%) of treatment. The likelihood of experiencing a positive response at any point over the 6-wk trial was 4.5 times greater in the adjunctive T3 cohort (95% CI 1.3-15.7). The study provides preliminary evidence that T3 can successfully be used in clinical practice to accelerate the antidepressant response and improve overall outcomes. The effectiveness model may be an untapped mechanism for evaluating the value of psychopharmacological agents.

Does Substitution of T4 with T3 Plus T4 for T4 Replacement Improve Depressive Symptoms in Patients with Hypothyroidism

Abstract: Substitution of T4 with T3 for T4 replacement in patients with hypothyroidism was undertaken using a randomized placebo controlled study design. Forty individuals were included who had depressive symptoms on stable doses of levothyroxine. Combined T4 plus T3 did not have a significantly different effect on mood and well‐being scores than did T4 alone.

Subclinical Hypothyroidism, Mood, and Cognition in the Elderly: A Review

To perform a critical review of the literature on the mood and cognitive changes associated with subclinical hypothyroidism (SCH), with an emphasis on older adults. To evaluate these data against the Consensus Statement on the management of SCH from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society.

Psychiatric aspects of endocrine disorders in women

Endocrine disorders are associated with significant psychiatric morbidity. Psychiatric symptoms may manifest as discreet psychiatric syndromes or, more commonly, with a heterogenous group of nonspecific symptoms. Research is needed to understand the relations between hormone excess or deficiency and alterations of mood, cognition, and perception. It is important for clinicians to carefully screen for psychiatric morbidity in patients who present with endocrine disorders. Moreover, patients who appear to present with primary psychiatric syndromes should be carefully evaluated by physical examination and biochemical screening when appropriate to exclude the presence of an underlying endocrine disorder.

Combined treatments for major depression

Major depression is a chronic disorder with a high morbidity and mortality. Approved treatment for major depression at present includes monotherapy with antidepressants of different pharmacologic classes. There is increasingly widespread use of two other options: augmentation, the addition to an antidepressant of a second compound that is not an antidepressant when used alone; and combination, which is the use of two antidepressants concurrently to enhance or accelerate response. This review focuses on the data available to support these various augmentation and combination treatments.