Cardiovascular and cerebrovascular risk factors and events associated with second-generation antipsychotic compared to antidepressant use in a non-elderly adult sample: results from a claims-based inception cohort study.

This is a study of the metabolic and distal cardiovascular/cerebrovascular outcomes associated with the use of second-generation antipsychotics (SGAs) compared to antidepressants (ADs) in adults aged 18-65 years, based on data from Thomson Reuters MarketScan® Research Databases 2006-2010, a commercial U.S. claims database. Interventions included clinicians' choice treatment with SGAs (allowing any comedications) versus ADs (not allowing SGAs). The primary outcomes of interest were time to inpatient or outpatient claims for the following diagnoses within one year of SGA or AD discontinuation: hypertension, ischemic and hypertensive heart disease, cerebrovascular disease, diabetes mellitus, hyperlipidemia, and obesity. Secondary outcomes included the same diagnoses at last follow-up time point, i.e., not censoring observations at 365 days after SGA or AD discontinuation. Cox regression models, adjusted for age, gender, diagnosis of schizophrenia and mood disorders, and number of medical comorbidities, were run. Among 284,234 individuals, those within one year of exposure to SGAs versus ADs showed a higher risk of essential hypertension (adjusted hazard ratio, AHR=1.16, 95% CI: 1.12-1.21, p<0.0001), diabetes mellitus (AHR=1.43, CI: 1.33-1.53, p<0.0001), hypertensive heart disease (AHR=1.34, CI: 1.10-1.63, p<0.01), stroke (AHR=1.46, CI: 1.22-1.75, p<0.0001), coronary artery disease (AHR=1.17, CI: 1.05-1.30, p<0.01), and hyperlipidemia (AHR=1.12, CI: 1.07-1.17, p<0.0001). Unrestricted follow-up results were consistent with within one-year post-exposure results. Increased risk for stroke with SGAs has previously only been demonstrated in elderly patients, usually with dementia. This study documents, for the first time, a significantly increased risk for stroke and coronary artery disease in a non-elderly adult sample with SGA use. We also confirm a significant risk for adverse metabolic outcomes. These findings raise concerns about the longer-term safety of SGAs, given their widespread and chronic use.

The significance of an isolated elevated TSH level in a depressed patient: a clinical commentary.

OBJECTIVE: To discuss the approach to the isolated finding of an elevated thyrotropin (TSH) level on routine biochemical screening of a depressed patient. METHOD: A focused literature review as well as discussion of published clinical guidelines and the formulation of a rational clinical approach. RESULTS: Screening for thyroid dysfunction is part of the routine assessment of the depressed patient. It is not uncommon for such patients to have an isolated elevation of TSH levels with nor laboratory or clinical features of thyroid disease. There is often misunderstanding about how to deal with this isolated laboratory finding which can lead to unnecessary investigation and treatment. CONCLUSIONS: A rational approach to evaluation and management of an isolated elevated TSH level is suggested.

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

OBJECTIVES: 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. METHOD: A comprehensive literature review. RESULTS: Subclinical hypothyroidism may be associated with an increased risk of mood and cognitive dysfunction, although the strength of this association and the efficacy of replacement hormone therapy require further investigation. CONCLUSION: It remains unclear whether SCH leads to significant mood and cognitive impairments in most older patients. More research is required to determine the nature and extent of this association and whether thyroid hormone replacement therapy is appropriate and effective in treating SCH-associated neurobehavioral impairments.

Hormone treatment of depression.

There is a well-established relationship between alterations of various hormonal systems and psychiatric disorders, both in endocrine and psychiatric patients. This has led to clinical and research studies examining the efficacy of the different hormones for treatment of depression. These data will be reviewed with particular regard to the thyroid, gonadal, pineal, and adrenal cortex hormones. The data generally provide limited, but varying evidence for the antidepressant efficacy of these hormones.

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.

Basal thyrotropin and major depression: relation to clinical variables and treatment outcome.

OBJECTIVE: There is a current argument in thyroidology about whether the normal range for basal thyrotropin (TSH) is too broad. Some groups suggest that a TSH of less than 2.5 mIU/L is a better cut-off for euthyroidism. Because major depression is associated with changes in thyroid hormone status and thyroid hormones may be an effective treatment for major depression, we examined whether TSH levels above or below 2.5 mIU/L were related to clinical variables or treatment outcome in euthyroid patients with major depression. METHODS: Outpatients with major depression (n =166) were assigned to high-normal and low-normal TSH groups based on their basal TSH levels. The 2 groups were compared along clinical variables and treatment outcome. RESULTS: The low-normal TSH group was significantly more depressed, as measured by Hamilton Depression Rating Scale scores, and had more anxiety symptoms and suicidal tendencies than the high-normal group. There was no difference in treatment response between the groups. CONCLUSIONS: A comparison of low-normal and high-normal basal TSH groups with major depression revealed significant differences in severity and symptoms of depression but no difference in treatment outcome. These data are preliminary and require replication in a larger sample.

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.

Increased rates of obesity in first-presentation adults with mood disorders over the course of four-year follow-up.

BACKGROUND: Patients with mood disorders have higher rates of obesity than the general population. With respect to this, little is known regarding how patient look like prior to treatment or the rates of change. OBJECTIVE: To identify changes in the rates of obesity in never-treated patients with mood disorder over 4 years of follow-up. METHODS: Sixty-six never-treated patients with mood disorders were evaluated via clinical interview, symptom assessment and body mass index (BMI). Patients were followed 4 years. Population attributable risk (PAR%) was calculated. RESULTS: Patients in underweight and normal weight groups fell by nearly 29%, with a corresponding increase in patients entering overweight and obese groups. Rates of PAR% increased to 16.0, a significant 5-point increase over baseline. LIMITATIONS: This study had a small sample size and the population was ethnically homogenous. BMI was used as a maker of weight and not waist circumference. CONCLUSIONS: Over 4 years there was a significant increase in BMI and the risk conferred by obesity. Shift from normal weight to overweight and obese is a significant risk for patients with a mood disorder and clinical programs should consider interventions that might ameliorate risk of this shift early in the course of the illness.

Treatment of clinical hypothyroidism with thyroxine and triiodothyronine: a literature review and metaanalysis.

Thyroxine is the standard replacement therapy for patients with clinical hypothyroidism. However, there has been recent interest in examining the potential advantages of combined thyroxine and triiodothyronine treatment for the treatment of hypothyroidism. The authors review the nine studies to-date and conclude that the variability and limitations in study design make definitive and clinically useful recommendations difficult. They therefore conducted a metaanalysis of the nine controlled studies examining the impact of combined thyroxine-plus-triiodothyronine versus thyroxine alone, with measures of psychiatric symptoms as the primary outcome. Their analysis reveals no significant difference in treatment effect on psychiatric symptoms in the nine controlled studies to date.

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.

Successful computer-assisted cognitive remediation therapy in patients with unipolar depression: a proof of principle study.

BACKGROUND: Despite increasing awareness of the extent and severity of cognitive deficits in major depressive disorder (MDD), trials of cognitive remediation have not been conducted. We conducted a 10-week course of cognitive remediation in patients with long-term MDD to probe whether deficits in four targeted cognitive domains, (i) memory, (ii) attention, (iii) executive functioning and (iv) psychomotor speed, could be improved by this intervention. METHOD: We administered a computerized cognitive retraining package (PSSCogReHab) with demonstrated efficacy to 12 stable patients with recurrent MDD. Twelve matched patients with MDD and a group of healthy control participants were included for comparison; neither comparator group received the intervention that involved stimulation of cognitive functions through targeted, repetitive exercises in each domain. RESULTS: Patients who received cognitive training improved on a range of neuropsychological tests targeting attention, verbal learning and memory, psychomotor speed and executive function. This improvement exceeded that observed over the same time period in a group of matched comparisons. There was no change in depressive symptom scores over the course of the trial, thus improvement in cognitive performance occurred independent of other illness variables. CONCLUSIONS: These results provide preliminary evidence that improvement of cognitive functions through targeted, repetitive exercises is a viable method of cognitive remediation in patients with recurrent MDD.

Lithium and triiodothyronine augmentation of antidepressants.

OBJECTIVE: To evaluate the relative benefits of the combination of lithium and triiodothyronine (T3) in augmentation of antidepressants, compared with either lithium or T3 alone. METHODS: We performed a 2-week, randomized, double-blind, placebo-controlled pilot study of the addition of lithium compared with T3 compared with the combination of both in subjects with major depressive disorder who had not responded to an antidepressant. RESULTS: All groups improved significantly over the 2 weeks of treatment, but there were no significant between-group differences. CONCLUSION: There may be no advantage to a combination of these augmenting agents, although we failed to show separation between active treatments and placebo.

A prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders.

BACKGROUND: There is a recent appreciation that patients with bipolar disorder spend a substantial period of time with minor or subsyndromal mood symptoms both manic and depressive. This study examined time spent in minor and subsyndromal mood states as well as with mania and depression in a cohort of well characterized bipolar I and II patients who were followed prospectively for an average of three years. METHOD: Detailed life-charting data were obtained from 138 patients with bipolar disorder. Mood states were characterized as euthymic, subsyndromal, minor or major affective episodes based on rigorously defined criteria. The amount of time spent in these mood states during follow-up was examined. RESULTS: Patients in the total sample and within each bipolar subtype spent approximately half of their time euthymic. The remainder of the time was spent in varying severity of mood states. However, the majority of time was spent with minor and subsyndromal symptoms, both manic and depressive. Bipolar I patients differ from bipolar II in that significantly more time was spent with subsyndromal, minor and manic symptoms. There was no difference in time spent with depressive symptoms between the two groups. CONCLUSIONS: Patients with bipolar disorder spend a substantial proportion of time with depressive or manic symptoms with the preponderance being minor or subsyndromal. Awareness of subthreshold symptoms in bipolar disorders and treatment of such symptoms may be improved by establishing guidelines that specifically outline appropriate strategies for reducing the duration of subsyndromal symptoms in bipolar disorder.

Does substitution of T4 with T3 plus T4 for T4 replacement improve depressive symptoms in patients with hypothyroidism?

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.