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Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Elevated glucocorticoids may increase the vulnerability of the brain to the adverse effects of repeated seizures. This study tested the hypothesis that higher ambient cortisol levels would predict increased cognitive impairment in depressed patients subsequent to receiving electroconvulsive therapy (ECT) for major depression., Methods: Sixteen subjects provided three samples of saliva the day before receiving unilateral nondominant ECT. Measures of mood, global cognitive functioning, attention, executive function, verbal and visuospatial memory, and visuospatial processing speed were obtained 1 day before the first ECT and 1 day after the sixth ECT treatment. The relationship between basal salivary cortisol obtained before the first ECT treatment and the change score of each cognitive measure after the sixth ECT treatment was examined and tested with Pearson correlation coefficients., Results: Electroconvulsive therapy treatments delivered over 2 weeks resulted in a significant improvement in mood and a decline in most measures of cognitive performance. Elevated basal cortisol was associated with a greater decline in performance of executive function, visuospatial processing speed, and verbal memory., Conclusions: Although this study is limited by the small number of subjects and the high number of comparisons, all significant correlations were consistent with the hypothesis that elevated cortisol predicts a greater degree of ECT-induced cognitive impairment.

Background and Objectives: Tourette syndrome (TS) is a neuropsychiatric disorder in which the pattern of symptom presentation can vary greatly between individuals. Although globally described, TS has not been well characterized in many parts of the world. Differences in individual and cultural perceptions of TS may impact its expression and recognition in some countries, confounding the identification of affected individuals. This study examines the phenomenology and presentation of TS in Costa Rica., Method: Clinical data on 85 Costa Rican subjects with TS (aged 5-29 years) initially recruited for a genetic study between 1996 and early 2000 were obtained by direct interview and review of medical records., Results: The clinical characteristics of TS were similar to that found elsewhere. The gender ratio was 4.6:1, the mean age of onset was 6.1 years, and 20% of subjects had coprolalia. However, the perceived impact of TS was different. Many subjects denied that their TS caused impairment or distress, even when objective evidence of impairment was available., Conclusions: TS in Costa Rica is phenomenologically similar to TS seen in other parts of the world, but differs in perceived impairment. In other countries where cultural forces affect disease definition, close scrutiny of symptom expression and possible adjustment of phenotype definition may be important.

Background: Estrogen replacement therapy (ERT) may delay dementia-related cognitive decline in post-menopausal women, but few studies have longitudinally examined this relationship and none has controlled for baseline functioning or concurrent medication., Methods: We report the results of a 1-year retrospective longitudinal study examining cognitive functioning in female estrogen and nonestrogen users (n = 3128) who presented to the state of California memory disorder clinics in a naturalistic multisite study of senile dementia, Alzheimer's type (SDAT), and other cognitive impairments., Results: At baseline, estrogen users had significantly lower rates of SDAT diagnoses (possible and probable) than nonestrogen users, and significantly higher rates of the lesser diagnoses of "cognitive impairment" and "no dementia." ERT was significantly associated with higher cognitive functioning at baseline and at 1 year follow-up (n = 358). Nonestrogen users deteriorated significantly from baseline to follow-up; estrogen users did not. Results were similar in groups matched on baseline Blessed-Roth Dementia Rating Scale (BRDRS) ratings (n = 32) and in a variety of subpopulations., Conclusions: These findings are consistent with estrogen acting as a protective factor against cognitive deterioration in post-menopausal women with SDAT and other cognitive impairments, and may suggest an increased effect in earlier stages of cognitive impairment.

Background: Hypercortisolemia is frequently observed in major depression but its pathophysiologic significance is unknown. In patients in whom hypercortisolism contributes to depressive symptomatology, antiglucocorticoid agents should have antidepressant effects., Methods: Twenty medication-free depressed patients (eight of whom were hypercortisolemic and twelve of whom were not) received either the cortisol biosynthesis inhibitor, ketoconazole (400-800 mg/d p.o.) or placebo for 4 weeks in a double-blind manner, and behavioral ratings were performed weekly., Results: Ketoconazole, compared to placebo, was associated with improvements in depression ratings in the hypercortisolemic, but not in the non-hypercortisolemic patients. The hormonal changes seen (decreased dehydroepiandrosterone and testosterone levels and increased pregnenolone and pregnenolone-sulfate levels) are consistent with enzymatic blockade of C17,20-lyase, 11-hydroxylase, and 17-hydroxylase. Ketoconazole was generally well tolerated with no occurrence of significant side effects or laboratory abnormalities., Conclusions: This small-scale double-blind study suggests that antiglucocorticoids have antidepressant activity in hypercortisolemic depressed patients. The data are consistent with a causal role of adrenocortical dysfunction in some depressed patients and suggest the need for larger-scale trials.

In the past year, findings from genetic studies in non-human organisms have yielded a number of exciting insights regarding the genetic basis of complex behaviors. Although there were encouraging developments in the genetic study of human behavioral traits, particularly those involved with cognitive function, there was relatively little progress in genetic mapping of the most common psychiatric phenotypes.

Background: Glucocorticoids have been linked to self-administration of a wide range of drugs in animals and are increased endogenously by chronic nicotine intake. Corticosteroids have also been shown to regulate nicotine receptor sensitivity and to be involved in behavioral sensitization to nicotine., Methods: Cortisol levels and cortisol suppression in response to dexamethasone were measured in a sample of smokers participating in a smoking cessation treatment trial., Results: Cortisol levels dropped significantly during the early quitting process (2 weeks post-quit) and returned to a level below baseline 1 month post-quit. The magnitude of the initial drop in cortisol was strongly related to post-quit distress and marginally predictive of abstinence. Neither baseline nor post-quit changes in percent cortisol suppression after dexamethasone were related to abstinence success or withdrawal distress., Conclusions: Withdrawal from cigarette smoking is marked by a reduction in cortisol levels that appears to be related to the degree of distress experienced during the early quitting period. Further work is needed to determine whether withdrawal-related cortisol changes or distress are predictive of abstinence success.

Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

The authors evaluated magnetic resonance imaging (MRI) of deep white matter hyperintensity (DWMH) in 90 adult psychiatric inpatients in whom MRIs were clinically indicated and 25 age-matched, medically healthy controls. Forty-two percent of the psychiatric patients and 12% of the controls had evidence of DWMH on MRI. Both incidence and severity of DWMH were significantly correlated with age in both groups. Even after controlling for age in the psychiatric population, DWMH was significantly associated with hypertension, history of myocardial infarction or angina, abnormal electrocardiogram, and abnormal neurological examinations.

The effect of intravenous d-amphetamine on memory functions in a group of depressed patients was examined in a double-blind placebo-controlled study. Active drug administration resulted in an increase in verbal free recall but no change in cued recall, suggesting specific effects on memory processes. The level of psychological processing of the presented stimulus was shown to interact with drug-induced facilitation of recall. Improvement in memory of more shallowly processed material under amphetamine related significantly to subjects' base-line indices of noradrenergic function. Drug-induced changes in mood did not correlate with improvement in cognitive functioning. The interrelationships between biochemical determinants of mood and memory are discussed in light of these findings.

The relationship between hypothalamic-pituitary-adrenal (HPA) dysregulation and skin conductance measures of habituation, stimulus specificity, and dishabituation was investigated in psychiatric patients exhibiting depressed affect. As a group, depressed patients showed a relative failure to dishabituate when compared with control subjects. Nonsuppression of cortisol following dexamethasone was associated with decreased response specificity as reflected in direct response measures and baseline skin conductance level. The impairment of response specificity to a novel stimulus is consistent with previous studies demonstrating a role for cortisol in the regulation of selective attention processes.

Animal studies have revealed two important aspects of vasopressin function which make this peptide a suitable candidate for involvement in complex behavioural syndromes: (1) vasopressin deficiency produces deficits of behaviour which are reversed by vasopressin; (2) well-developed systems exist for the distribution of vasopressin throughout the central nervous system (C.N.S.) via either peptidergic neurons or the cerebrospinal fluid (C.S.F.) and provide the means by which vasopressin may regulate cells controlling behavioural or physiological processes. Among the processes which vasopressin can influence are several of significance in the symptom-complex of affective illness, including alterations in memory, changes in pain sensitivity, synchronisation of biological rhythms, the timing and quality of R.E.M. sleep, and the regulation of fluid and electrolyte balance. In addition, vasopressin is functionally linked to monoamine neurotransmitter systems and, like them, is altered by pharmacological agents which affect mood. Some of the pharmacological and clinical data suggest that vasopressin function is diminished in depression and augmented in mania; sometimes, however, alterations in vasopressin function may be detectable only during crucial periods of the manic-depressive cycle. The hypothesis that vasopressin plays a role in disorders of human behaviour, particularly manic-depressive illness, can now be directly tested by radioimmunoassays of vasopressin in C.S.F. and plasma and by the administration of specific vasopressin analogues and inhibitors.

The dexamethasone suppression test (DST) has proven to be of clinical utility in the diagnosticc assessment of patients with primary endogenous depressive illness. Studies comparing individuals who show suppression of plasma cortisol after dexamethasone with those showing nonsuppression have thus far been unable to elicit clinical variables that might differentiate the two groups. Some investigators have suggested as an alternative strategy the usage of the biological variable of interest as the independent rather than the dependent variable. In this study we compared the objective and subjective characteristics of 118 psychiatric inpatients who underwent the DST and were divided on the basis of their response into suppressor and nonsuppressor categories. In the first analysis the diagnostic classification of the patient was not considered. In a secondary analysis the clinical characteristics of only those patients with primary endogenous depression are examined. The data show that independent of diagnosis nonsuppressors are noted to have a greater incidence of subjective complaints. These differences between groups are no longer evident on discharge illustrating a significantly better prognosis for the nonsuppression group.

Male and female Sprague-Dawley rats were tested for turning preferences in a multiple alley maze. The left and right caudate-putamen were dissected and assayed for norepinephrine and dopamine. Dopamine was not found to be lateralized contralateral to turning preference for females as a group. However, dopamine was significantly lateralized contralateral to the females turning preference if a strong turning bias was present. No relationship between dopamine asymmetry and turning preference was evident for males. Females were found to have norepinephrine significantly lateralized to the left caudate-putamen; in males greater striatal norepinephrine levels were equally distributed between left and right sides. This sexual dimorphism in norepinephrine lateralization was not related to turning preference.