Interferon-α induces negative biases in emotional processing in patients with hepatitis C virus infection: a preliminary study.

BACKGROUND: Treatment of medical patients with the inflammatory cytokine, interferon-α (IFN-α), is frequently associated with the development of clinical depressive symptomatology. Several important biological correlates of the effect of IFN-α on mood have been described, but the neuropsychological changes associated with IFN-α treatment are largely unexplored. The aim of the present preliminary study was to assess the effect of IFN-α on measures of emotional processing. METHOD: We measured changes in emotional processing over 6-8 weeks in 17 patients receiving IFN-α as part of their treatment for hepatitis C virus infection. Emotional processing tasks included those which have previously been shown to be sensitive to the effects of depression and antidepressant treatment, namely facial expression recognition, emotional categorisation and the dot probe attentional task. RESULTS: Following IFN-α, patients were more accurate at detecting facial expressions of disgust; they also showed diminished attentional vigilance to happy faces. IFN-α produced the expected increases in scores on depression rating scales, but there was no correlation between these scores and the changes in emotional processing. CONCLUSIONS: Our preliminary findings suggest that IFN-α treatment produces negative biases in emotional processing, and this effect is not simply a consequence of depression. It is possible that increased recognition of disgust may represent a neuropsychological marker of depressive disorders related to inflammation.

Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression.

Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.

Effect of interferon-α on cortical glutamate in patients with hepatitis C: a proton magnetic resonance spectroscopy study.

BACKGROUND: The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-α (IFN-α) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-α and ribavirin. METHOD: MRS measurements of glutamate and glutamine were taken from a 25 × 20 × 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks of treatment with IFN. RESULTS: IFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. CONCLUSIONS: We conclude that treatment with IFN-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally.

When less is more: a functional magnetic resonance imaging study of verbal working memory in remitted depressed patients.

BACKGROUND: Patients with depression show abnormalities in the neural circuitry supporting working memory. However, it is unclear if these abnormalities are present in unmedicated remitted depressed patients. To address this question, the current study employed functional magnetic resonance imaging (fMRI), in combination with a simple verbal n-back task, in a cohort of unmedicated remitted depressed patients. METHOD: We studied 15 healthy control subjects (HC) and 15 unmedicated remitted depressed patients (rMDD). Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing fMRI. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back versus 0-back) as well as quadratic modulation of cognitive demand. RESULTS: Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, rMDD showed a positive quadratic load response in the bilateral hippocampus; the converse was true for HC. CONCLUSIONS: Our data suggest that remitted depression was associated with a perturbed pattern of activation in the bilateral hippocampus during a verbal working memory task. We propose that a reduced ability to dampen task-irrelevant activity may reflect a neurobiological risk factor for recurrent depression.

The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis.

The 5-HTTLPR polymorphism has been widely regarded as a potential genetic risk factor for affective disorders. Consistent with this, this polymorphism has been associated with altered amygdala responses at rest and in response to aversive stimuli. However, the strength of this association remains uncertain. We sought to synthesize existing data on the association between the 5-HTTLPR polymorphism and amygdala activation and ascertain the strength of evidence for this association. Meta-analytic techniques were applied to data from relevant published studies and unpublished data sets to obtain an estimate of the likely magnitude of effect of any association. The large number of studies allowed us to apply a formal test of publication bias, as well as explore the impact of various study-level characteristics on the magnitude of the observed effect size. Our meta-analysis indicated that there is a statistically significant but small effect of 5-HTTLPR on left and right amygdala activity. However, there was considerable between-study heterogeneity, which could not be fully accounted for by the study design and sample characteristics that we investigated. In addition, there was evidence of excess statistical significance among published studies. These findings indicate that the association between the 5-HTTLPR and amygdala activation is smaller than originally thought, and that the majority of previous studies have been considerably under powered to reliably demonstrate an effect of this size.

Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients.

BACKGROUND: Antidepressant drugs such as selective serotonin re-uptake inhibitors (SSRIs) remediate negative biases in emotional processing in depressed patients in both behavioural and neural outcome measures. However, it is not clear if these effects occur before, or as a consequence of, changes in clinical state. METHOD: In the present study, we investigated the effects of short-term SSRI treatment in depressed patients on the neural response to fearful faces prior to clinical improvement in mood. Altogether, 42 unmedicated depressed patients received SSRI treatment (10 mg escitalopram daily) or placebo in a randomised, parallel-group design. The neural response to fearful and happy faces was measured on day 7 of treatment using functional magnetic resonance imaging. A group of healthy controls was imaged in the same way. RESULTS: Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls. However, this response was normalised in patients receiving 7 days treatment with escitalopram. There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo-treated patients. CONCLUSIONS: Our results suggest that short-term SSRI treatment in depressed patients remediates amygdala hyperactivity in response to negative emotional stimuli prior to clinical improvement in depressed mood. This supports the hypothesis that the clinical effects of antidepressant treatment may be mediated in part through early changes in emotional processing. Further studies will be needed to show if these early effects of antidepressant medication predict eventual clinical outcome.

Olanzapine-induced weight gain is associated with the -759C/T and -697G/C polymorphisms of the HTR2C gene.

Weight gain, a serious problem associated with some antipsychotic drugs, notably olanzapine and clozapine, was suggested to be associated with -759C/T polymorphism of the 5-HT2C receptor gene. This study aimed to examine a potential association of two functional polymorphisms of the promoter region of this gene: -759C/T (rs3813929) and -697G/C (rs518147), with weight gain after 6 weeks of olanzapine monotherapy. It included 107 patients with schizophrenia; among them 36 are first-episode drug-naive patients. Analysis was carried out by PCR-restriction fragment length polymorphism. A protective effect of -759T and -697C alleles was found: significantly less patients with -697C (3/51) and no patient with -759T (0/28) alleles experienced body mass index increase >or=10% (P=0.0006 and 0.002, respectively). The same was true for drug-naive patients possessing any of the variant alleles. There was a significant association of haplotypes with a >or=10% body mass index increase (P=0.001). On the basis of the additional statistical analysis, the more important role of -697C allele was suggested.

Determination of cobalt in blood using cathodic stripping voltammetry.

A method was developed to determine low levels of cobalt in whole blood, serum and plasma. Samples of blood (0.2 ml) were mineralized at 160 degrees C in the presence of concentrated nitric acid. Residual organic matter was destroyed by digestion using ultraviolet irradiation after dilution with water. The cobalt concentration was determined by catalytic cathodic stripping voltammetry (CSV) preceded by adsorptive collection of cobalt complexed with diphenylglyoxime (DPG). The optimized analytical conditions for the CSV analysis included a DPG concentration of 0.5 mumol l-1, 0.05 mol l-1 ammonium chloride buffer (pH 9.3), 0.15 mol l-1 nitrite, a deposition potential of -0.75 V, an adsorption time of 30-120 s and a negative potential scan using the differential-pulse modulation. The limit of detection was 40 pg of cobalt in 0.2 ml of blood, which was limited by the blank level of cobalt in the reagents after purification.

Mycotoxins in cereal grain. Part 5. Changes of cereal grain biological value after ammoniation and mycotoxins (ochratoxins) inactivation.

Ammoniation was proved to be a suitable detoxification procedure to remove toxicity of Aspergillus ochraceus mycotoxins (mainly ochratoxin A) from contaminated cereal grain (corn, wheat and barley). It was found that ammoniation should be performed to achieve decomposition of ochratoxin A to nondetectable level. Ammoniated grain can be used as feedstuff component without essential change of nutritive value during ammoniation.

Mycotoxins in cereal grain. Part III. Production of ochratoxin A in different varieties of wheat, rye and barley.

Kernels of several varieties of wheat, rye and barley were found to have different resistance to fungi attack and ochratoxin A production, particularly in first step of fungus development on kernels. Zinc was stated to be a limiting factor of ochratoxin production. viable sound kernels were very resistant against fungi. Dead (e.g. autoclaved) kernels were attacked by fungus very quickly. Varieties with stronger resistance to fungi invasion during storage were selected.

Mycotoxins in cereal grain. Part IV. Inactivation of ochratoxin A and other mycotoxins during ammoniation.

Addition of ammonia to final concentration 2% inactivates ochratoxin A, aflatoxin, citrinin, penicillic acid and partially zearalenon at temperature 20-50 degrees C. Detoxification of contaminated cereal grain (wheat, corn or barley) can be performed on a farm using ammoniation without special investment during 4 to 6 weeks. Ammoniation changes nutritional value of grain as feed in a small extent.

Mycotoxins in cereal grain. Part I. Ochratoxin, citrinin, sterigmatocystin, penicillic acid and toxigenic fungi in cereal grain.

Contamination with ochratoxin A mainly and also with citrinin, penicillic acid and sterigmatocystin was observed in moldy cereal grain samples (wheat, rye, and barley), during 1975-1978 years. The levels of cereal grain contamination in various years were very different. However usually during two months after harvest percentage of contaminated samples was 5-7% and ochratoxin A content not higher than 140 microgram/kg. During storage of grain with high moisture content slow increase of contamination level was observed-particularly during January and February - to level 1-3 mg/kg. Cereal grain from commercial channels was contaminated with fungi spores sometimes up to 10(9) spores per gram. Aspergillus and Penicillium were predominating species. Between 69 fungi isolates typical for barley kernels 13 were procedures of ochratoxin, sterigmatocystin, penicillic acid and F-2 toxin. Results for wheat and rye will be published later.