B. Godlewska

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.

Neurochemistry of major depression: a study using magnetic resonance spectroscopy

RationaleMagnetic resonance spectroscopy (MRS) is an acceptable non-invasive means of studying brain neurochemistry in depression. Previous studies in depressed patients have focused on measurement of the amino acid neurotransmitters, γ-aminobutyric acid (GABA) and glutamate.ObjectivesThe aim of this study is to use MRS in conjunction with the ultrashort echo time ‘SPECIAL’ technique to measure cortical levels of GABA, glutamate and glutathione (GSH) levels in unmedicated patients with major depression. We also examined the effect of 6-week treatment with the selective serotonin re-uptake inhibitor, escitalopram.MethodsWe studied patients with DSM-IV major depression and healthy age-matched controls using proton MRS. GABA, glutamate and GSH were measured relative to creatine in a voxel placed in occipital cortex.ResultsThere was no difference in GABA or glutamate levels between depressed participants and controls; however, depressed patients had lower GSH levels. Six-week escitalopram treatment, which resulted in significant clinical responses in some patients, did not alter concentrations of GABA, glutamate or GSH.ConclusionsThe sources of variability of GABA and glutamate measures in different studies of depressed patients require further study. Our results suggest that concomitant treatment with selective serotonin re-uptake inhibitors (SSRIs) is unlikely to be an important confounding factor. If lowered GSH levels can be confirmed, they may represent the presence of oxidative stress in some depressed patients.

Cortical glutathione levels in young people with bipolar disorder: a pilot study using magnetic resonance spectroscopy.

RationaleGlutathione (GSH) is a key scavenger for cellular free radicals, and patients with bipolar disorder may have lowered GSH levels in plasma and in post-mortem brain tissue.ObjectivesThe objective of the current study was to use magnetic resonance spectroscopy (MRS) to measure cortical GSH levels in young people with bipolar disorder to determine if lowered GSH might be a useful biomarker of vulnerability to the illness.MethodsWe studied 13 patients with DSM-IV bipolar disorder and 11 healthy age-matched controls using proton MRS in conjunction with the SPECIAL acquisition technique. Voxels were placed in prefrontal and occipital cortex. All patients were clinically euthymic at the time of study and unmedicated. GSH and other relevant neurometabolites were measured relative to creatinine.ResultsThere was no difference in GSH levels between bipolar participants and controls in either prefrontal or occipital cortex. Similarly, participants showed no difference from controls in other measured cortical metabolites including γ-aminobutyric acid, glutamate and N-acetylaspartate.ConclusionsThis pilot study suggests that levels of cortical GSH are unlikely to be a useful trait biomarker of bipolar disorder in young people with a history of relatively mild mood instability at an early stage of illness. Lowered GSH levels may be relevant to bipolar pathophysiology in more severely ill patients, particular those with significant current mood disturbance.

Early increase in marker of neuronal integrity with antidepressant treatment of major depression: 1H-magnetic resonance spectroscopy of N-acetyl-aspartate.

Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time-course of any effect on neuronal integrity is unclear. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on N-acetyl-aspartate (NAA), a marker of neuronal integrity. Thirty-nine participants with major depression were randomly assigned to receive either 10 mg escitalopram or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30×30×20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were significantly higher in patients treated with escitalopram than in either placebo-treated patients (p<0.01) or healthy controls (p<0.01). Our findings are consistent with the proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity.

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.

Polymorphisms of the histamine receptor (H1HR) gene are not associated with olanzapine-induced weight gain.

To the Editors: W eight gain is an important adverse effect of many atypical antipsychotics (most pronounced with clozapine and olanzapine) with a negative impact on both somatic health and subjective quality of life. Because it occurs in many but not all patients, and to a different degree in individuals, genetic predisposition has been suggested as a plausible underlying mechanism. Most studies to date have focused on genes relevant to the proposed mechanisms of action of antipsychotics (eg, D3 receptor gene) or to obesity (eg, leptin gene). The most consistent positive findings regard the role of the j759C/T variant of the HTR2C (2C serotonin receptor) gene. Another plausible candidate is the histamine H1 receptor (H1HR) gene. A number of studies have linked it with weight gain, showing, for example, a significant correlation between affinity of antipsychotics for H1HR and weight increase (2 meta-analyses),an increase in food intake, and obesity afterH1HR gene knockout in mice and an H1HR antagonist-induced increase and an agonist-induced suppression of food intake associated with a decrease in the receptor’s hypothalamic expression. This down-regulation in H1HR could lead to an increase in histamine levels. Interestingly, histamine may stimulate corticotropin-releasing hormone and activate the hypothalamic-pituitary-adrenal axis, both of which were shown to increase food intake. Although genetic variants of the H1HR gene have been described, genetic studies targeting H1HR gene polymorphisms are scarce. The present study aimed to assess an association between 5 polymorphisms in the coding region (Lys19Asn-rs2067466, Asp349Glu-rs2067467, Phe358

EFFECT OF INTERFERON-α ON CORTICAL GLUTAMATE IN PATIENTS WITH HEPATITIS C: A PROTON MRS STUDY

-rs2067469, A1068G-rs2067468, andLeu449Ser-rs2067470) and a polymorphism in the promoter (C-17TY rs901865) of the H1HR gene and weight gain after 6 weeks of monotherapy with olanzapine. Ninety healthy subjects were genotyped to control for differences in allelic distribution between the groups. The study included 90 patients with schizophrenia and 90 sexand age-matched healthy individuals. Patients (44 women) with the diagnosis of paranoid schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, were inpatients of the Department of Psychiatry of the Medical University of Lublin. All patients were of white (Polish) background. Exclusion criteria were comorbid mental disorder, somatic illness, addiction, concomitant treatment with psychiatric medications other than benzodiazepines, a history of atypical antipsychotics treatment, or resistance to drugs. All patients were on the same hospital diet (exact caloric intake was impossible to establish because families were allowed to bring in food, sweets, etc) and had a comparable exercise level (all patients were in the ward and some took part in offered exercises such as walks or gym classes but not to the extent that it would allow weight loss). Among 90 patients, 61 had a history of multiple episodes and treatment with typical but not atypical antipsychotics (switch to olanzapine mainly because of adverse effects); 29 were drug-naive first-episode patients (mean [SD] age, 23.9 [4.7] years). All patients and healthy controls gave written consent to the study. All the procedures were approved by the local ethical committee. Patients were treated with 20 to 25 mg/d of olanzapine in monotherapy (titrated up from 10 mg daily)Vonly benzodiazepines were permitted in the first 2 weeks of the treatment. Weight was measured on the first and 42nd day of the treatment. The coding region polymorphisms were analyzed by polymerase chain reactionrestriction fragment length polymorphism method using primers and protocols described by Mancama et al; the H1-17C/T polymorphism was analyzed by polymerase chain reaction-single strand conformation polymorphism using the customized method (Supplementary Table A, Supplemental Digital Content 1, http://links.lww.com/JCP/A176). All samples were genotyped twice. Distribution of genotypes was assessed using W test. Stepwise regression analysis and 1-way analysis of variance were performed to assess the influence of baseline variables on body mass index (BMI) change. One-way analysis of variance and independent-samples t tests were used to assess the association between polymorphisms and BMI change. A 2-tailed P value of less than 0.05 was considered significant. All analyses were performed using SPSS 16.0 (SPSS Inc, Chicago, IL). At baseline, mean (SD) age was 29.1 (9.7) years (women, 31.7 [11.8]; men, 26.7 [6.9]); mean (SD) age at onset, 23.5 (6.3) years; mean (SD) preolanzapine treatment duration, 5.3 (6.8) years; mean (SD) positive and negative syndrome scale (PANSS) score at baseline 103.80 (15.9); mean (SD) weight, 69.6 (14.4) kg; and mean (SD) BMI, 23.6 (4.5) kg/m. The polymorphisms were in the HardyWeinberg equilibrium (P 9 0.05). Stepwise regression analysis showed that only baseline BMI and baseline total PANSS score had a significant effect on BMI change (P = 0.001, A = j0.338 and P = 0.018, A = j0.239, respectively), and the influence of sex, age, age at onset, and duration of preolanzapine antipsychotic treatment were excluded. The H1-17C/T variant was the only polymorphism with minor allele frequency high enough to allow statistical analysis (alleles: T 0.16, C 0.84; genotypes: CC 0.71, CT 0.26, TT 0.03); the frequencies of minor alleles of other single-nucleotide polymorphism were considered too low: 0.016 for the 358

Effect of interferon-α on cortical glutamate in patients with chronic hepatitis C

allele of the Phe358

S.07.03 Short-term SSRI treatment remediates amygdala hyperactivity in depressed patients

polymorphism (3 Phe358/Phe358

Decreased neural response to fear after a short-term SSRI treatment: a 3T functional magnetic resonance imaging study

subjects, no Phe358