Aybala Saricicek

GABAergic Contributions to the Pathophysiology of Depression and the Mechanism of Antidepressant Action

Increasing evidence suggests that abnormalities in amino neurotransmission are associated with the neurobiology of depression. Preclinical studies demonstrate that GABA modulating agents are active in commonly used rodent behavioral models of antidepressant activity, and that chronic administration of antidepressant drugs induces marked changes in GABAergic function. In humans, depressed patients have lower plasma, CSF and brain GABA concentrations than non-depressed comparison subjects. The recent discovery that several anticonvulsant and GABA-mimetic agents possess mood stabilizing and antidepressant properties has further increased interest in these findings. This review outlines the existing literature investigating the possible involvement of GABA in the neurobiology of depression and briefly highlights how this information may afford new targets for antidepressant drug development.

Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder

BACKGROUND Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subjects. METHOD The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of β2*-nAChRs was quantified as VT/fP. Postmortem analysis of β2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects. RESULTS The β2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, β2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in β2*-nAChR number between groups in the postmortem study. CONCLUSIONS Depressed patients have lower β2*-nAChR availability than do healthy subjects. The difference between β2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.

Abnormal prefrontal activity subserving attentional control of emotion in remitted depressed patients during a working memory task with emotional distracters.

BACKGROUND Patients with major depressive disorder (MDD) show deficits in processing of facial emotions that persist beyond recovery and cessation of treatment. Abnormalities in neural areas supporting attentional control and emotion processing in remitted depressed (rMDD) patients suggests that there may be enduring, trait-like abnormalities in key neural circuits at the interface of cognition and emotion, but this issue has not been studied systematically. METHOD Nineteen euthymic, medication-free rMDD patients (mean age 33.6 years; mean duration of illness 34 months) and 20 age- and gender-matched healthy controls (HC; mean age 35.8 years) performed the Emotional Face N-Back (EFNBACK) task, a working memory task with emotional distracter stimuli. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure neural activity in the dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), orbitofrontal cortex (OFC), ventral striatum and amygdala, using a region of interest (ROI) approach in SPM2. RESULTS rMDD patients exhibited significantly greater activity relative to HC in the left DLPFC [Brodmann area (BA) 9/46] in response to negative emotional distracters during high working memory load. By contrast, rMDD patients exhibited significantly lower activity in the right DLPFC and left VLPFC compared to HC in response to positive emotional distracters during high working memory load. These effects occurred during accurate task performance. CONCLUSIONS Remitted depressed patients may continue to exhibit attentional biases toward negative emotional information, reflected by greater recruitment of prefrontal regions implicated in attentional control in the context of negative emotional information.

Enhanced Visual Motion Perception in Major Depressive Disorder

Major depressive disorder (MDD) is a mood disorder that is not traditionally considered to affect the visual system. However, recent findings have reported decreased cortical levels of the inhibitory neurotransmitter GABA in occipital cortex. To explore possible functional consequences of MDD on visual processing, we applied a psychophysical visual motion processing task in which healthy young adults typically exhibit impaired perceptual discrimination of large high-contrast stimuli. It has been suggested that this phenomenon, spatial suppression, is mediated by GABAergic center–surround antagonism in visual pathways. Based on previous findings linking MDD to occipital GABA dysfunction, we hypothesized that MDD patients would exhibit decreased spatial suppression, leading to the counterintuitive hypothesis of better psychophysical performance. Indeed, motion perception for typically suppressed stimuli was enhanced in patients with MDD compared with age-matched controls. Furthermore, the degree of spatial suppression correlated with an individuals illness load; patients with greater lifetime duration of depression exhibited the least spatial suppression and performed the best in the high-contrast motion discrimination task. Notably, this decrease in spatial suppression persisted beyond recovery and without the confound of acute illness or treatment; all patients had been clinically recovered and unmedicated for several months at the time of testing, suggesting that depression has ubiquitous consequences that may persist long after mood symptoms have receded. This finding raises the possibility that spatial suppression may represent a sensitive endophenotypic marker of trait vulnerability in MDD.

Levetiracetam in the Management of Bipolar Depression: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To study the efficacy of adjunctive levetiracetam therapy compared with placebo in the treatment of subjects with depression with bipolar disorder. METHOD This double-blind, placebo-controlled clinical trial randomly assigned outpatients with bipolar disorder type I and type II who were experiencing a major depressive episode (Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version criteria) to treatment with either placebo or adjunctive levetiracetam (up to 2,500 mg/d flexibly dosed) for 6 weeks. The subjects were recruited from October 2005 to June 2008. The primary efficacy measure was mean change from baseline to week 6 in the Hamilton Depression Rating Scale (21-item). Secondary efficacy assessments included the Montgomery-Åsberg Depression Rating Scale, the Beck Depression Inventory, the Clinical Global Impressions-Bipolar Version scale, the Hamilton Anxiety Rating Scale, and the Young Mania Rating Scale. RESULTS Of 42 subjects randomly assigned to placebo or drug, 32 received at least 1 postbaseline assessment and thus were included in the analysis. The mean (SD) levetiracetam daily dose at endpoint evaluation was 1,132 (425) mg/d. There was no significant difference in the mean change from baseline to week 6 in the Hamilton Depression Rating Scale scores for levetiracetam compared with placebo. There were no significant differences in any of the secondary outcome measures. CONCLUSIONS Levetiracetam adjunctive therapy was not superior to placebo in the short-term treatment of subjects with depression with bipolar disorder in the population studied. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00566150.

Facial emotion recognition deficits in abstinent cannabis dependent patients

BACKGROUND Cannabis is clearly the most popular illicit drug in North America, Europe and in other parts of the world. Evidence is accumulating for the involvement of the endocannabinoid system in emotional processing. However, only few studies examined emotional processing in chronic, heavy cannabis users and these studies were performed in cannabis dependent patients who were abstinent for 12-48 hours. The aim of this study was to investigate facial emotion identification and discrimination abilities in patients with cannabis dependence who were abstinent for at least 1 month. METHODS The study included 30 males with cannabis dependency according to DSM-IV criteria and who had been abstinent for at least 1 month and 30 healthy controls. All the subjects were evaluated with Facial Emotion Identification Test (FEIT) and Facial Emotion Discrimination Test (FEDT). RESULTS The main finding of this study was the presence of deficits in both identification and discrimination of facial emotions in cannabis dependent patients during abstinence. In addition, when we examined negative and positive emotions separately, we found out that abstinent cannabis dependent patients performed significantly worse than controls in the identification of negative emotions but not positive emotions. CONCLUSIONS Our findings indicate that facial emotion recognition deficits which have previously been observed in current cannabis users are still detectable in abstinent cannabis dependent patients and do not improve quickly with abstinence (an average of 3.2 months).

Abnormal white matter integrity in long-term abstinent alcohol dependent patients

A number of diffusion tensor imaging (DTI) studies have reported substantial white matter (WM) abnormalities in alcohol-dependent patients. These studies were usually performed in recovering alcohol-dependent patients who had been abstinent for days to several weeks. The current study was designed to examine WM microstructure and decision-making in a sample of long-term abstinent alcohol-dependent patients. The study included 12 subjects with alcohol dependence who had been abstinent for at least 6 months before testing and scanning and 13 healthy control subjects. The Iowa Gambling Task (IGT) was used to measure decision-making. We found that the long-term abstinent alcohol-dependent group had significantly higher radial and axial diffusivity (RD and AD, respectively) values in frontal, temporal and parietal WM than was found in the healthy control group despite showing no difference in fractional anisotropy (FA) values in comparison to controls. In conclusion, we found widespread WM changes in long-term abstinent alcohol-dependent patients compared with healthy controls. Our findings suggested that AD and RD should be included in analyses of DTI data in addition to the more commonly studied FA. In the current study, FA values of the detoxified alcoholics had recovered and were comparable to those of the controls, whereas significant changes in AD and RD were still observed in some clusters in the frontal, parietal and temporal lobes of detoxified alcoholics even after 27.8 months.

Rich club and reward network connectivity as endophenotypes for alcohol dependence: a diffusion tensor imaging study: Endophenotype for alcoholism

We aimed to examine the whole‐brain white matter connectivity and local topology of reward system nodes in patients with alcohol use disorder (AUD) and unaffected siblings, relative to healthy comparison individuals. Diffusion‐weighted magnetic resonance imaging scans were acquired from 18 patients with AUD, 15 unaffected siblings of AUD patients and 15 healthy controls. Structural networks were examined using network‐based statistic and connectomic analysis. Connectomic analysis showed a significant ordered difference in normalized rich club organization (AUD < Siblings < Controls). We also found rank ordered differences (Control > Sibling > AUD) for both nodal clustering coefficient and nodal local efficiency in reward system nodes, particularly left caudate, right putamen and left hippocampus. Network‐based statistic analyses showed that AUD group had significantly weaker connectivity than controls in the right hemisphere, mostly in the edges connecting putamen and hippocampus with other brain regions. Our results suggest that reward system network abnormalities, especially in subcortical structures, and impairments in rich‐club organization might be related to the familial predisposition for AUD.