Background:

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA.

Methods:

We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3β (p-GSK3β) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus.

Results:

Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3β, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3β by LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential. Limitations: It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3β and mTOR signalling, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study.

Conclusion:

Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3β and mTOR signalling function in the mPFC.

Background:

Although the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as it is in men, the role of estrogen in the risk for PTSD is not well understood. Deficits in fear inhibition and impaired safety signal learning may be biomarkers for PTSD. We examined menstrual cycle phase and serum estradiol levels in naturally cycling women while they were undergoing a novel conditioned inhibition procedure that measured their ability to discriminate between cues representing danger versus safety and to inhibit fear in the presence of safety cues.

Methods:

Sample 1 included healthy participants in whom we compared inhibition of fearpotentiated startle during the follicular (lower estrogen) and luteal (higher estrogen) phases of the menstrual cycle. We used the same paradigm in a traumatized clinical population (sample 2) in whom we compared low versus high estradiol levels.

Results:

In both samples, we found that lower estrogen in cycling women was associated with impaired fear inhibition. Limitations: In the clinical sample, the low estradiol group was on average older than the high estradiol group owing to the random recruitment approach; we did not exclude participants based on hormonal status or menopause.

Conclusion:

Our results suggest that the lower estrogen state during normal menstrual cycling may contribute to risk for anxiety disorders through dysregulated fear responses.

Background:

Dysfunction in the default mode network (DMN), a group of cortical areas more active during the resting state, has been linked to attentional deficits and symptoms associated with attention-deficit/hyperactivity disorder (ADHD). Prior imaging studies have shown decreased functional connectivity between DMN nodes in patients with ADHD, primarily between anterior and posterior regions. Using magnetoencephalography (MEG), we evaluated phase coherence (i.e., functional connectivity) among regions of the DMN in healthy controls and adults with ADHD before and after stimulant therapy.

Methods:

We obtained a resting-state MEG recording for all participants. Magnetoencephalography data were transformed into a ~30 node regional source model using inverse spatial filtering, including regions corresponding to the DMN. We computed the zero-lag phase coherence between these regions pairwise for 5 distinct frequency bands, and we assessed group and medication effects.

Results:

Twelve adults with and 13 without ADHD participated in our study. Functional connectivity was stronger between particular node pairs and showed frequency-specific effects. Unmedicated patients showed reduced phase locking between posterior cingulate/precuneus regions (PCC) and right inferior parietal cortices (RIPL), and between medial prefrontal regions (MPFC) and the left inferior parietal region (LIPL) and the PCC. Unmedicated patients had increased phase locking between the RIPL and LIPL regions compared with controls. Administration of stimulants improved phase locking abnormalities along the MPFC-PCC and LIPL-RIPL pathways in patients with ADHD. Limitations: Modest sample size and lack of duration of patient treatment history may limit the generalizability of our findings.

Conclusion:

Adults with ADHD exhibit hyper- and hypoconnectivity between regions of the DMN during rest, which were suppressed after stimulant medication administration.

Background:

Psychopathy is a severe personality disorder that has been linked to impaired behavioural adaptation during reinforcement learning. Recent electrophysiological studies have suggested that psychopathy is related to impairments in intentionally using information relevant for adapting behaviour, whereas these impairments remain absent for behaviour relying on automatic use of information. We sought to investigate whether previously found impairments in response reversal in individuals with psychopathy also follow this dichotomy. We expected response reversal to be intact when the automatic use of information was facilitated. In contrast, we expected impaired response reversal when intentional use of information was required.

Methods:

We included offenders with psychopathy and matched healthy controls in 2 experiments with a probabilistic cued go/no-go reaction time task. The task implicated the learning and reversal of 2 predictive contingencies. In experiment 1, participants were not informed about the inclusion of a learning component, thus making cue-dependent learning automatic/ incidental. In experiment 2, the instructions required participants to actively monitor and learn predictive relationships, giving learning a controlled/intentional nature.

Results:

While there were no significant group differences in acquisition learning in either experiment, the results revealed impaired response reversal in offenders with psychopathy when controlled learning was facilitated. Interestingly, this impairment was absent when automatic learning was predominant. Limitations: Possible limitations are the use of a nonforensic control group and of self-report measures for drug use.

Conclusion:

Response reversal deficits in individuals with psychopathy are modulated by the context provided by the instructions, according to the distinction between automatic and controlled processing in these individuals.

Background:

Visual scanning and planning of actions are reported to be abnormal in patients with schizophrenia. Most studies that monitored eye movements in these patients were performed under free-viewing conditions and used 2- dimensional images. However, images differ from the natural world in several ways, including task demands and the dimensionality of the display. Our study was designed to assess whether abnormalities in visual exploration in patients with schizophrenia generalize to active-viewing tasks in realistic conditions of viewing and to examine whether disturbances in action sequencing in these patients are reflected in their visual scanning patterns while executing natural tasks.

Methods:

We monitored visual scan paths in patients with schizophrenia and healthy controls. Participants performed several tasks in which they were asked to look at a realistic scene on a table (free-viewing) and perform 2 active-viewing tasks: a familiar task (sandwich-making) and an unfamiliar task (model-building). The scenes contained both task-relevant and task-irrelevant objects.

Results:

We included 15 patients and 15 controls in our analysis. Patients exhibited abnormalities in the free-viewing condition. Their patterns of exploration were similar to those of controls in the familiar task, but they showed scanning differences in the unfamiliar task. Patients were also slower than controls to accomplish both tasks. Limitations: Patients with schizophrenia were taking antipsychotic medications, so the presence of medication effects cannot be excluded.

Conclusion:

People with schizophrenia present a basic psychomotor slowing and seem to establish a less efficient planning strategy in the case of more complex and unfamiliar tasks.

Background:

Endophenotypes in genetic psychiatry may increase our understanding of the molecular mechanisms underlying disease risk and its manifestations. We sought to investigate the link between neuropsychological impairments and brain structural abnormalities associated with the COMT Val158Met polymorphism in patients with schizophrenia to improve understanding of the pathophysiology of this disorder.

Methods:

We performed a systematic review using studies identified in PubMed and MEDLINE (from the date of the first available article to July 2012). Our review examined evidence of an association between the COMT Val(158)Met polymorphism and both neuro psychological performance and brain structure in patients with psychosis, in their relatives and in healthy individuals (step 1). The review also explored whether the neuropsychological tasks and brain structures identified in step 1 met the criteria for an endophenotype (step 2). Then we evaluated evidence that the neuropsychological endophenotypes identified in step 2 are associated with the brain structure endophenotypes identified in that step (step 3). Finally, we propose a neurobiological interpretation for this evidence.

Results:

A poorer performance on the n-back task and the Continuous Performance Test (CPT) and smaller temporal and frontal brain areas were associated with the COMT Val allele in patients with schizophrenia and their relatives and met most of the criteria for an endopheno type. It is possible that the COMT Val(158)Met polymorphism therefore contributes to the development of these neuropsychological and brain structural endophenotypes of schizophrenia, in which the prefrontal cortex may represent the neural substrate underlying both n-back and CPT performances. Limitations: The association between a single genetic variant and an endophenotype does not necessarily imply a causal relationship between them.

Conclusion:

This evidence and the proposed interpretation contribute to explain, at least in part, the biological substrate of 4 important endophenotypes that characterize schizophrenia.

Background:

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is reported to be a safe and effective new treatment for treatment-resistant depression (TRD). However, the optimal electrical stimulation parameters are unknown and generally selected by trial and error. This pilot study investigated the relationship between stimulus parameters and clinical effects in SCC-DBS treatment for TRD.

Methods:

Four patients with TRD underwent SCC-DBS surgery. In a double-blind stimulus optimization phase, frequency and pulse widths were randomly altered weekly, and corresponding changes in mood and depression were evaluated using a visual analogue scale (VAS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17). In the open-label postoptimization phase, depressive symptoms were evaluated biweekly for 6 months to determine long-term clinical outcomes.

Results:

Longer pulse widths (270-450 µs) were associated with reductions in HAM-D-17 scores in 3 patients and maximal happy mood VAS responses in all 4 patients. Only 1 patient showed acute clinical or mood effects from changing the stimulation frequency. After 6 months of open-label therapy, 2 patients responded and 1 patient partially responded. Limitations: Limitations include small sample size, weekly changes in stimu lus parameters, and fixed-order and carry-forward effects.

Conclusion:

Longer pulse width stimulation may have a role in stimulus optimization for SCC-DBS in TRD. Longer pulse durations produce larger apparent current spread, suggesting that we do not yet know the optimal target or stimulus parameters for this therapy. Investigations using different stimulus parameters are required before embarking on large-scale randomized sham-controlled trials.

The acute tryptophan depletion (ATD) technique has been used extensively to study the effect of low serotonin in the human brain. This review assesses the validity of a number of published criticisms of the technique and a number of previously unpublished potential criticisms. The conclusion is that ATD can provide useful information when results are assessed in conjunction with results obtained using other techniques. The best-established conclusion is that low serotonin function after tryptophan depletion lowers mood in some people. However, this does not mean that other variables, altered after tryptophan depletion, are necessarily related to low serotonin. Each aspect of brain function has to be assessed separately. Furthermore, a negative tryptophan depletion study does not mean that low serotonin cannot influence the variable studied. This review suggests gaps in knowledge that need to be filled and guidelines for carrying out ATD studies.