Is the antidepressant effect of ketamine separate from its psychotomimetic effect? A review of rodent models.

Ketamine is an NMDA (N-methyl-d-aspartate) glutamate receptor antagonist, which has a myriad of dose-dependent pharmacological and behavioral effects, including anesthetic, sedative, amnestic, analgesic, and anti-inflammatory properties. Intriguingly, ketamine at subanesthetic doses displays a relevant profile both in mimicking symptoms of schizophrenia and also as the first fast-acting treatment for depression. Here, we present an overview of the state-of-the-art knowledge about ketamine as an antidepressant as well as a pharmacological model of schizophrenia in animal models and human participants. Ketamine's dual effect appears to arise from its mechanism of action involving NMDA receptors, with both immediate and downstream consequences being triggered as a result. Finally, we discuss the feasibility of a unified approach linking the glutamatergic hypothesis of schizophrenia to the promising preclinical and clinical success of ketamine in the treatment of refractory depression.

Stage-dependent sensitivity to Müller-Lyer visual illusion in schizophrenia patients.

RATIONALE: Schizophrenic patients show perceptual deficits, which may be detected in visual illusion tasks. Previous studies found that chronic patients show increased sensitivity to Müller-Lyer illusion as the disorder progresses, although there are a few conflicting reports in the scientific literature. To address these issues, moderate and chronic schizophrenic patients were tested on the Brentano version of the Müller-Lyer illusion task. Their performance was compared to first-degree relatives and unrelated matched controls. Chronic patients showed increased susceptibility to the illusion. Performance on the visual illusion task was not correlated to the number of years since disease onset, medication or (Positive and Negative Syndrome Scale) PANSS scores. The lack of association between illusion sensitivity and PANSS score may reflect the absence of the perceptual dimension in this scale. Based on these results, we suggest that susceptibility to the Müller-Lyer illusion is associated with the stage of schizophrenia rather than disease length.

MK-801 reduces sensitivity to Müller-Lyer's illusion in capuchin monkeys.

The Müller-Lyer's illusion (MLI) is a visual illusion in which the presence of contextual cues (i.e., the orientation of arrowheads) changes the perception of the length of straight lines. An altered sensitivity to the MLI has been proposed as a marker for the progression of perceptual deficits in schizophrenia. Since dizocilpine (MK-801), a noncompetitive antagonist of the NMDA glutamate receptor, induces schizophrenic-like sensory impairments, it may have potential value for investigating the neurochemical basis of the perceptual changes in schizophrenia. Here we tested the effects of MK-801 on the perception of the MLI in a nonhuman primate. Five capuchin monkeys Sapajus spp. were trained on a MLI task using a touch screen monitor. After training, the Point of Subjective Equality (PSE; i.e., the minimum difference in length between two lines which the subject can distinguish) was determined for each subject. Then, during 12 consecutive days, we evaluated changes in PSE in response to vehicle, MK-801 (5.6µg/kg, i.m.) and a no-treatment protocol (post- test). Each of these was given as a single daily treatment, on four consecutive days. Results showed that MK-801 increased the monkeys' performance in the MLI task, suggesting that NMDA receptor modulation reduces sensitivity to this illusion, similar to prodromal stage in schizophrenia patients. The MLI protocol may thus be used in nonhuman primates to screen potential antipsychotic drugs for early stages of this disease.

Sex differences in cardiac autonomic function of depressed young adults.

BACKGROUND: Cardiac autonomic dysfunction has been proposed as an important contributing factor to the increased cardiovascular risk observed in major depression (MDD). However, the evidence regarding alterations in heart rate variability (HRV) in otherwise healthy depressed subjects has been inconclusive. METHODS: A case-control study in 50 treatment-naïve young adults with a first MDD episode without comorbid psychiatric disorders and 50 healthy control subjects was conducted. Time- and frequency-domain indexes of HRV were determined at baseline supine and after 5-min of orthostatic stress at 60°. RESULTS: There were no significant differences in the time- or frequency-domain variables of HRV between depressed patients and controls. However, a random-effect ANOVA model showed that during orthostatic stress depressed men had a reduced HRV and decreased parasympathetic activity compared to control subjects, while no differences were found between depressed women and controls. CONCLUSION: These results suggest a sex-dependent relationship between major depression and cardiac autonomic dysfunction and provide one potential explanation for sex differences in the association of depressive symptoms with cardiovascular morbidity.

Neural correlates to seen gaze-direction and head orientation in the macaque monkey amygdala.

Human neuropsychological studies suggest that the amygdala is implicated in social cognition, in which cognition of seen gaze-direction, especially the direct gaze, is essential, and that the perception of gaze direction is modulated by the head orientation of the facial stimuli. However, neural correlates to these issues remain unknown. In the present study, neuronal activity was recorded from the macaque monkey amygdala during performance of a sequential delayed non-matching-to-sample task based on gaze direction. The facial stimuli consisted of two head orientations (frontal; straight to the monkey, profile; 30 degrees rightwards from the front) with different gaze directions (directed toward and averted to the left or right of the monkey). Of the 1091 neurons recorded, 61 responded to more than one facial stimulus. Of these face-responsive neurons, 44 displayed responses selective to the facial stimuli (face neurons). Most amygdalar face neurons discriminated both gaze direction and head orientation, and exhibited a significant interaction between the two types about information. Furthermore, factor analysis on the response magnitudes of the face neurons to the facial stimuli revealed that two factors derived from these facial stimuli were correlated with two head orientations. The overall responses of the face neurons to direct gazes in the profile and frontal faces were significantly larger than that to averted gazes. The results suggest that information of both gaze and head direction is integrated in the amygdala, and that the amygdala is implicated in detection of direct gaze.