Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.

Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.

In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [11C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared with healthy controls (mean difference 4%, P=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, P=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics.

A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid.

RATIONALE: Standardized Field Sobriety Tests (SFST) and oral fluid devices are used to screen for driving impairment and roadside drug detection, respectively. SFST have been validated for alcohol, but their sensitivity to impairment induced by other drugs is relatively unknown. The sensitivity and specificity for Δ(9)-tetrahydrocannabinol (THC) of most oral fluid devices have been low. OBJECTIVE: This study assessed the effects of smoking cannabis with and without alcohol on SFST performance. Presence of THC in oral fluid was examined with two devices (Dräger Drug Test® 5000 and Securetec Drugwipe® 5). METHODS: Twenty heavy cannabis users (15 males and 5 females; mean age, 24.3 years) participated in a double-blind, placebo-controlled study assessing percentage of impaired individuals on the SFST and the sensitivity of two oral fluid devices. Participants received alcohol doses or alcohol placebo in combination with 400 µg/kg body weight THC. We aimed to reach peak blood alcohol concentration values of 0.5 and 0.7 mg/mL. RESULTS: Cannabis was significantly related to performance on the one-leg stand (p = 0.037). Alcohol in combination with cannabis was significantly related to impairment on horizontal gaze nystagmus (p = 0.029). The Dräger Drug Test® 5000 demonstrated a high sensitivity for THC, whereas the sensitivity of the Securetec Drugwipe® 5 was low. CONCLUSIONS: SFST were mildly sensitive to impairment from cannabis in heavy users. Lack of sensitivity might be attributed to tolerance and time of testing. SFST were sensitive to both doses of alcohol. The Dräger Drug Test® 5000 appears to be a promising tool for detecting THC in oral fluid as far as correct THC detection is concerned.