Real-world effectiveness of vortioxetine in outpatients with major depressive disorder: functioning and dose effects.

BACKGROUND: Functional recovery is an important treatment goal in major depressive disorder (MDD). This study assessed the real-world effectiveness of vortioxetine in patients with MDD, with particular focus on functioning; dose-response was also assessed. METHODS: This was a non-interventional, prospective, multicenter study conducted in Greece. Adult outpatients with MDD (n = 336) initiating vortioxetine (5-20 mg/day flexible dosing) as treatment for a current major depressive episode were followed for 3 months. Analyses were stratified according to vortioxetine dosage at 3 months: 5-10 mg/day versus 15-20 mg/day. Functioning was assessed using the Sheehan Disability Scale (SDS). RESULTS: Mean ± standard error SDS total score decreased (improved) from 18.7 ± 0.3 at baseline to 12.9 ± 0.3 after 1 month of vortioxetine treatment and 7.8 ± 0.4 after 3 months (p < 0.001 vs. baseline for all comparisons). Functional recovery (SDS score ≤ 6) was achieved in 14.6% of patients after 1 month of treatment and 48.4% of patients after 3 months. Improvement from baseline in SDS total and domain scores at 3 months was more pronounced in patients receiving vortioxetine 15-20 mg/day than in those receiving vortioxetine 5-10 mg/day. The mean ± standard error change in SDS total score from baseline was 9.2 ± 0.8 in the 5-10 mg/day group and 12.1 ± 0.4 in the 15-20 mg/day group (p < 0.001). Limitations of this study include its non-interventional study design and lack of a control group or active comparator. CONCLUSIONS: Statistically significant and clinically relevant improvements in functioning were seen in patients with MDD treated with vortioxetine in a real-world setting. Higher doses of vortioxetine were associated with significantly greater improvements in functioning.

Preferences and perceptions of 617 migraine patients on acute and preventive migraine treatment attributes and clinical trial endpoints.

BACKGROUND: To identify the preferences and perceptions of migraine patients for acute and preventive treatment options and to investigate which treatment outcomes are the most important. DESIGN AND METHODS: The authors performed a choice-format survey in a cohort of migraine patients from Greece and Cyprus. A self-administered questionnaire developed in collaboration with the Greek Society of Migraine Patients was used. RESULTS: Questionnaires were collected from 617 migraine patients. Efficacy was preferred over safety as the single most important parameter, both in acute and preventive treatment. When analyzing single outcomes, patients prioritized a complete pain remission at 1-hour post-dose for acute therapies. Regarding migraine prevention, a 75% reduction in frequency, intensity of pain, accompanying symptoms and acute medication intake were considered as most important. Conversely, outcomes routinely used in clinical trials, namely complete or partial pain remission at 2-hours post-dose for acute treatment and 50% or 30% reduction in migraine frequency for prevention, were not deemed particularly relevant. Tablet formulation was mostly preferred, both in acute and preventive treatment. Conclusion: Listening to patients' needs may add a piece of the puzzle that is generally missing in clinical practice and often explains the lack of adherence in both acute and preventative anti-migraine therapies.

The cannabinoid CB1 receptor biphasically modulates motor activity and regulates dopamine and glutamate release region dependently.

Cannabinoid administration modulates both dopaminergic and glutamatergic neurotransmission. The present study examines the effects of high and low dose WIN55,212-2, a CB1 receptor agonist, on extracellular dopamine and glutamate release in vivo via brain microdialysis in the nucleus accumbens (NAc), striatum and prefrontal cortex (PFC) in parallel to its effects on locomotor activity. WIN55,212-2 increased extracellular dopamine in the NAc (1 mg/kg i.p.), striatum (0.1 and 1 mg/kg i.p.) and PFC (1 mg/kg i.p.). Glutamate release was also elevated by WIN55,212-2 in the PFC (1 mg/kg i.p.) whereas in the NAc (0.1 and 1 mg/kg i.p.) and striatum, it was reduced (1 mg/kg i.p.). WIN55,212-2 administration produced hyperlocomotion at the lower dose (0.1 mg/kg i.p.) and hypolocomotion at the higher dose (1 mg/kg i.p.). Co-administration with the CB1 antagonist, SR-141716A (0.03 mg/kg i.p.), prevented the above effects. According to the present results, WIN55,212-2 affected locomotor activity biphasically while exerting converging effects on dopamine activity but diverging effects on glutamate release between cortical and subcortical regions, especially at the higher dose. These findings emphasize the involvement of the CB1 receptor in the simultaneous modulation of dopaminergic and glutamatergic neurotransmission in brain regions involved in reward and locomotion and suggest possible underlying mechanisms of acute cannabinoid exposure and its psychoactive and behavioural manifestations.

Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain.

This study explored the behavioural, neurochemical and molecular effects of Delta9-tetrahydrocannabinol (Delta9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following Delta9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of Delta9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse.

Behavioural and dopaminergic alterations induced by a low dose of WIN 55,212-2 in a conditioned place preference procedure.

AIMS: This study investigated the role of the cannabinoid CB1 receptor agonist, WIN 55,212-2, on motor activity. Subsequently, the effects of a low, stimulatory dose of WIN 55,212-2 and cocaine, as a positive control, were evaluated using a conditioned place preference (CPP) procedure. Upon completion of CPP, in rats that had been treated with WIN 55,212-2, dopaminergic status and spontaneous and d-amphetamine-induced motor activity were assessed. MAIN METHODS: Sprague-Dawley rats were evaluated for habituated motor activity following WIN 55,212-2 (0, 0.1, 0.3, 1 mg/kg, i.p.) administration. A stimulatory dose of WIN 55,212-2 (0.1 mg/kg, i.p.) and cocaine (20 mg/kg, i.p.) was selected to assess CPP behaviour. Upon completion of CPP, in one group, tissue levels of dopamine and its metabolites were measured in distinct brain regions (dorsal striatum, nucleus accumbens, prefrontal cortex, amygdala, hippocampus) using High Performance Liquid Chromatography with electrochemical detection. In another group, spontaneous and D-amphetamine-induced motor activity was evaluated in an open-field apparatus. KEY FINDINGS: The lowest dose of WIN 55,212-2 increased motor activity but did not produce CPP. As expected, cocaine induced clear CPP. Dopaminergic status was increased in a region-specific way and motor activity was enhanced following a challenge of D-amphetamine in rats that had been administered with WIN 55,212-2 during conditioning. SIGNIFICANCE: A stimulatory effect of WIN 55,212-2 on motor activity was not accompanied by place preference. Upon completion of the CPP procedure, this dose was found to induce region-specific hyperdopaminergia along with a greater sensitivity to a subsequent challenge dose of D-amphetamine.