Christina Kurre Olsen

A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults

The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18–65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were −4.7 (10 mg: p < 0.0001) and −6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.

Evaluation of a neurodevelopmental model of schizophrenia—Early postnatal PCP treatment in attentional set-shifting

Phencyclidine (PCP) was administered to male and female Lister hooded rats on postnatal days (PND) 7, 9 and 11. All PCP animals tested in adulthood (PND 53-93) showed deficits in cognitive flexibility, specifically in their ability to shift attentional set, compared to controls. This novel finding is reminiscent of the impairment observed in schizophrenia patients, and supports the validity of the early postnatal PCP regimen as a disease-like model.

Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics

In the rat, selective suppression of conditioned avoidance response has been widely reported as a test with high predictive validity for antipsychotic efficacy. Recent studies have shown that the relationship between dopamine D2 receptor occupancy and the suppression of conditioned avoidance response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. In order to confirm the validity of the present conditioned avoidance response procedure, in vivo striatal dopamine D2 receptor occupancy was determined in parallel using 3H-raclopride as the radioligand. The PK/PD relationship was established by modelling the time-response and time-plasma concentration data. We found the order of dopamine D2 receptor occupancy required to suppress conditioned avoidance response behaviour according to EC50 measurements to be sertindole (+dehydrosertindole)=dehydrosertindole=paliperidone (the metabolite of risperidone)=haloperidol=olanzapine>risperidone>>clozapine. Overall, a good agreement was observed between the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels for sertindole (+dehydrosertindole) and olanzapine were 3-4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK/PD model may act as a guide for determining effective plasma concentrations of potential antipsychotics in the clinical setting and thereby accelerating the overall drug development process.

Antipsychotic-Like Effect of Retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic Acid Ester], a KCNQ Potassium Channel Opener, via Modulation of Mesolimbic Dopaminergic Neurotransmission

Dopaminergic (DAergic) neurons in the ventral tegmental area express both KCNQ2 and KCNQ4 channels, which opening is expected to decrease neuronal excitability via neuronal hyper-polarization. Because psychotic symptoms are believed to be associated with an increased excitability of dopamine (DA) cells in the mesencephalon, KCNQ channels might represent a new potential target for the treatment of psychosis. The aim of our study was to investigate the antipsychotic-like potential of KCNQ channel opening via modulation of neuronal activity within the mesolimbic DAergic system. We report that retigabine [N-(2-amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ opener, dose-dependently reduced basal DA firing rate and more potently suppressed burst firing activity in the ventral tegmental area, whereas XE-991 [10,10-bis(pyridinylmethyl)-9(10H)-anthracenone], a selective KCNQ blocker, induced opposite effects. In addition, retigabine prevented d-amphetamine-induced DA efflux in the nucleus accumbens and d-amphetamine-induced locomotor hyperactivity. In contrast, XE-991 potentiated both the locomotor hyperactivity and DA efflux evoked by d-amphetamine. These data strongly suggest that the activation of KCNQ channels attenuates DAergic neurotransmission in the mesolimbic system, particularly in conditions of excessive DAergic activity. In a model predictive of antipsychotic activity, the conditioned avoidance response paradigm, retigabine was found to inhibit avoidance responses, an effect blocked by coadministration of XE-991. Furthermore, retigabine was found to significantly inhibit the hyperlocomotor response to a phencyclidine (PCP) challenge in PCP-sensitized animals, considered as a disease model for schizophrenia. Taken together, our studies provide evidence that KCNQ channel openers represent a potential new class of antipsychotics.

The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials

Background: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. Methods: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5–20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen’s d) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). Results: Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25–0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial (p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). Conclusions: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.

Repeated administration of the neurotensin analogue NT69L induces tolerance to its suppressant effect on conditioned avoidance behaviour

Although acute neurotensin receptor stimulation exerts diverse behavioural effects that resemble those seen after administration of antipsychotic drugs, data on effects after repeated exposure to neurotensin receptor agonism is relatively sparse. Here, we demonstrate that repeated administration of the novel neurotensin-(8-13) analogue NT69L [(N-methyl-Arg), Lys, Pro, L-neo-Trp, tert-Leu, Leu] induce tolerance to its suppressant effect on conditioned avoidance behaviour in rats, a predictive assay for antipsychotic activity. In contrast, the inhibitory effect of haloperidol on this behaviour was sustained despite repeated administration of this classical antipsychotic drug. These findings indicate that repeated exposure to neurotensin receptor stimulation induces tolerance to the antipsychotic-like effects of neurotensin receptor agonists.

Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function

The hippocampus plays an important role in emotional and cognitive processing, and both of these domains are affected in patients with major depressive disorder (MDD). Extensive preclinical research and the notion that modulation of serotonin (5-HT) neurotransmission plays a key role in the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) support the view that 5-HT is important for hippocampal function in normal and disease-like conditions. The hippocampus is densely innervated by serotonergic fibers, and the majority of 5-HT receptor subtypes are expressed there. Furthermore, hippocampal cells often co-express multiple 5-HT receptor subtypes that can have either complementary or opposing effects on cell function, adding to the complexity of 5-HT neurotransmission. Here we review the current knowledge of how 5-HT, through its various receptor subtypes, modulates hippocampal output and the activity of hippocampal pyramidal cells in rodents. In addition, we discuss the relevance of 5-HT modulation for cognitive processing in rodents and possible clinical implications of these results in patients with MDD. Finally, we review the data on how SSRIs and vortioxetine, an antidepressant with multimodal activity, affect hippocampal function, including cognitive processing, from both a preclinical and clinical perspective.

Tonic immobility in guinea pigs: a behavioural response for detecting an anxiolytic-like effect?

Tonic immobility (TI) is considered to be an innate fear response characterized by a temporary state of profound and reversible motor inhibition. TI occurs in a wide range of species in a predator–prey confrontation and is hypothesized to be a terminal defence response occurring when there is physical contact between prey and predator. The objective of the present study was to investigate the validity of the TI model in guinea pigs for detection of anxiolytic and/or antidepressant drug activity. Compounds that reduced TI include the serotonin (5-HT) releaser fenfluramine, the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, the 5-HT2C/2B receptor antagonist SB206553, the 5-HT2A receptor antagonist MDL 100.151 – but only at doses thought also to inhibit 5-HT2C receptors–the noradrenaline (NA) reuptake inhibitor desipramine, the benzodiazepine inverse agonist FG-7142, the &agr;2-adrenergic receptor antagonist yohimbine, the neurokinin (NK)1 receptor antagonist L-733.060, and the NK2 receptor antagonist SR-48968. Compounds that increased TI include the benzodiazepine agonists diazepam and alprazolam, and the &agr;2-adrenergic receptor agonist clonidine. The selective 5-HT reuptake inhibitors citalopram, paroxetine and fluoxetine, the 5-HT1A receptor antagonist WAY100.635, the 5-HT2C receptor agonist MK-212, the 5-HT/NA reuptake inhibitor imipramine, the NA reuptake inhibitor talopram, the benzodiazepine antagonist flumazenil, the &agr;2-adrenergic receptor antagonist idazoxan and the psychostimulant amphetamine did not have any effect. These findings indicate that the serotonergic, noradrenergic and neurokinin systems are involved in mediating or modulating TI behaviour in guinea pigs. The potential of TI as a behaviour for detecting anxiolytic-like effect may be questioned due to the contradictory effect of the benzodiazepine ligands, which may be attributed to the sedative and/or ataxic effects of the compounds. Nevertheless, there is preclinical evidence suggesting that 5-HT1A receptor agonists, 5-HT2C receptor antagonists and NK1 and NK2 receptor antagonists possess anxiolytic potential. Only when results of clinical investigations of the anxiolytic potential of non-benzodiazepine ligands (for example the NK receptor antagonists) are available, will it be possible to determine fully the predictive validity of the TI model.

Positive modulation of glutamatergic receptors potentiates the suppressive effects of antipsychotics on conditioned avoidance responding in rats.

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist administration induces a syndrome indistinguishable from schizophrenia including positive and negative symptoms and cognitive deficits. Concordantly, augmentation of the NMDA receptor function by glycine-site agonists such as D-serine and D-cycloserine has been reported to improve negative symptoms and some cognitive deficits in schizophrenia patients when added to conventional antipsychotic treatment, although they appear less effective when combined with clozapine specifically. In contrast, administration of the AMPAkine CX-516 (which positively modulate the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor) as an adjuvant to clozapine, has been shown to exert some beneficial action on the negative symptoms and cognitive deficits in schizophrenia. In the rat, selective suppression of conditioned avoidance response (CAR) behaviour has been widely reported to be a test with high predictive validity for antipsychotic efficacy. We found that D-serine and CX-516, at doses ineffective by themselves, significantly potentiated the suppression of CAR induced by threshold doses of risperidone (0.16 mg/kg, s.c.), olanzapine (0.63 mg/kg, s.c.) and clozapine (1.3 mg/kg, s.c.) without causing additional motor disturbances. Thus, the adjunct enhancement of NMDA or AMPA receptor function observed clinically, appears reflected in the present rat CAR study. Consequently, our data lend further support to the potential use of the CAR test in the investigation of augmentation strategies involving the addition of non-dopaminergic target compounds to existing atypical antipsychotics.

5-HT6 Receptor Ligands and their Antipsychotic Potential

Publisher Summary This chapter provides an overview of the evidence for the involvement of 5-HT 6 receptors in the symptomatology of positive, negative, and cognitive symptom domains of schizophrenia and for the therapeutic potential of 5-HT 6 receptor ligands. Although some antipsychotics have receptor profiles, including high affinities for 5-HT 6 receptors, they are always associated with a variable range of additional target effects. The available information does not support that 5-HT 6 antagonists have significant potential for the treatment of the psychotic symptoms of schizophrenia as monotherapy. However, the robust efficacy demonstrated by 5-HT 6 antagonists for cognitive improvement in general, and more specifically in cognitive impairment associated with schizophrenia (CIAS) models, appears promising. There are many uncertainties regarding the molecular mechanisms of action, as most studies addressing this question are made in animals without impaired behavior. Animals with induced deficits may have very different neurotransmitter dynamics compared with the normal state, which can be involved in the contradictory similar findings with antagonists and agonists in some studies. Thus, well-controlled clinical trials are awaited with high interest.