What is the overlap between subjective and objective cognitive impairments in MDD?

BACKGROUND: Cognitive impairments, such as memory deficits and executive impairment, are common among patients with major depressive disorder (MDD) and can be captured with objective or subjective assessments. The aim of this post-hoc analysis of the CONNECT study was to assess the degree of overlap between subjective and objective cognitive impairment among MDD patients, and to evaluate associated clinical characteristics. METHODS: The study was conducted from April 2012 to February 2014 and enrolled a total of 602 patients with MDD who reported subjective cognitive impairment. Efficacy was assessed using a battery of objective tests of cognitive function representing multiple domains: Digit Symbol Substitution Test performance, Trail Making Test A, Trail Making Test B, Congruent and Incongruent Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task, and One-Back Task. The Cognitive and Physical Functioning Questionnaire (CPFQ) was used to capture patient-reported assessments of cognitive function. RESULTS: Although 48% of patients with MDD met our conservative criteria for subjectively defined marked cognitive impairment, 64% of patients with MDD met our conservative criteria for objectively defined cognitive impairment. Therefore, the proportion of patients defined as having impaired cognition was somewhat similar regardless of methodology. Overall, 80% of patients with MDD in this study reported either subjective or objective cognitive impairment per subjective and objective scales. However, the proportion of patients meeting criteria for both subjectively and objectively defined cognitive impairment was only 31%. This could be explained by the fact that the CPFQ total score was only modestly-although significantly-correlated with all but one of the objective tests. CONCLUSIONS: This post-hoc study shows that approximately 80% of patients with MDD participating in an antidepressant trial reported either subjective or objective cognitive impairment.

Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder.

This study assessed the efficacy, tolerability and safety of vortioxetine versus placebo in adults with recurrent major depressive disorder. This double-blind, randomized, placebo-controlled study included 608 patients [Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 26 and Clinical Global Impression - Severity score ≥ 4]. Patients were randomly assigned (1 : 1 : 1 : 1) to vortioxetine 15 mg/day, vortioxetine 20 mg/day, duloxetine 60 mg/day or placebo. The primary efficacy endpoint was change from baseline in MADRS total score at week 8 (mixed model for repeated measurements). Key secondary endpoints were: MADRS responders; Clinical Global Impression - Improvement scale score; MADRS total score in patients with baseline Hamilton Anxiety Rating Scale ≥ 20; remission (MADRS ≤ 10); and Sheehan Disability Scale total score at week 8. On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n = 158) of -5.5 (vortioxetine 15 mg, P < 0.0001, n = 149) and -7.1 MADRS points (vortioxetine 20 mg, P < 0.0001, n = 151). Duloxetine (n = 146) separated from placebo, thus validating the study. In all key secondary analyses, both vortioxetine doses were statistically significantly superior to placebo. Vortioxetine treatment was well tolerated; common adverse events (incidence ≥ 5%) were nausea, headache, diarrhea, dry mouth and dizziness. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder.

A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder.

The efficacy and tolerability of Lu AA21004 at 5 mg/day, a novel multimodal antidepressant, were assessed in elderly patients with recurrent major depressive disorder. Patients were randomly assigned (1:1:1) to Lu AA21004 5 mg/day, duloxetine 60 mg/day (reference) or to placebo in an 8-week double-blind study. The primary efficacy measure was the 24-item Hamilton Depression Scale (HAM-D(24)) total score (analysis of covariance, last observation carried forward). Patients (mean age 70.6 years) had a mean baseline HAM-D(24) score of 29.0. Lu AA21004 showed significantly (P = 0.0011) greater improvement on the primary efficacy endpoint compared with placebo at week 8 (3.3 points). Duloxetine also showed superiority to placebo at week 8, thereby validating the study. HAM-D(24) response (53.2 vs. 35.2%) and HAM-D(17) remission (29.2 vs. 19.3%) rates at endpoint were higher for Lu AA21004 than for placebo. Lu AA21004 showed superiority to placebo in cognition tests of speed of processing, verbal learning and memory. The withdrawal rate due to adverse events was 5.8% (Lu AA21004), 9.9% (duloxetine) and 2.8% (placebo). Whereas nausea was the only adverse event with a significantly higher incidence on treatment with Lu AA21004 (21.8%) compared with placebo (8.3%), the incidence of nausea, constipation, dry mouth, hyperhidrosis and somnolence was higher for duloxetine. In conclusion, Lu AA21004 was efficacious and well tolerated in the treatment of elderly patients with recurrent major depressive disorder.

Pharmacokinetics of sertindole and its metabolite dehydrosertindole in rats and characterization of their comparative pharmacodynamics based on in vivo D2 receptor occupancy and behavioural conditioned avoidance response.

The objectives of this study were to characterize the pharmacokinetics of sertindole and its active metabolite dehydrosertindole in rats and to evaluate the central modulatory and behavioural pharmacodynamics including a competitive interaction model between the compounds. Following oral administration of sertindole or dehydrosertindole, the plasma concentration-time courses were determined in conjunction with striatal dopamine D(2) receptor binding. In addition, the behavioural effects were recorded in the conditioned avoidance response (CAR) paradigm. A one-compartment model with Michaelis-Menten elimination best described the pharmacokinetics of sertindole. Formation of dehydrosertindole was incorporated into the pharmacokinetic model and exhibited first-order elimination. PK/PD modelling after administration of dehydrosertindole resulted in potency estimates of 165 and 424 ng/ml for D(2)-occupancy (Kd) and CAR measurements (EC(50)), respectively. The pharmacokinetics of the parent-metabolite system was integrated into a competitive pharmacodynamic E(max) model in order to quantitate the potency of sertindole with the pharmacodynamic parameters of the metabolite taken into account. Based on this approach, effect compartment concentrations of sertindole needed to attain 50% occupancy and half-maximal effect in the CAR paradigm were 133 and 338 ng/ml, respectively. The corresponding potency-estimates obtained after conventional modelling of the sertindole data without accounting for the metabolite amounted to 102 and 345 ng/ml. Based on competitive PK/PD analysis of the parent-metabolite interaction, the relative contribution of dehydrosertindole to the overall pharmacological effect after sertindole administration in rats appeared to be of minor significance. This could mainly be ascribed to the relatively low extent of bioconversion of sertindole into dehydrosertindole in this species.

Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia--sub-chronic and early postnatal PCP treatment in attentional set-shifting.

RATIONALE: Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present. OBJECTIVE: The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models. METHODS: Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56-95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5-40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally). RESULTS: The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516. CONCLUSION: Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID-ED attentional set-shifting task.

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.

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.

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.