Piotr Popik

Glutamate-based antidepressants: 20 years on

Depression is a chronic recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires > or =2-4 weeks of treatment and a first course of therapy provides symptom relief to only 60-65% of patients. Roche and Evotec recently announced plans to develop N-methyl-D-aspartate (NMDA) receptor antagonists targeting the NR2B subtype for treatment-resistant depression. This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101 606), has antidepressant effects in patients unresponsive to a serotonin selective reuptake inhibitor, as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist ketamine. Here we describe evidence that glutamate-based therapies might represent an effective alternative to biogenic-amine-based agents for depression and provide perspectives on the development of these agents.

Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study.

BACKGROUNDnOne of the main problems in the therapy of depression is the limited efficacy of antidepressants and the limited utility of augmentation strategies. Zinc, a non competitive NMDA receptor antagonist exhibits preclinical antidepressant efficacy. Moreover, a preliminary clinical report suggests augmentation of antidepressant therapy by zinc in depression.nnnMETHODSnA placebo-controlled, double blind study of zinc supplementation in imipramine therapy was conducted in sixty, 18-55-year old, unipolar depressed patients fulfilling the DSM-IV criteria for major depression without psychotic symptoms. After a one week washout period, patients were randomized into two groups treated with imipramine (approximately 140 mg/day) and receiving once daily either placebo (n=30) or zinc supplementation (n=30, 25 mgZn/day) for 12 weeks.nnnRESULTSnNo significant differences in CGI, BDI, HADRS and MADRS scores were demonstrated between zinc-supplemented and placebo-supplemented antidepressant treatment non-resistant patients. However, zinc supplementation significantly reduced depression scores and facilitated the treatment outcome in antidepressant treatment resistant patients.nnnCONCLUSIONnZinc supplementation augments the efficacy and speed of onset of therapeutic response to imipramine treatment, particularly in patients previously nonresponsive to antidepressant pharmacotherapies. These data suggest the participation of disturbed zinc/glutamatergic transmission in the pathophysiology of drug resistance.

Serum zinc level in depressed patients during zinc supplementation of imipramine treatment

BACKGROUNDnRecurrent major depression is associated with decreased blood zinc concentrations that may be increased by effective antidepressant therapy. Some clinical investigations point to alterations of the zinc level in blood as a potential marker of depression.nnnMETHODSnA placebo-controlled, double blind study of zinc supplementation to imipramine therapy was conducted on sixty patients fulfilling the DSM-IV criteria for major depression (18-55 years old, 40 females, 20 males). Moreover, a group of 25 healthy volunteers was recruited (16 females, 9 males). Blood samples were drawn for the assay of serum zinc once from the control subjects and four times (before, and then 2, 6 and 12 weeks after the beginning of treatment) from the depressed subjects.nnnRESULTSnWe report that: 1) the serum zinc level was significantly lower (by 22%) in depressed patients than in healthy volunteers, 2) all groups demonstrated a gradual increase in zinc concentrations over the period of imipramine treatment with or without zinc supplementation, 3) treatment-resistant patients demonstrated lower concentrations of zinc (by 14%) than treatment-non-resistant patients, 4) zinc concentrations were higher in zinc-supplemented patients than in placebo-supplemented patients, 5) zinc supplementation increased zinc concentrations over the period of treatment, and 6) at a 12-week imipramine treatment, a significant negative correlation was demonstrated between the Montgomery-Asberg Depression Rating Scale and the serum zinc level together with a concomitant increase in serum zinc in patients in remission.nnnCONCLUSIONSnSerum zinc is a state marker of depression.

Laughing Rats Are Optimistic

Emotions can bias human decisions- for example depressed or anxious people tend to make pessimistic judgements while those in positive affective states are often more optimistic. Several studies have reported that affect contingent judgement biases can also be produced in animals. The animals, however, cannot self-report; therefore, the valence of their emotions, to date, could only be assumed. Here we present the results of an experiment where the affect-contingent judgement bias has been produced by objectively measured positive emotions. We trained rats in operant Skinner boxes to press one lever in response to one tone to receive a food reward and to press another lever in response to a different tone to avoid punishment by electric foot shock. After attaining a stable level of discrimination performance, the animals were subjected to either handling or playful, experimenter-administered manual stimulation – tickling. This procedure has been confirmed to induce a positive affective state in rats, and the 50-kHz ultrasonic vocalisations (rat laughter) emitted by animals in response to tickling have been postulated to index positive emotions akin to human joy. During the tickling and handling sessions, the numbers of emitted high-frequency 50-kHz calls were scored. Immediately after tickling or handling, the animals were tested for their responses to a tone of intermediate frequency, and the pattern of their responses to this ambiguous cue was taken as an indicator of the animals optimism. Our findings indicate that tickling induced positive emotions which are directly indexed in rats by laughter, can make animals more optimistic. We demonstrate for the first time a link between the directly measured positive affective state and decision making under uncertainty in an animal model. We also introduce innovative tandem-approach for studying emotional-cognitive interplay in animals, which may be of great value for understanding the emotional-cognitive changes associated with mood disorders.

The effects of NMDA receptor antagonists on attentional set-shifting task performance in mice

Rationale and objectivesCognitive deficits, including an impaired ability to shift perceptual attentional set, belong to the core features of schizophrenia, are associated with prefrontal cortical dysfunctions, and may involve glutamate NMDA receptors. Although phencyclidine disturbs cognitive flexibility, little is known about the effects of ketamine and other NMDA antagonists that differ in receptor subunit selectivity, particularly in the mouse species.MethodsAt different times following the administration of ketamine, the NMDA NR2B-subtype specific antagonist Ro 25-6981, or the atypical antipsychotic sertindole, male C57Bl/6J mice were investigated in a modified version of attentional set-shifting task (ASST).ResultsSpecific extra-dimensional shift (EDS) deficit was observed in all control mice. As revealed by the increased number of trials, time and errors to reach criterion, ketamine at 10 or 20xa0mg/kg given 50xa0min prior to sessions, but not at 10xa0mg/kg given 3 or 24xa0h prior to sessions, further worsened the EDS performance. Sertindole (2.5xa0mg/kg) prevented ketamine-induced cognitive inflexibility, although it did not affect ASST performance when given alone. In contrast to ketamine, Ro 25-6981 at 10 but not 3xa0mg/kg, reduced the number of trials and errors to criterion, suggesting a facilitation of cognitive flexibility. Finally, as revealed by the number of trials and time to criterion measures, Ro 25-6981 (10xa0mg/kg) administration to ketamine (10xa0mg/kg)-pretreated mice inhibited ketamine-induced cognitive inflexibility.ConclusionThe present study provides an improved and reliable mouse ASST protocol and confirms and extends previous findings demonstrating that NR2B subunit-selective antagonists improve cognitive processes.

Long-lasting cognitive deficit induced by stress is alleviated by acute administration of antidepressants

Deficits in executive control associated with frontal lobe dysfunction have been reported in affective disorder, which is often precipitated by stressful life events. Here we examined the impact of repeated restraint stress (1h daily for 7 days) on rats performance in the attentional set-shifting task (ASST). To evaluate the persistence of cognitive deficits, the performance of separate groups of rats was assessed on the 4th, 7th, 14th and 21st day following stress cessation. Stressed rats exhibited unusually long-lasting extra-dimensional (ED) set-shifting impairments, since these deficits were demonstrated even 3 weeks following stress termination. An inhibitor of corticosterone synthesis, the drug metyrapone (50mg/kg, IP) protected rats from the cognitive impairment suggesting an involvement of endogenous adrenal steroids in the debilitating effects of stress. Acute intraperitoneal administration of four different antidepressants (desipramine, nomifensine, fluoxetine and escitalopram) at the minimum effective doses of 3, 0.3, 1 and 1mg/kg, respectively, reversed the deficits of ED set-shifting in stressed animals. Desipramine, nomifensine, fluoxetine and escitalopram at the minimum effective doses of 6, 1, 1 and 1mg/kg, IP, respectively, promoted also cognitive flexibility in unstressed groups. We conclude that stress-induced long-term set-shifting impairment may represent a useful model mimicking clinically relevant aspects of depression, i.e., the persistence of executive dysfunction. The potential utility of antidepressants in treating frontal-like cognitive impairments is suggested.

The effects of acute pharmacological stimulation of the 5-HT, NA and DA systems on the cognitive judgement bias of rats in the ambiguous-cue interpretation paradigm.

In the present study, we investigated the effects of acute pharmacological stimulation of the serotonergic (5-HT), noradrenergic (NA) and dopaminergic (DA) systems on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. To accomplish this goal, after initial behavioural training, different groups of rats received single injections of citalopram, desipramine or d-amphetamine and were subsequently tested with the ACI paradigm. Each drug was administered in 3 doses using a fully randomised Latin square design. Citalopram at the dose of 1mg/kg significantly biased animals towards positive interpretation of the ambiguous cue, while at higher doses (5 and 10mg/kg), the animals interpreted the ambiguous cue more negatively. Desipramine at all 3 tested doses (1, 2 and 5mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue, while d-amphetamine at the dose of 1mg/kg induced positive bias, having no effects at lower doses (0.1 and 0.5mg/kg). Our results indicate that cognitive bias in rats can be influenced by acute pharmacological intervention.

Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor.

Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 μM. The affinities of all three compounds were then assessed at NMDA receptors using [3H]MK-801 binding. The dose-response relationships of all 3 compounds in the forced swim test were also investigated in mice 30 min after IP administration. The effects of ketamine and norketamine (both 50 mg/kg) were then examined at 30 min, 3 days and 7 days post administration. Among the 80 potential targets examined, only NMDA receptors were affected with a magnitude of >50% by ketamine and norketamine at the concentration of 10 μM. The Ki values of ketamine, norketamine and dehydronorketamine at NMDA receptors were 0.119±0.01, 0.97±0.1 and 3.21±0.3 μM, respectively. Ketamine and norketamine reduced immobility with minimum effective doses (MEDs) of 10 and 50 mg/kg, respectively; dehydronorketamine did not affect immobility at doses of up to 50 mg/kg. Neither ketamine nor norketamine reduced immobility in the forced swim test 3 and 7 days following administration. Further, oral administration of ketamine (5-50 mg/kg) did not affect immobility. We demonstrate that ketamine and norketamine but not dehydronorketamine given acutely at subanesthetic doses reduced immobility in the forced swim test. These antidepressant-like effects appear attributable to NMDA receptor inhibition.

Effects of optimism on motivation in rats

In humans, optimism is a cognitive construct related to motivation; optimists exert effort, whereas pessimists disengage from effort. In this study, using a recently developed ambiguous-cue interpretation (ACI) paradigm we took the unique opportunity to investigate whether “optimism” as a trait is correlated with motivation in rodents. In a series of ACI tests (cognitive bias screening, CBS), we identified rats displaying “pessimistic” and “optimistic” traits. Subsequently, we investigated the trait differences in the motivation of these rats to gain reward and to avoid punishment using a progressive ratio (PR) schedule of reinforcement paradigm. Although “optimistic” and “pessimistic” animals did not differ in their motivation to avoid punishment, the “optimistic” rats were significantly more motivated to gain reward than their “pessimistic” conspecifics. For the first time, we showed an association between cognitive judgment bias and motivation in an animal model. Because both investigated processes are closely related to mental health and wellbeing, our results may be valuable for preclinical modeling of many psychiatric disorders.

The effects of cocaine and mazindol on the cognitive judgement bias of rats in the ambiguous-cue interpretation paradigm

Recent research has shown that pharmacological enhancement of dopaminergic function increases an optimism bias in humans. The present study investigated whether acute dopaminergic system stimulation through the administration of two dopamine-mimetic drugs, cocaine and mazindol, have similar effects in rats. To accomplish this goal, after initial behavioural training, two groups of rats received single injections of either cocaine or mazindol and were subsequently tested with the ambiguous-cue interpretation (ACI) paradigm. Both drugs were administered in three doses using the fully randomised Latin square designs. Cocaine (1, 2 and 5mg/kg) had no significant effect on the interpretation of the ambiguous cue. Mazindol at all three doses (0.5, 1 and 2mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue. The results are discussed in relation to pharmacological and behaviourally evoked actions of tested compounds.