Ceren Sahin

Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats.

The activation of Nod‐like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)‐1β and IL‐18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant‐like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down‐regulated the gene expressions of all stress‐induced NLRP3 inflammasome components (NLRP3, NF‐κB, PYCARD, caspase‐1, IL‐1β and IL‐18) in the hippocampus and prefrontal cortex (PFC) and reduced pro‐inflammatory cytokine levels not only in both brain regions, but also in serum. Stress‐reduced levels of IL‐4 and IL‐10, two major anti‐inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress‐activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant‐like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.

Towards the development of improved tests for negative symptoms of schizophrenia in a validated animal model.

Negative symptoms in schizophrenia remain an unmet clinical need. There is no licensed treatment specifically for this debilitating aspect of the disorder and effect sizes of new therapies are too small to make an impact on quality of life and function. Negative symptoms are multifactorial but often considered in terms of two domains, expressive deficit incorporating blunted affect and poverty of speech and avolition incorporating asociality and lack of drive. There is a clear need for improved understanding of the neurobiology of negative symptoms which can be enabled through the use of carefully validated animal models. While there are several tests for assessing sociability in animals, tests for blunted affect in schizophrenia are currently lacking. Two paradigms have recently been developed for assessing negative affect of relevance to depression in rats. Here we assess their utility for studying negative symptoms in schizophrenia using our well validated model for schizophrenia of sub-chronic (sc) treatment with Phencyclidine (PCP) in adult female rats. Results demonstrate that sc PCP treatment produces a significant negative affect bias in response to a high value reward in the optimistic and affective bias tests. Our results are not easily explained by the known cognitive deficits induced by sc PCP and support the hypothesis of a negative affective bias in this model. We suggest that further refinement of these two tests will provide a means to investigate the neurobiological basis of negative affect in schizophrenia, thus supporting the assessment of efficacy of new targets for this currently untreated symptom domain.

PT611. The combination of sub-effective doses of agmatine and ketamine reduces obsessive-compulsive-like behavior of mice in marble burying test

A substantial portion of schizophrenia patients with obsessive compulsive disorder fail to respond to regimen of antipsychotic and selective serotonin reuptake inhibitor. Herein, we report a schizophrenic patient who, after being switched from escitalopram to milnacipran, showed a rapid improvement of his debilitating OCD. A 23-year-old unemployed single man had been diagnosed with schizophrenia and OCD 4 years previously. A regimen with quetiapine 225 mg/day and escitalopram 20 mg/day has stabilized his psychotic symptoms, however, OCS persisted, with a score of 24 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). We switched escitalopram to milnacipran at an initial dosage of 100 mg/day, without adding on any psychological or behavioral interventions. By the end of the first week after initiating milnacipran, his Y-BOCS score had dropped to 13. The dose of milnacipran was raised to 150 mg/day at the third week, the patient showed a reduction of about 45% in Y-BOCS score, which is considered to be a significant treatment response. Milnacipran is a unique SNRI in that it is twice as potent in inhibiting norepinephrine than serotonin reuptake. Among schizophrenic patients, the serotonergic system may receive complex dopaminergic modulations which are further complicated with antipsychotic treatment. In the present case, it is possible that a paradoxical downregulation of serotonergic receptors following his previous antipsychotic treatment may have hindered the therapeutic efficacy of SSRIs in treating OCS. SNRIs with preferential norepinephrine reuptake inhibition, such as milnacipran, may exert a superior efficacy by acting primarily on the noradrenergic circuit. Due to the complex interplay between serotonergic, dopaminergic and noradrenergic systems, the pathogenesis of OCS in patients with schizophrenia may be more complicated than the well-known serotonin hypothesis of OCD. Milnacipran, with its preferable noradrenergic reuptake blockade, can be a reasonable alternative if OCS fail to respond to SSRIs or other SNRIs. PT610 Aripriprazole augmentation in patient with OCD partially responsive to SSRI Borjanka Batinic, Duisin Dragana Clinical Centre of Serbia, Serbia Abstract Objective: Despite the efficacy of SSRIs and clomipramine, 40%60% of patients with obsessive-compulsive disorder do not respond adequately to the first line of treatment. This was the case of our patient, a 34-year old female, who demonstrated pronounced magical thinking and an obsessive fear that something terrible would happen to family members. She sought to reduce the impact of these thoughts with mental and motor compulsions (counting, repeating thoughts, bringing things into order and symmetry). Obsessive thoughts and compulsions took up several hours a day, making her exhausted, depressed and inefficient. Aims: As the previous treatment with an SSRI (paroxetine) after 3 months at the maximum tolerated dose (40mg/day) gave only a partial therapeutic response, we augmented the treatment with aripriprazole at a dose of 5mg/day. Review of the literature indicates that adding aripiprazole to an SSRIs could be a valid strategy for treatment-resistant OCD patients or those with only a partial therapeutic response. Aripiprazole is associated with a lower risk of weight gain, sedation, and increase in prolactin compared to other antipsychotics. Method: The following instruments were applied before and two weeks after aripriprazole augmentation: The Beck Anxiety Inventory (BAI), the Beck Depression Inventory-II (BDI-II) and the Obsessive-Compulsive Inventory-Revised (OCI-R). We also followed patients for possible side-effects. Results: Scores on the applied instruments were as follows: before the augmentation with aripriprazole: BAI=10; BDI-II=28, OCI-R= 21; after augmentation with aripriprazole: BAI =3, BDI-II =10, OCI-R=8. Conclusions: Aripriprazole augmentation in a dose of 5mg/day was effective in reduction of obsessive-compulsive symptoms in a patient with partial therapeutic response to paroxetine, as well as in generalized anxiety and depression, with rapid onset of improvement (after 2 weeks of initiation) and good tolerability.Objective: Despite the efficacy of SSRIs and clomipramine, 40%60% of patients with obsessive-compulsive disorder do not respond adequately to the first line of treatment. This was the case of our patient, a 34-year old female, who demonstrated pronounced magical thinking and an obsessive fear that something terrible would happen to family members. She sought to reduce the impact of these thoughts with mental and motor compulsions (counting, repeating thoughts, bringing things into order and symmetry). Obsessive thoughts and compulsions took up several hours a day, making her exhausted, depressed and inefficient. Aims: As the previous treatment with an SSRI (paroxetine) after 3 months at the maximum tolerated dose (40mg/day) gave only a partial therapeutic response, we augmented the treatment with aripriprazole at a dose of 5mg/day. Review of the literature indicates that adding aripiprazole to an SSRIs could be a valid strategy for treatment-resistant OCD patients or those with only a partial therapeutic response. Aripiprazole is associated with a lower risk of weight gain, sedation, and increase in prolactin compared to other antipsychotics. Method: The following instruments were applied before and two weeks after aripriprazole augmentation: The Beck Anxiety Inventory (BAI), the Beck Depression Inventory-II (BDI-II) and the Obsessive-Compulsive Inventory-Revised (OCI-R). We also followed patients for possible side-effects. Results: Scores on the applied instruments were as follows: before the augmentation with aripriprazole: BAI=10; BDI-II=28, OCI-R= 21; after augmentation with aripriprazole: BAI =3, BDI-II =10, OCI-R=8. Conclusions: Aripriprazole augmentation in a dose of 5mg/day was effective in reduction of obsessive-compulsive symptoms in a patient with partial therapeutic response to paroxetine, as well as in generalized anxiety and depression, with rapid onset of improvement (after 2 weeks of initiation) and good tolerability.