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Cognitive dysfunctionality in schizophrenia


The degree of cognitive dysfunctionality in schizophrenia patients has been shown to be an important predictor of long-term prognosis for disease outcome. To elucidate the neurobiological underpinnings of cognitive deficits in schizophrenia the use of an integrative preclinical and clinical research approach will be necessary. Preclinically, the establishment of translational cognitive models in combination with in vivo biochemical methods will allow us to link molecules, brain regions and neuronal circuits to cognitive processes. Importantly, this approach could generate novel strategies for pharmacological intervention. Our studies indicate that increased nitric oxide (NO) formation in the medial prefrontal cortex (PFC) precipitates a deficit in pre-attentive information processing resembling that observed in schizophrenia. The PFC is defined by a complex interaction between major neurotransmitters such as glutamate, dopamine and GABA controlling the activity of cortical pyramidal neurons. The possibility of dysfunctional recurrent networks dependent on these neurons may help to explain the cognitive deficits of schizophrenia. NO is well positioned to play an important role in the PFC, putatively located to key synapses in this region, and with the ability to modulate glutamatergic, dopaminergic and GABAergic activity.

To evaluate this possibility, we have conducted a proof of concept study investigating the potential antipsychotic effects of the amino acid, L-lysine, in patients with schizophrenia (Wass et al. 2011). L-lysine, which occurs naturally in food, has been shown to inhibit NO formation. The proposed mechanism of action for this effect is a competitive inhibition of the transport of the substrate for NO synthase, L-arginine, into neurons and a subsequent reduction in NO formation (see Pålsson et al. 2007). A four-week L-lysine treatment regimen of the subjects investigated caused a significant increased in blood concentration of the amino acid which was tolerated well. Statistical analysis of the outcome measures showed a significant decrease in symptom severity as measured by the Positive and Negative Syndrome Scale (PANSS). Furthermore, the patient’s ability to solve the Wisconsin Card Sorting Task (WCST) was significantly improved indicating increased problem solving capacity and thinking flexibility. Thus, these findings suggest that there may be beneficial effects of L-lysine treatment on symptom severity and cognitive deficits in patients with schizophrenia.

The number of subjects investigated in our study was small, however, and a study has now been initiated with larger statistical power in the hope to further strengthen our hypothesis. The overbridging goal of our research is to gain an increased understanding of the underlying aetiology and pathophysiology of the cognitive core symptoms of schizophrenia. We also hope that our research will lead to improved treatment therapies against this illness.

References

Pålsson E, Fejgin K, Wass C, Engel JA, Svensson L, Klamer D (2007) The amino acid L-lysine blocks the disruptive effect of phencyclidine on prepulse inhibition in mice. Psychopharmacology (Berl) 192: 9-15

Wass C, Klamer D, Katsarogiannis E, Pålsson E, Svensson L, Fejgin K, Bogren IB, Engel JA, Rembeck B (2011) L-lysine as adjunctive treatment in patients with schizophrenia: a single-blinded, randomized, cross-over pilot study. BMC Med 9:40

 

Bild på Caroline Wass

Caroline Wass

Med Dr., Associate Professor, Principal Investigator
Phone: 46 31-786 34 20
Email: caroline@wass@pharm.gu.se

Research group members

Lennart Svensson,
Associate Professor

Daniel Klamer,
Associate Professor

Angela Bodden,
MD
 

Page Manager: Lennart Svensson|Last update: 5/18/2016
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