Pharmacological interventions in clozapine-refractory schizophrenia

This thesis focuses on treatment challenges such as severe cognitive impairments, prominent persistent negative symptoms and treatment-resistant positive symptoms. New treatment approaches to overcome glutamatergic deficits in schizophrenia seem promising in treatment-resistant schizophrenia. The glutamate hypothesis proposes that the specific combination of the glutamate agonist clozapine and the voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist memantine results in upregulation of the NMDA receptor. The encouraging results of a first proof-of-concept study with large effect size for all symptom domains of schizophrenia impelled me to further investigate this combination therapy. My research team and I have provided additional encouraging clinical results for memantine as an adjunctive to clozapine in refractory schizophrenia. Memantine slightly improved memory and negative symptoms after twelve weeks of treatment in a double-blind, placebo-controlled study. In an open-label, one-year extension study the small improvement of memory was sustained and a large improvement in negative and positive symptoms and impaired psychosocial functioning was found in the first 26 weeks and second 26 weeks. In conclusion, further research on memantine as clozapine augmentation strategy in patients suffering from treatment-resistant schizophrenia is justified