Neurobiological and Neurocognitive Disturbances in First-episode Schizophrenia

• 5-HT2A receptor binding and occupancy (PET) [ Time Frame: Baseline and after 6 months ] [ Designated as safety issue: No ]
• Structural MRI [ Time Frame: Baseline and after 6 months ] [ Designated as safety issue: No ]
• Functional MRI [ Time Frame: Baseline and after 6 months ] [ Designated as safety issue: No ]
• Information procession as measured with psychophysiological methods (P300, PPI, P50 gating ect.) [ Time Frame: Baseline and after 6 months ] [ Designated as safety issue: No ]
• An extensive battery of neurocognitive measures [ Time Frame: Baseline and after 6 months ] [ Designated as safety issue: No ]

• 5-HT2A receptor binding and occupancy (PET)
• Structural MRI
• Functional MRI
• Information procession as measured with psychophysiological methods (P300, PPI, P50 gating ect.)
• An extensive battery of neurocognitive measures
• PANSS (Positive and Negative Syndrome Scale)
• SANS (Scale for Assessment of Negative Symptoms)
• SABS (Scale for Assessment of Positive Symptoms)

We want to relate disturbances in first-episode schizophrenic patients in serotonin 5-HT2A receptors, brain structure, brain function, and information processing to each other and to psychopathology. Additionally, we want to examine the influence of 5-HT2A receptor blockade on these disturbances. We expect disturbances in the serotonergic system at baseline to correlate with specific structural and functional changes and with disruption in information processing as measured with psychophysiological and neurocognitive methods - and we expect 5-HT2A receptor blockade to reverse some of the functional and cognitive impairments. We do not expect any effect of treatment on brain structure

Patients and matched healthy controls are examined at baseline and again after the patients have been treated for 6 months with a combined 5-HT2A- and dopamine D2- receptor blocker. We have chosen the atypical antipsychotic compound, quetiapine, for the present study since this drug is characterized by a fast koff/low affinity for the dopamine D2 receptors. The purpose of the study is to examine pathophysiological and neuropsychological mechanisms - not treatment effects. We want to characterize neurobiological and functional endophenotypes or vulnerability indicators and to study their stability over time and their relation to treatment and contemporary psychopathology. To the extent that candidate endophenotypes can be characterized as stable and independent of treatment and contemporary psychopathology they will be analysed together with similar findings from previous (identical)cohorts of schizophrenic patients. Specific disturbances will also be related to candidate genes for schizophrenia.

• Ebdrup BH, Skimminge A, Rasmussen H, Aggernaes B, Oranje B, Lublin H, Baaré W, Glenthøj B. Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms. Int J Neuropsychopharmacol. 2011 Feb;14(1):69-82. Epub 2010 Aug 12.
• Ebdrup BH, Glenthøj B, Rasmussen H, Aggernaes B, Langkilde AR, Paulson OB, Lublin H, Skimminge A, Baaré W. Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia. J Psychiatry Neurosci. 2010 Mar;35(2):95-104.
• Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baaré W, Svarer C, Lublin H, Knudsen GM, Glenthoj B. Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 2010 Jan;67(1):9-16.

Inclusion Criteria:

• First-episode schizophrenia. The controls are matched for age, gender and parental socioeconomic status

Exclusion Criteria:

• Previous antipsychotic treatment, mental retardation, organic brain damage, and for the controls a psychiatric diagnosis or first-degree relatives with a psychiatric diagnosis

• Rigshospitalet, Denmark
• Copenhagen University Hospital, Hvidovre
• Glostrup University Hospital, Copenhagen
• The Danish Medical Research Council
• Copenhagen Hospital Corporation
• University of Copenhagen
• AstraZeneca