Neurobiological and Neurocognitive Disturbances in First-episode Schizophrenia

5-HT2A-receptor Binding: Implications for the Pathophysiology of Schizophrenia and Effects of Treatment With Antipsychotic Drugs

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

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: quetiapine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Neurobiology Research Unit, Rigshospitalet
  • Glostrup, Denmark, DK-2600
    • Center for Neuropsychiatric Schizophrenia Research, University of Copenhagen, Psychiatric Center Glostrup
  • Hvidovre, Denmark, DK-2650
    • Danish Research Center for Magnetic Resonance Imaging, Hvidovre Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: quetiapine; flexible doses according to the clinical condition

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
5-HT2A receptor binding and occupancy (PET)	Baseline and after 6 months
Structural MRI	Baseline and after 6 months
Functional MRI	Baseline and after 6 months
Information procession as measured with psychophysiological methods (P300, PPI, P50 gating ect.)	Baseline and after 6 months
An extensive battery of neurocognitive measures	Baseline and after 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
PANSS	Baseline and after 6 months

Collaborators and Investigators

• Sponsor: Birte Glenthoj
• Collaborators: AstraZeneca; Rigshospitalet, Denmark; University of Copenhagen; Glostrup University Hospital, Copenhagen; Copenhagen University Hospital, Hvidovre; The Danish Medical Research Council; Copenhagen Hospital Corporation
• Investigators: Study Director: Birte Glenthoj, MD, DMSc., Center for Neuropsychiatric Schizophrenia Research, University of Copenhagen, Psychaitric Center Glostrup, Ndr. Ringvej, DK-2600 Glostrup, Denmark

Publications and helpful links

General Publications

• Jessen K, Mandl RCW, Fagerlund B, Bojesen KB, Raghava JM, Obaid HG, Jensen MB, Johansen LB, Nielsen MO, Pantelis C, Rostrup E, Glenthoj BY, Ebdrup BH. Patterns of Cortical Structures and Cognition in Antipsychotic-Naive Patients With First-Episode Schizophrenia: A Partial Least Squares Correlation Analysis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 May;4(5):444-453. doi: 10.1016/j.bpsc.2018.09.006. Epub 2018 Sep 25.
• Ebdrup BH, Skimminge A, Rasmussen H, Aggernaes B, Oranje B, Lublin H, Baare W, Glenthoj 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. doi: 10.1017/S1461145710000817. Epub 2010 Aug 12.
• Ebdrup BH, Glenthoj B, Rasmussen H, Aggernaes B, Langkilde AR, Paulson OB, Lublin H, Skimminge A, Baare W. Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia. J Psychiatry Neurosci. 2010 Mar;35(2):95-104. doi: 10.1503/jpn.090049.
• Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baare 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. doi: 10.1001/archgenpsychiatry.2009.176.

Helpful Links

• Center for Neuropsychiatric Schizophrenia Research (CNSR)

Study record dates

Study Major Dates

• Study Start: April 1, 2004
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: September 10, 2005
• First Submitted That Met QC Criteria: September 20, 2005
• First Posted (Estimate): September 21, 2005

Study Record Updates

• Last Update Posted (Estimate): September 19, 2011
• Last Update Submitted That Met QC Criteria: September 16, 2011
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Keywords: MRI; quetiapine; fMRI; PPI; endophenotypes; P300; altanserin; P50 gating; first-episode; 5-HT2A receptors; vulnerability indicators
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Quetiapine Fumarate
• Other Study ID Numbers: 363055; H-KF-01-078/97 (Other Identifier: Ethical Comitee Copenhagen)