Cohort A

​This was the first of CNSR’s cohort studies on antipsychotic-naïve first-episode patients with schizophrenia and is thus also known as cohort A. The study began in 1998 and investigated the connection between extrastriatal dopamine D2/3 receptor availability, cognition, brain structure, and psychopathology in first-episode antipsychotic-naïve patients and matched healthy controls. Data from this cohort are still used in several current research projects at CNSR.

 

 

From 1998 to 2001, patients with first-episode schizophrenia were included in connection with their first psychotic episode and before they had received any antipsychotic medication. A control group of age- and gender-matched healthy controls were also included.

The subjects were investigated with an extensive test battery including MRI, cognitive testing, psychophysiology and rating scales, all of which can be compared to the availability of extrastriatal dopamine D2/3 receptors assessed with SPECT and the D2/3 receptor ligand [123I]epidepride. This ligand is suitable for the examination of extrastriatal D2/3 receptors.

 After baseline investigations, patients were randomized to treatment with either the first-generation (zuclopenthixol) or the second-generation (risperidone) antipsychotic tool compound, both with high affinity for dopamine D2 receptors.

The study is the first ever to relate cortical dopamine D2/3 receptor binding to cognition in schizophrenia patients. Among the clinically highly relevant data from cohort A was the finding of significant associations between verbal fluency, planning and attention, and frontal dopamine D2/3 receptor binding potentials (BP) in these antipsychotic-naïve patients (Fagerlund et al. 2013).

Held together with previous psychopathological data from the same cohort (Glenthøj et al. 2006), the data suggests an inverted U-curve for optimal frontal dopamine D2 receptor availability in schizophrenia patients, as has previously been demonstrated for dopamine D1 receptor activity in preclinical studies. The clinical implication is that it is important to find the optimal window for dopamine D2 receptor blockade in individual patients which our later analyses regarding e.g. cognitive deficits also support (Nørbak-Emig et al.  2016).

The results further suggested that cortical dopamine D2/3 receptor function may be more involved in cognition in patients with schizophrenia than in healthy subjects, suggesting that information processing in schizophrenia may be characterised by lower signal-to-noise ratios (Fagerlund et al. 2013).

Data from this cohort are still used in several studies at CINS/CNSR. At the moment, data from cohort A form the basis for an analysis of whether dopamine D2/D3 receptor BP in drug-naïve patients can serve as a biomarker for progressive brain changes and clinical outcome. Participants are currently being re-examined for the second time for a longitudinal investigation of cognition and brain changes, and finally data from the cohort is included in CINS/CNSR's machine learning study.

 

 

PhD theses based on data from this cohort:

  • Birgitte Fagerlund: The Impact of Age of Onset and Effects of Antipsychotics on Executive Functions, Attention, and Reaction Time: A Study of Cognitive Functions in First-Episode Psychotic Children and Schizophrenic Adults (2004)
  • Trine Hammer, "Schizophrenia: The clinical, psychophysiological and neurobiological manifestations of the disease" (2011)
  • Torben Mackeprang,"Information processing and dopamine activity in drug-naive schizophrenic patients" (2002)
  • Henrik Nørbak-Emig  "Dopamine D2 receptor binding, brain structure and psychopathology in antips ychotic-naïve first-episode schizophrenia patients: Associations before and after antipsychotic monotherapy" (2016)
  • Lea Klærke "Investigating the association between cognition and structural brain changes in patients with schizophrenia: A long-term follow-up study" (expected 2019)

 

Postdoctoral projets based on data from this cohort:

  • Louise Baruel Johansen

 

 

Selected articles based on data from this project:

  • Glenthoj BY, Mackeprang T, Svarer C, Rasmussen H, Pinborg LH, Friberg L, Baaré W, Hemmingsen R, Videbaek C. Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry. 2006 Sep 15;60(6):621-9
  • Fagerlund B, Pinborg LH, Mortensen EL, Friberg L, Baaré WF, Gade A, Svarer C, Glenthøj BY. Relationship of frontal D(2/3) binding potentials to cognition: a study of antipsychotic-naive schizophrenia patients. Int J Neuropsychopharmacol. 2013 Feb;16(1):23-36.
  • Nørbak-Emig, H., Ebdrup, B. H., Fagerlund, B., Svarer, C., Rasmussen, H., Friberg, L. A., Allerup, P. N., Rostrup, E., Pinborg, L. H. & Glenthøj, B. Y. Frontal D2/3 receptor availability in schizophrenia patients before and after their first antipsychotic treatment: Relation to cognitive functions and psychopathology. International Journal of Neuropsychopharmacology.Fagerlund B, Mackeprang T, Gade A, Glenthøj BY. Effects of low-dose risperidone and low-dose zuclopenthixol on cognitive functions in first-episode drug-naive schizophrenic patients. CNS Spectr. 2004 May;9(5):364-74.
  • Fagerlund B, Mackeprang T, Gade A, Hemmingsen R, Glenthøj BY. Executive Functions in Drug-Naive First-Episode Schizophrenics. Brain Cogn. 2001;47:249-252.

 

 

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