The applicant's long-term goal is a successful academic career in clinical psychology. This training grant will enable the applicant to develop a program of research focusing on translational research applying models of genetic vulnerability to research on the treatment-refractory negative symptoms of schizophrenia. There is growing need for association studies targeting endophenotypes in the search for the underlying biological mechanisms of schizophrenia. There evidence that one endophenotype, anhedonia, or the extent to which an individual reports pleasure or interest in social and physical stimuli, is associated with genetic liability to schizophrenia, and with differences in prodromal vulnerability to schizophrenia-spectrum disorders. Anhedonia has been most predictive of schizophrenia-spectrum disorders of any self-reported schizotypal symptom in multiple longitudinal studies. It has also been the only self-reported schizotypal trait to consistently differentiate first-degree relatives of people with schizophrenia from controls. In people with schizophrenia, anhedonia indicates poorer prognosis of the illness and poorer functional outcome. Despite its importance as an endophenotype, it has been unclear how anhedonia might directly relate to the neurobiological substrates of schizophrenia. Currently, there is evidence that anhedonia is associated with differences in emotion processing, specifically with decreased positive affect intensity. However, no one has yet studied this association in patients or their first-degree relatives. In addition, there is evidence for genetic underpinnings of anhedonia in first-degree relatives. First, aberrant dopamine transmission may relate to the processing of positive emotion, and is implicated in symptoms of schizophrenia and in genetic vulnerability to psychosis. One prior study has found that relatives with a high-activity polymorphism of the Val158Met catechol-o-methyl-transferase (COMT) gene, responsible for the inhibition of dopamine, have higher levels of self-reported anhedonia. Second, there is now evidence that anhedonia may be related to disrupted-in- schizophrenia-1 (DISC1) gene expression in humans, a gene that influences hippocampal function. However, possible associations of anhedonia with candidate single nucleotide polymorphisms have rarely been examined in first-degree relatives of people with schizophrenia. It is important to examine both emotion processing in anhedonia and endophenotype-genotype associations, to develop a better understanding of this treatment-refractory symptom. NIMH is currently seeking the unification of advanced statistical methodologies and enhancements in measurement that will facilitate the reduction of heterogeneity and further the search for the genetic basis of psychopathology. This study attempts to address that aim.
Project Summary: Relevance The current research has the potential to inform both prevention efforts and treatment for people with schizophrenia. Understanding the relationship between specific genetic mechanisms and subclinical schizotypal symptoms in first-degree family members, as well as the relationship between negative symptoms and affective processing in genetic liability to schizophrenia may impact both psychological and pharmacological treatments for schizophrenia. Moreover, understanding these mechanisms may help to improve functional outcome in people with schizophrenia, since anhedonia has been strongly associated with functional outcome.
|Docherty, Anna R; Sponheim, Scott R; Kerns, John G (2015) Self-reported affective traits and current affective experiences of biological relatives of people with schizophrenia. Schizophr Res 161:340-4|
|Docherty, Anna R; Sponheim, Scott R; Kerns, John G (2014) Further examination of ambivalence in relation to the schizophrenia spectrum. Schizophr Res 158:261-3|
|Eaton, Nicholas R; Krueger, Robert F; Docherty, Anna R et al. (2014) Toward a model-based approach to the clinical assessment of personality psychopathology. J Pers Assess 96:283-92|
|Docherty, Anna R; Sponheim, Scott R; Gizer, Ian R (2014) DISC1 loci not associated with anhedonia in individuals with genetic liability for schizophrenia. Psychiatr Genet 24:120-1|
|Vrieze, Scott I; Docherty, Anna; Thuras, Paul et al. (2013) Best practices: The electronic medical record is an invaluable clinical tool: let's start using it. Psychiatr Serv 64:946-9|