Etiopathogenic differences between affective and non-affective psychosis: filling the gaps

Student thesis: Doctoral ThesisDoctor of Philosophy


Background: Classical non-affective psychosis –NAP- and affective psychosis –AP- (in which we would include Bipolar disorder and Psychotic Depression) has constituted the two main pillars of psychosis since Kraepelin established the classical dichotomy back in the 8th century (1910). Due to their similarities in terms of clinical expression, social and individual impact, associated risk factors and high crossed heritability with proven genetic overlap, there has been in the last years a trend to overcome accepted classical diagnostic boundaries and switch towards the concept of psychotic spectrum in line with the notion of unique psychosis. Nonetheless, there are still grounds to believe that a future finer clustering may identify subgroups corresponding to current diagnostic categories. For instance, whereas overall incidence of psychosis is 21-43/100kpy; last meta-analyses pointed NAP to be around 18.7/100kpy, and AP around 4.8/100kpy. Part of the clustering is potentially supported by etiopathogenic factors. Firstly, there is polygenic evidence of differences over the shared liability, which is mostly true when we include major depression with psychotic symptoms. Secondly, despite known shared environmental risk factors (ERF) such as cannabis and childhood trauma, evidence in literature provides much more evidence for the NAP. Notwithstanding, part of these disparities may be caused by the significant gap observed in AP research compared with NAP.
Aims: The focus of this thesis is to explore the overview differences between AP and NAP while contributing to fill part of the gap in relevant areas related to etiopathogenesis. I aim to do this by compiling evidence on relevant environmental risk factor for AP meta-analysing prospective studies; calculating incidence of Bipolar Disorder and Psychotic Depression employing a large first episode psychosis (FEP) multinational sample; studying the genetic architecture of AP throughout the joint use of polygenic scores for major psychiatric disorder across clinical subgroups; and lastly, by studying etiopathogenic pathways differences analysing how polygenic liability and combined ERF exposure interplay in NAP and AP.
Methods: This PhD is mainly based on the EUGEI study (EUropean Network of national schizophrenia networks studying Gene-Environment Interactions); a multisite incidence and case-control study of genetic and environmental determinants involved in the development of psychotic disorders. It comprises a total of 2627 participants, including 1130 patients aged 18 to 64 years diagnosed with NAP, Bipolar Disorder or Psychotic Depression; and 1497 controls in 17 sites across 6 mostly European countries.
Results: Primarily, the performed meta-analysis supports a shared environmental load with NAP, showing significant associations of advanced paternal age (OR 1.17, 95%CI 1.12-1.23), early (OR 1.52, 95%CI 1.07-2.17) and late (OR 1.32, 95%CI 1.05-1.67) gestational age, childhood adversity (OR 1.33, 95%CI 1.18-1.50), substance misuse (OR 2.87, 95%CI 1.37–5.50), and being from an ethnic minority (OR 1.99, 95%CI 1.39-2.84) with onset of AP. Secondly, our results shows previously observed differences on overall incidence between psychotic phenotypes, being around 9.53/100kpy for schizophrenia, compared with around 2.42/100kpy and 2.72/100kpy for Bipolar Disorder and Psychotic Depression respectively, with marked differences across sites which partly account for ethnicity and owner occupancy. When looking at the genetic load employing polygenic risk scores for schizophrenia, bipolar disorder, depression and intelligence, both scores for schizophrenia (OR=0.7, 95 %CI 0.54-0.92) and depression (OR=1.31, 95%CI 1.06-1.61) differentiates AP from NAP; which talks in favour of some clustering over the known genetic overlap. Lastly, although no evidence was found of a synergistic effect of genetic loading on onset of AP, conditional on history of cumulative adverse environmental factors, differential genetic associations based on individual exposure to ERF talks in favour of distinct pathways of disease for AD and NAP. AP seems to be a product of cumulative environmental insults alongside a higher genetic liability for affective disorders; NAP seem to be due to two distinct pathways: PRS-SZ acting additively with ERF, and PRS-BD and PRS-D potentially acting through the affective pathway to psychosis in the light of ERF.
Conclusions and implications: Overall, this thesis provides support for the view that both environment and genetics play their specific role on AP. Despite these factors presenting a noticeable overlap with those factors replicated for NAP, which supports a transdiagnostic effect across psychosis, certain distinctions and differentiations were found for AP. These results require replication, but in combination with future avenues (from biology to sociology), ensure exciting findings in our understanding of the etiopatogenic underpinnings of AP, which will ultimately give us ground to set clearer splits over the lumps.
Date of Award1 Oct 2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRobin Murray (Supervisor) & Evangelos Vassos (Supervisor)

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