Individuals diagnosed with schizophrenia and related psychotic disorders (SZ) exhibit a markedly elevated risk of premature mortality, with a 10-20-year shorter lifespan relative to the general population. Increased mortality rates in SZ are largely attributable to the early manifestation of medical conditions that normally occur later in life, a process known as 'accelerated aging'. While unhealthy lifestyle behaviors, such as smoking and unhealthy diet, account, in part, for accelerated aging in SZ, the excess of physical comorbidities cannot be solely attributed to these factors. Remarkably, the direct adverse health effects of key clinical characteristics of SZ have rarely been considered. In the general population, the absence of social contact is known to pose enormous challenges for physical health, especially at older ages. Given that social isolation is a persistent and disabling feature of SZ, it is possible that this behavior may contribute to the premature manifestation of health conditions in SZ. Building on rich pilot data pointing to significant associations between social isolation and long-term perceived health in SZ, the overarching goal is to test whether and how social isolation contributes to the health challenges of individuals with SZ as they age. With participants from Europe (EU-GEI) and the US (Olin Neuropsychiatry Research Center), the researchers will create a longitudinal database of 650 participants, including 500 individuals with SZ, and 150 of their unaffected siblings. The researchers will apply an accelerated longitudinal design by reassessing and by examining medical records of research participants who were first evaluated between the ages of 20-55 and are now 40-70 years of age, a period when many medical conditions and health problems tend to manifest. The researchers will determine the age-related association between social isolation and adverse health outcomes in SZ, test for familiality, directionality, and factors moderating this association, and determine the extent to which the COVID-19 pandemic and the resulting imposed lockdowns impacted health in SZ. The researchers will consider generalizability across countries, sexes, and race/ethnicities. The rationale for the proposed research is that in order to facilitate much-needed targeted therapies to prevent early mortality in SZ, the researchers need to better understand factors that contribute to the excess of medical comorbidities in SZ. The central hypothesis is that social isolation, a common and persistent characteristic of SZ, contributes to the excess of physical comorbidities in SZ. To meet the overall goal, the following aims are: (1) Determine the association between social isolation and adverse health outcomes in SZ; (2) Test for the directionality, and moderating factors, of the association between social isolation and health outcomes in SZ, and; (3) Examine whether the COVID-19 pandemic modified associations between social isolation and health outcome in SZ. This study will be the first to comprehensively examine the health impact of social isolation in SZ. The project may show that in SZ socialization in midlife can reduce the risk for poor health outcomes and ultimately facilitate much-needed preventive targeted therapies to reduce early-age mortality in SZ

An accelerated longitudinal design is employed, combining prior research data collected when participants were aged 20-55 with new follow-up assessments now that they are aged 40-70.

Inclusion and exclusion criteria for participants with SZ:

• DSM-IV or V diagnosis of a SZ related disorder (295.x, 297.1, 298.8, or 298.9; e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, but not psychotic disorder that is solely substance induced) based on clinical interview;
• Between 40 and 70 years of age at time of study recruitment;
• Participant was enrolled in a previous research study between the ages of 20-55, and this study took place at least 5 years ago;
• Able to understand the spoken language of the participating country sufficiently to comprehend testing procedures;
• No history of serious head injury (i.e., loss of consciousness longer than 1 hour, no neuropsychological sequelae, no cognitive rehabilitation treatment post head injury);
• No history of IQ < 70, or developmental disability based on chart review;
• Clinically stable (i.e., no inpatient hospitalizations for three months prior to enrollment, no changes in medication in the four weeks prior to enrollment;

The inclusion and exclusion criteria for sibling participants in this study will be:

• No history of any DSM IV/V Axis I or axis II diagnosis that is known to be associated with social functioning (e.g. severe mood disorder, schizoaffective personality disorder, autism spectrum disorder);
• Between 40 and 70 years of age at time of study recruitment;;
• Participant was enrolled in a previous research study between the ages of 20-55, and this study took place at least 5 years ago;
• Able to understand the spoken language of the participating country sufficiently to comprehend testing procedures;
• No history of serious head injury (i.e., loss of consciousness longer than 1 hour, no neuropsychological sequelae, no cognitive rehabilitation treatment post head injury);
• No history of IQ < 70, or developmental disability based on chart review;
• Clinically stable (i.e., no inpatient hospitalizations for three months prior to enrollment, no changes in medication in the four weeks prior to enrollment

500 clinically stable schizophrenia participants, and 150 of their unaffected siblings from a list of eligible participants of large existing studies of schizophrenia: e.g. EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) and large scale research studies that took place at the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT. All participants consented to be recruited for future studies.

Data from this study available in publications is shared via the NIMH National Data Archives (NDA) and is available in NDA collection C4431.