Systematic Review and Meta-Analysis: Neurocognitive Alterations in Offspring of Individuals With Schizophrenia or Bipolar Disorder Compared to Offspring of Unaffected Parents.

OBJECTIVE: The aim of this study is to conduct a meta-analytic examination of neurocognitive functioning in offspring of parents with schizophrenia (FHR-SZ) and offspring of parents with bipolar disorder (FHR-BD), examining both their differences from healthy control offspring (HC) and from each other.

METHOD: A systematic search was conducted from inception to November 7, 2024. Studies included FHR-SZ and/or FHR-BD, a group of HC, and measures of neurocognitive performance. Exclusion criteria included studies without a control group or non-English-language publications. Data were extracted by 4 researchers and assessed using a modified version of the Newcastle-Ottawa Scale. Random-effects meta-analyses were conducted, with heterogeneity assessed using the Q statistic and I2 index. Meta-regressions examined the effects of age, sex, and study quality.

RESULTS: The sample comprised 3,475 FHR-SZ (mean age = 8.34 years, SD = 1.36; 54% female), 3,020 FHR-BD (mean age = 8.62 years, SD = 1.26; 46% female), and 5,272 HC (mean age = 8.48 years, SD = 1.23; 51% female). FHR-SZ showed significant impairments compared to HC across most cognitive domains, with the largest deficits in visual learning (g = -2.47), motor functioning (g = -1.85), and general intelligence (g = -1.30). In contrast, FHR-BD showed milder deficits, notably in visual learning (g = -0.87), verbal learning (g = -0.83), and processing speed (g = -0.53). FHR-SZ performed significantly worse than FHR-BD in attention, general intelligence, motor functioning, verbal memory and working memory.

CONCLUSION: Offspring of parents with SZ or BD show generalized neurocognitive dysfunction, with greater impairments in FHR-SZ. Neurocognitive functioning is a critical target for early interventions.

PLAIN LANGUAGE SUMMARY: In this meta-analysis, the authors reviewed 68 studies on children of parents with schizophrenia or bipolar disorder. Compared to children of healthy parents, children of parents with schizophrenia and bipolar disorder both showed worse cognitive functioning, especially in memory, learning, and intelligence. Cognitive deficits were more severe in children of parents with schizophrenia.

CLINICAL GUIDANCE: • Routine cognitive screening may be warranted in clinical settings for youth with familial risk for severe mental illness, even in the absence of symptoms.

STUDY REGISTRATION INFORMATION: Differences in Cognitive Performance Between Individuals at Familial High Risk for Schizophrenia or Bipolar Disorder and Healthy Controls: A Protocol for a Systematic Review and Meta-Analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024498909.

DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote sex and gender balance in our author group.