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Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies

Molecular Psychiatry volume 26, pages 3524–3535 (2021)Cite this article

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Abstract

Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large-sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.

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Fig. 1
Fig. 2: Forest plot depicting the effect sizes for studies reporting on the total hippocampus in the left and right hemisphere.
Fig. 3: Forest plot depicting the effect sizes for studies reporting on subiculum in the left and right hemisphere.
Fig. 4: Forest plot depicting the effect sizes for studies reporting on CA1 in the left and right hemisphere.
Fig. 5: Summary of overall meta-analysis findings between patients and control subjects: hippocampal volume, neuron number, neuron density, and neuron size changes by subfield and hemisphere.

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Acknowledgements

This study was supported by the Charlotte and Donald Test Fund and National Institutes of Health grants K23MH116339 (ASL) and R01MH70560 (SH). The authors thank Simon Vandekar, PhD and Ahra Kim, MPH for helpful comments on the paper.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Maxwell J. Roeske, Christine Konradi, Stephan Heckers & Alan S. Lewis

  2. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA

    Christine Konradi, Stephan Heckers & Alan S. Lewis

  3. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA

    Christine Konradi

  4. Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Christine Konradi, Stephan Heckers & Alan S. Lewis

  5. Center for Cognitive Medicine, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Alan S. Lewis

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Roeske, M.J., Konradi, C., Heckers, S. et al. Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies. Mol Psychiatry 26, 3524–3535 (2021). https://doi.org/10.1038/s41380-020-0853-y

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