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St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response

Molecular Psychiatry volume 9, pages 237–251 (2004)Cite this article

Abstract

Both the prototypic tricyclic antidepressant imipramine (IMI) and the herbal product St John's wort (SJW) can be effective in the treatment of major depressive disorder. We studied hypothalamic gene expression in rats treated with SJW or IMI to test the hypothesis that chronic antidepressant treatment by various classes of drugs results in shared patterns of gene expression that may underlie their therapeutic effects. Individual hypothalami were hybridized to individual Affymetrix chips; we studied three arrays per group treatment. We constructed 95% confidence intervals for expression fold change for genes present in at least one treatment condition and we considered genes to be differentially expressed if they had a confidence interval excluding 1 (or −1) and had absolute difference in expression value of 10 or greater. SJW treatment differentially regulated 66 genes and expression sequence tags (ESTs) and IMI treatment differentially regulated 74 genes and ESTs. We found six common transcripts in response to both treatments. The likelihood of this occurring by chance is 1.14 × 10−23. These transcripts are relevant to two molecular machines, namely the ribosomes and microtubules, and one cellular organelle, the mitochondria. Both treatments also affected different genes that are part of the same cell function processes, such as glycolytic pathways and synaptic function. We identified single-nucleotide polymorphisms in the human orthologs of genes regulated both treatments, as those genes may be novel candidates for pharmacogenetic studies. Our data support the hypothesis that chronic antidepressant treatment by drugs of various classes may result in a common, final pathway of changes in gene expression in a discrete brain region.

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Acknowledgements

We thank Aaron Bertalmio, Xueying Gu, Che Hutson, and Dr João R Oliveira for their technical help. We express our gratitude to Botanicals International for providing a large amount of SJW extract from a single lot for our studies, and to Dr. H. Howardsun from Pharmanox for his analysis of SJW extract. We thank Drs. David Heber and Vay Lian W. Go for their support.

This work was supported by NIH grants AT00151, MH062777, RR00865, and RR017365 (M-LW), RR017611, RR016996, HL004526, DK058851, DK063240, HG002500, and GM061394 (JL), and by awards from NARSAD (ML-W), Dana Foundation, and Stanley Foundation (JL), and the Neuropsychiatric Institute (University of California, Los Angeles, CA, USA).

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Authors and Affiliations

  1. Department of Psychiatry, Center for Pharmacogenomics, Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    M-L Wong, F O'Kirwan, J P Hannestad, K J L Irizarry & J Licinio

  2. Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    D Elashoff

  3. Division of Endocrinology, Department of Medicine, Diabetes and Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    J Licinio

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  1. M-L Wong
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Correspondence to M-L Wong.

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Wong, ML., O'Kirwan, F., Hannestad, J. et al. St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response. Mol Psychiatry 9, 237–251 (2004). https://doi.org/10.1038/sj.mp.4001470

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