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Decreased thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus of patients with major depression

Molecular Psychiatry volume 8, pages 838–839 (2003)Cite this article

SIR—Several studies have suggested that thyroid hormone comedication may increase response rates in subjects with major depression refractory to tricyclic antidepressants (TCA).1 In addition, intrathecal administration of thyrotropin-releasing hormone (TRH) has shown beneficial effects in one study involving patients with treatment-resistant depression.2 Furthermore, a number of subtle abnormalities in the hypothalamus–pituitary–thyroid (HPT)-axis occur in a large proportion of subjects with major depression. The thyroid-stimulating hormone (TSH) response to TRH is often blunted and the nocturnal TSH surge may be absent.3 We hypothesized that alterations in hypothalamic TRH may be involved in the pathogenesis of these endocrine changes, and studied TRH gene expression in the hypothalamic paraventricular nucleus (PVN) of seven subjects with unipolar depression (n=5 major depression, n=2 depressive syndrome not otherwise specified) and seven control subjects matched for age, sex and for nonthyroidal illness.4 In addition, we studied one subject with biochemically documented thyrotoxicosis 3 weeks before death (serum fT4 44.2 pmol/l (n: 10–23 pmol/l) and TSH<0.01 mU/l (n: 0.4–4.0 mU/l) as a reference point for possible changes in depression. Brain material was obtained from the Netherlands Brain Bank. The DSM-IV criteria were used for the psychiatric diagnosis. Both subjects with depressive syndrome not otherwise specified had suffered from severe chronic depression involving a long and consistent death-wish. Exclusion criteria were: drugs known to influence the HPT-axis and thyroidal or neurodegenerative disease. Methods for in situ hybridization and TRH mRNA quantification have been described previously.4,5

An important issue is whether the decrease in TRH mRNA can be attributed to a pharmacological effect of antidepressants, that is, TCA, selective serotonin reuptake inhibitors (SSRI), non-selective MAO inhibitors and lithium. Studies in rat have shown that repeated treatment with TCA and SSRIs does not alter TRH content in the hypothalamus,6 while in humans changes in serum TSH seem to result from the underlying psychiatric disease rather than from a direct effect of these antidepressants.7 One depressed subject in our study used lithium, which is known to induce a rise in basal TSH reflecting primary hypothyroidism in susceptible patients.7 Thus, the decrease in TRH mRNA that we found in this subject may even be underestimated. In sum, it is unlikely that the decreased TRH expression in our study results from pharmacological treatment.

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Authors and Affiliations

  1. Netherlands Institute for Brain Research, Meibergdreef 33, Amsterdam, 1105 AZ, The Netherlands

    A Alkemade, U A Unmehopa, D F Swaab & E Fliers

  2. Department of Endocrinology and Metabolism, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands

    A Alkemade, J P Brouwer, W M Wiersinga & E Fliers

  3. Department of Psychiatry, Vrije Universiteit, Amsterdam, The Netherlands

    W J G Hoogendijk

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  1. A Alkemade
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  2. U A Unmehopa
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  3. J P Brouwer
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  7. E Fliers
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Correspondence to A Alkemade.

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Alkemade, A., Unmehopa, U., Brouwer, J. et al. Decreased thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus of patients with major depression. Mol Psychiatry 8, 838–839 (2003). https://doi.org/10.1038/sj.mp.4001364

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