Thyroid Indices and Response to Fluoxetine and Nortriptyline in Major Depression

Abstract

We investigated: (i) the status of thyroid hormones and their clinical correlates in patients with major depression; (ii) changes in thyroid hormone status after treatment with fluoxetine versus nortriptyline; and (iii) whether blunted thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) challenge predicts improvement after 6 weeks of fluoxetine versus nortriptyline treatment. Patients with major depression entering a treatment trial were assessed with the Structured Clinical Interview for DSM-III-R and were rated on the Montgomery–Asberg Depression Rating Scale (MADRS). Blood samples were taken for TSH, thyroxine (T4) and free thyroxine (FT4) measurement, and the maximum TSH response (δmaxTSH) to a TRH challenge test was undertaken. Patients were then randomly assigned to receive fluoxetine or nortriptyline for six weeks. At 6 weeks, patients repeated the thyroid hormone assessment and completed the MADRS. Mean concentrations of TSH, T4, FT4 and δmaxTSH were within reference ranges. T4 and FT4 levels decreased significantly after treatment in responders, but not in nonresponders. After treatment,δmaxTSH concentrations decreased significantly in patients who responded to fluoxetine, and increased in patients who responded to nortriptyline. Patients with δmaxTSH blunting at pretreatment were more likely to be male, to have higher MADRS scores and have a history of alcohol and drug dependence. Patients with a pretreatmentδmaxTSH of < 3.0 µm/ml showed greater improvement on the MADRS when treated with fluoxetine than if treated with nortriptyline. We observed a decrease in T4 and FT4 in responders to treatment with fluoxetine or nortriptyline. Positive relationships between δmaxTSH blunting and alcohol and drug abuse and severity of depression were found. Patients with bluntedδmaxTSH responded better to fluoxetine than to nortriptyline. It is suggested that a blunted DmaxTSH may reflect a predominantly serotonergic disturbance in this group of patients with major depression.

Keywords

antidepressants major depression thyroid hormones treatment response

Get full access to this article

View all access options for this article.

References

Amsterdam J D , Fava M , Maislin G , Rosenbaum J , Hornig-Rohan M (1996) TRH stimulation test as a predictor of acute and long-term antidepressant response in major depression . J Affect Disord 38: 165–172

Arana G W , Zarzar M N , Baker E (1990) The effect of diagnostic methodology on the sensitivity of the TRH stimulation test for depression: a literature review . Biol Psychiatry 28: 733–737

Bauer M , Heinz A , Whybrow P C (2002) Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain . Mol Psychiatry 7: 140–156

Baumgartner A , Graf K J , Kurten I , Meinhold H (1988) The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects: parts 1–4 . Psychiatry Res 24: 271–283

Baumgartner A , Campos-Barros A , Meinhold H (1992) Thyroid hormones and depressive illness: Implications for clinical and basic research . Acta Medica Austrica 19: 98–102

Baumgartner A , Dubeyko M , Campos-Barros A , Eravci M , Meinhold H (1994) Subchronic administration of fluoxetine to rats affects triiodithyronine production and deiodination in regions of the cortex and limbic forebrain . Brain Res 635: 68–74

Brady K T , Anton R K (1989) The thyroid axis and desipramine treatment in depression . Biol Psychiatry 25: 703–709

Campos-Barros A , Meinhold H , Stula M , Muller F , Kohler R , Eravci M , Putzien O , Baumgartner A (1994) The influence of desimipramine on thyroid hormone metabolism in rat brain . J Pharmacol Exp Therapeut 268: 1143–1152

Cleare A J , McGreogor A , O’Keane V (1995) Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression . Clin Endocrino l43: 713–719

10.

Duval F , Mokrani M C , Bailey P , Correa H , Diep T S , Crocq M A , Macher J P (1999) Thyroid axis activity and serotonin function in major depressive episode . Psychoneuroendocrinology 24: 695–712

11.

Fava M , Labbate L A , Abraham M E , Rosenbaum J F (1995) Hypothyroidism and hyperthyroidism in major depression revisited . J Clin Psychiatry 56: 186–192

12.

Fava M , Rosenbaum J F , Birnbaum R , Kelly K , Otto M W , MacLaughlin R (1992) The thyrotropin response to thyrotropin releasing hormone as a predictor of response to treatment in depressed outpatients . Acta Psychiatrica Scand 86: 42–45

13.

Garbutt J C , Mayo J P , Little K Y , Gillette G M , Mason G A , Dew B , Prange A J (1996) Dose–response studies with thyrotropin releasing hormone: evidence for differential pituitary responses in men with major depression, alcoholism, or no psychopathology . Alcohol Clin Exp Res 20: 717–722

14.

Gewirtz G R , Malaspina D , Hatterer J A , Feureisen S , Klein D , Gorman J M (1988) Occult thyroid dysfunction in patients with refractory depression . Am J Psychiatry 145: 1012–1014

15.

Gold M S , Pottash A L C , Extein I (1981) Hypothyroidism and depression , JAMA 245: 1919–1922

16.

Hendrick V , Altshuler L , Whybrow P (1998) Psychoneuroendocrinology of mood disorders. The hypothalamic-pituitary-thyroid axis . Psychiatric Clin North Am 21: 277–292

17.

Howland R H (1993) Thyroid dysfunction in refractory depression: implications for pathophyiology and treatment . J Clin Psychiatry 54: 47–54

18.

Joffe R T (1999) Peripheral thyroid hormone levels in treatment resistant depression . Biol Psychiatry 45: 1053–1055

19.

Joffe R T , Levitt A J (1993) The thyroid and depression. In Joffe R T , Levitt A J (eds), The thyroid axis and psychiatric illness. American Psychiatric Press, Washington, DC

20.

Joffe R T , Levitt A J (1992) Major depression and subclinical (grade 2) hypothyroidism . Psychoneuroendocrinology 17: 215–221

21.

Joffe R T , Singer W (1987) Effect of phenelzine on thyroid function in depressed patients . Biol Psychiatry 22: 1033–1035

22.

Joffe R T , Singer W (1990) The effect of tricyclic antidepressants on basal thyroid hormone levels in depressed patients . Pharmaco-psychiatry 23: 67–69

23.

Kirkegaard C , Faber J (1998) The role of thyroid hormones in depression . Eur J Endocrinol 138: 1–9

24.

Langer G , Aschauer H , Koinig G , Resch F , Schussler H , Schonbeck G (1983) The TSH response to TRH: a possible predictor of outcome to antidepressant and neuroleptic treatment . Prog Neuropsychopharmacol Biol Psychiatry 7: 335-335

25.

Linnoila M , Gold P , Potter W Z , Wehr T A (1981) Tricyclic anti-depressants do not alter thyroid hormone levels in patients suffering from a major affective disorder . Psychiatry Res 4: 357–360

26.

Loosen O T , Prange A J (1982) Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review . Am J Psychiatry 139: 405–416

27.

Maes M , Meltzer H Y , Cosyns P , Suy E , Schotte C (1993) An evaluation of basal hypothalamic-pituitary-thyroid axis function in major depression: results of a large-scaled and controlled study . Psychoneuroendocrinology 18: 607–620

28.

Maes M , Vandewoude M , Maes L , Schotte C , Cosyns P (1989) A revised interpretation of the TRH test results in female depressed patients . J Affect Disord 16: 203–213

29.

Martin J B , Reichlin S (1987) The regulation of TSH secretion and its disorders. In Martin J B , Reichlin S (eds), Clinical neuroendocrinology. FA Davis, Philadelphia

30.

Miles L (1977) Handbook of radioimmunoassay. Marcel Dekker, New York

31.

Montgomery S A , Asberg M A (1979) A new depression scale designed to be sensitive to change . Br J Psychiatry 134: 382–389

32.

Rao M L , Ruhrmann S , Retey B , Liappis N , Fuger J , Kraemer M , Kasper S , Moller H-J (1996) Low plasma thyroid indices of depressed patients are attenuated by antidepressant drugs and influence treatment outcome . Pharmacopsychiatry 29: 180–186

33.

Schlienger J L , Kapfer M T , Signer F , Stephan F (1980) The action of clomipramine on thyroid function . Hormone Metab Res 12: 481–482

34.

Shelton R C , Winn S , Ekhatore N , Loosen P T (1993) The effects of antidepressants on the thyroid axis in depression . Biol Psychiatry 33: 120–126

35.

Singhai R L , Rastogi R B , Hrdina P D (1975) Brain biogenic amines amines and altered thyroid function . Life Sci 17: 1617–1626

36.

Spitzer R L , Willianms J B , Gibbon M , First M B (1992) The Structured Clinical Interview for DSM-III-R (SCID): I. history, rationale and description . Arch Gen Psychiatry 49: 624–629

37.

Vandoolaeghe E , Maes M , Vandevyvere K , Neels H (1997) Hypothalamic-pitiutary-thyroid-axis function in treatment resistant depression . J Affect Disord 43: 143–150

38.

Whybrow P (1995) Sex differences in thyroid axis function: Relevance to affective disorder and its treatment . Depression 3: 33–42

39.

Whybrow P , Prange A J (1981) A hypothesis of thyroid-catecholamine–receptor interaction . Arch Gen Psychiatry 38: 106–111