Brief report
The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS

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Abstract

Background

Thyroid hormone plays a role in both serotonin and catecholamine functions in the brain, and has been linked to abnormal mood states in bipolar disorder. Unlike most studies which have included only patients with bipolar I, this study evaluated triiodothyronine (T3) as an augmentation agent for treatment-resistant depression in patients with bipolar II and bipolar disorder NOS.

Methods

This study was a retrospective chart review of patients treated in a private clinic between 2002 and 2006. The charts of 125 patients with bipolar II disorder and 34 patients with bipolar disorder NOS were reviewed.

Results

Patients had been unsuccessfully treated with an average of 14 other medications before starting T3. At an average dose of 90.4 mcg (range 13 mcg–188 mcg) the medication was well tolerated. None of the patients experienced a switch into hypomania, and only 16 discontinued due to side effects. Improvement was experienced by 84%, and 33% experienced full remission.

Limitations

The limitations are those associated with the retrospective chart review design.

Conclusions

A high percentage of bipolar II and bipolar NOS patients with treatment resistant depression improved on T3. Despite the use of higher than usual doses in many of the patients, the medication was well tolerated. Augmentation with supraphysiologic doses of T3 should be considered in cases of treatment resistant bipolar depression.

Introduction

Sir William Osler in The Principles And Practice Of Medicine noted that Caleb Hillier Parry was the first to connect thyroid abnormalities with psychiatric disorders (Osler, 1901). Most studies concerning thyroid hormones in depression are more than twenty years old, some of them having good methodological designs but few participants (Bahls and de Carvalho, 2004). The recently completed STAR⁎D (Sequenced Treatment Alternatives to Relieve Depression) study was one of the largest studies to evaluate thyroid hormone in depression. Patients with major depressive disorder who had experienced inadequate benefits or drug intolerance in at least two previous drug trials were offered augmentation with triiodothyronine (T3). The dose was limited to 50 mcg, and 25% experienced remission.

Thyroid hormone plays a role in both serotonin and catecholamine function in the brain. Plasma serotonin levels have been found to be positively correlated to T3 concentrations (Cleare et al., 1995), and a hypothesized mechanism of this effect is the interaction between thyroid hormones and serotonergic auto-receptors. Thyroid hormones given to euthyroid animals, and those with induced hypothyroidism, caused a desensitization of the 5HT1A inhibitory auto-receptors, and increased serotonin in the cortex (Heal and Smith, 1998). Similarly, thyroid hormones have been found to influence the activity of beta-adrenergic post-synaptic receptors in which hypothyroid states can cause a functional decrease in noradrenergic neurotransmission (Hendrick et al., 1998).

Thyroid abnormalities have also been linked to abnormal mood states in bipolar disorder. Thyroid abnormalities have been associated with rapid-cycling (Cowdry et al., 1983, Bartalena et al., 1990, Oomen et al., 1996), mixed states (Chang et al., 1998), and slower treatment response (Cole et al., 2002).

There are no double-blind studies reporting the use of thyroid hormone in bipolar patients (Sachs and Thase, 2000). In an open-label trial, 10 of 11 rapid cycling bipolar patients with depression at baseline and five of seven patients with mania at baseline responded to supraphysiologic doses of levothyroxin (T4) added to their mood-stabilizing treatment regimens. (Bauer and Whybrow, 1990). Clinical response of patients was independent of initial thyroid status, and the effect was lost when the dose was reduced below supraphysiologic levels.

Most studies of thyroid hormone augmentation in bipolar disorder have included only patients with bipolar I disorder. Much less is known about bipolar II disorder and its treatment. In this study we performed a chart review of 159 patients with bipolar II or bipolar NOS disorders who suffered from refractory depression, and received augmentation with triiodothyronine (T3).

Section snippets

Methods

The charts of patients treated with T3 in a private clinic during the period of 2002–2006 were reviewed. The data were collected during the course of routine clinical practice by the lead author. The data were abstracted from the patient charts without identifying information. Patients were included in the analysis if they had a primary diagnosis of bipolar II or bipolar disorder NOS current episode depressed based on clinical examination, according to DSM-IV criteria, and had failed to attain

Results

The charts of 159 patients who met the inclusion criteria were reviewed. As shown in Table 1, the majority of patients were female. Patients had been tried on an average of 14.0 medications, exclusive of present medications, prior to being started on T3. Very few patients experienced worsening depression, and none experienced a switch into hypomania on T3. A high percentage of patients experienced improvement on T3, and approximately one third went into remission (Table 2).

There were no gender

Discussion

Thyroid augmentation is a commonly recommended treatment strategy for non-responsive bipolar mood episodes. The Expert Consensus Guidelines (Sachs et al., 2000) reported that experts frequently considered including thyroid hormone as an option in refractory bipolar disorder. Thyroid hormone was recommended for both rapid and non-rapid cycling patients for the treatment of acute depression, and the prevention of recurrent episodes of both depression and mania in rapid cycling patients. T3 was

Role of funding source

This is entirely self funded with no external support of any kind.

Conflict of interest

Tammas F. Kelly has received honoraria from GlaxoSmithKline, and AstraZeneca. Daniel Z. Lieberman has received grant support from AstraZeneca, Comentis, Eli Lilly, Epix, McNeil, Ono, Predix, Sanofi Aventis, Wyeth, and The Dalio Family Foundation, and has received honoraria from GlaxoSmithKline.

Acknowledgement

I wish to thank Lanny Douglas Nurse Practitioner for freeing up time for me to write, Drs. Larry Denmark, and Jim Phelps for their encouragement in writing the paper and finally to Charles Nemeroff, M.D., Ph.D. who encouraged me to go beyond the traditional 50 mcg of T3 that has helped so many of my patients.

References (35)

  • American Society of Health-System Pharmacists
  • American Society of Health-System Pharmacists
  • BahlsS.C. et al.

    The relation between thyroid function and depression: a review

    Rev. Bras. Psiquiatr.

    (2004)
  • BauerM.S. et al.

    Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study

    Arch. Gen. Psychiatry

    (1990)
  • BauerM. et al.

    Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression

    Mol. Psychiatry

    (2005)
  • CleareA.J. et al.

    Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression

    Clin. Endocrinol. (Oxf.)

    (1995)
  • ColeD.P. et al.

    Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function

    Am. J. Psychiatry

    (2002)
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