Abnormalities of thyroid regulation have been detected in many patients with depressive syndromes. Patients with major depression appear to have a higher incidence of subclinical thyroid abnormalities (1), and it is clear that diseases of the thyroid can have a profound effect on mood.
Thyroid hormone is important for protein synthesis and metabolism for virtually every organ, including the brain. The release of thyroid-stimulating hormone (TSH) from the anterior pituitary is regulated by thyroid-releasing hormone (TRH) from the hypothalamus. TSH in turn prompts the release of mainly levothyroxine (T4), and to a lesser extent T3, from the thyroid gland; T4 is considered a "prohormone" with very little intrinsic activity and is transformed in the peripheral tissues into T3, the biologically active form of thyroid hormone. Through negative feedback, pituitary TSH levels are regulated by the serum free T4 and free T3, and even subtle changes often lead to substantial changes in TSH levels, making TSH a particularly useful screening test for hypothalamic-pituitary-thyroid (HPT) axis function (2).
T3 acts in the cell nucleus, stimulating gene expression and energy metabolism in cells in every organ and potentially enhancing neurogenesis in the CNS (2). T3, both alone and in combination with fluoxetine, modulates gene transcription, with changes in mRNA coding for the 5-HT1A and 5-HT1B receptors (3). In the CNS, T4 conversion to T3 occurs intracellularly, which may be why T3 administration seems to have particular benefit in the treatment of affective disorders (4). The enzymes responsible for the conversion of T4 to T3 are also different in the CNS, perhaps explaining individual responses to T3 supplementation and the variability of symptoms in subclinical hypothyroidism. Cooper-Kazaz et al. (5) have demonstrated that genetic polymorphisms in the type 1 deiodinase (DIO1) gene, which assists in the conversion of T4 to T3, might help determine which patients will respond to T3 augmentation.
It is also possible that T3 acts directly as a neurotransmitter or that it directly influences neurotransmission through monoamines (3). Actions at noradrenergic, serotonergic, and beta-adrenergic neurons have all been demonstrated, largely through studies of hypo- and hyperthyroid states. Rodent studies have demonstrated serotonergic effects of T3 and T4, supporting the idea that serotonergic transmission is enhanced by normal thyroid functioning, potentially through desensitization of the 5-HT1A autoreceptor (6). T3 was initially thought to be active solely within the noradrenergic projection pathway, and it may serve as a co-transmitter with norepinephrine in the limbic system, but it has also been demonstrated in high concentrations in the serotonergic raphe nuclei and their projections (7).
A 37-year-old man with chronic severe major depression, poor response to antidepressants, and physical health problems, including morbid obesity, high blood pressure, and diabetes, is treated with T3 augmentation of an antidepressant.
"Mr. Y" is a 37-year-old man with a history of severe major depressive disorder who was brought to our community mental health clinic by his homeless outreach worker. His chief complaint was that he suffered with an "overwhelming low mood" along with poor sleep, poor energy, anhedonia, poor concentration, hypersomnia, and lack of motivation for basic day-to-day functioning. He had no history of bipolar symptoms. The current episode was chronic in duration, now having lasted at least 3 years, during which time Mr. Y lost his job and became homeless.
The patient's anergic symptoms were compounded by morbid obesity and gout, making it difficult and painful for him to move around. He also had type 2 diabetes, poorly controlled hypertension, recurrent nephrolithiasis, and chronic sinusitis. Mr. Y met diagnostic criteria for major depressive disorder, and he reported no improvement in depressive symptoms on his intake regimen of 40 mg of escitalopram and 100 mg of trazodone. On physical examination, his blood pressure was 180/110 mm Hg; heart rate, 83 bpm; height, 6 feet 2 inches; and weight, more than 350 lbs, the maximum of the clinic scale, representing a body mass index of at least 45. His blood pressure results were communicated to his internist at a community free clinic, who reported that Mr. Y consistently had similar blood pressure levels at clinic visits and that the patient's adherence to prescribed treatments was uncertain.
Psychiatric and Family History
Mr. Y reported a childhood onset of depressive symptoms, but his first disabling episode was in his freshman year of college. "I remember staying in my room for a year, and I did almost nothing." A year before he presented at our clinic, Mr. Y's shelter petitioned for an involuntary commitment for suicidal ideation, and he was admitted for a brief acute hospitalization. At that time, escitalopram and trazodone were started, and they were continued by his primary care doctor after his discharge.
Mr. Y's family history was strongly positive for depression, including in his mother, maternal grandmother, maternal uncle, and sister.
After initial assessment, Mr. Y declined therapy, but frequent meetings with the psychiatrist and outreach worker were scheduled to encourage behavioral activation. Trazodone was discontinued, as the patient reported sleeping most of the day. No benefit was obtained after bupropion was added to the escitalopram at up to 375 mg/day, so both antidepressants were cross-titrated to venlafaxine monotherapy. Venlafaxine was titrated in increments of 75 mg/day over 12 weeks to a dosage of 300 mg/day, which produced partial benefit for the patient's anergic symptoms. After 4 weeks at 300 mg/day with response but not remission, venlafaxine was further titrated to 450 mg, and the patient's blood pressure was monitored every 90 days. His blood pressure remained elevated as at baseline without significant change.
In the setting of residual symptoms of anhedonia and anergia, T3 supplementation (using liothyronine sodium, which is l-triiodothyronine, a synthetic T3) at 25 μg/day was chosen as an augmentation strategy with the goal of remission. Thyroid-stimulating hormone (TSH) at baseline was within normal limits. T3 supplementation was increased to 50 μg/day after 4 weeks with a very good clinical response. Mr. Y reported engaging in more activity, feeling more able to get out of bed, spending time with his family, and attempting daily activities. Given Mr. Y's improving response, including improvements in energy, anhedonia, and mood, T3 was continued at 50 μg/day.
After 18 months of treatment, Mr. Y's blood pressure was measured during routine 90-day monitoring at 200/120 mm Hg, his heart rate at 120 bpm, and his (nonfasting) blood glucose level at 196 mg/dl. He reported having missed his medications that morning, which included a beta-blocker, an angiotensin-converting enzyme inhibitor, and metformin, along with venlafaxine and T3. On assessment in the emergency department, an ECG was normal except for sinus tachycardia (108 bpm). After Mr. Y's usual doses of his missed medications were administered, his blood pressure decreased to 193/94 mm Hg and his heart rate to 92 bpm, and his blood glucose level was 147 mg/dl. Thyroid function testing showed low levels of TSH (0.13 μIU/ml; range=0.35–5.50) and free T4 (0.7 ng/dl; range=0.9–1.8) and a normal total T3 level (1.32 ng/ml; range=0.60–1.81).
After Mr. Y acknowledged intermittent nonadherence to his medication regimen, daily observed administration logs were requested from his shelter residence. The risks and benefits of continued treatment were discussed with the patient, and expectations for adherence to treatment were outlined. Switching his augmentation agent and antidepressant was considered, but his diabetes and severe obesity made use of any second-generation antipsychotic an unattractive option, and the potential for intermittent adherence made use of lithium seem comparatively dangerous. Mr. Y's response to T3, even without full adherence, made continuation seem likely to be of benefit. In general, nonadherence is not atypical for many patients in this clinic, and our first-line approach is to maintain a patient's existing treatment while addressing factors related to adherence.
Mr. Y's T3 dosage was lowered to 25 μg/day, and his medication adherence improved, with improved blood pressure control despite his high dosage of venlafaxine. Follow-up thyroid function testing after 90 days showed normal results (TSH level, 0.72 μIU/ml; total T3 level, 1.16 ng/ml; free T4 level, 1.0 ng/dl), and his clinical response was excellent.