Disorders of the thyroid axis have been closely linked to psychiatric disorders. While hyperthyroidism may present with a heterogenous range of psychiatric symptoms and syndromes, clinical hypothyroidism is invariably associated with depressive symptoms.
Although extensive research has shown that the vast majority of patients who present with major depression are euthyroid [normal thyroid], the close association between depression and hypothyroidism led to a large database of studies in which various hormones of the thyroid axis have been used to treat depression as monotherapy or, more commonly, as adjunct to standard antidepressants.
Each of the hormones of the thyroid axis will be reviewed.
Thyrotropin-releasing hormone (TRH) is a hypothalamic peptide that regulates thyroid hormone secretion by the thyroid gland through its effect on pituitary thyroidstimulating hormone (TSH) release.
TRH is also a peptide that occurs in brain, and has behavioral effects such as reversal of drug-induced sedation or anesthesia and stimulation of locomotor activity independent of its effect on the thyroid.
Due to its stimulation of the thyroid axis, as well as its independent effects on brain function, it has been tested as an antidepressant. Most studies have involved monotherapy, but there have also been studies of the use of TRH together with electroconvulsive therapy (ECT).
TRH has been administered to patients intravenously and by oral routes for depression.
at least half of these studies have reported no or very minimal therapeutic response to either intravenous or oral TRH administered as monotherapy with duration of treatment ranging from a single dose up to 30 days.
Thyrotropin (TSH) is a pituitary hormone which stimulates the thyroid gland, and thus would be expected to achieve an effect similar to the administration of peripheral thyroid hormones for the treatment of depression
The phrase “would be expected to achieve an effect” seems out of place in a scientific paper, which is supposed to present facts, not expectations.
The thyroid gland secretes two major hormones, levothyroxine (T4) and tri-iodothyronine (T3).
T4 is the major secretory product of the thyroid, and most T4 undergoes peripheral conversion to T3 in order to exert its physiological action.
T3 is the most broadly used thyroid hormone for treatment of depression, in contrast to in endocrine patients where T4 is routinely used for thyroid replacement therapy
In early studies, T3 was used as monotherapy for the treatment of depressed patients.
The data from these studies are largely inconclusive, as they involved small patient samples, inadequate clinical trial designs by current methodological standards, and the use of heterogeneous patient groups who, by today’s diagnostic criteria, would not necessarily have major depression.
There have been no well-designed studies of T3 monotherapy to date, and, therefore, its use as a single treatment for depression has not gained any clinical use.
T3 has been used in three other ways in the treatment of depression:
- In the initial few weeks of an antidepressant trial to reduce the delay in antidepressant effect – acceleration studies
- To improve treatment response in those who do not respond adequately to an antidepressant trial – augmentation studies
- To enhance antidepressant response by being used throughout the antidepressant trial – enhancement studies.
In the first of these studies in 1969, Prange and collaborators used T3 to accelerate the response to tricyclic antidepressants
In several studies, they demonstrated that if T3 was administered at the outset of a tricyclic antidepressant trial, there was a shorter lag in onset of therapeutic effect as compared with placebo controls. This acceleration effect was noted particularly in women as compared with men
In the next few years, several studies were performed, some of which replicated these findings, although some had negative results.
T3 has most commonly been used to augment response to antidepressants in those who failed to respond to an antidepressant trial.
These studies, whether open-label or controlled, generally show that up to half of patients who do not respond to an antidepressant trial will respond within 2 to 3 weeks after the addition of 25 to 50 g of T3.
Patients with T3 augmentation were approximately twice as likely to respond as were controls.
Recently, there has been emerging data on the use of T3 to augment SSRIs, the most commonly used antidepressants. The findings with the SSRIs are generally consistent with those for the tricyclics. Both open and controlled studies are generally positive, and indicate that T3 may be an effective augmentation agent for SSRI nonresponders.
Recent data from the STAR*D trial showed that T3 augmentation had comparable response and remission rates
T3 is added to an SSRI at the outset of the antidepressant trial and is administered throughout the acute treatment period.
These studies provide virtually no support for an acceleration effect of T3 when administered with SSRIs
As far as enhancement of SSRI response is concerned, the data are conflicting,
with enhancement studies, subjects include both potential responders and nonresponders to antidepressants and the aim is to accelerate and enhance rates of antidepressant response rather than to convert nonresponders to antidepressant responders.
This thyroid hormone has been used in two ways in the treatment of mood disorders.
- First, it has been used as an augmentation agent for the treatment of antidepressant nonresponders, and,
- second, as a mood stabilizer for rapidcycling bipolar disorder.
The efficacy of T4 and its comparable efficacy to T3 remain unresolved issues
In conclusion, the database on thyroid hormone treatment provides mixed findings in studies, often with methodological limitations and inconclusive data.
The strongest evidence is for an antidepressant augmentation effect of T3 in antidepressant nonresponders, but the use of T3 in other ways to accelerate and enhance antidepressant treatment, as well as the clinical utility of other hormones of the thyroid axis, require further study.
In addition, issues such as tolerability, long-term safety, and duration, as well as dose of treatment need to be addressed.
The doses employed in all these studies are less than the amount of endogenous T3 daily production so that there is little risk of induction of clinical hyperthyroidism.