Thyroid

Thyroxine, and Tri-iodothyronine Adjunctive Treatment of Depression

Adding thyroid or adding lithium are the two most researched adjunctive or add-on medications, perhaps best used if the current medication is helping some, but not enough. While lithium is an effective anti-depressant on its own, thyroid hormone does not help depression when given by itself. The on-going, 4000-patient STAR*D study of treatment-resistant depression should give some answer to what a psychiatrist should do. It will compared many different treatment options. Thyroid supplementation will be a 3rd level option, added when the first treatment for treatment-resistant depression fails (level 2).

Many anti-depressant treatments of depression have been found to work better with the addition of thyroid hormone, i.e., thyroxine (T4) and/or tri-iodothyronine (T3), the two forms of thyroid hormone in the human body. This benefit for depression treatment is true even when the patient has no thyroid deficiency. Indeed, the levels of thyroid used are slightly higher than those necessary to simply correct a thyroid deficiency. Thyroid supplements have been shown to help anti-depressants in at least nine double-blind studies with amitriptyline, imipramine, desipramine, clomipramine, lithium, and SSRIs. There are also case reports of benefit with MAO Inhibitors and positive research with fluvoxamine. The doses to thyroid hormones used are often somewhat higher than those used to treat thyroid deficiency. However, added thyroid in the treatment of depression seems to have less danger of negative side-effects than when used in thyroid deficiency.

T4 and T3 have been shown to make anti-depressants work more quickly and to work in cases where the medication alone was not being effective. At least one study has found that a combination of both T3 and T4 worked best on mood. Actually, this is what occurs in nature and what occurs when physicians give the traditional dessicated thyroid. However, a recent small double-blind study of non-depressed hypothyroid patients did not find any benefit for using both medications.

Despite having a reputation of wide variability, research suggests that dessicated thyroid does not have any clinically significantly larger amount of variability in pill content than individualized T3 or T4. Whereas the cost of generic dessicated thyroid is 40-80 cents per month wholesale, T4 costs $15-30 per month and T3 even more. Unfortunately, it may be a little difficult to find a pharmacy that still carries dessicated thyroid. One grain contains 12 micrograms of T3 and 64 micrograms of T4.

Despite many studies documenting these benefits since 1969, thyroid supplements are rarely used by psychiatrists in the treatment of depression. These supplements are very inexpensive generic medications, so no drug company has any interest in promoting them for the treatment of depression. While thyroid supplementation does not work miracles, it appears to be a good, temporary supplement for someone needing fast relief from depression, e.g. a person hospitalized due to depression, and a good long-term supplement for someone with refractory depression.

In the only comparative study of using lithium or thyroid as a supplement, both worked just as well as each other and better than placebo. Given the choice of all of the side-effects of lithium and its average of a 20# weight gain vs. the much more rare side-effects of thyroid medication, I personally would much prefer to try thyroid first. While the combination of both T4 and T3 has not been tried in psychiatry, research in hypothyroidism suggests that the combination may work better than either alone.

Thyroid Adjunct Helps: T-3 may accelerate (Altshuler ’01) and augment (Joffe ’93, Aronsen ’96) tricyclic action in treating depression. T-4 was also found helpful for rapid cycling bipolar disorder (Stancer ’82, Bauer ’86). Patients have been given T-4 for 3-5 years at 250-500 microg/d (0.25-0.5 mg/d) as an adjunct which was thought helpful. One case had an increased lithium tremor due to T-4. There was a low rate of side-effects with supraphysiologic doses compared to that of thyroid disorder patients. Four studies have found no bone demineralization with T-4 at supraphysiol doses. The author recommends long-term treatment only for refractory patients. Bauser ’02 Neuropsychopharm 27:620-8.

Thyroxine Reduces Lithium Cognitive Impairment: A preliminary study showed that adjunctive use of thyroid hormone significantly improves cognitive functioning in patients taking lithium. An animal study and two double-blind, placebo-controlled clinical studies examining the adjunctive use of thyroid hormone (T3) and ECT have confirmed that T3 significantly protects against ECT-related memory impairment compared to placebo. Tremont, Int J Neuropsychopharmacol 2000 Jun;3(2):175-186

Articles on Thyroid Profile Measurements and Depression Treatment: Abnormal T3-RU levels are rather uncommon in outpatient depression and do not correlate with the response to antidepressant treatment or lack thereof. MGH, Int J Psychiatry Med 2001;31(4):367-73; T3 blood levels and treatment outcome in depression. Iosifescu DV, Howarth S, Alpert JE, Nierenberg AA, Worthington JJ, Fava M.; But: 65 patients in the depressed phase of bipolar I disorder who were enrolled in a larger ongoing study. A panel of thyroid measures, including thyroid-stimulating hormone (TSH), thyroxine, triiodothyronine resin uptake, and free thyroxine index (FTI), were determined before initiation of algorithm-guided treatment. Both lower values of FTI and higher values of TSH were significantly associated with longer times to remission, i.e., slower response to treatment. Outcomes were relatively poor unless patients had FTI values above the median and TSH values below the median. Patients with this optimal profile experienced remission 4 months faster than the remainder of the study group. This study provides further evidence that patients with bipolar disorder are particularly sensitive to variations in thyroid function within the normal range. The results suggest that nearly three-quarters of patients with bipolar disorder have a thyroid profile that may be suboptimal for antidepressant response. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Cole DP, Thase ME, Mallinger AG, Soares JC, Luther JF, Kupfer DJ, Frank E. Am J Psychiatry 2002 Jan;159(1):116-21; UCLA, Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC.

Rat Study Shows Helping Action on T3: In the forced swimming test, the (DMI+T3) group showed a significantly decreased immobility time compared with that of the control group. The noradrenaline (NA) content in the prefrontal cortex was highest in the (DMI+T3) group. Although beta receptor was not altered in any brain region in the (DMI+T3) group, 5HT2A receptor was significantly decreased, and the dopamine (DA) turnover rate was significantly increased in the prefrontal cortex. This study suggests that the addition of T3 enhanced the action of DMI alone on the monoaminergic system in the prefrontal cortex. Tokyo, The influence of L-triiodothyronine on the action of desipramine on beta and serotonin 2A receptor, monoamines in the rat brain. Watanabe A. Nihon Shinkei Seishin Yakurigaku Zasshi 1999 Oct;19(4):139-46

RBC T3 Uptake Related to Clinical Benefit of Fluvoxamine: Red blood cell triiodothyronine uptake in unipolar major depression: effect of a chronic antidepressant treatment. Moreau X, Azorin JM, Lejeune PJ, Jeanningros R. Unite 501-INSERM, Faculte de Medecine, Marseille, France. The evolution of kinetic parameters (Vmax, maximal velocity, and Km, Michaelis constant) of red blood cell (RBC) triiodothyronine (L-T3) initial uptake was followed in 19 inpatients suffering from unipolar depression after 1 week (D7) and 4 weeks (D28) of a chronic administration of fluvoxamine, in relation with the clinical efficacy of the drug. In a drug-free state (DO), Vmax (in pmol/min/10(8) cells) and Km (in nM) were significantly increased in depressed patients (Vmax +/- S.D.= 1.02 +/- 0.29, p< 0.01 and Km +/- S.D.= 68.8 +/-15.4, p< 0.05; n=19) compared to healthy volunteers matched for age and sex (Vmax +/- S.D.= 0.82 +/- 0.15 and Km S.D.= 58.8 +/- 9.0; n= 19). When patients were dichotomized on the basis of their treatment response, responders (Vmax +/- S.D.= 0.91 +/- 0.13, NS; Km+/-S.D.= 65.7 +/- 7.4, NS). The results indicate that both RBC L-T3 uptake at the pretreatment level and its change during the first week of fluvoxamine treatment were related to the further clinical response to the antidepressant. RBC L-T3 uptake seems to be a biological correlate of the depressive symptomatology since the disturbances disappear only with the clinical remission.

Cognitive Effect: cognitive effects of thyroid hormones in euthyroid subjects are less studied and understood. The purpose of this study was to examine thyroid-cognition relationships in healthy, euthyroid older men. METHODS: We examined healthy men (N = 44, mean age = 72), excluding clinically hypothyroid/hyperthyroid or diabetic/hyperglycemic subjects and those with dementia, depression, CNS medications, or recent illness. Plasma samples obtained across a 24-hour period were pooled, then assayed for total thyroxine (TT4), total triiodothyronine (TT3), and T3 resin uptake. Free thyroxine index (FT4I) was calculated. A broad cognitive battery (including the Wechsler Adult Intelligence Scale-Revised [WAIS-R], the Dementia Rating Scale [DRS], and the Rivermead Behavioral Profile [PROFILE]) was administered to all subjects. RESULTS: Regression analyses controlling age and education showed TT4 and FT4I to have significant positive relationships with measures of overall cognition; TT4 accounted for 8% to 12% of the variance in omnibus cognitive measures such as WAIS Performance, WAIS Verbal score, and GLOBAL cognitive scores. CONCLUSIONS: Our findings suggest that within "normal" range of variation in plasma thyroid hormones, TT4 but not T3 positively associates with general cognition in healthy elderly men. U Wash, Thyroid hormones: positive relationships with cognition in healthy, euthyroid older men. Prinz PN, Scanlan JM, Vitaliano PP, Moe KE, Borson S, Toivola B, Merriam GR, Larsen LH, Reed HL. J Gerontol A Biol Sci Med Sci 1999 Mar;54(3):M111-6

Psychiatrists Rarely Use Thyroid: 300 fellows, members and inceptors of the Royal College of Psychiatrists were randomly selected and approached by postal questionnaire. They were asked to comment on management of a detailed clinical vignette of a case of depression with initial treatment failure. RESULTS: The response rate was 63% (n = 175). The most popular treatment choices were increasing dosage of tricyclic medication and change of medication of SSRI. The most rarely selected were augmentation with triiodothyronine (T3) and augmentation with tryptophan or MAOIs. Treatment choice was significantly influenced by previous experience. A large number (39%) of psychiatrists were not confident in treating refractory depression. CONCLUSION: Surprisingly few psychiatrists chose to use the best proven pharmacological treatments such as augmentation with lithium or T3. Pharmacological choices after one antidepressant fails: a survey of UK psychiatrists. Shergill SS, Katona CL. Maudsley Hospital, London, UK, J Affect Disord 1997 Mar;43(1):19-25

1% US Psychiatrists Chose Thyroid: 118 northeastern psychiatrists what they would do next in response to a clinical vignette of an inpatient with DMS-III-R major depression who failed to respond to 4 weeks of nortriptyline at adequate blood levels. Lithium augmentation was chosen by more than a third (33.9%) of psychiatrists. Other choices, in order of decreasing frequency, were continuing nortriptyline for another 2 weeks (17.8%) and switching to either fluoxetine (16.1%), electroconvulsive therapy (11.0%), or a monoamine oxidase inhibitor (6.8%). Only one psychiatrist each chose thyroid augmentation or bupropion. The authors state that thyroid supplementation is underutilized. McLean, Treatment choice after one antidepressant fails: a survey of northeastern psychiatrists. Nierenberg AA. J Clin Psychiatry 1991 Sep;52(9):383-5

TSH Level Inversely Related Cerebral Blood Flow in MDD: Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism. RESULTS: Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism. CONCLUSIONS: These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations. Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. Marangell LB, Ketter TA, George MS, Pazzaglia PJ, Callahan AM, Parekh P, Andreason PJ, Horwitz B, Herscovitch P, Post RM. National Institutes of Health, Am J Psychiatry 1997 Feb;154(2):224-30

No Benefit T3 with Nortriptyline in Open Study: no evidence for the efficacy of adjunctive T3 treatment was found in a sample of 14 inpatients. T3 augmentation was performed over a four-week period; during the last three weeks the daily dosage was 37.5 micrograms. The patients involved were suffering from refactory depression and previously had not responded to an adequate six-week course of treatment with a TCA (mainly nortriptyline). The Hague, An open study of triiodothyronine augmentation of tricyclic antidepressants in inpatients with refractory depression. Birkenhager TK, Vegt M, Nolen WA. Pharmacopsychiatry 1997 Jan;30(1):23-6

Meta-Analysis of T3 Says Good but Need More Study: Eight studies with a total of 292 patients, patients treated with triiodothyronine augmentation were twice as likely to respond as controls (relative response, 2.09; 95% confidence interval [CI], 1.31 to 3.32; P = .002). This corresponded to a 23.2% absolute improvement in response rates (95% CI, 4.5% to 41.9%; P = .02). Improvements in depression scores were moderately large (standardized effect size, 0.62; P < .001). However, study quality was uneven, and results were statistically heterogeneous. Among the four randomized double-blind studies, pooled effects were not significant (relative response, 1.53; 95% CI, 0.70 to 3.35; P = .29), but one study with negative results accounted for most of the intertrial heterogeneity in results. U Toronto, Arch Gen Psychiatry 1996 Sep;53(9):842-8. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Aronson R, Offman HJ, Joffe RT, Naylor CD.

Selenium Deficiency Decreases T3: type I thyroxine 5'-deiodinase as a Se-dependent enzyme provides a new potentially critical role for Se. plasma thyroxine concentrations were increased 67%, plasma triiodothyronine was decreased 23% and the plasma triiodothyronine:thyroxine ratio was decreased 55%, compared with rats fed 0.2 micrograms Se/g diet. J Nutr 1995 Apr;125(4):864-73; Growth and plasma triiodothyronine concentrations are modified by selenium deficiency and repletion in second-generation selenium-deficient rats. Thompson KM, Haibach H, Sunde RA.

T3 = Lithium as TCA Adjunct: In a 2-week DB PC study of 50 outpatients with unipolar, nonpsychotic major depression who had failed to respond to treatment with desipramine hydrochloride or imipramine hydrochloride, both liothyronine and lithium were more effective than placebo in reducing scores on the Hamilton Rating Scale for Depression. However, the antidepressant augmenting effect of these two compounds did not differ from each other. Ten of 17 subjects responded on liothyronine, nine of 17 responded on lithium and three of 16 responded on placebo. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Joffe RT, Singer W, Levitt AJ, MacDonald C. Arch Gen Psychiatry 1993 May;50(5):387-93;

Thyroid Antibody a Risk Factor in Post-Partum Depression: Six weeks after delivery, 43% of antibody positive women and 28% antibody negative women had mental health problems (p < 0.005). Follow up of the 110 antibody positive and 132 antibody negative women showed significantly greater depression in antibody positive women (47%) than antibody negative women (32%) regardless of thyroid dysfunction. Antibody positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003). Association between postpartum thyroid dysfunction and thyroid antibodies and depression. Harris B, Othman S, Davies JA, Weppner GJ, Richards CJ, Newcombe RG, Lazarus JH, Parkes AB, Hall R, Phillips DI. BMJ 1992 Jul 18;305(6846):152-6

T3 Helps Desipramine Treatment: In a study of 38 depressed patients, there was an increased response to antidepressant treatment with the addition of triiodothyronine but not equivalent doses of thyroxine (T4). The finding is consistent with the decreases in plasma T4 levels which accompany an antidepressant response to desipramine. U Toronto, Antidepressants and thyroid hormone levels. Joffe RT, Singer W. Acta Med Austriaca 1992;19 Suppl 1:96-7

T3 No Benefit is Very Small DB of OCD Adjunctive Rx: In a study of 16 OCD patients partially improved during at least 6 months of clomipramine, all were given an 8-week DB trial each of triiodothyronine and lithium carbonate. OCD and depressive symptoms did not significantly change after either. Neither adjuvant medication was associated with a clinically meaningful change (greater than 25%) in OCD symptoms. However, lithium, but not triiodothyronine, adjuvant therapy was associated with a 25% or greater reduction in depression scores in 44% of the patients. NIMH, A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine-treated patients with obsessive-compulsive disorder. Pigott TA, Pato MT, L'Heureux F, Hill JL, Grover GN, Bernstein SE, Murphy DL. J Clin Psychopharmacol 1991 Aug;11(4):242-8

T3 Helps Clomipramine in DB: Clomipramine (150 mg/day) with a daily dose of 50 micrograms of LT3 (CMI + LT3) compared to clomipramine + placebo) for 42 days in 20 patients with a normal thyroid status, but presenting a major depressive syndrome (DSM III). The minimum including score was 30 on the Montgomery Asberg Scale (MADRS). After 28 days of treatment, the efficacy of CMI + LT3 was found to be superior to CMI + placebo (p < 0.05). U Lausanne, Treatment of depression by a combination of clomipramine and triiodothyronine. Souche A, Baumann P, Koeb L, Thermoz P, Azorin JM, Dufour H. Encephale 1991 Jan-Feb;17(1):37-42

T3 Slightly Better Than T4 in DB: In a study of T3 as compared with T4, significantly more patients responded to 3 weeks of T3 as compared with T4 potentiation. Small but significant differential effects of the two thyroid hormones were noted on the Hamilton Rating Scale for Depression. U Toronto, A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Joffe RT, Singer W. Psychiatry Res 1990 Jun;32(3):241-51

T4 Helps Rapid Cycling Depression and Mania in Small DB: While 11 patients were taking added levothyroxine, scores on both depressive and manic symptom rating scales decreased significantly compared with baseline. This improvement was due to the clear-cut response of depressive symptoms in 10 of 11 patients, with manic symptoms responding in five of the seven patients who exhibited them during baseline evaluation. Four patients then underwent single- or double-blind placebo substitution; three patients relapsed into either depression or cycling. Treatment response did not depend on previous thyroid status. In 9 of 10 responsive patients, supranormal circulating levels of free thyroxine were necessary to induce clinical response. Side effects were minimal, and there were no signs or symptoms of levothyroxine-induced hypermetabolism. Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Bauer MS, Whybrow PC. University of Pennsylvania. Arch Gen Psychiatry 1990 May;47(5):435-40

T3 No Benefit with Imipramine in Small Open Trial: L-triiodothyronine (T3; 25 micrograms/day) in a sample of 20 outpatient unipolar depressives who had not responded to greater than or equal to 12 weeks of treatment with imipramine (mean dosage = 240 mg/day) and interpersonal psychotherapy. The overall response rate after 4 weeks of T3 was low (25%); the outcome did not differ significantly from a matched historical comparison group who received continued tricyclic treatment but not T3. U Pitt, Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine. Thase ME, Kupfer DJ, Jarrett DB. J Clin Psychiatry 1989 Oct;50(10):385-8

Two Cases T3 Helping MAOI: 2 patients not responsive to TCA, TCA + lithium, TCA + T3, or MAOI, responded with T3 added. Triiodothyronine potentiation of the antidepressant effect of phenelzine. U Toronto, Joffe RT. J Clin Psychiatry 1988 Oct;49(10):409-10

T3 No Benefit to Imipramine in Small DB: double-blind, placebo-controlled crossover design. Sixteen depressed patients who were unresponsive to 4 weeks of imipramine therapy (mean dose = 206 +/- 54 mg daily, mean combined blood level = 220 +/- 132 ng/dl) received T3 25 micrograms and placebo for 2 weeks each. There was no evidence of a T3 effect using both Hamilton depression scores and global improvement. No subgroup of responders using baseline TRH stimulation tests could be identified. T3 treatment lowered plasma free T4 (P = 0.001) and TSH (P greater than 0.02) while raising plasma T3 levels (P less than 0.01), indicating the physiological effect of the drug. UCLA, Failure of T3 to potentiate tricyclic antidepressant response. Gitlin MJ, Weiner H, Fairbanks L, Hershman JM, Friedfeld N. J Affect Disord 1987 Nov-Dec;13(3):267-72

T3 Helps Imipramine/Amitriptyline in Small BD: Six women and 6 men who were treated in double-blind fashion major depressive illness did not respond to imipramine or amitriptyline, 150-300 mg/day, during periods of 26-112 days. After the addition of 25 micrograms/day (10 patients) or 50 micrograms/day (2 patients) of L-triiodothyronine (T3), 9 patients showed statistically significant improvement in depression scores; in 8 patients the response was marked. Improvement generally began within 1-3 days and was noted in all aspects of the depressive syndrome; side effects were minimal. T3 did not change plasma levels of imipramine or desipramine or their ratio but did suppress serum thyroxine. Am J Psychiatry 1982 Jan;139(1):34-8 Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Goodwin FK, Prange AJ Jr, Post RM, Muscettola G, Lipton MA.

Older Studies: Controlled Trial: Hormonal potentiation of imipramine and ECT in primary depression. Feighner JP, King LJ, Schuckit MA, Croughan J, Briscoe W. Am J Psychiatry 1972 Apr;128(10):1230-8; Random Controlled Trial: Potentiation of amitriptyline by thyroid hormone. Wheatley D. Arch Gen Psychiatry 1972 Mar;26(3):229-33; Controlled Trial: Thyroid function and the response to liothyronine in depression. Whybrow PC, Coppen A, Prange AJ Jr, Noguera R, Bailey JE. Arch Gen Psychiatry 1972 Mar;26(3):242-5; Controlled Trial: The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine. Arch Gen Psychiatry 1972 Mar;26(3):234-41; Use of a thyroid hormone to accelerate the action of imipramine. Prange AJ Jr, Wilson IC, Lipton MA, Rabon AM, McClae TK, Knox AE. Psychosomatics 1970 Sep-Oct;11(5):442-4; Controlled Trial: Thyroid-hormone enhancement of imipramine in nonretarded depressions. N Engl J Med 1970 May 7;282(19):1063-7; Controlled Trial: Enhancement of imipramine antidepressant activity by thyroid hormone. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Am J Psychiatry 1969 Oct;126(4):457-69

T4 Alone No Benefit Preventing Post-Partum Depression in Thyroid AB+ Women: randomised double-blind placebo-controlled trial, 100 microg of thyroxine or placebo was given daily to 446 thyroid-antibody-positive women (342 of whom were compliant) from 6 weeks to 6 months post-partum, assessing their psychiatric and thyroid status at 4-weekly intervals. Women with thyroid antibodies are somewhat more prone to post-partum depression. However, T4 supplement had no impact on depression. Randomised trial of thyroxine to prevent postnatal depression in thyroid-antibody-positive women. Harris B, Oretti R, Lazarus J, Parkes A, John R, Richards C, Newcombe R, Hall R. Br J Psychiatry 2002 Apr;180:327-30

T3 in Meta-Analysis Speeds Anti-Depressant Effect: Five of the six studies found T(3) to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of T(3) acceleration were greater as the percentage of women participating in the study increased. UCLA. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC. Am J Psychiatry 2001 Oct;158(10):1617-22

Thyroid Supplementation No Increase Bone Demineralization: Study of women on thyroid supplement for depression at TSH suppressing doses for over 12 months found no evidence demineralization. U Penn. Bone mineral density in pre-and post-menopausal women with affective disorder treated with long-term L-thyroxine augmentation. Gyulai L, Bauer M, Garcia-Espana F, Hierholzer J, Baumgartner A, Berghofer A, Whybrow PC. J Affect Disord 2001 Oct;66(2-3):185-91

TSH Suppression No Worse Than Standard T4 Rx: Over one year, 1180 patients on thyroxine replacement had clinical and biochemical assessment; 59% had a suppressed TSH and 38% 'normal' TSH. Patients with a suppressed TSH exhibited higher median serum thyroxine levels (146 nmol/l, range 77-252 vs 119 nmol/l, 58-224; P < 0.001). Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease compared to the general population (female 2.7 vs 0.7%, P < 0.001; male 6.4 vs 1.7%, P < 0.01), but the risk was no different between those with suppressed and normal TSH. There was no increase in risk for overall fracture, fractured neck of femur or breast carcinoma in those on thyroxine with suppressed or normal TSH. Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH. Leese GP, Jung RT, Guthrie C, Waugh N, Browning MC. Clin Endocrinol (Oxf) 1992 Dec;37(6):500-3

T4 200-500microg/d Helped in Open Trial: 200-500 micrograms T4/day has excellent effects in 50-65% of patients a) with bipolar disorder, with or without, "rapid cycling" course, who were previously resistant to all prophylactic drugs and b) in the treatment of therapy-resistant depression. T4 is effective only in combination with an antidepressant or a prophylactic drug. Side effects are minimal, even when T4 is administered over several years. High dosage thyroxine treatment in therapy and prevention refractory patients with affective psychoses, Bauer M, Hellweg R, Baumgartner A. Nervenarzt 1998 Nov;69(11):1019-22

T4 Better if Used Before Lithium Trial for Rx Resistant: 22 outpatients with major depression not responsive to 4 weeks of antidepressant treatment, the effect of subsequent 4 weeks of thyroxine administration followed by 4 weeks of lithium augmentation was compared with the effect of the same treatments in reverse order. RESULTS: The percentage reduction in MADRS score was significantly greater in patients who started on thyroxine. CONCLUSIONS: Thyroxine augmentation should precede lithium augmentation. LIMITATIONS: We used relatively small doses of lithium. U Helsinki, Should thyroid augmentation precede lithium augmentation--a pilot study. Spoov J, Lahdelma L. J Affect Disord 1998 Jun;49(3):235-9

High Dose T4 (482 microg/d) Adjunct Helped in Open: Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 +/- 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 +/- 72 micrograms/day. The patients' scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 +/- 4.7 prior to the addition of T4 to 11.6 +/- 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of < or = 9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 +/- 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild. Free Univ, Berlin, Treatment of refractory depression with high-dose thyroxine. Bauer M, Hellweg R, Graf KJ, Baumgartner A. Neuropsychopharmacology 1998 Jun;18(6):444-55

Start T4 After Mood Stabilizer in Bipolar in Open: open study of 11 patients (10 females--9 of them premenopausal--1 male) with rapid cycling disorder adjunctive treatment with TSH suppressive doses of T4 (T4 levels at approximately 150% of normal) reduced the manic and depressive phases in both amplitude and frequency and even led to remittance in some patients. T4 treatment was begun only after stable "therapeutic" blood levels of lithium carbonate and/or anticonvulsants have been reached, since it has been shown that T4 therapy alone can precipitate dysphoric manic like symptoms which require treatment with neuroleptics. Careful evaluation of possible side effects like osteoporosis revealed surprisingly an even higher bone density in treated patients. U Penn, The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric disorder. Whybrow PC. Acta Med Austriaca 1994;21(2):47-52

Older Reports: Effects of triiodothyronine on drug levels and cardiac function in depressed patients treated with imipramine. Garbutt J, Malekpour B, Brunswick D, Jonnalagadda MR, Jolliff L, Podolak R, Wilson I, Prange A Jr. Am J Psychiatry 1979 Jul;136(7):980-2

Thyroxine and Tri-iodothyronine Adjunctive Treatment of Depression

What do you do if the first anti-depressant treatment isn’t working? This issue is often faced by psychiatrists, but amazingly little research shows what is the ideal next step. The choice is between switching to a new medication or adding a second, supplementary medication. Of course, if the medication is switched, the assumption tends to be that the first medicine was of no value. Adding thyroid or adding lithium are the two most researched adjunctive medications. While lithium is an effective anti-depressant on its own, thyroid hormone is the one medicine that does not help depression when given by itself.

Many anti-depressant treatments of depression have been found to work better with the addition of thyroid hormone, i.e., thyroxine (T4) and/or tri-iodothyronine (T3). This is true even when the patient has no thyroid deficiency. Indeed, the levels of thyroid used are generally higher than those necessary to simply correct a thyroid deficiency. Thyroid supplements have been shown to help anti-depressants in at least nine double-blind studies with amitriptyline, imipramine, desipramine, clomipramine, lithium, and SSRIs. There are also case reports of benefit with MAO Inhibitors and positive research with fluvoxamine. The doses to thyroid hormones used are often somewhat higher than those used to treat thyroid deficiency. However, added thyroid in the treatment of depression seems to have less danger of negative side-effects than when used in thyroid deficiency. T4 and T3 have been shown to make anti-depressants work more quickly and to work in cases where the medication alone was not being effective.

In the only comparative study of using lithium or thyroid as a supplement, both worked just as well as each other and better than placebo. Given the choice of all of the side-effects of lithium and its average of a 20# weight gain vs. the much more rare side-effects of thyroid medication, I personally would much prefer to try thyroid. While the combination of both T4 and T3 has not been tried in psychiatry, research in hypothyroidism suggests that the combination may work better than either alone.

No Diff SSRI Response by T3 Levels: 321 outpt depressives Rx 8 weeks fluoxetine 20. T3 is most sensitive test for subclinical thyroid pathology. No cases hypo and 2 of hyperthyroidism. 5% had low T3 and 2% high. No relationship between clinical improvement and T3 levels. Dan Losifescu, MGH, APA 5/17/99

T3 Added to T4 Improved Cognitive: In 33 pt with hypothyroidism rx T4 randomized to 12.5 microg T3 substituted for 50 microg of their T4. After 5 weeks, crossover. Combined thyroid therapy better for fatigue, depression, anger, attention, and others. Thyroid produces both altho T4 converted to T3 peripherally. UNC, NEJM 99;340:424

T-3 Helps Tricyclics Work Faster: A meta-analysis of 5 imip and 1 amitrip studies from the 70’s found not only a higher percentage of responders but also a more rapid rate of response, esp for females. Dosages ranged from 20-25 micrograms/d. AJP 01;158:1617

High Dose Adjunctive for Refractory Depression: 9 pt MDD or dysthymia treatment resistant. T4 50 microg/d added and increased by 50microg every 3 days til T4 level twice pretreatment and either TSH completely suppressed or improved or sever side-effects. ECGs BIW. Two d/c due to side-effects. 5 responders (>50% decr HAM-D and under 9). 5 responded within 8 weeks and one at 11 weeks. One non-responder. T4 150-300 microg/d. All pt normalrange at baseline. T4 incr from 82 to 139 microg/L. TSH fell to 0.09 mU/L. Says reserve at rx of last resort due to unknown s-e. Rudas, Vienna, Biol Psych 99;45:229

Thyroid Adjunct Helps: T-3 may accelerate (Altshuler ’01) and Augment (Joffe ’93, Aronsen ’96) tricyclic action. T-4 helpful for rapid cycling (Stancer ’82, Bauer ’86). T-4 for 3-5 years at 250-500 microg/d adjunct thought helpful. One case increased lithium tremor due to T-4. Low rate of side-effects with supraphysiol dose compared to that of thyroid disorder patients. Four studies have found no bone demineralization with T-4 at supraphysiol doses. Recommens long-term only for refractory patients. Bauser ’02 Neuropsychopharm 27:620-8.

Abnormal T3-RU levels are rather uncommon in outpatient depression and do not correlate with the response to antidepressant treatment or lack thereof. MGH, Int J Psychiatry Med 2001;31(4):367-73; T3 blood levels and treatment outcome in depression. Iosifescu DV, Howarth S, Alpert JE, Nierenberg AA, Worthington JJ, Fava M.; But: 65 patients in the depressed phase of bipolar I disorder who were enrolled in a larger ongoing study. A panel of thyroid measures, including thyroid-stimulating hormone (TSH), thyroxine, triiodothyronine resin uptake, and free thyroxine index (FTI), were determined before initiation of algorithm-guided treatment. The effect of each thyroid measurement on time to remission was estimated by using the Cox proportional hazards model. RESULTS: Both lower values of FTI and higher values of TSH were significantly associated with longer times to remission, i.e., slower response to treatment. Outcomes were relatively poor unless patients had FTI values above the median and TSH values below the median. Patients with this optimal profile experienced remission 4 months faster than the remainder of the study group. CONCLUSIONS: This study provides further evidence that patients with bipolar disorder are particularly sensitive to variations in thyroid function within the normal range. Our results suggest that nearly three-quarters of patients with bipolar disorder have a thyroid profile that may be suboptimal for antidepressant response. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Cole DP, Thase ME, Mallinger AG, Soares JC, Luther JF, Kupfer DJ, Frank E. Am J Psychiatry 2002 Jan;159(1):116-21; UCLA, Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC.

Severe Depression in Those Unresponsive to Lithium Predicts Benefit: Seventy-one in-patients with depression refractory to tricyclic antidepressants had received lithium augmentation as part of a standardised treatment protocol. RESULTS: Within 4 weeks 37 patients (52%) responded to lithium augmentation. Five variables with predictive value were found. Responders were more severely depressed according to the Bech-Rafaelsen Melancholia Scale. The duration of their index episode was shorter. Triiodothyronine serum levels were lower and neuroleptic co-medication and co-diagnosis of personality disorder were less frequent. Freie Universitat, Berlin, Predictors of response to lithium augmentation in tricyclic antidepressant-resistant depression. Bschor T, Canata B, Muller-Oerlinghausen B, Bauer M. J Affect Disord 2001 May;64(2-3):261-5

Thyroxine Helps PTSD with Depression Partial Responsive to SSRI: T3 (25 microg/day) was added to treatment in open trial with a selective serotonin reuptake inhibitor (SSRI) (paroxetine or fluoxetine, 20 mg/day for at least 4 weeks and 40 mg/day for a further 4 weeks) of 5 patients who fulfilled DSM-IV criteria for PTSD but not for major depressive disorder (although all patients had significant depressive symptoms). The Clinician-Administered PTSD Scale, the 21-item Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Severity of Illness scale were administered every 2 weeks, and self-assessments were performed with a 100 mm visual analog mood scale. RESULTS: In 4 of the 5 patients, partial clinical improvement was observed with SSRI treatment at a daily dose of 20 mg with little further improvement when the dose was raised to 40 mg/day. This improvement was substantially enhanced by the addition of T3. Improvement was most striking on the Hamilton Rating Scale for Depression. Hadassah-Hebrew U, Jerusalem, Triiodothyronine augmentation of selective serotonin reuptake inhibitors in posttraumatic stress disorder. Agid O, Shalev AY, Lerer B. J Clin Psychiatry 2001 Mar;62(3):169-73

Rat Study Shows Helping Action on T3: In the forced swimming test, the (DMI+T3) group showed a significantly decreased immobility time compared with that of the control group. The noradrenaline (NA) content in the prefrontal cortex was highest in the (DMI+T3) group. Although beta receptor was not altered in any brain region in the (DMI+T3) group, 5HT2A receptor was significantly decreased, and the dopamine (DA) turnover rate was significantly increased in the prefrontal cortex. This study suggests that the addition of T3 enhanced the action of DMI alone on the monoaminergic system in the prefrontal cortex. Tokyo, The influence of L-triiodothyronine on the action of desipramine on beta and serotonin 2A receptor, monoamines in the rat brain. Watanabe A. Nihon Shinkei Seishin Yakurigaku Zasshi 1999 Oct;19(4):139-46

Cognitive Effect: cognitive effects of thyroid hormones in euthyroid subjects are less studied and understood. The purpose of this study was to examine thyroid-cognition relationships in healthy, euthyroid older men. METHODS: We examined healthy men (N = 44, mean age = 72), excluding clinically hypothyroid/hyperthyroid or diabetic/hyperglycemic subjects and those with dementia, depression, CNS medications, or recent illness. Plasma samples obtained across a 24-hour period were pooled, then assayed for total thyroxine (TT4), total triiodothyronine (TT3), and T3 resin uptake. Free thyroxine index (FT4I) was calculated. A broad cognitive battery (including the Wechsler Adult Intelligence Scale-Revised [WAIS-R], the Dementia Rating Scale [DRS], and the Rivermead Behavioral Profile [PROFILE]) was administered to all subjects. RESULTS: Regression analyses controlling age and education showed TT4 and FT4I to have significant positive relationships with measures of overall cognition; TT4 accounted for 8% to 12% of the variance in omnibus cognitive measures such as WAIS Performance, WAIS Verbal score, and GLOBAL cognitive scores. CONCLUSIONS: Our findings suggest that within "normal" range of variation in plasma thyroid hormones, TT4 but not T3 positively associates with general cognition in healthy elderly men. U Wash, Thyroid hormones: positive relationships with cognition in healthy, euthyroid older men. Prinz PN, Scanlan JM, Vitaliano PP, Moe KE, Borson S, Toivola B, Merriam GR, Larsen LH, Reed HL. J Gerontol A Biol Sci Med Sci 1999 Mar;54(3):M111-6

1% US Psychiatrists Chose Thyroid: 118 northeastern psychiatrists what they would do next in response to a clinical vignette of an inpatient with DMS-III-R major depression who failed to respond to 4 weeks of nortriptyline at adequate blood levels. RESULTS: Lithium augmentation was chosen by more than a third (33.9%) of psychiatrists. Other choices, in order of decreasing frequency, were continuing nortriptyline for another 2 weeks (17.8%) and switching to either fluoxetine (16.1%), electroconvulsive therapy (11.0%), or a monoamine oxidase inhibitor (6.8%). Only one psychiatrist each chose thyroid augmentation or bupropion. McLean, Treatment choice after one antidepressant fails: a survey of northeastern psychiatrists. Nierenberg AA. J Clin Psychiatry 1991 Sep;52(9):383-5

Meta-Analysis of T3 Says Good but Need More Study: eight studies with a total of 292 patients, patients treated with triiodothyronine augmentation were twice as likely to respond as controls (relative response, 2.09; 95% confidence interval [CI], 1.31 to 3.32; P = .002). This corresponded to a 23.2% absolute improvement in response rates (95% CI, 4.5% to 41.9%; P = .02). Improvements in depression scores were moderately large (standardized effect size, 0.62; P < .001). However, study quality was uneven, and results were statistically heterogeneous. Among the four randomized double-blind studies, pooled effects were not significant (relative response, 1.53; 95% CI, 0.70 to 3.35; P = .29), but one study with negative results accounted for most of the intertrial heterogeneity in results. U Toronto, Arch Gen Psychiatry 1996 Sep;53(9):842-8. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Aronson R, Offman HJ, Joffe RT, Naylor CD.

Selenium Deficiency Decreases T3: type I thyroxine 5'-deiodinase as a Se-dependent enzyme provides a new potentially critical role for Se. plasma thyroxine concentrations were increased 67%, plasma triiodothyronine was decreased 23% and the plasma triiodothyronine:thyroxine ratio was decreased 55%, compared with rats fed 0.2 micrograms Se/g diet. J Nutr 1995 Apr;125(4):864-73; Growth and plasma triiodothyronine concentrations are modified by selenium deficiency and repletion in second-generation selenium-deficient rats. Thompson KM, Haibach H, Sunde RA.

T3 = Lithium as TCA Adjunct: DBPC 2 weeks 50 outpatients, males and females, with unipolar, nonpsychotic major depression who had failed to respond to treatment with desipramine hydrochloride or imipramine hydrochloride. RESULTS: Both liothyronine and lithium were more effective than placebo in reducing scores on the Hamilton Rating Scale for Depression. However, the antidepressant augmenting effect of these two compounds did not differ from each other. When response was defined as a 50% or more reduction in the Hamilton Rating Scale for Depression scores and a final score less than 10, we found that 10 of 17 subjects responded to liothyronine, nine of 17 responded to lithium and three of 16 responded to placebo. Arch Gen Psychiatry 1993 May;50(5):387-93; A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Joffe RT, Singer W, Levitt AJ, MacDonald C.

Thyroid Antibody Risk Factor in Post-Partum Depression: Six weeks after delivery the general health questionnaire showed 62 (43%) antibody positive women and 65 (28%) antibody negative women had mental ill health (chi 2 = 8.18, p less than 0.005). Follow up of 110 antibody positive and 132 antibody negative women showed significantly greater depression by research diagnostic criteria in antibody positive women (47%) than antibody negative women (32%) regardless of thyroid dysfunction. Antibody positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003). CONCLUSION--Depressive symptoms are associated with positive thyroid antibody status in the postpartum period. Association between postpartum thyroid dysfunction and thyroid antibodies and depression. Harris B, Othman S, Davies JA, Weppner GJ, Richards CJ, Newcombe RG, Lazarus JH, Parkes AB, Hall R, Phillips DI. BMJ 1992 Jul 18;305(6846):152-6

T3 Helped TCA-T4 Non-responders in Open Trial: T3 augmentation therapy for eight depressed patients who had not responded to an adequate antidepressant drug trial and who were receiving T4 therapy for thyroid disease. T3 was prescribed in open-label fashion, and response was judged by the clinician, whose assessment was supplemented by the use of standardized rating scales. RESULTS: Seven of the nine patients were judged to respond to T3 augmentation. U Toronto, T3 augmentation of antidepressant treatment in T4-replaced thyroid patients. Cooke RG, Joffe RT, Levitt AJ. J Clin Psychiatry 1992 Jan;53(1):16-8

T3 Helps Desipramine Rx: 38 depressed patients, we observed an increased response to antidepressant treatment with the addition of triiodothyronine but not equivalent doses of thyroxine (T4). The finding is consistent with the decreases in plasma T4 levels which accompany an antidepressant response to desipramine. U Toronto, Antidepressants and thyroid hormone levels. Joffe RT, Singer W. Acta Med Austriaca 1992;19 Suppl 1:96-7

T3 No Benefit is Very Small DB of OCD Adjunctive Rx: 16 OCD partially improved during at least 6 months of clomipramine sequentially treated with triiodothyronine and lithium carbonate in an 8-week double-blind cross-over study. Both triiodothyronine and lithium carbonate have been reported to be efficacious in open trials as adjunctive agents when combined with tricyclics in the treatment of OCD and depressed patients. However, in our controlled study, OCD and depressive symptoms, as assessed by standardized rating scales in the patient group as a whole, did not significantly change after either. Further analysis on an individual patient basis revealed that neither adjuvant medication was associated with a clinically meaningful change (greater than 25%) in OCD symptoms. However, lithium, but not triiodothyronine, adjuvant therapy was associated with a 25% or greater reduction in depression scores in 44% of the patients. NIMH, A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine-treated patients with obsessive-compulsive disorder. Pigott TA, Pato MT, L'Heureux F, Hill JL, Grover GN, Bernstein SE, Murphy DL. J Clin Psychopharmacol 1991 Aug;11(4):242-8

T3 Helps Clomipramine in DB: clomipramine (150 mg/day) associated with a daily dose of 50 micrograms of LT3 (CMI + LT3) compared to a treatment with clomipramine (150 mg/day) (CMI + placebo) for a period of 42 days has been examined in a pilot study, randomized in double-blind conditions, including 20 patients with a normal thyroid status, but presenting a major depressive syndrome (DSM III). The minimum including score was 30 on the Montgomery Asberg Scale (MADRS). The patients were considered as remitted when the MADRS-score was < or = 10. After 28 days of treatment, the efficacy of CMI + LT3 was found to be superior to CMI + placebo (p < 0.05). U Lausanne, Treatment of depression by a combination of clomipramine and triiodothyronine. Souche A, Baumann P, Koeb L, Thermoz P, Azorin JM, Dufour H. Encephale 1991 Jan-Feb;17(1):37-42

T3 Slightly Better Than T4 in DB: randomized, double-blind evaluation of the antidepressant-potentiating effect of T3 as compared with T4. Significantly more patients responded to 3 weeks of T3 as compared with T4 potentiation. Small but significant differential effects of the two thyroid hormones were noted on the Hamilton Rating Scale for Depression. U Toronto, A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Joffe RT, Singer W. Psychiatry Res 1990 Jun;32(3):241-51

T4 Helps Rapid Cycling Depression and Mania in Small DB: While 11 patients were taking added levothyroxine, scores on both depressive and manic symptom rating scales decreased significantly compared with baseline. This improvement was due to the clear-cut response of depressive symptoms in 10 of 11 patients, with manic symptoms responding in five of the seven patients who exhibited them during baseline evaluation. Four patients then underwent single- or double-blind placebo substitution; three patients relapsed into either depression or cycling. Treatment response did not depend on previous thyroid status. In 9 of 10 responsive patients, supranormal circulating levels of free thyroxine were necessary to induce clinical response. Side effects were minimal, and there were no signs or symptoms of levothyroxine-induced hypermetabolism. U Penn, Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Bauer MS, Whybrow PC. Arch Gen Psychiatry 1990 May;47(5):435-40

T3 No Benefit to Imipramine in Small DB: In a DB PC crossover study of 16 depressed patients who were unresponsive to 4 weeks of imipramine therapy (mean dose = 206 mg daily), all received T3 25 micrograms and placebo for 2 weeks each. There was no evidence of a T3 effect using both Hamilton depression scores and global improvement. No subgroup of responders using baseline TRH stimulation tests could be identified. T3 treatment lowered plasma free T4 (P = 0.001) and TSH (P greater than 0.02) while raising plasma T3 levels (P less than 0.01), indicating the physiological effect of the drug. UCLA, Failure of T3 to potentiate tricyclic antidepressant response. Gitlin MJ, Weiner H, Fairbanks L, Hershman JM, Friedfeld N. J Affect Disord 1987 Nov-Dec;13(3):267-72. Ed: This is a very small study for a very short period at the lowest dose used in any studies.

T3 Helps Imipramine/Amitriptyline in Small BD: Six women and 6 men who were treated in double-blind fashion major depressive illness did not respond to imipramine or amitriptyline, 150-300 mg/day, during periods of 26-112 days. After the addition of 25 micrograms/day (10 patients) or 50 micrograms/day (2 patients) of L-triiodothyronine (T3), 9 patients showed statistically significant improvement in depression scores; in 8 patients the response was marked. Improvement generally began within 1-3 days and was noted in all aspects of the depressive syndrome; side effects were minimal. T3 did not change plasma levels of imipramine or desipramine or their ratio but did suppress serum thyroxine. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Goodwin FK, Prange AJ Jr, Post RM, Muscettola G, Lipton MA. Am J Psychiatry 1982 Jan;139(1):34-8

Older Studies: Controlled Trial: Hormonal potentiation of imipramine and ECT in primary depression. Feighner JP, King LJ, Schuckit MA, Croughan J, Briscoe W. Am J Psychiatry 1972 Apr;128(10):1230-8; Random Controlled Trial: Potentiation of amitriptyline by thyroid hormone. Wheatley D. Arch Gen Psychiatry 1972 Mar;26(3):229-33; Controlled Trial: Thyroid function and the response to liothyronine in depression. Whybrow PC, Coppen A, Prange AJ Jr, Noguera R, Bailey JE. Arch Gen Psychiatry 1972 Mar;26(3):242-5; Controlled Trial: The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine. Arch Gen Psychiatry 1972 Mar;26(3):234-41; Use of a thyroid hormone to accelerate the action of imipramine. Prange AJ Jr, Wilson IC, Lipton MA, Rabon AM, McClae TK, Knox AE. Psychosomatics 1970 Sep-Oct;11(5):442-4; Controlled Trial: Thyroid-hormone enhancement of imipramine in nonretarded depressions. N Engl J Med 1970 May 7;282(19):1063-7; Controlled Trial: Enhancement of imipramine antidepressant activity by thyroid hormone. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Am J Psychiatry 1969 Oct;126(4):457-69

T4 Alone No Benefit Preventing Post-Partum Depression in Thyroid AB+ Women: In a DB PC study of 100 microg of thyroxine or placebo given daily to 446 thyroid-antibody-positive women from 6 weeks to 6 months post-partum, assessing their psychiatric and thyroid status at 4-weekly intervals, women with thyroid antibodies are somewhat more prone to post-partum depression. However, T4 supplement had no impact on depression. Randomised trial of thyroxine to prevent postnatal depression in thyroid-antibody-positive women. Harris B, Oretti R, Lazarus J, Parkes A, John R, Richards C, Newcombe R, Hall R. Br J Psychiatry 2002 Apr;180:327-30

Thyroid Supplementation No Increase Bone Demineralization: A study of women on thyroid supplement for depression at TSH suppressing doses for over 12 months found no evidence demineralization. Bone mineral density in pre-and post-menopausal women with affective disorder treated with long-term L-thyroxine augmentation. Gyulai L, Bauer M, Garcia-Espana F, Hierholzer J, Baumgartner A, Berghofer A, Whybrow PC. University of Pennsylvania. J Affect Disord 2001 Oct;66(2-3):185-91

TSH Suppression No Worse Than Standard T4 Treatment: Over one year, 1180 patients on thyroxine replacement had clinical and biochemical assessment; 59% had a suppressed TSH and 38% 'normal' TSH. Patients with a suppressed TSH exhibited higher median serum thyroxine levels (146 nmol/l vs 119 nmol/l; P < 0.001). Patients under the age of 65 on L-thyroxine had an increased risk of ischaemic heart disease compared to the general population (female 2.7 vs 0.7%, P < 0.001; male 6.4 vs 1.7%, P < 0.01), but the risk was no different between those with suppressed and normal TSH. There was no increase in risk for overall fracture, fractured neck of femur or breast carcinoma in those on thyroxine with suppressed or normal TSH. Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH. Leese GP, Jung RT, Guthrie C, Waugh N, Browning MC. Clin Endocrinol (Oxf) 1992 Dec;37(6):500-3

T4 Better if Used Before Lithium Trial for Treatment Resistant: In a study of 22 outpatients with major depression not responsive to 4 weeks of antidepressant treatment, the effect of a subsequent 4 weeks of thyroxine administration followed by 4 weeks of lithium augmentation was compared with the effect of the same treatments in reverse order. The percentage reduction in MADRS scores was significantly greater in patients who started on thyroxine. Researchers conclude that thyroxine augmentation should precede lithium augmentation. They did use relatively small doses of lithium. Should thyroid augmentation precede lithium augmentation--a pilot study. Spoov J, Lahdelma L. University of Helsinki. J Affect Disord 1998 Jun;49(3):235-9

Dessicated Thyroid Good Mix T3 and T4: Triiodothyronine (T3) and thyroxine (T4) radioimmunoassay of four lots each of 1- and 2-grain tablets of desiccated thyroid (Thyroid, Armour) and thyroglobulin (Proloid, Warner-Chilcott). One grain of desiccated thyroid contained 12 +/- 1 and 64 +/- 3 microgram (mean +/- SD) of T3 and T4 per tablet, respectively (T4/T3 molar ratio, 4.3). A 1-grain tablet of thyroglobulin contained 16 +/- 2 and 55 +/- 5 microgram of T3 and T4, respectively with a T4/T3 ratio of 2.9. Two-grain tablets generally contained twice the quantity of T3 and T4 in the 1-grain preparations. The variation in T3 and T4 content between the four lots of each tablet strength for each product was 10% or less. These estimates of T3 and T4 content are 1.5- to 2-fold greater than those previously published. This difference probably results from the more sophisticated methodology now available which does not require chromatographic separation of T3 and T4 or iodometry. Using calculations based on published estimates of T4 and T3 absorption and of the T3/T4 potency ratio, it would appear that the T3 content of desiccated thyroid and thyroglobulin provide approximately 39% and 51%, respectively, of the thyromimetic activity of these two medications. Triiodothyronine and thyroxine content of desiccated thyroid tablets. Rees-Jones RW, Larsen PR. Metabolism. 1977 Nov;26(11):1213-8.

No Loss of Bone Mineral Density: In 21 affective disorder patients receiving adjunctive maintenance therapy with supraphysiological doses of levothyroxine (L-T4), bone mineral density (BMD) of the spine and femur was measured by dual energy X-ray absorptiometry (DXA). BMD measurement was performed first after patients had been on thyroid-stimulating hormone (TSH)-suppressive therapy with L-T4 (mean dose=411 mcg/d) for an average of 16.4 months and again after 33.6 months of L-T4 (mean dose=416 mcg/d) therapy. There was no statistically significant difference between the actual percentage decline in bone mineral density and the expected percentage decline in any of the measured bone regions. In a stepwise linear regression analysis, age was identified as a predictor of percentage change in BMD. After controlling for age, the only other variable that showed a consistent trend was the dose of L-T4, with higher doses being positively correlated with the percentage decline of BMD. Bone mineral density during maintenance treatment with supraphysiological doses of levothyroxine in affective disorders: a longitudinal study. Bauer M, Fairbanks L, Berghofer A, Hierholzer J, Bschor T, Baethge C, Rasgon N, Sasse J, Whybrow PC. Charite-University Medicine Berlin, Berlin, Germany. J Affect Disord. 2004 Dec;83(2-3):183-90.

No Difference in SSRI Response by T3 Levels: In a study of 321 outpatients with depression treated for 8 weeks with fluoxetine 20 mg/day, there was no relationship between who improved and what their initial T3 levels were. T3 is most sensitive test for subclinical thyroid pathology. There were no cases of hypothyroidism and two of hyperthyroidism. 5% had low T3 and 2% high. Dan Losifescu, MGH, APA 5/17/99

T3 Added to T4 Improved Cognitive: In a 5-week each phase DB PC crossover study of 33 patients with hypothyroidism treated with T4, while on 12.5 microg T3 substituted for 50 microg of their T4 in combined thyroid therapy, patients did better for fatigue, depression, anger, attention, and others. Thyroid produces both altho T4 converted to T3 peripherally. UNC, NEJM 99;340:424. Ed: Most studies do not agree with this finding.

Combined T-3 and T-4 No Better than T-4 Alone for Hypothyroid Patients: Thyroid supplementation with T-4 or T-3 has been found to increase the speed and responder percentage of anti-depressant treatments in psychiatric patients. No study has looked at combining the two. For general medical patients with low thyroid, the standard treatment is T-4 alone. Some of the T-4 is converted in the body to T-3 and the body uses both forms. Some physicians use both T-4 and T-3 thinking that this is more physiologic and might work better. A first study looking at this issue using a 46-patient, 4-month DB PC study has found no added benefit to the combination over T-4 alone. Bethesda Nation Naval Med Center. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. Clyde PW, Harari AE, Getka EJ, Shakir KM. JAMA. 2003 Dec 10;290(22):2952-8

T-3 Helps Tricyclics Work Faster: A meta-analysis of 5 imipramine and 1 amitriptyline studies from the 70’s found not only a higher percentage of responders but also a more rapid rate of response, especially for females. Dosages ranged from 20-25 micrograms/d. Amer J Psychiatry 01;158:1617

Open Trial Reports

Open trials are pretty worthless reports, since they prove nothing. These are included since they show that top university medical centers are still using thyroid supplementation for treatment resistant depression.

Harvard Using T-3 for Treatment Resistant Depression as Second Step with SSRI: In an open trial of 20 patients with major depression resistant to an SSRI for at least 8 weeks, 4-weeks of open-label augmentation treatment with T(3) 50 microg/day was associated with a drop in HAM-D-17 depression score from 20.5 to 14.0 (p < .001). An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. Iosifescu DV, et al. MGH- Harvard. . J Clin Psychiatry. 2005 Aug;66(8):1038-42

UCLA Using T-4 for Bipolar Depression: Affects Brain Circuits Hampered by Depression: In 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day), L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders. Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression. Bauer M, et al. University of California Los Angeles. . Mol Psychiatry. 2005 May;10(5):456-69.

Hadassah-Hebrew University Still Using Thyroxine in PTSD with Depression Partial Responsive to SSRI: T3 (25 microg/day) was added to treatment in open trial with a selective serotonin reuptake inhibitor (SSRI) (paroxetine or fluoxetine, 20 mg/day for at least 4 weeks and 40 mg/day for a further 4 weeks) of 5 patients who fulfilled DSM-IV criteria for PTSD but not for major depressive disorder (although all patients had significant depressive symptoms). The Clinician-Administered PTSD Scale, the 21-item Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Severity of Illness scale were administered every 2 weeks, and self-assessments were performed with a 100 mm visual analog mood scale. RESULTS: In 4 of the 5 patients, partial clinical improvement was observed with SSRI treatment at a daily dose of 20 mg with little further improvement when the dose was raised to 40 mg/day. This improvement was substantially enhanced by the addition of T3. Improvement was most striking on the Hamilton Rating Scale for Depression. Triiodothyronine augmentation of selective serotonin reuptake inhibitors in posttraumatic stress disorder. Agid O, Shalev AY, Lerer B. Hadassah-Hebrew U, Jerusalem. J Clin Psychiatry 2001 Mar;62(3):169-73

T4 200-500microg/d Helped in Open Trial: Authors claim that 200-500 micrograms of T4/day has excellent effects in 50-65% of patients a) with bipolar disorder, with or without, "rapid cycling" course, who were previously resistant to all prophylactic drugs and b) in the treatment of therapy-resistant depression. T4 is effective only in combination with an antidepressant or a prophylactic drug. Side effects are minimal, even when T4 is administered over several years. High dosage thyroxine treatment in therapy and prevention refractory patients with affective psychoses, Bauer M, Hellweg R, Baumgartner A. Nervenarzt 1998 Nov;69(11):1019-22

Two Cases T3 Helping MAOI: 2 patients not responsive to TCA, TCA + lithium, TCA + T3, or MAOI, responded after T3 was added. Triiodothyronine potentiation of the antidepressant effect of phenelzine. U Toronto, Joffe RT. J Clin Psychiatry 1988 Oct;49(10):409-10