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Treatment of Refractory Depression with High-Dose Thyroxine Michael Bauer, M.D., Ph.D., Rainer Hellweg, M.D., Klaus-Jürgen Gräf, M.D., and Andreas Baumgartner, M.D. In an open clinical trial we investigated whether addition of weeks and two others fully remitted within 12 weeks. Seven supraphysiological doses of thyroxine (T4) to conventional patients did not remit. The 10 remitted patients were antidepressant drugs has an antidepressant effect in maintained on high-dose T4 and followed up for a mean of therapy-resistant depressed patients. Seventeen severely ill, 27.2 6 22.0 months. Seven of these 10 remitted patients had therapy-resistant, euthyroid patients with major depression an excellent outcome, two had milder and shorter episodes (12 bipolar, five unipolar) were studied. The patients had during T4 augmentation treatment, and one failed to profit 6 been depressed for a mean of 11.5 13.8 months, despite from T4 treatment during the follow-up period. Side effects treatment with antidepressants and, in most cases, were surprisingly mild, and no complications were observed augmentation with lithium, carbamazepine, and at all. In conclusion, augmentation of conventional neuroleptics. Thyroxine was added to their antidepressant antidepressants with high-dose T4 proved to have excellent medication, and the doses were increased to a mean of 482 6 antidepressant effects in approximately 50% of severely 72 mg/day. The patients’ scores on the Hamilton rating therapy-resistant depressed patients. Scale for Depression (HRSD) declined from 26.6 6 4.7 [Neuropsychopharmacology 18:444–455, 1998] 6 prior to the addition of T4 to 11.6 6.8 at the end of week 8. © 1998 American College of Neuropsychopharmacology. Eight patients fulfilled the criteria for full remission (a 50% Published by Elsevier Science Inc. reduction in HRSD score and a final score of ø9) within 8 KEY WORDS: High-dose thyroxine; Major depression; and Wilkinson 1994; Thase and Rush 1995; Thase et al. Therapy-resistant depression 1995). All of these epidemiologic studies investigated the course of mood disorders in a more or less “natural- Major depression is generally viewed as a disorder with istic” design, i.e., the long-term therapy of the de- a relatively favorable prognosis. Nonetheless, in recent pressed patients was not standardized. The question years several epidemiologic studies have unanimously therefore arises as to whether chronically depressed pa- reported that between about 5 and 15% of depressed tients might profit from more rigid, standardized thera- patients become chronically ill, i.e., they fail to recover peutic strategies. Such strategies could include treat- over a period of several years (Lee and Murray 1988; ment with different classes of antidepressants in Scott 1988; Keller et al. 1992; Howland 1993; Picinelli sufficiently high doses over not less than 6 weeks re- spectively, as well as several “augmentation strategies” From the Department of Psychiatry (MB, RH) and Nuclear Medi- such as the addition of lithium, triiodothyronine (T ) or cine (AB), Klinikum Benjamin Franklin, Free University of Berlin, 3 Berlin, Germany; and the Department of Medicine (K-JG), Klinikum neuroleptics, and electroconvulsive therapy (Thase and Rudolf-Virchow, Humboldt University, Berlin, Germany. Rush 1995; Thase et al. 1995). With respect to thyroid Address correspondence to: Dr. A. Baumgartner, Department of hormones, several older studies reported that the addi- Nuclear Medicine (Radiochemistry), Klinikum Benjamin Franklin, m Hindenburgdamm 30, D-12200 Berlin, Germany. tion of low-dose (25–50 g/day) triiodothyronine (T3) Received July 21, 1997; accepted August 21, 1997. induced an acceleration of the response to tricyclic anti- NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 6 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(97)00181-4 NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 6 Treatment of Refractory Depression with High-Dose Thyroxine 445 depressants (e.g., Prange et al. 1969). Later, the addition ence of two independent raters, using information from of T3 to conventional antidepressants was found to be a diagnostic interview and from previous psychiatric highly effective in treatment-resistant depressed pa- case notes, which were available in all cases (see below). tients in some studies (e.g., Goodwin et al. 1982; Joffe For inclusion in the study the patient had to be consid- and Singer 1990; Joffe et al. 1993), but not all (e.g., Gar- ered therapy resistant, according to the following crite- butt et al. 1986; Gitlin et al. 1987; Thase et al. 1989a; for a ria (standardized criteria for nonremission according to review, see Joffe et al. 1995). An interesting hypothesis Nierenberg and Amsterdam 1990): on the mechanism of action of T was put forward by 3 • Nonremission after administration of at least two Joffe et al. (1984, 1995), namely, that depression is a chemically different antidepressant medications, each state of relative T excess and that T acts by lowering 4 3 administered in standardized doses for a period of at the serum concentrations and subsequently also the least 6 weeks: tricyclics and tetracyclics .150 mg/ brain concentrations of T via inhibition of thyroid- 4 day, selective serotonin reuptake inhibitors (SSRI) stimulating hormone (TSH) secretion. .20 mg/day; MAO-inhibitor tranylcypromine .30 On the other hand, thyroxine (T ) itself has now been 4 mg/day). Nonremission was defined as a failure to reported to be effective in the prophylaxis of previously achieve a reduction of at least 50% on the 21-item therapy-resistant, rapid-cycling bipolar disorders (Stancer version of the Hamilton Rating Scale for Depression and Persad 1982; Leibow 1983; Bauer and Whybrow (HRSD) (Hamilton 1960) or a final HRSD score of ù15. 1986, 1990; Hurowitz and Liebowitz 1993). Our own • Nonremission on the basis of an analysis of the case group recently reported that treatment with supraphys- history: 13 of the 17 patients who were finally in- iological doses of T stabilized previously completely 4 cluded had been hospitalized at the psychiatric clinic treatment-resistant, severely ill nonrapid cycling bipo- during previous episodes, most of them several lar patients (Baumgartner et al. 1994a). In some of these times (see Table 1). Case notes giving detailed infor- patients prophylaxis with high-dose T was initiated 4 mation on their response or nonresponse to antide- during a depressed episode. We gained the impression pressant therapies during previous episodes were that in these patients the depressive episode subsided therefore available. For the remaining four patients, much faster than previously. These observations this information was obtained from other medical prompted us to conduct an open clinical trial in which centers or outpatient facilities. Almost all of the pa- we investigated the effects of high-dose T augmenta- 4 tients had indeed been resistant to several different tion in depressed patients who had failed to respond to antidepressant treatments in previous episodes. We conventional pharmacotherapy. decided that in these cases when previous nonremis- sion to one or more antidepressants was already evi- dent from the records, one 6-week trial with a suffi- PATIENTS AND METHODS ciently high dose of a standard antidepressant would be sufficient to consider the patient to be treatment As the administration of high doses of T must still be 4 resistant during the present episode also. Five pa- regarded as an experimental therapeutic strategy, we tients for whom nonremission to both tricyclics and thus intentionally accepted for this study only the most lithium had already been established in previous ep- severely ill and treatment-resistant depressed patients isodes were thus considered to be treatment resistant who sought treatment at the in-or outpatient facilities of after only one 6-week trial with one antidepressant the psychiatric clinic between 1990 and 1995. The pa- (patients nos. 2, 3, 5, 6, and 10; see Table 1). tients were not included in the trial unless several other available therapeutic and/or prophylactic treatments The patients were also required to fulfil the following had already proved ineffective, either during the present additional criteria: episode or previously, and the idea of high-dose T 4 • no history or concomitant abuse of alcohol or addic- treatment thus presented itself as a kind of “last resort” tive drugs, including benzodiazepines treatment. The patients included in the study were • no serious somatic illnesses or diseases considered to therefore most likely to be more strongly resistant to be a contraindication for high-dose T treatment, treatment and had a more serious course of depressive 4 such as severe cardiac insufficiency, a history of illness than the patients usually included in “augmenta- myocardial infarction, cardiac arrhythmias, or a his- tion studies,” who have as a rule failed to respond to tory of thyroid adenoma or hyperthyroidism. only one previous trial of one antidepressant (Thase and Rush 1995; Thase et al. 1995). Four patients who were already receiving T4 in phys- Formally, all patients were required to meet the iological doses due to lithium-induced subclinical hy- DSM-III-R (American Psychiatric Association 1987) cri- pothyroidism and whose laboratory values showed teria for major depression or bipolar disorder, de- them to be euthyroid, were accepted for the study. pressed. Consensus diagnoses were made at a confer- Twenty-one patients fulfilling the above criteria 446 M. Bauer et al. NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 6 were considered for inclusion in the study. Four of enoma (n 5 2). Thus, a total of 17 patients was finally them then had to be excluded owing to benzodiazepine accepted for the study. and amphetamine abuse (n 5 1), severe cardiac ar- The following clinical and laboratory investigations rhythmias (n 5 1) and a recent history of autonomic ad- were performed for all patients: routine laboratory Table 1.

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