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1 SUBJECTIVE RESPONSE TO AND TOLERABILITY OF LONG-TERM SUPRAPHYSIOLOGICAL DOSES OF LEVOTHYROXINE IN REFRACTORY MOOD DISORDERS Michael Bauer* 1,2 Ph.D., M.D., Stefan Priebe 3, M.D., Anne Berghöfer 1, M.D., Tom Bschor 1, M.D., Ursula Kiesslinger 1, M.A., Peter C. Whybrow 2, M.D. 1 Department of Psychiatry, Klinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany, 2 Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles (UCLA), Los Angeles, USA, 3 Department of Psychiatry, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, London, UK. * Supported by Deutsche Forschungsgemeinschaft (# Ba 1504/3-1). Corresponding author: Michael Bauer, Ph.D., M.D. Neuropsychiatric Institute & Hospital Department of Psychiatry and Biobehavioral Sciences University of California at Los Angeles (UCLA) 300 UCLA Medical Plaza Los Angeles, Ca, 90095-6968 Tel: (310) 825-4908; Fax: (310) 206-4310 E-mail: [email protected] 2 Summary Background: Although supplementation with supraphysiological doses of levothyroxine (T4) has been an effective treatment for refractory affective disorders in open studies, questions remain as to the tolerability of this treatment. This is the first study to investigate subjective patient response and tolerability to long-term treatment with adjunctive T4. Methods: Of 24 patients with refractory affective disorders or schizoaffective disorder who were consecutively included into an open trial with supraphysiological T4, 16 were eligible for this study. Four measures were used to rate tolerability to T4 treatment. Subjective response was graded on a scale ranging from - 33 (maximal negative response) to +33 (maximal positive response). Positive and negative effects were assessed on a structured questionnaire. Clinical tolerance was assessed with the clinician-rated Thyroid Symptom List and the self-rated Von Zerssen Complaint Lists. Outcome was assessed with the CGI for prophylactic ratings (CGI-BP). Results: At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 µg/d) for a mean of 54 months. The total subjective response score was + 25.2. Positive subjective response and observerrated treatment success were moderately correlated. Ratings on the Thyroid Symptom List indicated an overall favorable side effect profile. General physical and mental symptoms were only slightly higher than in the general population. Limitations: This was an open, cross-sectional study that only included responders and partial responders to T4 treatment. Conclusions: Subjective response and side-effect tolerability of long-term supraphysiological doses of T4 is favorable in patients with refractory mood and schizoaffective disorders who respond to the intervention. Key words: Thyroid hormone, levothyroxine, subjective response, tolerability, refractory mood disorders. 3 Introduction The successful treatment of periodic catatonia and cyclic mood disorders with hypermetabolic doses of dessicated thyroid gland (Gjessing 1938), coupled with findings of an increased frequency of low thyroid function in rapid cycling bipolar disorder (Bauer et al. 1990, Gyulai et al., submitted), has prompted investigators to administer supraphysiological doses of levothyroxine (T4) in patients with refractory affective disorder. In a series of open studies supraphysiological doses of T4 alone (Stancer and Persad 1982) or in addition to conventional mood stabilizers has been reported to improve the course of patients with rapid cycling and non-rapid cycling bipolar disorder (Bauer and Whybrow 1990, Baumgartner et al. 1994, Bauer 1997, Afflelou et al. 1997). Additionally, preliminary data from recent open studies suggests that augmentation with supraphysiological doses of T4 may cause substantial improvement in some patients with treatment-resistant depression (Bauer et al. 1998, Spoov and Lahdelma 1998, Rudas et al. 1999). Although supraphysiological T4 has been recommended as a treatment option in reviews and treatment algorithms on refractory mood disorders (e.g., APA 1994, Sachs 1996, Goodwin and Nolen 1997, Post et al. 1997), there have been concerns about tolerability and safety (Joffe 1998). In most of the studies of affectively ill patients, the physiological criteria for treatment with T4 were suppression of TSH and elevation of serum T4 levels to approximately 150% of normal (Bauer and Whybrow 1990). As determined by protocol, the serum levels of circulating thyroid hormones rose, but this "hyperthyroxinemia" did not result in clinical evidence of a thyrotoxic state. Indeed, a substantial proportion of patients reported no side effects that could be related to treatment with supraphysiological T4 (Bauer and Whybrow, 1990; Baumgartner et al. 1994; Bauer et al. 1998). Cross-sectional studies in pre- and postmenopausal women with affective disorders showed no significant bone loss 4 (Gyulai et al. 1997, Gyulai et al. submitted). To date, published reports on the use of supraphysiological T4 in mood disorders have focused on the clinical outcome rather than on subjective response and tolerability of this treatment. The subjective response to a given drug is a central factor in patient compliance and is, given the importance of the user perspective in treatment evaluation, an outcome criterion in its own right. An unfavorable subjective response to various forms of drug treatment has repeatedly been found associated with early termination of treatment. Furthermore, even if the treatment is administered continuously and properly, patients experiencing a negative subjective response appear to benefit less from the treatment over time (e.g. van Putten and May 1978, Hogan et al. 1985, Priebe and Bröker 1997). The aim of the present study, therefore, was to investigate patients' subjective response to and tolerability of long-term supraphysiological T4 supplementation within the context of its use as an option for refractory mood and schizoaffective disorders. Methods Design and Subjects Patients with refractory (schizo-) affective disorders (refractoriness was defined as being non responsive to 2 or more adequate prophylactic drug trials; Bauer and Ströhle 1999) were recruited from an open prophylactic clinical trial of the efficacy of adjunctive supraphysiological T4 conducted at the Department of Psychiatry, Freie Universität Berlin. Patients were given T4 in addition to the prophylactic drugs they had been receiving during the preceding weeks. The starting dose was 50 µg T4/day, subsequently the dosage was increased by 50 µg/day every three days until a dose of 500 µg/day was reached, if tolerated (for details see Baumgartner et al. 1994). If side effects occurred prior to this dose, the treatment was stabilized at the dose at which 5 the side effects occurred. During the T4 study, there were no changes in the prophylactic drug regimen. Acute affective episodes were treated with antimanic and antidepressive medication and the treatments terminated within 6 weeks of remission. The eligibility criteria for participation in the present study were 1) refractory (schizo-) affective disorder (for definition see above), 2) duration of treatment with supraphysiological T4 (> 250 µg/d) > 1 year, 3) confirmed TSH suppression on the day of clinical evaluation for this study and during prophylactic T4 treatment as measured monthly or bimonthly, 4) knowledge of German sufficient to communicate with the investigator and understand the self-rating scales. Exclusion criteria were 1) current major depressive episode or manic episode (DSM-III-R criteria), 2) psychotic features, 3) score of > 10 on the Bech-Rafaelsen Melancholia Scale (BRMES; Rafaelsen et al. 1980), 4) score of > 5 on the Bech-Rafaelsen Mania Scale (BRMAS; Rafaelsen et al. 1980), 5) concurrent medical illness. Eight of 24 patients consecutively admitted into the prophylactic T4 study were not eligible for the present study. Three patients were non-responsive as judged by clinical global impression. One patient had a severe episode of depression with psychotic features. One patient was excluded because of language constraints. One patient was lost for follow-up (continued T4 treatment in private practice) and one patient did not fulfill the one-year inclusion criteria. In one patient T4 was discontinued after three months due to an increase of a lithium tremor. Of the 16 (67%) patients (11 women, 5 men) who participated in this study, eight were diagnosed with bipolar disorder, three with recurrent major depression, and four with schizoaffective disorder. Before T4 treatment, their mean number of lifetime episodes was 27.6 + 21.3 (range 3-62) and hospitalizations was 6.7 + 4.4 (range 115). Their mean age at the time of the study was 49.6 years (SD=8.0; range 31-61) while the mean age at the first episode was 32.0 years (SD=9.9). The mean dose of 6 T4 received at the time of the study was 368.7 g/d (SD=77.1; range 250-500). In addition to T4, patients were taking one or more psychotropic drugs (lithium 11, carbamazepine 6, valproate 1, clozapine 3, perazine 2, nortriptyline 2, paroxetine 2, thioridazine, imipramine and clomipramine 1 each). Non psychotropic drugs included estrogens (2), acetylsalicylicacid, amiloride & hydrochlorothiazide combination and potassium (1 each). Clinical Assessments Patients were diagnosed according to DSM-III-R criteria on the basis of a clinical interview and a checklist of symptoms. Severity of depressive and manic symptoms was observer-rated with the BRMES, the BRMAS, and the Clinical Global ImpressionsBipolar Illness Version (CGI-BP; Spearing et al. 1997). Assessment of Subjective Response Subjective response to T4 treatment was assessed by three questions according to van Putten and May (1978): 1. How does the medication agree with you? 2. Does it affect your mood? 3. Do you think this is the right medication for you? For each question patients rated their answers on a scale ranging from minus 11 (negative extreme) to plus 11 (positive extreme) with 0 being the neutral middle point. Thus the total subjective response ranged between –33 (maximal negative response) to +33 (maximal positive response). In addition, a structured interview was administered. Patients were asked open questions on positive and negative effects of T4 treatment, how it compared to other medications, and whether the treatment effects had an impact on their living situation. Answers were recorded and subjected to content analysis using a posteriori formed categories. 7 Adverse Effects Assessment A Thyroid Symptom List (TSL) was administered to patients to track the degree of symptoms and signs of hyperthyroidism from treatment with T4. The TSL is a clinician-rated instrument assessing symptoms associated with hypermetabolic thyroid hormone conditions. The 24-item list, developed by the investigators, is based on an evaluation of signs and symptoms in the available endocrine literature (Larsen and Ingbar 1992; Bauer et al. 1999). Patients were asked to what extent each symptom was present during the week before the interview and if they experienced other physical symptoms not included on the TSL. Answers were scaled from 0 (not present) to 3 (severe). In addition, patients self-rated general physical and mental symptoms on a combined 48-item scale (von Zerssen Complaint List B-L and B-L’; AMDP and CIPS 1990), covering a broad range of physical and mental symptoms that has been widely administered to healthy subjects as well as physically and mentally ill samples (Von Zerssen 1971). Each symptom is rated between 0 (“not at all“) to 3 (“severely“). To obtain a total raw score for the Complaint List (B-L sum), the scores of the two 24-item versions B-L and B-L’ are added together (scores in the general population: B-L 14.26 (SD=10.75), B-L’14.26 (SD=10.74), total raw score of both lists combined 14.26 (SD=10.33); AMDP and CIPS 1990). Outcome Measure and Statistical Analyses The overall clinical outcome during T4 treatment was assessed with the CGIBP, III, Change from Worst Phase of Illness, developed for prophylactic ratings (ranging from 1=very much improved to 8=not applicable) (Spearing et al. 1997). Data was expressed as mean values (SD; range). For correlations between the total subjective response score and clinical variables (CGI-BP, B-L sum) Spearman‘s 8 rank correlation coefficients (rho) were calculated. Results At the time of assessment, patients had been treated with supraphysiological T4 for an average of 54.5 months (SD=21.9; range: 28-97). The mean scores on the BRMES (3.0, SD=4.3) and BRMAS (0.5, SD=1.2) indicated that patients were euthymic by inclusion criteria; the CGI-BP (I. Severity of Illness) score was 1.8 (SD=1.0). For prophylactic assessment, 11 patients were rated as “very much improved“ (score 1), four as “much improved“ (score 2), and one as “minimally improved“ (score 3) on the CGI-BP, Change from Worst Phase of Illness (mean score: 1.3, SD=0.6). The total subjective response score was +25.2. The first question (How does medication agree with you?) was rated with a +7.5 (SD=3.9; range 0 to +11). The second question (Does the medication affect your mood?) was rated with +7.4 (SD=3.6; range 0 to +11), and the third question (Do you think this is the right medication for you?) was rated +10.3 (SD=1.5; range +5 to +11). The latter question was rated with the highest possible score (+11) by 12 (75%) patients. Asked about positive and negative effects of supraphysiological T4 treatment, 48 positive effects and 8 negative effects were reported by the patients. The most frequent answers on positive effects were “Illness has improved and stabilized” (n=9), “No negative effects” (n=9), “I am doing better” (n=7), “No more hospitalizations” (n=5), and “Positive impact on partnership or job” (n=5). Seven patients stated one side effect each as a negative effect of T4 treatment; one patient stated “No knowledge about long-term effects” as a negative effect. The symptoms with the highest scores on the observer-rated Thyroid Symptom List were (in descending order) excessive sweating, tremor, impaired concentration, 9 heat intolerance, and easy fatigability (Table 1). The mean score on the self-rated Von Zerssen Complaint List B-L was 17.00 (SD=9.23), and on the B-L‘ 14.31 (SD= 9.70). The total raw score combining both lists was 15.65 (SD=8.77). The most frequent “moderately“ and “severely“ rated complaints were “tiredness“ (49%), “extreme sensitivity to heat“ (43%), “a tendency to become exhausted quickly“ (37%), “fatigue“ (37%), and “trembling“ (37%) (Table 2). There was a significant negative correlation between subjective response and the CGI-BP (rho=-0.42, p<0.05, one-tailed) indicating that a more favorable subjective response was associated with a more positive observer-rated outcome. A more negative subjective response was correlated with a higher B-L sum score (rho=-0.41). The correlation coefficient, however, just failed to reach statistical significance (p=0.056, one-tailed). Discussion This first report on subjective response and clinical tolerability during long-term prophylactic treatment with adjunctive supraphysiological doses of T4 yielded two major findings of interest. First, patients‘ subjective response and attitude to supraphysiological T4 treatment appears to be favorable. No patient expressed a negative response on any of the three items, and the majority of patients felt that this was the right medication for them. Second, the clinical tolerability seems to be surprisingly good as expressed by the relatively low scores on the clinician-rated Thyroid Symptom List and the self-rated Complaint Lists. Scores on the latter scale were – on average – only slightly higher than in the general population (AMDP and CIPS 1990). The reason why patients with mood disorders tolerate supraphysiological T4 doses so well remain speculative. In contrast to patients with endogenous production of thyroid hormone secondary to hyperthyroidism, treatment with high dose 10 levothyroxine in patients with mood disorders does not result in excessive peripheral levels of triiodothyronine (T3), the hormone with the highest biologic activity in peripheral tissues (Bauer and Whybrow, Baumgartner et al. 1994, Bauer et al. 1998). This suggests that the underlying autoimmune process in hyperthyroidism may contribute to the clinical syndrome in the endocrine disorder, and such symptoms are absent in iatrogenic „hyperthyroxinemia“. Nevertheless, it is important to note that this evaluation has limitations that could confound interpretation of the data. First, eight patients (33%) who had discontinued treatment with supraphysiological doses of T4 or were not eligable for this study were not included in this evaluation. It is possible that their side effect profile was different from that reported here. However, only one (4%) out of the original 24 patients discontinued high-dose T4 treatment due to side effects (tremor). Secondly, no comparison was made with a control group. However, this selection bias and lack of a comparison group does not disqualify the finding that 67% of the initial total sample of 24 patients with refractory mood or schizoaffective disorders had a positive subjective response to supraphysiological doses of T4 for at least a year. Third, it is difficult to define the unique side effect profile of supraphysiological doses of T4 because there is considerable overlap between symptoms of depression and side effects symptoms of hyperthyroxinemia (Whybrow and Bauer 1999, Bauer et al. 1999). Although patients were euthymic at the time of the investigation, some of the symptoms, e.g., tiredness, excessive need to sleep, impaired concentration, may be, at least in part, the result of the underlying mental disorder. It must be emphasized that the patients who entered the open T4 trial belonged to the most refractory affectively ill patients we have seen during the past decade. Therefore, some symptoms and complaints reported may not be adverse effects from thyroid treatment, but rather residual affective disease. Fourth, since all patients were also taking one or 11 more psychotropic drugs, it is difficult to determine if subjective response and adverse effects were specific to treatment with T4. However, it must be emphasized that the patients were asked to rate their subjective response to T4. As determined by inclusion criteria, all patients had extensive experience with the use of other psychotropic agents, the majority of them for many years. Furthermore, the prophylactic regimen of psychotropic agents was not changed during the T4 trial. Thus novel side effects were easily distinguished by the patients. The favorable subjective response was associated with a lower degree of self rated general symptoms and a more positive observer-rated outcome. The plausible, yet moderate coefficients are in line with similar findings reported in the literature (e.g. Edwards et al. 1978, Conte et al. 1989, Priebe et al. 1998). They indicate that subjective response is a criterion in its own right, relatively independent from observer-rated outcome and not fully explained by symptoms. As indicated by the scores on the CGI-BP version, the overall clinical outcome during prophylactic T4 treatment was favorable in approximately two-thirds of the patients. Although results from this and previous studies must be seen as preliminary, the study indicates that in otherwise treatment-refractory patients with mood or schizoaffective disorders long-term treatment with supraphysiological doses of T4 is a viable augmentation strategy. With respect to bone demineralization, it has recently been demonstrated that pre- and postmenopausal women (n=26) with mood disorders who received supraphysiological T4 treatment (> 12 months) had no clinically significant loss of bone mineral density compared to the age-matched reference population standard (Gyulai et al., submitted). The long-term effects of treatment with supraphysiological doses of T4 on the cardiovascular system remain to be objectively studied. Nonetheless, we continue to recommend that adjunctive supraphysiological doses of T4 be reserved for patients with the most refractory of affective disorder. 12 Table 1. Symptoms and Signs on the Clinician-Rated Thyroid Symptom List in Patients with Refractory Affective/Schizoaffective Disorders During Treatment with Supraphysiological Doses of Levothyroxine1 Symptoms and Signs2 (in descending order) Sweating excessive Tremor Concentration impaired Heat intolerance Easy Fatigability Sleep disturbance Inner restlessness Irritabilty Nails broken Nervousness Diarrhea Muscle weakness/pain Pulse increase/tachycardia Hairloss Lack of appetite Weight loss Palpitations Anxiety Hot flushes Hyperactivity Vertigo2 Dyspnea on exertion 1 2 Not present (score 0) % 37 43 43 56 37 56 56 50 62 56 56 68 62 81 81 75 81 87 81 87 81 87 Mildly (score 1) % 31 25 25 18 18 31 31 37 18 31 37 12 25 6 12 18 12 6 18 6 6 12 Moderately (score 2) % 18 25 12 12 37 0 6 12 12 12 6 18 12 12 0 6 6 6 0 6 12 0 Severely (score 3) % 12 6 12 12 6 12 6 0 6 0 0 0 0 0 6 0 0 0 0 0 0 0 Table lists only symptoms and signs that occurred in > one patient Symptoms that were reported in addition to those given on the Thyroid Symptom List 13 Table 2: Most Frequent Self Rated Symptoms on the Von Zerssen Report Scales B-L and B-L‘ in Patients with Refractory Affective/Schizoaffective Disorders Treated with Supraphysiological Doses of Levothyroxine1 Symptoms (in descending order) Tiredness Excessive need of sleep A tendency to become exhausted quickly Diminished ability to concentrate Extreme sensitivity to heat A lack of energy Fatigue Irritability Perspiring heavily Trembling Brooding Headaches, pressure in the head or pains in the face Lumbago or back pains Pains in the shoulders and neck A lack of sexual excitability Cold feet Gloomy thoughts Inner restlessness A feeling of weakness A sensation of heaviness or fatigue in the legs Heartburn or beichung due to stomach acidity Constipation Feeling cold Inner tension Insomnia 1 Not at all (score 0) % 25 31 25 Mildly (score 1) % 25 31 37 Moderately (score 2) % 37 18 31 Severely (score 3) % 12 18 6 31 37 37 25 18 37 43 37 43 37 18 31 37 62 31 18 31 31 12 31 18 31 12 18 25 25 18 18 12 12 6 6 12 12 6 6 37 43 56 56 43 43 50 50 43 31 18 12 37 37 25 25 12 18 12 25 12 12 25 25 6 6 12 6 6 6 0 0 56 18 18 6 62 56 43 43 18 25 43 50 6 12 12 0 12 6 0 6 only symptoms with a total score of > 10 are listed 14 References Afflelou S., Auriacombe M., Cazenave M., Chartres J. 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