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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]
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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.
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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
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(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
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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
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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.
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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
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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,
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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
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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
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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.
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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
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