Treatment of Anergic Depression in Hashimoto's Thyroiditis with Fluoxetine and D-Amphetamine
The Thyroid/Depression Connection Explored
by Alan Cohen, M.D.
Hashimoto's thyroiditis has been known to produce symptoms of severe anergia fatigue and depression. The hypothyroidism impairs cerebral function causing marked motor slowing which complicates the treatment of concomitant depression. In this open trial, three patients with documented Hashimoto's thyroiditis and Major Depression responded to a combination of fluoxetine and d-amphetamine. Dcspite improvement in mood with fluoxetine alone, all three patients had persistent anergia which resolved after the addition of d-amphetamine to their regimen. A discussion of the unique aspects of anergia and depression associated with hypothyroidisms follows, with a focus on the cerebral impairment and delayed reaction time that complicates this illness The neorotransmitter enhancing properties of serotonin re-uptake inhibitors and direct-acting psychostimulants may in combination, provide a unique treatment approach to anergic depression associated with hypothyroidism Depression 1:110-114 (1993). 43 1993 Wiley- Liss Inc.
Key words: Hashimoto's thyroiditis , anergia fatigue, depression, fluoxetine , d-amphetamine
Hashimoto s thyroiditis is an autoimmune disorder characterized by inflammation and destruction of the thyroid gland by auto-antibodies directed against thyroid tissue ( Volpe , 1986). This is often a slow, insidious process which results in progressive thyroid failure and marked hypothyroidisms . There are multiple somatic symptoms associated with this disorder, including anergia depression, cold intolerance, weight gain, muscle aches, constipation, and dry skin ( Volpe , 1986). Depression may be one of the first symptoms of this illness (Gold, 1987; Hall, 1982; Whybrow , 1969; Krahn 1987, Nemeroff , 1985; Wilson 1985; Reus, 1986). One study suggested that 15% of patients admitted for depression in a psychiatric facility had elements of subclinical (mild) or overt hypothyroidism by Laboratory evaluation (Gold, 1987).
The treatment of choice for autoimmune hypothyroidism is replacement of thyroid hormone to correct abnormally low levels of T-3 and T-4 and reduce an elevated thyroid stimulating hormone (TSH) When the TSH returns to the normal range most symptoms will resolve. However, it has become apparent in clinical practice that depressive symptoms and anergia may persist despite correction of the hypothyroid state by replacement of thyroid hormone (Cooper, 1984; Reus, 1989; Wilson, 1985).
This report documents the effectiveness of a combination therapy using a selective serotonin re-uptake inhibitor, fluoxetine , and a direct stimulant, d-amphetamine, to treat symptoms of depression, severe fatigue and anergia related to hypothyroidism. Psychostimulants have been demonstrated to be effective in treating apathetic geriatric patients who are quite anergic and fatigued fatigued ( Kaplitz , 1975; Kauffman, 1982). In addition, stimulants have been found to be helpful in AIDS dementia depression associated with medical illnesses, attention deficit disorder, narcolepsy , and refractory depression ( Chiarello , 1987; Kauffman, 1982; Woods, 1986).
This is the first report of the effectiveness of d-amphetamine in combination with fluoxetine for treatment of anergia fatigue associated with Hashimoto's thyroiditis , whose hallmark symptoms are fatigue and depression
Three patients with documented Hashimoto's thyroiditis and hypothyroidism presented to the outpatient setting for treatment of depression and severe anergia With the addition of d-amphetamine to their regimen of fluoxetine and thyroid hormone, a complete remission of both depressive symptoms and severe anergia was achieved.
Ms. A is a forty-year-old single white female with a long history of chronic depression of 15 years duration. There was no history of mania. Her depression worsened 3 years prior to her treatment. Depressive symptoms included: labile mood, dysphoria anergia fatigue, anhedonia and carbohydrate binge eating with weight gain. She also reported irritability periods of anxiety, hypersomnia and decreased concentration. There was no suicidality nor psychotic symptoms. She met DSMIII R criteria for Major Depression (moderate, nonpsychotic ). Her GAF was 35. A history of Hashimoto's thyoiditis with goiter was diagnosed several years prior to her current evaluation. Additional medical history included an iron deficiency anemia. Her symptoms worsened premenstrually . Mental status exam revealed a mildly obese white female with a blunted affect. Her mood was dysphoric. Psychomotor slowing was present without any abnormal involuntary movements. Her cognition was intact and she was alert and oriented times three.
Blood tests revealed the patient had an iron deficiency anemia with a hemoglobin of 11.7 gm/100 ml. and hematocrit of 35.9%. She also had a speckled pattern antinuclear antibody (ANA) of 1:40 and an erythrocyte sedimentation rate (ESR) of 17 nm /hr. Her TSH was 5.8 uU /ml (normal 0.50-5.0 Her antithyroglobin antibodies and antimicrosomal antibodies were both abnormally elevated. Thyroglobulin was 8.6u /ml (normal being less than 1.0 U/ml) and microsomal antibodies were listed as > I 0.0 U/ml (normal being < 1.0 U/ml). Chem 20 was within normal limits except for a cholesterol of 2 03 ma/ 100 ml. The folate and B-12 levels were within normal limits. The free T-4 was 1.1 ng /dl (normal 0.8-2.3 ng /dl). The F 11 was 2.2 (normal being 1.4-3.8) and the thyroxine level was 7.6 mcg/dl nrmal 4.5-12 mcg/dl).
The patient was started on fluoxetine 20 mg per day for her depressive symptoms and restarted on l-thyroxine 50 mcg per day, her prior dose. In addition, iron supplements with a multi-vitamin were started. She responded quite well to this regimen, with weight loss and decreased carbohydrate te binges. Her mood was somewhat dysphoric but improved over her initial presentation, following 3 months of treatment. She was still sleeping twelve hours per day, but felt more rested. The dose of fluoxetine was titrated upwards to 40 mg per day with increased improvement in mood and affect. She no longer felt depressed, her mood was brighter and there was no anhedonia . Despite these improvements, her "leaden" fatigue and anergia persisted in the absence of depressive symptoms, 4 months into the therapy with fluoxetine and l-thyroxine. She was euthyroid at 88 mcg per day l-thyroxine Her hemoglobin also returned to the normal range of 12.4 gm/100 ml. Despite correction of her anemia and her thyroid disorder, the TSH was 3.7 uU ml, she continued to describe anergia , fatigue, lack of energy and listlessness. A trial of d-amphetamine, 10 mg spansule q/am., was initiated to address the refractory fatigue and titrated upwards to 10 ma. twice a day. The patient reported a dramatic increase in energy and activity level without euphoria or psychotic symptoms. She described increased energy, increased mood, an ability to perform up to her usual standards at work, and a normalized sleep cycle. She continued to respond to the combination of fluoxetine , 40 mg q/day; synthroid , 88 mcg per day; ferrous sulfate, 325 mg q/day; and d-amphetamine 10 mg spansules twice a day. Her response continued over the course of one year with improvement in mood activity level, job performance and social life. There has been no evidence of increasing doses of d-amphetamine, tolerance to the stimulant effects, cardiovascular complaints nor evidence of abuse. Her GAF at this point in the treatment was 65.
This patient is a forty-five-year-old married white female with a long history of recurrent depression, Hashimoto's thyroiditis , and mixed connective tissue disease of 6 years duration. She was referred by her primary medical doctor for evaluation of severe depressive symptoms, suicidal preoccupation, anxiety, somatization and anergia . The Hashimoto's thyroiditis was associated with periods of weight gain, multiple aches and pains, difficulty in concentration and attention, and memory impairment. She reported that she had felt depressed for many years, and had episodes of binge eating on carbohydrates with fluctuations in her weight from forty to eighty pounds at times. There was no history of mania. Mental status exam revealed a pleasant but at times tearful white female. She was mildly obese with a full range in her affect but quite dysphoric and anxious. There was no evidence of psychotic symptoms, hallucinations, or delusions. She was not suicidal at the time of evaluation. There was evidence of memory impairment both short and long term. She was alert and oriented times three. Psychological testing included Bender Interference, Trail-making A and B. WAIS -R and MMPI It revealed no evidence for organic brain syndrome. Her GAF was 3 7. DSM-III R criteria were met with seven symptoms listed above. She was diagnosed with Major Depression (severe, nonpsychotic ) vs. organic mood disorder secondary to Hashimoto's thyroiditis . Laboratory evaluation revealed that the patient had a normal CBC, a normal chemistry panel except for a cholesterol level of 207 mg/100 ml. Her thyroxine was 11.4 mcg/dl and TSH at the time of admission was less than 0.2uU /ml. Her T-3 was 190 ng /dl with top normal being 185 ng /dl. Thyroglobulin antibodies were 2.0 U/ m1 , normal being up to 1.0 U/ml. Antimicrosomal antibodies were negative at 0.0 U/ml. Folate and B-12 levels were within normal limits. Sedimentation rate was 50 mm/hr. It appeared that the patient at the time of evaluation was iatrogenically hyperthyroid , by overreplacement of thyroid hormone with dessicated thyroid extract, 2 grains q/day. An EEG was performed which was reported as normal. In addition, an MRI scan of the brain was reported as negative. The patient had trials of bupropion which caused some relief but increased her agitation and interrupted her sleep pattern. L-thyroxine was substituted for thyroid extract at 0.075 mg/day with normalization of her TSH at 0.50 Uu /ml. However, she remained depressed despite 450 mg/day of bupropion for 6 weeks. Fluoxetine was initiated and titrated up to 40 mg per day without significant side effects, except for anorgasmia and lack of sexual feelings." Her affect brightened, she had improved outlook, no suicidality , and more hope for the future. She returned to work and her daily activities. However, she continued to report lack of energy, and a leaden " feeling after six months of treatment with fluoxetine , despite complete absence of dysphoria, suicidality , and anhedonia . Dextroamphetamine was tried with a dose of 10 mg spansule twice daily titrated upwards to IS mg twice a day. The patient responded quite well to this regimen with increased activity level and cognitive performance Sexual dysfunction was treated with cyproheptadine with good re sponse She had increased self esteem and was able to participate more actively in her treatment. L-thyroxine doses were adjusted up to 125 mcg q/day, without adverse effect. D-amphetamine was reduced to 15 mg q day due to agitation and insomnia. There was no reported hypertension, chest pain, nor cardiovascular complaints She continued with 15 mg spansule d dextroamphetamine q/day; fluoxetine , 40 ma. q/day; and L-thyroxine 125 mcg q/day for one year with positive results. Her GAF was 72.
his patient, Ms. C., is a thirty-one-year-old married white female who was referred by her psychotherapist for medication evaluation. Following the birth of her two daughters, the patient developed postpartum depression and Hashimoto's thyroiditis with thyroid failure. Her symptoms had increased dramatically one year following the birth of her twins with increased agitation, rage attacks, dysphoria and irritability. There was no report of mania. In addition she had significant fatigue, anergia , lethargy and cognitive dysfunction. She was not actively suicidal but had very poor frustration tolerance and at times was "shaking her babies" when upset. She was fearful of her behavior and sought psychiatric help. She also described significant carbohydrate binge eating, particularly in her pre-menstrual cycle. Past psychiatric history had been negative prior to the onset of Hashimoto's thyroiditis . There was no history of mania, past or present. She was treated with 0.150 mg of 1-thyroxine for her hypothyroidism Somatic complaints included multiple aches and pains, including back, leg and neck pain with a negative exam for rheumatoid disease (ANA Rheumatoid Factor were negative). She took no other medications except oral contraceptives. She also reported some weight gain secondary to her pregnancy which was persistent following the birth of her twins.
Mental status exam showed the patient to be anxious, mildly agitated and slightly overweight. She was quite tearful and psychomotorically slowed without tremor or abnormal motor movements. Her affect was blunted with marked dysphoria at times. She had some tangentiality , but no psychotic symptoms, delusions, or hallucinations. Her response to questions was slowed at times. There was no thought blocking, distortion, confusion, or gross impairment in cognition. She was alert and oriented with a clear sensorium . Hashimoto's thyroiditis , major depression, non-psychotic severe by DSM-III R criteria was diagnosed. Her GAF was 31. She was also evaluated for organic mood disorder. An EEG and MRI of the brain were within normal limits Thyroid functions were done and revealed the patient had a TSH of 7.4 uU /ml., sedimentation rate of 25 mm/hr., with a top normal of 20 mm/hr. Her thyroxine, T-4, level was 13 mcg/dl. and a T-3 of 153 ng /dl (normal range being 100-220 ng /dl). Folic acid and B-12 levels were within normal limits. Thyroglobulin antibodies were reported as 2 700 U/ml, normal being < 1.0 U/ml. Thyroid micros omal antibodies were reported as 468 6 U/ml, with less than 0.3 U/ml being normal. L-thyroxine w as increased due to mild hypothyroidism. Adjustment in this dose of thyroxine did help improve the patient's general energy level and her affect slightly. Her TSH came down to 5.8 uU /ml at 0.175 mg of synthroid . The dose was further titrated to 0.2 mg of 1-thyroxine with normalization of her TSH to 0.7 uU /ml. After two years of thyroid replacement therapy, the patient remained quite depressed with somatization and reports of fibromyalgia , muscle aches and pain. Initially a dose of fluoxetine 20 mg q/am was started with lorazepam 1 mg given as needed for anxiety and agitation. The patient had a positive response to fluoxetine with a brightening in her mood and affect, after I month. She was no longer rageful , tearful, labile or dysphoric. She was able to care for her infants without difficulty and felt general optimism and improvement in her outlook. However, despite improvement in her mood, agitation level and anxiety she remained quite anergic and lethargic. A trial of methylphenidate , 10 mg twice daily was started and initially had a positive result. After three days, she returned to her sleepiness and lethargy. Six months after starting fluoxetine , dextroamphetamine spansule was started at 15 mg. q/am. This dose was titrated over a course of two weeks to 15 mg twice a day with good results. The patient had a reduction in sedation, anergia and fatigue, which she described as unrelated to her prior depressed mood. She reported increased activity levels and increased functional capacity to tolerate the demands of raising two infant children. Occasional use of chlorazepate 7.5 mg at bedtime was helpful for transient sleep disturbance. She noted that fluoxetine induced some of her sleepiness and was better tolerated at the eveninghour . Her current dose of medication is fluoxetine , 20 mg at bedtime; chlorazepate , 7.5 mg at bedtime as needed for insomnia, and dextroamphetamine spansules , 15 ma. twice a day. Her fibromyalgia syndrome resolved significantly with this medication regimen. There were no cardiovascular complaints. She had continued improvement in mood and affect with increased activity levels, no euphoria, tolerance, or patterns of abuse for six months. Time away from her teaching position was significantly reduced and her ability to care for her infant twins was greatly improved. Her GAF was 71.
Fatigue and anergia are classic symptoms of hypothyroidism ( Volpe 1986; Wilson, 1985). They may also co-exist with depression (Gold, 1987; Whybrow 1969; Loosen, 1987). In these cases, fatigue and anergia persisted after depressive symptoms were treated successfully with fluoxetine , based on improvement in mood, affect, sleep disturbance and suicidality . Each patient was euthyroid several months prior to the initiation of dextroamphetamine treatment. DSM-III R criteria for Major Depression was met by each patient with multiple symptoms, including anergia . The persistence of this fatigue and leaden feeling in the absence of symptoms of mood disturbance suggests a separate phenomenon is occurring in this group of patients. Hypothyroidism is most likely the cause of this persistent anergia , despite complete hormone replacement ( Strakosch , 1986). D-amphetamine successfully reversed the fatigue stare generated by the hypothyroidism. There are several theories put forward to explain the effect of hypothyroidism on basal metabolic rate, energy level, oxygen utilization, and neurotransmitter/receptor interactions ( Whybrow , 1969; Whybrow , 1984). There is evidence of change in beta-adrenergic receptor activity in hypothyroidism ( Bilezikian , 1983). Hypothyroid patients are relatively insensitive to catecholamine infusion ( Whybrow , 1981), suggesting a neurotransmitter deficiency" state. One study demonstrated the enhanced effect of d-amphetamine on reaction time in hypothyroid patients (Murray, 1958). Fluoxetine and d-amphetamine would counter this condition by enhancing neurotransmitter activity. The malaise and anergia of hypothyroidism has been reported topersist despite correction of the hormonal deficiency and normalization of TSH ( Strakosch , 1986; Reus, 1989; Wilson, 1985). In these three cases, the patients had autoimmune thyroiditis with hypothyroidism. Autoimmune diseases, including Hashimoto's thyroiditis , are known to cause malaise, fatigue, and anergia of unclear etiology ( deShazo , 1992). This would explain the persistence of fatigue in patients whose hypothyroidism and depression were effectively treated. Depression and autoimmune thyroiditis are more common in women. Hashimoto's thyroiditis has a female to male distribution of 20: 1 ( Volpe 1986). Depression is at least twice as likely to occur in women than men ( Nadelson , 1985). Antithyroid antibodies have been detected in euthyroid patients with major depression at a rate of 20% in one study ( Nemeroff , 1985). In a "normal" population the incidence of antithyroid antibodies detected is 5-10%, the vast majority being in females. The incidence of antithyroid antibody detection increases with the age of the population tested (Reus, 1989). The significance of these findings remains unclear, although theories linking subtle thyroid impairment ("symptomless" autoimmune thyroiditis ), depression, and gender have been described (Reus, 1986). In these three patients, all women, their illness had progressed to clinically significant hypothyroidism and depression. Psychostimulants have been demonstrated to be effective in treating apathetic, anergic geriatric patients. They have also proved useful in medically ill depressed patients as well as in the more classic syndromes of attention deficit disorder, narcolepsy , and refractory depression ( Chiarello , 1987). Chronic, pathological fatigue, and neurasthenia have also responded to this class of medication ( Chiarello , 1987; Wilbur, 1937), without specific mention of fatigue associated with hypothyroidism. The mechanism action of psychostimulants , such as d-amphetamine, is to increase catecholamines by indirect release from storage granules in synaptic terminals, as well as inhibition of re-uptake ( Chiarello , 1987). The effect of enhanced noradrenergic and dopaminergic activity includes increased psychomotor activity, improved mood, and decreased fatigue ( Chiarello , 1987). In this particular set of cases it seems apparent that the two symptoms of depression and fatigue were co-existent but also separate. After the depressive symptoms were resolved, fatigue states persisted. Only after the addition of a psychostimulant did the fatigue resolve It may well be argued that the fatigue was a remnant of the depressive symptoms and d-amphetamine simply augmented the anti depressanteffects of the fluoxetine However, in each case the patients clearly reported that their mood had improved significantly prior to d-amphetamine and that the fatigue was a separate phenomenon non-responsive to fluoxetine . Psychostimulants are controversial as treatment modalities. This is due to their abuse potential and overusage in an attempt to achieve euphoria. However they have a well deserved place in the treatment armamentarium for particular cases where standard therapy is ineffective or only partially effective. Patients with medical illnesses such as hypothyroidism where chronic fatigue is a hallmark of the illness, may benefit significantly from the activating effects of stimulating antidepressants such as fluoxetine . Additional benefits can be achieved with the use of psychostimulants which have been demonstrated to be effective in chronic severe pathological fatigue states. This study is hampered by a small sample size, nonblind conditions and subjective reporting of treatment response. Further research, using objective ratings and double-blind conditions, is recommended in the use of these agents in illnesses such as Hashimoto's thyroiditis .
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