David W. Stephenson, MD, PharmD, is with the Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Alan N. Peiris, MD, PhD, MRSP, FACP, FACE, is with the Department of Endocrinology, Mountain Home VA Medical Center, Mountain Home, TN, and Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University. Shantha Pandian, MD, is Chief, Mental Health Clinic, Department of Psychiatry, Mountain Home VAMC. Francisco Rodriguez, MD, is with the Department of Psychiatry, Mountain Home VA Medical Center.
Address correspondence to: David W. Stephenson, MD, PharmD, 1406 Skyline Drive, Apt. H-52, Johnson City, TN 37604; fax 423-439-6386 or e-mail:firstname.lastname@example.org.
KS is a 33-year-old, unemployed, white man with a past medical history for hypothyroidism, bipolar disorder, panic attacks, and hepatitis C. The patient presented with progressive confusion, visual hallucinations, fatigue, and generalized weakness of 1 month’s duration. The patient reported diffuse myalgias. He stopped taking his levothyroxine 6 months earlier but continued to take his psychotropic medications. He was admitted to the hospital 6 months earlier for suicidal ideation. At that time, he stated he had not taken his medications for 3 to 4 months. During that admission, his thyroid-stimulating hormone level (TSH) was noted to be elevated to 480 μIU/mL, with a free T4 0.4 ng/dL. He had begun taking oral levothyroxine and was given follow-up instructions on discharge.
His current medication regimen includes levothyroxine 0.1 mg once daily, venlafaxine 225 mg at bedtime, quetiapine 200 mg at bedtime, and divalproex sodium 1,000 mg at bedtime. His past psychiatric history includes four to five inpatient psychiatric hospitalizations related to his bipolar disorder, with one suicide attempt in which he shot himself in the shoulder. He also had an admission for opiate dependence and previous cocaine and heroin use. He stated his self-esteem and appetite were intact but indicated difficulty with concentration and low energy levels. The patient denied anhedonia and suicidal or homicidal ideation. He drinks alcohol occasionally (once per month).
His social history includes being divorced, and he has one child from that marriage. His parents support him financially, and he is currently living with his parents.
The patient appeared disheveled but was alert and oriented to all spheres. He was mildly dysphoric but responsive to questions with normal speech. Mood was congruent without paranoia or delusions. Mild impairment of insight and judgment was evident. The rest of his physical examination, including vital signs, were normal, with the exception of generalized muscle tenderness and reduced deep tendon reflexes. Delayed relaxation of tendon reflexes was not observed.
An initial glucose level of 60 mg/dL was noted, but this improved to 100 with repeat measurement. The complete blood count and basic metabolic panel was normal. Abnormal findings included an alkaline phosphatase of 163 IU/L (normal 42–121), AST 386 IU/L (normal 10–40), ALT 91 IU/L (normal 10–60). Total CK was 772 (normal 30–165 IU/L), CKMB 12 ng/mL (normal 0–5), CK index normal at 1.6%, troponin was negative x 3. Random cortisol 16.8 μg/dL (normal 4–22), TSH 424 μIU/mL (normal 0.35–5.5), free T4 0.5 ng/dL (normal .7–1.6), thyroperoxidase antibodies 262 IU/mL (normal 0–3.9). B12 and folate were normal. Depakene level < 1 μg/mL (therapeutic level 50–100). He had a urine drug screen that was positive for opiates and amphetamines. Serum 25-OH vitamin D level was 8 ng/mL (normal 30–80).
Radiographic evaluation with computerized tomography (CT) of head and chest x-ray were normal. EKG showed normal sinus rhythm at 60 bpm, with no abnormalities.
The patient was admitted with severe hypothyroidism resulting in myxedema, hypovitaminosis D, and bipolar disorder with subtherapeutic depakene level secondary to noncompliance. His underlying hypothyroidism was believed to contributed to his elevated creatinine kinase. His hepatitis C was a likely contributor to his abnormal liver function tests. The patient had not received treatment for hepatitis C before admission.
Therapy was initiated to reverse his hypothyroidism with levothyroxine 50 μg intravenously daily over 3 days then 150 μg IV on day 4 (total IV levothyroxine dose 300 μg). This was changed to oral levothyroxine 125 μg daily on day 5. He was started on hydrocortisone 50 mg IV every 6 hours concurrently with intravenous levothyroxine.
His hospital course was uneventful with management of his pain with fentanyl patch 50 μg every 3 days and MSIR 15 mg every 6 hours as needed for breakthrough pain. His psychotropic medications were restarted, and he was to follow-up with his primary care physician and mental health clinic within 1 week. His depakene level was still subtherapeutic upon discharge (< 1.0 μg/mL). His hypovitaminosis was treated with vitamin D 50,000 IU weekly x 8 weeks. His TSH has improved within 1 week to 173 μIU/mL, with a free T4 of 0.6 ng/dL.
This patient had multiple admissions for medication noncompliance. On discharge, he was scheduled to receive levothyroxine 700 μg given by mouth once weekly under direct observation by home health nurses. The initiation of supervised weekly oral thyroxine represents a unique strategy for management that may provide improvement in his thyroid status. To our knowledge, the patient had not been readmitted for hypothyroidism within the past 6 months.
The catastrophic developmental effects of thyroxine deficiency are well known in infants. The longstanding interaction between the hypothyroidism and mental illness in adults was noted by Richard Asher several decades ago.1 In adults, psychiatric disorders can be linked to mild hypothyroidism, and thyroid function tests are routinely checked in current clinical practice during hospitalization for psychiatric illness.2 Moreover, medications, such as lithium, are associated with hypothyroidism, goiter, and autoimmune thyroid disease.
Hypothyroidism is readily managed with levothyroxine treatment, customarily taken on a daily basis. Medication compliance is an important aspect that can affect medical outcomes. It is estimated that 20% to 50% of patients do not take their medications as prescribed.3 Poor compliance as a significant occurrence in psychiatric patients is well documented.4,5 This non-compliance leads to poor outcomes, higher hospitalization rates, and increased healthcare costs.6,7
One key to the success of maintaining psychiatric patients out of institutional care is the provision of medications and ensuring patient adherence to the medications regimen. The patient described had evidence of repeated medication noncompliance. It was decided that the customary daily replacement with thyroxine was likely to be ineffective. The cost for hospitalization in this patient was in excess of $15,000. The option of supervised weekly oral thyroxine administration was adopted as a cost-effective approach in our patient. To our knowledge, this represents a novel approach to managing hypothyroidism in patients with psychiatric illness. The use of “directly observed therapy short course (DOTS)” has been advocated by the World Health Organization (WHO) to ensure compliance in the treatment of tuberculosis and in some AIDS services.8 The use of directly observed parenteral antipsychotic administration once or twice a month to improve compliance is well documented.
In addition to the effect of mental illness on compliance, hypothyroidism, per se, can have significant effects on mood and cognition, including psychomotor slowing, memory impairment, dementia, paranoia, and visual hallucinations.
These effects are likely to be additive in promoting noncompliance in patients with pre-existing mental disorders.
The relatively long half-life of thyroxine suggests that weekly dosing is a possibility. Pharmacokinetic studies concluded the viability of weekly administration of thyroxine with a dose of 1 mg/m2 sufficient to maintain euthyroidism.9 Similar studies by demonstrated that 1.5 mg weekly for 4 weeks achieved normal T4 concentrations. A higher dose (2 mg weekly) resulted in mild elevation of thyroxine levels.10
Bernstein et al was the first investigator to use weekly oral administration of thyroxine in seven patients and concluded that it was a safe and effective.11 The largest study of the effect of weekly dosage of l-thyroxine was performed by Goretzki et al.12 In a prospective, randomized, controlled study of 64 bilateral subtotal thyroidectomized patients, they compared 1 mg of l-thyroxine administered orally each week with 0.1 mg daily. They followed the patients for 52 weeks and assessed response clinically and measured TSH, free T4, and free T3 levels. During treatment, the T3 and T4 remained within the normal range, without any significant difference between the two groups. No patients complained of symptoms of hyperthyroidism.
In a recent evaluation, Carvalho et al compared daily levothyroid administration with seven times the daily dose administered once weekly in a randomized crossover trial. They evaluated 19 women over 12 weeks. They measured serum free thyroxine, total triiodothyronine, and TSH levels. Compared with daily administration, the mean TSH after 6 weeks was higher (weekly 4.41 compared with daily 3.38; P < .05), and the mean free thyroxine level was lower (weekly 1.00 compared with daily 1.2; P < 0.05). Free triiodothyronine were unchanged. Echocardiographic evaluation showed no evidence of cardiac stress in the weekly group.13
Several other studies have confirmed the utility of weekly administration of thyroxine. Taylor et al, in a single-blind, randomized, crossover designed study, evaluated the administration of thyroxine twice weekly to seven elderly women (mean age 86 years). Efficacy of the twice weekly was achieved without significant changes in left ventricular ejection time or induction of thyrotoxicosis.14
Grebe et al compared seven times the normal daily dose administered once weekly to 12 hypothyroid subjects in a randomized cross-over trial. They also reported success in achieving a euthyroid state without evidence of treatment toxicity, including cardiac toxicity with weekly dosing. Serum cholesterol as a marker for hypothyroidism was similar when compared with the daily regimen.15 Rangan et al described two cases (47- and 48-year-old women) of primary hypothyroidism in which large daily doses of thyroxine (400 μg/day) did not restore biochemical euthyroidism. It was suspected that noncompliance was the most likely diagnosis for this problem. Therefore, they were started on supervised once weekly thyroxine of 750 μg. Once weekly thyroxine treatment was determined to be a safe, well-tolerated, and effective therapy for patients who are noncompliant.16
In cases where oral administration is not applicable, the option of a weekly parenteral administration remains an option. Anderson et al report a rare case of apparent true thyroxine malabsorption in a young woman with multiple autoimmune endocrinopathies and its effective treatment with weekly intramuscular thyroxine.17 Wenzel et al report that weekly intravenous thyroxine administration may be efficacious in patients with gastrointestinal complications.18
Thyroid replacement traditionally requires indefinite daily administration of oral levothyroxine. The elimination half-life of levothyroxine is about 7 days, making it a good candidate for longer dosing intervals. Although weekly thyroxine administration has been demonstrated to be efficacious in treating hypothyroidism, it has not been widely adopted. In the case presented here, it was decided that supervised weekly administration under direct observation was likely to be the most cost-effective approach to maintaining an euthyroid state. Adoption of a weekly oral or parenteral protocol for thyroxine replacement for select groups of individuals may also need to be considered.
- Asher R. Myxoedematous madness. Br Med J. 1949;2(4627):555–562. doi:10.1136/bmj.2.4627.555 [CrossRef]
- Almeida C, Brasil MA, Costa AJ, et al. Subclinical hypothyroidism: psychiatric disorders and symptoms. Rev Bras Psiquiatr. 2007;29(2):157–159. doi:10.1590/S1516-44462007000200013 [CrossRef]
- Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487–497. doi:10.1056/NEJMra050100 [CrossRef]
- Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: Reliability and discriminative validity. Psychol Med. 1983;13(1):177–183. doi:10.1017/S0033291700050182 [CrossRef]
- Weiden P, Rapkin B, Mott T, Zygmunt A, et al. Rating of medication influences (ROMI) scale in schizophrenia. Schizopr Bull. 1994;20(2):4297–4310.
- DiMatteo MR, Giordani PJ, Lepper HS, Croghan TW. Patient adherence and medical treatment outcomes: a meta-analysis. Med Care. 2002;40(9):794–811. doi:10.1097/00005650-200209000-00009 [CrossRef]
- Sokol MC, McGuigan KA, Verbrugge RR, et al. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care. 2005;43(6):521–530. doi:10.1097/01.mlr.0000163641.86870.af [CrossRef]
- API TB Consensus Guidelines 2006. J Assoc Physicians India. 2006;54:219–234.
- Sekadde CB, Slaunwhite WR, Aceto T, Murray K. Administration of thyroxine once a week. J Clin Endocrinol Metab. 1974;39(4):759–764. doi:10.1210/jcem-39-4-759 [CrossRef]
- Thein-Wan W, Larsen PR. Effects of weekly thyroxine administration on serum thyroxine, 3.5,3’-triiodothyronine, thyrotropin and the thyrotropin response to thyrotropin-releasing hormone. J Clin Endocrinol Metab. 1980;50(3):560–564. doi:10.1210/jcem-50-3-560 [CrossRef]
- Bernstein RS, Robbins J. Intermittent therapy with l-thyroxine. N Engl J Med. 1969;281(26):1444–1448.
- Goretzki P, Roeher HD, Horeyseck G. Prophylasis of recurrent goiter by high-dose l-thyroxine. World J Surg. 1981;5:855–857. doi:10.1007/BF01657975 [CrossRef]
- Carvalho GA, Bornschein A, Perez LS, et al. Evaluation of an alternative form of levothryxoine administration and its clinical and laboratory repercussions in the treatment of primary hypothyroidism. Thyroid. 2008;18:S27.
- Taylor J, Williams BO, Frater J, Stot DJ, Connell J. Twice-weekly dosing for thyroxine replacement in elderly patients with primary hypothyroidism. J Int Med Res. 1994;22(5):273–277.
- Grebe SK, Cooke R, Ford HC, et al. Treatment of hypothyroidism with once weekly thyroxine. J Clin Endocrinol Metab. 1997;82(3):870–875. doi:10.1210/jc.82.3.870 [CrossRef]
- Rangan S, Tahrani AA, Macleod AF, Moulik PK. Once weekly thyroxine treatment as a strategy to treat non-compliance. Postgrad Med J. 2007;83(984):e3. doi:10.1136/pgmj.2007.060244 [CrossRef]
- Anderson L, Joseph F, Goenka N, Patel V. Isolated thyroxine malabsorption treated with intramuscular thyroxine injections. Am J Med Sci. 2009;337(2):150–152. doi:10.1097/MAJ.0b013e31817ee556 [CrossRef]
- Wenzel KW. Once-weekly intravenous L-thyroxine replacement in hypothyroidism. Schweiz Med Wochenschr. 1978;108(11):416–418.
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