Hypothyroidism lithium treatment

Thyroid Hormone (Thyroxine, Synthroid). The most common use of thyroxine in bipolar patients is the treatment of lithium-induced hypothyroidism. Approximately 5% of patients receiving long-term lithium treatment ultimately develop hypothyroidism. When this occurs, the patient with bipolar disorder may present with symptoms of a depressive episode. Therefore, periodic thyroid axis monitoring, that is, a serum thyroid stimulating hormone (TSH) test, is required for all patients taking lithium and should always be performed when the bipolar patient experiences a depressive episode. 

Reversible hypothyroidism may occur in as many as 20% of the patients receiving lithium (Lindstedt et al. 1977 Myers et al. 1985). Lithium-induced hypothyroidism occurs more frequently in women. Thyroid function should be evaluated every 6-12 months during lithium treatment or if symptoms develop that might be attributable to thyroid dysfunction, including depression or rapid cycling. 

Long-term side effects of lithium treatment include weight gain. The treatment is associated with development of hypothyroidism in about 10-15% of cases. There is an association with kidney disease. Birch has expressed the general view that Li may interact with magnesium-dependent processes, and theoretical chemistry supports this view. Despite the widespread clinical significance of Li, there is presently no consensus on its mode of action. One postulate for the mechanism is termed hyperpolarization . Li affects the conductivity in cell transport channels. Other explanations include modulation of neurotransmitter concentrations and inhibition of Na+/K+/Mg2+/ Ca2+ ATPases. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enzyme that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, hypothyroidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

When 60 patients (22 men, 38 women) who had taken lithium for 1 year or more (mean 6.9 years mean serum concentration 0.74 mmol/1) were interviewed about adverse effects, 60% complained of polyuria-polydipsia syndrome (serum creatinine concentrations were normal) and 27% had hypothyroidism requiring treatment (108). Weight gain was more common in women (47 versus 18%) as were hypothyroidism (37 versus 9%) and skin problems (16 versus 9%), while tremor was more common in men (54 versus 26%). Weight gain of over 5 kg in the first year of treatment was the only independent variable predictive of hypothyroidism. 

Stancer EIC, Forbath N. Elyperparathyroidism, hypothyroidism, and impaired renal function after 10 to 20 years of lithium treatment. Arch Intern Med 1989 149 1042-1045. 

Endocrine Thyroid Thyroid abnormalities are common during lithium treatment 20% develop hypothyroidism and 40% develop goiter if untreated [33 ]. In one study of elderly people (over 65 years old) taking lithium (n=79), 28 were hypothyroid [34 ]. This compares with a rate of only 7.1% of a matched non-lithium-treated control group (n = 85), a rate that is similar to that of the general population. This effect is not mediated by production of antithyroid antibodies, since antibodies were present in 27% of the patients who were tested, a rate that is similar to that in non-lithium-treated patients in this age group. The lack of association with antithyroid antibodies in lithium-related thyroid dysfunction is true for all age groups [35 j. 

Treatment of Manic—Depressive Illness. Siace the 1960s, lithium carbonate [10377-37-4] and other lithium salts have represented the standard treatment of mild-to-moderate manic-depressive disorders (175). It is effective ia about 60—80% of all acute manic episodes within one to three weeks of adrninistration. Lithium ions can reduce the frequency of manic or depressive episodes ia bipolar patients providing a mood-stabilising effect. Patients ate maintained on low, stabilising doses of lithium salts indefinitely as a prophylaxis. However, the therapeutic iadex is low, thus requiring monitoring of semm concentration. Adverse effects iaclude tremor, diarrhea, problems with eyes (adaptation to darkness), hypothyroidism, and cardiac problems (bradycardia—tachycardia syndrome). 

Lithium. In the lithium carbonate treatment of certain psychotic states, a low incidence (3.6%) of hypothyroidism and goiter production have been observed as side effects (6,36) (see Psychopharmacologicalagents). It has been proposed that the mechanism of this action is the inhibition of adenyl cyclase. Lithium salts have not found general acceptance in the treatment of hyperthyroidism (see Lithiumand lithium compounds). 

Other causes include magnesium-containing antacids in patients with renal insufficiency, enteral or parenteral nutrition in patients with multiorgan system failure, magnesium for treatment of eclampsia, lithium therapy, hypothyroidism, and Addison s disease. 

The next step in the management of the depressed bipolar patient is to evaluate thyroid function. This is especially important for patients treated with lithium in order to rule out lithium-induced hypothyroidism. When this occurs, the addition of thyroid hormone replacement may relieve the depressive symptoms without any additional changes to the bipolar treatment regimen. 

Kleiner, J., Altshuler, L., Hendrick, V, and Hershman, J.M. (1999) Lithium-induced subclinical hypothyroidism review of the literature and guidelines for treatment. / Clin Psychiatry 60 249-255. 

A common mistake is to treat bipolar depression in the same manner that one treats unipolar depression, overlooking the need for a mood stabilizer. In bipolar depression, the first pharmacological intervention should be to start or optimize treatment with a mood stabilizer rather than to start administering an antidepressant medication. In addition, thyroid function should be evaluated, particularly if the patient is taking lithium. Subclinical hypothyroidism, manifested as an increased thyroid-stimulating hormone level and normal triiodothyronine and thyroxine levels, may present as depression in affectively predisposed individuals. In such cases, the addition of thyroid hormones may be beneficial, even if there is no other evidence of hypothyroidism. 

Lithium Plus Thyroid Supplementation. Treatment-resistant and rapid-cycling bipolar patients may have an increased frequency of thyroid dysfunction. Further, some patients suffer from subclinical hypothyroidism and improve with the addition of thyroid supplementation. In this context, several case reports involving this population found that high doses of the thyroid hormone levothyroxine sodium (T ) were clinically beneficial (122,123 and 124). Kusalic (1.25) found that 6 of 10 rapid cyclers had hypothyroidism, based on their thyrotropin-releasing hormone stimulation tests. Further, the average number of mood episodes per year decreased by more than 75% (i.e., from 9.7 to 2.2) after thyroxine was added to the treatment regimen. 

The many effects of lithium on thyroid physiology and on the hypothalamic-pituitary axis and their clinical impact (goiter, hypothyroidism, and hyperthyroidism) have been reviewed (620). Lithium has a variety of effects on the hypothalamic-pituitary-thyroid axis, but it predominantly inhibits the release of thyroid hormone. It can also block the action of thyroid stimulating hormone (TSH) and enhance the peripheral degradation of thyroxine (620). Most patients have enough thyroid reserve to remain euthyroid during treatment, although some initially have modest rises in serum TSH that normalize over time. 

Lithium-induced hypothyroidism has been briefly reviewed (626). Some patients develop more persistent subclinical hypothyroidism (TSH over 5 mU/1, free thyroxine normal) and others overt hypothyroidism (higher risk in women, in those with pre-existing thyroid dysfunction, and those with a family history of hypothyroidism). Since subclinical hypothyroidism is not necessarily asymptomatic, treatment with thyroxine may be necessary in this group (627), as well as in those with more obvious hypothyroidism (628). 

In 1705 patients, aged 65 years or over, who had recently started to take lithium, identified from the 1.3 million adults in Ontario receiving universal health care coverage, the rate of treatment with thyroxine was 5.65 per 100 person-years, significantly higher that the rate of 2.70/100 person-years found in 2406 new users of valproate (629). Of 46 adults taking lithium in a psychiatric clinic, 17% developed overt hypothyroidism while 35% had subclinical hypothyroidism (raised concentrations of thyroid stimulating hormone, TSH) (630). 

Despite the predominantly antithyroid effects of lithium, thyrotoxicosis continues to be described during treatment and after withdrawal (642-644). In a retrospective review of 201 patients taking lithium (mean duration 6.4 years), hypothyroidism requiring supplemental thyroxine developed in 10% (3.4% of men, 15% of women) after a mean duration of 56 months. Women over 50 years of age tended to have an earlier onset. Two patients developed goiter requiring surgery and two others developed thyrotoxicosis (631). 

Euthyroid or hypothyroid goiter can also complicate lithium therapy, although the goiter is seldom of clinical importance and tends to resolve on withdrawal or with thyroxine treatment. In one ultrasound study, there was a... 

The production of thyroid disorders by lithium is common and requires constant concern throughout the treatment. Lithium-induced hypothyroidism can produce depression and other mental dysfunction, greatly confusing and complicating the patient s clinical picture. 

Neonates born to mothers taking lithium included a boy with a goiter and chemical hypothyroidism who required temporary treatment with oral thyroxine for 11 weeks... 

In a cross-sectional study of 12 octogenarians (average age 84 years) who had taken lithium for an average of 54 months (mean serum concentration 0.42 mmol/1), none became toxic and none had to stop treatment because of adverse effects. Transient renal function abnormalities were noted one patient developed nephrogenic diabetes insipidus and one became hypothyroidic (510). For lithium therapy in very old people, the authors advised close monitoring in a specialized setting. 

The adverse effects of lithium in elderly patients include cognitive status worsening, tremor, and hypothyroidism. The authors suggested that divalproex is also useful in elderly patients with mania and that concentrations of divalproex in the elderly are similar to those useful for the treatment of mania in younger patients. They noted that carbamazepine should be considered a second-line treatment for mania in the elderly. A partial response would warrant the addition of an atypical antipsychotic drug. For bipolar depression, they recommended lithium in combination with an antidepressant, such as an SSRI. They also noted that lamotrigine may be useful for bipolar depression. Electroconvulsive therapy (ECT) may also be useful, but there have been no comparisons of ECT and pharmacotherapy in elderly patients with bipolar depression. 

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