Lithium therapy

Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 2004 161 217-222. 

Lee, S. (1993). Side effect of chronic lithium therapy in Hong Kong Chinese an ethnopsychiatric perspective. Cult. Med. Psychiatry, 17, 301-20. 

Miiller-Oerlinghausen, B. Greil, W. Berghofer, A. (Eds.) Die Lithium-therapie Springer Berlin, 1997. 

Macrocyclic compounds with ion-chelating properties occur naturally and often function as ionophores, translocating ions across biological membranes many of these compounds are small cyclic polypeptides. Some natural carboxylic polyethers are selective for Li+ and are, therefore, ionophores for Li+. Monensin, shown in Figure Id, is a natural ionophore for Na+ but it will also complex with Li+ and it has been shown to mediate the transport of Li+ across phospholipid bilayers [21]. It has been proposed that synthetic Li+-specific ionophores have a potential role as adjuvants in lithium therapy, the aim being to reduce the amount of... 

Abnormalities in the movement of Li+ across the erythrocyte membrane have been related to psychiatric disorders and also in response to lithium therapy itself. As yet there is relatively little definitive information about the Li+ transport mechanisms operating in therapeutically relevant cell types. 

Inositol monophosphatase catalyzes the hydrolysis of inositol-1-phosphate, inositol-4-phosphate, and various nucleoside 2 -phosphates. The enzyme has attracted considerable interest in recent years because it is believed to be an important target for lithium therapy in treatment of manic-depression. Inositol monophosphatase inhibited in the presence... 

Long-term lithium therapy is associated with a 10% to 20% risk of morphologic renal changes (e.g., glomerular sclerosis, tubular atrophy, and interstitial nephritis). 

Up to 30% of patients on maintenance lithium therapy develop transiently elevated serum concentrations of thyroid-stimulating hormone, and 5% to 35% of patients develop a goiter and/or hypothyroidism, which is dose-related and more likely to occur in women. This is managed by adding levothyroxine to the regimen. 

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. 

Lithium is the simplest therapeutic agent for the treatment of depression and has been used for over 100 years—lithium carbonate and citrate were described in the British Pharmacopoeia of 1885. Lithium therapy went through periods when it was in common use, and periods when it was discouraged. Finally, in 1949, J.J.F. Cade reported that lithium carbonate could reverse the symptoms of patients with bipolar disorder (manic-depression), a chronic disorder that affects between 1% and 2% of the population. The disease is characterized by episodic periods of elevated or depressed mood, severely reduces the patients quality of life and dramatically increases their likelihood of committing suicide. Today, it is the standard treatment, often combined with other drugs, for bipolar disorder and is prescribed in over 50% of bipolar disorder patients. It has clearly been shown to reduce the risk of suicide in mood disorder patients, and its socioeconomic impact is considerable—it is estimated to have saved around 9 billion in the USA alone in 1881. 

Lithium therapy should be initiated at 300-900 mg/day. The dose shonld be increased every 3-7 days until a sernm level of 0.6-1.2mEq/L is achieved. Lithinm blood levels shonld be measured approximately 12 hours after the last dose. Therapeutic levels are lower for elderly patients, but young adnlts often reqnire sernm levels of 0.8-1.4mEq/L or greater for a fnll therapeutic effect. 

Lithium therapy necessitates the monitoring of thyroid function every 6-12 months in stabilised patients. Occurrence of symptoms such as lethargy, which may reflect hypothyroidism, should be monitored. 

Renal function impairment Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have occurred in patients on chronic lithium therapy. The relationship between such changes and renal function has not been established. 

Lactation Lithium is excreted in breast milk. Do not nurse during lithium therapy. Children Safety and efficacy for use in children younger than 12 years of age have not been established. 

Parameters to monitor Perform the following laboratory tests prior to and periodically during lithium therapy Serum creatinine complete blood count urinalysis sodium and potassium fasting glucose electrocardiogram and thyroid function tests. Check lithium serum levels twice weekly until dosage is stabilized. Once steady state has been reached, monitor the level weekly. Once the patient is on maintenance therapy, the level may be checked every 2 to 3 months. 

A. Approximately 5% of patients taking lithium over the long term develop hypothyroidism, and thyroid status should be followed as routine care for these patients. Mr. Smith s symptoms are classic for hypothyroidism. Impairment in glucose metabolism, hepatic function, red blood cell production, and prolactin secretion are not typical complications of lithium therapy. 

Vignette 4.2 Model-based, Goal-oriented Individualization of Lithium Therapy... 

A 17-year-old boy with bipolar disorder is started on lithium therapy at 600 mg bid. The initial lithium concentration is 0.8 mmol/L. As the patient s pressured speech and labile mood do not improve with time, the psychiatrist in charge wonders whether the lack of efficacy is due to insufficient coverage or to noncompliance. A repeat trough level is 0.3 mmol/L (Fig. 4.4A). 

Lithium produces neutrophilia and may also increase platelet counts, perhaps because of lithium s stimulation of the pluripotent stem cell (AHFS, 2000). Neutrophilia is seen generally within 3-7 days after lithium therapy is initiated and rapidly reverses when the drug is discontinued (AHFS, 2000). 

Abou-Saleh, M.T (1993) Who responds to prophylactic lithium therapy Br J Psychiatry Suppl 21 20—26. 

Strober, M., DeAntonio, M., Schmidt-Lackner, S., Freeman, R., Lam-pert, C., and Diamond,/. (1998) Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania. / Affect Disord 51 145-151. 

Naylor, G.D., Donald, J.M., LePoidevin, D., and Reid, A.H. (1974) A douhle-hlind trial of long-term lithium therapy in mental defectives. Br J Psychiatry 124 52—57. 

The treatment of the major depressive disorders such as unipolar and bipolar depressions was initially considered to be uniform, ffowever, with psychopharmacological advances, it has been demonstrated that the patients with bipolar depression may be partially responsive, at least prophylactically responsive, to lithium therapy, whereas the patients with unipolar depression are not as responsive (Abou-Saleh 1992). In addition, the treatment of depression may contribute through serendipity to the confirmation of a subgroup of patients with a bipolar disorder referred to as bipolar II. These patients, following treatment with antidepressants, will switch over to a hypomanic or fully manic phase resulting from pharmacological mechanisms. Thus, another subgroup of the bipolar disorder may be identified in the future. 

Following these studies, Fieve and colleagues [Dunner et al. 1976 Fieve et al. 1976] also demonstrated a significant effect for prophylactic lithium therapy in patients with bipolar type 11. In summary, 248 patients treated with lithium for 5-40 months had a pooled relapse rate of 32% compared with 260 patients who received placebo and had a relapse rate of 75%. 

Forrest DV Bipolar illness after right hemispherectomy a response to lithium carbonate and carbamazepine. Arch Gen Psychiatry 39 817-819, 1982 Forstner U, Bohus M, Gebicke-JJarter PJ, et al Decreased agonist-stimulated Ca " response in neutrophils from patients under chronic lithium therapy. Eur Arch Psychiatry Chn Neurosci 243 240-243, 1994 Fozard JR Neuronal 5-HT receptors in the periphery. Neuropharmacology 23 1473-1486, 1984... 

Hokin-Neaverson M, Jefferson JW Deficient erythrocyte Na,K-ATPase activity in different affective states in bipolar affective states in bipolar affective disorder and normalization by lithium therapy. Neuropsychobiology 22 18-25, 1989a Hokin-Neaverson M, Jefferson JW Erythrocyte sodium pump activity in bipolar affective disorder and other psychiatric disorders. Neuropsychobiology 22 1-7, 1989b... 

Hokin-Neaverson M, Burckhardt WA, Jefferson JW Increased erythrocyte Na" pump and Na-K-ATPase activity during lithium therapy. Research Communications in Chemical Pathology and Pharmacology 14 117-126, 1976 Holazo AA, Winkler MB, Patel IH Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol 28 1040-1045, 1988... 

Jope RS, Jenden DJ, Ehrlich BE, et al Choline accumulates in erythrocytes during lithium therapy. N Engl J Med 299 833-834, 1978 Jope RS, Jenden DJ, Ehrlich BE, et al Erythrocyte choline concentrations are elevated in manic patients. Proc Natl Acad Sci USA 77 6144-6146, 1980 Jope RS, Morrisett RA, Snead OC Characterization of lithium potentiation of pilocarpine induced status epilepticus in rats. Exp Neurol 91 471-480, 1986 Jordan D, Spyer KM Brainstem integration of cardiovascular and pulmonary afferent activity. Prog Brain Res 67 295-314, 1986... 

Nasrallah HA, Varney N, Coffman JA, et al Opiate antagonism fails to reverse post-ECT cognitive deficits. J Clin Psychiatry 47 555-556, 1986 Nasrallah HA, Coffman JA, Olson SC Structural brain-imaging findings in affective disorders an overview. J Neuropsychiatry Clin Neurosci 1 21-26, 1989 Naylor GJ, Smith AHW Defective genetic control of sodium-pump density in manic depressive psychosis. Psychol Med 11 257-263, 1981 Naylor GJ, McNamee HB, Moody JP Erythrocyte sodium and potassium in depressive illness. J Psychosom Res 14 173-177, 1970 Naylor GJ, McNamee HB, Moody JP Changes in erythrocyte sodium and potassium on recovery from depressive illness. Br J Psychiatry 118 219-223, 1971 Naylor GJ, Dick DAT, Dick EG, et al Lithium therapy and erythrocyte membrane cation carrier. Psychopharmacologia 37 81-86, 1974 Naylor GJ, Smith AHW, Dick EG, et al Erythrocyte membrane cation carrier in manic-depressive psychosis. Psychol Med 10 521-525, 1980... 

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