Lithium is the first medicine to be found to help bipolar patients and is still an excellent medication.  It's psychiatric benefit was discovered in 1960 by an Australian researcher who noticed the mice in the cages were unusually calm while on lithium.  He was studying its effect on blood pressure. 

Lithium is much better at reducing suicide rates in bipolars than divalproex (Depakote) and also better than carbamazepine (Tegretol) in this regard.  It is only slightly better at reducing the frequency of mania, although it has an advantage in helping depression.  Some patients to experience side-effects from lithium that make them want to try something else.  These include weight gain, sometimes marked, acne, trembling, frequent urination, and others.  Blood levels are checked to be sure that patients are getting enough and also to avoid toxicity which manifests itself in a type of unpleasant staggering. 

I need to get a lot more studies on this page, but suffice it to say, lithium does have the best proven record at preventing suicides in bipolar patients.  However, about two-thirds of patients need the addition of a second anti-manic agent (e.g. carbamazepine, divalproex, an anti-psychotic) or an anti-depressant or both.

Lithium Prevents Suicides, Self-Harm, and Death Better than Others: In a comprehensive review of 32 studies of 1,389 patients were randomly assigned to receive lithium and 2,069 to receive other compounds, those on lithium were much less likely to die by suicide (2 vs. 11 suicides; odds ratio=0.26). The composite measure of suicide plus deliberate self-harm was also lower in patients who received lithium (odds ratio=0.21). There were fewer deaths overall in patients who received lithium (9 vs. 22 deaths; odds ratio=0.42). Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Cipriani A, et al. University of Oxford, UK. . Am J Psychiatry. 2005 Oct;162(10):1805-19.

Mechanism of Action: Too Complex: Inositol Monophosphatase and Glycogen Synthase Kinase-3 Probably Most Important: Lithium activates the ERK MAP kinase signaling cascade, which increases Bcl-2 promoter activity and Bcl-2 levels. Bcl-2 is a major neuroprotective protein, protecting against a variety of potential toxic effects from free radicals, ischemia, glutamate, deprivation of growth factor, MPTP and beta-amyloid. Bcl-2 also enhances the regeneration of CNS axons. Lithium enhances other trophic factors in the brain including pERK 42, pERK 44, pRSK, pCREB, and pBAD. Lithium increases gray matter volumes in bipolar patients in a regionally selective manner. Thus, lithium may reverse the atrophy associated with bipolar illness. Also, lithium inhibition of inositol monophosphatase, an enzyme required for inositol recycling and de novo synthesis, suggests that lithium depletes brain inositol and attenuates phosphoinositide signaling. Valproate also depletes inositol in yeast, and rat neurons as a result of myo-inositol-1-phosphate (MIP) synthase inhibition. Biol Psychiatry. 2004 Dec 1;56(11):868-74. Ed: There you have it. Nice and simple. Glad you asked. 

Lithium Test Dose:  There is a method of giving a single 600mg or 1200 mg dose then drawing a blood level 24 hours later to quickly determine the necessary long-term dose. Lithium dose prediction based on 24 hours single dose levels: a prospective evaluation. It was developed long ago by Perry but is apparently rarely used. Gervasoni N, Zona-Favre MP, Osiek Ch, Roth L, Bondolfi G, Bertschy G. Pharmacol Res. 2003 Dec;48(6):649-53; Prediction of lithium maintenance doses using a single point prediction protocol. Perry PJ, Prince RA, Alexander B, Dunner FJ. J Clin Psychopharmacol. 1983 Feb;3(1):13-7 (This has worked very well for me in the past.); Best: A simple mathematical model for predicting lithium dose requirement. Zetin M, Garber D, Cramer M. J Clin Psychiatry. 1983 Apr;44(4):144-5 and J Clin Psychiatry. 1986 Apr;47(4):175-8; For children: The lithium test dose prediction method in aggressive children. Malone RP, Delaney MA, Luebbert JF, White MA, Biesecker KA, Cooper TB. Psychopharmacol Bull. 1995;31(2):379-82

Lithium Dose by Weight: A method for predicting steady-state lithium concentration based on body weight calculated at 0.5 mEq/kg/day produced serum levels within the therapeutic range of 0.6 to 1.2 mEq/l in 20 of 23 patients (22 patients if the less conservative level of 1.4 mEq/l had been used). Had the one-point method been used, in which doses are based on the serum lithium concentration 24 h after a 600 mg test dose, the doses would have been lower in 20 of 23 patients. Predicting lithium dose by the body-weight method. Groves GE, Clothier JL, Hollister LE. Int Clin Psychopharmacol. 1991 Spring;6(1):19-23

Lithium + Carbamazepine Together Did Better: In a study of 52 outpatients ages 19-75 by NIMH (half Bipolar I half Bipolar II, half had rapid cycling, half had a history of psychosis), patients were all treated on monotherapy of one agent for 1 year, crossed over to the second agent the second year, given both agents the third year. One-third did well on each monotherapy and one half did well on combo. There was no difference in the three treatments for depression. Denicoff K et al: Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psyc 97;58:470-8.

Poor Quality Report From Harvard Encourages Lithium Plus Carbamazepine for Treatment Failures: Researchers found 14 small, usually brief, clinical trials of maintenance treatment with lithium plus carbamazepine which suggested added benefit of combination treatment over either agent alone. In a low-quality "post hoc analysis", of 46 bipolar I patients identified as not improving during long-term monotherapy in a mood disorders clinic, comparing days per year hospitalized in 3 consecutive time periods: before prophylactic treatment, during monotherapy with lithium (N = 31) or carbamazepine (N = 15), and during their combined use (N = 46), there was a significant reduction in hospitalized days per year during combination therapy, averaging a decrease of 55.9% (p = .004). Hospitalizations per year fell by 36.1%, and median time to recurrence nearly doubled during combination therapy. Rates of adverse effects increased 2.5-fold and use of adjunctive psychotropic agents increased by 21.9%. The researchers claimed that "combining lithium with carbamazepine yielded substantial benefit," but such a poor quality, uncontrolled study cannot be used to support any type of conclusion. Long-term combination therapy versus monotherapy with lithium and carbamazepine in 46 bipolar I patients. Baethge C, Baldessarini RJ, et al. Harvard- McLean. J Clin Psychiatry. 2005 Feb;66(2):174-82.

Relapse After D/C Lithium Equal in Pregnant and Non-Pregnant; Higher Post-Partum: Retrospective study 42 bipolar d/c within 6 weeks of conception vs. 59 who stopped for other reasons. Relapse in 1^st 40 weeks same 52% in pregnant v 58% in non-pregnant. Both groups only 21% relapse rate in year before d/c lithium. Relapse after 40 weeks 2.9 times higher in postpartum v nonpregnant (70% v 24%). None of 9 on lithium during pregnancy relapsed but 3 did within 2 weeks of delivery despite staying on lithium. Women who d/c lithium rapidly (1-14 days) 63% relapse rate v those d/c gradually (15-30 days) and shorter interval to recurrence (8 v 20 weeks). Therefore, if d/c, do so gradually. Viguera, MGH, AJP 00;157:179

Both Valproate and Lithium Failed in Maintenance: DB PC 52 weeks 372 pt after 3 month recovery from manic episode. Univ. Texas authors try to tease out some advantages for divalproex by pointing to secondary measures. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC, Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ. Arch Gen Psychiatry 2000 May;57(5):481-9

Adolescent Mania Seems to Respond OK to Lithium: An open trial report of 100 teens ages 12-18 suffering from acute mania reports a 63% response rate and 26% remission in 4 weeks. Lithium treatment of acute mania in adolescents: a large open trial. Kafantaris V, Coletti DJ, Dicker R, Padula G, Kane JM. J Am Acad Child Adolesc Psychiatry. 2003 Sep;42(9):1038-45. Ed: Such open trials are of little value, although this one is larger than usual and at least suggests that lithium doesn't make children worse.

Divalproex No Better than Lithium for Bipolar Children: Youths (139) ages 5-17 years with bipolar I or II disorder were initially treated with Lithium and divalproex (DVPX). Then, in a DB PC study of 60 patients achieving remission criteria for four consecutive weeks, half were given either Lithium or DVPX for up to 76 weeks. The treatment groups did not differ in survival time until emerging symptoms of relapse (p = .55) or survival time until discontinuation for any reason (p = .72). Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. Findling RL, McNamara NK, et al. Case Western Reserve University. J Am Acad Child Adolesc Psychiatry. 2005 May;44(5):409-17. 

Lithium = Divalproex (Depakote) = Carbamazepine (Tegretol) in Bipolar Teens: 42 outpatients ages 6-18 with mixed or manic episodes and YMRS mania scores greater than 13 were treated in a DB study to a lithium level of 0.8-1.2 mEq/L or carbamazepine level of 7-10 microg/L or divalproex level of 85-110 microg/L. The Clinical Global Improvement scores were 46%, 31%, and 40%, respectively with the YMRS 50% response rates 38%, 38%, and 53%. Kowatch, Univ. of Texas, J Amer Acad Child Adol Psyc 00;39:713. Ed: This study was just too small.

Highly Faulty Study Criticizes Lithium Treatment for Children: In a 2-week DB PC discontinuation study of 40 children with acute mania after 4 weeks of lithium treatment, there was only a  slightly lower exacerbation rate of those maintained on lithium ( 52.6%) vs. those switched to placebo ( 61.9%). Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study. Kafantaris V, Coletti DJ, et al. Zucker Hillside Hospital, Glen Oaks, NY J Am Acad Child Adolesc Psychiatry. 2004 Aug;43(8):984-93. Ed: I strongly disagree with the concept of discontinuation studies.  I think that they are a bogus type of research.  Also, this small study is highly unusual in finding a 53% exacerbation of mania for individuals on lithium which occurred after more than four weeks on the medication.  It suggests that either lithium or something else (the psychiatric unit program or separation from family?) was making the children feel worse. For the authors to demean lithium treatment of children based on such a faulty study makes no sense whatsoever, but that is just what they did.

Suicide Much Higher with Divalproex than Lithium: 20,638 14yo+ outpatient diagnosis of bipolar disorder and at least one filled prescription for lithium, divalproex, or carbamazepine between Jan. 1, 1994, and Dec. 31, 2001. Divalproex vs. lithium emergency department suicide attempt (31.3 vs. 10.8 per 1,000 person-years; 80% increased risk), suicide attempt resulting in hospitalization (10.5 vs. 4.2 per 1,000 person-years; 70% increased risk), and suicide death (1.7 vs. 0.7 per 1,000 person-years). Risk of completed suicide death was 2.7 times higher on divalproex after adjustment for clinical factors including age, sex, health plan, year of diagnosis, comorbid conditions, and use of other psychotropic drugs. JAMA. 2003;290:1467-1473, 1517-1519; Suicide in patients with bipolar disorder represents a 22-fold increase in mortality, from an estimated 0.017% per year to 0.40% per year, in an international general patient population. Long-term use of lithium previously has been shown to be associated with an 8.85 reduced risk of completed suicide compared with no treatment in bipolar disorder, but completed suicide rates were still 10 times higher in lithium-treated patients than in the general population. Prescribing for lithium compared with divalproex has steadily decreased in recent years, from a ratio of 6:1 in 1994 to 1:2 in 2001. Suicide attempts occurred 6.2 times more frequently than suicide deaths in study. Other comparisons (e.g., lithium vs. carbamazepine or combination treatment) yielded less stable and consistent results. Another much smaller study suggests more suicide risk with carbamazepine than lithium: 175 BAD patients discharged on lithium or carbamazepine in DB PC study with no suicide attempts with lithium but 9 with carbamazepine. Suicide attempts with carbamazepine in the JAMA study were 40% higher compared to lithium and 50% more deaths, but divalproex were 80% higher with 170% more deaths. Only 4% of patients were on carbamazepine which limits that reliability of the findings.

Valproate = Lithium Except More Weight, Alopecia, Tremor: Patients abstracted from other studies. 12 months duration with 372 participants comparing lithium, divalproex and placebo. No reliable difference between the treatments, although there was a trend for divalproex to be more effective than lithium. No significant difference in the numbers of patients in receipt of divalproex compared with those in receipt of lithium who left the study because they suffered any mood episode. (RRI 22%; RR 0.78). There was insufficient information to allow sub-group analyses of rapid-cycling disorder. The divalproex group had significantly more tremor (RRI 223%; RR 3.23), weight gain (RRI 187%; RR 2.87) and alopecia (RRI 143%) than the placebo group. In comparison with the lithium, divalproex was associated with more frequent sedation (RRI 58%; RR 1.58) and infection (RRI 107%; RR 2.07), but less suffered thirst (RRI 62%; RR 0.38) and polyuria (RRI 57%; RR 0.43). U Oxford, Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Macritchie KA, Geddes JR, Scott J, Haslam DR, Goodwin GM. Cochrane Database Syst Rev 2001;(3):CD003196

Rapid Cyclers Improve Just as Much: Observational study 360 patients treated with lithium. Rapid cycling is 4 mood episodes in any year. 30% bipolar II vs. 6% bipolar I rapid cyclers. Women 18% vs. men 12%. Both groups were ill on lithium 20% of time vs. 60% for rapid and 38% for others pretreatment. Annual rate of hospitalization same at 8% on lithium. Baldessarini, J Aff Disorders 00;60:13

Lithium Relapse Less Now: Patients not on meds have relapse rate per month 19 times that of lithium. Monthly recurrence rates in treated patients now only 0.5% in studies published between 1982 and 1996 v 2.7% between 1970 and 1982. Baldessarini, Arch Gen Psychiatry 00;57:187

Rapid Lithium Loading: Bipolar Disord 2001 Apr;3(2):68-72, Keck, U Cinn. Open study using 20 mg/kg/d with blood levels 2^nd, 3^rd, 4^th, 5^th, 7^th, and 10^th days. All had 0.6 mEq/L after 1^st day and maintained around 1.1 mEq/L.

Low Dose Lithium Maybe Not So Bad: Authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder. In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4-0.6 meq/liter) or a standard (0.8-1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium. The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study's finding of superiority for lithium levels > or =0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder. Perlis, MGH, Am J Psychiatry 2002 Jul;159(7):1155-9

Lithium + Divalproex Length of Stay: 47 patients hospital stays 13.7 vs. 11.9 (lithium) days. Dalkilic, Psychiatric Services 00;51:1184, Yale. Author comment that more time is needed to determine the lithium steady-state level of medication suggests he may not be using test dose approach.

Lithium May Increase Grey Matter: After 4 weeks treatment, 8 of 10 pt significant increase by 3% without affecting white or water content. Vogel, Science 00;290:258

Thyroid: Lithium, Carbamazepine & Thyroxine: In the first 2 years, 30 patients with bipolar mood disorder were randomly assigned to 1 year of lithium and then 1 year of carbamazepine, or vice versa; in the third year, they received lithium plus carbamazepine. By stepwise regression analysis, the degree and timing of lithium- and carbamazepine-induced thyroid changes and their subsequent relationship to long-term mood stability were evaluated. RESULTS: During the lithium phase, there was a significant inverse relationship between morbidity and mean serum level of free T4, i.e., a lower mean serum level of free T4 was associated with more affective episodes and greater severity of depression as shown by the Beck Depression Inventory. During the carbamazepine phase, there was an inverse relationship between mean level of total T4 and global severity rating. During the combination phase, no relationships between thyroid indices and clinical outcome were significant. Am J Psychiatry 1999 Dec;156(12):1909-14, NIMH

Thyroid Dysfunction in 47% Lithium Patients: 42 subjects with bipolar affective disorder receiving regular lithium therapy were analyzed and their thyroid glands were examined by ultrasonography. Following the receipt of lithium therapy (duration 4-156 months), three subjects displayed subclinical hypothyroidism (7.1%), three subclinical hyperthyroidism (7.1%) and one hyperthyroidism (2.4%). Moreover, goiter was detected in 16 (38.1%) subjects. An increase in the conversion of free thyroxine (T4) to free tri-iodothyrosine (T3), which is an indication of mild thyroid dysfunction, was identified in 20 (47.6%) subjects, and was mostly seen in male subjects under 40 years of age and in those having weight gain. Turkey, Thyroid abnormalities in lithium-treated patients with bipolar affective disorder. Caykoylu A, Capoglu I, Unuvar N, Erdem F, Cetinkaya R. J Int Med Res 2002 Jan-Feb;30(1):80-4

Thyroid Dysfunction: Weight Gain Predicts It: The polyuria-polydipsia syndrome affected 36 (60%) of 60 patients. More men than women reported tremor (54% v. 26%, p < 0.05), but weight gain during the first year of treatment was more frequent in women than men (47% v. 18%, p < 0.05), as was the development of clinical hypothyroidism (37% v. 9%, p < 0.05). Weight gain during the first year of treatment (and not sex) was the only significant predictor of hypothyroidism. 60 bipolars on lithium at least 1 year. Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder: sex differences. Bordeaux, France. Henry C. J Psychiatry Neurosci 2002 Mar;27(2):104-7

Thyroxine Reduces Lithium Cognitive Impairment: A preliminary study showed that adjunctive use of thyroid hormone significantly improves cognitive functioning in patients taking lithium. An animal study and two double-blind, placebo-controlled clinical studies examining the adjunctive use of thyroid hormone (T3) and ECT have confirmed that T3 significantly protects against ECT-related memory impairment compared to placebo. Tremont, Int J Neuropsychopharmacol 2000 Jun;3(2):175-186

Weight Gain: Lithium & Carbamazepine, #16 average difference after 1 year: 31 pt. stable on lithium. Half switched to carbamazepine in DB for one year. 9# wt gain on lithium vs. 7# wt loss on carbamazepine. Relapses 6 on carbamazepine and 8 on lithium, but most on carbamazepine near beginning suggesting withdrawal effect. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Coxhead N, Silverstone T, Cookson J. Acta Psychiatr Scand 1992 Feb;85(2):114-8

Weight Gain: Lithium: 65% gain an Average of 22 Pounds: 70 manic-melancholic patients who had been in treatment for 2 to 10 years. Their case records were reviewed and they answered a questionnaire. Out of 70 patients, 45 increased in weight with a mean weight gain of about 10 kg. The patients who increased in weight during the treatment were overweight already before the start and reached a weight about 20% higher than their ideal weight. Lithium treatment and weight gain. Vendsborg PB, Bech P, Rafaelsen OJ. J Clin Psychiatry 2000 Mar;61(3):196-202

Withdrawal: Abrupt Increases Relapse: 92% of 37 pt abruptly withdrawn relapsed over 4 years vs 71% of 61 who were gradually withdrawn. Peters, NYU, APA ’98

Withdrawal: Gradual Better: Withdrawal over 2-4 weeks lower relapse rate and longer relapse-free than rapid d/c <2 weeks. 161 patients stable bipolar on lithium > 1 yr. 77% d/c due to doing well and 22% due to pregnancy. Median time to recurrence 20 months gradual, 7 months abrupt. After 3 years, 37% graduals still no relapse. Baldessarini R, et al: Effects of the rate of discontinuing lithium maintenance treatment on bipolar disorders. J Clin Psyc 96;57:441-8, Harvard.; Another 78 patients with same finding. At 2 years f/u, 31% gradual vs 5% abrupt still relapse free. Baldessarini R: Reduced morbidity after gradual discontinuation of lithium treatment for bipolar I and II disorders: a replication study. Amer J Psyc 97;154:551.

Lithium = Carbamazepine, Combo Better: 52 bipolars put of lithium or carbamazepine 1 year, the opposite the second, and combo the third. 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05). NIMH, Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Denicoff KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM.

Polyuria: Amiloride for Lithium Diabetes Insipidus: Clinicians have been aware of lithium toxicity for many years and traditionally have administered thiazide diuretics for lithium-induced polyuria and nephrogenic diabetes insipidus. Recently, amiloride, a potassium-sparing diuretic, has been reported as a successful treatment for nephrogenic diabetes insipidus. Aubrun U., Treatment of lithium-induced diabetes insipidus with amiloride. Finch CK, Kelley KW, Williams RB. Pharmacotherapy 2003 Apr;23(4):546-50

Polyuria: More Common with SSRIs: A study of 75 Dutch patients found the prevalence of polyuria (3 liters/d) among lithium users was 37%. Concomitant use of serotonergic antidepressants was strongly associated with polyuria (odds ratio 4.25). Risk factors for the development of lithium-induced polyuria. Movig KL, Baumgarten R, Leufkens HG, van Laarhoven JH, Egberts AC. Br J Psychiatry. 2003 Apr;182:319-2

Psoriasis (Lithium-Associated) Treated with Omega-3 EPA: Two bipolar patients on lithium long-term developed psoriasis. Both took 4-6 g/d of omega-3 fatty acids. There was no change in depression, but after 3-4 weeks the psoriasis was completely gone. In one, 2 g/d had not affected the psoriasis. The skin disorder recurred in both when the fatty acids were stopped. Akkerhuis G, Nolen W: Lithium-associated psoriasis and omega-3 fatty acids. Am J Psychiatry 2003;160:1355. Utrecht.

Psoriasis Triggered by Lithium: Inositol Helps: Lithium can trigger and exacerbate psoriasis. Inositol depletion underlies the action of lithium in bipolar affective disorders. In a 15-patient DB PC crossover study, inositol reduced the psoriasis of lithium patients. No similar benefit was found for other psoriasis patients. The effect of inositol supplements on the psoriasis of patients taking lithium: a randomized, placebo-controlled trial. Allan SJ, Kavanagh GM, Herd RM, Savin JA. Edinburgh, U.K. Br J Dermatol. 2004 May;150(5):966-9

Case of an Herbal Diuretic Causing Lithium Toxicity: Am J Psychiatry 01;158:1329

B6 Helped Lithium Tremor in Open Trial: 4wk 900-1200mg/d (six) helped dramatically decrease and eliminate lithium tremor in 5 patients. Lithium-induced tremor treated with vitamin B6: a preliminary case series. Ben-Gurion U, Miodownik C, Witztum E, Lerner V. Int J Psychiatry Med 2002;32(1):103-8; Tremor worse with