Lithium: The Forgotten Wonderdrug

Lithium: 

The Forgotten 

Wonderdrug 

Workshop TM4 

Alex Golin,MD 

Department of Psychiatry 

Bergen Regional Medical Center 

Paramus, New Jersey

Introduction

What Is Lithium

History 

• 1817 Johan Arfwedson discovered a new alkali 

in a sample of minerals from an island near 

Stockholm, Sweden 

–Named lithion by Jons Jacob Berzelius, Arfwedson’s 

lab chief 

• 1843 Alexander Ure introduced lithium into 

medicine for gout and uric acid bladder stones 

• 1871 William A. Hammond, Surgeon General of 

US Army, described using lithium in acute mania

History 

• 1880s to early 1900s lithium was 

embraced by public for many ailments in 

the form of mineral water

History 

• By 1907 there were 43 medicinal preparations 

containing lithium listed in the Merck Index and 

awareness of side effects began to emerge 

– Generalized weakness 

–Tremor 

– Diarrhea 

–Vomiting 

– Ataxia 

– Dysarthria

Psychiatric Uses For Lithium 

• Antimanic, mood stabilizer 

• Lithium also appears to be an effective 

treatment of aggression among 

nonepileptic patients with history of 

violence such as prisoners, mentally 

retarded and handicapped patients, and 

among conduct-disordered children with 

explosive behavior

US Indications 

• 1970 FDA approved lithium for treatment 

of acute mania 

• 1974 FDA approved lithium for 

maintenance therapy in patients with 

bipolar disorder 

– To prevent or diminish the intensity of 

subsequent mood episodes

Advantages of Lithium 

• Well established efficacy in treating manic 

episodes 

– Response rate of as much as 78% over one to three 

weeks 

• Evidence of efficacy in depression 

• Effectiveness of maintenance therapy to prevent 

relapse of affective symptoms is better 

established than for any other drug 

• Documented to reduce risk of suicide 

Jefferson JW, Greist JH. Lithium. In Comprehensive Textbook of Psychiatry. Seventh Ed. 

Sadock BJ and Sadock VA, Editors. Lippincott Williams & Wilkins, New York, 2000; pp. 2377-2390.

Disadvantages of Lithium 

• Narrow window between therapeutic and toxic blood levels 

– Requires careful monitoring of blood levels 

• Thyroid reactions 

– Hypothyroidism 

– Hyperthyroidism 

• Renal reactions 

– Polyuria 

– Interstitial fibrosis 

– Possibility of reduced filtration rate 

• Cardiovascular reactions 

– Heart block 

– Reversible T wave changes on EKG 

• Weight gain

Decline In Lithium Use

Trends in Treatment of Bipolar 

Disorder by Outpatient Psychiatrists 

• Sample from the National Ambulatory Medical 

Care Survey between 1992 and 1999 

– 1992 to 1995 more than half of visits for bipolar 

disorder included a prescription for lithium 

– 1996 to 1999 only 30% included a prescription of 

lithium 

Blanco C, Laje G, Olfson M, Marcus SC, Pincus HA. Trends in the treatment of bipolar 

disorder by outpatient psychiatrists. Am J Psychiatry. 2002 Jun;159(6):1005-10.

Trend in Veterans Affairs Medical 

Center in Palo Alto, CA 

• Between 1989 and 1994 for patients with 

bipolar disorder 

– Lithium monotherapy declined from 84% to 

43% 

– Lithium in combination with divalproex 

increased from 0 to 25% 

Fenn HH, Robinson D, Luby V, Dangel C, Buxton E, Beattie M, Kraemer H, 

Yesavage JA. Trends in pharmacotherapy of Schizoaffective and bipolar 

affective disorders: a 5-year naturalistic study. Am J Psychiatry. 1996 

May;153(5):711-3.

Possible Reasons for Decreased 

Prescription of Lithium in the U.S. 

• Perception that lithium is difficult to use 

and possibly toxic 

• Decreasing time for each patient and the 

need to monitor patients on lithium closely 

• Advent of other mood stabilizers that do 

not require blood monitoring 

– AEDs 

– Atypical antipsychotics

Lithium Therapy And 

Suicide Risk In Affective 

Disorders

Suicide Risk in General Population 

• International annual suicide rates are on 

average 16 per 100,000 population 

– 0.016% per year 

• Attempt rate in general population is 10 to 

20 times greater than suicide rate 

– Up to 0.32% per year 

Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective 

disorders: update and new findings. J Clin Psychiatry. 2003;64 Suppl 5:44-52.

Suicide Risk in Mood Disorders 

• Bipolar I disorder, all suicidal acts 

– 2.73% per year 

• Bipolar II disorder, all suicidal acts 


• Unipolar depression, all suicidal acts 


• Attempts to completed suicide in persons with mood disorders is 3:1 

• 15% to 25% of all deaths in patients with bipolar disorder are from 

suicide 

Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on 

suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60 Suppl 2:77-84; 

discussion 111-6.

Lithium Therapy and Suicide Risk 

Data Available for Analysis 

• 34 reports between 1970 and 2002 

• Total number of patients was over 16,000 

– Bipolar Disorder 

– Major Depressive Disorder 

– Schizoaffective Disorder 

• Exposure to lithium at the time of studies was 

average of 3.36 years 

Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: update and 

new findings. J Clin Psychiatry. 2003;64 Suppl 5:44-52.

Overall Rates 

• Suicides and attempts without lithium 

therapy 

– 3.1% of study population per year 

• Suicides and attempts with lithium therapy 




Rates of Completed Suicide 

• Suicides without lithium therapy 


• Suicides with lithium therapy 




Rates of Suicide Attempts 

• Suicide attempts without lithium therapy 


• Suicide attempts with lithium therapy 




Risk Ratios 

• Risk was reduced 14.8-fold or 93.2% in 

lithium treated group when looking at 

suicides and attempts overall 

• For completed suicides considered alone 

risk was reduced 5.4-fold or 81.5% 

• For suicide attempts considered alone risk 

was reduced 14.9-fold or 93.3% 



Risk Reduction in Diagnostic 

Subtypes 

• Bipolar disorder, all suicidal acts 

– From 6.1% per year without lithium to 0.295% per 

year with lithium 

• 20.7-fold or 95.2% reduction of risk 

• Mixed groups of recurrent depressive and 

schizoaffective disorders, all suicidal acts 

– From 2.12% per year without lithium to 0.193% per 

year with lithium 

• 11.0-fold or 90.9% reduction of risk 

Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major 

affective disorders: update and new findings. J Clin Psychiatry. 2003;64 Suppl 5:44-52.

Lithium and Suicide Risk Reduction 

• Overall risk of suicidal behavior during 

lithium treatment is 33% lower than 

comparable estimated rates for the 

international general population 

– 0.32% vs 0.21% per year 

• This may represent the substantial risk of 

suicidal behavior in the general population 

due to untreated affective illness

Other Important Risk Factors in 

Suicide That Must Be Treated: 

Going Beyond Lithium 

• Substance abuse 

• Relentless anxiety 

• Pain

Other Medications and Suicide 

Risk 

• Weak evidence suggesting little or no 

effect 

– Antidepressants 

– Mood stabilizers other than lithium 

• Clozapine may also have protective effect 

studied in schizophrenia

Limitations of Evidence 

• Lack of retention of subjects in some of 

the trials 

• Biased self-selection for medication 

compliant patients who may also be less 

likely to be suicidal

Possible Mechanisms By Which 

Lithium Reduced Suicide Risk 

• Reduction of impulsivity or aggressive 

behavior 

• Benefit of a supportive long-term 

relationship requiring close monitoring 

• Reduction of risk or severity of 

recurrences of manic and depressed 

states

Rationale For Long Term 

Treatment With Lithium in 

Bipolar Disorder

Relapse in Bipolar Disorder 

• Manic episodes occur more than 

once in 90% of patients 

• Many patients continue to experience 

subthreshold symptoms even after 

recovery from a full mood episode 

Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long term 

lithium treatment. J Clin Psychiatry. 2002;63 Suppl 10:5-12.

Relapse in Bipolar Disorder 

• Despite continual maintenance treatment, 

there is evidence that 5-year risk of 

relapse into mania or depression of 73% 

• Of those who relapsed, two-thirds had 

multiple relapses 

Gitlin MJ, Swendsen J, Heller TL, Hammen C. Relapse and impairment in bipolar disorder. Am J 

Psychiatry. 1995;152:1635-1640.

Relapse Before and After Lithium 

• Bipolar I patients 

– N 188 

Maintenance Therapy 

• Bipolar II patients 

– N 129 

• Patients followed for average of 8 years before 

lithium treatment and same patients were 

followed for 6 years during lithium therapy 

Tondo L, Baldessarini RJ, Hennen J, Floris G. Lithium maintenance treatment of depression and 

mania in bipolar I and bipolar II disorders. Am J Psychiatry. 1998 May;155(5):638-45.

Episode Recurrence in Bipolar I 

Disorder – Before Lithium 

• Mania 

– 1.1 recurrences per year 

– 24.7% of time ill 

• Depression 





Episode Recurrence in Bipolar II 

Disorder – Before Lithium 

• Hypomania 

– 1.0 recurrence per year 







Episode Recurrence in Bipolar I 

Disorder – With Lithium 

• Mania 








Episode Recurrence in Bipolar II 

Disorder – With Lithium 

• Hypomania 

– 0.16 recurrence per year 




– 12.6 of time ill 



Reduction of Episode Recurrence 

• Bipolar I 

with Lithium Treatment 

– Yearly Episodes > 50% fewer in 56.4% of the patients 

– More than 50% less time ill in 59% of patients 

• Bipolar II 

– Yearly Episodes > 50% fewer in 72.9% of the patients 

– More than 50% less time ill in 72.9% of patients 



Improvement in Course of Bipolar 

Disorder With Lithium Treatment 

• For all patients in study 

– The time from end of an episode to start of 

next episode in 50% of cases was prolonged 

4.4-fold during lithium maintenance treatment 



Risk vs Benefit Of Lithium 

Maintenance

Potential Toxicity of Long Term 

Lithium Use 

• Long term treatment with lithium can induce 

functional and/or structural disturbances in the 

kidneys 

– Patients who had received lithium salts for a mean 

period of 17.7 years showed mean reduction in 

creatinine clearance of 2.23 ml/min/year 

– In 7 patients treated a mean of 22 years, progression 

towards terminal kidney failure required periodical 

dialysis 

Presne C, Fakhouri F, Kenouch S, Stengel B, Kreis H, Grunfeld JP. Progressive renal failure 

caused by lithium nephropathy. Presse Med. 2002 May 25;31(18):828-33.

Potential Toxicity of Long Term 

Lithium Use 

• Thyroid function was investigated in 100 manicdepressive 

patients 

– Goiter was more common in patients treated with 

lithium for 1-5 years (44%) and more than 10 years 

(50%) than in patients who never received lithium 

(16%) 

– Hypothyroidism was found in 21% of patients treated 

with lithium for more than 10 years 

Perrild H, Hegedus L, Baastrup PC, Kayser L, Kastberg S. Thyroid function and 

ultrasonically determined thyroid size in patients receiving long-term lithium 

treatment. Am J Psychiatry. 1990 Nov;147(11):1518-21.

Not Everyone Responds to Lithium 

Maintenance 

• Rapid Cycling 

– Rapid cycling reduces efficacy of 

maintenance therapy with lithium 

• Amount of time with bipolar disorder 

before lithium maintenance initiation 

– The less time the greater the benefit 

• Lithium responders tend to present with 

episodic, fully remitting course and with 

euphoric rather than dysphoric mania

Reducing Risk, Increasing Benefit: 

Rationale for Using Lithium in Combination 

With Other Mood Stabilizers 

• Results from comparison of lamotrigine 

and lithium suggest that the two have 

complementary actions 

– Lithium has a greater effect on recurrence of 

mania in maintenance 

– Lamotrigine has greater effect on recurrence 

of depression in maintenance 

Goodwin FK. Rationale for using lithium in combination with other mood stabilizers in the 

management of bipolar disorder. J Clin Psychiatry. 2003 May;64 Suppl 5:18-24.

Rationale for Using Lithium in 

Combination With Other Mood 

Stabilizers 

• Open trials of lithium with divalproex 

suggest greater improvement than either 

mood stabilizer alone 

• There is potential to reduce side effects 

because both drugs can be given in a 

lower dose if they act synergistically 

Goodwin FK. Rationale for using lithium in combination with other mood stabilizers in the 

management of bipolar disorder. J Clin Psychiatry. 2003 May;64 Suppl 5:18-24.

Initiating and Monitoring 

Lithium Therapy

Initiating Lithium 

• Lithium should generally not be given to 

patients with significant renal or 

cardiovascular disease 

• The risk of lithium toxicity is very high in 

patients receiving diuretics or ACE 

inhibitors 

• Lithium should be avoided in pregnant 

women because of a risk of cardiac 

malformation in the fetus

Initiating Lithium 

• Prior to initiating lithium kidney, thyroid 

and cardiac function should be assessed 

–BUN 

– Creatinine 

– TSH, T3, T4 

– Full blood count 

– Electrolytes 

– EKG if history of cardiac dysfunction

Starting Dose 

• Conservative dose of 300 mg BID 

– In presence of normal kidney function, typical 

dose for treatment of acute mania is 1200 mg 

to 1800 mg of lithium and for maintenance 

treatment 900 mg to 1200 mg

Blood Monitoring 

• Lithium can be found in any body fluids 

including saliva and tears but currently 

only blood assays are available 

• Regular blood monitoring is essential for 

lithium treatment as lithium has a narrow 

window between therapeutic level and 

toxic level

Blood Monitoring 

• First measurement should be done 4 to 7 

days after initiation 

• Blood draws should be 12 hours after last 

dose 

• Weekly monitoring until level stable for 4 

weeks 

• Monthly for six months 

• Once stable, monitor every three to six 

months

Therapeutic Levels 

• Upper end: 1.5 mEq/L 

– At 1.5 mEq/L the likelihood of achieving a response is 

outweighed by the possibility of toxicity 

• Lower end is a source of debate 

– Evidence exists that patients maintained between 0.4 

and 0.6 mEq/L were 2.6 times more likely to relapse 

than those between 0.8 and 1.0 mEq/L 

• Package inserts recommend between 0.6 and 

1.2 mEq/L concentrations 

Gelenberg AJ, Kane JM, Keller MB, Lavori P, Rosenbaum JF, Cole K, Lavelle J. Comparison 

of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. 

N Engl J Med. 1989 Nov 30;321(22):1489-93.

Monitoring Frequently Not Done in 

Practice 

• Approximately two-thirds of lithium users in 

one study had a lithium blood level in a 12 

month period 

– Fewer than one half were tested for thyroid 

function and even less for renal function in that 

year 

Marcus SC, Olfson M, Pincus HA, Zarin DA, Kupfer DJ. Therapeutic drug monitoring of mood 

stabilizers in Medicaid patients with bipolar disorder. Am J Psychiatry. 1999 Jul;156(7):1014-8.

Lithium Discontinuation

Why Discontinue Lithium 

• If it is not effective in controlling 

recurrences and symptoms 

• If not tolerated 

– Side effects 

– Too much weight gain 

• Patients may request a drug holiday after 

prolonged remission 

• Pregnancy

Reduced Morbidity After Gradual 

Discontinuation 

• Median time to recurrence of affective 

symptoms after lithium discontinuation 

was 4.7 times as great for gradual 

discontinuation (2 to 4 weeks) as for rapid 

discontinuation (less than 2 weeks) 

Baldessarini RJ, Tondo L, Floris G, Rudas N. Reduced morbidity after gradual discontinuation of 

lithium treatment for bipolar I and II disorders: a replication study. Am J Psychiatry. 1997 

Apr;154(4):551-3.

Lithium Discontinuation and 

Subsequent Effectiveness 

• 54 bipolar patients who stopped taking 

lithium then resumed lithium after one or 

more affective episodes 

– Although they had been symptom free on 

lithium for at least two years prior to 

discontinuation, 18.5% relapsed in the year 

following resumption of lithium 

Maj M, Pirozzi R, Magliano L. Nonresponse to reinstituted lithium prophylaxis in previously 

responsive bipolar patients: prevalence and predictors. Am J Psychiatry. 1995 Dec;152(12):1810-1.

Lithium Discontinuation and 

Subsequent Effectiveness 

• In 86 patients with bipolar disorder, the efficacy of lithium 

did not differ significantly between the first and second 

treatment periods 

– Morbidity was similar in the first and second treatment periods 

(mean number of episodes = 0.83 and 0.94 per year, 

respectively; mean percentage of time ill = 18.0% and 24.2%) 

– No differences in numbers of manic and depressive episodes or 

differences by gender, diagnostic type, length of first treatment, 

interval between treatments, or discontinuation rate 

Tondo L, Baldessarini RJ, Floris G, Rudas N. Effectiveness of restarting lithium treatment after its 

discontinuation in bipolar I and bipolar II disorders. Am J Psychiatry. 1997 Apr;154(4):548-50.

Lithium Discontinuation After 

Maintenance Therapy in Bipolar 

Pregnant Women 

• Rates of recurrence during the first 40 weeks after lithium 

discontinuation were similar for pregnant and nonpregnant 

women 

– Risk was much lower during preceding treatment and less 

with gradual discontinuation 

• Depressive or dysphoric-mixed episodes were more prevalent in 

pregnant than nonpregnant women (63% versus 38% of 

recurrences) 

• Postpartum recurrences were 2.9 times more frequent than 

recurrences in nonpregnant women during weeks 41-64 (70% 

versus 24%) 

Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ. Risk of recurrence of 

bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am 

J Psychiatry. 2000 Feb;157(2):179-84.

APA Treatment Guidelines 

For Bipolar Disorder 

American Psychiatric Association. Practice guideline for 

the treatment of patients with bipolar disorder (revision). 

Am J Psychiatry. 2002 Apr;159(4 Suppl):1-50.

Acute Manic or Mixed Episodes 

• Mild/Moderate 

– First line, lithium monotherapy or valproate or 

antipsychotic like olanzapine 

• Severe 

– First line is initiation of lithium plus an antipsychotic or 

valproate and an antipsychotic 

• If the episode is breakthrough while patient is 

already on lithium maintenance 

– Optimize dose 

– Add valproate to the lithium

Bipolar Depression 

• First line therapy is initiation of lithium or 

lamotrigine 

– Antidepressant monotherapy is not recommended 

– Can initiate lithium with antidepressant together 

• If the episode is breakthrough while patient is 

already on lithium maintenance 

– Optimize dose 

– Add lamotrigine and/or bupropion to the lithium

Rapid Cycling 

• Four or more mood episodes within single year 

demarcated by partial or full remission or switch 

to episode of opposite polarity 

• Look for causes 

– Comorbid substance use 

– Thyroid dysfunction 

– Antidepressant can contribute 

• Initial treatment should be lithium, valproate, 

lamotrigine or a combination

Maintenance 

“The medications with the best empirical 

evidence to support their use in maintenance 

treatment include lithium and valproate…Long 

term treatment with lithium has been associated 

with reduction of suicide risk…Lithium may also 

diminish the greater mortality risk observed 

among bipolar disorder patients from causes 

other than suicide. It is unknown whether 

prolonged survival is also seen with the 

anticonvulsant maintenance agents.”

Under certain conditions magmatic fluids, found in molten igneous rocks 

before they reach the surface, can be very rich in specific elements. 

Under these peculiar circumstances giant crystals of a single element can 

be formed. This photograph shows giant lithium crystals in the Black Hills 

of South Dakota. 

http://www.science.uwaterloo.ca/earth/geoscience/pegmat.html

Lithium: The Forgotten Wonderdrug

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