bipolar disorder in adults and lithium - pharmacology, administration, and side effects.pdf

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Official reprint from UpToDate

www.uptodate.com2013 UpToDate

AuthorPhilip Janicak, MD

Section EditorPaul Keck, MD

Deputy EditorDavid Solomon, MD

Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects

Disclosures

All topics are updated as new evidence becomes available and ourpeer review process is complete.

Literature review current through:Oct 2013. | This topic last updated:Ago 1, 2013.

INTRODUCTION The efficacy oflithiumfor treating mania was discovered in 1949, making it the first

medication specifically developed to treat bipolar disorder [1]. Lithium remains a mainstay of treatment for bipolar

disorder, especially for acute mania and maintenance treatment. In addition, lithium appears to reduce the risk of

suicide in patients with bipolar disorder. (See "Bipolar disorder in adults: Maintenance treatment", section on

'Reduced risk of suicide'.)

The pharmacology, administration, and side effects of lithiumare reviewed here. Choosing a medication (including

lithium) to treat acute mania, hypomania, mixed states, and bipolar depression is discussed separately, as is the

choice of medication for maintenance treatment of bipolar disorder, and the epidemiology, clinical manifestations,

and diagnosis of bipolar disorder.

(See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".)

(See "Bipolar disorder in adults: Pharmacotherapy for acute depression".)

(See "Bipolar disorder in adults: Maintenance treatment".)

(See "Bipolar disorder in adults: Clinical features".)

(See "Bipolar disorder in adults: Assessment and diagnosis".)

The use oflithiumto treat unipolar major depression is also discussed separately. (See "Unipolar depression in

adults: Treatment with lithium".)

DEFINITION Bipolar disorder is a mood disorder that is characterized by episodes of mania (table 1),

hypomania (table 2), and major depression (table 3), as well as mixed episodes (major depression concurrent with

mania or hypomania) [2]. The subtypes of bipolar disorder include bipolar I and bipolar II . Patients with bipolar I

disorder experience manic and mixed episodes, and nearly always experience major depressive and hypomanic

episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode,

and the absence of manic and mixed episodes. Additional information about the clinical features and diagnosis of

bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features"and "Bipolar disorder in

adults: Assessment and diagnosis", section on 'Diagnosis'.)

STRUCTURE AND FUNCTION Lithiumis the third element of the periodic table, and is a monovalent cation that

shares certain properties with sodium, potassium, and calcium [3,4].

Lithiums mechanism of action in treating mania and mixed states is unknown. One hypothesis is that it depletes

inositol in the central nervous system and dampens neurotransmission dependent upon this second messenger

[5,6]. Other hypotheses are that lithium works by inhibiting the activity of glycogen synthase kinase 3 in regulating

an intracellular signaling peptide called Wnt, or by inhibiting overactive protein kinase C intracellular signaling [ 5-7].

Lithium appears to affect multiple neurotransmitter systems including norepinephrine, dopamine, serotonin,

glutamate, and gamma aminobutyric acid; and second messenger systems including cyclic adenosine

monophosphate and cyclic guanosine monophosphate [5,6,8]. In addition, lithium also appears to increase

neurogenesis and neuroprotective factors, and in patients with bipolar disorder, preserve or increase cortical gray

matter and hippocampal volume [9-11].

ROLE IN TREATING BIPOLAR DISORDER The two primary considerations in choosing a medication are

olar disorder in adults and lithium: Pharmacology, administration, an... http://www.uptodate.com/contents/bipolar-disorder-in-adults-and-lithi...

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clinical efficacy and tolerability. These two factors involve issues such as past response to medications, comorbid

medical illnesses, concurrent medications, and specific symptoms. Another consideration is cost.

Lithiumis one of many medications that can be selected to treat acute mania, hypomania, mixed states, and

bipolar and unipolar depression, and is also a potential choice for maintenance treatment of bipolar disorder

[12-20]. The choice of pharmacotherapy for bipolar disorder is discussed separately. (See "Bipolar disorder in

adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania", section on 'Lithium' and "Bipolar

disorder in adults: Pharmacotherapy for acute depression"and "Bipolar disorder in adults: Maintenance treatment",

section on 'Lithium'.)

Lithiumis generally avoided in patients with significant renal disease and often not used during the first trimester of

pregnancy. In addition, lithium can significantly affect thyroid function. (See 'Long-term side effects'below and

"Renal toxicity of lithium"and "Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy",

section on 'Lithium'and "Lithium and the thyroid".)

Few studies have examined whether certain subgroups of patients respond preferentially to a specific drug. In

patients with mixed states or a greater lifetime number of mood episodes, lithiummay be inferior to valproate

[21-24].

Reduced risk of suicide Long-term treatment with lithiumis associated with a reduced risk of suicide attempts

and suicide deaths. This is discussed separately. (See "Bipolar disorder in adults: Maintenance treatment", section

on 'Reduced risk of suicide'.)

Severely ill patients For patients with severe mania or mixed states, the combination oflithiumplus an

antipsychotic is often useful [12,25]. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed

episodes, and hypomania", section on 'Severe manic and mixed episodes'.)

PHARMACOKINETICS The absorption, distribution, and elimination of lithiumare well-described [26-28].

Lithium is rapidly absorbed through the gastrointestinal tract; food does not alter lithium absorption [29]. Peak

serum levels occur in one to two hours with standard, immediate release preparations of lithium and within four to

five hours with slow release preparations. Absorption of immediate release lithium is complete within six to eight

hours, and for slow release preparations in approximately 8 to 12 hours. Lithium is not protein bound and isdistributed throughout total body water. Brain levels are highest within two hours of peak serum levels. Steady

state is achieved within four to five days after the last dose change.

Lithiumis not metabolized and is excreted almost exclusively through the kidneys. Thus, lithiums elimination half-life

is determined primarily by renal function. The half-life in healthy young patients is about 24 hours, and increases as

renal function declines with age.

Additional information about the pharmacokinetics oflithiumis discussed separately.

PRESCRIBING LITHIUM There are several basic points to discuss with patients before prescribing lithium,

including potential side effects, the need to take the medication as prescribed rather than on as-needed basis, and

to expect that response and remission may not occur until a few days to weeks have elapsed after a therapeuticdose/level has been achieved.

Lithium dose and serum concentrations The starting dose oflithiumis usually 300 mg two or three times

daily [5,30-32]. The dose is then increased by 300 to 600 mg every one to five days based upon response,

tolerability, and body mass index. The goal is to reach a therapeutic serum level, which generally occurs with a

dose of 900 mg to 1800 mg per day. Dose increases generally occur more frequently at the beginning of

treatment, and less often as clinicians approach the target dose.

The half-life oflithiumis approximately 24 hours. Thus, it takes at least four or five days for serum lithium

concentrations to reach steady state after the dose is changed.

Lithiumcan be dosed either once daily or in a divided dose regimen. Clinicians should start with a twice daily or

three times daily dosing schedule to minimize side effects (especially nausea) early in treatment and consolidate

the dose schedule to once daily after a number of weeks or months of treatment. Some patients may have to

continue taking lithium in two or four divided doses to minimize peak level side effects. However, adherence


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generally decreases as the frequency of dosing increases [33].

The target serum level for acute phase management and maintenance treatment is between 0.8 and 1.2 mEq/L

(0.8 and 1.2 mmol/L), and levels should usually not exceed 1.2 mEq/L (1.2 mmol/L) [32]. Patients who cannot

tolerate a level of 0.8 mEq/L (0.8 mmol/L) may respond to a level of 0.6 mEq/L (0.6 mmol/L) [34].

After reaching the estimated therapeutic dose range (generally 900 mg to 1800 mg per day), the serum lithium

concentration should be checked. Subsequently, a level should be measured five to seven days after each dose

increase. In addition, if the dose is not changed and a level not checked for two or more weeks, a level should be

checked before increasing the dose. An office-based instrument for fingerstick tests of lithium levels is available

[35].

Lithiumlevels should be drawn approximately 12 hours after the last dose (12-hour serum trough level) and

generally collected in the morning, before the first dose of the day. Changes in the serum level per unit time are not

dramatic 12 hours after the last dose. Thus, a level drawn 11 to 13 hours after the last dose, or even 10 to 14

hours, provides meaningful information. In contrast, a serum level drawn a few hours after lithium ingestion is

subject to marked fluctuation if the level is drawn one hour sooner or later, leading to unreliable information.

Serum lithiumlevels are closely related to renal function, salt balance, and water balance. Clinicians can expect

lithium concentrations to change as follows:

Dehydration (may occur with gastrointestinal viral infections or high fever) causes higher lithiumlevels

Increasing sodium intake causes increased sodium and lithiumexcretion and lower lithium levels

Decreased sodium intake causes sodium and lithiumreabsorption in the proximal tubule and an increase in

serum lithium levels.

When lithiumis taken once per day, serum concentrations are approximately 25 percent higher compared with

levels that are observed when lithium is taken two or three times per day; this is due to changes in renal excretion

[36]. Therefore, a once daily lithium level of 1.0 mEq/L (1.0 mmol/L) is expected to drop to a level of 0.8 mEq/L

(0.8 mmol/L) if the patient switches to a divided dose regimen. Virtually all studies examining optimal lithium levels

have used divided dose regimens.

Elderly patients The use oflithiumin elderly patients is discussed separately. (See "Geriatric bipolar

disorder: Acute treatment", sect ion on 'First line medications'.)

Lithium preparations Multiple preparations oflithiumare available, varying in dose from 100 to 1000 mg.

There is no difference in treatment efficacy or serum concentrations among the various lithium preparations.

The most commonly prescribed preparation in the United States contains 300 mg of lithiumcarbonate, which

provides 8 mEq/L (8 mmol/L) of lithium. Lithium carbonate is available as a tablet or capsule. In addition, lithium is

available as a liquid in the form of lithium citrate for patients who have difficulty swallowing pills. A dose of 5 mL

contains 300 mg of lithium.

Several slow-release lithiumtablets are available. Slow-release lithium may cause less nausea than conventional,

immediate release forms at least in the beginning of treatment, but also a slightly higher incidence of diarrhea, due

to more distal gastrointestinal absorption. Slow-release tablets should be swallowed whole, rather than crushed or

chewed.

Additional information about lithiumpreparations is discussed separately.

Contraindications Lithiumis contraindicated in patients with:

Significant renal impairment

Sodium depletion

Dehydration

Significant cardiovascular disease

Renal impairment, sodium depletion, and dehydration increase the risk of lithiumtoxicity. In addition, lithium can

rarely cause sinus node dysfunction (eg, sinus bradycardia and sinoatrial block), atrioventricular node dissociation

with atrioventricular block and junctional rhythms, and ventricular premature beats.


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Psoriasis, which lithiumexacerbates, is a relative contraindication.

Lithium toxicity Excessive lithiumlevels can lead to toxicity with severe side effects and multisystem

dysfunction that can be fatal if not recognized. Lithium toxicity is a clinical diagnosis that is confirmed by serum

lithium levels [5]. Relatively mild toxicity usually does not occur until serum lithium reaches a level of 1.5 mEq/L (1.5

mmol/L). Levels 2.5 mEq/L (2.5 mmol/L) constitute a medical emergency, even in patients who appear relatively

asymptomatic. Symptoms and treatment of toxicity are discussed separately. (See "Lithium poisoning".)

Lithiumhas a narrow therapeutic index, which means that the dose at which it is clinically effective is only slightly

lower than the dose at which it becomes toxic. One study found that the mortality rate from lithium toxicity was

approximately 25 percent with an acute overdose and 9 percent in patients intoxicated during maintenance therapy;

an additional 10 percent in the latter group suffered permanent neurologic damage [37].

The likelihood oflithiumintoxication is increased when lithium excretion is impaired. This most commonly occurs

with:

Underlying renal insufficiency

Effective volume depletion

Elderly patients (low glomerular filtration rate)

Drug interactions with lithium Medications that change renal function, salt balance, or water balance can alterlithiumexcretion and serum lithium concentrations. Lithium levels must be closely monitored in patients taking these

medications. These drug interactions are as follows [5]:

Increases lithiumlevel

Thiazide diuretics

Nonsteroidal antiinflammatory drugs (NSAIDS) except aspirin

Angiotensin converting enzyme (ACE) inhibitors

Antibiotics tetracyclines and metronidazole

Decreases lithiumlevel

Potassium-sparing diuretics

Theophylline

May increase or decrease lithiumlevel

Loop diuretics

Calcium channel blockers

These medications are not contraindicated for patients taking lithium. Rather, patients receiving medications thatmay interact with lithium should have their serum levels monitored more closely. Specific interactions of any

particular drug with other medications may be determined using the drug interactions tool (Lexi-Interact Online)

included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual

drug information topics in the section on Drug interactions.

Laboratory tests and monitoring Before prescribing lithiumand during ongoing treatment, laboratory tests

need to be obtained because lithium can adversely affect several organ systems. Management of abnormal test

results and adverse effects resulting from lithium are described elsewhere in the topic, as is management of a

positive pregnancy test. (See 'Long-term side effects'below and 'Pregnancy'below.)

Prior to beginning lithium, the following tests should be obtained [12,38]:

Urinalysis, blood urea nitrogen (BUN), creatinine, thyroid function studies, and calcium

Pregnancy test for women of childbearing potential


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Electrocardiogram (ECG) for patients with risk factors for coronary heart disease, including diabetes

mellitus, hypertension, dyslipidemia, and cigarette smoking. (See "Overview of the risk equivalents and

established risk factors for cardiovascular disease".)

Lithiumlevels should be checked five to seven days after the dose is changed. In addition, a lithium level should be

checked if a dose increase is under consideration and a level has not been measured for at least two weeks.

Patients on steady doses should have their levels checked every 6 to 12 months.

In addition to checking lithiumlevels during ongoing treatment, renal, thyroid, and parathyroid function should be

monitored as follows:

Urinalysis, BUN, and creatinine every 2 to 3 months during the first 6 months of therapy, and every 6 to 12

months thereafter (See "Renal toxicity of lithium".)

Thyroid function tests once or twice during the first 6 months, and every 6 to 12 months thereafter or more

frequently in higher risk patients (See "Lithium and the thyroid".)

Serum calcium is monitored yearly

LITHIUM SIDE EFFECTS Lithiumcan cause many acute and long-term adverse effects that are not necessarilyassociated with toxicity [39].

Acute side effects The most common acute side effects associated with lithiumare [5,6,40-42]:

Nausea

Tremor

Polyuria (related to nephrogenic diabetes insipidus) and thirst

Weight gain

Loose stools

Cognitive impairment (including apathy, decreased creativity, and changes in verbal learning, memory, and

concentration)

Some side effects can be managed. Nausea can be reduced by taking lithiumwith food. Nausea, tremor, and

cognitive dulling are dose-related and may diminish with either dose reduction, or dividing the daily dose to take

smaller amounts more often, in order to decrease peak serum levels. Diuretics (eg, the potassium-sparing diuretic

amiloride) may decrease polyuria, but caution must be used because many diuretics alter lithium levels; lithium

doses may need to be adjusted and lithium levels checked more often.

Severe or a sudden worsening of side effects may be a sign of lithiumtoxicity. (See 'Lithium toxicity'above and

"Lithium poisoning".)

Tremor Lithium-induced tremor is common and classified as a postural tremor [43]. Onset typically occurs

when the drug is started or t itrated up, but tremor can appear at any time during treatment. Lithium tremor is

generally symmetric, limited to the hands or upper limbs, related to dose and serum concentration, and

nonprogressive. Factors that increase the risk of tremor include anxiety, caffeine, medications (eg, antiarrhythmics,

beta-adrenergic agents, carbamazepine, and valproate), emotional and physical stress, and fatigue.

The evaluation oflithiumtremor is discussed separately. (See "Overview of tremor", section on 'Evaluation'.)

Although lithiumtremor often resolves over time, clinicians should be aware that tremor is the most common

symptom of lithium toxicity [43]. (See 'Lithium toxicity'above.).

Initial management oflithiumtremor that is troublesome and persistent includes modifying aggravating factors (eg,

decreasing caffeine intake) and reducing the dose if feasible [43]. In addition, it may help to change the lithium

preparation from long acting to short acting, or to a different salt (ie, from carbonate to citrate), or to divide the

daily dose to take smaller amounts more often. For lithium tremor that does not respond to initial management and

causes moderate to severe functional problems, we suggest pharmacotherapy (eg, beta blockers such as

propranolol). The use of pharmacotherapy is discussed separately. (See "Pharmacologic treatment of essential

tremor".)


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Long-term side effects The two most common long term adverse effects of lithiuminvolve the kidneys and

thyroid gland [5,40].

Renal Renal function is adversely affected by lithiumand thus monitored with laboratory tests. In a

systematic review of lithium toxicity, the findings regarding renal damage were as follows [42]:

A meta-analysis of four case-control studies found that tubular renal function (expressed as urinary

concentrating ability) was significantly reduced by approximately 15 percent

Lithiummay increase the incidence of end-stage renal failure, but the absolute risk appears small; in a

cohort study of 3369 patients treated with lithium, renal replacement therapy was required by 0.5 percent,

compared with 0.2 percent in the general population. The renal toxicity of lithium is discussed separately.

(See "Renal toxicity of lithium".)

A meta-analysis of five case-control studies (372 cases treated with lithiumand 307 untreated controls)

found that glomerular f iltration rate was reduced by 6 mL/minute in patients who took lithium compared with

controls, but the difference was neither statistically nor clinically significant

Lithiuminitially reduces the ability of the kidney to concentrate urine, leading to dilute urine and polyuria

(nephrogenic diabetes insipidus) [44]. Over months and years, this functional deficit becomes structural. Biopsy

specimens from patients chronically treated with lithium show interstitial fibrosis that is consistent with chronic

interstitial nephritis in more severe cases. If patients drink enough when they are thirsty, this is not dangerous.

However, this process can lead to increased serum creatinine and, rarely, to progressive renal failure [44,45].

Thus, monitoring renal function with serial serum creatinine concentrations is an essential part of ongoing lithium

therapy. Clinicians should consult a nephrologist and discontinue lithium when the serum creatinine approaches or

exceeds 1.6 mg/dL (140 mmol/L) [46]. The most important r isk factor for renal damage from lithium is repeated

episodes of lithium intoxication. It is not clear whether higher mean serum lithium levels correlate with greater risk

of renal damage. Taking lithium once per day instead of in divided doses may correlate with less tubular

dysfunction, especially if this regimen is instituted early on in treatment before structural tubular changes have

occurred [47]. Additional information about renal toxicity and lithium is discussed separately. (See "Renal toxicity of

lithium".)

Abnormal renal function tests are managed in collaboration with a nephrologist to determine the need for further

testing, a reduction in the dose oflithium, or switching to an alternative medication for treating bipolar disorder.

Thyroid Thyroid function is adversely affected by lithiumand thus monitored with laboratory tests; lithium

can cause goiter, hypothyroidism, chronic autoimmune thyroiditis, and possibly hyperthyroidism [48]. A

meta-analysis of eight case-control studies (869 cases treated with lithium and 578 untreated controls) found that

hypothyroidism occurred in significantly more cases than controls (14 versus 2 percent) [42]. In addition, lithium

increased thyroid stimulation hormone by 4 iU/mL. The adverse effects of lithium on thyroid function and their

management are reviewed separately. (See "Lithium and the thyroid".)

Neither pretreatment hypothyroidism (presumably treated adequately with T4) nor lithium-induced hypothyroidism isa contraindication to lithium therapy [48]. Reasonable recommendations are to monitor serum thyrotropin (TSH)

and if it rises much above the upper value of normal, to start T4 while continuing the lithium. Consultation with an

endocrinologist may also be indicated. (See "Clinical manifestations of hypothyroidism"and "Treatment of

hypothyroidism".)

Parathyroid Lithiummay also cause hypercalcemia, elevated serum parathyroid hormone, and

hyperparathyroidism [39,49-51]. A meta-analysis of 13 case-control studies (730 cases treated with lithium and

699 untreated controls) found that serum calcium concentration was significantly increased in cases by 0.1 mmol/L

compared with controls, and that lithium was associated hyperparathyroidism [42].

An elevated calcium level should prompt a serum parathyroid hormone concentration. If the hormone level is

abnormal, an endocrine consult is obtained. Hypercalcemia, hyperparathyroidism secondary to lithium, and

measurement of serum calcium are discussed separately. (See "Pathogenesis and etiology of primary

hyperparathyroidism", section on 'Lithium therapy'and "Diagnosis and differential diagnosis of primary

hyperparathyroidism", section on 'Measurement of serum calcium'and "Management of primary


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hyperparathyroidism".)

Cardiac Lithiummay rarely cause cardiac dysrhythmias in patients without pre-existing cardiac disease

[5,39,40]. In addition, lithium may lead to the following abnormalities on the ECG, which may anticipate the onset of

dysrhythmias [39]:

Repolarization abnormalities of the T wave or ST segment

Findings consistent with the sick sinus syndrome (See "Manifestations and causes of the sick sinus

syndrome", section on 'Other'.)

An unmasked or modulated Brugada pattern (See "Brugada syndrome", section on 'Provoking factors'.)

These ECG findings should prompt a cardiology consult.

PREGNANCY Although lithiumis generally regarded as teratogenic due to increased risks of cardiac defects

(eg, Ebsteins anomaly) [52-54], many authorities consider the absolute risk small [55-59]. The use of lithium during

pregnancy and risks of lithium exposure during pregnancy and breastfeeding are discussed separately. (See

"Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Refractory

patients'and "Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy", section on 'Lithium'

and "Use of psychotropic medications in breastfeeding women", section on 'Lithium'.)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics andBeyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond

the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written

at the 10th to 12th grade reading level and are best for patients who want in-depth information and are

comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

patient info and the keyword(s) of interest.)

Basics topics (see "Patient information: Reducing the costs of medicines (The Basics)")

Beyond the Basics topics (see "Patient information: Bipolar disorder (manic depression) (Beyond the

Basics)"and "Patient information: Reducing the costs of medicines (Beyond the Basics)")

The United States National Library of Medicine and National Institutes of Health have created an educational

document entitled "Lithium that explains the use of lithium. It is available online at the website

http://www.nlm.nih.gov/medlineplus/druginfo/meds/a681039.html , and copies may be printed free of charge.

The United States National Institute of Mental Health has a document entitled, Mental Health Medications, that is

available online at http://www.nimh.nih.gov/health/publications/mental-health-medications/complete-index.shtml , or

through the toll-free number 866-615-6464. Copies may be printed free of charge.

The Depression and Bipolar Support Alliance (http://www.dbsalliance.orgor 800-826-3632) is a national

organization whose mission is to educate members about bipolar disorder and how to cope with it. Other functions

include increasing public awareness of the illness and advocating for more research and services. The organization

is administered and maintained by patients and family members, and has local chapters.

The National Alliance on Mental Illness (http://www.nami.orgor 800-950-6264) is a similarly structured organization

devoted to providing education, support, and advocacy for patients with any mental illness. Bipolar disorder is one

of their priorities.

SUMMARY AND RECOMMENDATIONS

Lithiumis one of many medications that can be selected to treat acute mania, hypomania, mixed states, and

bipolar depression, and is also a potential choice for maintenance treatment of bipolar disorder. (See

"Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania"and "Bipolar


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disorder in adults: Pharmacotherapy for acute depression"and "Bipolar disorder in adults: Maintenance

treatment".)

Lithiumis a mainstay of treatment for bipolar disorder and may reduce the risk of suicide. (See 'Introduction'

above and 'Role in treating bipolar disorder'above and "Bipolar disorder in adults: Maintenance treatment",

section on 'Reduced risk of suicide'.)

Lithiumis rapidly absorbed through the gastrointestinal tract. Peak serum levels occur in one to two hours

with immediate release preparations of lithium and within four to five hours with slow release preparations.Lithium is distributed throughout total body water. Steady state is achieved within four to five days after the

last dose change. Lithium is excreted almost exclusively through the kidneys. The half-life is about 24 hours

in healthy young patients, and increases as renal function declines with age. (See 'Pharmacokinetics'

above.)

The starting dose oflithiumis usually 300 mg two or three times daily. The dose should be increased by 300

to 600 mg every one to five days based upon response, tolerability, and body mass index. The goal is to

reach a therapeutic serum level, which generally occurs with a dose of 900 mg to 1800 mg per day. Dose

increases generally occur more frequently at the beginning of treatment, and less often as clinicians

approach the target dose. (See 'Lithium dose and serum concentrations'above.)

The target serum level for acute phase management and maintenance treatment is between 0.8 and 1.2

mEq/L (0.8 and 1.2 mmol/L), and levels should not exceed 1.5 mEq/L (1.5 mmol/L). Patients who cannot

tolerate a level of 0.8 mEq/L (0.8 mmol/L) may respond to a level of 0.6 mEq/L (0.6 mmol/L). (See 'Lithium

dose and serum concentrations'above.)

Levels should generally be measured five to seven days after each dose increase. In addition, a lithiumlevel

should be checked if a dose increase is under consideration and a level has not been measured within the

past two weeks. Patients on steady doses should have their levels checked every 6 to 12 months. Lithium

levels should be drawn 12 hours after the last dose (12-hour serum trough level) and generally collected in

the morning, before the first dose of the day. (See 'Lithium dose and serum concentrations'above and

'Laboratory tests and monitoring'above.)

Lithiumlevels are closely related to renal function, salt balance, and water balance. Dehydration causes

higher lithium levels, increasing sodium intake causes lower lithium levels, and decreased sodium intake

causes an increase in serum lithium levels. (See 'Lithium dose and serum concentrations'above.)

Lithiumis contraindicated in patients with significant renal impairment, sodium depletion, dehydration,

significant cardiovascular disease. (See 'Contraindications'above.)

Excessive lithiumlevels can lead to toxicity with severe side effects and multisystem dysfunction which can

be fatal if not recognized. Lithium toxicity is a clinical diagnosis that is confirmed by serum lithium levels.

Relatively mild toxicity usually does not occur until serum lithium reaches a level of 1.5 mEq/L (1.5 mmol/L).

Levels 2.5 mEq/L (2.5 mmol/L) constitute a medical emergency, even in patients who appear relativelyasymptomatic. (See 'Lithium toxicity'above and "Lithium poisoning".)

Many medications can alterlithiumconcentrations. Lithium levels are increased by thiazide diuretics,

nonsteroidal antiinflammatory drugs (NSAIDS) except aspirin, angiotensin converting enzyme (ACE)

inhibitors, tetracyclines, and metronidazole. Lithium levels are decreased by potassium-sparing diuretics and

theophylline. Lithium levels are increased or decreased by loop diuretics and calcium channel blockers. (See

'Drug interactions with lithium'above.)

Prior to beginning lithium, clinicians should obtain a urinalysis, blood urea nitrogen (BUN), creatinine, thyroid

function studies, calcium, pregnancy test for women of childbearing potential, and an electrocardiogram

(ECG) for patients over age 40. BUN and creatinine should be checked every two to three months duringthe first six months of therapy, and every 6 to 12 months thereafter. Thyroid function should be checked

once or twice during the first six months, and every 6 to 12 months thereafter. (See 'Laboratory tests and

monitoring'above.)


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The most common acute side effects associated with lithiumare nausea, tremor, polyuria and thirst, weight

gain, loose stools, and cognitive impairment. Severe or a sudden worsening of side effects may be a sign of

lithium toxicity. Important long term adverse effects of lithium involve the kidneys and thyroid gland. In

addition, cardiac rhythm disturbances have been described; these almost always occur in patients with

preexisting cardiac disease. (See 'Lithium side effects'above and "Lithium poisoning".)

ACKNOWLEDGMENT The editorial staff at UpToDate, Inc. would like to acknowledge Dr. Jeffrey Stovall, who

contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 15317 Version 19.0


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GRAPHICS

DSM-IV-TR diagnostic criteria for mania

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting

at least 1 week (or any duration if hospitalization is necessary).

B. During the period of mood disturbance, three (or more) of the following symptoms have

persisted (four if the mood is only irritable) and have been present to a significant degree:1) Inflated self-esteem or grandiosity

2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep)

3) More talkative than usual or pressure to keep talking

4) Flight of ideas or subjective experience that thoughts are racing

5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli)

6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor

agitation

7) Excessive involvement in pleasurable activities that have a high potential for painful consequences

(eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C. The symptoms do not meet criteria for a mixed episode.

D. The mood disturbance 1) is sufficiently severe to cause marked impairment in occupational

functioning, usual social activities, or relationships with others, 2) necessitates hospitalization to

prevent harm to self or others, or 3) has psychotic features.

E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of

abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision,Fourth Edition (Copyright 2000). American Psychiatric Association.


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DSM-IV-TR diagnostic criteria for hypomania

A.A distinct period of persistently elevated, expansive, or irritable mood, lasting at least 4 days,

that is clearly different from the usual nondepressed mood.

B.During the period of mood disturbance, three (or more) of the following symptoms have

persisted (four if the mood is only irritable) and have been present to a significant degree:

1) Inflated self-esteem or grandiosity

2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep)

3) More talkative than usual or pressure to keep talking

4) Flight of ideas or subjective experience that thoughts are racing

5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli)

6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor

agitation

7) Excessive involvement in pleasurable activities that have a high potential for painful consequences

(eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C.The episode is associated with an unequivocal change in functioning that is uncharacteristic of

the person when not symptomatic.

D.The disturbance in mood and the change in functioning are observable by others.

E.The episode 1) is not severe enough to cause marked impairment in social or occupational

functioning, 2) does not necessitate hospitalization, and 3) does not have psychotic features.

F.The symptoms are not due to the direct physiological effects of a substance (eg, a drug of

abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).

Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (eg,

medication, ECT, light therapy) should not count toward a diagnosis of bipolar II disorder.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision,

Fourth Edition (Copyright 2000). American Psychiatric Association.


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DSM-IV-TR diagnostic criteria for major depression

A. Five (or more) of the following symptoms have been present during the same 2-week

period, and represent a change from previous functioning. At least one of the symptoms is either

depressed mood or loss of interest or pleasure.

(Note: Do not include symptoms that are clearly due to a general medical condition, or

mood-incongruent delusions or hallucinations.)

Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in childrenand adolescents)

Markedly diminished interest or pleasure in all, or almost all, activities, nearly every day

Significant weight loss while not dieting, weight gain, or decrease or increase in appetite

Insomnia or hypersomnia nearly every day

Psychomotor agitation or retardation nearly every day

Fatigue or loss of energy nearly every day

Feelings of worthlessness or excessive or inappropriate guilt nearly every day

Diminished ability to think or concentrate, or indecisiveness, nearly every day

Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specificplan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms do not meet criteria for a Mixed Episode.

C. The symptoms cause clinically significant distress or impairment in social, occupational, or other

important areas of functioning.

D. The symptoms are not due to the direct physiological effects of substance or a general medical

condition.

E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one,

the symptoms persist for longer than two months or are characterized by marked functional

impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, orpsychomotor retardation.

Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed, Text Revision. American Psychiatric Association, Washington, DC 2000.


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