HALF-LIFE: 18-24 hours
INITIAL DOSE: 300mg-600mg PO per day (divided doses)
TARGET DOSING RANGE: 600mg-1,200mg per day (Target level 0.8-1.0 mEq/L)
>> Initial 300mg-600mg PO QHS
>> Gradually increase dose gradually to target serum level of 0.8 mEq/L
>> Max dose 2,400mg/day
>> Dosing is usually BID or TID to minimize peak dosing side effects
>> Many patients tolerate once daily dosing
PREGNANCY: Avoid if possible (but not a contraindication) – Risk of Epstein Anomaly 
BREASTFEEDING: Avoid if possible (but not a contraindication)
1) Acute mania
2) Bipolar Disorder Maintenance in children and adults




Lithium’s interactions with the brain are complex and include:


  • Desensitizing presynaptic 5HT-1A auto receptors in the raphe nuclei and thereby increasing serotonin release
  • Decoupling G-protein linked production of second messengers
  • Directly increasing transcription of fast response genes (e.g. KREB, PHOS, and JUN)


Proposed Mechanisms of Action of Lithium:


  • Alters sodium transport in myocytes/neurons
  • Alters metabolism of catecholamines (DA, NE, Epinephrine)
  • Alters intracellular signaling via second messengers (IP3 and PKC pathways)


Lithium is a cation metal first used in the 19th century to treat gout and discovered by John Cade in 1949 to exert anti-manic effects


  • Lithium does not undergo metabolism and is not protein bound.  It is cleared via the kidneys.
  • Benign leukocytosis is common due to demarginalization of WBCs
  • Despite being highly effective, lithium is not widely used due to its narrow therapeutic index.  Optimal plasma concentrations for treatment of bipolar mood disorder are 0.8 to 1.2 meq/L, however, toxic signs and symptoms may begin at concentrations as low as 1.5 meq/L and serious toxicity with risk of permanent neurological injury may occur at concentrations as low as 2.0 meq/L.
  • Lithium may worsen skin conditions such as acne and psoriasis
  • Lithium use during the first trimester of pregnancy may be associated with an increased risk of Epstein’s anomaly (downward displacement of tricuspid valve into a malfunctioning right ventricle) although this is controversial. Note that lithium has been safely used in pregnancy in select patients.
  • Lithium is easily dialyzed and can be administered to patients on hemodialysis (Give dose after dialysis treatment)
  • Caffeine may decrease lithium levels
  • Lithium + Haloperidol may increase the risk of NMS and delirium
  • Lithium may cause abnormal involuntary movements
  • Lithium may increase the risk of serotonin syndrome if administered with serotonergic agents
  • An increase or decerase of 300mg/day changes serum Li levels approximately 0.25 mEq/L (rough estimate)
  • Best for euphoric mania
  • Effective for chronic suicidal thoughts in bipolar and unipolar depression
  • Effective for aggressive and violent behaviors
  • Increased risk of nephrogenic diabetes insipidus (usually reversible)
  • Propranolol effective for tremors associated with lithium
  • Bradycardia, cardiac arrhythmia, sinus node dysfunction may be seen
  • Common finding on EKG: flattened or inverted T waves


Lithium Monitoring

Lithium Toxicity



What Does “Mood” Mean?


Mood is defined as a person’s internal emotional state that is sustained over time. Mood is subjective and experienced by the person. Terms used to describe mood: Normal, Sad, Angry, Irritable, Anxious, Happy


What Does “Affect” Mean?


Affect is a term used to describe the outward expression of a mood state. In other words, an individual’s affect is visible to others. Healthcare providers obtain important information about an individual’s internal emotional experience (mood) based on their emotional expression (affect). Terms used to describe an individual’s affect: Dysphoric, Happy, Excited, Irritable, Angry, Tearful, Blunted, Euthymic, Flat, Blunted, Constricted, Restricted, Appropriate, Congruent.


What Are Mood Disorders?


Mood disorders are group of psychiatric disorders in which disturbances of mood or affect are severe and persistent enough to cause significant problems in an individual’s life. Moods by themselves are not pathological and many of us have experienced a wide range of mood states. When moods become severe and persistent enough to cause dysfunction and issues in an individual’s life, then we use the term “mood disorder.”  Mood disorders are better defined as syndromes consisting of a cluster of signs and symptoms that often “come and go” in “episodes” which persist for weeks, months, or even years. During these “episodes,” there is a significant change in the individual’s mood which may negatively impact work performance, relationships, or other important areas of functioning. The most common mood disorder is major depressive disorder (MDD), often referred to as “Unipolar depression.” Bipolar disorders are also mood disorders that differ from unipolar depression by the presence of elevated mood states called hypomania or mania.


What is Mania?


Mania is characterized by a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary). During this period of elevated/expansive mood/energy, individuals may experience any combination of the following: Inflated self-esteem or grandiosity; Decreased need for sleep (e.g., feels rested after only 3 hours of sleep); More talkative than usual or pressure to keep talking; Flight of ideas or subjective experience that thoughts are racing; Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed; Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (i.e., puroseless non-goal-directed activity); Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments). As with any “disorder,” the mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. If the mood disturbance can be attribute dto a drug, medication, or medical condition then the term “manic episode” should not be used. 


What is Hypomania?


Hypomania is a less severe form of mania and is characterized by a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and present most of the day, nearly every day with the same symptoms that characterize mania (see above). 


Subtypes of Bipolar Disorder:

Bipolar 1 Disorder: Manic or Mixed episode +/- Major Depressive Episode (Only manic episode required) 

Bipolar 2 Disorder: Hypomanic episode + Major Depressive Episode (both are required)

With rapid cycling: 4 or more mood episodes in a 12-month period




Neurobiology of Bipolar Disorder 


The underlying biochemical abnormalities that cause or contribute to bipolar disorder remain unclear. However, studies have suggested neurobiological differences between unipolar and bipolar depression which is further supported by the relative lack of efficacy of classic antidepressant monotherapy in the treatment and prevention of bipolar depression. Human studies have found increased concentrations of noradrenaline (norepinephrine) and dopamine (DA) and decreasedconcentrations of serotonin (5-HT) in manic patients which suggests that norepinephrine and dopamine dysregulation may play a primary role in manic symptoms. In patients with unipolar depression, both serotonin (5-HT) and norepinephrine concentrations are low. Perhaps the imbalance partially explains bipolarity? Lastly, glutamate and GABA dysregulation have been implicated in the pathophysiology of bipolar disorder. Animals studies suggest increased glutamatergic neurotransmission via NMDA receptors in manic patients. In addition, the efficacy of anticonvulsants and benzodiazepines in the treatment of bipolar disorder suggests the likelihood that glutamate and GABA systems are involved in uncertain ways. 


It is likely that the combination of vulnerable genetics and environmental stressors lead to intracellular changes in transcription, signal transduction, and synaptic functioning that ultimately give rise (via poorly understood mechanisms) to symptoms of bipolar disorder.



Functional Imaging Studies


Functional Connectivity Studies have demonstrated or suggested


(1) Decreased connectivity between the amygdala and anterior cingulate cortex

(2) Increased connectivity between the amygdala and the supplemental motor area


Functional Neuroimaging Studies have demonstrated or suggested


(1) Decreased size and activity in the PFC of patients with bipolar disorder—similar to that found in patients with unipolar depression.

(2) Increased gray matter volume in bipolar patients after 4 weeks of lithium treatment (Note: Valproic acid (depakote) has not been shown to have the same effect.

(3) Amygdala are larger and more active in the bipolar patients.

(4) Bipolar disorder may be the result of abnormal interactions between the PFC and subcortical regions such as the amygdala—an abnormality not usually seen with unipolar depression.



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