Bipolar Disorders and Lithium: Pharmacokinetics, Pharmacodynamics, Therapeutic Effects and Indications of Lithium: Review of Articles

Review Article

Austin J Psychiatry Behav Sci. 2016; 3(2): 1053.

Bipolar Disorders and Lithium: Pharmacokinetics, Pharmacodynamics, Therapeutic Effects and Indications of Lithium: Review of Articles

Ayano G*

Research and Training Department, A Manuel Mental Specialized Hospital, Ethiopia

*Corresponding author: Ayano G, Research and Training Department, A Manuel Mental Specialized Hospital, Adidas Ababa, Ethiopia

Received: July 02, 2016; Accepted: August 10, 2016; Published: August 17, 2016


Lithium is a mood stabilizer which is approved for use in acute and maintenance mania. It is the first medications approved for the treatment of bipolar disorders. The drug has narrow therapeutic index 0.6-1.2meq/l.

The specific mechanism of action of lithium in stabilizing mood is unknown. Alters sodium transport across cell membranes in nerve and muscle cells, It alters metabolism of neurotransmitters including catecholamines and serotonin. May alter intracellular signaling through actions on second messenger systems. Specifically, inhibits inositol monophosphatase, possibly affecting neurotransmission via phosphatidyl inositol second messenger system. Also reduces protein kinase C activity, possibly affecting genomic expression associated with neurotransmission.

Common side effects include tremor, nausea, fatigue, increased thirst and slowed thinking. Important Serious side effects include hypothyroidism, weight gain and diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. There is an increased risk of fetal abnormalities if lithium is taken in pregnancy. Lithium concentrations are known to be increased with concurrent use of diuretics especially loop diuretics (such as furosemide) and thiazides and Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) such as ibuprofen, ACE inhibitors such as captopril, enalapril, and lisinopril. Its level decrease when used with drugs includes theophylline, caffeine, and acetazolamide. Concurrent use of lithium with antidepressants and antipsychotics may associate with serotonin syndrome and neuroleptic malignant syndrome respectively.

Keywords: Lithium; Pharmacokinetics; Pharmacodynamics; Side effects; Drug interactions


Lithium, which is an effective mood stabilizer, is approved for the treatment of mania and the maintenance treatment of bipolar disorder. It is the “classic” mood stabilizer, the first to be approved by the US FDA, and still popular in treatment. The efficacy of lithium for treating mania was discovered in 1949, making it the first medication specifically developed to treat bipolar disorder [1,2]. 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 [3].

History and uses of lithium

Lithium is the third element of the periodic table and is a monovalent cation that shares certain properties with sodium, potassium, and calcium. Lithium is the only medication to reduce suicide rate [4-6]. It decreases rate of completed suicide in 15% of bipolar patients [3,7-10]. It is effective in long-term prophylaxis of both mania and depressive episodes in 70% of bipolar I patients. Factors predicting positive response to lithium include prior response or family member with good response, classic pure mania and mania is followed by depression. It is an effective mood stabilizer approved for the treatment of mania and the maintenance treatment of bipolar disorder. The main use of lithium is in the treatment of acute mania and prophylaxis of bipolar disorder relapses, however it also has indications in other psychiatric conditions such as treatment resistant depression, schizoaffective disorder and schizophrenia [1,2,6].

Lithium is simple inorganic ion. It occurs naturally in animal tissue but has no known physiological function. Lithium has very low therapeutic index. Sodium depletion and dehydration can decrease renal excretion of lithium thus leading to lithium toxicity [4-6]. Lithium not only treats acute episodes of mania and hypomania but was the first psychotropic agent shown to prevent recurrent episodes of illness. Lithium may also be effective in treating and preventing episodes of depression in patients with bipolar disorder. It is least effective for rapid cycling or mixed episodes. Furthermore, many patients are unable to tolerate it because of numerous side effects, including gastrointestinal symptoms such as dyspepsia, nausea, vomiting, and diarrhea, as well as weight gain, hair loss, acne, tremor, sedation, decreased cognition, and in co-ordination. There are also long-term adverse effects on the thyroid and kidney. Lithium has a narrow therapeutic window, requiring monitoring of plasma drug levels [7,11].

It is FDA approved for effective antimanic, mood stabilization and bipolar depression treatments. If discontinued relapse near 100% in 2 years. Therapeutic level of lithium is 0.6-1.2meq/L, when exceed that 1.5, seriously toxicity begins to start. Maintenance drug level 0.4-8meq/l [1-4,6]. Lithium was used during the 19th century to treat gout. Lithium salts such as lithium carbonate (Li2CO3), lithium citrate, and lithium orotate are mood stabilizers. They are used in the treatment of bipolar disorder, since unlike most other mood altering drugs, they counteract both mania and depression. Lithium can also be used to augment other antidepressant drugs. It is also sometimes prescribed as a preventive treatment for migraine disease and cluster headaches. The active principle in these salts is the lithium ion Li+, which having a smaller diameter, can easily displace K+ and Na+ and even Ca+2, in spite of its greater charge, occupying their sites in several critical neuronal enzymes and neurotransmitter receptors [12-15].

Mechanism of action of lithium (pharmacodynamics)

The specific biochemical mechanism of lithium action in stabilizing mood is unknown. Alters sodium transport across cell membranes in nerve and muscle cells, It alters metabolism of neurotransmitters including catecholamines and serotonin. May alter intracellular signaling through actions on second messenger systems. Specifically, inhibits inositol monophosphatase, possibly affecting neurotransmission via phosphatidyl inositol second messenger system. Also reduces protein kinase C activity, possibly affecting genomic expression associated with neurotransmission. Increases cytoprotective proteins, activates signaling cascade utilized by endogenous growth factors, and increases gray matter content, possibly by activating neurogenesis and enhancing trophic actions that maintain synapses [16-24]. One mechanism is the drug modulates synaptic transmission mediated by monoamine neurotransmitters, accelerates presynaptic destruction of Catecholamine’s, inhibits transmitter release at the synapses and decreases post synaptic receptor sensitivity (NE, DA, Serotonin) [24].

Serotonin neurotransmission: Lithium may also increase the release of serotonin by neurons in the brain. In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization. Lithium may increase the release of serotonin to the synapse, perhaps by inhibiting 5-HT1A and 5-HT1B auto receptors. According to different evidences this effect of lithium is responsible for antidepressant effects of lithium [18]. Inhibition of Phospho Adenine Phosphate (PAP) phosphatase: PAP phosphatase is an enzyme which metabolizes phosphate group from PAP. Lithium Inhibit of Phospho Adenine Phosphate (PAP) phosphatase. This hypothesis was supported by the low Ki of lithium for human PAP-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). Importantly, the Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of PAP-phosphatase by lithium leads to increased levels of pAp (3'-5' phosphoadenosine phosphate), which was shown to inhibit PARP-1[24-26]. Glutamate neurotransmission: Another mechanism proposed in 2007 is that lithium may interact with Nitric Oxide (NO) signaling pathway in the central nervous system, which plays a crucial role in the neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the forced swimming test in mice. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness. Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in postsynaptic neurons. The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium [24].

Dopamine neurotransmission: During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder [24]. Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action [24].

GABA neurotransmission: GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins [24].

Cyclic AMP secondary Messengers: The Cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor coupled stimulation of cyclic AMP production [24]. It is hypothesized that the dual effects of lithium are due the inhibition of G-proteins that then mediate cyclic AMP production. Over a long period of lithium treatment, Cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors [24].

Ion transport theories: make use of lithium’s similarities to both monovalent (sodium, potassium) and divalent (calcium, magnesium) cations to focus on ion pumps and channels in cell membranes. For example, some investigators have found altered levels of sodium, potassium-adenosine triphosphatase (Na, K-ATPase) activity in patients with bipolar disorder. Since neuronal transmembrane potential differences are maintained by the Na, K-ATPase pump (also known as the sodium pump), perturbations of this system are felt to cause neurotransmitter aberrations that translate into mania and depression. Because lithium crosses cell membranes by four independent mechanisms (sodium pump, sodium leak channel, sodium- lithium counter transport, and lithium –bicarbonate exchange), it is possible that it could stabilize membrane function through such an interaction. Synapse-specific accumulation of lithium has been demonstrated in intracellular micro domains. In addition in 2014, it was proposed that lithium treatment works by affecting calcium signaling by blocking excitotoxic processes such as antagonizing N-methyl-d-aspartate (NMDA) receptors and inhibiting Inositol Monophosphatase (IMPase) [24,27].

Inositol depletion hypothesis: Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2. This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction is effected by lithium. Myo-inositol is also regulated by the high affinity Sodium Mi Transport System (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle [24-26].

Pharmacokinetics of lithium: Lithium is rapidly and completely absorbed, with serum concentrations peaking in 1 to 1.5 hours with standard preparations and in 4 to 4.5 hours with the slow and controlled release forms. Unlike most psychiatric drugs, lithium has no clinically important protein binding properties and no metabolites. It is excreted almost entirely by the kidneys, although small amounts are also lost in sweat and feces. A substantial amount of filtered lithium is reabsorbed (primarily in the proximal tubules), so that renal lithium clearance is about one fifth of creatinine clearance. The elimination half-life of lithium is about 18 to 24 hours, although it is considerably longer in the elderly because of the age-related decrease in Glomerular Filtration Rate (GFR) (and correspondingly shorter in youth for the opposite reason. Lithium is not liver metabolized. It is excreted through kidney. The drug is not protein bound and 70- 80% reabsorbs proximal tubule of the kidney. Its level increase with decrease in serum level of sodium ion especially during dehydration, administration with thiazide diuretics. It has half-life of 24 hrs with steady state of 5 days. Plasma peak Levels concentration of lithium reaches in 2 hrs [2,24].

Pre lithium work up and monitoring: Before starting lithium treatment we need to get baseline creatinine, TSH, CBC and ECG for age greater than 40 years. In women check a pregnancy test due to lithium use during the first trimester is associated with Ebstein’s anomaly 1/1000 (20X greater risk than the general population). Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst [28-31]. Lithium concentrations in whole blood, plasma, serum or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal over dosage. Serum lithium concentrations are usually in the 0.5–1.3 mmol/l range in well-controlled people, but may increase to 1.8–2.5 mmol/l in those who accumulate the drug over time and to 3–10 mmol/l in acute overdose [28-42]. Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 to 1.2 mmol Li+/l (lower end of the range for maintenance therapy and the elderly, higher end for children) on samples taken 12 hours after the preceding dose [36-42] (Table 1).