The Effects of Lithium on Manic-depressive Disorder

Our emotional goal is to be happy. Unfortunately some people cannot reach their goal of happiness. This disorder is called depression. Not only do those who suffer depression try to find ways to become happy again, but also others who want to help are in a constant search to find a means to offset depression. One way to offset depression is through medication, and one of the many medications is lithium.

Lithium has been found to be effective in manic-depressive disorder. Manic-depressive Disorder (also called bipolar disorder) is a mood disorder in which a person alternates between depression and mania. Mania (or a manic episode) is a mood disorder in which a person tends to be hyperactive and wildly optimistic. A person suffering from a manic phase is overtalkative, overactive, elated, loud, and hard to understand. He or she has little need for sleep, shows fewer sexual inhibitions, and has grandiose optimism. Though people who suffer from mania find advice irritating, they need protection from their own poor judgment (Myers, 2001). Lithium aids to control manic episodes, but is not as effective at controlling depressive episodes. This is why patients who respond to lithium most effectively are those with manic depressive psychosis and a predominate behavior of mania. Patients whose behavior alternates between manic and depressive often, do less well with lithium treatment (Kolb, 1973).

Lithium is one of the alkali metals (the first group in the periodic table). These are soft silvery metals that produce hydrogen when they come in contact with water (Jones & Atkins, 2000). When alkali metals react with water, they do so quickly and produce a spark that flies around in the water, possibly even jumping out of the water. Lithium is the least reactive of all the alkali metals, but more reactive than metals that are not in the alkali metal group, such as sodium and magnesium (Jones et al). Lithium has the atomic number three and a molar mass of 6.94 grams per mole. Because lithium has one valance electron it is most stable when it combines with another element or compound by giving away one electron. This makes the common lithium ion to be a cation with one positive charge. Also lithium has a high melting point at 181 degrees Celsius and a boiling point of 1347 degrees Celsius. The density of lithium is .53 grams per milliliter (Jones et al).

Because lithium is so reactive one cannot find lithium in nature. Instead it is found as parts of mineral compounds and mineral waters. In fact such mineral waters have been used throughout history for therapy. There are records stating that both the Greek and Romans used mineral water therapy from specific alkali springs for certain physical and mental illnesses. In 1817 August Arfvedson discovered lithium while working in a Swedish laboratory. When people realized lithium could be found in mineral waters that have been used for healing, they started to connect lithium with the power to heal (Fieve, 1984). In 1949 John F. Cade, an Australian Psychiatrist, discovered lithium’s therapeutic effect against mania. This led to further studies on the effects of lithium on both mania and depression. In 1970 the Lithium Task Force in America and the United States Food and Drug Administration approved of lithium for treatment of mania (Fieve, 1984).

Scientists have discovered that norepinephrine (also called noradrenaline) is overabundant during mania. Norepinephrine is a neurotransmitter that increases arousal and boosts mood. To control mania drugs must reduce norepinephrine (Myers, 2001). Once in the body lithium first reduces the sensitivity of the postsynaptic norepinephrine receptor. If the receptor is less sensitive, then the receptor is less likely to receive norepinephrine and less norepinephrine transfers throughout the body. Lithium also increases uptake of norpinephrine into synaptosomes. Synaptosomes are pinched off nerve endings that cannot release hormones such as norpinephrine. Less norpinephrine reduces mania (Van Praag, 1977). The exact way lithium reduces norpinephrine is unknown, but based on what is known about lithium chemically and the human body; there are many hypotheses that provide insight in lithium’s capabilities.

Lithium is given to patients either as lithium carbonate or as lithium citrate. Lithium carbonate weighs 73.88 grams per mole. It is a white, granular, odorless powder that is sparingly soluble in water, very slightly soluble in alcohol, and it dissolves with effervescence in dilute mineral acids. Lithium citrate, on the other hand, is prepared in solution from lithium hydroxide and citric acid in a ratio approximating dilithium citrate (Physicians’ desk reference, 1993).

Once in the body and the compound (either lithium carbonate or lithium citrate) dissolves, the lithium cation competes with sodium cations, potassium cations, magnesium cations, and calcium cations. Lithium cations also substitutes for sodium cations and/or potassium cations. The lithium cation interacts with ammonium groups, which may alter the biochemistry of neurotransmitter substances (such as norpinephrine). Also lithium has a very high energy of hydration, which is the energy needed to strip off water molecules (Fieve, 1984).

Lithium cation, sodium cation, and potassium cation are monovalent (are cations with one positive charge). Lithium’s ionic radius (.08nm) is similar to both the sodium ionic radius (.1nm) and the magnesium ionic radius (.07nm). Also the lithium ion has a similar charge density to both the sodium ion and calcium ion (Fieve, 1984).

Lithium competes with sodium, potassium, magnesium, and calcium in nerve tissues that maintain impulse conduction. By attaching itself to a binding site on the nerve tissue, lithium may change the impulse conduction. This change is a caused by either direct action of itself on the macromolecular structure or by displacing one of the other cations. The nerve impulses may change in frequency, change direction, or alter in some other way. This change will probably lead to a change in behavior. Also, lithium substitutes for sodium extracellularly allowing lithium to pass rapidly through sodium channels of cell membranes during impulse conduction. Using sodium channels lithium can travel throughout the body. Substituting for sodium, lithium may also block narrow potassium channels. This affects electrolyte gradients on either side of the cell membrane. (The impulse conduction is still permitted to continue.) By affecting the electrolyte gradients nerve impulses may come less frequently. This would aid a person who is hyperactive to slow down (Fieve, 1984)

Lithium competes for calcium-binding sites. This affects calcium-dependent release of neurotransmitters (such as norepinephrine). If norepinephrine is dependent on calcium in order to be released and lithium takes the place of some of the calcium at the calcium-binding sites, then the norepinephrine will be released less. Less norepinephrine means less mania. Also cyclic AMP is dependent on calcium for production. If lithium replaces calcium around cyclic AMP cites then there will be less calcium to produce cyclic AMP. Less AMP means less production of energy, which would help relax a person with mania (Fieve, 1984).

Cellular protein carriers bind to or transport sodium, potassium, calcium, and magnesium. The membranes of these proteins allow neurotransmitter hormones to cross into the protein. Lithium may alter the structure of these proteins not allowing the neurotransmitters into the protein. Neurotransmitter hormones need to enter the protein in order to be carried throughout the body. If lithium decreases the amount neurotransmitter hormones like norepinephrine to enter the protein, less norepinephrine will be able to travel through and affect the body (Fieve, 1984).

In order to reach these proteins, neurotransmitters, and AMP production lithium must be able to travel through the body. Lithium travels through the body by the way of red blood cells (Gosenfeld, Ehrlich, & Diamond, 1981). Lithium gets in and out of the red blood cell by four major processes. Lithium enters in the cell mainly (70%) by an anion exchange pathway. The lithium cation pairs with either the carbonate ion or the chloride ion and passes inwardly in the presence of the hydrogen carbonate ion. (This may be why lithium is prescribed in the form of lithium carbonate.) The other 30% of the inward transport of lithium is by passive leak diffusion. In the absence of bicarbonate the lithium cation can diffuse into the red blood cell (Fieve, 1984).

Hydrogen carbonate

stimulated

Na-K ATPase

Sodium ion-sodium ion exchange accounts for 90% of lithium exiting out of the red blood cell. The lithium ion substitutes for the sodium ion. Because both ions are positively charged the lithium ion is repelled out of the red blood cell by the sodium ion gradient across the cell wall. The sodium ion-potassium ion ATPase pump accounts for the remaining 10% that transports the lithium ion out of the cell. The pump mechanism converts energy into movement of the four cations against concentration gradients pushing the cations out of the cell (Fieve, 1984).

Experimentally scientists have found that the choline concentrations have increased in red blood cells when patients undergo lithium treatment. However, the concentration of choline in plasma remains constant. Lithium irreversibly decreases the transport of choline out of the red blood cell. The decrease of outward transport is similar to the sodium ion-lithium ion exchange (the replacement of the lithium ion in the sodium ion-sodium ion exchange). Somehow this exchange allows lithium out of the red blood cell, but reduces the amount of choline leaving the red blood cell. The exact procedure remains unknown. Choline produces acetylcholine. When acetylcholine levels are raised in hyperactive humans whether endogenously induced (manic) or chemically induced, people experience a calming effect (Gosenfeld, Ehrlich, & Diamond, 1981).

Though lithium is very helpful at reducing mania, one must be very careful when using lithium. In order for the lithium to be effective, patients take about 300-600mg of lithium per day. The concentration of serum lithium in the urine should be between 0.6 to 1.0 millimoles per liter and for patients with acute mania (which requires hospitalization) the serum lithium concentration in urine should be 1.0 to 1.4 millimoles per liter. If any patient exceeds 1.5 millimoles per liter the patient is in danger to lithium toxicity (Fieve, 1984). Physical signs of lithium toxicity include diarrhea, vomiting, tremor, drowsiness, or muscular weakness. Children under twelve have a strong chance for toxicity. This means children under twelve, pregnant women, or women who are nursing should not undergo lithium treatment (Physicians’ desk reference, 1993).

Other side effects include excessive urination, hand tremor, dry mouth, thirst, occasional nausea, and occasional diarrhea. Patients with cardiovascular disease infrequently experience pulse irregularity and reversible T-wave changes on an electrocardiogram. Patients with central nervous system disease are more at risk for neurotoxicity, electroencephalograph changes, and seizures. Patients with renal disease are more at risk for lithium toxicity, and if the kidneys were not originally well, the kidneys may or may not be affected. Five to ten percent of patients on long term lithium develop hypothyroidism and goiter, which is easily treated by thyroid replacement. (Lithium treatment can be continued after replacement). Fifteen to twenty percent of patients gain weight (Fieve, 1984).

Despite the side effects those people who suffer from manic-depression and respond positively to lithium treatment consider the drug well worth the risk. Those who will respond positively to lithium include those with a definite diagnosis of bipolar I primary affective disorder. They have an occurrence of fewer than four effective episodes in one year. They have psychotic features during mania and a grandiose-elated picture during manic episodes. Also, they have a family history of bipolar illness. Patients who have an ill family member who responds positively to lithium are more likely to respond positively to lithium themselves (Fieve, 1984).

Though the exact route lithium takes within the body is unknown, the above hypotheses are very plausible. It is amazing that with all the organic and other complex compounds that are used for medication, lithium is effective as just one element. Lithium is so effective because of our body’s use of similar elements (sodium, potassium, calcium, and magnesium). By replacing and competing with these elements lithium alters the chemistry inside our bodies (most likely resulting in a decrease of norepinephrine). The altered chemistry controls a person’s mania allowing those who suffer from mania to regain control of their lives.

References

Fieve, R.R. of chapter 8. (1984). Lithium: its clinical uses and biological mechanisms of action. In R.L. Habig (Ed.), The brain, biochemistry, and behavior (pp. 170). Washington DC, USA: The American Association for Clinical Chemistry, Inc.

Gosenfeld, L.F., Ehrlich B.E., & Diamond J. M. of chapter 5. (1981). Affective disorders and lithium. In E.A. Serafetinides (Ed.), Psychiatric research in practice biobehavioral themes (pp.85). New York, NY, USA: Grune & Stratton, Inc.

Jones, L. & Atkins, P. (2000). Chemistry molecules, matter, and change. New York, NY, USA: W.H. Freeman and Company.

Kolb, L.C., (1973). Modern clinical therapy. Philadelphia, PA, USA: WB Saunders Company.

Myers, D.G. (2001). Psychology (6^th ed.). New York, NY, USA: Worth Publishers.

Physicians’ desk reference. (1993). Montvale, NJ, USA: Medical Economics Data.

Van Praag, H.M. (1977). Depression and schizophrenia. Jamaica, NY, USA: Spectrum Publications, Inc.