BIOLOGICAL BASIS OF BEHAVIOR
Psychology 321
Spring, 2005 HGH 225
Dr. John M. Morgan MWF, 8am to 9:00
Lithium's Use in Manic Depressive Treatments
Yasaman Abbasov
James Eubanks
P.J. Hall
Monica Wood
Introduction
Lithium was discovered in 1949 by John Cade as a treatment
for bipolar disorder. Since then, lithium has become a highly
utilized medication for manic depression.
Monica Wood
Chemistry of Lithium and Route of Access
Name: Lithium
Group number: 1
Symbol: Li
Group name: Alkali metal
Atomic weight: [6.941 (2)] g m r
Period number: 2
CAS Registry ID: 7439-93-2
Block: s-block
Standard state: solid at 293 K
Color: silvery white/gray
Classification: Metallic
Lithium is a Group 1 (IA) element containing just a single
valence electron (1s22s1). Group 1 elements are called "alkali
metals". Lithium is a solid only about half as dense as water. A
freshly cut chunk of lithium is silvery, but tarnishes in a
minute or so in air to give a gray surface.
Lithium is mixed (alloyed) with aluminum and magnesium for
lightweight alloys, and is also used in batteries, some greases,
some glasses, and in medicine.
Lithium would not normally be made in the laboratory as it
is so readily available commercially. All syntheses require an
electrolytic step as it is so difficult to add an electron to
the poorly electronegative lithium ion Li+.
The ore spodumene, LiAl(SiO3)2, is the most important commercial
ore containing lithium. The a form is first converted into the
softer b form by heating to around 1100°C. This is mixed
carefully with hot sulphuric acid and extracted into water to
form lithium sulphate, Li2SO4, solution. The sulphate is washed
with sodium carbonate, Na2CO3, to form a precipitate of the
relatively insoluble lithium carbonate, Li2CO3.
Li2SO4 + Na2CO3 Na2SO4 + Li2CO3 (solid)
Reaction of lithium carbonate with HCl then provides lithium
chloride, LiCl.
Li2CO3 + 2HCl 2LiCl + CO2 +H2O
Lithium chloride has a high melting point (> 600°C) meaning that
it should be expensive to melt it in order to carry out the
electrolysis. However a mixture of LiCl (55%) and KCl (45%)
melts at about 430°C and so much less energy and so expense is
required for the electrolysis.
cathode: Li+(l) + e- Li (l)
anode: Cl-(l) 1/2Cl2 (g) + e-
(http://www.webelements.com/webelements/elements/text/Li/key.htm
l)
Soluble lithium compounds are readily absorbed through the
gastrointestinal tract but not the skin; distribution is rapid
to the liver and kidneys but slower to other organ systems
(Jaeger et al., 1985). Lithium crosses the human placenta
(ACGIH, 1991) and can also be taken up by infants through breast
milk. Lithium is not metabolized and is excreted primarily in
the urine.
Lithium is distributed rapidly to the liver and kidneys
following ingestion, but equilibrium between serum and brain,
bone and muscle is reached after 8-10 days (Jaeger et al.,
1985). Both the pituitary and thyroid glands concentrate lithium
(Ellenhorn and Barceloux, 1988). During chronic therapy, lithium
levels in the brain are equal to those in the serum (Schou,
1976). In overdose patients, the lithium concentration in brain
tissue may remain high even after blood serum levels are reduced
(Jaeger et al., 1985). Lithium can be present in breast milk at
30-100% of the concentration in the mother's serum (Arena,
1986).Lithium is not bound to plasma proteins and does not
undergo hepatic metabolism (Jaeger et al., 1985; Ellenhorn and
Barceloux, 1988).
The gastrointestinal diffusion system (GDS), containing
lithium acetate, releases the drug by a controlled source of
diffusion energy. The unit can possibly be used for all soluble
drugs in which solubility is independent from the pH of the
gastrointestinal contents. The one-compartment unit is obtained
by tabletting the drug and coating the tablets with a membrane
of cellulose acetate to which soluble porofores-gum arabic,
sodium chloride, 1-are added. When the pore-creating substance
is dissolved out of the coating, there remains a porous film,
which controls the rate of release of the drug. The release
characteristics depend on membrane composition and mass.
(http://risk.lsd.ornl.gov/tox/profiles/lith.shtml)
When the lithium enters the stomach and gut, lithium ions
separate from their anionic partners and rapidly enter the
bloodstream (Gatozzi, 1970). Once in the bloodstream, it is
distributed to all parts of the body and they pass with facility
from blood into various tissues. Lithium does not bind to
protein carriers of any sort, but it is freely transported with
blood cells by the blood plasma (Gatozzi, 1970). In rats and
humans, the passage of lithium from blood occurs at a different
rate for different tissues, moving quickly into kidney, more
slowly into liver, bone, and muscle, and most slowly into brain
(Gatozzi, 1970). Eventually, an equilibrium establishes between
the blood and tissues. However the ion is not evenly distributed
inside and outside cells (Beck, 1995). According to animal
studies, there are varying tissue-plasma ratio at equilibrium
(Beck, 1995). Cerebrospinal fluid and liver contain half the
amount present in plasma; brain and plasma show the same amount;
muscle, kidney, and bone, show twice as much as plasma; and
thyroid gland contains three to four times the amount present in
plasma (Beck, 1995). These are only approximate ratios because
in reality the tissue-plasma ratio is dynamic as plasma level
constantly changes as it rises and falls (Beck, 1995).
It is the kidney that mainly excretes the lithium ion via
urine. The lithium ion travels through the glomerular membrane,
where it is filtered and excreted in urine. Only fifth of the
ion is excreted and four fifths is reabsorbed in the tubules
(Gatozzi, 1970). This excretion factor is constant per unit
time. For the removal of half the lithium, it takes
approximately 24 hours for average adults, 30 to 36 hours for
elderly people, and little less than 18 hours for youngsters
(Gatozzi, 1970). Since, variability of lithium excretion exists
among individuals, doctors must determine the patient's lithium
clearance, so it may serve as a guide to proper dosage.
Researchers reported that renal lithium clearance range from 15
to 30 milliliters per minute and 10 to 15 milliliters per minute
for the normal adult and elderly people on an ordinary diet,
respectively (Gatozzi, 1970). Before lithium is consistently
given to a patient, the clinician must first ascertain that
there is an adequate amount of clearance for doses given, in
order to avoid lithium accumulation and toxicity in the blood.
(http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_422.
html)
References
Barlow, David H. and Durand, Mark V. (2003). Essentials of
Abnormal Psychology. California: Wadsworth.
Feldman, Robert S. (2005). Essentials of Understanding
Psychology. New York: McGraw-Hill Co.
Freyhan, Fritz A. and Zubin, Joseph. (Eds.) (1972). Disorders of
Mood. Baltimore: The Johns Hopkins Press.
Goldstein, Michael J. and Miklowitz, David J. (1997). Bipolar
Disorder: A Family-Focused Treatment Approach. New York: The
Guilford Press.
Johnson, Sheri L. and Leahy, Robert L. (Eds.) (2004). Psychology
Treatment of Bipolar Disorder. New York: The Guilford Press.
Kalat, James W. (2004). Biological Psychology. Canada:
Wadsworth.
Knable, Michael B. and Torrey E. Fuller. (2002). Surviving Manic
Depression. New York: Basic Books.
Leavitt, Fred. (1995). Drugs and Behavior. California: Sage
Publications.
Lithium's Effects on Bipolar Disease. Retrieved: March 5, 2005.
From:
http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_422.h
tml
Opresko, Dennis M. (May 1995). Toxicity Summary for Lithium.
Retrieved: March 3, 2005. From:
http://risk.lsd.ornl.gov/tox/profiles/lith.shtml.
Winter, Mark (1993-2003). Chemistry: WebElements Periodic Table:
Professional Edition: Lithium: Key Information. Retrieved:
February 28, 2005. From:
http://www.webelements.com/webelements/elements/text/Li/key.html
.
PJ Hall
Part of the Neuron Affected
Bipolar disorder is a type of manic depression classified
by those affected having extreme polar opposite emotions. Those
who suffer from bipolar disorder, go from extreme highs (mania)
to very lows, (depression). Because this illness deals with such
drastic changes in behavior, it is essential that those who
suffer take medical action in treatment of their disorder,
unlike other depressions that may be treated with therapy only.
Medical treatment with the use of drugs is so important when
treating those who suffer from bipolar disorder, because its
causes can be predicted to begin at the neuron level. One of
these treatments, as discussed throughout this paper, is Lithium
in its common for, Lithium Carbonate.
Lithium is thought to affect the way the way the synaptic
transmitters carry information across the neurons in the body.
Although it is unknown how exactly this process works,
researches believe that the synapse is the location of the
neuron that is affected by lithium use. The synapse of a cell
can be defined as a point of communication at the gap between
two neurons or between a neuron and a muscle, (Kalant, 2004).
Because the synapse deals with communication, the synapse is an
extremely busy and complicated part of the neuron.
Due to the belief that Lithium is impacts a cell primarily
at the synapse, it also affects the cell at the axon of the pre-
synaptic cell, and the dendrites of the post-synaptic cell. An
axon is the part of the cell that conducts information away from
the cell body, and eventually across the synapse, where the
branch like fibers of the post-synaptic dendrites receives the
information.
The figure provided below illustrates the sites of action
in the synapse of mood altering drugs, such as lithium.
Synaptic Transmitters Involved
Exact Process Unknown:
As illustrated above, lithium involves the synapse of
particular cells. The process of transmitting information from
one cell to the next that occurs at the synapse is largely do to
the various synaptic transmitters throughout the body. Although
lithium as been used for thirty or more years, research on
lithium as a treatment for bipolar patients brings more
questions than answers. One approach researchers have taken to
better understand this unclear process is to examine the causes
in general of bipolar disorder. Theories range from focusing on
genetic factors, to environmental factors, to the way
biochemistry imbalances shape a person's mood.
Bipolar disorder is a manic-depressive illness, and is the
most recognizable and dramatic of the depressive disorders.
People with bipolar disorder are different from those who suffer
from other depressive disorders, because of the swing from the
extreme lows, the depressive state, to the extreme highs, the
manic state. The theories that provide the most insight into the
causes of bipolar disorder from a biological perspective are the
theories the focus on the biochemistry of the disorder because
the research involved in these theories suggest that
neurotransmitters, chemicals that allow information to be passed
from cell to cell, become imbalanced at various phases of the
disorder. (American Psychiatric Association, 1992.) Some of this
research suggests that lithium impacts the re-uptake of the
messages held in the various chemicals that transmit information
from cell to cell. (MedicineNet, 2005). Essentially, lithium
brings the various transmitters in the brain into balance, which
scientists think may shape the impact the transmitters have on
the brain, and therefore alter moods, (American Psychiatric
Association, 1992).
Anime Hypothesis:
The large amount of uncertainty regarding the transmitters
in the brain and the use of lithium as a treatment for bipolar
disorder mediates a use of a variety of hypothesis to examine
how exactly lithium is effective as a treatment for bipolar
disorder. One of the major hypotheses is The Anime Hypotheses,
which includes the Catecholamine Hypothesis, and a discussion of
norepinephrine and dopamine, as well as the permissive
hypothesis of serotonin. In general, the anime hypothesis uses a
biological perspective when examining manic-depressive illness,
and looks at each anime transmitter system separately.
Initially, the anime hypothesis came from researchers observing
the change in central anime functioning in animals caused by the
clinical effects of particular drugs. (Faldman et al, 1997).
Serotonin:
One of these transmitters is Serotonin. Serotonin is an
organic compound that was first found in the blood. In 1948, it
was partially purified, crystallized, and named. (Columbia
Encyclopedia, 2005). Later research on serotonin found that
serotonin is widely found throughout nature, and found in other
parts of the body besides the blood. It has also been found in
wasp stings, as well as scorpion venom, and in a variety of
foods such as pineapple, bananas plums, nuts, turkey, ham, milk
and cheese. In addition, serotonin has been predicted to found
in the human intestine, blood platelet, and brain, in levels of
approximately five to ten milligrams. (Colombia Encyclopedia,
2005)
One role serotonin plays in the body is as a transmitter of
in the brain. This role of serotonin deals with the functions of
sleep, learning, and the control of moods(Colombia Encyclopedia,
2005). The controlling of moods factor of serotonin is primarily
how it is connected to bipolar or manic depressive disorders.
Lack of serotonin in the body may result in an individual
suffering from a lack of rational emotion, feelings of
irritability, sudden unexplained tears, and sleep problems.
Furthermore, in terms of psychological well being, the product
of serotonin is overall emotional stability.
Lithium has been connected to the neural release of
serotonin from terminals, and some studies have found serotonin
to promote some actions of the serotonin brain function, which
is especially essential in its role as an anti-depressant
(Khoury et. al, 2001). For example, taking lithium as a
treatment for depression over a long period of time has been
shown to increase serotonin release and decrease serotonin
receptor in the hippocampus (Shastry, 2004). According to
Serretti and colleagues in the Department of Neuropsychiatric
Sciences at the University of Milan School of Medicine in Italy,
"Disturbances of the serotoninergic neurotransmitter system have
been implicated in the pathogenesis of mood disorders and
serotonin has also been repeatedly implicated as the mechanism
of action of lithium, (2000). In addition, lithium enhances the
uptake serotonin into the synaptosomes, thus reducing their
actions. Close behind serotonin is norepinephrine.
Norepinephrine:
Norepinephrine is a transmitter found in the catecholamine
family, and is thought it mediate chemical communication in the
sympathetic nervous system, a branch of the autonomic nervous
system (Colombia Encyclopedia, 2005). Norepinephrine can be
found in foods such as lean beef, shellfish, fowl, and soy
products. The function of norepinephrine in the body is in the
areas of arousal, energy, and drive, and when absent or
deficient, can be associated with lack of ambition, drive, and
major depression.
Similarly to the effect of lithium on serotonin, lithium
promotes the uptake of norepinephrine into the synaptosomes,
reducing its action. Furthermore, lithium reduces the release of
norepinephrine from synaptic vesicles and inhabits production of
cyclic AMP. (Long, 2005). Lithium blocks the cyclic AMP
excitation produced by adrenergic agonists, beyond the receptor,
which interacts with the second massager system of the cell
(Goodwin & Jamison, 1990). Clearly, research available
regarding norepinephrine and lithium use as treatment for
bipolar disorder is minimal. However, less research is available
regarding Dopamine.
Dopamine:
In addition to norepinephrine, dopamine is another
transmitter in the catecholamine family. Dopamine is an
"intermediate in the synthesis of epinephrine",(Colombia
Encyclopedia, 2005). Dopamine is associated with pleasure,
reward, and good feelings towards others, and like
norepinephrine can be found in products such as lean beef,
shellfish, fowl, and soy products. A lack or deficiency in
dopamine may result in anhedonia, which essentially is living in
a world with out pleasure, with the inability to feel remorse
about personal behavior. Researchers Depue and Iacono (1989)
found that "anatomical evidence supports a serotonin input onto
dopamine containing neurons..."(Faldman et. al, 1997).
Conclusion:
Although much research has been done on lithium, the
process in which it affects the synaptic transmitters is still
for the most part unknown. Scientist today continues to vary in
their opinions and argue over the particular transmitters
involved in lithium use as treatment in patients with bipolar
disorder. While must is uncertain, a majority of research done
on lithium in regards to treatment for bipolar disorder, suggest
that serotonin, norepinephrine, and dopamine are among the top
transmitters influenced by the use of lithium.
Reference
American Psychiatric Association. (1992) Manic Depression,
Bipolar Disorder Over View.
Columbia Encyclopedia, Sixth Ed. (2005)
Feldman, R.S., Meyer, J.S., Quenzer, L.F., (1997). Principals of
Neuropsychopharmocology. Summerland MA: Sinaver Assoc. Inc
Goodwin, F.K., & Jamison, K.R. (1990). Manic Depressive Illness.
New York: Oxford.
Kalat, James W. (2004). Biological Psychology. Canada:
Wadsworth.
Khoury, Aram El, et al. (2001) Effects of Long Term Lithium
Treatment on Monoaminergic functions in major depression.
Psychiatry Research, 105, 33-44.
Lithium-Drug Class, Medical Uses, Medication Side Effects, and
Drug Interactions. (1998). Retrieved March 6, 2005 from
http://www.medicinenet.com
Long, Phillip W. (2005) Pharmacology in Lithium Carbonate.
Retrived March 6, 2005 from http://mentalhealth .com/drug/p30-
102.html
Schimelpfening, Nancy. The Chemistry of depression. Retrieved
February 28, 2005 from
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Serretti, A. Et al. (2000). Serotonin Receptor 2A, 2C, 1A genes
and response to lithium prophylaxis in mood disorders. Journal
of Psychiatric Research, 35, 89-98.
Shastry, Barkur s. (2005) Bipolar Disorder: an update.
Neurochemistry International, 46, 273-279.
James Eubanks
Inhibitory and Excitatory Potential Changes
The excitatory postsynaptic potential (EPSP) is the graded
depolarization of a neuron. The EPSP is the result of sodium
ions entering the cell. While the inhibitory postsynaptic
potential (IPSP) is a temporary hyper-polarization of a
membrane. An IPSP occurs when synaptic input selectively opens
the gates for potassium ions to leave the cell (carrying a
positive charge with them) or for chloride ions to enter the
cell (carrying a negative charge) (Kalat, 2003). Lithium has two
known effects on the nervous system:
1. Lithium can mimic the role of sodium in the generation of
action potentials by neurons; however it is not pumped out
(by the Na/K/ATPase) and therefore tends to accumulate
inside excitable cells, leading to depolarization.
2. Lithium blocks inositol-1-phosphatase, an enzyme in the
IP3 second messenger system for many neurons (Ikonomov,
Manji, 1999).
A messenger influenced by lithium is adenylyl cyclase (AC),
which catalyses the formation of cyclic adenosine monophosphate
(cAMP) from adenosine triphosphate (ATP) (Lenox et al. 1998). It
is reported that lithium inhibits the accumulation of cAMP by
various neurotransmitters at high therapeutic concentrations in
vivo and at higher concentration in vitro by AC (adenylate
cyclases) inhibition (Lenox et al. 1998). The sensitivity of
this second messenger system is lower than the phosphoinositide
system, and the sensitivity of AC inhibition by lithium in
different neurotransmitter systems varies, some are not affected
at therapeutically concentrations (Lenox et al. 1998). It is
generally thought that the inhibition of the AC causes two of
lithium's common side effects, namely nephrogenic diabetes
insipidus and hypothyroidism. It has not been shown that the
effects on AC have therapeutic properties. However, how these
two physiological effects of lithium are related to clinical
efficacy is not clear (Lenox et al. 1998). Lithium prevents the
swings of mood, and thus reduces both mania and depression in
bipolar disorder. A clinically effective dose has a narrow
therapeutic index: high doses of lithium are toxic; acute
lithium toxicity progresses from confusion and motor impairment
to convulsions, coma, and death (Ikonomov, Manji, 1999).
Norepinephrine is thought to play a role in bipolar
disorder. In experimental tests, levels of norepinephrine in
patients with affective disorders were higher than patients
without disorders (Leszczynska-Rodziewicz, 2002; Lake, 1982).
It's been shown in recent studies that manic patients had the
highest norepinephrine levels. Also, some research has shown
that in red blood cells, the ratio of intracellur to
extracellular lithium ion (Li+) is higher in bipolar patients
than in normal controls when both have been administered lithium
(Meyer, 2005).
Lithium is a common drug prescribed to bipolar patients. It
is believed that lithium works by interfering with the release
of norepinephrine, and increasing the re-uptake of
norepinephrine by the presynaptic neuron (Ebadi, 2002). Some
scientists have found that lithium has a large range of targets,
not just norepinephrine, and hinders a wide range of cell
processes (Harwood, 2003). It is still uncertain to say what the
actual mechanism of action of lithium is. As a result, there is
a demand to create new mood stabilizing drugs, especially for
bipolar disorder. Manic-depressive treatments vary, but some
are mainly just variations of the somewhat successful use of
lithium; Eskalith®, Lithobid®, Lithonate®, Lithotabs®. Although
lithium has been used for over three decades in the U.S., newer
drugs are proving more beneficial in manic-depressive
treatments.
Ions Channels Affected
There is evidence that lithium alters sodium transport and
may interfere with ion exchange mechanisms and nerve conduction
(Long, 2005). Some research has suggested that lithium can
replace sodium in extra cellular fluid, and during the process
of depolarization create extreme, rapid intracellular influx.
However, it's not efficiently removed by the sodium pump,
thereby preventing the cellular re-entry of potassium (Long,
2005). Other research has indicated that lithium's effects on
the phosphoinositide (PI) cycle have generated a great deal of
excitement: because the phospholipids 2nd messenger is coupled to
both excitatory and inhibitory neurotransmitter receptor,
lithium can have both an antimanic and or an antidepressant
effect (Feldman, 1997).
Lithium ions are rapidly absorbed from the gastrointestinal
tract and plasma lithium peaks are attained at 2-4 hours after
administration. The distribution of lithium in the body is
similar to body water, but its means of access across the blood-
brain barrier is slow (Long, 2005).
Physiological (whole body) Changes
It has been estimated that at least one-third of patients
on lithium gain weight for a variety of reasons, such as altered
lipid and carbohydrate metabolism, use of high-calorie fluids to
combat polydipsia and polyuria, hypothyroidism, and the use of
other drugs associated with weight gain (Jefferson, 2002). Acne
and psoriasis appear and may worsen during lithium therapy. It's
unclear why hair loss during lithium therapy happens, but some
say it's related to hypothyroidism.
Lithium, in its physiologically active form, is a
monovalent cation which also belongs to the same group of alkali
metals as sodium, potassium, rubidium, cesium, and francium.
Being highly reactive, lithium is administered as a carbon salt.
Dosage should always be monitored by a registered physician or
better, a psychiatrist. Any variation of the amount of lithium
taken can be dangerous. The toxicity of lithium is close to its
therapeutic relevant serum concentration, which lies at 0.6-1.2
mmol/L (Manji et al. 1995). Antidepressants are usually used to
treat unipolar depression, in which the mood swings are always
in the same direction (depression). There is a second category
of mood disorder, bipolar disorder, in which the mood swings
between depression and mania over a period of a few weeks
(occurs in 10-15% of all depressions); this condition is usually
treated with the mood stabilizer lithium (Sanders, 2005).
Lithium does have its fair share of side effects. It has
serious side effects, such as tremors, ataxia (Loss of
coordination by an animal with neurological damage),
epileptiform seizures, slurred speech, dizziness,
hallucinations, poor memory, slowed intellectual functioning,
cardiac arrhythmia, hypotension, anorexia, nausea, vomiting,
diarrhea, gastritis and many more (Manji et al.1999). None the
less, it is still a contending choice for the treatment of
bipolar disorder. However, alternatives to lithium for treatment
of bipolar disorder are growing and include antipsychotic drugs
that are equally effective in treating acute mania; they act
more quickly and are considered safer. The depressive phase of
bipolar disorder can also be managed with antidepressants. As
for the moment, certain antiepileptic drugs are under
investigation: carbamazepine and valproate (Manji et al.1999).
These drugs may prove beneficial as treatment for manic
depression and bipolar affective disorder.
Lithium has acute affects in manic episodes, but also
prophylactic or chronic effects and prevents the manic and
depressive episodes from breaking out (Manji et al.1999). Since
the effects are so severe, the patients usually have to take the
Lithium constantly for the rest of their life. Once the
supervision is stopped, the patient will fall back into the
cycles of mania and depression within several days, usually
starting with a manic episode. Adjustment of the dosage can
reduce the side effects dramatically; therefore it is important
to find the threshold concentration of physiological activity
(Jamieson, 1995).
References
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Press.Pp.469, 669-70. 2002.
Feldman, Robert S, Meyer, Jerrold S, Quenzer, Linda F.
Principles of Neuropsychopharmacology. Sinaver Associates
Inc. Sunderland, MA. 1997.
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stabilizers. Biochem Pharm 66: 179-189. 2003.
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Molecular Mechanisms Underlying Mood Stabilization in
Manic-Depressive Illness: The Phenotype Challenge. American
Journal of Psychiatry 156:1506-1514, October 1999.
Jamieson, K. An Unquiet Mind. First Vintage Books. 1995.
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therapy. Vol. 1, No. 12. December 2002.
http://www.currentpsychiatry.com/2002_12/1202_lithium.asp.
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Leszczynska-Rodziewicz A, Czerski PM, Kapelski P, Godlewski S,
Dmitrzak-Weglarz M, Rybakowski JK, Hauser J. A Polymorphism
of the Norepinephrine Transporter Gene in Bipolar Disorder
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Implications. Journal of Clinical Psychiatry: 60 (suppl2):
27-38, 1999.
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http://www.bio.davidson.edu/people/vecase/SeniorColloquium/
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2005.
Yasaman Abbasov
The Efficacy of Lithium in Treating Bipolar Disorder
Lithium is a psychotropic drug that became available in
1970 as a mood stabilizing medication for the long-term
treatment of bipolar disorder. It has been shown to reduce the
frequency and severity of manic states, as well as the
depression that is concomitant with bipolar disorder. Much
research has been done in the short duration of lithium's
employment to evaluate its efficacy and side effects.
As stated above, "Lithium stabilizes the mood of a bipolar
patient, preventing a relapse into either mania or depression"
(Kalat, 2004, p.472). Bipolar disorder (also known as manic-
depressive illness), is characterized by the presence of the
following symptoms: motor hyperactivity, flight of ideas,
elation, a diminished need for sleep, grandiosity, poor
judgment, aggressiveness, and possible hostility (FDA, 2005,
4). Manic-depressives are recognized by their constant mood
swings, wherein they may be overly euphoric, subsequently
becoming rapidly irritable, sad, or hopeless. A person is
experiencing a depressive episode if five or more of the
following symptoms are experienced for most of the day, every
day, for at least two weeks: difficulty concentrating, loss of
interest in sex or formerly enjoyed activities, a lasting empty
mood, decreased energy, difficulty making decisions, chronic
pain that is not caused by physical injury, and recurring
thoughts of death or suicide (MedicineNet, 2005, 3). A manic
episode is diagnosed if a person displays three or more the
following symptoms for most of the day, every day, for one week
or more: increased energy and restlessness, extreme
irritability, distractibility, unrealistic beliefs in one's
abilities, denial that anything is wrong, spending sprees using
poor judgment, increased sexual drive, and abuse of drugs,
alcohol, or sleeping medications (MedicineNet, 2005, 2). Prior
to pursuing treatment for these symptoms however, the type of
bipolar disorder a person has should be clarified. People who
have a history of manic episodes are diagnosed as bipolar I
depressives, while bipolar II depression is characterized by a
history of hypomania, which can go undetected. The main
difference between hypomania and mania is that the former
induces rapid thoughts which lead to feelings of euphoric
elation and omnipotence, whereas rapid thoughts in the latter
induce feelings of anger, fear, confusion, and
uncontrollability. It is important to remember that people
suffering from bipolar disorder often have periods of normal
behavior in between their mania and depression. It is the
abnormal behaviors that lithium aims to modify, and several
primary behavior changes occur once a patient is on lithium
treatment.
To begin, the Food and Drug Administration warns that
lithium is harmful to the offspring of pregnant and nursing
mothers (2005, 5). The FDA further warns that, "the ability to
tolerate lithium is greater during the acute manic phase and
decreases when symptoms subside" (2005, 8). Therefore, in
order to avoid neurotoxicity from lithium which can lead to
fatality, patients must consult a physician regularly to be sure
they are not consuming excessive doses. Lithium appears to be
the most effective medication to date in changing primary
behaviors. However, those with bipolar I disorder, characterized
by depression and forceful manic phases, are most notably
assisted by lithium treatments (Kalat, 2004, p.473). Within days
of their first dosage, bipolar I patients will display antimanic
effects rendering them, "…more settled, tidier, less
disinhibited, and less distractible" (Kusumakar, 2002, p.142).
Furthermore, multiple research studies have indicated that
lithium is more effective than antipsychotic drugs in managing
manic patients. One double-blind study done in 1970 by Platman,
monitored 23 manic patients, administering either lithium or
chlorpromazine treatment to them. After three weeks of
treatment, it was shown that lithium was more effective than
chlorpromazine for typical manic symptoms such as, "…motor
hyperactivity, flight of ideas, euphoria, expansiveness, and
pressured speech"(Kusumakar, 2002, p.145). Lithium also relieves
depressive symptoms, though not as dramatically as manic
symptoms. This is exemplified in a 1971 study done by Stokes,
where 11 patients with depression were treated with lithium,
while 15 patients with depression took a placebo. The results
showed that, "Fifty-nine percent of the lithium treated episodes
improved as compared to 48% of the placebo treated episodes"
(Kusumakar, 2002, p.148). As the percentages are so close, we
can see that this study did not give overwhelming evidence that
lithium alone can effectively relieve depression. Mixed patients
in other studies, meaning those with dysphoric manic episodes or
rapid cycling manic episodes, were shown to have a generally
poor response to lithium treatments, but found that
anticonvulsant mood stabilizers were extremely effective for
their symptoms (Kusumakar, 2002). Going further in describing
the disparate efficacy of lithium treatment in different types
of bipolar disorder, it has been shown that, "Patients with
typical manic episodes generally respond rapidly, within 1-3
weeks" whereas improvement in patients in the depressed phase,
"…may not occur until the third or fourth week of treatment"
(Basco & Rush, 1996, p.47). In summary, patients who are in need
of medication primarily for bipolar depression, rather than
mania, typically have to supplement lithium with an
antidepressant or another mood stabilizer.
Despite the miraculous relief that lithium offers from
manic-depressive episodes, there are side effects to be
considered. Some adverse reactions listed by the FDA during
initial use of lithium are: a fine hand tremor, mild nausea, and
mild thirst (FDA, 2005, 12). These side effects typically
disappear once a person is using lithium regularly.
Additionally, most side effects subside entirely if treatment is
discontinued. Other common side effects in lithium patients
include: "tremor, diarrhea, drowsiness, and blurred vision"
(Burrows & Werry, 1987, p.36). There is a question as to whether
or not long-term lithium use can cause damage to the
microanatomy of the kidney, about which research is currently
being done (Burrows & Werry, 1987, p.37). If lithium poisoning,
as discussed above, occurs in a patient, miscellaneous side
effects such as leukocytosis, skin rashes, and reversible
nephrogenic diabetes insipidus can occur (Burrows & Werry, 1987,
p.37) It should be noted that although lithium is the primary
therapeutic agent in treating bipolar disorder, between 20% and
30% of patients are unable to tolerate its toxic side effects
and find that their bodies are rebellious to the positive
effects of the drug (Ellison (Ed.), 1989, p.133). A more recent
estimate reports that 30% to 40% of patients with bipolar
disorder either do not respond significantly to lithium
treatment or are simply unable to tolerate it (Prien & Robinson
(Eds.), 1994, p.328). Some popular alternatives to lithium are
carbamazepine and valproate which are sold under a variety of
brand names. Both, "…share lithium's mood-regulating effects but
present a different spectrum of adverse effects which may be
more acceptable to individual patients" (Ellison (Ed.), 1989,
p.133). More research needs to be done regarding carbamazepine
and valproate alternatives to determine if they are superior to
lithium treatments, however they are currently being utilized in
treating bipolar disorder.
Lithium can be used as monotherapy, or in combination with
other medications. Some popular brand names of lithium are:
Carbolith, Duralith, Eskalith, Lithobid, Priadel, and Quilonum
(RemedyFind, 2005). This is just a fragment of the plethora of
lithium variations that a patient can receive, and all induce
similar side effects. One user of lithium carbonate, taking
300mg. capsules twice daily for several years described it as,
"An excellent mood stabilizer. If I was doing things differently
I'd have used more of this and less of the expensive things.
Might have needed fewer antidepressants. As for the side
effects, yes, I eat more. It's worth it!" (RemedyFind, 2005).
Weight gain is a common downside to lithium treatments. One
Eskalith user said, "I have been maintained on lithium for 20
years. This is the best stabilizer, in my opinion for bipolar,
you do gain weight, so you have to watch what you eat and
exercise. I have experienced thyroid problems recently and was
put on a thyroid suppressant" (RemedyFind, 2005). Yet another
patient, who was taking 600mg. of Lithobid twice daily for
several years stopped after experiencing some scary results,
"Seemed to be working though I was still cycling a little. I had
problems with my memory while on it. Had to stop because I was
hospitalized for lithium poisoning. The result of the poisoning
was becoming very ill and once recovered, my hair started
falling out" (RemedyFind, 2005). Memory and hair loss while
taking lithium is commonly described. A meta-analysis done in
the Netherlands regarding the cognitive side-effects of lithium
treatment reported that, "lithium had a negative effect on
memory and speed of information processing, often without
subjective complaints or awareness of mental slowness" (Honig &
Riedel, 1999, p.1). A patient taking 330mg. of Lithicarb daily
reported that, "Lithium has been very effective for me. But you
must make sure you get your levels tested regularly. I did get
lithium toxic and that was not a good experience" (RemedyFind,
2005). Experiencing lithium poisoning at least once in a
patient's lifespan, when using lithium for twenty years or more
is commonly reported. The FDA reports that no antidote for
lithium poisoning is known. However, if the symptoms are
discovered early on it can easily be treated by cessation or
reduction of dosage of the drug, followed by a resumption of the
treatment within 24 to 48 hours (FDA, 2005). Table I gives a
comprehensive set of signs to determine whether or not a person
is experiencing lithium toxicity. In some cases, more than just
lithium is needed to combat bipolar disorder. One patient
described Eskalith treatment as only being successful for him in
combination with Prozac. He said "Lithium has kept me stable for
years, with an antidepressant, mostly Prozac for seven or more
years. There are a few reasons why I want to get off lithium
though. It is because of thyroid, and kidney problems, the
constant getting up in the evening, and going to the bathroom is
difficult" (RemedyFind, 2005).
In peroration, the negative side effects that are most
commonly reported by lithium users are: weight gain, hair loss
after an episode of lithium poisoning, some memory loss, and
there can be changes to the kidney and thyroid. The positive
effects of using lithium are the continual maintenance of a
normal mood, and thus relief from the debilitating symptoms of
mania and depression.
In looking to the future of treating bipolar disorder,
researchers have identified at least one promising treatment
involving sleep regulation. This procedure regulates the
abnormally low or high amounts of sleep bipolar sufferers get
when they are either in the manic phase,(sleeping just three to
four hours a night) or the depressed phase,(going to bed late
and sleeping for abnormally long periods). Researchers have
found that making bipolar sufferers consistently sleep ten hours
a night in a dark, quiet atmosphere greatly relieves mood swings
(Kalat, 2004, p.473).
References
Basco, Monica Ramirez, & Rush, A. John. (1996). Cognitive-
Behavioral Therapy for Bipolar Disorder. New York, NY: The
Guilford Press.
Burrows, Graham D., & Werry, John S. (Eds.). (1987).
Advances in Human Psychopharmacology: Vol.4. Greenwich, CT: JAI
Press Inc.
Ellison, James M. MD, (Ed.). (1989). The Psychotherapist's
Guide to Pharmacotherapy. London: Year Book Medical Publishers,
Inc.
Food and Drug Administration electronic reference.
Retrieved March 5, 2005, from
http://www.fda.gov/cder/foi/label/2002/18027s40s46s49lbl.pdf
Honig, A., & Riedel, WJ. (1999). Lithium induced cognitive
side-effects in bipolar disorder: a qualitative analysis and
implications for daily practice. National Library of Medicine,
1-2. Retrieved March 5, 2005, from
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmb.htm
Kalat, James A. (2004). Biological Psychology (8th ed.).
Canada: Thomson Learning Incorporated.
Kusumakar, V., Kutcher, S.P., & Yatham, L.N. (Eds.).
(2002). Bipolar Disorder: A Clinician's Guide to Biological
Treatments. Great Britain: Brunner-Routledge.
MedicineNet electronic reference. Retrieved March 5, 2005,
from http://www.medicinenet.com/bipolar_disorder/page2.htm
Prien, R.F., Ph.D., & Robinson, D.S., M.D. (Eds.). (1994).
Clinical Evaluation of Psychotropic Drugs: Principles and
Guidelines. New York, NY: Raven Press.
RemedyFind electronic reference. Retrieved March 5, 2005,
from http://www.remedyfind.com/rem.asp?id=931
Table I
Signs of Lithium Toxicity
Mild Moderate Severe
Mild apathy,
lethargy Increased Lethargy Somnolence
Weakness Confusion, drowsiness Gross confusion
Unsteady balance Gross ataxia Profound loss of
balance
Nausea Vomiting Urinary incontinence
Decreased Slurred speech Random muscle twitching
concentration
Worsening hand Muscle twitching Coma
tremor
Diarrhea
Note. From Cognitive-Behavioral Therapy for Bipolar Disorder
(p.48), by Monica Ramirez Basco and A. John Rush,
1996, New York, NY: The Guilford Press.
Conclusion
At this point in time, it is not known exactly how lithium
alleviates the symptomatology of bipolar disorder, only that it
is highly effective and will be continue to be one of the
primary treatments in alleviating bipolar disorder until new
remedies are discovered.
Go back to the beginning
Copyright © 2005, Dr. John M. Morgan, All rights
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This page last edited 1-3, 2005
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