BIOLOGICAL BASIS OF BEHAVIOR

Psychology 321                     	                   
Spring, 2005					HGH 225
Dr. John M. Morgan                 	MWF, 8am to 9:00                                                   



Hanna Clement 
Martin Overstreet 
Roslyn McCoy
Nicole Musone
Psych 321 
March 7, 2005 
 
                   Prozac: Fluoxetine
				
       By Hanna Clement

Introduction 
 
     Many people, both those who have experienced the illness 
and families and friends that have helped loved ones cope 
with it, are familiar with the far reaching effects of 
depression. Depression is one of the most common medical 
conditions in United States and around the world. At some 
point in their lives one in four, approx 18 million, 
Americans will experience some episode of depression. For 
people struggling with depression there is help available. 
Antidepressant medications and other treatments can often 
make an astonishing difference in depressive symptoms within 
a few weeks. With the right treatment eight out of ten people 
improve. Before the 20th century, most people experiencing 
depression went without diagnosis and treatment. Early, crude 
forms of sedatives were given to people with severe 
agitation, anxiety or psychotic depression. Like many other 
aspects of science there has been an evolutionary growth of 
the quality and range of availability of help for illnesses 
like this. The involvement and evolution of anti-depressant 
drugs is an important role in the fight against depression. 
In the 1950s the fist generation of anti depressants was  
discovered. It was not until the 1980s that a newer class of 
antidepressants revolutionized the treatment of depression. 
Selective serotonin reuptake inhibitors (SSRIs) were the 
first of these medications to be available in the United 
States. Fluoxetine (Prozac) was the first of its kind.  
(Kramlinger, 2001) 
     Fluoxetine first appeared in scientific literature as 
Lilly 110410 (the hydrochloride form), a selective serotonin 
uptake inhibitor, in August 15, 1974 issue of, Life Sciences 
(Wong,). On December 29, 1987, the Food and Drug 
Administration approved and introduced Prozac. Since this 
approval, Prozac has become the most prescribed 
antidepressant in the world. After twenty plus years of 
extensive investigations, inhibition of serotonin  
uptake remains the major mechanism of action for fluoxetine 
serotonergic neurotransmission in the central nervous system. 
     Some of the steps in the historical basis of 
antidepressants were the evidence that depression is the 
result of a functional inefficiency  
in the monoamine neurotransmitter system. In the 1950s it was 
found that reserpine, an agent used in the treatment for 
hypertension, precipitated a depressive-like syndrome. 
Subsequent work showed that reserpine depleted the  
storage of serotonin and norepinephrine by causing these 
substances to leak out their presynaptic storage vesicles, 
this allowed them to be degraded by the enzyme monoamine 
oxidase (Blais, 1997). Iproniazid was found to be a  
mood enhancer for tuberculosis patients and an inhibitor of 
monoamine oxidase. Then in the early 1960’s, tricyclic 
antidepressant agents were found to inhibit the reuptake of 
monoamine to the synapse, increasing the longevity of these 
transmitters in the synapse and increasing neurotransmission. 
In 1965, Joe Schildkraut created the catecholamine  
hypothesis of affective disorders; this stated that 
depression is caused by a deficiency in the availability of 
catecholamine. Some examples of catecholamine are dopamine, 
norepinephrine and epinephrine. Shortly after, the theory was 
extended to include serotonin (Blais, 527).

Specific Chemical Mechanisms

Serotonin is the most prominent neurotransmitter substance 
inthe study of depression. Serotonin (5-hydroxytryptamine or 
5HT) is a brain monoamine (anindoleamine) that is synthesized 
from tryptophan, creating 5hydroxytryptophan, and stored in 
reserpine-sensitive granules in the nerve terminal. Then it 
is catalyzed by another enzyme, 5-HT decarboxylase, creates 
serotonin. (See Figure 1, Wong) 




When serotonin remains inside the vesicle until it is 
electrically charged impulses eventually create an action 
potential. The action potential causes calcium channels to 
open, the over abundance of calcium causes the vesicles to 
burst into the gap/cleft.  
After being released into the synaptic cleft, serotonin is 
inactivated by means of reuptake into the presynaptic neuron. 
Then it is either restored into vesicles or broken down into 
its main metabolite by monoamine oxidase. Antidepressants are 
classified according to chemical structures and 
pharmacological properties of the parent compound (Sanchez, 
1999). Fluoxetine's parent compound is (+/-)-3-[(4-
trifluoromethyl) phenoxy]-n-methyl-3-phenyl-1-propanamine.Its 
main metabolite is Norfluoxetine ;(+/-)-3-[(4- 
trifluoromethyl) phenoxyl]-3-phenyl-1-propanamine, none.(See 
Figure 2,Wong)  





Serotonergic neurons are somewhat centralized in the raphe 
nuclei in the brain stem, with widespread terminal 
projections throughout the cerebral cortex,thalamus, 
cerebellum and spinal cord (Vazquez, 2002). Serotonin is felt 
to be involved in a variety of physiological, behavioral and 
physiological events. There are least fourteen separate 5-HT 
receptors divided into seven main families. The seven 
serotonin receptors that are located presyaptically are:5-
HT(1a,b,c,d,f), 5-HT (2c), 5-HT(3), 5-HT(7). Alterations in 
these receptors occur in a variety of disturbances. In 
general, the selected antidepressants and their metabolites 
have low affinities (in the micro molar concentration range) 
for 5-HT (1a) receptors, whereas the affinities for 5-HT (2a) 
and 5-HT (2c) receptors vary from compound to compound. The 
adaptive desensitization of somatodendritic 5-HT (1a) auto 
receptors in the dorsal raphe nucleus is suggested to play an 
important role in the time lag between actually induced 
facilitation of serotonergic neurotransmission after 
flouxetine is ingested. It has been hypothesized that the 
antidepressant effect can be accelerated by blockade of 5-HT 
(1a) (Sanchez, 1999). 
     Fluoxetine is an orally administered psychotropic 
medication. It is absorbed through the small bowel, it enters 
portal circulation (undergoing presynaptic metabolism by the 
liver, known as the first pass effect), and then enter 
systematic, ultimately traveling through the blood brain 
barrier to access the central nervous system. Fluoxetine in 
capsule form contains intestinal P-glycoprotein P (PGP), is a 
carrier protein that medicates absorption. It may allow for a 
prolonged period of absorption, potentially resulting in 
increased plasma levels. Food also will interact with the  
consumption of the drug in a positive or negative way. Food 
may affect absorption by binding to the drug (forming 
insoluble complexes), slowing or speeding up the gastric 
emptying, or modifying the PH of the gastrointestinal tract. 
Drugs such as fluoxetine are distributed through out  
the body in receptor and organ sites through systematic 
circulation. The extent of a drugs distribution is determined 
by various factors, such as regional blood flow, drugs 
lipophilicity or the degree in which a drug is lipid soluble 
and the extent that it binds to plasma proteins, such as  
albumin, alpha(1), glycoprotein and lipoproteins. Most 
psychotropic drugs (except for lithium) bind to plasma 
proteins in varying degrees. To be considered highly protein 
bound more than 90% of the drug has to bind to protein. The 
degree of the protein binding is an important kinetic  
consideration because only the unbound potion of the drug is 
available to interact with at target receptor sites. A small 
change in the ratio of bound to unbound binding can increase 
or decrease drug affectability. Flouxetine is highly protein 
bound; it exhibits greater than 95% protein binding(Blais, 
1997). Fluoxetine is also a racemic mixture (50/50) of R-
fluoxetine and S-fluoxetine enantiomers. The S-fluox. 
Enantiomer is eliminated more slowly and in the predominant 
enaniomer present in plasma in a steady rate. Also like other 
selective serotonin inhibitors and fluoxetine inhibits the  
specific hepatic cytochrome P540 isozyme (IID6) which is 
responsible for the metabolism of debrisoquine and spartine. 
P450 is part of the CYP450 family. In this family there are 
approximately thirty known enzymes (and related enzymes) that 
are located in the endoplasmic reticulum of the hypatocytes  
(liver cells) but also expressed in the wall of the small 
intestine, lungs, brain and kidneys. These isoenzymes can 
bind and transfers oxygen and electrons to organic 
substances, a process that serves in oxidative metabolism. 
The clinical significance of the inhibition of P540, has not  
been established, but it may lead to elevated plasma levels 
of co-administered drugs which are metabolized by this 
isozyme (Science Direct, 2003). Many biogenic amine reuptake 
inhibitors, such as the ones in fluoxetine, contain a 
tertiary or secondary amino group, and the principle route of 
metabolism is N-demethylation of these groups to form 
dementhyl metabolites. These structures may undergo further 
biotransformation, an example being oxidation. Fluoxetine is 
extensively metabolized through the liver to norfluoetine, 
the desmethyl metabolite, which is also a serotonin  
reuptake inhibitor. Norfluoxetine contributes to the duration 
of action of fluoxetine. Elimination of metabolites occurs 
primarily in the urine with a smaller amount also being 
present in feces (Diamond, 1998). 
     When you receive fluoxetine from your doctor it comes in 
a pulvule form or tablet form. Each Prozac tablet contains, 
fluoxetine HCI equivalent to 10mg of fluoxetine. These 
tablets also contain microcrystalline cellulose, which is 
derived from a special grade of alpha cellulose, and it is 
also a naturally accruing polymer. Fluoxetine also contains 
magnesium stearate, crospovidone, hydroxypropyl 
methylcellulose, titanium dioxide, polyethylene glycol and 
yellow iron oxide. Hydroxypropyl methylcellulose is typically 
used in medications as a lubricant, and is commonly called 
fake tears. Magnesium stearate is also a lubricant that is 
added to dry powders as flow aid and as a water-in-oil 
emulsifier to impart water repelance. Crospovidone is also an 
important part in the packaging process. Crospovidone is a 
polyplasdone polymer. Polyplasdone polymers are non-ionic  
and as a result, their disintegration performance will not be 
impacted by ph changes in the gastrointestinal tract nor will 
they compete with ionic drug activities (Edwards, 2002). 
      There has been extensive research done on Fluoxetine, 
due to the popularity of the drug. Research in rat's 
hippocampal neurons, suggest that Fluoxetine inhibits A-type 
potassium (Science Direct, 2003). Despite this and other 
criticisms Fluoxetine and other antidepressants have a 
magnitude of positive affects. It is proven that depression 
has a negative correlation with all aspects of life, 
including physical, mental and social health.  
Drugs such as this have a dramatic influence on our society. 
Most people who receive treatment for depression experience a 
noticeable change in two important areas: their personal 
relationships and performance of daily work (Kramlinger, 13). 
When used correctly and not over prescribed antidepressants  
can be extremely helpful to the improvement of life of people 
with this disease. 
 
References 
 
Blais, Mark A., (1997).Selective Serotonin Reuptake       
Inhibitors and Atypical Antidepressants: A Review and Update 
for Psychologists.(vol.28, No.6, 526-536)American 
Psychological Association.Inc. 
 
Diamond, Ronald J., (1998).Instant Psychopharmacology. (2nd                          
Ed.). New York, New York: W.W Norton & Company 
 
Edwards, Virginia M.D., (2002).Depression and Bipolar 
Disorders 
Buffalo, New York: Firefly Books (U.S.) Inc. 
 
Kramlinger, Kieth, M.D. (2001).Mayo Clinic on Depression. 
New York, New York: Kensington Publishing. 
 
Rivas-Vazquez, Rafael A., (2001).Understanding Drug 
Interactions.  
Proffesional Psychology: Research and Practice, Vol.32, No.5, 
543-547:  
American Physiological Association Inc. 
 
Sanchez, Connie, & Hyttel, John, (1999). Comparison of the 
Effects of  
Antidepressants and Their Metabolites on Reuptake of Biogenic 
Amines and on  
Receptor Bindings. Cellular and Molecular Neurobiology, 
Vol.19,  
No.4.Denmark: Plenum Publishing Co. 
 
 
Science Direct, (2003).Fluoxetine inhibits A-type Potassium 
Currents in  
Primary Cultured Rat Hippocampal Neurons. Department of 
Physiology, Medical  
Research Center, South Korea. 
http://www.sciencedirect.com/science?_ob=ArticleURL. 
 
 
 
Wong, David T., (1995).Prozac (Fluoxetine, Lilly 110140), The 
First  
Selective Serotonin Uptake Inhibitor and Antidepressant Drug. 
Life Sciences,  
Vol.57, No.5. Indianapolis, In: Elserver Science Ltd. 
(Figure 1 & 2) 



 
 
Serotonin Receptors and Transport

By Martin Overstreet

Overview

       Being that Fluoxetine (commercial name Prozac) basically 
functions as a selective reuptake inhibitor for the 
neurotransmitter serotonin, some discussion of this 
transmitter is needed before its reuptake inhibition can be 
addressed. Serotonin (5 hydroxytrytophan or 5HT, for short) 
is synthesized from the precursor amino acid tryptophan 
through the enzyme action of tryptophan hydroxylase (Abelson 
& Andrews,1997,p.794).  This synthesis process occurs in the 
terminal boutons and the serotonin is contained in vesicles 
awaiting release when an action potential opens the calcium 
gates in the presynaptic terminal. Calcium flowing through 
the gate adheres to the vesicle membrane and to the terminal 
membrane causing the vesicle to rupture and release the 
transmitter across the synaptic gap (Kalat,2004,p.61).
	Serotonin has multiple receptor types and subtypes that 
are linked to many diverse neurological functions. Beginning 
in the 1970’s, radioligand techniques identified two broad 
categories of receptors, namely types 5-HT1 and 5-HT2, 
however, research has since identified another twelve types 
and associated subtypes bringing the current total to 
fourteen: 5HT1a,b,d,e,f, 5HT2a,b,c  5HT3, 5HT4, 5HT5a,b  
5HT6, and 5HT7 (numbered suffixes represent types, lettered 
suffixes are subtypes).  These serotonin receptor types vary 
by location within the brain, e.g., the highest density of 
5HT1A receptors a found in the hippocampus and dorsal raphe 
nucleus, whereas the highest concentration of 5-HT2 sites are 
found in the medial prefrontal cortex (Abelson et al. 
1997,p.794). 
	Once released into the synaptic gap, serotonin is not 
broken down by an enzyme to limit its effect, but rather its 
action is terminated by being taken up again into the 
terminal from which it was released or by reuptake into 
adjacent glial cells. The importance of this is that 
serotonin is ready for reuse and does not waste additional 
metabolic energy in having to be re-synthesized. However, 
serotonin does need a chemical transport mechanism to pick it 
up from the cytoplasm in the synaptic gap and carry it back 
to the terminal (Siegel,Agranoff,Albers,& Molinoff, 
1994,p.292). This serotonin transporter (SERT) is key to 
understanding serotonin selective reuptake inhibitors 
(SSRI’s)of which fluoxetine is just one (Williams & 
Mauro,1998,p.3291). The transporter and specific receptor 
sites will be discussed in greater detail in the following 
sections. 
	Research has shown that serotonergic neurons typically 
have a slow, rhythmic pattern of firing and the pattern 
suggests a mechanism that regulates the rhythm. Research on 
dorsal raphe neurons reveals a complex interplay of ion 
currents including a voltage dependent outward potassium 
current and a low-threshold inward calcium current. These 
rhythms are modulated by various transmitters including 
norepinephrine, GABA, and serontonin itself by acting upon 
serotonin autoreceptors that inhibit neurons by opening 
potassium channels (Adelman,1987,p.1082).

Serotonin Receptor Sites

	Some discussion of the number and complexities of the 
various serotonin receptors and their discovery may be 
instructive for understanding the present state of knowledge 
concerning the actual mechanism of inhibition. Interest in 
the chemical functioning and behavioral implications of 
serotonin receptors began around 1950 with the realization 
the molecular structure of the receptor resembled that of 
lysergic acid diethylamide (LSD) which led to speculations 
that the hallucinations associated with LSD were due to  
blockage of the serotonin receptors in the central nervous 
system.  The intervening years has seen this theory 
considerably modified (Shepherd,1994,p.176). 
       The suggestion that there might be more than one 
serotonin receptor site came from experiments conducted by 
Gaddum and Picarrelli in 1957. Using guinea pigs, the 
researchers demonstrated that only a portion of serotonergic 
response could be blocked by morphine, while the remainder of 
the response could be blocked by phenoxybenzamine. They 
therefore concluded that there must be two different types of 
serotonin (5HT) receptors (Siegel et al. 1994,p.295).
       Radioligand binding techniques in the 1970’s led to the 
categorization of the major 5HT sites. Initially, the names H 
5HT, H LSD, and H spiperone were used to label receptor 
sites, but eventually gave way to the classifications 5HT1 
and 5HT2 (Abelson et al, 1997,p.794). Because of the 
inconsistent affinity that spiperone had for the 5HT1 
receptor, further research was designed to explore this 
inconsistency and revealed that the 5HT1 receptor was not a 
single type of receptor, but in actuality a class of 
receptors with related subtypes. The serotonin receptor 
subtype with a high affinity for spiperone became known as 
5HT1A, whereas the subtype with a low affinity for spiperone 
became 5HT1B (Siegel et al. 1994,p.295). The highest 
concentration of 5HT1A receptors is in the hippocampus and 
dorsal raphe nucleus, with the highest density of 5HT1B 
receptors in the substantia nigra and globus pallidus 
(Abelson et al. 1997,p.794).
       Yet another 5HT1 type was isolated when it was 
discovered that a particular subset of receptors did not meet 
the pharmacological requirements of the 1A and 1B subtypes. 
This new subtype was found to be densely concentrated in the 
choroid plexus (the tissue in the brain that produces 
cerebrospinal fluid) was soon labeled 5HT1C. The 5HT1D 
subtype was initially identified in bovine brains and 
subsequently identified by pharmacological criteria only in 
the brains of species without the 1B receptor such as pig, 
cow, guinea pig, and human (Siegel et al. 1994,p.295).
       Research of type 5HT2 receptors was facilitated by the 
introduction of ketanserin, an antagonist of the type 2 
sites.  The highest density of 5HT2 was found to be in the 
medial prefrontal region of the cortex as demonstrated in 
various mammalian brains including humans.  On the whole, the 
5HT2 sites are characterized by a low affinity for serotonin 
agonists, but a high affinity Type 2 antagonists. Recently 
several phenylaklyamines have been indicated as strong 5HT2 
agonists (Abelson et al. 1997,p.794).
       Research using ketanserin on the Type 2 sites lead to 
the discovery of another pharmacologically distinct type of 
receptor, and the additional development of specific agonists 
and antagonists led to the classification of this new type 
(Siegel et al. 1994,p.296).  Labeled 5HT3, this receptor 
group is highly concentrated in the cortical regions and 
areas of the brain stem. Subsequently, an additional type of 
serontonin receptor, the 5HT4 group was identified.  
Originally found to be stimulated by serotonin to increase 
adenylyl cyclase, it was later determined to be 
pharmacologically distinct from previous types. In addition 
to being found in the central nervous system where it is 
concentrated in the hippocampus and limbic areas (Abelson et 
al. 1997,p.795), the 5HT4 group is also found in the 
peripheral nervous system, notably in the gastrointestinal 
tract and in the heart (Siegel et al. 1994,p.296). 
        In summary, the 5HT1 family of receptors is 
characterized by an affinity (tendency to bind to a receptor) 
for 5HT and 5carboxyamidotryptamine and only slight affinity 
for 5HT2 antagonists (drugs that block a transmitter). 
Additionally, the 5HT1 class of receptors is linked to G 
protein cAMP (cyclic adenosine monophosphate) second 
messenger systems which regulate K+ and Ca2+ ion channels 
(Shepherd,1994,p.176) and activates specific protein kinases 
(Abelson et al. 1997,p.795). Each of the 5HT subtype 
receptors has a distinctive chemical profile and pattern of 
distribution in the brain (Abelson et al. 1997,p.794).

Serotonin Transport and Inhibition 

	Serotonin is carried across the synaptic gap by being 
chemically bound to a particular transporter protein 
(generally abbreviated SERT) and has an absolute requirement 
dependent on the external gradient of sodium (Na+) and 
chloride ions (Cl). Serotonin transport is inhibited by both 
metabolic inhibitors and by the effect of the sodium and 
potassium gradient. Fluoxetine (Prozac) is a highly selective 
serotonin reuptake inhibitor at the presynaptic neural 
membrane (Williams et al,1998,p.3291). The exact mechanism 
for the inhibition is not, as yet, fully understood, however, 
a more complete chemical analysis of the likely processes is 
provided in the preceding section entitled “Specific Chemical 
Mechanisms.” 

	
References
Abelson, J., & Andrews, P.(Eds.)(1997). Encyclopedia of Human 
Biology. San Diego, CA: Academy Press.
Adelman, G. (Ed.)(1987). Encyclopedia of Neuroscience 
(Vol.2). Boston: Birkhauser.
Kalat, J. W. (2004). Biological Psychology (8th ed.). 
Belmont, CA: Thompson-Wadsworth.
Siegel, G.J., Agranoff, B.W., Albers, R.W., & Molinoff, P.B. 
(1994). Basic neurochemistry (5th ed.). New York: Raven 
Press.
Shepherd, G.M. (1994). Neurobiology (3rd ed.).    London: 
Oxford University Press.
Williams, S., & Mauro, S. (1998). European journal of 
neuroscience, 10(10),3288-3295.



Primary Side Effects, Behavioral Changes, 
and Effects Reported by Users.

By Roslyn McCoy

Side effects have played a significant role in the development 
of SSRI’s.  The first drug, iproniazid, was developed to fight 
tuberculosis in the early 1950's, and had a noticeable side 
effect on mood elevation.  Soon it was known as a "happy drug".  
This drug immediately gained attention from physicians and 
depression researchers.  At that time the only drug on the 
market for depression was opium, which was a highly addictive 
substance (Turkington 49-50).  Ten years of specific drug 
research to identify different models of nerve transmissions and 
tailoring chemicals to affect these processes resulted in the 
development of Prozac (Turkington,61). 

"Eli Lilly and Co.'s (Prozac's manufacturer) official product 
information acknowledges that tremors alone occur in 10% of 
patients on Prozac. Any side effect occurring in 1% or more of 
patients is acknowledged as "frequent" by the pharmaceutical 
industry (Glenmullen).  Some of these side effects that have 
been reported are feelings of jitteriness, sleep problems 
"tardive dyskinesia," and "sexual dysfunction". Other side 
effects from Prozac include weight gain, tiredness, increased 
appetite, feeling weak, sore throat, and trouble with 
concentration (Smith).
  
Side effects of antidepressants fall in three different 
categories: sedation; dry mouth, blurry vision, constipation, 
urinary problems, increased heart rate, and memory problems; and 
dizziness on standing up, orthostatic hypotension. Those that 
interfere with dopamine, such as Effexor and Asendin, may 
produce movement disorders and endocrine system changes. 
Blocking serotonin may create stomach problems, insomnia, and 
anxiety.  The newer drugs such as Prozac, Paxil, and Zoloft have 
had fewer side effects, and many of these will disappear or 
diminish within a few weeks (Turkington,56-57). Prozac and other 
SSRIs are said to zero in on serotonin without affecting other 
brain systems. Adding drugs such as thyroid hormone, lithium 
buspirone(BuSpar), or Ritalin to Prozac can decrease the dosage 
alleviating many symptoms, and boosting the effects alleviating 
patients depression (54).  

If while taking Prozac you become psychotically depressed with 
hallucinations or delusions, the physician could add 
antipsychotic drugs such as haloperidol (Haldol), 
thiothixene(Navane), or chlorpromazine (Thorazine) to your 
antidepressant.  This practice may increase the risk of drug 
interaction (Turkington,54-55). 

The most serious pharmacodynamically mediated drug-drug 
interactions is serotonin syndrome and hypertensive crisis. 
Hyperpyrexia and death may be the outcome of this rare drug-drug 
interaction. "For this reason, it is mandatory to wait at least 
2 weeks before switching from an SSRI to an MAOI, and at least 5 
weeks when switching from fluoxetine to an MAOI, particularly 
tranylcypromine" (Janicak,300).

Tardive dyskinesia is a condition where the individual loses 
control over their fine motor control.  One example of this 
condition was displayed in a 39-year-old woman that began with 
small facial tics around her eyes and then progressed too 
involuntary chewing motions and twitching of her lips.  She was 
not able to control her tongue that kept darting and then out of 
her mouth.  It took this woman more than six months to slowly 
withdraw off of Prozac and see the worst of her symptoms subside 
with only a remnant of a facial tech around her mouth 
(Turkington,114).  

Doctors have been reporting that they have been seeing a range 
of motor control loss such as, tics, twitches, muscle spasms, 
immobilizing fatigue, and tremors. Tardive dyskinesia has been 
reported in 10% of patients receiving Prozac at this rate the 
pharmaceutical industry would consider this as a frequent 
occurrence.  Glenmullen also describes a condition called 
"overstimulation reaction" which causes an individual to have 
compulsive thoughts of suicide and violence.  Withdraw from 
Prozac can take months with symptoms of dizziness, anxiety, and 
difficulty in balancing.  It is also been reported in a third of 
the clients that the effectiveness of Prozac will weather off 
within a year, requiring the patient to change medications 
(Glenmullen).

Sexual dysfunction (SD) at this present time has an estimation 
of 75% of the consumers may experience sexual dysfunction as a 
result of consuming Prozac for both long-term or acute 
treatments.  The initial impact of sexual dysfunction was 
significantly under estimated leaving the consumer unprepared 
for the potential side effect. "Sexual functioning is typically 
divided into four stages: desire, excitement or arousal, and 
orgasm (Turkington,57).  Prozac is commonly associated with the 
arousal stage, but it is difficult to discern from the symptoms 
of depression.  Libido/arousal can be significantly impact by 
depression, but when the medication begins to take effect the 
individual libido begins to return if after this point the 
libido again drops it would be considered a side effects of the 
medication.  Orgasmic disorders have been reported to have 
significant susceptibility to disturbance from Prozac and other 
antidepressants medications.  For man this dysfunction usually 
manifests as anorgasmia, the time required to achieve orgasm or 
an absent of orgasm prompting cessation.  Women have also 
reported similar symptoms of delayed orgasm or not being able to 
reach orgasm even if they did have normal arousal.  Also there 
were reports of spontaneous orgasms when the women is engaging 
in normal life or with vigorously exercised on a treadmill 
(Rivas-Vazquez).

Maryland medical examiner's office performed a retrospective 
chart review finding that" Prozac users have an increased 
frequency of violent suicides compared to tricyclic 
medications".(Mason) Mason cites a second study which found that 
Prozac patients exhibited a higher level of anger and aggression 
without antisocial behaviors(Mason).  UK's  Medicine and 
Healthcare products Regulatory Agency presented a study with 
more than 40,000 people who took part in 477 separate studies.  
In these studies that there were 16 suicides, 172 incidences of 
nonfatal self harm, and 177 incidences of suicide thoughts among 
the patients."Researchers found no evidence that SSRI use 
increased the risk of suicide or suicidal thoughts more than 
placebo treatment."  Though the authors concluded the risk with 
SSRI use "cannot be ruled out." (Boyles)

An estimated one to three percent of users have experienced "  
Overstimulation reaction,” a condition linked to compulsive 
thoughts of suicide and violence. Eli Lilly and Co.'s were 
required to post warning labels on their product release in 
Germany to the German consumers (Glenmullen).

Eli Lilly and Co. so far have only published risks based on 
short-term studies. Glenmullen suggest that no one really 
understands the normal functioning of the brain, and Prozac type 
antidepressants may impair the brain in the long run.  The March 
2000 issue of “Brain Research,” indicates that Prozac and Zoloft 
may be toxic to the very cells they target in the brain" 
(Glenmullen). 

Throughout the books and journal articles a clear understanding 
on who would benefit and why, is not exactly known.  This is an 
area of ongoing research, and self reports from individuals who 
have and are taking these drugs will add to our understanding 
and provide very valuable information.

A 38-year-old woman named Susan described her depression lasting 
her entire life.  She went to a doctor feeling “icky, clumsy, 
and not feeling right.”  When she began taking antidepressants 
she began having feelings of well-being, which she had never 
experienced in her entire life (Turkington xii). 

Eleanor, a 40-year-old woman, struggled for 25 years with 
overwhelming feelings of sadness, lethargy, and the sensation 
that her body ached as if she was catching the flu.  After a car 
accident her depression deepened.  She was in therapy, but 
reported crying all day long without any significant reason.  
Eleanor and her psychiatrist tried many drugs before they found 
that a combination of Paxil and lithium brought back Eleanor's 
sense of humor and feeling of being normal.  Eleanor felt ripped 
off that she had spent so much time in her deep depression(2).

Joan a 42-year-old business owner reported her depression 
as the inability to see the point of life, and having 
trouble functioning.  During the height of her depression 
going out and getting the newspaper off of her driveway was 
about all she could do.  Now after taking Prozac Joan 
reports being optimistic about life (Turkington,59)

"I was resistant to seeing Prozac as a cure-all," says Miriam, 
26, a Virginia artist. "I never felt it was a lifesaver, but it 
really did give me a calming effect. It got me out of the house, 
brought me up from the depths, and removed my feeling of panic" 
(Turkington,64).

"My psychiatrist started me out on Zoloft," recalls Linda, 38. 
"After six weeks, it had done nothing for me, so he switched me 
to Wellbutrin. I took that for two weeks, but I became 
oversensitive. So then I was on Prozac for three days, but it 
made me manic. Then he tried Paxil and added lithium to keep me 
from getting manic. That's what I've been on for over a year, 
and it's been great."


References

Boyles, S. (2005). Mixed results on antidepressants 
and suicide. Web MD. News Feb, 18.
 
Janicak, P. G.,& Davis, J.M. (2001). Principles and       
practice of psychopharmacotherapy (3rd ed.). New 
York: Lippincott, Williams, & Wilkins.

Glenmullen, J. (2000). Prozac: pro and Con,WebMD Feature June,2.
 
Mason, S. E. (2002). Prozac and crime: Who is the victim? 
American Journal of Orthopsychiatry,72(3)445-455.

Rivas-Vazquez, R. A., & Blais, M.A. (2000). Sexual dysfunction 
associated with antidepressant treatment. Professional 
Psychology: Research and practice,31(6)641-651.

Smith, M. (2003). Medication for bipolar depression. 
Approved WebMD Medical News December, 29. 

Turkington, C.A., & Kaplan, E.F. (1994).  Making the 
prozac decision: Your guide to antidepressants.  Los 
Angeles: Lowell House.


   				Ion Channel Effects,
		Behavioral and Physiological Changes

	 			 By Nicole Musone

	The drug Prozac, otherwise known as Fluoxetine, has been 
believed to cause few side effects in general.  Evidence also 
indicates that fluoxetine has various additional effects on 
several ion channels within the brain.  Fluoxetine has 
demonstrated exerted effects on a variety of ion channels, the 
drug inhibited K+ and Na+ currents in lens and corneal 
epithelium, and the inhibitory effects of fluoxetine on ionic 
currents (Hahn, 1999).  This suggests that since local 
concentration of fluoxetine may rise in the small extracellular 
space surrounding neurons, fluoxetine could act as an ion 
channel inhibitor in the brain.  Research done by the Department 
of Physiology, College of Medicine, at the Catholic University 
of Korea, showed that fluoxetine is a potent inhibitor of 
voltage activated K+, Ca2+, and Na+ channels in PC12 cells.  The 
inhibition of K+ channels by fluoxetine was concentration 
dependent but was not voltage dependent (Hahn, 1999).  The 
inhibitory effects of fluoxetine on K+ currents were not 
abolished by inhibitors of protein kinases (H7, staurosporine, 
Rp cAMPS), indicating that protein kinases and G proteins were 
not involved in the inhibition of K+ currents by fluoxetine 
(Hahn, 1999).  The study concluded that the overall effects of 
fluoxetine on neurons will be determined by the expression 
pattern of individual ion channels in different neurons, and 
this phenomenon may have pharmacological implications (Hahn, 
1999).  
	Norfluoxetine is the most important active metabolite of 
the antidepressant compound, flouxetine.  In a study done by the 
University Medical School of Debrecen, the effects of fluoxetine 
and its major metabolite, norfluoxetine, were studied using the 
patch clamp technique on a cloned neuronal rat K+ channel Kv3.1, 
expressed in Chinese hamster ovary cells.   Their results 
indicated that norfluoxetine is more potent than its parent 
compound, fluoxetine, in inhibiting kv3.1 currents.  The active 
metabolite of flouxetine, Norfluoxetine can inhibit K+ channels 
(Magyar, 2004).  They concluded that at clinically relevant 
concentrations, fluoxetine, and its major metabolite, 
norfluoxetine inhibits Kv3.1, and that fluoxetine’s metabolite 
directly inhibits Kv3.1 as an open channel blocker.
	 The British Journal of Pharmacology, 2003, did a study of 
the effects of fluoxetine on specific ion channels.  The effects 
of fluoxetine on G protein activated inwardly rectifying K+ 
channels (GIRK,Kir3) were investigated using Xenopus oocyte 
expression assays.  In ooxytes injected with mRNAs for 
GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, fluoxetine 
reversibly reduced inward currents through the basal GIRK 
activity (Kobayashi, 2003).  The inhibition by fluoxetine showed 
a concentration dependence, a weak voltage dependence and a 
slight time dependence with a predominant effect on the 
instantaneous current elicited by voltage pulses and followed by 
a slight further inhibition (Kobyashi, 2003).  In the oocytes 
expressing GIRK1/2 channels and the cloned Xenopus A1 adenosine 
receptor, GIRK current responses activated by the receptor were 
inhibited by fluoxetine. On the other hand, ROMK1 and IRK1 
channels in other Kir channel subfamilies were insensitive to 
fluoxetine.  The inhibitory effect on GIRK channels was not 
obtained by intracellularly applied fluoxetine and not affected 
by extracellular pH, which changed the proportion of the 
uncharged to protonated fluoxetine, suggesting that fluoxetine 
inhibits GIRK channels form the extracellular side (Kobayashi, 
2003). 
	 The study demonstrated that fluoxetine inhibits GIRK 
channels, at low micromolar concentrations.  These channels play 
an important role in the inhibitory regulation of neuronal 
excitability in most brain regions and the heart rate through 
activation of various G protein coupled receptors(Wong, 1995).  
The results presented suggest that inhibiton of GIRK channels by 
fluoxetine may contribute to some of its therapeutic effects and 
adverse side affects observed in clinical practice.
	
Physiological Changes

    	The drug Prozac or fluoxetine was thought of as a 
breakthrough because it is "selective" for serotonin.  Prozac is 
designed to prevent the reuptake of serotonin into the brain by 
binding to the cell receptors and the presynaptic cell membranes 
that serotonin passes through within the brain, thereby blocking 
the serotonin so that it cannot pass through into the blood 
stream where it is quickly inactivated or metabolized 
(Glenmullen, 2001).  It is thought that the binding effect of 
Prozac will raise the level of serotonin by holding it in the 
brain and not allowing it to be expelled by the body. 
	 The neurotransmitters that are involved in the brain are 
serotonin, adrenaline and dopamine, usually referred to as the 
brain’s "feel good" neurotransmitters.  Joseph Glenmullen, PHD, 
states that serotonin is one of the oldest neurotransmitters in 
the evolution of life forms.  He says, in humans only about 5% 
of serotonin is found in the brain.  The other 95% is 
distributed throughout the rest of the body.  The majority is in 
the gastrointestinal tract where serotonin modulates the 
rhythmic movements, kneading food through out the stomach.  Some 
frequent reported effects from fluoxetine within the 
gastrointestinal region of the body have been nausea, 
disturbances of appetite, and diarrhea. Some infrequent effects 
were reported to be vomiting, stomatitis, dysphagia, eructation, 
esophagitis, gastritis, gingivitis, glossitis, melena, thirst, 
and abnormal liver function tests.  In the cardiovascular 
system, serotonin helps regulate blood vessels to control the 
flow of blood. While taking fluoxetine, some infrequent reports 
have been made about chest, hypertension, syncope, hypotension, 
angina pectoris, arrhythmia, and tachycardia.  
	Prozac is a highly protein binding durg (94%) thus blocking 
primarily serotonin in the brain for extended periods.  It also 
binds to other protein or toxins in the blood, making them too 
large to be broken down and expelled readily by the body 
(Glenmullen, 2001).  All of this binding to body proteins would 
cause excess stress to be placed on the organs involved in 
metabolizing and elination, the liver, pancreas, etc.   Prozac, 
and prozac -type drugs inhibit or block reuptake, thereby 
boosting the level of serotonin, prolonging serotonin signals in 
the brain (Glenmullen, 2001).  Prozac is extensively metabolized 
through the liver, with a combination of fluoxetine (prozac) and 
alcohol or other drugs or excessive intake of processed sugars 
or the inability of the body to maintain balanced blood sugar 
levels, the liver would go into overload and not be able to 
function normally (Tracy, 2003).  People with liver problems 
need to be extra cautious when taking the drug.
    Physiological changes commonly mentioned related to taking 
SSRIs, like Prozac, are sexual sysfunctions, such as inability 
to have orgasms.  Various neurotransmiter systems, acting 
centrally and peripherally, including dopamin, serotonin, 
adrenaline, acetylcholine, and gamma-aminobutyric acid, have 
been demonstrated to mediate sexual behavior (Walker, 1993).  
Serotonin affects sexual functioning either directly by its 
activity at central or peripheral serotonin receptors or 
indirectly by altering levels of other neurotransmitters that 
mediate sexual functioning at central or peripheral sites 
(Gitlin, 1994).  This direct or interactive role of serotonin 
can affect different stages of the sexual cycle.  Increased 
serotonin levels in this pathway may inhibit dompamine levels 
and subsequently result in reduced sexual arousal or libido, and 
possibly decreased sexual satisfaction (Gitlin, 1994).  
     In Glenmulllen’s most current research, he believes that 
prozac boosts neurotransmitters beyond levels achieved under 
ordinary circumstances.  The drug creates serotonin levels 
beyond the physiological range achieved under normal 
environmental/biological conditions.  "Boosting serotonin to 
this degree might more appropriately be considered pathological, 
rather than reflective of the normal biological role of 5-HT" 
(Glenmullen, 2001).   

Behavioral changes
		        
	The most common behavior change while taking Prozac is that 
the persons negative feelings or depressed thoughts are uplifted 
and they are able to function happier and more positive in their 
day to day life and in society.  Prozac works by restoring the 
balance of natural substances (neurotransmitters) in the brain, 
thereby improving mood and feelings of well-being (Greens 
Fortuna Pharmacy, 2005).  Depressive episodes imply a prominent 
and relatively persistent depressed or dysphoric mood that 
usually interferes with daily functioning it should include 4 
out of the 8 symptoms: change in appetite, change in sleep, 
psychomotor agitation, loss of interest in usual activities, 
feelings of guilt or worthlessness, slowed thinking or impaired 
concentration, and a suicide attempt or suicidal ideation 
(Kalat, 2004).  After being prescribed Prozac, these symptoms 
usually greatly decrease, and their behavior changes to more of 
the opposite of these symptoms, they sleep better, have a 
regular appetite, aren’t as agitated, and have interest in 
activities that they once were active in again.  
	Prozac has also been prescribed for the help, and positive 
behavior change of the following disorders; Bulimia Nervosa, 
Obsessive-Compulsive disorder, Anxiety-disorder, and 
Premenstrual Dysphoric disorder.  People with Bulimia Nervosa 
binge eat and then purge the food, they don’t feel good about 
themselves and their physical appearance. Doctors have found 
that Prozac has a positive effect on these patients and their 
negative behaviors tend to drop and great deal and have even 
stopped.  Prozac has also been FDA approved in the treatment of 
obsessive-compulsive disorder and Anxiety disorders.  Prozac has 
helped up to 70% of individuals with this disorder, the patients 
generally felt better and more relaxed about their environment 
(Turking, 1994).  Premenstrual Dysphoric Disorder (PMDD) is 
characterized by depression, tension, and severe mood changes, 
as well as physical symptoms such as weight gain, bloating, and 
tenderness (Turking, 1994), which occur between ovulation and 
menstruation.  FDA sponkewoman said that Prozac was 
significantly more effective in improving mood, physical 
symptoms, and social functiong than some other antidepressant 
drugs.  Patients reported feeling almost like a different person 
while taking Prozac and that their families liked their change 
in mood and their more positive out look in general (Twersky, 
2000).

References

Blake, Anne T., Family Health News, 2003. 

Gitlin, M.J. Journal of Clinical Psychiatry, 55, 406-413 (1996)

Glenmullen, Joseph, PhD. Prozac Backlash, 2001

Greens Fortuna Pharmacy, patient information leaflet, (2005)

Hahn, J., The effects of Prozac on the Brain, (1999)

Kalat, James W., Biological Psychology, 8th ed., (2004)

Kobayashi, Toru, Kazuo, Washiyama, Kazutaku, Ikeda, Inhibitin of 
G protein-activated inwardly rectifying K+ channels by 
fluoxetin(Prozac), British Journal of Pharmacology,(2003), 138, 
1119-1128.

Magyar J, Swentandrassy N, Banyasz T, Kecskemeti V, and Nanasi 
PP, Department of Physiology, University Medical School of 
Debrecen, Hungary, (2004)

Turking, Carol Ann, and Kaplan, Eliot F.,M.D., Making the Prozac 
Decision, (1994)

Twersky, Ori. FDA Approves Prozac for Treating Severe form of 
PMS, WebMD, Medical News, (2000)

Walker, P.W. Cole, J.O., and Gardner E.A. , Improvement in 
Fluoxetine-associated dysfunctions, (1993)

Copyright © 2005, Dr. John M. Morgan, All rights reserved - This page last edited 1-3, 2005
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