BIOLOGICAL BASIS OF BEHAVIOR
Psychology 321
Spring, 2005 HGH 225
Dr. John M. Morgan MWF, 8am to 9:00
Samara Miles-Prystowsky
Bio Basis of Behavior
February 2005
Introduction:
Fluoxetine Hydrochloride and Unipolar Depression:
Composition, Small-Scale Effects and The Larger Life Outcome
Unipolar Depression is a historically documented affliction
that many people experience in their lifetime. B.E. Leonard
describes it as "a heterogeneous disease state characterized by
complex alterations in several Central Nervous System
neurotransmitter and receptor systems" (1992). Episodes of
depression range from severe bouts that last a minimum of 2
weeks, to years (also known as Dysthymia," requiring a 2 year
minimum duration for appropriate diagnosis). Depression
interferes with a person's functioning and well-being on the
general level of daily tasks and experiences that most of us
participate in and take for granted: people experience loss of
interest in previously enjoyed activities, major changes in
sleep patterns (sleeping too much or waking early in the
morning), appetite, and feelings of hopelessness, helplessness,
irritation and/or listlessness. (Davison, 2004.)
Researchers have long struggled to pinpoint the origins of
depression in order to improve quality of life for those who
experience it. While no one causal relationship can be labeled
as the main factor in depression (genetics, biology, and
environment always interplay a complex role in all human
experiences), specific correlational evidence has been found.
The neurotransmitter serotonin (5 hydroxytryptamine) acts on
areas of the Central Nervous System that are responsible for
maintaining and regulating anxiety, sleep, aggression, appetite,
temperature, sexual behavior and pain sensation, and has been
found to have exceptionally low activity level in depressed
people. Selective Serotonin Reuptake Inhibitors (such as
fluoxetine, better known as Prozac) limit the reabsorption of
serotonin by blocking receptors at neural level, raising
serotonin activity levels and proving effective in helping to
treat depression. SSRIs are equally effective as tricyclic
drugs, with the particular advantages of not being associated
with anticholinergic adverse effects, sedation, cardiotoxicity
or massive weight gain, while retaining massive life changing
effects. (Leonard.) In this paper, we investigate the synthesis
of serotonin, the chemistry and route of access of Fluoxetine,
and how the two interact to produce their effects. We study this
interaction at the neural level, analyzing the behavioral and
physiological changes and results as reported by those who have
used the drug. Thus, we progress from profiling the micro level
of action to a larger-scale, investigating how fluoxetine and
serotonin interact with biology and environment to create the
resulting positive and negative effects and, hopefully, to
ultimately relieve Unipolar Depression.
Samara Miles-Prystowsky
Bio Basis of Behavior
Serotonin and Fluoxetine: A Prelude to SSRI Functions
February 2005
Serotonin: Synthesis and Action
Serotonin (5 hydroxytryptamine) is classified as a
monoamine neurotransmitter from 5 hydroxytryptophan, synthesized
directly as the metabolite from the amino acid L tryptophan (LT)
and resulting from subsequent hydroxylation and decarboxylation.
The monoamines are subdivided into two groups: catecholamines
(dopamine, norepinephrine, and epinephrine) and indolamines, of
which serotonin is a member. Serotonin is active in the
essential regions of the blood cells, peripheral nervous system,
cardiovascular tissue, and the Central Nervous System. While the
greatest concentration of serotonin is in the enterochromaffin
cells of the gastrointestinal tract, Dr. Michael W. King notes
that the effects of 5 Hydroxytryptamine are felt most
prominently in the cardiovascular system, with vasoconstriction
being a typical response (2004). Within the Central Nervous
System, it tends to act as an inhibitory neurotransmitter on
inhibitory parts of the brain, thus creating an excitatory
behavioral effect; depletion of serotonin has been implicated in
a variety of disorders, including Unipolar Depression. Research
finds that using 5 Hydroxytryptamine therapeutically tends to
bypass the conversion of LT into 5 Hydroxytryptophan, the
synthesis of which causes a much slower effect (Birdsall, 1).
Although other cells throughout the body make serotonin,
serotonin itself cannot cross the blood-brain barrier alone, so
it must either be made within the neurons to be effective in the
brain, or it requires a specific transport molecule, which binds
to five additional amino acids. As a result of this
complication, serotonin synthesis is very much dependent the
availability of LT. If LT supply is therefore lacking,
serotonin levels will remain low.
LT levels are influenced by elevated cortisol levels
(induced by stress), deficiency in vitamin B6, or, interestingly
enough, excessive quantities of LT. Excessive amounts of LT
stimulate its conversion into kynurenine (extra amounts of any
chemical stimulate conversion because the body tries to maintain
balanced substance levels). Kynurenine, in turn, inhibits the
transport of LT into the Central Nervous System, thus reducing
Central Nervous System serotonin levels. (Birdsall.) In addition
to its importance in serotonin synthesis, LT is used in other
areas of the body for metabolism, including the creation of
niacin and protein synthesis; transportation of LT itself into
the Central Nervous System further necessitates binding to a
transport molecule.
In the presence of the above circumstances, serotonin
synthesis occurs in a two step process that involves a
tetrahydrobiopterin dependent hydroxylation reaction, which is
catalyzed by tryptophan 5 monoxygenase, otherwise known as
tryptophan hydroxylase (King, 2004). Following this reaction is
a decarboxylation, which is catalyzed by aromatic L amino acid
decarboxylase. After the synthesized serotonin is released, it
is typically recaptured by the presynaptic neuron in an
automatic reuptake mechanism. In Unipolar Depressed individuals,
the reuptake process is either overabundant or serotonin
quantities are inefficient (under abundant), either way
promoting low levels of 5 Hydroxytryptamine. The resulting
function of Selective Serotonin Reuptake Inhibitors' is to
inhibit reuptake by filling up reuptake receptors, thus creating
elevated levels of active serotonin within the synaptic gap.
(King, 2004.)
5 Hydroxytryptamine influences a range of behaviors through
interaction with multiple brain 5 Hydroxytryptamine receptor
subtypes (Cowen, 1991). Resulting behaviors and subsequent areas
of the brain involved include sensory, autonomic, cognitive,
psychological, neuroendocrine, and emotional functioning.
(Grahame Smith, 1992.) The cell bodies of neurons that house
serotonin are present in multiple anatomically different
neuronal tracts that extend from the raphe nuclei in the
medulla, pons, parts of the hypothalamus, limbic system, and
emanate through the neocortex and into the spinal cord. (Grahame
Smith, 1992.) Serotonin is also responsible for the production
of melatonin, which results from interaction with N
acetyltransferase, an enzyme required for the process found in
the retina and pineal gland.
According to Messer, amino acid sequences of 5 HT receptor
groups are very similar to one another and to the beta
adrenergic receptor, "including a conserved aspartate residue in
the third membrane spanning segment" (retr. 2005). At least
seven serotonin subtype receptors have been identified, three of
which are 5HT1, 5HT2, and 5HT3, which differ in binding affinity
for selective ligands, regulatory behavioral processes, and
their receptor effector coupling mechanisms. (Grahame Smith.)
Additionally, serotonin receptors can be postsynaptic as well as
presynaptic, and there further exist receptor subtypes within
subtypes, for they were thus divided based on functional
similarities (Messer).
Most of the receptors are paired to G proteins, which
affect activities of either Phospholipase Cy or adenylate
cyclase (King, 2004), but the 5HT3 class of receptors are direct
ion channels. Interestingly, 5HT3 receptors found in the
gastrointestinal tract are responsible for vomiting, a function
important enough as one of the body's survival mechanisms to
require immediate receptor action. Clearly then, the functions
of the receptors differ depending on individual specialization.
For example, research on obese mice indicated a lack of the gene
for 5HT2c, which is consequently thought to be involved in the
control of food intake (King). It is the 5HT6 and 5HT7 receptors
distributed throughout the limbic system most pertinent for our
purposes, for researchers believe that 5HT6 receptors have an
affinity for antidepressant drugs. The 5HT6 receptor and others
are currently under investigation, as the exact mechanism for
their therapeutic influence is uncertain.
For example, 5HT1 receptors are paired to adenylyl cyclase
inhibition (Messer, 2005). Selective agonists for 5-HT1
receptors include 8 hydroxy 2(di n propylamino) tetralin (8 OH
DPAT), the function of which is to modulate adenylyl cyclase
activity within the hippocampus. 5HT1 receptors can be found
within the cerebral cortex, hippocampus, raphe nuclei, thalamus
and amygdale. 5HT1A receptors are presumed to be autoreceptors
responsible for regulating serotonin release; Pindolol, an
antagonist for 5HT1A, is involved in furthering therapeutic
benefits for Selective Serotonin Reuptake Inhibitors. (Messer,
2005.)
There have been some studies that show Selective Serotonin
Reuptake Inhibitors to cause an overabundance of Serotonin.
According to Birmes, et al. (2003), "Serotonin Syndrome" is the
result of over stimulation of 5HT1A receptors by SSRIs,
tricyclic antidepressants, and Monoamine Oxidase Inhibitors
(MAOs). Onset occurs within 24 hours after administration of a
serotonergic agent, and age or gender don't appear to play a
role in determining effect. The syndrome is characterized by a
triad of autonomic, mental, and neurological disorders, and is
confirmed by the presence of either four major symptoms, or a
combination of three major symptoms and two minor ones (Birmes
et al., 2003). While Serotonin Syndrome can be fatal,
appropriate prognosis can reduce the likelihood. Situations that
might indicate the Syndrome include "excess precursors of
serotonin or its agonists and higher release, lower recapture or
metabolic slowdown of serotonin" (Birmes et al., 2003).
Diagnosis of serotonin syndrome can be difficult, for symptoms
range from benign, to toxic, which includes coma, generalized
tonic clonic seizures, and fever exceeding 40°C. Also indicative
of Serotonin Syndrome are raised amounts of the total creatine
kinase and leukocyte count, lowered bicarbonate levels, or and
elevated transaminase amounts. Other indicators include kidney
failure, disseminated intravascular coagulation, acidosis or
acute respiratory distress syndrome. (Birmes et al., 2003.) To
treat Serotonin Syndrome, one must not only discontinue use of
Selective Serotonin Reuptake Inhibitors, but benzodiazepines ma
be prescribed to reduce anxiety levels, and beta blockers have
also been shown effective.
We now turn our attention to an SSRI responsible for
affecting serotonin levels in people with Unipolar Depression:
Fluoxetine, or Prozac.
Fluoxetine Hydrochloride:
Chemistry and Route of Access
Fluoxetine hydrochloride, marketed under the name Prozac,
is a phenylproplamine derived antidepressant taken by oral
admission with a half life of 1 to 3 days (AHFS, 2002). It is
commercially available as hydrochloride salt and is a selective
inhibitor of serotonin, preventing reuptake in brain
synaptosomes and platelets and thus increasing serotonin
activity levels in the Central Nervous System. The drug's high
selectivity may be due to its containing a p trifluromethyl
substituent, possibly resulting in an electron withdrawing
effect and lipophilicity (ASHP, 2002). Fluoxetine does not
interfere with postsynaptic receptors, but after long term use,
presynaptic receptors are desensitized. (Drugs.com.)
With a molecular weight of 345.79, fluoxetine's emperical
formula is C17 H18 F3 NO HCL and it is designated N methyl 3
phenyl 3 propylamine hydrochloride. (Lilly, 1998.) Additionally,
each Prozac Pulvule contains afluoxetine hydrochloride equal to
10 mg, 20 mg, or 40 mg of fluoxetine, and also contains
silicone, titanium dioxide, iron dioxide, microcrystalline
cellulose, magnesium stearate, hydroxypropyl methylcellulose,
polyethylene glycol, and yellow iron oxide (rxlist.com). The
onset of antidepressant activity after administration most often
happens in the first 1 to 3 weeks, but full therapeutic effect
may take up to 4 weeks, possibly from delayed distribution to
the Central Nervous System. (ASHP, 2002.)
Fluoxetine hydrochloride seems to be well absorbed from the
GI tract after oral administration (ASHP, 2002). Plasma
concentrations peak about 6 to 8 hours after ingestion and range
from 15 to 55 nanograms per mL. Fluoxetine exhibits nonlinear
pharmacokinetics, resulting in higher doses leading to
disproportionately higher plasma concentrations. (Drugs.com.)
According to AHFS Drug Information (2002), at plasma
concentrations of 200-1000 ng/mL in vitro, fluoxetine is 94.5%
bound to plasma proteins that include albumin and glycoprotein.
Food affects the rate of fluoxetine concentration, but does not
affect the extent of absorption.
Fluoxetine is metabolized in the liver by the cytochrome
P450 enzyme system into form its active metabolite,
norfluoxetine. (Holladay, 1998.) As it is very lipophilic,
fluoxetine is widely dispersed in peripheral tissues with a mean
volume of distribution of 36 to 50 liters/kg in humans
(Holladay, 1998), one study finding the mean ratio of brain
concentration to plasma concentration of fluoxetine plus its
metabolites to be 2.6 (Drugs.com.). The N demethylation of
fluoxetine resulting in norfluoxetine is polygenic. Research on
long-term use in animals indicates norfluoxetine levels in body
tissue to be highest in the and in the lungs. In rats both
fluoxetine and norfluoxetine have been found to cross the
placenta following oral administration, and both are distributed
into breastmilk (ASHP, 2002). In vivo studies find connections
between cytochrome P450 2D6 (CYP2D6) and fluoxetine metabolism,
and an in vitro study indicates that CYP2C9 and CYP3A may also
be implicated. (Drugs.com.)
According to the American Society of Hospital Pharmacists
(ASHP, 2002), elimination of fluoxetine and norfluoxetine is
slow process. After a mere single oral dose in healthy adults,
the elimination half-life ranges from 1 day to a full 9 days for
fluoxetine (as stated previously, 2 to 3 days is average), and 3
to 15 days for norfluoxetine (averaging 7 to 9 days). The
extreme individual variation in plasma half-life for fluoxetine
might be related to genetic differences in the liver's N
demethylation of the drug. (ASHP, 2002.) Metabolism might
further be under polygenic control, due to the absence of
trimodal or bimodal clearance distribution. Some studies report
plasma concentration being lower in patients with cirrhosis or
other chronic liver diseases, and some studies suggest
fluoxetine clearance decreases about 75% after multiple doses
once steady state concentrations are reached. Regardless, after
oral admission, fluoxetine and resulting metabolites are
excreted principally through the urine, at a rate of about 60%
within 35 days in healthy individuals. Since fluoxetine and
norfluoxetine bind extensively to proteins and have large-volume
distribution, forced diuresis, peritoneal dialysis,
hemoperfusion, and exchange transfusion are probably ineffective
to remove large amounts of the substance. (ASHP, 2002.)
Thus fluoxetine is metabolized by the liver, and crosses
the blood-brain barrier in both humans and animals; the route of
access to the brain is through the drug transporting P
glycoprotein at the barrier. Levels of brain penetration
differed depending upon the presence of the mdr1a gene, which
"may account for variable response patterns at different
episodes and development of therapy resistance." (Steckler et
al., 2000.) In the essays that follow, we discuss how
fluoxetine hydrochloride interacts with serotonin to produce
psychological and physiological effects at the microscopic and,
later, at a larger lifespan level.
References
American Society of Hospital Pharmacists. (2002.) American
Hospital Formulary Service Drug Information: Antidepressants:
Fluoxetine Hydrochloride. Bethesda Md. 1984 on. (annual).
Birdsall, T. 5 hydroxytryptophan: a clinically effective
serotonin precursor. 2005 Feb: available at:
http://www.thorn.com
Birmes. P. et al. (2003.) Serotonin Syndrome: a brief
review. CMAJ: 168(11).
Briley, M & Moret, C. (2003.) Neurobiological mechanisms
involved in antidepressant therapies. Clin. Neuropharmacol.
16(5):387 to 400.
Brownlee, C. (2004.) Anti depressants might rewire young
brains. Science News: 188 no 18, 278.
Cowen, PJ. (1991.) Serotonin Receptor Subtypes:
implications for psychopharmacology. Br J Psychiatry
Suppl.(12):7 to 14.
Davison. GC et al. (2004.) Abnormal Psychology, 9th ed. John
Wiley & Sons Inc: United States.
Fluoxetine Hydrochloride Drug Information. Retrieved Feb
2005. Available at:
http://www.drugs.com/MMX/Fluoxetine_Hydrochloride.html
Fortunecity.com. Fluoxetine/Prozac. Retrieved Feb 2005.
Available at:
http://www.fortunecity.com/campus/psychology/781/prozac.htm
Grahame Smith, DG. (1992.) Serotonin in affective
disorders. Int Clinical Psychopharmacology. 6; 4:5 to 13.
Holladay, J.W. et al. (1998.) Pharmacokinetics and
Antidepressant Activity of Fluoxetine in Transgenic Mice with
Elevated Serum Alpha 1 Acid Glycoprotein Levels.
26, Issue 1, 20-24. Available at:
http://dmd.aspetjournals.org/cgi/content/full/26/1/20.
Kalat, JW. (2001.) Biological Psychology. Australia:
Wadsworth.
King, MW. (2005.) Serotonin. The Medical Biochemistry Page,
Available at:
http://web.indstate.edu/thcme/mwking/nerves.html#5ht.
Leonard, B.E. (1992.) Pharmacological differences of
Serotonin Reuptake Inhibitors and possible clinical relevance.
Department of Pharmacology, University College, Galway, Ireland.
2:3-9; discussion 9 to 10.
Levy, AD. & Van de Kar, LD. (1992.) Endocrine and receptor
pharmacology of serotonergic anxiolytics, antipsychotics and
antidepressants. Life Sci. 51(2): 83 to 94.
Lilly, E. and Co. (1998.) Prozac. [online]
Messer, WS. MBC 3320 Serotonin. Retrieved 2005 Feb.
Available at:
http://www.neurosci.pharm.utoledo.edu/MBC320/serotonin.htm.
Peroutka, SJ & Snyder, SH. (1983.) Multiple Serotonin
Receptors and their Physiological Significance. Fed Proc. 42(2):
213 to 7.
RxList inc. Prozac Online. 2004. Available at:
http://www.rxlist.com/cgi/generic/fluoxetine.htm.
Uhr M, Steckler T, Yassouridis A, Holsboer F. (2000.)
Penetration of amitriptyline, but not of fluoxetine, into brain
is enhanced in mice with blood brain barrier deficiency due to
mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology.
22(4):380 to 7.
Dean Chelossi
Biological Basis
Psy 321
3-07-2005
Part of the Neurons affected by SSRI Inhibitor/Prozac
Pharmacological Effects
SSRI selectively blocked the reuptake of 5HT through their
inhibiting effects on the Na+/K+ adenosine triphosphatase
(ATPase) dependant carrier in presynaptic neurons.
A standard TCA such as amitriptyline, which has about an
equal tendency to block neuronal reuptake of 5HT and
norepinephrine, Fluoxetine in 200 times more selective in
blocking the reuptake of 5HT than of norepinephrine. Florentine
is approximately 4 times as potent as 5-HT reuptake inhibitor in
vito as is amitriptyline and paroxetine is approximately 80
times as potent an inhibitor as amitriplyline.
Of the five available SSRI's, paroxetine and citalopram
appear to be the most potent 5HT uptake blockers. The reuptake
blocking properties of the SSRI's enhance general serotonergic
tone in at least two distinct steps. Initially the SSRI's
contribute to a significant increase in the availability of 5HT
in the synaptic cleft.
Serotonin (5HT) interacts with multiple brain receptors.
Three receptors subtype to influences a wide range of behaviors.
There main families of 5HT receptors (5HT, 5HT2, 5HT3) have been
described which differ in their binding affinity for selective
ligands their receptor effectors coupling mechanism and the
behavioral processes they regulate. Manipulation of several
different %HT receptor subtypes (5HT1A, 5HTIC, 5HT2 and may
produce anxiolytic effects; 5HTIA and 5HT2 receptors maybe
involved in the etiology of major depression and the therapeutic
effects of antidepressants treatment. 5HT3 receptors have been
linked to reward mechanisms and cognitive processes. These
advances offer therapeutic possibilities, the value of which can
only be satisfactorily assessed by controlled clinical trails.
SSRI class antidepressant drugs are believed to have a
similar mechanism of action, we wanted to explore whether the
prototype SSRI drug Fluoxetine, share the effects of catalpa on
subcortical dopamine neurotransmission. Eight healthy male
volunteers were studied design. Striatal and thalamic D2-
receptor binding with measured at baseline,
after a single oral dose (20mg ld). The D2 receptor binding
potential (BP) was assessed using [1 raclopide and 3D position
emission topography. Repeated dosing of Fluoxetine decreased BP
in the right medial thalamus (p=0.022). Fluoxetine did not
decrease Striatal BP, but there was a trend (P=0.090) towards
increased BP in the left putamen after repeated dosing. A single
dose of Fluoxetine did not affect BP, in the thalamus or
striatum. Fluoxetine appears to have a regionally selective
effect on the dopaminergic neurotransmission in various areas of
the brain. The current results after Fluoxetine together with
our previous data on citalopram suggest that the modulatory
effects of these drugs on Striatal dopaminergic
neurotransmission are different upon repeated dosing and further
substantiates pharmacological differences between SSRI class
drugs.
Dopaminergic and glutamatergic neurotransmissions in the
stratum play an essential role in motor-reward related behavior.
Dysfunction of these neurotransmitter systems has been found in
Parkinson's disease, schizophrenia disease, and drug addiction.
Cyclindependant kinase 5(CDK) negatively regulates postsynaptic
signaling of dopamine in the striatum. This kinase also reduces
the behavioral effects of cocaine. Here we demonstrate that in
addition to at postsynaptic role, (CDK5) negatively regulates
dopamine release in the striatum. Inhibilators of CDK5 increase
envoked dopamine release in a way that is addictive to that of
cocaine. This presynaptic action of CDK5 increases the activity
and phosophrylation of N-methyl-D-asparate receptors and these
effects are reduced by dopamine D1 receptor antagonist. Using
mice with a point mutation of the CDK5 site of the postsynaptic
protein DARP-32.
Dopamine-and CAMP regulated phosoprotein molecular mass of
32 KDA, in the absence or in the presence of a dopamine D1
receptor antagonist, will provide evidence that CDK5 inhibitors
potentiate dopaminergic transmission at both presynaptic and
postsynaptic locations. The finding together with the known
ability of this class of compounds could potentially be used as
a manual treatment for disorders associated with dopamine
deficiency, such as Parkinson's disease. Pairing sub thresholds
excitatory postsynaptic potentials with back-propagating action
potentials has been repeated to result in the amplification of
dendritic action potentials and the induction of long term
potentials, in the dendrites of Hippocampal CA1 pyramidal
neurons.
Furthermore, the presence of the action potentials in the
dendrites was shown to be required for this L.T.P. induction
protocol. These findings led to the suggestion that
amplification or boosting of dendritic action potentials might
provide the postsynaptic depolarization required for the
unblocking of N methyl D asparate (NMDA) receptors to induce Ca
influx that is necessary for induction of LTP (2 to 4). Several
studies have shown that induction of L.T.P. by pairing
postsynaptic action potentials with EPSPs requires that the
spikes coincide with the EPSPs within a narrow time window (5 to
8). But if they occur within about 10 to 20ms from the beginning
of the EPSP, LTP is induced and if Ap and EPSP are separated by
more than 100ms, no plasticity is elicited. (5,6). This precise
timing relationship between the postsynaptic action potentials
and the EPSP is somewhat surprising, given that the deactivation
rate for NMDA receptors is around 200ms. (9). One possible
explanation for this narrow time window
is that the boosting of the amplitude of the dendritic action
potential by the increased activation of dendritic Na+ cannels
(10) and/or inactivation of dendritic K+ channels (2) is
required for LTP induction. Here we explore the relationship
between the boosting of action potential and LTP induction in
terms of spike timing. It was also tested the involvement of K+
channels in this relationship by using the mitogen-activated
protein kinas (MAPK) inhibitor U0126, which was found to
increase dendritic K+ currents. The results provided strong
support for the hypothesis that spike boosting is required for
this form of pairing induced L.T.P., and that dendritic K+
channels play a critical role in this phenomenon. The selective
cartooning reuptake inhibitors are similar to tricyclics but
specific to the neurotransmitter serotonin.
Florentine blocks the reuptake of serotonin by the
presynaptic terminal.
SSRIS produce only mild side effects. Anti-depressants
drugs have delayed effects that limit the excitation of the past
synaptic cell. One such effect is to decrease the postsynaptic
cell. One such effect is to decrease the sensitivity of the
postsynaptic receptors. One of the receptors that are involved
is the auto receptor. It is a negative feedback receptor on the
presynaptic terminal. After an axon releases much of its
neurotransmitter, some of the molecules come back to stimulate
the auto receptors, which then decreases further release of the
neurotransmitter.
In vivo microdialysis was used to examine the effects of
peripheral uptake inhibition on extracellular serotonin (5-HT).
Previous results from this lab indicated that systematic
Fluoxetine caused a decrease in 5HT when terminal uptake was
inhibited by local infusion of the uptake blocker. We
hypothesized that the decrease in 5HT levels in the terminal
region was due to an increase in 5-Ht in the vicinity of the
inhibitory somadentritic Autoerceptors in the dorsal raphe
nucleus (DRN). To test this prediction, rats were implanted with
probes in both the basal diencephalon (a nerve terminal region)
and the DRN (the cell body region). Fluoxetine (10mg/kg I.p.
increased extra cellular 5HT, in a depolarization - dependent
manner by approximately 140% in both areas. In a separate
experiment, Fluoxetine, seratraline, or paroxetine produced a
50% decrease in intracellular 5HT in the diencephalons,
presumably due to activation of the 5Ht 1A
somadentritic auto receptors. Consistent with this hypothesis
systemic administration of the 5-HT1 antagonists spiperone,
penbutalol or WAY100135 reversed the Fluoxetine induced decrease
in 5-HT to approximately 85% of the pre-Fluoxetine baseline
levels. Likewise, pretreatment with penbutalol but not selective
B-adrenergic antagonists, blocked the Fluoxetine induced
decreased in release. These findings suggest that the ability of
acute systematic 5HT uptake inhibition to elevate nerve terminal
5Ht is limited
by auto receptors activation following elevation of 5HT in the
DRN.
These selective serototin reuptake inhibitors (SSRIs) have
emerged as a major therapeutic advance in psychiatry. The
treatment has emphasized the pathophysiological role of
serototin and the (5Ht) in affective disorders. Indeed, SSRIs
were developed for inhibition of the neuronal uptake for
serototin (5Ht), a property shaved with the TCAs (tricycli anti-
depressants, but without affecting the other various central
neuroreceptors) that are responsible for many of the safety and
tolerability problems with TCAs. In this way, Fluoxetine and
other SSRIs represent major advance over tricyclic, because of
their lower toxicity.
While the position Fluoxetine relative to other selective
serotoninergic antidepressants requires favorable tolerability
profile for similar efficacy in comparison to tricyclic and
antidepressants. The pharmacokinetic and pharmacodynamic
properties of Fluoxetine are well described. After oral
administration, Fluoxetine is almost completely absorbed. Due to
hepatic first- pass metabolism, the oral bioavailablity is <
90%. Fluoxentine has a half- life of 2-7 days, whereas, two
half-life of nonfluoxetine ranges between 4 and 15 days. The
half-life of norfluoxetine/man is advantageous when the patient
omits a dose since drug concentrations decrease slightly. On the
other hand, in the case of Fluoxetine non-response, long washout
periods are necessary before switching the avoid drug
interactions or the development of 5Ht syndrome. As a class,
SSRIs are considerably more selective in comparison to TCAs in
terms of their central nervous system mechanisms, but differ in
other clinically relevant aspects. This action affects several
specific 5ht receptors, which turn, affects a multitude of
neural systems and signalization of pathways. However, the
direct mechanism by which a SSRI exerts its anti-depressant
activity remains uncertain. But the therapeutic response in a
major depression for SSRIs (15days), maybe due to a progressive
desensitization of Somatodendritic 5-Ht auto receptors in the
midbrain of the nucleus. On the other hand, it has also been
postulated that "HT" is a modulator of several neurophsiological
pathways including dopamine, nor adrenaline, but also
neurotrophic factors, intra-cytoplasm phosphorylations and
nuclear genes expression. Therapeutic activity of SSRIs may
finally results in a complex modulation and neuronal plasticity
in term of health-care, the 1980's has radically changed the
treatment of depressive disorder worldwide, and they have
emerged as a first line of treatment for depressive disorder.
Indeed, this efficacy has been assessed in numerous clinical
controlled trails involving patients with major depressive
disorders. Meta-analysis would carried out and confirmed that
Fluoxetine was a effective as the tricyclic anti-depressants,
and appeared more effective than another, but not all patients
respond to the same agent. Looking to the future, we need
further comparative studies of the SSRIs with the next
generation of anti-depressants such as neither 5HT nor
adrenaline reuptake inhibitors (SNSIs Venlafaxine). Actually, it
is interesting to note that, whereas the emphasis with the SSRIs
has been on their selectivity, recent developments have tended
to move towards less selective agents, and now to other
neurobiological pathways (neurotrophic factors). Finally
Fluoxetine shares in common with other SSRIs remain as today a
first-line treatment option for major depressed disorders.
References
Selective Serototin Reuptake Inhibitors.
By: Battista, Charles De; Cole, Jonathan O.; Schatzberg, Alan F.
Manual of Clinical Psychopharmacology Fourth Edition, 2003,p47-
50.
Cyclin- Dependent Kinase 5 regulates Dopaminergic and
Glutamatergic transmission in the Striatum.
By: Chergui, K; Greengard, P. Processing of the National Academy
of Sciences of the United States of America, Feb17, 2004,Vol.101
no.7, p2191-2196.
Dendritic K+ channels contribute to spike- timing dependent
long-term potentiation in Hippacampal Pyramidal Neurons. By:
Hoffman, Dax A; Johnston, Daniels; Migliare, Michele; Watanabe,
Shigeo. Proceedings of the National Academy of Sciences of The
United States of America, June4, 2002, vol.99,p8366-8371.
Moods disorders that used to control Selective Serotonin
Reuptake Inhibitors. By: Kalat, James. W. Wasworth, a division
of Thomason Learning Inc.,2004,Ch.15,p467-468.
Serotonin receptors subtypes: implications for
psychopharmacology. By: PJ, Coen. National Library of Medicine
Pub Med. Br. J Psychiatry Suppliment, Sept1991, Vol. 12, p7-14.
Effects of Fluoxetine on Dpoamine D2 receptors in the human
brain: a positron emission topography study with [11c] recopied.
By: Aalto J; Hietala J; Hirvonen J; Illonen T; Kajander J;
Nagren K; Penttila J; Syvalahti E. National Library of Medicine
Pub Med. Int J. Neuropsychopharmacol, Dec7,2004, Vol. 4, p431-
439.
Systemic Uptake inhibition Decreases Serotonin release via
Somatodendritic Autoreceptor Activation. By: Auerbach, Sidney B;
Gundalah, Christine; Rutter, John J. M. Wiley Inter Science on-
line, 1995, Vol.20, Issue 3, p225 to 233.
Fluoxetine: an update of its use in major depressive
disorder in Adults. By: Gourion, D; Perrin, E; Quintin, P.
National Library of Medicine Pub Med. Encephale, 2004Jul Aug30;
4: p392 to 399.
Marnie Lucas Zerbe
Psychology 321
Dr. Morgan
7 March 2005
Inhibitory Potential Changes of Fluoxetine (Prozac)
Over the past several decades many scientists have explored
the various possible links between the function of
neurotransmitters in the brain and mood disorders. The
neurotransmitter serotonin, found widely in plants, animals
and humans has been a particular focus. Scientists who
specialize in examining the function and effect of serotonin
on the mind and body argue that imbalances in the levels and
function of serotonin can be linked to disturbances in mood,
anxiety, satiety, cognition, aggression and sexual drives
(Tollefson and Rosenbalum, 2001). More specifically, these
scientists suggest that this "decreased serotonergic
neurotransmission plays an important role in the etiology of
depression" (Xia, Gopal, and Gross, p. 157, 2002). Indeed
studies that have examined serotonin via its major
metabolite, 5-hydroxyndoleacetic acid (5-HIAA) consistently
indicate that 5-HIAA levels are low in the cerebrospinal
fluid of depressed patients (Davison, Neale and Kring, 2004).
Because serotonin does not cross the blood-brain barrier, it
must be synthesized locally. That is, it must be synthesized
from within neurons in the brain. Once it is synthesized is
then "released into the synapse from the cytoplasmic and
vesicular reservoirs. Following release, serotonin is
principally inactivated by reuptake into nerve terminals
through a sodium/potassium (Na+/K+) adenosine triphosphatase
(ATPase) dependent carrier." (Tollefson and Rosenbalum, p.
27, 2001). Problems arise when too much serotonin is
recaptured in the reuptake process during synapse or when to
little serotonin is being locally manufactured in the central
nervous system. As a result, too few serotonin
neurotransmitters are able to make it across the synaptic
cleft to stimulate postsynaptic receptors. Moreover, "in the
absence of pharmacological manipulation, the reuptake of
serotonin into the presynaptic nerve terminal typically leads
to its inactivation" (Tollefson and Rosenbalum, p. 32, 2001).
Low levels of serotonin have been most commonly linked to
depression. For this reason, there have been many attempts by
neuroscientists to develop antidepressant drugs that can
interfere with the enzymes that eliminate serotonin
neurotransmitters from the synapse. Indeed, though reuptake
inhibition scientists hoped to be able to increase levels of
serotonin in the CNS and thus ameliorate the negative affects
of depression.
One of the most recent breakthroughs in this pursuit was the
development of the antagonist drug, fluoxetine. Fluoxetine
(or Prozac) is a selective serotonin reuptake inhibitor, and
functions by acting as a barrier in the serotonin synaptic
reuptake process. One of the most exciting things about the
development of prozac was that it was not a "dirty drug".
Unlike other antidepressant medicines that had the unintended
affect of acting on several neurotransmitters in addition to
serotonin, Prozac selectively affects only serotonin. (Eli
Lilly and Co. 2005 www. Prozac.com)
More specifically, Prozac "acutely enhances serotonergic
neurotransmission by permitting serotonin to act for an
extended time at synaptic binding sites" The result is an
acute increase in synaptic serotonin" (Tollefson and
Rosenbalum, p. 32, 2001). In other words, by inhibiting the
reuptake, and thus the inactivation, of serotonin back into
the presynaptic nerve terminals, prozac is able to increase
the amount of serotonin in the synaptic cleft available for
postsynaptic stimulation. The subsequent increase in
serotonin levels in the CNS is said to be affective in
treating not only depression but also several other common
psychological disorders, including obsessive compulsive
disorder, bulimia and panic disorder.
In addition to Prozac's reputation as an effective 'clean
drug' recent studies suggest an additional benefit that it
may provide to those suffering from acute depression. Because
a common symptom in depressed patients is poor memory
performance, scientific studies have been done to see what
effect fluoxetine might have on memory. In one recent study,
selective serotonin reuptake inhibitors were found to be more
"advantageous over noradrenergic drugs in their effects on
major depression associated with memory
deficiency"(Levkovitz, Caftori, Avital, and Richter-Levin,
p.349, 2001). Indeed, when "comparing the improvement in
performance of memory tasks among major depressive patients
during acute episodes, patients treated with Fluoxetine
exhibited a significant improvement in memory task
performance"(Levkovitz, Caftori, Avital, and Richter-Levin,
p.349, 2001). Thus, this study, like so many doctors,
concludes that Prozac remains the drug of choice for treating
major depression.
References
Davison, G., Neale, J., & Kring. A. (2004). Abnormal
Psychology: Ninth Edition. John Wiley & Sons, Inc.
Eli Lilly and Company. How Prozac Can Help. www.prozac.com.
Levkovitz, Y., Caftori, R., Avital, A., Richter-levin, G.
(2002). The SSRIs drug Fluoxetine, but not the noradrenergic
tricyclic drug Desipramine, improves memory performance drug
acute major depression. Brain Research. 58(4), 345-350.
Tollefson, G., Ph.D., & Rosenbaum, J. (2001). Selective
Serotonin Reuptake Inhibitors. In Schatzberg and Nemeroff.
(Eds.), Essentials of Clinical Psychopharmacology. (pp. 27-
41). Washington: American Psychiatric Publishing, Inc.
Xia, Y., Gopal, K, & Gross, G (2003). Differential acute
effects of flouxetine on frontal and auditory cortex networks
in vitro. Brain Research. 973, 151-160.
Marnie Lucas Zerbe
Psychology 321
Professor Morgan
03/07/05
Primary Behavior Changes
Selective Serotonin Reuptake Inhibitors have been approved
for use in the treatment of a wide area of psychological
disorders, including major depression, obsessive-compulsive
disorder, bulimia nervosa, panic disorder, social phobia,
post traumatic stress disorder, and premenstrual dysphoric
disorder. They are also said to be effective in treating
dysthymia and chronic depression. (Tollefson and Rosenbaum,
2001) The manufacturer of Prozac, Eli Lilly advertises that
this drug is particularly effective in treating clinical
depression, obsessive compulsive disorder, bulimia and panic
disorder. The manufacturer argues that, "While Prozac cannot
be said to 'cure' depression, it does help control symptoms
of depression, allowing many people with depression to feel
better and return to normal functioning." (Eli Lilly,
www.prozac.com) The diminished side effects of Prozac and its
overall effectiveness in treating depression, OCD, bulimia
and panic disorder has made it the drug of choice for over
two decades.
More than this, many psychiatrists have attributed to the
drug some amazing transformative properties above and beyond
that of just diminishing the negative symptoms associated
with depression. As one physician put it, "Prozac seemed to
give social confidence to the habitually timid, to make the
sensitive brash, to lend the introvert the social skills of a
salesman." (Kramer, Peter, D., p. xvii, 1993) Indeed, he
argued that Prozac made patients 'better than well' and
actually served to transform personality. "The
transformative powers of the medicine went beyond treating
illness to changing personality, it entered into our struggle
to understand the self." (Kramer, Peter, D., p. xviii, 1993)
Prozac's approval for use for patients under the age of 18
has also been a particular selling point for Eli Lilly. As
recently as summer 2004, NPR reported that the Journal of the
American Medical Association showed that "Prozac, in
combination with cognitive behavioral therapy, is highly
effective for treating depression in teens. But the study
also showed a small increase in 'harm-related behaviors,'
including suicide attempts, among teens on Prozac." (Baron,
National Public Radio, 2004, www.npr.org) Other doctors have
been more cautious about the behavioral change benefits of
Prozac. They warn that Prozac has produced some very serious
side effects leading to several lawsuits against Eli Lilly.
"These side effects include akathisia (a condition in which a
person feels compelled to move about), permanent neurological
damage, and suicidal obsession and acts of violence." (Null
and Feldman, 1998, www.garynull.com.) While Eli Lilly
acknowledges the risks that have been associated with the
administration of Prozac to children, warning that,
"antidepressants increased the risk of suicidal thinking and
behavior in children and adolescents with depression" it has
not recommended against its further administration to
children.
Thus it is safe to say that the psychological community's
confidence in this 'wonder drug' for consistently and safely
delivering positive behavioral changes to patients suffering
from depression is not at all unanimous. From studies that
point to its proven potential for fostering positive
transformative changes in personality to those that warn
against its proven propensity to increase the risk of
suicidal tendencies and suicide in some children, it is
difficult to know whether this the Dr. Hyde or Mr. Jeckel of
antidepressant medications. Nonetheless, Prozac still remains
one of the post popular anti-depressants on the market.
As is often the case, further studies on both the drug and
the brain will continue to be necessary. It will be
necessary, for example to come to a greater understanding of
the exact function of serotonin and the exact extent it
influences mood. While SSRIs have been a breakthrough in
biological science for their ability to target only serotonin
neurotransmitters, it seems clear that, (at least for some
patients), increasing levels of Serotonin is not the key to
treating all depressive symptoms. Moreover, it is important
to remain cognizant of the added benefit of cognitive
behavioral therapies in preventing relapses should patients
need/want to discontinue Prozac.
References
Baron, D., (2004) Gauging Risks, Benefits of Prozac in Teens.
National Public Radio: All things considered. www.npr.org.
Eli Lilly and Company. How Prozac Can Help. www.prozac.com.
Kramer, P.D. 1993. Listening to Prozac. New York: Viking
Null, G., Feldman, M. (1998) The dangers of Prozac: part 1.
www.garynull.com.
Tollefson, G., Ph.D., & Rosenbaum, J. (2001). Selective
Serotonin Reuptake Inhibitors. In Schatzberg and Nemeroff.
(Eds.), Essentials of Clinical Psychopharmacology. (pp. 27 to
41). Washington: American Psychiatric Publishing, Inc.
Kellie Housel
Morgan
3-5-05
Side Effects of Prozac
Unlike earlier forms of antidepressants, such as MAO
inhibitors, Prozac and other SSRIs tend to produce fewer
and less severe side effects (Hockenbury, 200). According
to Prozac's manufacturer, Eli Lilly (2005), side effects
caused by Prozac may include nausea, difficulty sleeping,
drowsiness, nervousness, weakness, loss of appetite,
tremors, dry mouth, sweating, or yawning. Other side
effects listed included a change in sexual desire or
satisfaction and a formation of a rash or hives. Eli Lilly
(2005) states that these side effects generally go away
after a few weeks of usage and are not serious enough to
discontinue use of the drug.
Other side effects of Prozac reported by PDRhealth include
abnormal vision, itching, flu like symptoms, gas,
sinusitis, and sore throat. Less common side effects
reported included abnormal taste, bleeding problems,
chills, ear pain, fever, frequent urination, high blood
pressure, loss of memory, palpitations, and ringing in the
ear.
The most common side effects reported in controlled study
of patients receiving Prozac, and those receiving a
placebo, patients receiving Prozac more frequently reported
experiencing anxiety, dizziness, lightheadedness,
nervousness, insomnia, drowsiness, fatigue, tremors,
nausea, diarrhea, dry mouth, abnormal vision, decrease in
libido, rash, sweating, and abnormal ejaculation (American
Hospital Formulatory Services, AHFS, 2002). Of these
patients, fifteen percent had to discontinue use of Prozac.
The main reason reported for discontinuation was the onset
of anxiety, nervousness, headaches, dizziness, nausea, and
rashes. Fluoxetine tends to remain in the metabolic system
for sometime, and because of this any adverse side effects
may take a few weeks to dissolve after discontinuation
(AHFS, 2002).
Side effects reported by patients receiving the weekly dose
of fluoxetine in delayed-release capsules, reported
relatively the same side effects as those taking a daily
dose. Although, problems with cognition and diarrhea were
reported more frequently with the delayed-release capsules
(AHFS, 2002).
The percentages of patients experiencing adverse side
effects of Prozac are as follows: twenty percent
experienced headaches, nine percent felt anxious or
nervous, fourteen percent experienced insomnia, four
percent reported drowsiness or fatigue, six percent
experienced tremors, and one to two percent reported
adverse affects to the nervous system such as confusion,
agitation, abnormal dreams, and sedation. The majority of
these effects may be caused by the dosage a patient
receives, and few patients in each group discontinued the
use of Prozac (AHFS, 2002). In one case mania was reported
in a patient, although that patient had received an
unusually high dose (140mg per day). After the patient was
switched to a lower dose (60mg per day) the symptoms of
mania did not appear (AHFS, 2002). The incident of
seizures in patients receiving Prozac was rarely reported
at less than one percent.
There is little information on the effects to the fetus of
women who take Prozac during pregnancy. In a study done on
pregnant rats, there was evidence that fluoxetine crossed
over into the placenta (AHFS, 2002). Another study
conducted on rats showed a correlation between rats exposed
to fluoxetine from four to twenty one days old and anxiety
and depression later in life. The time period of exposure
to the rats relates to the third trimester of pregnancy to
age eight in humans (Brownlee, 2004). According to
researchers, this correlation of early exposure to
fluoxetine and later development of depression and anxiety,
suggests that early blockage of serotonin transporters in a
developing brain may permanently disrupt the transporters
function (Brownlee, 2004). It is not known at this time
how this study on rates relates to effects on human
fetuses, but the evidence suggests that further studies are
needed (Brownlee, 2004). Fluoxetine can also be found in
breast milk, and it is recommended that women who take
Prozac should not breastfeed, and should be aware that
fluoxetine does not leave the body immediately after
discontinued use (AHFS, 2002).
Very few patients taking Prozac reported having increases
in suicidal thoughts and behaviors, and these instances
have not yet been associated as a direct cause of
fluoxetine, but rather a coincident (AHFS, 2002). SSRIs
tend to cause a mild reaction to any overdose, unlike that
of tricyclics, which can have life-threatening cardiotoxity
effects if an overdose occurs. Because of this, it is more
beneficial to treat patients experiencing suicidal thoughts
or actions with an SSRI, such as Prozac (AHFS, 2002). The
side effects often associated with an overdose of Prozac
are nausea, rapid heartbeat, seizures, sleepiness, and
vomiting. Less common effects are coma, delirium,
fainting, high fever, irregular heartbeat, low blood
pressure, mania, rigid muscles, sweating, and stupor
(PDRhealth).
The prevalence of increased suicidal thought among patients
treated with fluoxetine seems to increase in adolescent and
young children. Eli Lilly (2005) has stated that Prozac
may increase suicidal thinking and actions by children and
adolescents, and that the use of Prozac in any patient
should be strictly clinical. The manufacturer also states
that children and adolescents should be closely monitored
on Prozac for evidence of behavior changes related to
suicidal thoughts. Studies have shown that SSRIs are more
effective in treating childhood depression than MAO
inhibitors and tricyclics (AHFS, 2002). On January 3,
2003, Prozac became the first (and only) antidepressant
approved by the FDA to treat children with depressive
disorder (U.S. Food and Drug Administration, 2003). The
FDA reports that children typically experience the same
side effects as adults do on Prozac, including nausea,
tiredness, nervousness, dizziness, and difficulty
concentrating. Few patients experienced weight loss, and
there is no research to date on the long term effects
Prozac may have on children, although Eli Lilly has agreed
to conduct a long term evaluation (U.S. Food and Drug
Administration, 2003).
The side effects reported in geriatric patients of Prozac
were similar to side effects reported by younger adults.
SSRIs may be more beneficial to geriatric patients because
troublesome side effects found in tricyclic antidepressants
such as constipation, dry mouth, confusion and memory
impairment are typically not as common with treatment of
SSRIs.
Mixing Prozac with other drugs can have drastic and life
threatening effects. Prozac should never be taken with MAO
inhibitors such as Nardil or Parnate, and patients should
discontinue use of either drug five weeks prior to starting
a different one (PDRhealth). Other medications that should
be discussed with a doctor before combining with Prozac
include Xanax, Tegretol, Clozaril, Valium, Crystodigin,
sleep aids, painkillers, Tambocor, Haldol, Eskalith,
Elavil, Dilantin, Orap, Tryptophan, Velban, and Coumadin
(PDRhealth). Eli Lilly (2005) also warns that anyone
taking the antipsychotic medicine Mellaril (thioridazine)
should discontinue use five weeks before starting Prozac.
Effects Reported by Patients/Survivors
Since its release in the 1980's, Prozac has been a widely
controversial drug. Most of the controversy is directed at
the slight and rare side effect of mania, and the issue
surrounding an increase in suicidal thoughts. The Suicide
and Mental Health Association International (2003) claims
that since Prozac's release, incidences of violence and
suicide are higher in patients taking Prozac. One doctor
claimed a patient he had given Prozac to for slight
depression became acutely psychotic after only three days
on the drug (Cohen, 2003). The Alliance for human Research
Protection also states that patients with no prior history
of suicidal thoughts became suicidal after being treated
with Prozac (2003). There have been a number of lawsuits
filed relating to patients who report having serve and
drastic side effects from Prozac, as well as numerous
defense claims that Prozac caused an individual to become
violent or psychotic. Although there has been considerable
backlash against Prozac from these lawsuits and trials, it
should be noted that there is still no evidence that Prozac
was the direct cause in any of these instances.
Not all of the reports from patients have shown negativity
towards Prozac. A Report in the BBC News (1999) claimed
many users reported very positive effects and outcomes from
using Prozac for different psychological disorders.
Although the majority of testimony from previous Prozac
patients is fueled with negativity, this select population
does not represent every individual taking (or who has
taken) Prozac. Prozac still remains a widely popular drug
used to treat many different psychological disorders.
References
Alliance for Human Research Protection (2003, June 27).
Retrieved March 1, 2005, from
http://www.ahrp.org/infomail/0603/27.php
American Society of Hospital Pharmacists. (2002) American
Hospital Formulary Service Drug Information. Bethesda, MD:
American Society of Pharmacists.
BBC News. Prozac Celebrates 10th Birthday (1999, January
21). Retrieved February 27, 2005, from
http://news.bbc.co.uk/2/hi/health/259344.stm
U.S. Food and Drug Administration. FDA Talk Paper (2003,
January 3). Retrieved February 28, 2005, from
http://www.fda.gov./bbs/topic/ANSWERS/2003/ANS01187.html
Brownlee, C. (2004). Antidepressants might rewire young
brains. Science News, 18, 278. Retrieved February 21,
2005, from WilsonLink.
Cohen, J.S., M.D. Suicide and Homicides in Patients taking
Paxil, Prozac, and Zoloft: Why they keep happening And why
they will continue (2003). Retrieved March 1, 2005, from
http://suicideandmentalhealthassociationinternational.org/s
uihom.html
Eli Lilly and Company, Prozac Safety Information (2005).
Retrieved March 1,2005, from
http://prozac.com/common_pages/safety_information.jsp?reqNa
vId=undefined
Hockenbury, D.H. and S.E. (2000). Psychology (Sec. Ed.).
New York, NY: Publishers.
PDRhealth, Prozac. Retrieved February 25, 2005, from
http://pdrhealth.com/drug_info/rxdrugprofiles/drugs/pro1362
.shtml
Go back to the beginning
Copyright © 2005, Dr. John M. Morgan, All rights
reserved -
This page last edited 1-3, 2005
If you have any feedback for the author, E-mail me
