---------- ADVANCED PSYCHOPHARMACOLOGY ----------
---------- SPRING, 2005 ----------
---------- A Syllabus ----------

                            
                            
                       ADVANCED PSYCHOPHARMACOLOGY

Psychology 572                       	                                 Spring, 2005
Dr. John M. Morgan                                   Tuesday & Thursday, 8am to 9:20
                                                                      Natural Resources 201

Selective Serotonin Reuptake Inhibitors(SSRIs)
physiological,inhibitory,excitatory potential,effects and behaviors

Group Project: Debra Pizzuto, Joseph Waters, Autumn Spears, Socorro 
Valdez

Serotonin is an indoleamine found in plants animals and humans.   In 
humans, several limbic structures manifest high levels of serotonin 
receptors found though out important fear structures in the brain. It is 
useful in our consideration of serotonergic drug action to briefly 
discuss the comparison of serotonin fiber distribution with specific 
serotonin receptor localization in the role of serotonin receptor 
subtypes within specific serotonin circuits. They are located 
heterogeneously in the brain stem which further divides into two 
subdivisions.  The rostral division localized from midbrain and pons 
ascends initially to the forebrain before branching to innervate 
specific target regions, with the proportion from each area varying in 
different brain structures.  The caudal division, located in the medulla 
oblongata, sends descending projections to the spinal cord.  Most 
ascending projections forming a duel projection system originate form 
the raphe nuclei. The dorsal raphe nuclei  located in the  ventral 
portion of the periaqueductal gray  matter, contains the largest 
number of serotonin neurons in the brain,  estimated at 1650,000 in 
the human (Shatzberg 62). In each receptor projection area 
seratongenic intervention pattern is distinct. Several studies indicate 
that SSRIs transiently inhibit dorsal raphe firing, decrease terminal 
autoreceptor function and increase net serotonin synaptic 
transmission within CA3 primmidal cells in the hippocampus.  

Brain Graphic
			Figure  1             Brain graphic

Serotonin abnormalities are widely reported in patients with 
depression, especially those with suicidal behavior.  Much research in 
post mortem brains of patients with depression has focused on high 
concentrations of serotonin in the raphe nuclei. Drug development is 
most currently  based on knowledge and theory regarding how an 
agent might affect the pathology underlying a specific disorder by 
neuronal uptake pump for a specific neurotransmitter, receptor 
subtype, or a subunit of an ion channel. 
[5HT.sub.1a] is the most extensively studied serotonin receptor 
(Taylor 2005) binding sites include both somatodendritic and 
presynaptic autoreceptors and hippocampal post synaptic receptors, 
which inhibit(negatively regulate) serotonin firing. Sensitivity is 
increased after chronic antidepressant exposure.  Drugs that modify 
serotonin [5HT] activity by inhibiting its uptake carrier have been most 
productive in antidepressant therapy. This form of antidepressants 
beneficial effect lies in its ability to block neurotransmitter uptake. 

To date there are at least 15 different serotonin receptors identified 
and divided into seven different families(Taylor et al 2005). Less 
conclusive evidence suggests reduced sensitivity of [5HT.sub.1b] sites 
may uniquely characterize SSRIs. [5HT.sub.2] receptors are located 
post synaptically throughout the hippocampus, cortex, and spinal 
cord. They inhibit post synaptic propagation of a nerve impulse. The 
upregulation of [5HT.sub.2] binding site is widely implicated in major 
depression.  Many studies indicate that with chronic administration, 
antidepressants downregulate or reduce the density of 
[5HT.sub.2]binding sites in rat frontal cortex.  These adapting sites are 
sited as necessary for antidepressant response (Cowen1991). The 
[5HT.sub.2] agonists (including SSRI receptors) contribute to sexual 
dysfunction, anxiety, and insomnia.  To date, findings remain 
somewhat inconclusive as to the exact nature.
 
Much of the existing research has indicated that specific receptor 
effects may not be independent.  SSRIs as a class have been reported 
to normalize receptor density in both [5HT.sub.1] and [5HT.sub.2] 
among depressed patients. This may further suggest interactions 
between individual binding sites. (Taylor 2005) indicated that 
antidepressants enhance net serotonin transmission after chronic use 
via reduced sensitivity of somatadendritic [5HT.sub.1a] and terminal 
autoreceptors [5HT.sub.1d]. This view suggests that alterations exist 
in the functioning of the receptor site or the secondary messenger 
systems modulating the activity of the receptor site postsynaptically.  
Psychopharmacologic treatment is based on the restoration of 
normality to neurotransmitter systems by (1) blocking 
neurotransmitter uptake in the presynaptic nerve ending (2) inhibiting 
neurotransmitter breakdown (3) stimulating the release of 
neurotransmitters.  The various differences in individual brain 
mechanisms may offer additional explanation in explaining response 
differences of SSRIs in clinical use.  However, there are significant 
structural activity differences between contemporary SSRI's. 
The structural differences are related to both pharmacokinetic and 
pharmacodynamic heterogeneity. All SSRIs tend to be highly protein 
bound(80% to 90%)but have significant differences in half lives, 
ranging from a few hours to nine days or longer.  Steady state for 
fluoxetine(Prozac) can take 6 to 8 weeks. Paroxetine(Paxil) appears to 
be the most potent invito SSRI.   Citalopram (Celexa) may be the most 
selective.   This does not relate exclusively to dosing experience, 
clinical efficacy, or  adverse event profile. Invitro radioligand binding 
techniques show SSRI's have a lower probability of many of the side 
effects associated with TCAs.  It appears that SSRIs are relatively 
selective in their serotonin reuptake inhabition while retaining an 
individual variability in their receptor pharmacology.  


Neuron
				Figure   2 

Treatment with SSRI antidepressants causes downregulation of 
[5HT.sub.2] receptors (Taylor etal,2005).  In agreement with these 
finding [5HT.sub.2a.2c] receptor agonists are anxiogenic. The fact that 
serotonin is both anxiolytic and anxiogenic highlights the complexity 
of brain responses to stress. There is no known receptor subtype 
singularly responsible for depression.

Serotonin syndrome is but one important side effect in the 
management of SSRIs.  The evidence suggests that the denervation 
like induced alterations in serotonin receptors is vital to the 
development of serotonin syndrome.  While increased [5HT] levels in 
intact animals lead to the syndrome, it is not as clear that serotonin 
syndrome is mediated solely by serotonin.  Dopamine appears to play 
some role in the expression of the syndrome.  

Recent studies suggest that neurogenesis (i.e. the process of neuronal 
stem cell proliferation, differentiation, and survival) is involved in the 
action of antidepressants.  According to Taylor, antidepressants 
mediate their effects through the increase of serotonin by SSRI and NE 
levels allowing neurotransmitters to stimulate the cAMP or Ca, leading 
to the increase in CREB and BDNF.  Continued research efforts are 
important in understanding and alleviating side effects from what are 
now current medications.

A series of studies offer promise pertaining to the next generation of 
antidepressants.  (Meager etal. 2001)found a reduction in the delay of 
therapeutic benefit may be in co-administration of 5HT.sub1a 
antagonist and an SSRI to be beneficial in several groups to 
accelerate antidepressant effects. Further they suggest that an 
achievable merging of [5HT.sub.1a] antagonism and [5HT] transporter 
reuptake inhabition into one molecular entity to be a superior 
antidepressant. (Evrad,etal 2005)expand on this theory with 
methodology tested on rat and human [5Ht] receptors in their effort to 
design a dual acting [SSRI.5HT.sub.1a] antagonists as possible next 
generation antidepressants.
These and other future research efforts are important for the 17 to 
20% of the population in the United States that suffer from depression.

References
Carvey,P. (1998) Drug Action in the Central Nervous System. New 
York. Oxford University Press.
Evrad, D.A.,etal. (2005)  Studies towards the next generation of 
antidepressants. Part 4: Derivatives of cyclohexylamine with affinity 
for the serotonin transporter and the [5HT.sub.1a] receptor. Bioorganic 
& medicinal chemistry letters 15 (911.914). 
Grabowski,J. & VandenBos,G.(eds.), Psychopharmacology: Basic 
mechanisms and applied interventions. Washington, DC American 
Psychological Association
Keltner, N. (2001) Psychotropic Drugs 3rd ed. St.Louis,MO. Mosby inc. 
Harcourt Health Sciences inc.
Meager,K.L.,etal. (2001) Studies Towards the next generation of 
antidepressants. Part 1 indolycyclohexylimines as potent serotonin 
reuptake inhibitors.  Bioorganic & medical chemistry letters 
11(1885.1888).
Post,R. & Ballenger,J.(eds). Neurobiology of Mood Disorders vol.1. 
Baltimore,MA. Williams & Wilkens.
Schatzberg,A. & Nemeroff,C. (1998) The American Psychiatric Press 
Textbook of Psychopharmacology 2nd.ed.Washington,DC. American 
Psychiatric Press inc.
 	Taylor, C., etal. (2005) Mechanisms of action of antidepressants: 
from neurotransmitter systems to signaling pathways.  Cellular 
Signaling 17(549.547).







There are many different kinds of neurotransmitters in the body; but 
the ones linked to depression are the monoamines; serotonin, 
norepinephrine, and dopamine. Substances that affect one of these 
neurotransmitters will also affect the others. Each of the three 
monoamines is more prevalent in some areas of the brain than others 
so their effects may vary. When the level of these neurotransmitters 
are low, it is likely that a mood or anxiety disorder will follow. As 
serotonin is released into the brain it is reabsorbed by the brain cells 
and used at another time for another message. This is the process 
referred to as reuptake, allowing the synapse to recycle their 
materials. SSRIs target the neurotransmitter serotonin. In doing this it 
is "selective". SSRIs also inhibit the reuptake of serotonin alone 
explaining the name Selective Serotonin Reuptake Inhibitor. An 
individual suffering from a mood disorder, and anxiety disorder, or an 
eating disorder has some or all of the following symptoms: emotional 
distress caused by feelings of vulnerability, apprehension, fear, 
episodes of deep sadness and despair, feelings of helplessness, 
suicidal ideation, and loss of appetite and/or overeating. The 
neurotransmitters associated with the aforementioned are the 
monoamines; serotonin, dopamine, and norepinephrine. 
SEROTONIN
Serotonin (5HT) is known to have an effect on sleep, appetite, mood, 
memory, emotion, and learning. Serotonin has been found on fruit, 
nuts, plants, and animals. Serotonin is found more abundant in the 
brain stem (involved in arousal and sleep) and thalamus. Research 
indicates that dysfunction of serotonergic neurotransmission is 
strongly correlated with the development of mood disorders such as 
depression and anxiety. One of the main targets of the serotonergic 
system is the prefrontal cortex which is associated with the control of 
emotion and cognition (Zhong & Yan, 2004). Slight changes in the 
chemical structure of serotonin result in hallucinogens such as LSD, 
ecstasy, and mescaline.
SSRIs are the more popular method of chemically treating depression 
because of the nature of their delivery. SSRIs have been a more 
popular method of treatment in comparison to other medications 
(MAOIS, trycyclics, lithium) because they target only serotonin thus 
decreasing excess side-effects.    
NOREPINEPHRINE  
Norepinephrine, also known as noradrenaline is found throughout the 
brain and spinal cord (Central Nervous System, CNS), but is found in 
higher concentrations in the cortex and limbic system. Norepinephrine 
is known to affect eating, sleep arousal, and emotional activity.   
DOPAMINE
Although dopamine can be found in many regions of the brain, it is 
most prominent in the limbic system (associated with the regulation of 
emotion, learning, and memory), the cerebellum (associated with gross 
motor activity), and the basal ganglia (associated with the 
coordination of fine motor activity). Dopamine is largely associated 
with schizophrenia and Parkinson's disease. Individuals with 
Parkinson's disease show decreases levels of dopamine in the basal 
ganglia. Drugs used to treat schizophrenia work by blocking the 
effects of dopamine.
ION CHANNELS EFFECTED
Ions are electrically charged molecules, some are positively charged 
and some are negatively charged. Two of the more important 
positively charged ions are the sodium ions (Na+) and the potassium 
(K+) ions. Some ions are negatively charged, the most prominent being 
chloride (Cl-). Another prominent negatively charged ion is a cluster of 
similar molecules called anions (An-). Anions are not simple elements 
they are complex proteins. 
Ions usually travel via diffusion, moving from an area of higher 
concentration to an area of low concentration. They flow in the 
opposite direction of their charge. So positively charged ions will 
diffuse toward negatively charged ions and negatively charged ions 
will diffuse toward positively charged ions dispersing themselves 
evenly throughout the cell. Ions that do not travel via diffusion are 
carried over by carrier proteins. When a neuron is at rest it is not 
always allowed to mix freely. Potassium ions can flow readily across 
the membrane but sodium ions cannot. Chloride can flow freely across 
the membrane but the anions cannot move outside the cell. This is 
why the membrane is called a selectively permeable membrane. So 
what happens is the sodium ions collect outside the cell and the 
anions collect inside the cell. Sodium-potassium pumps establish and 
maintain this initial ionic imbalance. Some ions are prevented from 
reaching equilibrium due to the selectively permeable membrane so a 
charge potential is created known as the resting potential. This 
potential represents stored energy, which allows the cell to respond 
quickly if needed. As ions move through the membrane via diffusion, 
they move through channels created by proteins. If the channels can 
be opened and closed they are called gated channels. There are three 
types of gated ion channels; ligand gated, mechanically gated, and 
voltage gated. Ligand gated channels open or close in response to the 
binding of a small signaling molecule. Some ion channels are gated by 
extra cellular ligands, and some my intracellular ligands. Mechanically 
gated channels pen or close due to a mechanical force cause by an 
interaction between the ion channel and the cytoskeleton. Voltage 
gated channels are found in muscles cells and neurons. They open or 
close in response the changes in the charge across the membrane. 
References
Edwards, J. G., & Anderson, I. (1999). Systematic review and guide to 
selective serotonin reuptake inhibitors.  Drugs. 57, 507-533
Klimek, V., Schenck, J., Stockmeier, C., & Ordway, G. (2002). 
Dopaminergic abnormalities in amygdaloid nuclei in major depression: 
a postmortem study.  Biological Psychiatry. 52, 740
Leonard, B. E., (1997). The role of noradrenaline in depression: a 
review.  Jounal of Psychopharmacology. 11, S39
Schloss, P., Williams, D. C., (1998). The serotonin transporter: a 
primary target for antidepressant drugs.  Jounal of 
Psychopharmacology. 12, 115
Schwartz, S., Abnormal Psychology. Mountain View, CA: Mayfield 
Publishing Company.
Wortman, C., Loftus, E., Weaver, C., Psychology Fifth Edition. Boston, 
MA: McGraw-Hill College.
Weiten, W., Psychology Themes & Variations Sixth Edition. Belmont, 
CA: Wadsworth/Thomson Learning
Online (2005). My.webmd.com/content/article/87/99352.htm
Online (2005) depression.about.com/cs/brainchem101/a/
Online (2005) lilt.ilstu.edu/vfdouga/_borders/
Online (2005) omedon.co.uk/ionchan

Physiological Changes and effect:
The serotonin selective reuptake inhibitors (SSRIs) produce multiple 
physiological changes in the body.  These changes vary from person to 
person depending upon each individual's unique body chemistry.  
These changes may be positive and/or negative.  Researchers find it 
difficult to draw conclusions on the effects that SSRIs have on the 
body physiologically and cognitively.  There are several different types 
of serotonin selective reuptake inhibitors and because each type has 
different pharmokinetics involved such as how it is absorbed, 
distributed, metabolized, and eliminated in the body, it is complicated 
to predict specific effects that will occur in an individual.  The 
individual's age, body weight, gender, and other prescribed 
medications will contribute to the effect that the SSRI will have on 
their body (www.dft.gov.uk).

Typically, normal serotonin levels in the brain regulate sleep, appetite, 
mood, biorhythms, anxiety, and aggression, which are common 
physiological dysfunctions in depression. SSRIs stimulate 5-HT activity 
which can cause positive changes in the body as well as negative 
effects. The SSRIs have been shown to reduce depressive feelings by 
increasing serotonin levels in the brain, to reduce hostile sentiment, 
violent outbursts, anxiety, improved concentration, and decreased 
irritability in individuals, (Knutson et al., 1998; Palfai & Jankiewicz, 
2001).

The SSRIs may have multiple effects on an individual physiologically.  
The increase in 5-HT activity can result in gastrointestinal distress 
which may cause nausea, vomiting, and diarrhea in an individual.  The 
SSRIs may also produce reactions such as nervousness, insomnia, 
perspiration, dizziness, tremors, and headache. Other common 
physiological reactions may include anxiety, sleep disruption, loss of 
appetite which may result in weight loss, lethargy, and dry mouth.  
Sexual dysfunctions are common effects when taking an SSRI.  This 
may cause impotence and/or delayed ejaculation in males and the 
inability to reach orgasm in women.  They may also effect an 
individual's ability to drive or operate heavy machinery or equipment.  
Less common physiological changes may include, but are not limited 
to, chest pains, fever, muscle pain, enlarged lymph glands, abdominal 
pain, convulsions, and difficulty breathing.  Long-term use of the SSRIs 
may lead to increased risk for breast cancer. Researchers have also 
found SSRIs responsible for other physiological changes in the body, 
specifically in the extrapyramidal system.  This system is partially 
accountable for the secondary motor system which helps to control 
large movements and voluntary muscle control. Some physiological 
changes that may occur in this system as a result of taking SSRIs are: 
akathisia (a compulsive restlessness), dystonias (sudden, jerky 
movements), and akinesia (reduced movements).  These extra 
pyramidal effects are somewhat rare and may cause long-term 
problems in the individual (Palfai & Jankiewicz, 2001; 
 HYPERLINK "http://www.sulcus.berkeley.edu/"
www.sulcus.berkeley.edu
 HYPERLINK "http://www.acnp.org/"
www.acnp.org
 HYPERLINK "http://www.studenthealth.co.uk/"
www.studenthealth.co.uk
).    
	
There are three syndromes related to the use of SSRIs that lead to 
severe complications.   The first of these is serotonergic syndrome 
which may occur when other 5-HT enhancers are used concurrently.  It 
may also occur when an individual is taking an SSRI.  This involves 
physiological effects on one's body including seizures, high blood 
pressure, increased body temperatures, and possible death as a result.  
The second syndrome that may result following the use of SSRIs is 
neonatal withdrawal syndrome.  This may possibly occur when a 
pregnant mother uses SSRIs during the last trimester.  Physiological 
reactions in the newborn include, but are not limited to, premature 
delivery, low birth-weight, respiratory distress, cyanosis, apnea, 
seizures, instable temperature, feeding difficulty, vomiting, 
hypoglycemia, hypotonia, hypertonia, hyperflexia, tremor, jitteriness, 
diminished pain reactivity, irritability, and constant crying. This 
syndrome can potentially require hospitalization of the newborn 
including respiratory support and tube feeding.  The third syndrome is 
known as discontinuance syndrome.  This syndrome typically follows 
termination of or a reduction in dosage of an SSRI. The occurrence 
rate for this syndrome has been found to range from 35% to 86%. The 
criteria for this syndrome states that two or more of the following 
symptoms must be present: dizziness, lightheadedness, vertigo, 
feelings of fainting, nausea, emesis, headache, visual disturbance, 
anxiety, shock-like sensations, parathesis, tremor, fatigue, insomnia, 
irritability, gait instability, and diarrhea.  The criteria also states that 
the symptoms present must cause clinically significant distress  in 
daily functioning and cannot be due to a general medical condition, a 
mental disorder, or withdrawal from a substance ( Palfai et al., 2001; 
Tamam & Ozoyraz, 2002; & 
 HYPERLINK "http://www.ssricitizen.org/"
www.ssricitizen.org
). 

Physiological effects reported by users of SSRIs include, but are not 
limited to, a reduction of their depression, anxiety, improvements in 
sleep, interpersonal relationships, and appetite.  Some negative 
physiological effects reported by individuals are as follows: increased 
agitation, nervousness, feeling anxious, sudden outbursts of anger, 
trouble sleeping, nightmares, headaches, nausea, dizziness, vomiting 
with stomach cramps, shortness of breath, fatigue, poor 
concentration, insomnia, paraesthesias, flu-like symptoms, and gait 
disturbances (Tamam et al., 2002).

A concern that should be addressed when taking SSRIs is the 
possibility of adverse drug reactions.  When prescribing SSRIs, 
physicians must be cautious with other drugs that may be 
contraindicated for an individual and may potentially be dangerous and 
sometimes life threatening.  Alcohol, illicit drugs, MAO Inhibitors, 
tricyclic antidepressants, lithium, carbamaepine, and St. John's Wort 
are just a few that may cause harmful or even fatal reactions (Preston 
& Johnson, 2004).

There are currently studies underway that are examining the effects, 
physiological changes, and mechanisms of action of the herbal remedy 
for depression, St. John's Wort.  Researchers have found that St. 
John's Wort significantly reduces corticosterone and cortical in the 
brain which leads them to believe that this action in the brain is what 
helps to alleviate depressive symptoms in individuals when taking this 
herbal remedy.  In comparison to SSRIs, St. John's Wort has been 
found to be significantly effective in the reduction of depressive 
symptoms.  In individuals with mild to moderate depression, St. John's 
Wort was found to be more effective than SSRIs.  It was suggested 
that St. John's Wort be used more regularly with individuals with mild 
to moderated depression due to its effectiveness in reducing 
depressive symptoms, less undesirable side effects, and its cost-
effectiveness.  Studies are still inconclusive as to whether or not St. 
John's Wort is effective for moderate to severe depression and its 
effectiveness over time.  It should be noted that St. John's Wort is 
extremely dangerous when taken with SSRIs.  There is still much 
research to be done to make definite conclusions on St. John's Wort's 
efficacy in the treatment of depressive symptoms and Major 
Depression Disorder (Roder, Schaefer, & Leucht, 2004). 
References
Knutson, B., Wolkowitz, O.M., Cole, S.W., Chan, T., Moore, E.A., 
Johnson, R.C., Terpstra, J., Turner, R.A., & Reus, V.I. (1998). Selective 
alteration of personality and social behavior by serotonergic 
intervention. The American Journal of Psychiatry, 155, 373-379.
Palfai, T. & Jankiewicz, H. (2001) Drugs and Human Behavior (2nd 
edition). New York, NY: McGraw-Hill Primis, 279-282.
Preston, J. & Johnson, J. ((2004). Clinical Psychopharmacology: Made 
ridiculously simple. Miami, FL: MedMaster, Inc., 1-19.
Schweizer, E., Rickels, K., & Uhlenhuth, E.H. Issues in the Long-Term 
Treatment of Anxiety Disorders. 
 HYPERLINK "http://www.acnp.org/"
http://www.acnp.org
 
Tamam, L. & Ozpoyraz, N. (2002). Selective serotonin reuptake 
inhibitor discontinuation syndrome: two case reports.  Yeni 
Symposium, 40 (4), 156-160.
Serotonin re-uptake inhibitor antidepressants (SSRIs). 
 HYPERLINK "http://www.studenthealth.co.uk/"
http://www.studenthealth.co.uk
 
Anti-depressants and road safety: a literature review and commentary 
(no.18). 
 HYPERLINK "http://www.dft.gov.uk/"
http://www.dft.gov.uk
 
Are Antidepressants the superior treatment? (code 935). 
 HYPERLINK "http://sulcus.berkeley.edu/"
http://sulcus.berkeley.edu
 
Educating the public about the dangers of SSRIs. 
 HYPERLINK "http://www.ssricitizen.org/"
http://www.ssricitizen.org
 
 
Behavioral Effects:
SSRIs have been shown to be the only effective drug treatment for 
depression in children and adolescents youth. There is great concern 
about the SSRI's effects on suicide in children and adolescents. The 
potential for SSRIs to activate suicidal behavior was first detected 
over ten years ago through a sequence of case reports describing a 
small number of individuals whose suicidality worsened during 
treatment and then sometimes improved after stopping the SSRI; all 
except one of those reports (King et al., 1991) were in adults (Teicher 
et al, 1991; Tothschild et al, 1991; Creaney et al, 1991; Wirshing et al, 
1992; Lane et al, 1998). However, in a few cases, patients were re-
started on the SSRIs and the suicidal behavior re-emerged.  A separate 
analysis published in 1992, found similar case reports of suicidal 
behavior with every class of antidepressants, including drugs against 
psychosis and anxiety (Kapur et al, 1992) the results indicated that 
there was no evidence from these case reports of an effect confined to 
one pharmacological class of drug, or a clear dose-response 
relationship; they reported that the only common characteristic in 
these reports was psychiatric disorder known to carry a risk of 
suicidality. In 1993, the ACNP Task Force concluded that there was no 
scientific evidence indicating that SSRIs could trigger suicidal 
behavior. However, other research has shown that there is a link 
between suicide and SSRIs. Andrew Mosholder (2004) of the Office of 
Drug Safety of the FDA and others reported that 2-3 out of 100 
antidepressant-treated children will develop suicidal behaviors.  
According to Mosholder, a suicidal event would occur once in every 
twelve patient-years.  In 2003, the American College of  
Neuropsychopharmachology (ACNP), which evaluated the safety and 
efficacy of  SSRIs antidepressants for depressed youth under 18 years; 
raised some concerns claiming that children and adolescents treated 
with SSRIs may  increase the risk for suicidal ideation or suicide 
attempts; furthermore, in 1993, the U.K. Department of health reported 
similar findings; claiming that with the exception of fluoxetine 
(Prozac), the SSRIs antidepressants were not effective, but rather, its 
use would increase the level of suicidal ideation, and suicide attempts 
for children and adolescents less than 18 years of age.  Toxicological 
analysis has been used to determine if SSRIs influenced individuals to 
commit suicide. Evidence from many sources confirms that selective 
serotonin reuptake inhibitors (SSRIs) commonly cause or exacerbate 
wide range of abnormal mental and behavioral conditions. On the other 
hand, a resent study on 49 adolescent suicides, conducted by a 
research team in Utah, recently reported that 24 percent of the victims 
had been prescribed antidepressants, but there no evidence that 
either of those victims had tested positive for SSRIs at the time of 
their death (Gray et al, 2003). Another study conducted on 5000 adult 
suicides, one research team found that most victims had not taken an 
antidepressant (most commonly SSRIs or other new generation 
antidepressants) immediately before their death, even though the 
majority had been depressed.  Only 4% had toxic concentration of 
antidepressants, meaning that the drugs were used in an intentional 
overdose (Isacsson et al, 1997). After all the inconclusive evidence, 
The FDA conducted a thorough investigation of eight antidepressants, 
including all currently approved SSRIs, and the results indicated that 
the evidence reviewed so far was insufficient to determine whether or 
not there was a correlation between SSRIs and suicidal behavior in 
youth.  Nevertheless, the FDA advised physicians to monitor children 
and adolescents for changes in their clinical state and for increased 
suicidal risk ACNP (2004) Andrew Molsholded of the office of Drug 
Safety of the FDA and others reported at the FDA Public Hearing on 
Antidepressants and Suicide, that 2-3 out 100 antidepressant-treated 
children will develop suicidal behaviors; Breggin estimated that a 
suicidal event would occur once in every twelve-patient years;  which 
according to him, those figures were underestimated. Furthermore, 
Beggin claims that the short-tem studies frequently conducted by 
drug-companies, were biased and habitually disregarded or ignored 
data regarding the adverse drug effects; in order to confirm the 
effectiveness of the SSRIs Breggin & Breggin 1994).  Breggin claims 
that the FDA disregarded other related hazards that increase the 
number of children afflicted with life-threatening drug reaction (Emslie 
et al. 1997). Furthermore, Breggin reported that the FDA hearings are 
more about deception than science; the drug companies have 
conspired together to hide the dangerousness of the newer 
antidepressants in the treatment of children and adults. Amazingly 
enough, the FDA has become more accepting of the idea that the 
newer antidepressants, particularly the SSRIs and Effexor 
(venlafaxine), cause suicide in children (Breggin and Breggin 1994). 
Breggin summarized the deceptive drug company practices, focusing 
on Prozac and its manufacturer, Eli Lilly; he reported a brief summary 
of some of the ways that Eli Lilly, often in collaboration with the FDA, 
has hidden data on the dangerousness of the SSRIs (many of these 
deceptions are discussed in Breggin and Breggin, 1994, and all of them 
are documented in Breggin, 1997)
In the last few days before the FDA approved Prozac marketing, Bob 
Temple of the FDA went thorough the Prozac label and drew lines 
through adverse drug reaction that he considered unnecessary; he 
specifically expunged "depression" from the list of frequently reported 
psychiatric adverse drug reaction. Therefore, "depression" as a drug-
induced effect went from frequent to nonexistent in the drug label. The 
information that depression was "frequent" reaction to Prozac had 
poured into Eli Lilly and Company from principle investigators funded 
by the company to do clinical trial, but recognition of its existence 
was eradicated. Amazingly enough, the FDA has become more 
accepting of the idea that the newer antidepressants, particularly the 
SSRIs and Effexor (venlafaxine), cause suicide in children (Breggin and 
Breggin 1994).   

Reference:
American College of Neuropsychopharmacology (2004) Preliminary 
report of the Task on SSRIs and suicidal behavior in youth: Executive 
summary
Breggin, P. (1997) Brain-disabling treatments in psychiatry, New York: 
Springer Publishing Company.
Breggin, P. and Breggin, G. (1994).  Talking back to prozac. New York: 
St. Martin's Press.
Breggin, P. (2003/2004). Suiciadality, violence and mania cused by 
selective serotonin reuptake inhibitors SSRIs: a review and analysis. A 
review and analysis> International Journal of Risk and Safety in 
Medicine. 
Creaney W, Murray I, Healy D (1991). Antidepressant induced suicidal 
ideation. Hum
Psychopharmacol 6:329-32.
	Emslie GJ, Rush AJ, Weinberg WA, et al (1997). Double-blind, 
randomized
placebo-controlled trial of fluoxetine in depressed children and 
adolescents. Arch Gen
Psychiatry 54: 1031-7.
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