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.
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.
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.
Healy, D. 1991 The marketing of 5- hydroxytryptamine:
Depression
IOM ( Institute of Medicine), 2003. Gulf War and Health Gulf: Volume 2.
Insecticides and Solvents, Committee on Gulf War and Health:
Literature Review of Pesticides and Solvents.
Washington, DC: National Academies Press.
Gray D, Moskos M, Keller T (2003, April 25). Utah Youth Suicide
Study New Findings.
Presented at the annual meeting of the American Association of
Suicidology, Sante Fe, New
Mexico
Isacsson G, Holmgren P, Druid H, Bergman U: The utilization of
antidepressants-a keyissue in the prevention of suicide: an analysis
of 5281 suicides in Sweden during the period1992-1994. Acta
Psychiatr Scand 96(2):94-100, 1997.
Kapur, S., Mieczkowski, T. & Mann, J. J. (1992) Antidepressant
medications and the relativerisk of suicide attempt and suicide.
Journal of the American Medical Association, 268: 3441-3445.
King RA, Riddle MA; Chapell PB; Hardin Mt; Anderson; & GM, Lombroso
P (1991) Emergence of self-destructive pehomena in children ad
adolescents during fluoxetine treatmen: J Am Acad Hild Adosc
Psychiatry 30: 171-6
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.
Lane RM (1998). SSRI-induced extrapyramidal side effects and
akathisia: implications for treatment. J Psychopharmacol 12:192-214.
Masand P, Gupta S, Dwan M (1991). Suicidal ideation related to
fluoextine treatment [letter].N Engl J Med 324:420.
Rothschild AJ, Locke CA (1991). Re-exposure to fluoxetine after
serious suicide attempts by 3 patients: the role of akathisia. J Clin
Psychiatry 52:491-3.
Teicher, M. H., Glod, C. A. & Cole, J. O. (1993) Antidepressant
drugs and the emergence of suicidal tendencies. Drug Saf, 8: 186-212.
Go back to the beginning
Copyright © 2005, Dr. John M. Morgan, All rights reserved -
This page last edited 02-23, 2004
If you have any feedback for the author, E-mail me
