Selective Serotonin

Reuptake Inhibitors
(SSRIs)
Psychopharmacological Medications
Presentation- EDPS 674
Alicia Marchini, Sarah Juchnowski & Lindsay Birchall

Agenda

History of drug class - Alicia

Characteristics of Drug class - Alicia
Applications for Adults and Children - Sarah
Applications for Learning - Sarah
Controversies Regarding Application - Lindsay
Negative Effects - Lindsay

Introduction
SSRIs: Selective Serotonin Reuptake Inhibitors
FDA approved drug class
Antidepressant drug category (treat depression)
How do they work?
o They selectively inhibit the reuptake of serotonin
in the CNS synapses and consequently increases the
intra-synaptic concentration of serotonin

History of Drug Class

History of SSRIs
Antidepressants had many adverse side effects and dangerous
overdose effects
Early 1970s: First SSRI, fluoxetine
Initiated the growth and popularity of antidepressants
1988: Prozac was introduced
First antidepressant to be marketed
directly to the consumer
2008: 5 of the 6 SSRIs were among the
most dispensed prescription drugs in the US

Characteristics of Drug
Class

Mechanism of Action
Inhibit the active membrane transport
mechanism for reuptake of
serotonin
Heightens the concentration of the
serotonin at the synaptic cleft
and
extends activity
at synaptic receptor sites
Enhances serotonergic neurotransmission
by reducing turnover of

Fluoxetine
Generic Name: Fluoxetine hydrochloride
Brand Names: Prozac, Sarafem, Fontex, Foxetin, Ladose, Fluctin, Prodep, Fludac,
Lovan
US FDA Approved: December 1987
Originally Discovered: 1971 by Bryan Molloy
Affected Neurotransmitter: Serotonin
FDA Approved Indications:
Major depressive disorder
Obsessive-compulsive disorder
Bulimia nervosa
Panic disorder
Premenstrual dysphoric disorder

Fluoxetine
Potent and selective inhibitor of serotonin uptake, but not of
norepinephrine or dopamine uptake, in the central nervous system
Norepinephrine, epinephrine and dopamine levels are significantly
increased after acute and prolonged treatment with fluoxetine
Prozac: capsule, tablet, liquid form, delayed-release capsule
Sarafem: capsule
Time of Onset: 4 and 6 weeks for Fluoxetine to take full effect
o A lack of onset at 4-6 weeks may meant that there is a 73%-88% chance
that the patient will not have an onset of response by 8 weeks
o May take up to 1 to 2 months for the active substance to disappear from
the body

Sertraline
Generic Name: Sertraline hydrochloride
Brand Names: Zoloft, Lustral, Sertranex, Apo-Sertral, Asentra,
Gladem, Serlift, Stimuloton, Xydep, Serlain, Concorz
US FDA Approved: 1991
Originally Discovered: 1977 by biochemist Kenneth Koe and
chemist Willard Welch (Pfizers pharmaceutical company)
Affected Neurotransmitter: Serotonin
FDA Approved Indications: Major depressive disorder,
Obsessive compulsive disorder, Panic disorder, Posttraumatic
stress disorder, Social Anxiety Disorder

Sertraline
Weak activity in inhibiting the reuptake of dopamine
Sertraline: tablet, concentrate (liquid)
Time of Onset:
o May take a few weeks or longer
to feel full benefit
o Half-life of about 26 hours, so
it could take 5 to 6 days to leave
the body

Paroxetine
Generic Name: Paroxetine hydrochloride
Brand Names: Paxil, Paxil CR, Seroxat, Brisdelle, Aropax, Pondera,
Deroxat, Paroxat, Cebrilin; Pexeva (paroxetine mesylate)
US FDA Approved: December 1992; Brisdelle (low-dose paroxetine 7.5 mg):
2013
Originally Discovered: 1975 by Jorgen Buus-Lassen and associates at
Ferrosan (Danish company)
Affected Neurotransmitter: Serotonin
FDA Approved Indications: Major depressive disorder, Obsessive compulsive
disorder, Panic disorder, Social anxiety disorder, Generalized anxiety disorder,
Posttraumatic stress disorder, Premenstrual dysphoric disorder (controlled
release formulation), Hot flashes associated with menopause

Paroxetine

Most potent inhibitor of the reuptake of serotonin

Very weak inhibitor of norepinephrine uptake
Paroxetine: tablet, liquid, extended release tablets (Brisdelle)
Time of Onset:
o Depression: 1 to 6 weeks to feel the full effect
o GAD: Core symptoms are reduced after about a week and a
significant reduction in symptoms occurs after only 8 weeks of
treatment
o PTSD: Up to 12 weeks to feel significant reduction of symptoms
o Half-life can range between 3 and 65 hours, so the time it takes
to clear out of the body varies from 5 to 12 days

Fluvoxamine
Generic Name: Fluvoxamine
Brand Names: Luvox, Luvox CR
US FDA Approved: October 1993
Originally Discovered: 1984 by Solvay Pharmaceutical
Affected Neurotransmitter: Serotonin
FDA Approved Indications: Obsessive-compulsive
disorder, social anxiety, and sometimes depression

Fluvoxamine
Fluvoxamine: tablet or extended-release capsule
Time of Onset:
o Can take up to several weeks or more to have full
effect

Citalopram
Generic Name: Citalopram hydrobromide
Brand Names: Celexa, Cipramil, Sipralexa, Seropram,
Celepram
US FDA Approved: July 1998
Originally Discovered: 1989 by pharmaceutical researchbased company, Lundbeck
Affected Neurotransmitter: Serotonin
FDA Approved Indications: Depression

Citalopram
Highly selective and potent SRI
Minimal effects on the neuronal reuptake of
norepinephrine and dopamine
Citalopram: tablet or liquid
Time of Onset:
o 1 and 4 weeks before the patient will feel the full
effects
o Half-life of about 35 hours, so it can take 7-8 days to
be eliminated from the body

Applications for Adults

and Children

General use of SSRIs

Depression
Anxiety
Panic Disorder
Social Anxiety
Obsessive Compulsive Disorder
Post Traumatic Stress Disorder
Phobias
Bulimia
Chronic Pain

Most Common use

Major Depressive Disorder in adults is the
most common use for SSRI but usually in joint
treatment with Cognitive Behavioural
Therapy.

Treatment
Dose: Typically patients start with the lowest dose
possible
Duration: SSRIs usually need to be taken for about 2-4
weeks before effective.
Findings suggest that about half of those with major
depressive disorder do not receive treatment of any
kind.

Efficacy
Adults
SSRIs are most effective in adults diagnosed with
major depressive disorder.
Some studies suggest 41% of patients relapsed when
switched to a placebo.
50-60% of patients with depression show response to
SSRIs

Efficacy
Children and Teens
While SSRIs show effectiveness in some, a combination
of pharma therapy and CBT is most effective.
Only about 60% of teens with depression show
adequate clinical response to SSRIs

Long Term Effects

Long term use is associated with less
chance of relapse of depressive and anxious
symptoms
Possible long term side effects are more
serious than the short term side effects
(Most side effect studies however are based on
short term use)

Application for Children

Who? Use of SSRIs in children 10-19 years old has
increased dramatically over the past few years
What? Fluoxetine has been one of the only FDA
approved SSRI for use in children under 8 and Lexapro
for age 12 and older
How many? 3.7% of children 12-19 report taking an
antidepressant

Increased suicide risk in youth?

A percentage of children that
may experience an increase in
suicidal thoughts and behaviours
after using SSRIs in placebo
controlled studies.

There is speculation to the

effect pharmaceuticals have in
incidents such as school
shootings.

Off label uses

Premature ejaculation
Premenstrual syndrome (PMS)
Migraine Headaches
Fibromyalga
Irritable Bowel Syndrome (IBS)
Low energy
Hot Flashes

Applications for Learning

SSRIs and neuroplasticity

SSRIs promote synaptic
plasticity
A change in brain
plasticity affects how
people learn
SSRIs may prime the
adult brain to rewire
faulty circuits by
making more serotonin
available

Cell changes in the Hippocampus

The Hippocampus is responsible for memory and
emotions.
Changes in granule cells in the hippocampus are
caused by serotonin. This in turn increases their
activity and puts them into a immature state. This
ultimately decreases anxiety.
Differences in ones pattern of behaviour may be due
to this dematuration of granule cells in the
hippocampus.

Cognitive effects
Recall memory
Attention deficit
Somnolence
Evidence shows there are no significant
differences between cog effects depending on
if patients are diagnosed with depression or
anxiety.

Implications for the classroom

Common side effects of SSRIs in children
may interfere with classroom functioning.
Improved social processing can improve
learning because SSRIs help to create a
more positive learning environment.

Controversies Regarding
Application

The Placebo Effect

Irving Kirsch
Prozac vs. Placebo - placebo
duplicated 89% of drug effect
Placebo created a powerful
expectation of healing
Mild/Mod Depression
o no difference
Extremely severe depression
o Clinically significant
difference

(Kirsch, 2008)

60 Minutes: Treating Depression: is there

a placebo effect? February 19th, 2012
http://www.cbsnews.com/videos/treating-depression-is-the
re-a-placebo-effect/

The Placebo Effect-Considerations

((Leo & Lacasse, 2012; Kirsch, 2008; Turner et al., 2008)

People still get better!

Research vs. Clinical Practice
Success Rates
o Mild/Moderate-10-14%
o Severe->14%-33%
Long term use
Placebo-patients relapse
Large effect for subset of people

The Serotonin Theory

Should we question the

Serotonin theory?

Age of Application
Risk of suicide
o Adults<2%
o Teens 4-5% (2x rate of
placebo)
Risk of no treatment?
Enough benefit to warrant
exposure?
(Weller, Tucker & Weller, 2005; nimh.org)

Britain: Ban on SSRIs under 18 yrs

Canada & USA: Strong warning label

Power of the Drug Manufacturer

Billions$: Advertising & Research
Canadian approval process-HPFB
(Health Canada www.hc-sc.gc.ca)

Selective Publications
Ghostwriters

(Kirsch, 2008; Turner et al., 2008)

Negative Effects

Common Adverse Side Effects

Worse with long-term use (Ferguson, 2001)
Different side effects for different SSRIs
helio.com)

(mayo clinic.org;

Pregnancy-Birth Defects
Birth Defects: 3-4%
Cardiovascular defects-1st trimester
Miscarriage, stillbirth, persistent pulmonary hypertension,
neonatal withdrawal syndrome, abortion
Untreated severe depression (alcohol, drug abuse, smoking,
poor nutrition, stress related fetal problems, postpartum
depression)
Canadian Label warning the potential benefit should
outweigh the potential risk
(MacLeans.ca; Weller, Tucker & Weller, 2005)

Suicide

60% of Canadians in 2013 that died from suicide

were diagnosed with depression - highest rates in
40-59 yr. (statscanada.gc.ca)

Depression, SSRIs & Suicide Risk

(Babbington, 2006)

Increase suicidal ideation higher for adolescents

Increase of SSRIs prescribed: Suicide mortality decreased
(Ludwig, Marcotte & Norberg, 2009)

Fourfold increase of attempts within first 9 days

Careful monitoring upon initiation of SSRIs
Comparative risk to other antidepressants

Potential Drug Interactions

Other Drug Interactions
Multiple Prescriptions for comorbid disorders
Over the counter: Aspirin,
Ibuprofen, Naproxen (Aleve)
((Weller, Tucker & Weller, 2005)

Linezolid, methylene blue dye,

Monoamine oxidase inhibitors
(MAOIs) including moclobemide,
phenelzine, tranylcypromine,
selegiline and methylene blue,
Lithium, Sibutramine, MDMA
(ecstasy), Dextromethorphan,
Tramadol, Pethidine/meperidine,
St. John's wort, Yohimbe,
Tricyclic antidepressants (TCAs),
Serotonin-norepinephrine reuptake i
nhibitors
(SNRIs), Buspirone, Triptan,
Mirtazapine

Overdose
The Serotonin Syndrome Serotonin Toxicity

Large Amounts: Potentially life

threatening
myoclonus
hyperreflexia
sweating
shivering
incoordination
mental status changes
(Ferguson, 2001)

Withdrawal

(Ferguson, 2001)

Worse with long-term use

Worse with paroxetine and fluvoxamine
Begins within first week
Subside within 3 weeks
Neuropsychological readjustment
o

dizziness, lethargy, nausea, headaches, anxiety,

agitation

References
AHFS Consumer Medication Information. (2014). Citalopram. In Medicine Plus. Retrieved February 22, 2015,
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699001.html
AHFS Consumer Medication Information. (2014). Fluoxetine. In Medicine Plus. Retrieved February 22, 2015,
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a689006.html
AHFS Consumer Medication Information. (2014). Fluvoxamine. In Medicine Plus. Retrieved February 22, 2015,
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695004.html
AHFS Consumer Medication Information. (2014). Paroxetine. In Medicine Plus. Retrieved February 22, 2015,
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a698032.html
AHFS Consumer Medication Information. (2014). Sertraline. In Medicine Plus. Retrieved February 22, 2015,
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a697048.html

References
Babbington, G. (2006). SSRI use reduces suicide rate. Australian Doctor (Nov 3, 2006): 6.
eMed Expert. (2014). Citalopram HBr (Celexa). In eMed Expert. Retrieved February 22, 2015,
http://www.emedexpert.com/facts/citalopram-facts.shtml
eMed Expert. (2014). Fluoxetine (Prozac). In eMed Expert. Retrieved February 22, 2015,
http://www.emedexpert.com/facts/fluoxetine-facts.shtml
eMed Expert. (2014). Paroxetine (Paxil). In eMed Expert. Retrieved February 22, 2015,
http://www.emedexpert.com/facts/paroxetine-facts.shtml
eMed Expert. (2014). Sertraline (Zoloft). In eMed Expert. Retrieved February 22, 2015,
http://www.emedexpert.com/facts/sertraline-facts.shtml
Experts, FDA debate whether SSRIs are safe for children and adolescents. The Brown University Psychopharmacology Update,
April 2004 (15)4:1-3.

References (contd)
Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Side Effects and Tolerability. Prim Care Companion J Clinic
Psychiatry, 3(1):22-27
Harmer, C. J., & Cowen, P. J. (2013). 'It's the way that you look at it'--a cognitive neuropsychological account of SSRI action in
depression. Philosophical Transactions Of The Royal Society B: Biological Sciences, 368(1615), 1-8. doi:10.1098/rstb.2012.0407
(hc.gc.ca), Health Canada: How Drugs are Reviewed in Canada, Retrieved from:
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/fs-fi/reviewfs_examenfd-eng.php, March 3rd, 2015
Helio.com. Selected SSRI Side Effects, Retrieved from: http://supsgoodfood.com/2013/08/14/take-the-green-pill/, March 4th,
2015
Ingrahm, P. (2013). SSRI Antidepressants Are Not Medicine Frightening side effects, cover-ups on the record, and no reason to
believe they do what they are supposed to. Retrieved from: https://www.painscience.com/articles/anti-depressants.php, February
27th, 2015
Kirsch et al. (2008). Initial severity and antidepressant benefits: a met-analysis of data submitted to the Food and Drug
Administration. PLos Medicine.

References (contd)
Leo, J. & Lacasse, J. (2012). 60 Minutes, The SSRIs, and The Dirty Little Secret, Mad in America: Science, Psychiatry and
Community. Retrieved From: http://www.madinamerica.com/2012/02/60-minutes-the-ssris-and-the-dirty-little-secret-2/, February
20, 2012
Levin, A. P. (2009, January). SSRI treatment of children and adolescents: how risky? How to manage the risk? Psychiatric Times,
26(1), 26. Retrieved from
http://go.galegroup.com.ezproxy.lib.ucalgary.ca/ps/i.do?id=GALE%7CA192001120&v=2.1&u=ucalgary&it=r&p=AONE&sw=w&
asid=bc77dba7d138a6a97c70eec7881629e2
mayoclinic.org. Mayo Clinic: Selective Serotonin Reuptake Inhibitors, Retrieved From:
http://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825, February 28th, 2015
mayo clinic.org. Mayo Clinic: Diseases and Conditions: Teen Depression, What you do before you child starts taking an
antidepressant?, Retrieved from:
http://www.mayoclinic.org/diseases-conditions/teen-depression/in-depth/antidepressants/art-20047502?pg=2 Feb 27, 2015
Mutalik, S. (2014). A Short History of the SSRI. In Psychiatric Times. Retrieved February 22, 2015, from
http://www.psychiatrictimes.com/psychopharmacology/short-history-ssri#sthash.P0JC1xjB.dpuf

References (contd)
nimh.org. National Institute of Mental Health: Antidepressant Medications for Children and Adolescents: Information for Parents
and Caregivers, Retrieved from,
http://www.nimh.nih.gov/health/topics/child-and-adolescent-mental-health/antidepressant-medications-for-children-and-adolescent
s-information-for-parents-and-caregivers.shtml
, March 5th, 2015
nimh.org. National Institute of Mental Health: Directors Blog: Antidepressants: A complicated Picture, Retrieved from,
http://www.nimh.nih.gov/about/director/2011/antidepressants-a-complicated-picture.shtml,Feb. 27, 2015
Popovic, D., Vieta, E., Fornaro, M., & Perugi, G. (2015). Cognitive tolerability following successful long term treatment of major
depression and anxiety disorders with SSRi antidepressants. Journal Of Affective Disorders, 173211-215.
doi:10.1016/j.jad.2014.11.008
PRNewswire. (1993). FDA Advisory Committee Recommends Luvox (Fluvoxamine) Tablets for Obsessive Compulsive Disorder.
In The Free Library. Retrieved February 22, 2015, from
http://www.thefreelibrary.com/FDA+ADVISORY+COMMITTEE+RECOMMENDS+LUVOX+(FLUVOXAMINE)+TABLETS+FOR...-a0
14258615

References (contd)
Statscanada.gc.ca. Navaneelan, T. Suicide rates: An overview: Statistics Canada Catalogue no. 82-624-X. Retrieved From:
http://www.statcan.gc.ca/pub/82-624-x/2012001/article/11696-eng.htm
Turner, E. H., Matthews, A. M., Linardatos, B. S., Tell, R. A. & Rosenthal, R. (2008). Selective Publication of Antidepressant Trials
and Its Influence on Apparent Efficacy. New England Journal of Medicine, 358:252-60
Treatment of SSRI-resistant depression in adolescents. (2008, June). The Brown University Psychopharmacology Update, 19(6),
3. Retrieved from http://
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223f2a8452398c4d9f5ba61f5b0200
, March 1st, 2015
Weller, E. B., Tucker, S. & Weller, R. A. (2005). The selective serotonin reuptake inhibitors controversy in the treatment of
depression in children. Curr Psychiatry Rep. 7(2):87-90.
White, C., Wigle, P. R., Elizabeth, E., Albert, L. G., Udom, L. (2010). Answers to your
questions about SSRIs. Journal of Family Practice, 59(1), 19-25. Retrieved from
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