Sertraline Pharmacology and New Indication Proposal

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Pharmacology or Sertraline and a
proposed new indication
Post-Graduate Certificate in Clinical Research
Management and GCP

Sertraline Hydrochloride
• Sertraline Hydrochrloride (Zoloft) was created by Pfizer in 1991 for the
purpose of treating Major Depressive Disorder
• Sertraline HCL is an SSRI, Selective Serotonin Reuptake Inhibitor, class
antidepressant
• It’s efficacy in the treatment of a major depressive episode was
established in 6-8 week controlled trials of outpatients whose
diagnoses corresponded most closely to the DSM-III category of
major depressive disorder
• It’s efficacy in maintaining a response for up to 44 weeks following
8 weeks of open-label acute treatment was demonstrated in a
placebo-controlled trial
• It is also used to treat social anxiety, panic and obsessive compulsive
disorders.

Selective Serotonin Reuptake Inhibitors (SSRI)
• The monoamine theory of depression states that depression might be caused
by a decrease in serotonergic and noradrenergic neurotransmission
• SSRIs are believed to increase the extracellular level of the neurotransmitter
serotonin by limiting its reabsorption into the presynaptic cell, increasing the
level of serotonin in the synaptic cleft available to bind to the postsynaptic
receptor
• Serotonin (5HT) is thought to be a contributor to feelings of well-being and
happiness
• SSRIs have degrees of selectivity for the other monoamine transporters, with
pure SSRIs having only weak affinity for the norepinephrine and dopamine
transporters

Pharmacodynamics
• Sertraline specifically inhibits central nervous system neuronal re-uptake of serotonin and increases
the concentration of the serotonin at the synapse, enhancing of serotonergic neuronal transmission
• The increased availability of serotonin is thought to be linked with the improvement in depression
accounted for by sertraline treatment
• Sertraline has no direct effect on the re-uptake of noradrenaline, dopamine or GABA and Unlike most
tricyclic antidepressants, it has no significant affinity for alpha1-adrenergic, H1-histamine, and
muscarinic receptors
• Sertraline does not show significant affinity for D1 and D2 dopaminergic, alpha2 and œ adrenergic,
benzodiazepine and opioid receptors
• The selectivity of sertraline may account for the lower incidence of some adverse effects such as
sedation, orthostatic hypotension and anticholinergic effects
• Like tricyclic antidepressants, MAOIs, and other SSRIs, sertraline significantly reduces REM (rapid eye
movement) sleep density, REM time and the REM percentage of total sleep time in patients with major
depression

In the depressed state, there is believed to
be low Serotonin signalling and the
number of 5HT receptors is upregulated,
including pre-synaptic 5HT1A
autoreceptors as well as postsynaptic 5HT
receptors
When given an SSRI, it blocks serotonin
reuptake. This causes serotonin to
initially increase only at the soma
dendritic area of the neuron.

Due to the serotonin increasing in the
somatodendritic area of the neuron,
the 5HT1A receptors downregulate.
Once the receptors downregulate, there is
no longer inhibition of impulse flow and
5HT release increases at the terminal. This
is the delayed effect as it takes time for the
downregulation.

Once the SSRIs have blocked the
reuptake, increased
somatodendritic 5HT, desensitised
receptors, turned on the impulse
and released 5HT at the terminal,
the post synaptic 5HT receptors
become desensitized. This
desensitization may cause the
reduction of side effects of SSRIs
as tolerance develops.
Overall this is the theorized action
of SSRIs that increases the
serotonin at the synapse and
creates feelings of happiness,

Sertraline Target receptors
Sertraline has dopamine reuptake
inhibitor (DRI) and sigma 1
receptor binding in addition to
serotonin reuptake inhibitor (SRI).
SRI is the main target SSRI target.
Sertraline’s DRI is though to
contribute to improved energy,
motivation and concentration. The
sigma binding may contribute to
anxiolytic actions and patients with
psychotic depression.

• Sertraline has 2 candidate mechanisms that distinguish it: dopamine transporter
(DAT) inhibition and sigma 1 receptor binding
• It may also have some weak CYP 2D6 inhibitory properties at high doses
• The DAT inhibitory actions are controversial since they are weaker than the
Serotonin reuptake transporter (SERT) inhibitory actions, suggesting that there is
not sufficient DAT occupancy by sertraline to be clinically relevant
• It is not clear that high degrees of DAT occupancy are necessary or even
desirable in order to contribute to antidepressant actions, perhaps only a small
amount of DAT inhibition is sufficient to cause improvement
• The sigma 1 actions are not well understood but might contribute to anxiolytic
effects especially in psychotic and delusional depression

Pharmacokinetics-Absorption
-Sertraline is slowly and completely absorbed from the
gastrointestinal tract
-Peak plasma concentrations (Cmax) occur between 4.5
and 8.5 hours after ingestion of a single 100 mg dose
-The presence of food slightly increases sertraline
bioavailability and Cmax increases by 25 %

Pharmacokinetics-Distribution
• Widely distributed throughout body tissues and highly bound to
plasma proteins (about 98 %)
• The apparent volume of distribution is 20 L/kg
• The plasma sertraline level was reported to be 20 to 48 µg/L after at
least 1 week of treatment with 100 mg sertraline daily, and it ranged
from 40 to 187 µg/L after 200 mg
• Plasma sertraline concentrations increase proportionally to the
administered dose, unlike fluoxetine and paroxetine
• Cmax and area under the plasma concentration-time curve values
are increased, and elimination half-life is prolonged in elderly
patients but these changes do not appear towarrant dose adjustment
in this patient group

Pharmacokinetics- Metabolism
• Sertraline undergoes extensive first pass metabolism in the liver.
• It is metabolized into N-desmethylsertraline, whose half-life is 2 to 3 times
longer than sertraline
• N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104
hours
• N-desmethylsertraline is 10 times less active as an inhibitor of serotonin re-
uptake in vitro, and has almost no activity in animal models
• Both sertraline and N-desmethylsertraline undergo oxidative deamination
and subsequent reduction, hydroxylation, and glucuronide conjugation

Pharmacokinetics- Excretion
• N-desmethylsertraline is oxidatively deaminated to
desmethylsertraline ketone which, in turn, undergoes hydroxylation
to an alpha-hydroxyketone and alcohol
• these metabolites are then conjugated and excreted in equal
amount in the urine and feces
• a small amount of unchanged drug (less than 0.2 %) is excreted in
the urine
• There is little data about the excretion of sertraline and its
metabolites in breast milk
• It was not detected in the serum of an infant exclusively breastfed by
his mother, after 3 weeks and 7 weeks of treatment, although
sertraline could be detected in breast milk.

Pharmacokinetics- Pediatric
• Sertraline pharmacokinetics were evaluated in a group of 61
pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years).
Patients included both males (N=28) and females (N=33)
• that pediatric patients metabolize sertraline with slightly greater
efficiency than adults. Nevertheless, lower doses may be
advisable for pediatric patients given their lower body weights,
especially in very young patients, in order to avoid excessive
plasma levels
• No gender associated differences were observed

Pharmacogenomics
• SSRIs can affect gene expression resulting in changes in receptor number, increase
brain derived neurotrophic factors and synthesis of various proteins
• Patients with CYP2C19 poor metabolizer genotypes need a reduced sertraline dose
by 50%
• Patients with CYP2C19 intermediate metabolizer genotypes have a higher
occurance of adverse drug events
• Large bodies of research are devoted to using genetic markers to predict whether
patients will respond to SSRIs or have side effects that will cause their
discontinuation
• Single-nucleotide polymorphisms of the 5-HT(2A) gene correlated with paroxetine
discontinuation due to side effects in a group of elderly patients with major
depression, but not mirtazapine (a non-SSRI antidepressant) discontinuation

Neurotransmitters
are increased by
SSRI use, the
cascading
consequence of
this is to change
the expression of
critical genes.

Sertraline effects on body systems
• Body as a Whole-General Disorders- Rare: allergic reaction, allergy.
• General-Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors,
generalized edema; Rare: face edema, aphthous stomatitis.
• Cardiovascular-Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia,
postural dizziness, postural hypotension, periorbital edema, hypotension, peripheral
edema, peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest
pain, substernal chest pain, aggravated hypertension, myocardial infarction,
cerebrovascular disorder.
• Musculoskeletal System Disorders-Frequent: myalgia; Infrequent: arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
• Respiratory System Disorders-Frequent: rhinitis; Infrequent: coughing, dyspnea, upper
respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation,
bradypnea, stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
• Autonomic Nervous System Disorders-Frequent: impotence; Infrequent: flushing,
increased saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism,
vasodilation.

 Central and Peripheral Nervous System Disorders-Frequent: hypertonia, hypoesthesia; Infrequent:twitching,
confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination, hyperesthesia, leg cramps, abnormal
gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia, hypotonia, ptosis, choreoathetosis,
hyporeflexia.
 Gastrointestinal Disorders-Frequent: appetite increased; Infrequent: dysphasia, tooth caries aggravated,
eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup, stomatitis, tenesmus,
colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer, proctitis,
ulcerative stomatitis, tongue edema, tongue ulceration.
 Urinary System Disorders-Infrequent: micturition frequency, polyuria, urinary retention, dysuria, nocturia,
urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury.
 Liver and Biliary System Disorders-Rare: abnormal hepatic function.
 Endocrine Disorders-Rare: exophthalmos, gynecomastia.
 Reproductive-Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal hemorrhage,
amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis, breast enlargement, atrophic
vaginitis, acute female mastitis.

 Disorders of Skin and Appendages-Infrequent: pruritus, acne, urticaria, alopecia, dry skin, erythematous
rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema, dermatitis, contact
dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
 Hearing and Vestibular Disorders-Rare: hyperacusis, labyrinthine disorder.
 Hematopoietic and Lymphatic-Rare: anemia, anterior chamber eye hemorrhage.
 Metabolic and Nutritional Disorders-Infrequent: thirst; Rare: hypoglycemia, hypoglycemia reaction.
 Psychiatric Disorders-Frequent: yawning, other male sexual dysfunction, other female sexual
dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy, abnormal
dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated depression,
delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism, illusion.
 Special Senses-Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal
accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual field
defect.

A proposed new indication: Sertraline in stroke recovery
• It is proposed that Sertraline be used in post stroke recovery
• Research has shown that Sertraline and SSRIs in general can increase brain-derived
neurotrophic factors (BDNF). The gene for BDNF has recently received attention in relation
to the therapeutic action of antidepressant treatment. In one study a down-regulation of the
BDNF gene was detected at 4 h (TCP and fluoxetine) and an up-regulation at 24 h (TCP,
paroxetine, fluoxetine, sertraline) after the last of twice daily injections for 14 days (Coppell et
al, 2003). A study in mice found that Sertraline prolongs survival, improves motor
performance, and ameliorates brain atrophy in the R6/2 HD mouse model. These beneficial
effects of sertraline are associated with enhanced neurogenesis and increased BDNF levels
in brain treated with sertraline (Peng et al, 2008). These findings would suggest that taking
sertraline will increase levels of BDNF.

 It has also been found that increased BDNF leads to neurogenesis and has been found to play a role in
the recovery after a stroke. BDNF is a member of the neurotrophin family of growth factors. BDNF acts
on certain neurons of the central nervous system and the peripheral nervous system, helping to support
the survival of existing neurons, and encourage the growth and differentiation of new neurons and
synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain, areas vital to
learning, memory, and higher thinking. It is also expressed in the retina, motor neurons, the kidneys,
saliva, and the prostate. A study in rats was the first to identify a critical role for BDNF in rehabilitation-
induced recovery after stroke, and would suggest that new treatments to enhance BDNF would
constitute a promising therapy for promoting recovery of function after stroke (Ploughman et al, 2009).
Recovery of motor function after stroke involves relearning motor skills and is mediated by
neuroplasticity. BDNF has emerged as a key facilitator of neuroplasticity involved in motor learning and
rehabilitation after stroke.
 These findings would suggest that the increase in BDNF that can occur with sertraline use could
contribute to the neurogenesis and growth required in stroke recovery.

Study Design
• Randomized, Double Blind, Placebo controlled
study of sertraline as a neurotrophic agent
Arms Treatment
Placebo Placebo tablet
Active Medication Sertraline 50 mg daily

Inclusion Criteria:
age >40 years, male or female, within 12 months post-stroke
Exclusion Criteria:
use of antidepressant medications or initiation of antidepressant medications during the
study
Primary Outcome Measures:
-increased motor function
-increased cognition
-total brain grey matter
Secondary Outcome Measures:
-serum BDNF
-serum Sertraline

References
• Inchem.org,. 'Sertraline (PIM 177)'. N.p., 2015. Web. 4 Aug. 2015.
• Dailymed.nlm.nih.gov,. 'Dailymed - SERTRALINE- Sertraline Hydrochloride Tablet'. N.p.,
2015. Web. 4 Aug. 2015.
• Stahl, Stephen M. Essential Psychopharmacology. Cambridge, UK: Cambridge University
Press, 2000. Print.
• Coppell, A.L, Q Pei, and T.S.C Zetterström. 'Bi-Phasic Change In BDNF Gene Expression
Following Antidepressant Drug Treatment'. Neuropharmacology 44.7 (2003): 903-910. Web.
• Matrisciano, Francesco et al. 'Changes In BDNF Serum Levels In Patients With Major
Depression Disorder (MDD) After 6 Months Treatment With Sertraline, Escitalopram, Or
Venlafaxine'. Journal of Psychiatric Research 43.3 (2009): 247-254. Web.
• Brunoni, André R. et al. 'BDNF Plasma Levels After Antidepressant Treatment With
Sertraline And Transcranial Direct Current Stimulation: Results From A Factorial,
Randomized, Sham-Controlled Trial'. European Neuropsychopharmacology 24.7 (2014):
1144-1151. Web.

• Ploughman, M. et al. 'Brain-Derived Neurotrophic Factor Contributes To Recovery
Of Skilled Reaching After Focal Ischemia In Rats'. Stroke 40.4 (2009): 1490-1495.
Web.
• Peng, Qi et al. 'The Antidepressant Sertraline Improves The Phenotype, Promotes
Neurogenesis And Increases BDNF Levels In The R6/2 Huntington's Disease
Mouse Model'. Experimental Neurology 210.1 (2008): 154-163. Web.
• Wikipedia,. 'Brain-Derived Neurotrophic Factor'. N.p., 2015. Web. 4 Aug. 2015.
• Rosenblat, Joshua D., Ron Kakar, and Roger S. McIntyre. 'The Cognitive Effects
Of Antidepressants In Major Depressive Disorder: A Systematic Review And
Meta-Analysis Of Randomized Clinical Trials'. International Journal of
Neuropsychopharmacology (2015): pyv082. Web.
• Wikipedia,. 'Sertraline'. N.p., 2015. Web. 4 Aug. 2015.
• Mang, C. S. et al. 'Promoting Neuroplasticity For Motor Rehabilitation After Stroke:
Considering The Effects Of Aerobic Exercise And Genetic Variation On Brain-
Derived Neurotrophic Factor'. Physical Therapy 93.12 (2013): 1707-1716. Web.
• PharmGKB,. 'Dutch Pharmacogenetics Working Group Guideline For Sertraline
And CYP2C19'. N.p., 2015. Web. 5 Aug. 2015.

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