crown clinical research post-graduate certificate 2016 - sertraline pharmacolggy and new proposed...

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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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