Dr. Sarang PanditPost Graduate Final year

Lata Mangeshkar HospitalNagpur

With introduction of Fluoxetine attitude abt pharmacological treatement changed because of better tolerance than existing treatments, simplicity of dosing.

Subsequently other SSRIs were introduced.

SSRI YEAR

Fluoxetine 1988

Sertraline 1992

Paroxetine 1993

Fluvoxamine 1994

Citalopram 1998

S-Citalopram 2002

These compounds are structurally unrelated.

This may account for the differential response we see in some patients with one antidepressant vs. another.

Rationale for differential response may be related to different morphology of the serotonin transport protein.

Fluvoxamine

F3C C CH2 CH2 CH2 CH2 O CH3

N

O CH2 CH2 NH2

Paroxetine

N

O

OO

CH2

Fluoxetine

O CH

CH2 CH2 N

CH3

H

Sertraline

HN

CH3

Cl

Cl

Citalopram

S-citalopram F

O

NC

CH2CH2CH2N(CH3)2·HBr

Absorption – Well absorbed orally and have peak effects in the range of 3-8 hrs. Absorption of Sertraline may be slightly increased by food.

Distribution – Differences in plasma protein binding percentages; with Sertraline, Fluoxetine & Paroxetine most highly bound; & Escitalopram least bound.

Metabolism – All SSRIs are metabolized in the liver by CYP 450 enzymes.

Wide Therapeutic Index-So their concentration not affected by other drugs. But, potential for slowing/blocking the metabolism of many drugs.

Elimination –

Drug Half-life

1. Fluoxetine 4-6 days

Norfluoxetine (Active Metabolite)

7-9 days

2. Citalopram 35 hours

3. Escitalopram 27-32 hours

4. Sertraline 26 hours

(Less active metabolite) 3-5 days

5. Paroxetine 21 hours

6. Fluvoxamine 15 hours

Hormone found in Digestive Tract Pineal Gland Platelets Brain- Acts as neurotransmitter i.e. works at neural synapse to

transmit electrical impulses from one nerve to the next.

Role in depression Regulates many functions of body and brain Mood Sleep Apetite Sexual Desire Cognition

Serotonin deficiency can cause depressive symptoms. Levels can be decreased due to ↓ production in brain cells ↓ no. of receptor sites Inability to bind properly with receptor sites Shortage of precursor chemical tryptophan.

‣ SSRIs treat this deficiency of Serotonin

‣ SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well. Because of this, SSRI’s lack some of the side effects of the more general drugs.

/SERT(monoamine transporter protein) blocked

Depression

All SSRIs except, Fluvoxamine have been approved by the FDA for T/t of Depression.

Direct comparison have not revealed any one to be superior to others. However, considerable diversity is seen in response to various SSRIs among individuals.

Hence, in non-responders, before shifting to other classes of antidepressants, it is most reasonable to try other agents in SSRI class.

Suicide – Few patients become anxious, agitated on starting SSRIs. These symptoms can conceivably provoke or aggravate suicidal ideation. Thus, should be closely monitored during the period of maximal risk i.e. the 1st

few days and weeks they are taking SSRIs.

Anxiety disorders

OCD -

Adults – Fluvoxamine, Paroxetine, Sertraline & Fluoxetine.

Pediatric – Fluvoxamine, Sertraline.

SSRI dosages for OCD may need to be higher than those required to treat depression.

OCD spectrum – Non-suicidal self mutilation (Trichotillomania, nose-picking, eyebrow picking, nail-biting, etc.); Compulsive shopping, compulsive gambling, Hypochondriasis and Body dysmorphic disorder

Panic Disorder (with/without Agoraphobia) -

Paroxetine and Sertraline are drugs of choice.

Social anxiety disorder –

Safer than BDZs and MAOIs

Post-traumatic stress disorder – SSRIs are a/w marked improvement of both intrusive and

avoidant symptoms.

BDZ augmentation is useful in acute symptomatic state.

Generalized Anxiety Disorder –

SSRIs may be useful for T/t of Specidic phobias, GAD & separation anxiety disorder.

Bulimia Nervosa and other Eating disorders – Bulimia Nervosa - Fluoxetine of 60mg/day is significantly more effective than

20mg/day.

Anorexia Nervosa – Fluoxetine is used to treat co-morbid mood disturbances

and OC symptoms.

Obesity – Fluoxetine- moderately beneficial.

Premenstrual Dysphoric Disorder - Sertraline, Fluvoxamine, Fluoxetine and Paroxetine.

Off-label uses – Premature Ejaculation –

The antiorgasmic effects of SSRIs make them useful as a T/t for premature ejaculation.

Fluoxetine and Sertraline have been shown to be effective.

Paraphilas – SSRIs may reduce obsessive-compulsive behavior in people

with paraphilias, thus reducing avg time spent/day in unconventional sexual fantasies, urges & activities.

Autism – Sertraline and Fluvoxamine trials have shown to mitigate

aggressiveness, self-injurious behavior, repetitive behaviors, some degree of language delay and rarely, lack of social relatedness in adults with autistic spectrum disorders.

Fluoxetine has been reported to be effective for features of autism in children, adolescents and adults.

Pregnancy and Postpartum-All SSRIs are rated pregnancy category C, with the exception of paroxetine, which is a category D. No increased risk is seen for major congenital malformation.Risk of relapse into depression when newly pregnant mother is taken off SSRIs is several times higher than the risk to fetus of exposure to SSRIs.

Breast Feeding –Sertraline is the drug of choice followed by Paroxetine(upto 40 mg).

Geriatric -Safe & well tolerated.No cardiotoxic, anticholinergic, antihistaminic or α adrenergic adverse effects except Paroxetine which has some anticholinergic activity.

Paediatric-Only Fluoxetine has FDA approval for use as an andidepressant.

Renal Impairment-No agent clearly preferred to another, however: citalopram and sertraline are suggested as reasonable choices.

Hepatic Impairment- Fluoxetine (longer half life) to be avoided. Citalopram & Escitalopram have minimal effects on hepatic enzymes so

they are SSRIs of choice.

Diabetes Mellitus-Fluoxetine has been associated with improvement in HbA 1c levels, reduced insulin requirements, weight loss and enhanced insulin sensitivity.

Cardiac Disorders-Sertraline is recommended. but other SSRIs are also likely to be safe (Minimal effect on heart rate,minimal effect on blood pressure,no effect on QTc interval.)

Post Stroke Depression-Fluoxetine, citalopram are the most studied and seem to be effective and safe and widely recommended for post-stroke depression. Stroke can be embolic or haemorrhagic –SSRIs may protect against the former and provoke the latter.

Parkinson’s Disease-SSRIs are considered to be first-line treatment. Motor symptoms may be worsened(low risk)SSRIs + Selegiline → Risk of Serotonin Syndrome

Cancer Pts – Sertraline, Escitalopram are preferred due to least risk of drug interaction

The side effects of SSRIs shd be considered in terms of their onset,durtion, and severity.Example-Nausea &- Jitteriness are early,generally mild, and time-limited side effects.

Sexual Dysfunction-M.C. adverse effect of all SSRIs with long term treatement . Most common complaints are anorgasmia ,inhibited orgasm, and decrease

libido. Strategies to counter include addition of Bupropion,Cyproheptadine and

Sildenafil.

Gastrointestinal Adverse Effects –They are mediated largely through effects on the serotonin 5HT3 receptors. Most frequent side effects include-

Nausea,diarrhoea,anorexia,vomitting,flatulence and dyspepsia. Sertraline and Fluvoxamine produce the most intense GI symptoms. Paroxetine is most commonly associated with wt gain amongst all SSRIs.

This wt gain is gradual and is usually resistant to diet control and exercise regimens.

Headaches – Fluoxetine is the SSRI most likely to cause headache. On the other hand, SSRIs are effective prophylaxis against both migraine

and tension-type headaches.

Central nervous system – Anxiety – Most common with Fluoxetine & Sertraline. Least common with Paroxetine & Escitalopram so used in conditions like

mixed anxiety depressive disorder where sedation is required. Insomnia & Sedation – Fluoxetine – Insomnia Sertraline & Fluoxetine – Insomnia & sedation (equally likely) Citalopram & Paroxetine – Somnolence Other sleep effects of SSRIs include bruxism, restless legs, nocturnal

myoclonus, and sweating. Yawning – Not a result of fatigue or poor sleep but, because of SSRI effects on

Hypothalamus.

Emotional blunting – Feeling of apathy or indifference, or a restriction in the intensity of emotional experiences

(inability to cry in response to emotional situations).

Seizures – 0.1-0.2%

Frequent at highest doses of SSRIs (e.g. Fluoxetine ≥ 100mg/ day)

Extrapyramidal side effects- Rare.

Anticholinergic effects – Paroxetine has mild anticholinergic activity in a dose-dependent fashion

Hematologic adverse effects- Functional impairment of platelet aggregation, but not reduction in no. of platelets.

Electrolyte & Glucose disturbances- Rarely, Hyponatremia and SIADH esp in patients treated with diurectics. Can actuely decrease glucose (diabetics s/b carefully monitored).

Endocrine & Allergic reactions – Decrease prolactin levels (reversible mammoplasia, galactorrhea in men/women) SSRI treatment may have to be discontinued in patients with drug-related rashes.

Administration of an SSRI in presence of another highly serotonergic drug such as MAOI, Lithium and L-Tryptophan life-threatening ‘serotonin syndrome’

Excess of serotonin Diarrhea, restlessness, agitation, hyperreflexia, autonomic instability, myoclonus, seizures, hyperthermia, rigidity, delirium, coma, cardiovascular collapse & death.

Treatment – Removal of offending agent, comprehensive supportive care with nitroglycerine, cyproheptadine, methysergide, cooling blankets, chlorpromazine, dantrolene, BDZ, anticonvulsants, mechanical ventilation, paralyzing agents.

Abrupt withdrawal of SSRIs esp those with

shorter half-life (Paroxetine/Fluovoxamine).

Fluoxetine lowest risk.

Symptoms include: headache, nausea, malaise,

dizziness, weakness, agitation, irritability, flu-like

symptoms, nervousness, poor concentration,

rebound depression.

Doesn’t appear until at least 6 weeks of

treatment & usually resolves spontaneously in 3

weeks.

Fluoxetine

Citalopram

Escitalopram

Sertraline Paroxetine

Fluvoxamine

Pharmaceruticalforms

Tab-10/20/40 mgSolution-20mg/5mL

Tab-10/20/40mg

Tab-5/10/20mg

Tab-25/50/100 mg

Tab-10/20/30/40 mgCR-12.5/25/37.5 mg

Tab-25/50/100 mg

Brand names

Prodep, Flunil, Fludac, Flupar

Celica,Citadep

Nexito, Recita, S-citadep, Feliz-S, Rexipra

Serlift, Serta,Daxid

Paxidep,Pari CR,Xet CR

Uvox, Fluvoxin

Half-life 4-6 days 35 hours 27-32 hours

26 hours 21 hours 15 hours

Time to Steady state

30-60 days

7 days 7 days 7-14 days

10-14 days

5-10 days

Recommendeddoses

10-80 mg/day

20-40 mg/day

10-20mg/day

50-100 mg/day

10-50 mg/day

50-300 mg/day

Fluoxetine

Citalopram

Escitalopram

Sertraline Paroxetine

Fluvoxamine

Most common sideeffects (Nausea)

HeadacheInsomniaNervousnessAnxietyDrowsnesAnorexiaDiarrhea

DrymouthDrowsnesInsomniaIncreased sweatingDiarrhea

InsomniaDiarrheaHeadache

HeadacheInsomniaDiarrheaDrymouthEjaculatnfailure, ↓ libidoDrowsnesDizzinessFatigue

DrowsnesHeadacheDrymouthDizzinessWeaknessFatigueSexual dysfunctnSweatingDiarrheaInsomnia

Sexual Dysfunction,Gastrointestinal,Sedation

Least common side effects

DizzinessWeaknessDrymouthAnxietyAgitationTremorSweatingSexual dysfunction

TremorEjaculatn, ↓ libido, impotnceFatigueAnxietyAgitationAnorexia

Abnormal ejaculatn, ↓ libido, impotnceDrymouthDrowsnesFatigueSweatingDizzinessAnxietyAnorexia

TremorSweatingAgitationAnorexiaNervousnessAnxiety

TremorConstipation, ↓ appetiteAnxietyNervousness

Tremors,Bruising,Rare bleedingSeizures

Fluvoxamine > Fluoxetine > Paroxetine > Sertraline > Citalopram > Escitalopram

Interacting effects may be dose dependent.

SSRI levels tend not to be altered by other drugs but can potentially increase levels (inhibit metabolism) of certain drugs

Examples:

paroxetine > ↑ risperidone

fluoxetine > ↑ buspirone

fluvoxamine > ↑ olanzapine