Psychopharmacology

1. Dr. Sarang Pandit
Post Graduate Final year
Lata Mangeshkar Hospital
Nagpur

2.  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

3.  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.

4. Fluvoxamine
F3C C CH2 CH2 CH2 CH2 O CH3
N
O CH2 CH2 NH2
Paroxetine
N
O
O
O
CH2
Fluoxetine
O C
H
CH2 CH2 N
CH3
H
Sertraline
HN
CH3
Cl
Cl
Citalopram
S-citalopram F
O
NC
CH2CH2CH2N(CH3)2·HBr

5.  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.

6.  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

7.  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

8.  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.

9. /SERT(monoamine transporter protein) blocked

10.  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.

11.  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.

12.  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.

13.  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.

14.  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.

15.  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.

16.  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

17.  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.

18.  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.

19.  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.

20.  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.

21.  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.

22. Fluoxetin
e
Citalopra
m
Escitalopr
am
Sertraline Paroxetin
e
Fluvoxam
ine
Pharmace
rutical
forms
Tab-
10/20/40
mg
Solution-
20mg/5m
L
Tab-
10/20/40
mg
Tab-
5/10/20
mg
Tab-
25/50/10
0 mg
Tab-
10/20/30
/40 mg
CR-
12.5/25/
37.5 mg
Tab-
25/50/10
0 mg
Brand
names
Prodep,
Flunil,
Fludac,
Flupar
Celica,Cit
adep
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
Recomme
nded
doses
10-80
mg/day
20-40
mg/day
10-20
mg/day
50-100
mg/day
10-50
mg/day
50-300
mg/day

23. Fluoxetin
e
Citalopra
m
Escitalopr
am
Sertraline Paroxetin
e
Fluvoxam
ine
Most
common
side
effects
(Nausea)
Headache
Insomnia
Nervousn
ess
Anxiety
Drowsnes
Anorexia
Diarrhea
Drymouth
Drowsnes
Insomnia
Increased
sweating
Diarrhea
Insomnia
Diarrhea
Headache
Headache
Insomnia
Diarrhea
Drymouth
Ejaculatn
failure, ↓
libido
Drowsnes
Dizziness
Fatigue
Drowsnes
Headache
Drymouth
Dizziness
Weakness
Fatigue
Sexual
dysfunctn
Sweating
Diarrhea
Insomnia
Sexual
Dysfuncti
on,Gastro
intestinal,
Sedation
Least
common
side
effects
Dizziness
Weakness
Drymouth
Anxiety
Agitation
Tremor
Sweating
Sexual
dysfuncti
on
Tremor
Ejaculatn,
↓ libido,
impotnce
Fatigue
Anxiety
Agitation
Anorexia
Abnormal
ejaculatn,
↓ libido,
impotnce
Drymouth
Drowsnes
Fatigue
Sweating
Dizziness
Anxiety
Anorexia
Tremor
Sweating
Agitation
Anorexia
Nervousn
ess
Anxiety
Tremor
Constipat
ion, ↓
appetite
Anxiety
Nervousn
ess
Tremors,
Bruising,
Rare
bleeding
Seizures

24.  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