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PSYCHOPHARMACOLOGY: PART 1
ANTIDEPRESSANTS AND ANXIOLYTICS
Dr. Prashant Tibrewal
LITTLE BIT OF HISTORY

Serendipitous discovery in the 1950s led to the
development of the first antidepressant agents:
Iproniazid (for tuberculosis)
Imipramine (for psychosis)

Further investigations revealed their
pharmacological activity on monoamine
systems.
A BIT MORE……

In 1960s specific search for serotonin reuptake
inhibitors started

Culminating in the derivation of first SSRIZimelidine (withdrawn)

Further search for specific SSRIs led to the
development of landmark SSRI- Fluoxetine
CLASSIFICATION
Since then more than two dozen
antidepressants, which work by seven distinct
mechanisms, have been developed
1.
2.
3.
4.
5.
6.
7.
TCA
SSRI
NDRI
NaSSA
SNRI
SARI
MAOI
MECHANISM


1.
2.
3.
Given the structural diversity of the members of
each class, they may not resemble each other in
terms of their pharmacokinetics, metabolism or
toxicity.
However, most have an action on the metabolism
and at the receptor for monoamine
neurotransmitters:
Norepinephrine
Serotonin
Dopamine
ADDITIONAL MECHANISMS

Augmentation of intracellular cyclic AMP

Augment levels of neurotrophic and
transcription factors such as CREB and BDNF

Modulate excitatory transmission by
decreasing binding at NMDA receptors or by
inducing changes at AMPA receptors.
MONOAMINE HYPOTHESIS
MAO enzyme destroying
monoamine
neurotransmitter
neurotransmitter
NORMAL STATE -- no
depression
DEPRESSION -- caused by
neurotransmitter deficiency
Stahl S M, Essential
Psychopharmacology (2000)
MAO inhibitor blocks the
enzyme from destroying
monoamine
neurotransmitter
reuptake pump blocked by
antidepressant
Increase in neurotransmitters causes
return to normal state
Stahl S M, Essential
Psychopharmacology (2000)
Monoamine Receptor Hypothesis of Depression
Normal
functioning
Receptors upregulate due to
lack of NT
Decrease in
NT
Stahl S M, Essential
Psychopharmacology (2000)
CIRCUIT
CIRCUIT
CIRCUIT
Ser
Ne
CIRCUIT
Ser
Ne
CLASSICAL ANTIDEPRESSANTS

MAO inhibitors
and

Tricyclics
15
TYPES OF MAOI

Irreversible and non selective
Phenelzine, Tranylcypromine, Isocarboxazid

RIMAs- Moclobemide

Selective for MAO B-- Deprenyl
MAOI

Fell out of fame due to ‘cheese reaction’ –
dietary tyramine metabolism inhibited by MAOI
leading on to hypertensive crisis

Rigid dietary restrictions

RIMAs – Moclobemide fewer restrictions

Reserved for resistant or atypical cases
MAOI

Risk of SSRI syndrome
 Do
not combine with TCAs or SSRIs
 Never
 RIMA
with an SSRI
can be better tolerated but less effective.
TRICYCLICS
First agents marketed in 1950’s
Amitryptiline
Doxepine
Imipramine
Clomipramine
Trimipramine
Desipramine
Nortriptyline
TCAs
Therapeutic action
Therapeutic action
Psychopharmacology of antidepressants: Stephen Stahl
Side effects
Psychopharmacology of antidepressants: Stephen Stahl
Side effects
Psychopharmacology of antidepressants: Stephen Stahl
Side effects
Psychopharmacology of antidepressants: Stephen Stahl
Mechanism
Block reuptake of Serotonin (5HT) and
Norepinephrine (NE)
Onset of antidepressant effect: 3-4 weeks
SIDE EFFECTS
Alpha-1 Blockade:
Orthostasis, Sexual Dysfunction, Potential for cardiac conduction
delays (QT prolongation)
Histamine Blockade:
Potential for weight gain, Sedation
Acetylcholine Blockade:
Cognitive Dulling
Blurring of Vision
Tachycardia
Exacerbation of Asthma
Sexual Dysfunction
CONTRAINDICATIONS





Hypertensive patients
Cardiac conduction abnormalities (esp.
prolonged QT)
Acute narrow angle glaucoma
GI dysmotility syndromes
Benign Prostatic Hypertrophy
PROS AND CONS
Strengths
Effective, especially in severe
depression.
Weaknesses
Anticholinergic SEs.
Low cost.
Cardiovascular toxicity in
overdose.
Sedation perceived as a benefit.
weight Gain.
Can be used in pain,
fibromyalgia and migraine
Multiple daily dosing.
Titration.
Overall SE Profile.
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS (SSRIs)
 Fluoxetine
 Fluvoxamine
 Sertraline
 Citalopram
 Escitalopram
 Paroxetine

No or only weak effects at other monoamine
transporter

That distinguishes them from the older TCAs,
thus they are named selective.




Widely used, first-line treatments for
depression and anxiety
Multiple FDA indications
Safety in overdose
Tolerability- better side effect profiles than
older drugs like TCAs and MAOIs
SEROTONIN IS PRODUCED
tryptophan transporter
AAADC
5HTP
Tryptophan
TRY-OH
5HT (Serotonin)
5--34
Stahl S M, Essential
Psychopharmacology (2000)
SEROTONIN IS DESTROYED
serotonin
transporter
MAO
5--35
Stahl S M, Essential
Psychopharmacology (2000)
SEROTONIN RECEPTORS
5HT1D
autoreceptor
alpha 2 hetero
receptor
serotonin
transporter
5HT2C
5HT2A
5HT1A
5--36
5HT3 5HT4
5HTX
5HTY
5HTZ
Stahl S M, Essential
Psychopharmacology (2000)
5HT1A






Presynaptic and post synaptic
Antidepressant action
OCD
Panic
Social phobia
Bulimia
5HT1D

Anti- migraine actions
5HT2






Agitation
Akathisia
Anxiety
Panic attacks
Insomnia
Sexual dysfunction
5HT3




Nausea
GI distress
Diarrhoea
Headache
Serotonin Pathways
Raphe Nucleus
Stahl S M, Essential
Psychopharmacology (2000)
PATHWAYS INVOLVED




Depression: disinhibition of pathway to
prefrontal cortex
OCD: to basal ganglia
Panic Disorder: To limbic cortex and
hippocampus
Bulimia: to hypothalamus
Frontal Cortex
Mood
Stahl S M, Essential
Psychopharmacology (2000)
Basal Ganglia
Akathisia/
Agitation
OCD
Stahl S M, Essential
Psychopharmacology (2000)
Limbic
Anxiety
Stahl S M, Essential
Psychopharmacology (2000)
Hypothalamus
Appetite/bulimia
Stahl S M, Essential
Psychopharmacology (2000)
Sleep Centers
Insomnia
Stahl S M, Essential
Psychopharmacology (2000)
Spinal Cord
Sexual Dysfunction
Stahl S M, Essential
Psychopharmacology (2000)
Brainstem Vomiting
Center
Nausea and
vomiting
Stahl S M, Essential
Psychopharmacology (2000)
Gut
GI cramps/Diarrhea
Stahl S M, Essential
Psychopharmacology (2000)
COMMON FEATURES





Similar mechanism of action
Efficacy equivalent to TCAs
Higher therapeutic index than TCAs
Safer and better tolerated
- minimal cardiac effects
- fewer anticholinergic effects
Better patient compliance
ARE THEY IDENTICAL?
Differ
 structurally
 pharmacodynamically
- potency & selectivity
 pharmacokinetically
- half-life, metabolic activity
- Cytochrome P450 enzyme inhibition
SELECTIVITY




Differ in selectivity & potency
Citalopram is the most selective
- inhibits 5-HT uptake 3400 times more
than NE
Paroxetine : inhibits uptake of NE
Sertraline: inhibits uptake of DA
PHARMACOKINETICS



Half-life: FLX longest half-life
- FLX & SER: metabolites with long
half-lives
Time to steady-state: 3-4 weeks for FLX
- 5 to 10 days for other SSRIs
All highly plasma bound
- Citalopram the least (80%)
PHARMCOKINETICS (CONTD)

Nonlinear for most

Citalopram: linear pharmacokinetics across all
dose ranges

Up-titration predictable with citalopram
EFFECT ON CYTOCHROME
P450

Potent inhibitors

Exception: Citalopram

Least drug-drug interactions with citalopram
ADVANTAGES OF FLX

Discontinuation symptoms least

Reemergence of depression slower
ADVERSE EFFECTS

Paroxetine:
- highest anticholinergic effects
- weight gain
- delayed ejaculation

Citalopram:
- higher sedation
- weight gain
ADVERSE EFFECTS…..

Fluoxetine
- anxiety, nervousness & agitation
- weight loss
- Headache

Fluvoxamine & sertraline
- GI symptoms
- tremors
SEXUAL DYSFUNCTION

Prospective multicenter study (n=1022).

Spanish working group for the study of
psychotropic related sexual dysfunction.

All had normal sexual function previously.

Fluoxetine - 58%, Sertraline - 63%
Paroxetine - 71%, Fluvoxamine - 62%
Citalopram - 73%
Look for alternatives in patients
with



Sexual dysfunction
Consistent insomnia and agitation
Nocturnal myoclonus
NDRI

BUPROPION

The only antidepressant that ignores
the serotonin system.

Therefore, the therapeutic profile,
side effects and clinical applications
are different from and complementary
to others.

Dopamine deficiency could lead to symptoms
such as psychomotor retardation, anhedonia,
cognitive slowing, inattention, pseudodementia
and craving.

These could be the target symptoms.

To amplify therapeutic effects

To eliminate side effects (esp sexual dysfunction)

Other uses: ADHD, nicotine cessation

Side effects: Proadrenergic. Therefore
possibility of overstimulation, agitation,
insomnia, nausea, seizures.
AVOID USE IN PATIENTS
WITH



Seizure disorder
Non compliance to twice daily dosing
Agitated patient with insomnia
SNRI

Venlafaxine

Desvenlafaxine

Duloxetine

Milnacipran (not available in Australia)
VENLAFAXINE





Dose dependent pharmacology
At low doses , it is essentially an SSRI
At medium to high doses,additional NE reuptake
occurs
At very high doses some DA reuptake inhibition
also occurs.
Dual mechanism of action leads to better
remission when compared to SSRIs

5.5% incidence of rise in BP at doses above 200
mg/day.

Risk increases to 13% above 300 mg.

Indicated for GAD and social anxiety as well.

Initial dose 75 mg

Recommended upper dosage is 225 mg/day.
However, can be titrated up to 375 mg/day
DESVENLAFAXINE

DVS is the salt form of the isolated major
active metabolite of venlafaxine.

Developed for the treatment of depression and
for the alleviation vasomotor symptoms
associated with menopause.

Initial dose 50 mg. Titrate up to 200 mg/day.

Can be safer than Venlafaxine in hepatic
dysfunction.
DULOXETINE
Indicated for the treatment of
1.
depression,
2.
generalized anxiety disorder,
3.
and painful diabetic neuropathy
? stress urinary incontinence

Formulated as a delayed-release capsule to
reduce the risk of severe nausea associated
with the drug.

Extensive hepatic metabolism—avoid in
alcoholism.

Initial dose 20 mg. titrate up to 60 mg/day.

Dose can be divided to minimise side effects.
SARI - NEFAZODONE

Serotonin-2 receptor antagonism with serotonin
reuptake blockade.

SSRIs with a difference.

Block 5HT2 in addition leading to amelioration
of 5HT2 related side effects.

So, less sexual side effects and sleep disruption
associated with the SSRIs

Nevertheless found to produce problematic
sedation, nausea, dizziness, and visual
disturbances

Consequently, Nefazodone was never
extensively adopted in clinical practice.
NASSA- MIRTAZAPINE





Designer antidepressant
Four principle actions
Proadrenergic as well as proserotonergic
action – due to ά 2 antagonism
Serotonin 2 and 3 antagonist
Strong antihistamine properties
Useful in depression with
 Anxiety
 Agitation
 Insomnia
Also useful in counteracting side effects of SRIs
such as:
Sexual dysfunction
Nausea, GI disturbances, agitation , panic weight
loss.
SHOULD NOT BE USED IN




Hypersomnia
Motor retardation
Cognitive slowing
Overweight patients
BUSPIRONE AND BZDS
Buspirone
 Presynaptic agonist at 5HT1a receptors
 Thrice daily dosing
 Not first line drugs
Benzodiazepines
 GABA facilitatory drugs
 Good anxiolytics but addiction potential, sedation
 Long acting agents preferred
Propranolol – for isolated anxious situations
Newer Antidepressants

Agomelatine:
Agomelatine is a novel antidepressant that is both a melatonergic agonist and
a 5-HT 2C antagonist. Agomelatine also enhances dopaminergic and
adrenergic input to the frontal cortex. Dose 25 – 50 mg at bedtime. Not
avaialble in US.

Vortioxetine is a 5-HT3, 5-HT1D, and 5-HT7 antagonist, a 5-HT1A
agonist, and a 5-HT1B partial agonist. Dose 5mg – 20 mg/day.
Conceptualising the current
scenario

Major depressive disorder accounts for 4.4
percent of the total overall global disease
burden.

Affects 5-13% of medical outpatients

Yet often undiagnosed and untreated

Often under treated when correctly diagnosed
Conceptualising the current scenario

Among persons both with major depressive
disorder and bipolar disorder, 75 to 85 percent
have recurrent episodes.

10 to 30% recover incompletely and have
persistent, residual depressive symptoms, or
dysthymia.
Conceptualising the current scenario

Patients who have diabetes, epilepsy, or
ischemic heart disease with concomitant major
depression have poorer outcomes than do
those without depression.

The risk of death from suicide, accidents, heart
disease, respiratory disorders, and stroke is
higher among the depressed.
Conceptualising the current scenario

The prescription and use of anti-depressants has received a
lot of attention in the medical literature, the media and
legislation

The task for medical professionals is made more complex
by the bewildering array of apparently efficacious drugs
from which to choose
GPs diagnose most episodes of depression amongst
Australians and prescribe more than 85% of
antidepressants
Mant A, Hickie IB et al MJA 2004

HOW TO CHOOSE ?

Largely based on your clinical assessment.

Side effects, tolerability, safety and
convenience play a major role in decision
making.

Differential efficacy plays little role.
INITIAL CLINICAL ASSESSMENT
Should include an evaluation of :








Patient’s previous treatment outcomes
Mood-disorder subtype
Severity of the current episode of depression
Risk of suicide
Coexisting psychiatric and physical conditions,
Non psychiatric medications and substance abuse
Psychosocial stressors
Family history
How to choose?
Consider some of the
following questions:







The patient’s particular symptoms
Possible side effects
Whether it worked for a close relative
Interaction with other medications
Pregnancy and breast feeding
Co-existing health conditions
Cost and health insurance coverage
The patient’s particular symptoms
Poor sleep/ global insomnia
Agitation and anxiety
Atypical depression-
Sedative AD- TCA, Mirtazapine
SNRI, MAOIs
weight gain, hypersomnolence
Obsessive symptoms
SSRIs
Low energy
Stimulating AD- Bupropion,
Venlafaxine, Desvenlafaxine,
Nortriptyline
Pain, Weight loss and GI
symptoms
TCAs
Interaction with other medications

SSRIs reduce platelet aggregation- adds to the effect
of NSAIDs/Aspirin

SSRIs increase levels of medications metabolized by
cytochrome p450 isoenzymes in the liver eg losartan,
chlorpheniramine, diazepam, risperidone

MAOIs and TCAs- lower blood pressure and cause
tachycardia, potential interaction with antihypertensive
medications

MAOIs and hypertensive crisis-tyramine reaction
Co-existing medical condition

Potential interactions:
1.
Drug-illness interaction
Drug-drug interaction
2.




Parkinson’s disease- MAOIs slows down dopamine
metabolism
Use Venlafaxine with care in patients with established
hypertension
Avoid TCAs and Paroxetine in people with angle closure
glaucoma, benign prostatic hypertrophy
Citalopram drug of choice in individuals on multiple medical
medications
Suicide and antidepressant treatment

All antidepressants reduce risk of suicide

TCAs and SNRIs have lower safety thresholds
in OD

SSRIs may initially worsen anxiety and
agitation and suicidal ideation (particularly in
<25 years )
BIPOLAR DEPRESSION

Bipolar patients are three times more likely to
experience depression than mania.

Patients are 30 times more likely to suicide
during the depressed phase of their illness.

Three agents are FDA approved:
Olanzapine+ Fluoxetine
Quetiapine
Lurasidone
1.
2.
3.
BIPOLAR DEPRESSION

Largest study till date: STEP BD

Supportive evidence for Lithium, Lamotrigine,
Olanzapine

Lack of evidence and potential for harm with traditional
antidepressants

They should therefore be avoided as first line treatment
for Bipolar Depression.
In case of resistance





Ensure adequate compliance/dosage/duration
Reconsider your diagnosis
Look for co-morbid GMC
Look for co-morbid Psychiatric conditions
Psychosocial stressors/Family EE
In case of resistance

Optimizing antidepressant dose

Augmenting or combining therapies

Switching therapies
FUTURE CHALLENGES

1.
2.

Identification of antidepressants
That act more quickly than those currently
available,
That do not require continuation and
maintenance treatment.
A biologic classification system of subtypes
of major depression is needed to facilitate
the selection of the best antidepressant for
each patient.
PHASES OF TREATMENT
Jan 04
June 04
Jan 05
June 05
Acute
Continuation
Maintenance
PHASES OF TREATMENT
Jan 04
June 04
Jan 05
June 05
Acute
Continuation
Maintenance
PHASES OF TREATMENT
Jan 04
June 04
Jan 05
June 05
Acute
Continuation
Maintenance
PHASES OF TREATMENT