22/11/2010

PHARMACOLOGY OF THE
CENTRAL NERVOUS SYSTEM
DRUGS FOR MOOD DISORDERS
Kirsten Culver, PhD

Neuropsychopharmacology
 An interdisciplinary science related to fundamental
neuroscience and psychopharmacology
 Involves research into the mechanisms of neuropathology,
pharmacodynamics, psychiatric illness, and states of
consciousness
 To appreciate how psychoactive drugs affect the mind
and how they may be used clinically to treat psychiatric
ill
illness, we must first
fi di discuss:
 The neurotransmitters involved in human thought, feelings and
behaviour
 The brain areas believed to mediate these thoughts, feelings
and behaviours

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Neurotransmitters and the CNS

 Many neurotransmitter systems exist in the
h
human b
brain
i
 Over 100 different neurotransmitters have been
identified in the central nervous system
 Theseneurotransmitters can be divided into 3 major
classes:
 Small molecule neurotransmitters (ie: dopamine)
 Neuropeptides (ie: substance P)
 Neurotransmitter gases (ie: nitric oxide)

Neurotransmitters and the CNS

 Small Molecule Neurotransmitters
 Acetylcholine
A l h li Alzheimer’s Disease
 Monoamines
 Dopamine (DA) Schizophrenia, Parkinson’s Disease
 Norepinephrine (NE)
Depression, Bipolar Disorder
 Epinephrine (E)
 Serotonin (5
(5-HT)
HT)
 Amino acids
 Glutamine Excitatory Neurotransmitter
 GABA Inhibitory Neurotransmitter

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Pathogenesis of Psychiatric Disorders

 Most psychiatric disorders (except major depression)

are tho
thought
ght to be associated with EXCESSIVE CNS
stimulation
 Pathogenesis of mental illness may involve one or
more of the following mechanisms:
 Excessive amounts of excitatory neurotransmitters
 Increased number or sensitivity of excitatory receptors
 Insufficient amounts of inhibitory neurotransmitters
 Decreased number or sensitivity of inhibitory receptors

Under typical conditions….

PRESYNAPTIC STIMULATORY
POSTSYNAPTIC NEURON
NEURON
(+)
X
Enervation of the postsynaptic neuron (-)
leads to signal transduction

The level of signal transduction is mediated

by stimulatory and inhibitory inputs

The level of stimulation/inhibition is tightly PRESYNAPTIC INHIBITORY

regulated NEURON

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Excessive stimulatory neurotransmitter

release…
PRESYNAPTIC STIMULATORY
POSTSYNAPTIC NEURON
NEURON
(+)
X
Increased release of neurotransmitter from (-)
the stimulatory presynaptic neuron
produces EXCESSIVE stimulation of the
postsynaptic neuron

This excessive stimulation is so significant

that the inhibitory input is not sufficient to PRESYNAPTIC INHIBITORY
moderate the postsynaptic signal and NEURON
return it to normal levels

Increased amount/sensitivity of postsynaptic

stimulatory receptors …
PRESYNAPTIC STIMULATORY POSTSYNAPTIC NEURON
NEURON

(+)
X
Increased numbers and/or sensitivity of (-)
stimulatory postsynaptic receptors results in
EXCESSIVE stimulation of the postsynaptic
neuron.

This excessive stimulation is so significant

that the inhibitory input is not sufficient to PRESYNAPTIC INHIBITORY
moderate the postsynaptic signal and NEURON
return it to normal levels.

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Insufficient inhibitory neurotransmitter

release…
PRESYNAPTIC STIMULATORY
POSTSYNAPTIC NEURON
NEURON
(+)
X

(-)
Decreased release of neurotransmitter
f
from the
th inhibitory
i hibit presynapticti neuron
leads to improper modulation of the
postsynaptic signal, ultimately producing
EXCESSIVE postsynaptic signaling PRESYNAPTIC INHIBITORY
NEURON

Decreased amount/sensitivity of
postsynaptic inhibitory receptors…
PRESYNAPTIC STIMULATORY
POSTSYNAPTIC NEURON
NEURON
(+)
X

(-)
Decreased numbers and/or sensitivity of
i hibit
inhibitory postsynaptic
t ti receptors
t leads
l d to
t
improper modulation of the postsynaptic
signal, ultimately producing EXCESSIVE
postsynaptic signaling
PRESYNAPTIC INHIBITORY
NEURON

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 22/11/2010

Neurotransmitter Systems
 Noradrenergic System
 Norepinephrine (NE)
 Important brain areas:
 Locus ceruleus projects to the limbic system
 Neocortex, amygdala, hippocampus,
cerebellum
2 receptor classes
 Alpha adrenergic receptors
 Beta adrenergic

Neurotransmitter Systems
 Noradrenergic System
 Involved in maintaining emotional tone (mood,
arousal, wakefulness and reward)
 Decrease in noradrenergic activity associated
with depression
 Increase in noradrenergic
g activityy associated with
manic symptoms observed in bipolar disorder

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Neurotransmitter Systems
 Serotonergic System
 Serotonin (5-HT)
 Synthesized from the amino acid tryptophan
 Important brain areas
 Raphe nuceli projects to the limbic system & cerebral
cortex
 Co-localized with the noradrenergic system
 Receptor Classes
 5-HT1 to 5-HT7 with at least 10 known subtypes

Neurotransmitter Systems
 Serotonergic System
 Active in maintaining sleep-wake cycle, emotional
tone & sensory perceptions (e.g. pain)
 Increase in serotonergic activity associated with
schizophrenia
 Decrease in serotonergic activity associated with
depression and anxiety

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Norepinephrine, Serotonin & Mood

 Major (Unipolar) Depression
 Affects approximately 6% of the adult Canadian population
 Average depressive episode lasts approximately 5 months
 Symptoms include:
 Depressed mood (sadness, hopelessness, despair)
 Inability to derive pleasure or experience interest in most activities
 Loss of energy, fatigue
 Diffi l thinking
Difficulty hi ki & concentrating
i
 Inappropriate feelings of worthlessness
 Lack of interest in appearance, sex, leisure activities
 Change in appetite and weight to
 Sleep disorders
 Suicidal Ideation

Norepinephrine, Serotonin & Mood

 Major Depression
 Biological cause
 Family history
 Minor Depression
 Short-lasting, often situational or reactive
 P t
Post-partum
t Depression
D i
 Presents 2 weeks to 6 months after childbirth
 Seasonal affective disorder

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Antidepressant Drugs

Antidepressant Drugs
 Indications
 Treatment of major depression
 Prevention of recurrence of major depression

 Prevention of panic attacks

 Treatment of obsessive-compulsive disorder (even

when depression is not a symptom)
 Pain syndromes

 Childhood enuresis

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Monoamine Oxidase Inhibitor Drugs

 MAO enzyme (MAO-A & MAO-B)

 D
Deaminates
i t DA DA, NE
NE, & 5
5-HT
HT
 Inhibition of MAO enzyme increases monoamine levels
 Reversible vs Irreversible MAO inhibition
 Moclobemide (MAO-A inhibitor)
 Onset of therapeutic
p effect: 4 - 8 weeks
 Side effects include orthostatic hypotension, headache,
insomnia, diarrhea, hypertensive crisis (tyramine)
 Used to treat depression when TCAs, SSRIs or SNRIs are
not effective (refractory cases)

Monoamine Oxidase Inhibitor Drugs

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MAOIs and Tyramine

 Tyramine
 Form
F off the
h amino
i acid
id tyrosine
i
 Found in many common foods
 Red wine, cheese and other dairy products, chocolate, some
fruits, vegetables and meat products
 Deaminated by MAO enzymes
 Inhibition
of MAO activity by MAOI drugs increases plasma
tyramine levels
 Results in increased in NE levels
 Produces acute hypertension
 Headache, stiff neck, flushing, palpitations, sweating

Tricyclic Antidepressant Drugs

 Inhibit NE, 5-HT and DA reuptake into the presynaptic
neuron
 Increase NE, 5-HT and DA levels in the synapse
 Onset of therapeutic effect: 2 - 6 weeks
 Exhibit an affinity for histamine and muscarinic receptors
 Blurred vision, dry mouth, urinary retention, constipation,
tachycardia, sedation, orthostatic hypotension
 90% of TCAs are bound to serum albumin
 Interaction with oral contraceptives
 Used to treat depression in refractory cases

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Tricyclic Antidepressant Drugs

Selective Serotonin Reuptake Inhibitors

 Inhibit serotonin reuptake into the presynaptic neuron
 Onset of therapeutic effect: up to 5 weeks
 No affinity for histamine and muscarinic receptors
 No sympathomimetic or anti-cholinergic effects
 Preferred drug class (reduced side effect profile)
 Nausea
 Sleep disturbances
 Weight gain
 Sexual dysfunction
 PEDIATRIC CASES!!!
 Discontinuation of drug should be gradual to avoid withdrawal
effects

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Selective Serotonin Reuptake Inhibitors

Serotonin Syndrome (SES)

 Associated with extreme increases in serotonin levels
 Results
R l iin confusion,
f i anxiety,
i restlessness,
l hhypertension,
i
tremors, sweating, hyperpyrexia, and ataxia
 Caused by co-administration of drugs that increase
serotonin levels
 SSRIs + MAOIs
 SSRIs + TCA

 SSRIs + lithium

 SSRIs + St. John’s Wart

 MDMA (ecstasy)

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Atypical Antidepressants
 Serotonin/Norepinephrine Reuptake Inhibitors
 Used
U d to
t ttreatt d
depression
i iin th
those individuals
i di id l who h
are not responding to treatment with SSRIs
 Onset of therapeutic effect: 2 weeks

 Norepinephrine/Dopamine Reuptake Inhibitors

 Used to treat depression, low side effect profile

 Smoking cessation aid

Antidepressant Drugs
 Major depression is associated with NE & 5-HT
d fi i
deficiency
 Anti-depressant medications increase the amount of
these two neurotransmitters at the synapse

Then why the disparity between pharmacological

effect and onset of therapeutic response?

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Antidepressant Drugs
 Increases in NE & 5-HT only an initial pharmacological
effect
 Therapeutic effect likely related to:
 Down-regulation/decreased sensitivity of presynaptic
5-HT and NE autoreceptors
 Decreased density/sensitivity of autoreceptors
increases synthesis and release of NE & 5-HT in the
synapse
 Increase in endogenous NE & 5-HT release
 Down-regulation of postsynaptic 5-HT2 receptors
 Down-regulation of postsynaptic beta-adrenergic
receptors

Norepinephrine, Serotonin & Mood

 Bipolar Disorder
 Ch
Characterized
i d by
b alternating
l i periods
i d off depression
d i & mania
i
 Mania includes the following symptoms (≥ 1 week):
 Grandiose ideas, inflated self-esteem
 Reduced need for sleep

 Constant talking & movement

 Racing thoughts

 Distractibility or agitation

 Impulsiveness, attention seeking, dangerous behaviours

 Depression

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Mood Stabilizers
 Lithium
 Effective for the prevention of mania and depressive recurrences
 Antidepressant drugs and benzodiazepines may be added to improve
response
 Drug interactions
 Some prostaglandin inhibitors (NSAIDs) decrease renal clearance and
increase lithium levels (e.g. indomethacin)
 Diuretics increase renal clearance
 Monitoring
 12 hour blood level must be monitored every 3 months
 Thyroid function test, BUN, creatine, urinalysis every 3-6 months
 Take at bedtime – may be more protective of kidneys

Mood Stabilizers
 Carbamazapine
 A
Anticonvulsant
l widely
d l used
d ffor temporall lobe
l b epilepsy
l
 Effective in acute mania and prevention of manic and depressive
recurrences
 Used in patients with an ineffective response to lithium or when there is a
contraindication to lithium
 Adverse Effects
 Bone marrow suppression – must monitor WBC and discontinue use is WBC<
3500-4000
 Liver Damage – monitor liver enzymes
 Nausea, vomiting, ataxia, sedation
 Cannot be given concurrently with Clozapine because of increased risk of
bone marrow suppression

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