INTRODUCTION
• Depression afflicts approximately 5% of the population,
1-2% with bipolar disorder.
• Suicide from depression is 25-30% of depressed
population.
• Depression 2-3 X higher in women.
• 70% of patients have response to drugs.
• There is major depression and secondary mood
disorders
“BREAKING OUT OF THE
BOX”
• Results from a recent national survey
• Myths
– 54% believe depression is a weakness not an illness.
– 62% believe depression is not a health problem.
– >50% believe depression is “normal” and will not seek
treatment.
MAJOR DEPRESSIVE DISORDER
Genetic factors influence risk of illness and
sensitivity to environmental factors
A family history of depression is a risk factor for
developing depression
Neural circuits implicated:
limbic structures: cingulate cortex, hippocampus,
anterior thalamus
reward structures: nucleus accumbens, amygdala,
ventral tegmentum, prefrontal cortex
hypothalamus and anterior temporal cortex
Depression: a multifactorial brain disorder
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Symptoms reflect abnormal functioning in many parts of the brain:
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sleep disturbances to brainstem and hypothalamus
appetite and energy to various hypothalamic areas
anhedonia or mania to limbic structures
anxiety to amygdala
alterations in thought content to cortex
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Abnormal overactivation of the HPA in half of those with major depression:
likely also a hypersecretion of CRF with increased CRF in CSF.
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Long-term exposure to glucocorticoids can damage hippocampal neurons
and suppress new neurons postnatally
CLINICAL SYMPTOMS OF
DEPRESSION
• loss of pleasure
(anhedonia)
• loss of energy
• social withdrawal
psychomotor
retardation or
agitation
• insomnia
• loss of appetite
• decreased hygiene
• crying spells
• difficulty
concentrating
• indecisiveness
• sad thoughts/thoughts
of suicide
• hopelessness
• helplessness
• guilt/shame
BIOLOGY OF DEPRESSION
• the “amine hypothesis” based on pharmacological
studies stated depression resulted from a lack of
biogenic amines (eg. -methyl-p-tyrosine; reserpine;
antidepressants themselves).
• current theory favors the notion of a dysregulation of
both NE and 5-HT leading to alterations in NE and 5-HT
receptors.
• antidepressants re-regulate receptor sensitivity.
• drug-induced re-regulation of the receptors takes weeks
(downregulation of some).
The Five Steps of Neurotransmission—Sites of Drug Action
SEROTONIN-A KEY PLAYER
Serotonin has widespread distribution and density of innervation in
CNS (mood, memory, pleasure, aggression, hypothalamic control)
Alterations of serotonin in depressed drug-free patients: The reduction
point of view
decreased 5-HT levels in CSF
increased amounts of 5-HT2 receptors in brain and platelets
reduced levels of plasma tryptophan
blunted neuroendocrine responses to the serotonin releasing drug
fenfluramine
efficacy of SSRI’s in treating depression
loss of SSRI efficacy with tryptophan depletion
Increased presynaptic alpha-2 noradrenergic receptor
sensitivity=greater reduction in 5-HT release
SEROTONIN--A KEY PLAYER
The overactive point of view
In some depressives CSF 5-HT is elevated
Approx. 30% of depressed patients do not respond to SSRIs
Depletion of 5-HT by inhibition of tryptophan hydroxylase
(TH) alleviates depressive symptoms in some patients
Tianeptine, a 5-HT reuptake enhancer that works opposite to
SSRIs, is a marketed antidepressant
A selective TH inhibitor shows activity in an animal model of
depression
The activation of TH by stress can be blocked by Prozac
MAJOR ANTIDEPRESSANT
DRUG CLASSES
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tricyclics
SSRI’s
SNRI’s
MAOI’s
other cyclics
PHARMACOLOGY
• ALL tricyclics block the reuptake of both NE and 5-HT.
• SSRI’s block 5-HT reuptake.
• SNRI’s block NE reuptake.
• other cyclics have mixed effects on NE and 5-HT
reuptake.
• MAOI’s prevent metabolism of the neurotransmitters
(elevation of synaptic levels).
REGULATION OF SEROTONIN
NEUROTRANSMISSION
POSSIBLE MECHANISMS
• All antidepressants downregulate -adrenergic receptors; -2
receptors and presynaptic 5-HT-1a/b
• Antidepressants decrease number of amine transporters
• Long-term treatment with SSRI causes 6-fold increase in 5-HT
release
• Postsynaptic 5-HT-1a receptor does not desensitize in some brain
structures (eg. Hippocampus)
• Antidepressants increase formation of new synapses by increasing
BDNF (BDNF increases 5-HT fiber sprouting)
• In raphe nucleus SSRIs first decrease firing but over weeks increase
firing with an increase in 5-HT release
• Increase response to 5-HT in prefrontal cortex
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CLINICAL PHARMACOLOGY OF
ANTIDEPRESSANTS
• Indications: depression, panic and phobias, OCD,
enuresis, anorexia nervosa, bulimia
• Drug Choice: past response, tolerance to side effects,
drug-drug interactions
• Treatment: 1-6 months; recent report suggests changing
if no improvement by 4 weeks
• Note: All antidepressants now carry a “black box”
warning that they may lead to suicidal thoughts/behavior
SIDE EFFECTS OF TCA’s
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antimuscarinic effects
postural hypotension
tachycardia, arrhythmias
sedation
weight gain
jittery feeling
sexual dysfunction (ejaculatory)
TCA TOXICITIES
• a commonly used drug for suicide (less common
with increased use of SSRIs)
• lowers threshold for convulsions
• cardiac arrhythmias
• cardiac conduction defects
SIDE EFFECTS OF SSRI’s
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nausea, GI disturbances
headache
nervousness
insomnia
some sedation
anorgasmia/impotence
possible fatal interaction with MAOI’s
SEROTONIN SYNDROME
• A potentially fatal interaction when SSRI’s
and MAOI’s are combined
• Symptoms:
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autonomic instability (labile HR/BP)
hyperthermia
rigidity and myoclonus
confusion,delirium
seizures
coma
SIDE EFFECTS OF MAOI’s
• “Wine-cheese” interaction
• antimuscarinic effects—but unusual compared to
TCAs
• sedation
• irritability/insomnia
• weight gain
• anorgasmia/impotence
• postural hypotension
“WINE-CHEESE EFFECT”
• MAOI’s enhance any indirectly acting
sympathomimetic.
• tyramine in certain foods is not metabolized in
presence of MAOI and potentiates
catecholamine release.
• ingredients in OTC cold preps can also lead to
markedly enhanced sympathomimetic effects.
SYMPTOMS OF MANIA
• increased energy
(buying, phoning, sex)
• increased
gregariousness
• pressured speech,
talkativeness
• decreased sleep
• drunkenness
• combative, dangerous
behavior
• distractibility
• racing thoughts
• impulsive actions and
decisions
• elevated mood
• euphoria
• grandiosity
• irritability/hostility
(easily angered)
MANIA—too much neurotransmission?
Increased production of inositol phosphate (IP-3) which
increases intracellular Ca2+ signalling
Increased DAG which:
activates PKC which phosphorylates a number of
substrates including myristoylated alanine rich C kinase
(MARCK)
MARCK activates nuclear transcription factors and
modulates genes that increase neuromodulatory
peptide hormones and alters cell signalling which:
changes neurotransmitter synthesis
neuronal excitabiltiy
synaptic plasticity
neuronal cell loss (prefrontal cortex?)
LITHIUM
• a monovalent ion that can enter neurons but is
not readily removed.
• major mechanism is the reduction of neuronal PI
second messenger resulting in reduced
response of neurons to ACh and NE
• may actually enhance 5-HT
CLINICAL PHARMACOLOGY
• primary therapy for mania
• a narrow therapeutic window (0.8-1.2 meq/L;
some guides say 0.6-1.4 meq/L)
• absolutely necessary to monitor serum level
(trough level approx. 5 days after initial dose)
• solely eliminated by kidney, therefore assess
patient’s kidney function
ADVERSE EFFECTS
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tremor
decreased thyroid function
polydipsia/polyuria
edema
ECG changes (depression of T-wave)
excreted in breast milk
Other Medications
• Anticonvulsants: carbamazepine and valproic
acid for rapid cyclers
• Olanzepine approved for treatment of mania
• St. John’s Wort: questionable efficacy, but high
potential for drug-drug interactions
STRESS & ANTIDEPRESSANTS
Limbic hypothalamic-pituitary-adrenal axis
[LHPA] regulates arousal, sleep, appetite,
capacity to experience & enjoy pleasure, and
mood
In depression the LHPA is overactive--an effect
mediated by neurotransmitters
Adrenal glucocorticoids and mineralcorticoids
interact with 5-HT receptors in brain during
conditions of chronic stress
Corticoid receptor function is impaired in MDD
patients
TREATING DEPRESSION
Interpersonal and cognitive therapy are
effective
Pharmacotherapy plays important role,
but still a high incidence of nonresponders
Shortcomings in developing new AD
high rate of response to placebos
inadequate duration of treatment
outcome measures too insensitive to
measure differences between active and
inactive treatments
STRESS &
ANTIDEPRESSANTS
TCA’s can prevent overactivity of the LHPA
caused by chronic unpredictable stress
TCA’s reverse stress-induced downregulation of
5-HT-1A in hippocampus and upregulation of 5HT-2A in cortex
SSRIs do not prevent stress-induced elevation
of activity in LHPA
This could explain why some patients with
severe depression exhibit “treatment resistance
STRESS & ANTIDEPRESSANTS
Mineralcorticoid & glucocorticoid receptors are lower in
hippocampus and prefrontal cortex in suicide victims with a
history of depression
Hypercortisolemia may damage hippocampal (HPC) neurons
postmortems of depressed patients finds smaller left HPC volume
suicide victims with history of depression also have fewer 5-HT-1As
in HPC
5-HT-1A & 2A receptors are associated with the neurobiology of
mood
PET imaging studies find widespread reductions in 5-HT-1A
receptors
Antidepressants (AD) upregulate (sensitize) 5-HT-1A receptors
in hippocampus but down-regulate 5-HT2A’s elsewhere.
STRESS &
ANTIDEPRESSANTS
Patients with melancholia, a severe form of
depression, tend to have high cortisol levels and
are more effectively treated with TCAs than
SSRIs
Patients with major depression, and resistant to
AD treatments, have been reported to improve
after receiving steroid suppression agents (eg.
Ketoconazole)
CRF receptor antagonists which decrease the
release of steroids are being developed as AD
DEPRESSION: UNANSWERED
QUESTIONS
What are the suspectibility genes and their
environmental modifiers?
What are the pathophysiologies of the neural
systems underlying this complex disorder?
How do we understand the therapeutic
mechanisms underlying the currently available
pharmacological and ECT approaches?
How do we improve our success rate in treating
MDD?
PHARMACOGENOMICS
Pharmacogenomics: genetic differences
that relate to medication response
differences
long (L) form and short (S) form
polymorphisms for 5-HT transporter gene
promotor site have been found
the “L” form is associated with more
transporter being expressed
the “S” form is associated with greater
psychopathology
PHARMACOGENOMICS-CONT’D
102 patients homozygous for short
(S/S) allele demonstrate a worse
antidepressant response to fluxoamine
than those with L?S or L/L
51 patients with homozygous L/L allele
improve with Prozac in sooner than
those with L/S or S/S
Allelic variations in 5-HT-1A or -2
receptors suspected of role in efficacy
of antidepressant medications
SEROTONIN-A KEY PLAYER
Efficacy of SSRI’s in treating depression
Loss of SSRI efficacy with tryptophan
depletion
