Transcript Antidepressant Presentation

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
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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