Depression afflicts approximately 5% of the population, 1-2% with bipolar disorder.

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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

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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.
• gt50 believe depression is normal and will not
  seek treatment.

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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

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Depression a multifactorial brain disorder

• Symptoms reflect abnormal functioning in many
  parts of the brain
• 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
• Abnormal overactivation of the HPA in half of
  those with major depression likely also a
  hypersecretion of CRF with increased CRF in CSF.
• Long-term exposure to glucocorticoids can damage
  hippocampal neurons and suppress new neurons
  postnatally

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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

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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).

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The Five Steps of NeurotransmissionSites of Drug
Action
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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 SSRIs in treating depression
• loss of SSRI efficacy with tryptophan depletion
• Increased presynaptic alpha-2 noradrenergic
  receptor sensitivitygreater reduction in 5-HT
  release

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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

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MAJOR ANTIDEPRESSANT DRUG CLASSES

• tricyclics
• SSRIs
• SNRIs
• MAOIs
• other cyclics

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PHARMACOLOGY

• ALL tricyclics block the reuptake of both NE and
  5-HT.
• SSRIs block 5-HT reuptake.
• SNRIs block NE reuptake.
• other cyclics have mixed effects on NE and 5-HT
  reuptake.
• MAOIs prevent metabolism of the
  neurotransmitters (elevation of synaptic levels).

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REGULATION OF SEROTONIN NEUROTRANSMISSION
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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

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SIDE EFFECTS OF TCAs

• antimuscarinic effects
• postural hypotension
• tachycardia, arrhythmias
• sedation
• weight gain
• jittery feeling
• sexual dysfunction (ejaculatory)

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TCA TOXICITIES

• a commonly used drug for suicide (less common
  with increased use of SSRIs)
• lowers threshold for convulsions
• cardiac arrhythmias
• cardiac conduction defects

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SIDE EFFECTS OF SSRIs

• nausea, GI disturbances
• headache
• nervousness
• insomnia
• some sedation
• anorgasmia/impotence
• possible fatal interaction with MAOIs

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SEROTONIN SYNDROME

• A potentially fatal interaction when SSRIs and
  MAOIs are combined
• Symptoms
• autonomic instability (labile HR/BP)
• hyperthermia
• rigidity and myoclonus
• confusion,delirium
• seizures
• coma

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SIDE EFFECTS OF MAOIs

• Wine-cheese interaction
• antimuscarinic effectsbut unusual compared to
  TCAs
• sedation
• irritability/insomnia
• weight gain
• anorgasmia/impotence
• postural hypotension

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WINE-CHEESE EFFECT

• MAOIs 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.

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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)

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MANIAtoo 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?)
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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

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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
  patients kidney function

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ADVERSE EFFECTS

• tremor
• decreased thyroid function
• polydipsia/polyuria
• edema
• ECG changes (depression of T-wave)
• excreted in breast milk

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Other Medications

• Anticonvulsants carbamazepine and valproic acid
  for rapid cyclers
• Olanzepine approved for treatment of mania
• St. Johns Wort questionable efficacy, but high
  potential for drug-drug interactions

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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

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TREATING DEPRESSION

• Interpersonal and cognitive therapy are effective
• Pharmacotherapy plays important role, but still a
  high incidence of non-responders
• 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

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STRESS ANTIDEPRESSANTS

• TCAs can prevent overactivity of the LHPA caused
  by chronic unpredictable stress
• TCAs reverse stress-induced downregulation of
  5-HT-1A in hippocampus and upregulation of
  5-HT-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

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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-HT2As elsewhere.

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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

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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?

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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

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PHARMACOGENOMICS--CONTD

• 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

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SEROTONIN-A KEY PLAYER

• Efficacy of SSRIs in treating depression
• Loss of SSRI efficacy with tryptophan depletion

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