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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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introduction
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
“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
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
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
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

CLINICAL SYMPTOMS OF DEPRESSION
biology of depression
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).
serotonin a key player
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 player9
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
MAJOR ANTIDEPRESSANT DRUG CLASSES
  • tricyclics
  • SSRI’s
  • SNRI’s
  • MAOI’s
  • other cyclics
pharmacology
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).
possible mechanisms
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

.

clinical pharmacology of antidepressants
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
SIDE EFFECTS OF TCA’s
  • antimuscarinic effects
  • postural hypotension
  • tachycardia, arrhythmias
  • sedation
  • weight gain
  • jittery feeling
  • sexual dysfunction (ejaculatory)
tca toxicities
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
SIDE EFFECTS OF SSRI’s
  • nausea, GI disturbances
  • headache
  • nervousness
  • insomnia
  • some sedation
  • anorgasmia/impotence
  • possible fatal interaction with MAOI’s
serotonin syndrome
SEROTONIN SYNDROME
  • A potentially fatal interaction when SSRI’s and MAOI’s are combined
  • Symptoms:
      • autonomic instability (labile HR/BP)
      • hyperthermia
      • rigidity and myoclonus
      • confusion,delirium
      • seizures
      • coma
side effects of maoi s
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
“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)

SYMPTOMS OF MANIA
slide27

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
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
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
ADVERSE EFFECTS
  • tremor
  • decreased thyroid function
  • polydipsia/polyuria
  • edema
  • ECG changes (depression of T-wave)
  • excreted in breast milk
other medications
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
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
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
stress antidepressants34
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 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
stress antidepressants35
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 antidepressants36
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
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
  • 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
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 player41
SEROTONIN-A KEY PLAYER
  • Efficacy of SSRI’s in treating depression
  • Loss of SSRI efficacy with tryptophan depletion
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