Report Back from SGO: What’s New in Uterine Cancer?.pptx
Antidepressant drugs
1.
2. Drugs that are used to relieve or prevent
psychic depression.
Work by altering the way in which specific
chemicals, called neurotransmitters, work
in our brains (i.e. in the case of
depression, some of the neurotransmitter
systems don’t seem to be working
properly).
They increase the activity of these
chemicals in our brains
3. The precise cause of affective disorders
remains elusive.
Evidence implicates alterations in the
firing patterns of a subset of biogenic
amines in the CNS, Norepinephrine (NE)
and Serotonin (5-HT).
Activity of NE and 5 -HT systems?.
4. 1950: Reserpine Induce depression
Study: Reserpine depletes storage or amine
neurotransmitters such as serotonin and
norepinephrine
Break-through: MAOI and TCA
Then: Depression Amine-dependent
synaptic transmission
(Antidepressants Amine by means of
reuptake and metabolism)
Conclusion: Major model for the subsequent
antidepressants, except Buproprion.
7. Almost all NE pathways in the brain originate from the
cell bodies of neuronal cells in the locus coereleus in
the midbrain, which send their axons diffusely to the
cortex, cerebellum and limbic areas (hippocampus,
amygdala, hypothalamus, thalamus).
Mood: -- higher functions performed by the cortex.
Cognitive function: -- function of cortex.
Drive and motivation: -- function of brainstem
Memory and emotion: -- function of the hippocampus
and amygdala.
Endocrine response: -- function of hypothalamus.
and receptors.
9. Reuptake of NE
Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
Selective inhibitor,
reboxetine
Cocaine blocks the NET
Antidepressant
MAO Inhibitors
Stimulant
11. Why does a small amount of stress help you learn better?
But, too much chronic, severe stress
DEPRESSION
12.
13. As with the NE system, serotonin neurons
located in the pons and midbrain (in groups
known as raphe nuclei) send their projections
diffusely to the cortex, hippocampus,
amygdala, hypothalamus, thalamus, etc. --
same areas implicated in depression. This
system is also involve in:
• Anxiety.
• Sleep.
• Sexual behavior.
• Rhythms (Suprachiasmatic nucleus).
• Temperature regulation.
• CSF production.
17. Major depression – recurring and disabling.
Symptoms must last for at least two weeks
and impair one’s ability to interfere with a
person's ability to work, sleep, study, eat,
and enjoy once-pleasurable activities.
Chronic depression – less disabling than
major depression, but symptoms can last
longer, sometimes being unhappy for two
years. More common in women, affects 11
million people.
Atypical depression, rather than the other
two, is characterized less by pervasive
sadness and more by overeating,
oversleeping, sensitivty to rejection
18. Bipolar/manic depression oscillates between
major depression and epsidoes of mania
(extreme elation), Bipolar I – episode of
mania with or without depression. Bipolar II –
episode of depression with episode of
hypomania or mania.
Seasonal depression (SAD) – often occurs
where winters are short or there is a big
change in the amount of sunlgiht, and often
treated with light therapy.
19. persistently sad, anxious, or empty moods
loss of pleasure in usual activities (anhedonia)
feelings of helplessness, guilt, or worthlessness
crying, hopelessness, or persistent pessimism
fatigue or decreased energy
loss of memory, concentration, or decision-making capability
restlessness, irritability
sleep disturbances
change in appetite or weight
physical symptoms that defy diagnosis and do not respond to
treatment (especially pain and gastrointestinal complaints)
thoughts of suicide or death, or suicide attempts
poor self-image or self-esteem (as illustrated, for example, by
verbal self-reproach)
20. Extensive patient and family history
Blood test for hypothyroidism
Current medication
DSM-IV
One of the first two symptoms
FOUR other symptoms
29. Side effects have put MAOIs in the second or
third line of defense despite superior efficacy
MAO-A inhibitors interfere with breakdown of
tyramine
High tyramine levels cause hypertensive crisis (the
“cheese effect”)
Can be controlled with restricted diet
MAOIs interact with certain drugs
Serotonin syndrome (muscle rigidity, fever,
seizures)
Pain medications and SSRIs must be avoided
31. Imipramine was first tried as an
antipsychoti drug for schizophrenia,
proved to be insufficient but proved to
have antidepressant qualities, in the 50s
around the same time as MAOIs.
Imipramine is very good for severe
depression, but it’s almost too good – also
causes hypomania and mania
33. Side effects have made them second line of
defense to SSRIs but they are good for treatment
resistant depression bc they are so strong.
Amitriptyline – most widely used, most effectve
Desipramine – active metabolite of imipramine,
used for neuropathic pain
Doxepin – used for depression and insomnia
Imipramine – used for major depression and
enuresis
Nortriptyline – same thing
Protriptyline – depression UNIQUE BECAUSE IT IS
ENERGIZING rather than sedating
Trimipramine – depression, insomnia, and pain
34. TCAs inhibit serotonin,
norepinephrine, and
dopamine transporters,
slowing reuptake
TCAs also allow for the
downregulation of post-
synaptic receptors
All TCAs and SSRIs contain an
essential amino group that
appears to interact with Asp-
98 in hSERT
35. Muscarinic M1 receptor antagonism - anticholinergic
effects including dry mouth, blurred vision,
constipation, urinary retention and impotence
Histamine H1 receptor antagonism - sedation and
weight gain
Adrenergic α receptor antagonism - postural
hypotension
Direct membrane effects - reduced seizure threshold,
arrhythmia
Serotonin 5-HT2 receptor antagonism - weight gain
(and reduced anxiety)
36. Nonselectivity results in greater side effects
TCAs can also lead to cardiotoxicity
Increased LDH leakage
Slow cardiac conduction
High potency can lead to mania
Contraindicated with persons with bipolar disorder
or manic depression
37. Current Drugs
Mirtazapine (Remeron)
Mechanism of Action
Same as TCAs
Side Effects
38. Most commonly prescribed class
Current drugs
Mechanism of action
Side effects
Serotonin
39. Also first rationally designed drug class,
up until the 70s the antidepressants were
sort of found by accident
Serotonin is also referred to as 5-
hydroxytryptamine
41. More trade names once patent is over but I kept
original trade names
Citalopram: Major depression
Dapoxetine: Premature Ejaculation
Escitalopram: Major depression and various other
anxiety disorders
Fluxoetine: Major depression, OCD, bulimia, etc
Fluvoxamine: OCD
Paroxetine: Major depression or anxiety
Sertraline: Major depression or anxiety
Zimelidine had neurological problems like
Guillan Barre
Indalpine had problems with fetal low WBC
42. Exact mechanism remains uncertain
Ser-438 residue in the human serotonin
transporter (hSERT) appears to be a
determining factor in SSRI potency
Antidepressants interact directly with hSERT
http://www.mayoclinic.com/health/antidepre
ssants/MM00660
43. Anhedonia
Apathy
Nausea/vomiting
Drowsiness or
somnolence
Headache
Bruxism (involuntarily
grinding of the teeth)
Extremely vivid and
strange dreams
Dizziness
Fatigue
Changes in sexual
behavior
Suicidal thoughts
44. Many disappear within 4 weeks (adaption
phase)
Side effects more manageable compared to
MAOIs and TCAs
Sexual side effects are common
SSRI cessation syndrome
Brain zaps
Sexual dysfunction
45. Slightly greater efficacy than SSRIs
Slightly fewer adverse effects than SSRIs
Current drugs
Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Mechanism of Action
Very similar to SSRIs
Works on both neurotransmitters
Side effects
Similar to SSRIs
Suicide
Venlafaxine 1:1
Duloxetine
46. Current drugs
Bupropion (Wellbutrin)
Mechanims of Action
Similar to SSRIs and SNRIs
More potent in inhibiting dopamine
Also anα3-β4 nicotinic antagonist
Adverse effects
Lowers seizure threshold
Suicide
Does not cause weight gain or sexual dysfunction
(even used to treat the two)
Bupropion 1:1
47. 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
48.
49. 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
51. 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?)
52. 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
53. 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
54. tremor
decreased thyroid function
polydipsia/polyuria
edema
ECG changes (depression of T-wave)
excreted in breast milk
55. 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
56. Features of illness,
e.g. agitation,
hypersomia
Suicide risk
Other therapy
Other illness.
Side effects
Cost
Special problems
e.g. Age, driving,
pregnancy
57. Non compliance.
Inadequate dosage.
Other drugs e.g. alcohol, caffeine.
Unresolved outside problems.
Up to 26% failure even if above don’t apply.
58. Realm of specialists
Lithium,
carbamazepine
Mixtures i.e. SSRI
and TCA
Dangerous – need
expert supervision
59. NEUROENDOCRINE THEORY
Depression is associated with elevated
plasma cortisol level that is due to
excessive release of hypothalamic CRH.
This elevated CRH may reflect defective
monoamine transmission.
N.B hypothalamic neurons controlling
pituitary function receive noradrenergic and
serotonergic inputs which control their
discharge
60. This theory is supported by:
High CRH concentration in brain & CSF in
depressed patients
High plasma cortisol level in depressed
patients
CRH injected into brain of experimental
animals gives symptoms like that of
depression
Cushing’s syndrome is often associated with
depression
61. NEURODEGENERATION THEORY
Major depression may be associated with
neurodegeneration in the hippocampus &
prefrontal cortex and antidepressants may
act by inhibiting or actually reversing this
loss by stimulating neurogenesis
62. This theory is supported by:
Imaging studies showed shrinkage of hippocampus &
prefrontal cortex of depressed patients
Functional imaging reveals reduced neural activity in these
regions
Antidepressants promote neurogenesis in these regions and
restore functional activity
Preventing hippocampal neurogenis in depressed rats
prevents the behavioral effects of antidepressants
Antidepressants increase the production of brain derived
neurotrophic factor (BDNF) which promotes neurogenesis
and protects neurons against apoptosis