Download Antidepressants

Julie Kennedy
Symptoms
•Anhedonia- loss of interest
in everyday activites
•Despondent mood
•Altered sleep patterns
•Changes in
weight/appetite
•Persistent feelings of guilt
•Morbid thoughts
•Agitation
•Inability to concentrate
•Loss of executive
memory
•Indecisiveness
Physiological effects
•Depleted monoamine
neurotransmitters:
serotonin,
norepinepherine,
dopamine
•Degeneration of
neurons and synaptic
connectivity
•Decreased GABA
levels
•Imbalanced HPT
(hypothalamic-pituitarythyroid) axis
•Increased cytokine
levels
Systems of diagnosis
DSM-IV
• Major depressive
disorder: 2 weeks
depressed mood or
loss of interest
accompanied by 4
additional symptoms
• Dysthymic disorder: 2
yrs depressed mood
for more days than not
ICD-10
• Mild to moderate
depression: common
symptoms + functional
impairment
• Severe depression:
physical symptoms
Treatments available
• Antidepressant drugs (SSRIs, TCAs,
MAOIs)
• Counseling (Cognitive therapy, interpersonal
psychotherapy, non-directive counseling, befriending,
exercise, problem solving therapy)
• Natural supplements (St Johns Wort)
• Electroconvulsive therapy (ECT)
Electric shock
• Anaesthetisia,treatment
muscle
relaxant administered
• 10% inpatients receive
to avoid self-injury
• Electrical current
passed through brain
to induce seizure
• Unknown method of
action (thought to
involve NTs)
• Mainly for drug
resistant depressed
patients
ECT
• 70% of all patients
receiving ECT are
women
• Older patients more
common
• More common in Asia,
S. America, Africa-may be used without
anaesthesia & muscle
relaxants
Targets of antidepressants
• Monoamine
neurotransmitter receptors
• Monoamine reuptake
transporters
• Glutamate receptors
(NMDA, mGluRs)
• GABA receptors,
transporters
Serotonin
Norepinepherine
Dopamine
Glutamate
GABA
Monoamine Oxidase Inhibitors
• 1st antidepressants
introduced (iproniazid,
antitubercular agent)
• Inhibit degradation of
catecholamine to
aldehydes
• Mechanis of MAOI
action not well
understood
• More likely to have
side effects
• Used more commonly
for atypical depression
• Interaction with
tyramine (cheese)-MAOIs enable its
systemic circulation
Tricyclic antidepressants
• Three fused rings (6,7,6
carbons)
• Inhibit serotonin and
norepinepherine reuptake
• Developed from
antihistamines
• Common side effects: dry
mouth, constipation,
dizziness
Desipramie
Imipramine
Selective Serotonin
Reuptake Inhibitors
•Similar efficacy with
Tricyclic’s, but lower side
effects
•Introduced in the 1980s90s
•Block serotonin uptake
@ presynaptic 5-HT
transporter
•Act on 4-TM ion channel
receptors and 7-TM
GCPRs
•Mode of action
remains largely
inconclusive
•Direct-to-consumer
marketing
•Sales exceed $17
billion worldwide in
2003
•Interference with
MDMA, cocaine,
TCAs
•May intitially increase
suicide risk
Theories for 2-3 week delay in
effectivness
• Quickly increase serotonin concentraion, which
inhibits 5-HT firing, autorecptors become
desensitized after prolonged SSRI exposure
• Feedback regulation at 5-HT receptors requiring
chronic administration to sustain therapeutic
sertonin levels
• Need for alterations in genetic ∂ and ß-adrenergic
receptor expression
• Changes in nerve connectivity and neurotrophic
factors
Common SSRIs
• Fluoxetine (Prozac): best
selling antidepressant, 1st
SSRI to have real success
• Sertraline (Zoloft): 6th
best-selling overall med.
In the US in 2004 ( >$3
bill.)
• Paroxetine (Paxil)” short
half-life, controlled
release available
Serotonin-Norepinepherine
reuptake inhibitors
• Even newer, less selective
• Faster onset
• Venlafaxine (Effexor):
1993, generic 2006
• Duloxetine (Cymbalta):
lower risk of relapse
• Common side effects:
sweating, weightloss,
nausea, diarrhea,
constipation, vomiting,
dry mouth
Norepinepherine reuptake
inhibitors
• Introduced in 1970s to
increase selectivity
• Reboxetine: most
effective at improving
social functioning
• Side effects: blurred
vision, hypotension
tremors, headache,
urinary hesitancy
Dopamine agonists
• Bupropion
(Wellbutrin): blocks
reuptake of
norepinepherine and
dopamine, less risk of
side effects, used as an
aide to quit smoking
(Dopamine)
Lithium
• Lithium bicarbonate (Li2CO3)
• Most commonly used for bipolar disorder
• Mode of action poorly understood, thought
to reduce the action of the HPT system
• Dosed by augmentation (increasing until
desired effects acheived)
Antidepressant Discontinuation Syndrome
• Occurs within 3 days of
cessation, only occurs after
taking antidepressants for
at lease 6 weeks
• Also occurs when
switching antidepressants
or switching to generic
“equivalent” (may be up
to 20% different)
• Flu-like symptoms,
insomnia, nausea,
imbalance, sensory
disturbances,
hyperarousal
• Generally resolves itself
after 2 weeks
• Misleadingly termed
“withdraw,” since
antidepressant are not
habit-forming
Future of anitdepressants
• Many aspects of both depression and action
of antidepressants remain not well
understood
• Much room for development: increased
specificity, decreased side effects, decreased
time for onset of action