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Antidepressants and Mood Stabilizers

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Title: Antidepressants and Mood Stabilizers


1
Chapter 14
Antidepressants and Mood Stabilizers
2
Types of antidepressants
First Generation antidepressants Monoamine
Oxidize Inhibitors (MAOIs) Tricyclic
Antidepressants Second generation
antidepressants Selective Serotonin Uptake
Inhibitors (SSRIs) Norepinephrine Reuptake
Inhibitors (NARIs or SNRIs) Miscellaneous drugs
Mood stabilizers
3
MAOIs
Ipronazid (no longer used) phenelzIne
(Nardil) phenelzine (Nardil), tranylcypromine
(Parnate), moclobemide (Ludiomil).
Tricyclics amitriptyline (Elavil) desipramine
(Norpramin) nortriptyline (Aventyl) doxepin
(Adapin) mirtazapine (Remeron)
4
Second Generation Drugs
maprotiline (Manerex), amoxapine
(Asendin) trazodone (Desyrel) mianserin
(Tolvon) nomifensine (Merital, now withdrawn),
bupropion (Wellbutrin or Zyban, a DA reuptake
inhibitor) (NOTE spelled incorrectly as
buproprion in the text) reboxetine (Edronax or
Vestra, a NARI) SSRIs fluoxetine
(Prozac) fluvoxamine (Luvox) sertraline
(Zoloft) paroxetine (Paxil) citalopram (Celexa).
5
The nature of Mania and Depression DSM IV
A. Five (or more) of the following symptoms have
been present during the same 2-week period and
represent a change from previous functioning at
least one of the symptoms is either (1) depressed
mood or (2) loss of interest or pleasure. Note
Do note include symptoms that are clearly due to
a general medical condition, or mood-incongruent
delusions or hallucinations. (1) depressed mood
most of the day, nearly every day, as indicated
by either subjective report (e.g., feels sad or
empty) or observation made by others (e.g.,
appears tearful). Note In children and
adolescents, can be irritable mood. (2) markedly
diminished interest or pleasure in all, or almost
all, activities most of the day, nearly every day
(as indicated by either subjective account or
observation made by others) (3) significant
weight loss when not dieting or weight gain
(e.g., a change of more than 5 of body weight in
a month), or decrease or increase in appetite
nearly every day. Note In children, consider
failure to make expected weight gains. (4)
insomnia or hypersomnia nearly every day (5)
psychomotor agitation or retardation nearly every
day (observable by others, not merely subjective
feelings of restlessness or being slowed
down) (6) fatigue or loss of energy nearly every
day (7) feelings of worthlessness or excessive or
inappropriate guilt (which may be delusional)
nearly every day (not merely self-reproach or
guilt about being sick) (8) diminished ability to
think or concentrate, or indecisiveness, nearly
every day (either by subjective account or as
observed by others) (9) recurrent thoughts of
death (not just fear of dying), recurrent
suicidal ideation without a specific plan, or a
suicide attempt or a specific plan for committing
suicide
6
Mood Stabilizers
Lithium carbonate (Carbolith, Eskalith,
Lithonate, Lithotabs) Anticonvulsants Carbamazine
(Tegritol) Valproic acid (Depakine) Lamotrigine
(Lamictal)
7
Bipolar disorder (manic depressive psychosis)
Bipolar II Disorder--Diagnostic Features (DSM-IV,
p. 359) The essential feature of Bipolar II
Disorder is a clinical course that is
characterized by the occurrence of one or more
Major Depressive Episodes accompanied by at least
one Hypomanic Episode. Hypomanic Episodes should
not be confused with the several days of euthymia
that may follow remission of a Major Depressive
Episode. Episodes of Substance- Induced Mood
Disorder (due to the direct effects of a
medication, or other somatic treatments for
depression, a drug of abuse, or toxin exposure)
or of Mood Disorder Due to a General Medical
Condition do not count toward a diagnosis of
Bipolar I Disorder. In addition, the episodes are
not better accounted for by Schizoaffective
Disorder and are not superimposed on
Schizophrenia, Schizophreniform Disorder,
Delusional Disorder, or Psychotic Disorder Not
Otherwise Specified. . . .
8
DSM IV criteria for a manic episode
A) A distinct period of abnormally and
persistently elevated, expansive or irritable
mood, lasting at least 1 week (or any duration if
hospitalization is necessary) B) During the
period of mood disturbance, three (or more) of
the following symptoms have persisted (four if
the mood is only irritable) and have been present
to a significant degree 1) inflated self-esteem
or grandiosity 2) decreased need for sleep (e.g.,
feels rested after only 3 hours of sleep) 3) more
talkative than usual or pressure to keep
talking 4) flight of ideas or subjective
experience that thoughts are racing 5)
distractibility (i.e., attention too easily drawn
to unimportant or irrelevant external stimuli) 6)
increase in goal-directed activity (at work, at
school, or sexually) or psychomotor agitation 7)
excessive involvement in pleasurable activities
that have a high potential for painful
consequences (e.g., engaging in unrestrained
buying sprees, sexual indiscretions, or foolish
business investments)
9
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10
Depression The Common Cold of Mental Illness
Affective Mood Disorder More frequent in every
generation since WW2 Within any 6 month 3 of the
US population experience a mood disorder 6-26
have a mood disorder during their lifetime, only
20 will get professional help Twice as likely in
women as men to have depression but the same
frequency for bipolar disorder Depression is a
chronic illness, 1/3 relapse rate
11
Monoamine Theory of Depression
Mood is controlled by the level of Monoamine
(biogenic amine) activity in the brain.
(Serotonin, Norepinephrine and Dopamine) Psychomot
or stimulants like cocaine improve mood and drugs
like reserpine that block monoamines cause
depression. All antidepressant drugs increase
serotonin activity, this is a necessary, but not
sufficient effect to act as an antidepressant.
Mood is clearly a result of a complex interaction
between all monoamines and other
neurotransmitters.
Monoamine fibers from midbrain or brainstem a) NE
fibers from the locus coeruleus b) 5-HT fibers
from the Raphé system c) Dopamine fibers from the
VTA Project to limbic system and forebrain
through the medial forebrain bundle
12
History
MAOI ipronazid was first tested to treat
tuberculosis. Problems with determining adequate
dose levels for antidepressant effect and
interaction with foods. In the 1950s the
tricyclic imipramine first developed as
antipsychotic drug. Did not have antipsychotic
properties, but did improve mood. Many second
generation antidepressants were introduced for
other purposes. The first SSRI, fluoxitine
(Prozac) was introduced in 1987 and caused much
controversy. Since then many SSRIs have been
developed. Other drugs that have different
affinities for other monoamines have also been
marketed.
13
Lithium
In the 1940s, an Australian psychiatrist, John
Cade, discovered accidentally that lithium salt
would calm his manic patients. Lithium was not
available commercially till the 1970s because it
was an element and could not be patented. Lithium
is classed as a mood stabilizer or an antimanic
rather than an antidepressant because it will
relieve manic symptoms and block both mania and
depression, but it cannot treat depression.
John Cade
14
Pharmacokinetics Absorption and Distribution
Most reach maximum concentration in blood in 1-3
hrs, 4-8 hrs for SSRIs Significant first pass
metabolism which is inhibited by alcohol for most
antidepressants except SSRIs High levels of
protein binding. Readily crosses
barriers Lithium rapid absorption, peak 30
min-2hrs, because Li as a low therapeutic index
rapid absorption can be a problem. Most Lithium
is now in a slow release form. Enters and leaves
the brain slowly. Crosses the placental barrier
15
Excretion
MAOIs half-life 2-4 hrs so must be taken
several times a day. Older MAOIs have an
irreversible effect on MAO and can be taken once
a day. TCAs - half- life 24 hrs. Daily dose is
required Most SSRIs have half life of 15-20 hrs
with no active metabolites, but fluoxitine has a
long half life ( 6 days) and long lasting
metabolites. Takes 75 days to reach a steady
state and for the body to eliminate it
all. Considerable individual variability in
excretion pharmacokinetics of antidepressants. Lit
hium is excreted unchanged and has a half-life of
12-21 hrs. Varies between individuals and may be
as long as 36 hrs. Because of its low TI, blood
levels need to be carefully monitored.
16
Neurophysiology A dogs Breakfast
How antidepressants alter monoamine
functioning MAOIs block Monoamine oxidase, MOA.
Newer MAOIs selectively block metabolism of 5HT
and NE, but not DA. Tricyclics block reuptake of
MAs, but newer TCAs have other effects as
well. SSRIs selectively block reuptake of
serotonin Reboxetine and malprotiline selectively
block NE Amitriptyline is an agonist at 5HT2 and
NEa2 receptors. Bupropion blocks MA uptake
especially DA. Nefazadone and terazadone are
5HT2a agonists and block MA reuptake. Sulpride
and amisulpride block D2, D3 and D4
receptors Buspirone is a 5-HT1 receptor agonist.
17
  • Even though the pharmacological effect of these
    drugs starts immediately, the therapeutic effect
    may take a week or two to start so
  • The monoamine theory is wrong, or
  • B) there is some sort of delay in a crucial
    monoaminergic connection.
  • Down regulation a decrease in sensitivity of a
    synapse after excessive stimulation. Maybe
    depression is caused by a supersensitivity of MA
    synapses and antidepressant drugs cause a
    down-regulation of these systems after two weeks
    of exposure.
  • Or
  • Autoreceptors on serotonin synapses detect excess
    serotonin and reduce serotonin release. It takes
    about a week or two to exhaust this system and
    for activity at the synapse to increase.
  • Electrical activity in serotonin synapses only
    increases after one to two weeks of exposure to
    an antidepressant.

18
Monoamine theory of mood The bulk of evidence
supports the theory that (a) depression is a
result of diminished activity in the 5-HT system
in the brain, which runs from the Raphé nuclei
through the medial forebrain bundle to the
forebrain, and (b) mania is a result of excessive
activity in this system. Clearly there is a
complicated interaction between different
monoamines and the balance between them. Other
theories suggest the involvement of GABA, ACh,
DA, second messengers, biological rhythms,
hormones, stress and the immune system.
19
Mood Stabilizers ands Antimanics
Possible mechanisms of Lithium (a) Altering the
balance of ions such as Cl- and K, which are
important in the formation of resting and action
potentials and post synaptic potentials (b)
Altering the functioning of many transmitters,
such as 5-HT, NE, DA, ACh, and GABA (c)
Inhibiting the second-messenger cyclic AMP. (d)
Lithium also causes a down-regulation of some NE
receptors (e) Stabilizes membranes makes them
less excitable Anticonvulsants Valproic acid
blocks GABA-transaminase and increases
GABA Carbamazepine and lamotrigine block sodium
channels and inhibit release of glutamate and
aspartate. Membrane stabilization is probably
involved.
20
Effects on the Body
Tricycles Anticholinergic Effects Dry mouth,
constipation, dizziness, irregular heart beat,
blurred vision, etc. Excessive sweating,
tremors Usually subside in 2 weeks. Confusion and
delirium in older patients Rarely, Parkinsonian
symptoms. Weight gain often reported (1.3 to 2.9
lbs/mo.)
21
Effects on the Body
SSRIs Nausea, headache, nervousness
dissipate Insomnia may last Serotonin syndrome
caused by excessive acute serotonin
activity Disorientation, agitation,
confusion Fever shivering, diarrhea Parkinsonian
symptoms Often caused when SSRIs are taken with
psychomotor stimulants, or are taken with other
SSRIs Long washout time needed after fluoxitine
before starting another antidepressant
22
Effects on the Body
MAOIs Lowers blood pressure postural
hypotension Block metabolism of other all
biogenic amines and therefore potentates the
effect of any drug that increases biogenic amine
levels such as psychomotor stimulants,
decongestants, nose drops, etc Also potentates
alcohol and opioids. Blocks metabolism of
tyramine found in aged cheese, pickled herring,
beer wine, chocolate. Accumulation of tyramine
causes high blood pressure causes internal
bleeding, stroke.
23
MAO-A and MAO-B
Two types of MAO A and B MAO-A enzyme for NE
and 5-HT. Found in intestine. First line defense
against tyramine MAO-B enzyme for DA. Found in
liver and lungs. Second line defense against
tyramine Old MAOIs blocked both MAO-A and B,
newer drugs (moclobemide) block only MAO-A
leaving the B team to take care of the
tyramine, yet blocking CNS 5-HT.
24
Lithium
Many unwanted side effects including hand
tremors, increased thirst, nausea and vomiting,
diarrhea, swelling, and weight gain, fatigue and
muscle weakness. Another problem associated with
long-term use is kidney damage
Anticonvulsant drugs The anticonvulsant drugs
used as mood stabilizerscarbamazepine and
valroic acid and lamotriginecan cause frequent
urinatation, nausea, and vomiting and in higher
doses can cause tremors, weight gain, hair loss,
and dizziness, and lamotrigine causes a rash in
about 10 percent of patients.
25
Sleep
Acute tricyllics (amitriptyline) cause
sleepiness. Fluoxitine reduces REM, but increase
vividness of dreams. (REM deprivation can
actually reduce depression?) Other SSRIs have no
effect on REM Bupropion increases REM.
26
Subjective Effects
The antidepressants do not produce euphoric or
even pleasant effects. At low doses,
imipramines effects are similar to those of the
antipsychotics tiredness, apathy, and weakness.
Higher doses produce impaired comprehension and a
confusion. Amitriptyline causes feelings of
calmness and relaxation). Lithium has few, if
any, Subjects sometimes report a feeling of
mental slowing and difficulty in concentration
27
Effects on Performance
Tricyclic antidepressants imipramine and
mitriptyline can have detrimental effects on
vigilance tasks and can cause cognitive, memory,
and psychomotor impairment that seems to be
related to sedation. Tolerance may develop. No
motor impairment with SSRIs. Lithium small but
significant slowing of information processing and
memory . There appear to be few effects on
performance of tasks and reaction time. Similar
sedating effect with anticonvulsants
28
Personality and Prozac
cosmetic psychopharmacology Peter Kramer claimed
that people could alter their personality using
fluoxitine (Prozac) Prozac seemed to give
social confidence to the habitually timid, to
make the sensitive brash, and to lend the
introvert the social skills of a
salesman Became a fad in the 90s
29
Van Gough
Before After
30
Effectiveness of Antidepressants
Meta-analysis of clinical trials Placebo group
Improvement 29.7 Antidepressant group
improvement 50.1 Over the years, the
responders in placebo group has been increasing
??? Considerable individual differences in the
side effects and effectiveness of different
antidepressants. Newer drugs are not better
antidepressants they have fewer side
effects. Tricyclics do not work with children,
but SSRIs do (fluoxitine), but there is a high
incidence of side effects (violence and suicide).
31
Discriminative Stimulus Properties
Tricyclics and MAOIs Only very high doses are
discriminated and there is no generalization to
any other class of drugs Lithuum No
discriminative properties SSRIs and NARIs Do
have discriminative properties. Citalopram SSRI
blocked by 5-HT2c receptor blockers
generalized to SSRIs only Bupropion DA reuptake
inhibitor Reboxetine NARI blocked by NE
alpha1 blockers Stimulus properties do not
appear to be related to antidepressant properties.
32
Withdrawal
Tricyclics restlessness, anxiety, chills, muscle
aches, and akathesia, a feeling of a compulsion
to move. SSRIsdizziness, light-headedness,
insomnia, fatigue, anxiety, nausea, headache, and
sensory disturbances.
33
Self-administration
No antidepressants are self-administered and
imipramine is avoided at high doses. They do not
appear to have any reinforcing properties. Some
SSRIs are effective in treating alcohol
cravings. Bupropion is Zyban, used to aid
smoking cessation. Compliance Best for SSRIs
which have fewer side effects
34
Harmful Effects
  • Reproduction
  • Tricyclics impair sexual functioning and interest
    in both sexes
  • MAOIs delayed or impaired ejaculation
  • SSRIs delayed ejaculation and loss of interest
    in sex.
  • Violence and suicide
  • Fluoxitine was thought to cause violence and
    suicide. Apperars in case studies, but does not
    show up in popuration studies.
  • May arise in patients who show akathesia after
    taking the drug for 3-4 weeks
  • Racing thoughts, restlessness agitation
    compulsion to be active.
  • Does occur in teens and children after taking
    fluoxitine.

35
Black Box Warning
36
Overdose
Tricyclics Third highest rate of overdose
deaths after alcohol-drug combinations, and
heroin. TI 10-15 Clomiprimine few
deaths amitriptyline many deaths MAOs Tranvlcypro
mine many deaths Isocarboxazide few
deaths SSRIs Very safe. No overdose deaths
attributed to fluoxitine
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