Transcript Affective and Anxiety Disorders

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found throughout history
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unipolar or major depression
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bipolar or manic depression
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must be evident daily or almost every day for
at least 2 weeks
often comorbid with anxiety
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Depression
◦ over 10% with ~ 5% (11,000,000) suffering from a
depressive episode in any given year
◦ untreated - 25 - 30% will attempt or commit suicide
◦ 2X greater prevalence in women than men
◦ estimated only ~ 50% receive specific treatment
◦ increased rate of and suicide attempts
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Pharmacologically
◦ drugs have been available for ~ 40+ years
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antidepressants typically require 10 – 30 days to
start working – full effect may take 6 weeks and in
many cases – improvement can continue over
several months
what takes so long?
◦ 2 lines of thought
◦ role of upregulation and downregulation of receptors
◦ effects on intracellular processes such as 2nd
messengers and their functions in the neuron
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an intracellular target of 2nd messenger
system is called cAMP response element
binding protein (or cREB)
◦ CREB increases in the hippocampus with chronic
antidepressant medication
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cREB activates genes that control the
production of BDNF – a neurotrophin
neurotrophins promote neural health, growth,
etc
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two of the functions of 2nd messengers is
◦ 1)protect neurons from damage due to injury or
damage;
◦ 2) promote and maintain health and stability of
newly formed neurons
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Pharmacologically
◦ drugs have been available for ~ 40+ years
Traditional Antidepressants
1. tricyclic antidepressants
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Blocks reuptake of NE and 5HT
blocks histamine receptors
block ACh receptors
widely used
fairly significant side effects
◦ mainly because they block ACh receptors
 blurred vision, dry mouth, urinary retention, irregular
heart rate, constipation, sexual dysfunction,
◦ effects on other NT
 sedation, weight gain
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tricyclics estimated to be effective in ~ 60 - 70% of
moderately to severely depressed individuals
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Pharmacologically
◦ drugs have been available for ~ 40+ years
Traditional Antidepressants
1. tricyclic antidepressants
2. MAO inhibitors- MAO
- enzyme that breaks down excess DA, NE, 5HT
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phenelzine (Nardil)
Isocarboxazid (Marplan)
tranylcypromine (Parnate)
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2003 – nonselective MAOI selegiline (Eldapril)
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◦ transdermal skin patch
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mechanism of action:
reversible inhibitors of MAO A – NE/5HT
◦ moclobemide (Aurorix) – not in U.S. – not particularly
effective
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MAO B inhibitors - DA
◦ selegiline (Deprenyl- used at low doses for PD)
◦ proved as effective (if not more so) than
traditional tricyclics or SSRIs particuarly for
unresponsive depression
◦ not used as first level txt due to risk (or
perceived risk) of adverse side effects
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Alters the metabolism of amino acid
tyramine
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Alters the metabolism of amino acid
tyramine
◦ foods high in tyramine include: aged cheeses,
wine, smoked fish, yeast products
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Alters the metabolism of amino acid
tyramine
◦ foods high in tyramine include: aged cheeses,
wine, smoked fish, yeast products
◦ consumption of these can result in a
hypertensive crisis:
 severe headaches, heart palpitations. Flushing,
nausea, vomiting, stroke
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Alters the metabolism of amino acid
tyramine
◦ foods high in tyramine include: aged cheeses,
wine, smoked fish, yeast products
◦ consumption of these can result in a
hypertensive crisis:
 severe headaches, heart palpitations. Flushing,
nausea, vomiting, stroke
◦ very long 1/2 life (2 weeks)
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from late 1970’s - mid 1980’s- looked for
agents that could overcome some of the – of
TCA
◦ slow onset, limited efficacy, side effect profile,etc
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amoxapine (Asendin)
◦ primarily SNRI (but also blocks DA)
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Trazodone (Desyrel)
◦ doesn’t block NE or 5HT
 less anti ACh; quicker action?
 5HT agonist… (5HT2)
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Buproprion (Wellbutrin, Zyban)
◦ antidepressant, anticraving (for nicotine
dependence)
◦ antidepressant effect much like the SSRIs but with
less nausea, diarrhea, somnolence and sexual
dysfunction
◦ selectively inhibits DA, NE reuptake
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Fluoxetine (Prozac) - first introduced in US in
1988
SSRIs have a more favorable side effect profile
than earlier antidepressants
relatively safe (esp in OD situations)
some controversy…...
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6 SSRIs
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fluoxetine (Prozac)
paroxetine (Paxil)
sertraline (Zoloft)
fluvoxamine (Luvox)
citalopram (Celexa)
escitalopram (Lexapro)
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Block reuptake of 5HT
◦ selective serotonin reuptake inhibitor
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single action antidepressant
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occurs in ~ 60% of people who discontinue
experience withdrawal
onset usually within a few days and persists
for 3 – 4 weeks (fluoxetine even longer due to
its ½ life)
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disequilibriam (dizziness, vertigo, ataxia)
GI distress
Flulike symptoms (fatigue, lethargy, chills)
sensory disturbances
sleep disturbances
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most often seen when individual takes 2 or
more drugs that increase 5HT activity
◦ ex. SSRIs, MAOIs, TCA
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incidence – rare
more than 80% resolve
no specific criterion for diagnosis
can be mild or potentially lethal
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may be more effective at treating somatic
symptoms associated with depression
 ex. pain
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older tca with dual actions
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new antidepressants with dual actions
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Nefazodone (Serzone) –
◦ strongest pharmacological action is 5HT2 blockade
◦ also inhibits reuptake of NE and 5HT
◦ black box warning – liver failure
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sequenced treatment alternatives to relieve
depression
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Some patients do not respond well to first
treatment
most take 3 - 4 weeks to exert significant
therapeutic effects
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Incidence ~ 1%
◦ population-based epidemiologic studies found
age-corrected lifetime risks ranging from 0.3
percent to 1.5 percent, with = risks to men and
women in 10 countries as divergent as Lebanon and
Korea.
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Less favorable profile than for depressive
disorders
Most come to the attention of docs
Age of onset –
◦ Wide range with average ~ 30
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Bipolar disorder patients have a relatively
high rate of nonadherence to
pharmacotherapy, estimated at 32–45% of
treated patients (Rothbaum & Astin, 2000).
Approximately 25-50% of individuals with
bipolar attempt suicide, and 11% actually
commit suicide.
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~ 50 percent bipolar I disorder patients have
at least one parent with a mood disorder,
most often major depressive disorder.
◦ mode of inheritance - complex and likely involves
multiple interacting genes.
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If one parent has bipolar I disorder, 25
percent chance that a mood disorder;
if both parents have bipolar I disorder, there
is a 50 to 75 percent chance that their child
has a mood disorder.
Encephalitis lethargica
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amphetamine
cocaine
corticosteroids
hallucinogens
l-dopa
pcp
methylphenidate
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stabilize acute mania, mixed and depressive
symptoms
don’t induce mood alterations
prevent future relapses
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Until the last 10 – 15 years – lithium only
approved drug for treating bipolar
now number of drugs referred to as “Mood
stabilizers”
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Lithium
Anticonvulsants
Atypical antipsychotics
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Lithium (Duralith, Eskalith, Lithobid)
◦ Metal isolated in 1818
◦ Introduced into medicine in 1840 for txt of bladder
stones and gout
◦ lithium bromide - 1873- used to treat manic
episodes although thought was that bromide was
active ingredient
◦ 1886 - prophylactic and short term effects of
lithium for txt depression
◦ Late 1880's - early 1900's - general public so
enthusiastic endorsing taking of waters
1940's - lithium chloride used as replacement for
NaCl
◦ 1949 - lithium caused lethargy when injected in
animals ◦ 1950's - 1960's - did FDA trials demonstrating
short-term prophylactic efficacy of lithium for
bipolar 1 disorder
◦ 1970's - reintroduced to treat mania
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◦ 2003 - Evidence suggests that lithium, unlike any
other mood stabilizer, may have a specific
antisuicide effect
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pharmacokinetics
◦ kidneys excrete 95%
◦ sweat – 4-5%
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pharmacodynamics:
◦ good question!!!!!
◦ modulation of the levels of several genes maybe?
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ethnic differences –
◦ AA with similar plasma levels as Caucasians had on
average 60% higher intracellular levels
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 many AA respond better with lower
plasma Li levels and lower side effects
does not produce dependence or
withdrawal
Frequency of bipolar relapses in 2 years
◦ In 20 – 40% of patients on lithium
◦ In 65 – 90% of patients without lithium
Suicidal attempts rose 22-fold, and fatalities
increased 14-fold, within the first year after
discontinuing the lithium.
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Side Effects:
◦ Gastric distress: nausea, decreased appetite,
vomiting, diarrhea
◦ Weight gain - poorly understood effect of lithium
on carbohydrate metabolism
 (in long-term therapy ~ 30% become obese);
◦ tremor - recognized in 4th edition of DSM IV usually noticed in hands and fingers
◦ cognitive effects , - dysphoria, lack of
spontaneity, slowed reaction times, impaired
memory
◦ potential teratogenicity
◦ renal: polyuria with 2ndary polydipsia - urinary
output can be up to 3 liters/day (for most of us it is
1 - 2) due to antagonism of ADH; Most serious
renal adverse effects - renal failure
◦ thyroid effects - causes generally benign and often
transient dimunition in concentrations of circulating
thyroid hormones
◦ cardiac - can result in sinus dysrhythmias
◦ dermatological effects - various kinds of acne,
possible worsening of psoriasis ; risk of
tetracycline; alopecia◦ lithium toxicity and overdose
 antipsychotics – TI ~ 100; TCAs/MAOI TI ~ 10
Lithium ~ 3
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Doses are adjusted to achieve plasma
concentrations of 0.6 to 1.2 mM Li (lower
end of the range for maintenance therapy
and elderly patients) on samples taken 12
hours after the preceding dose.
Overdosage - usually with plasma
concentrations over 1.5 to 1.8mM Li –
◦ keep in mind individual differences
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Symptoms: Shaking and trembling,
confusion, slurred speech, nausea and
vomiting, diarrhea, abdominal pain,
unsteadiness on the feet, coma, seizures
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At plasma levels of 1.5 to 2.0 mEq/l - most
reactions involve GI tract with nausea,
vomiting, diarrhea and abdominal pain
◦ Neurological side effects commonly seen at this
dose include slight tremor, lethargy, impaired
concentration, dizziness, slurred speech, ataxia,
muscle weakness and nystagmus
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once get above 2.0 mEq/l - more severe side
effects;
above 2.5 mEq/l - can cause stupor, coma,
renal failure, cardiac arrythmias and death
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no antidote to lithium; usually add sodium
containing fluids immediately; if toxic signs
are severe, may use hemodialysis, gastric
lavage, diuretic, antiepileptic, etc
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- although li prevents manic and depressive
episodes < 50% achieve complete relief
Recommendations:
◦ maintain bipolar patient on Li for 9 – 12 months
after manic episode
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introduced in 1990’s to treat bipolar
possible mechanism?
Kindling - electrophysiological process in
which repeated sub-threshold stimulation
of a neuron eventually generates an action
potential
 kindling in temporal lobes?
◦ carbamazepine reduces kindling (in animal models)
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carbamazepine (Tegretol), divalproex
(Depakote), gabapentin (Neurontin) and
lamotrigine (Lamictal), valproic acid
(Depakene)
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valproate (Depakote®) – approved in 1995
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Most serious side - liver toxicity and failure
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◦ also reduces kindling, has anticonvulsant effects
and GABAergic effects
◦ Persons taking more than one type of
anticonvulsant seem to be at higher risk.
Most common side effects with valproic acid
therapy are nausea, vomiting and
indigestion; abdominal pain, constipation or
diarrhea
Both loss of appetite with weight loss and
appetite stimulation with weight gain have
been reported.
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carbamazepine (Tegretol®)
◦ altered effectiveness of birth control pills
◦ rarer side effects - clumsiness, double vision,
edema (excess of fluid in tissue or body cavity),
skin rash, and cardiovascular complications.
◦ < 1 day: seizures
◦ 6 – 12 days; mania
◦ > 30 days aggression not caused by mania
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full effect
◦ within hours for epilepsy
◦ 2 weeks for mania
◦ 2 – 3 weeks for depression
Potential interactions for
carbemazepine
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grapefruit juice, influenza vaccine, isoniazid (treats tb),
cimetidine (heartburn), erythromycin (antibiotics), and
phenelzine (MAOI) increase plasma levels
Phenytoin (anticonvulsant), alprazolam, clonazepam,
primidone (anticonvulsant), and phenobarbital decrease
both CBZ level and levels of interacting agents;
fluoxetine increases levels
decreases levels of imipramine, phenothiazines,
haloperidol, theophylline, thyroid hormones, ritonavir,
saquinavir, contraceptives, risperidone, thiothixene,
cyclosporine, corticosteroids, doxycycline, trazodone,
doxepin, and amitriptyline
can reduce its own level by "autoinduction;"
coadministration with lithium increases toxicity of both
CBZ and the interacting agents;
coadministration with clozapine further increases bone
marrow toxicity and resulting agranulocytosis
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risperidone (Risperdal) – more antidepressant
than antimanic
clozapine – may be more antimanic than
antidepressant
olanzapine (Zyprexa) – useful for both acute
mania and (now available in combination with
fluoxetine) as Symbyax
quetiapine (Seroquel)
ziprasidone (Geodon)
aripiprazole (Abilify)