found throughout history

unipolar or major depression

bipolar or manic depression

must be evident daily or almost every day for at least 2 weeks

often comorbid with anxiety

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

Pharmacologically◦ drugs have been available for ~ 40+ years

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

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

cREB activates genes that control the production of BDNF – a neurotrophin

neurotrophins promote neural health, growth, etc

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

Pharmacologically◦ drugs have been available for ~ 40+ years

Traditional Antidepressants1. tricyclic antidepressants

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

tricyclics estimated to be effective in ~ 60 - 70% of moderately to severely depressed individuals

Pharmacologically◦ drugs have been available for ~ 40+ years

Traditional Antidepressants1. tricyclic antidepressants

2. MAO inhibitors- MAO - enzyme that breaks down excess DA, NE, 5HT

phenelzine (Nardil) Isocarboxazid (Marplan) tranylcypromine (Parnate)

2003 – nonselective MAOI selegiline (Eldapril)◦ transdermal skin patch

mechanism of action:

reversible inhibitors of MAO A – NE/5HT◦ moclobemide (Aurorix) – not in U.S. – not particularly

effective

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

Alters the metabolism of amino acid tyramine

Alters the metabolism of amino acid tyramine◦ foods high in tyramine include: aged cheeses,

wine, smoked fish, yeast products

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

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)

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

amoxapine (Asendin)◦ primarily SNRI (but also blocks DA)

Trazodone (Desyrel)◦ doesn’t block NE or 5HT

less anti ACh; quicker action? 5HT agonist… (5HT2)

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

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…...

6 SSRIs◦ fluoxetine (Prozac)◦ paroxetine (Paxil)◦ sertraline (Zoloft)◦ fluvoxamine (Luvox)◦ citalopram (Celexa)◦ escitalopram (Lexapro)

Block reuptake of 5HT◦ selective serotonin reuptake inhibitor

single action antidepressant

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)

disequilibriam (dizziness, vertigo, ataxia) GI distress Flulike symptoms (fatigue, lethargy, chills) sensory disturbances sleep disturbances

most often seen when individual takes 2 or more drugs that increase 5HT activity◦ ex. SSRIs, MAOIs, TCA

incidence – rare more than 80% resolve no specific criterion for diagnosis can be mild or potentially lethal

may be more effective at treating somatic symptoms associated with depression

ex. pain

older tca with dual actions

new antidepressants with dual actions

Nefazodone (Serzone) – ◦ strongest pharmacological action is 5HT2

blockade◦ also inhibits reuptake of NE and 5HT◦ black box warning – liver failure

sequenced treatment alternatives to relieve depression

Some patients do not respond well to first treatment

most take 3 - 4 weeks to exert significant therapeutic effects

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.

Less favorable profile than for depressive disorders

Most come to the attention of docs Age of onset –

◦ Wide range with average ~ 30

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.

~ 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. 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

amphetamine cocaine corticosteroids hallucinogens l-dopa pcp methylphenidate

stabilize acute mania, mixed and depressive symptoms

don’t induce mood alterations prevent future relapses

Until the last 10 – 15 years – lithium only approved drug for treating bipolar

now number of drugs referred to as “Mood stabilizers”

Lithium Anticonvulsants Atypical antipsychotics

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

◦ 2003 - Evidence suggests that lithium, unlike any other mood stabilizer, may have a specific antisuicide effect

pharmacokinetics◦ kidneys excrete 95%◦ sweat – 4-5%

pharmacodynamics:◦ good question!!!!!◦ modulation of the levels of several genes maybe?

ethnic differences –◦ AA with similar plasma levels as Caucasians had

on average 60% higher intracellular levels 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.

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 ~ 10Lithium ~ 3

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

Symptoms: Shaking and trembling, confusion, slurred speech, nausea and vomiting, diarrhea, abdominal pain, unsteadiness on the feet, coma, seizures

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

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

no antidote to lithium; usually add sodium containing fluids immediately; if toxic signs are severe, may use hemodialysis, gastric lavage, diuretic, antiepileptic, etc

- although li prevents manic and depressive episodes < 50% achieve complete relief

Recommendations:◦ maintain bipolar patient on Li for 9 – 12 months

after manic episode

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)

carbamazepine (Tegretol), divalproex (Depakote), gabapentin (Neurontin) and lamotrigine (Lamictal), valproic acid (Depakene)

valproate (Depakote®) – approved in 1995◦ also reduces kindling, has anticonvulsant

effects and GABAergic effects Most serious side - liver toxicity and failure

◦ 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.

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

full effect◦ within hours for epilepsy◦ 2 weeks for mania◦ 2 – 3 weeks for depression

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

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)