p harm antidepressants
TRANSCRIPT
Therapy of Major Depression and Manic-Depressive Illness
Igor Spigelman, Ph.D.
Division of Oral Biology & Medicine, UCLA School of Dentistry, CA
Rm. 63-078 CHSEmail: [email protected]
MAJOR DEPRESSION
• unipolar disorder
• lifetime risk 17%
• intense sadness and despair
• disruption of circadian rhythms
• suicidal behavior 10-15%
• good response to therapy with antidepressant drugs (~70%)
• ECT for drug resistant cases
Economic costs of depresssion in US in 1990
$11.7 billionAbsenteeism(26.8%)
$8.3 billionInpatient care(19.0%)
$12.1 billionDecreasedProductive Capacity(27.7%) $7.5 billion
Death from Suicide(17.1%)
$1.2 billionPharmaceutical costs(2.8%)
$2.9 billionOutpatient care/partial care(6.6%)
Andrews & Nemeroff, Am. J. Med., 1994
Major Classes of Antidepressant Drugs
Tricyclics(Im ip ram ine & Am itripy lin e)
SecondGeneration
(Am oxap ine , B uproprion,M apro tiline , T razodon e)
ThirdGeneration
(M irta za pin e , Ve nla fax ine,N e fazod on e)
NON-SELECTIVE Selective SerotoninReuptake Inhibitors (SSRI)
(F luoxe tine , P aro xitine , Se rtra line)
Am ine ReuptakeBlocking Drugs
Monoam ine OxidaseInhibitors
(Ph en e lzine , T ra ny lcyp rom ine)
ANTIDEPRESSANTS
ECT Shock (70-130 V)• delivered unilaterally• increases NE and 5-HT• 9 to 10 sessions• Side effect: memory dysfunction• generally returns fully
Trephination
Monoamine Hypothesis of Monoamine Hypothesis of Major DepressionMajor Depression
• Involves brain monoamines– Norepinephrine (NE)– Serotonin (5-HT)– Dopamine (DA)
• Hypothesis says – Functional in amine-dependent synaptic
transmission resulting in depression
Key to Monoamine Hypothesis of Depression
• Drugs that deplete monoamines are depressant.• Most antidepressants enhance monoaminergic
transmission at some point in the synaptic signaling process.
• The concentration of monoamines and their metabolites is reduced in the CSF of depressed patients.
• In various post-mortem studies, the most consistent finding is elevation in cortical 5-HT2 binding.
What’s wrong with monoamine What’s wrong with monoamine hypothesis?hypothesis?
• Multiple problems with hypothesis• If it works then should see mood elevation• However: therapeutic drugs cause
– Change in amine activity within hours but takes weeks to see clinical effects
– A slow down-regulation of amine receptors
TRICYCLIC ANTIDEPRESSANTS
• Mixed NE and 5-HT uptake inhibitors at presynaptic terminal; some amount of DA uptake block.
• All TCAs have some affinity for – H1 and muscarinic receptors 1 and 2 adrenoceptors
• Dangerous in overdose due to cardiotoxicity
N
N
HCl
Imipramine HCL
Depressed patients: side effects as in normal people
REM, stage 4
mood elevating effect
2-3 weeks for effect
Normal people: lethargy, clumsiness
dry mouth, blurred vision
REM, stage 4 sleep
ACTIONS OF TRICYCLIC ANTIDEPRESSANTS
TRICYCLIC ANTIDEPRESSANTS• Drugs quite effective.
– Cost effective– Decline in use not related to efficacy– Have low margin of safety in overdose, poor adverse
reaction profiles and drug interaction profiles.– Children and elderly particularly susceptible
• Display – M1, H1, 1 blockade – Dry mouth, constipation, urinary retention, sinus
tachycardia, blurred vision, postural hypotension, sedation, sexual dysfunction.
– Quinidine-like effects on cardiac conduction
ANTIDEPRESSANT TOXICITYANTIDEPRESSANT TOXICITY
• Tricyclic Overdose– Often suicidal intent– Extremely hazardous– Manifestations
• Agitation, delirium, neuromuscular irritability, convulsions, coma
• Respiratory depression and circulatory collapse• Hyperpyrexia• Cardiac conduction defects and severe
arrhythmias
– Anticholinergics
– Alcohol and CNS depressants
– Local anesthetics + vasoconstrictorsSympathomimetic effects may be enhancedUse epinephrine cautiouslyAvoid levornordefrin
TCAs: Drug Interactions
Monoamine Oxidase Inhibitors (MAOIs)
• Drugs– Tranylcypromine (Parnate)– Phenelzine (Nardil)– Irreversibly inhibit both MAO A and
MAO B leading to increased levels of all 3 NTs.
– Use reserved for refractory or atypical depression or those associated with panic disorder and/or phobias.
– Limited due high incidence of side effects, serious food/drug and drug/drug interactions.
H2N
MONOAMINE OXIDASE
• Monoamine oxidase A (MAO A)• Deaminates
– 5-HT– NE– TyramineSelective blocker: clorgiline
• Monoamine oxidase B (MAO B)• Breaks down primarily DASelective blocker: selegiline
MAOIMAOIPharmacokineticsPharmacokinetics
• Monoamine Oxidase Inhibitors (MAOI)– Clinical effect persists after drug
discontinued and absent from blood– Pharmacokinetics parameters no good for
predicting doses– Must assume effects last for 7 days
(Tranylcypromine) to 2-3 weeks (Phenelzine) after discontinuing drug
MAOIMAOITherapeutic EffectsTherapeutic Effects
• Antidepressant effect (2-3 weeks) REM sleep• Correction of sleep disorder in depressed
patients
MAOIMAOIAdverse EffectsAdverse Effects
– Headache– CNS stimulation– Dry mouth– Weight gain– Postural hypotension– Sexual disturbances
MAOIMAOIAdverse EffectsAdverse Effects
– Deceptive absence of overt signs of MAO blockade
– Major change in capacity to handleendogenous and exogenous amines
MAOIMAOIDrug InteractionsDrug Interactions
• Indirectly acting sympathomimetics(hypertensive crisis)
• Opioid analgesics (esp. meperidine)
• Alcohol and CNS depressants
Serotonin-Specific Reuptake Inhibitors (SSRIs)
• Drugs– Fluoxetine (Prozac)– Sertraline (Zoloft)– Paroxetine (Paxil)– Fluvoxamine (Luvox)– Citalopram (Celexa)
• Better tolerated than TCAs and MAOIs, with less severe side effects and have a wide margin of safety in overdose.
• Onset: 2-4 weeks (up to 12)
F3C O CHCH2CH2NHCH3
SSRIs - Paxil®• Used for
– Depression– OCD (Obsessive Compulsive Disorder)– Social Anxiety
• # 9 in sales on the list of the top 200 drugs of 1999• # 15 in prescriptions on the list of the top 200
drugs of 1999• Generates sales in excess of $1.5 billion/year
(2000)
SSRIs: Adverse Effects Adverse Effects
• Anxiety, insomnia, increased appetite, tremors
• GI symptoms• Headache• Rashes Libido, sexual dysfunction• Contraindicated with MAOIs
(Serotonin syndrome)
Serotonin syndrome
• Interaction when serotonergic drugs are taken together– example: SSRI & MAOI– Fever, agitation, hypertension, hyperthermia,
rigidity, myoclonus– Can lead to seizure, coma, death
• Always get complete list of drugs prior to starting therapy
• Must have “washout” period between meds
2nd Generation nonselective monoamine reuptake blockers
Trazodone (Desyrel)
– 1st non-lethal in overdose antidepressant
– Adverse effects: sedation, hypotension, priapism,dry mouth, blurred vision, nausea, headache
2nd Generation nonselective monoamine reuptake blockers
Buproprion (Wellbutrin, Zyban)
– Uses: depression, smoking cessation– Adverse effects: anxiety, insomnia, weight loss– Dosing: Start low, taper up– Contraindications:
• Seizure disorder, head injury, electrolyte imbalance, alcoholism
– lowers seizure threshold
3rd Generation nonselective monoamine reuptake blockers
Venlafaxine (Effexor)
• Adverse effects– Drowsiness, nervousness, dizziness, sexual
dysfunction, fatigue BP, HR and cholesterol with higher doses
• Drug interactions: MAOIs
An illness characterized by extreme changes in mood, behavior and energy levels
Also called manic-depressive illness
Quotes:• "It seems as though my mind has slowed down and
burned out to the point of being virtually useless. I [am] haunt[ed] with the total, the desperate hopelessness of it all."
• "Ideas are fast...all shyness disappears...people, things become intensely interesting...unbelievable feelings of ease, power, well-being...you can do anything."
• "The fast ideas become too fast and there are far too many...overwhelming confusion replaces clarity...everything is now against the grain...you are irritable, angry, uncontrollable, and trapped."
Mania (the "high")
• 1. Inflated self-esteem • 2. Severe insomnia • 3. Excessive talkativeness • 4. Racing thoughts • 5. Distractibility • 6. Activities done to excess
(e.g. spending money) • 7. Pursuit of risky behaviors or activities
Depression (the "low")
• 1. Loss of interest in activities enjoyed previously• 2. Changes in appetite resulting in weight gain or
loss • 3. Changes in sleep patterns resulting in difficulty
sleeping or oversleeping • 4. Agitation • 5. Loss of energy • 6. Trouble concentrating or thinking • 7. Repeated thoughts of suicide or death
LITHIUM SALTS
• Primary use– Bipolar affective (manic-depressive) disorder
• Decreases manic behavior• Modulates frequency and magnitude of mood
swings• Usually used together with antidepressant drugs
or anticonvulsants (e.g. valproate)• Antipsychotic therapy may also be indicated
Lithium carbonate, lithium citrate
Lithium: Pharmacokinetics• Absorption
– Virtually complete within 6-8 hrs
– Peak plasma levels in 30 min to 2 hrs
• Distribution– Total body water– Slow entry into
intracellular compartment
– No protein binding
• Metabolism– None
• Excretion– Almost entirely in
urine– Lithium clearance
about 20% of creatinine
– Plasma T/2 about 20 hrs
LITHIUM SALTS
• THERAPEUTIC OVERDOSE – More common than those due to deliberate
or accidental ingestion of drugs– Usually due to accumulation of lithium due
to some change in patient statusSymptomsSymptoms::Nausea, vomiting, diarrhea, tremor, confusion,
arrhythmias, convulsions
Lithium: Adverse Effects Tremor Sedation Ataxia Aphasia Thyroid
enlargement (dysfunction rare)
Polyuria Salivary gland
dysfunction Arrhythmias Edema Leucocytosis