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: igor@ucla.edu

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