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 CHS Email: 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 billion Absenteeism (26.8%) $8.3 billion Inpatient care (19.0%) $2.9 billion Outpatient care/partial care (6.6%) $12.1 billion Decreased Productive Capacity (27.7%) $1.2 billion Pharmaceutical costs (2.8%)

$7.5 billion Death from Suicide (17.1%)

Andrews & Nemeroff, Am. J. Med., 1994

Major Classes of Antidepressant Drugs

ANTIDEPRESSANTS
Amine Reuptake Blocking Drugs Monoamine Oxidase Inhibitors (Phenelzine, Tranylcypromine)

NON-SELECTIVE

Selective Serotonin Reuptake Inhibitors (SSRI) (Fluoxetine, Paroxitine, Sertraline) Third Generation (Mirtazapine, Venlafaxine, Nefazodone)

Tricyclics (Imipramine & Amitripyline)

Second Generation (Amoxapine, Buproprion, Maprotiline, Trazodone)

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 Major 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.

Whats wrong with monoamine 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
N

HCl
N

Dangerous in overdose due to cardiotoxicity

Imipramine HCL

ACTIONS OF TRICYCLIC ANTIDEPRESSANTS

Normal people: lethargy, clumsiness

dry mouth, blurred vision

REM, stage 4 sleep Depressed patients: side effects as in normal people REM, stage 4

mood elevating effect

2-3 weeks for effect

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 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

TCAs: Drug Interactions

Anticholinergics
Alcohol and CNS depressants Local anesthetics + vasoconstrictors
Sympathomimetic effects may be enhanced Use epinephrine cautiously Avoid levornordefrin

 Drugs

Monoamine Oxidase Inhibitors (MAOIs)

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.

H 2N

MONOAMINE OXIDASE
Monoamine oxidase A (MAO A)
Deaminates
5-HT NE Tyramine Selective blocker:

clorgiline

Monoamine oxidase B (MAO B)

Breaks down primarily DA
Selective blocker: selegiline

MAOI Pharmacokinetics
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

MAOI Therapeutic Effects

Antidepressant effect (2-3 weeks) REM sleep Correction of sleep disorder in depressed patients

MAOI Adverse Effects

Headache CNS stimulation Dry mouth Weight gain Postural hypotension Sexual disturbances

MAOI Adverse Effects

Deceptive absence of overt signs of MAO blockade Major change in capacity to handle endogenous and exogenous amines

MAOI Drug Interactions

Indirectly acting sympathomimetics (hypertensive crisis) Opioid analgesics (esp. meperidine)

Alcohol and CNS depressants

Serotonin-Specific Reuptake Inhibitors (SSRIs)

Drugs FC CHCH CH NHCH 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)
3

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

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")

Inflated self-esteem Severe insomnia Excessive talkativeness Racing thoughts Distractibility Activities done to excess (e.g. spending money) 7. Pursuit of risky behaviors or activities 1. 2. 3. 4. 5. 6.

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
Lithium carbonate, lithium citrate

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: Pharmacokinetics
Absorption
Virtually complete within 6-8 hrs Peak plasma levels in 30 min to 2 hrs

Metabolism
None

Excretion
Almost entirely in urine Lithium clearance about 20% of creatinine Plasma T/2 about 20 hrs

Distribution
Total body water Slow entry into intracellular compartment No protein binding

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 status Symptoms: 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