Prevalence: In Canada the prevalence of major depression is approximately 11%. One in five people experience an episode of depression in their lifetime.
Episodes can last months or years
Morbidity: Depression has marked impact on a person's occupational, social, and family life.
It affects:
        sleep
        interest in job/family
        guilt
        energy
        concentration
        appetite

Mortality: Depression is responsible for 1 suicide per day in British Columbia
Risk Factors:
        Females twice as likely as males to suffer from depression
        urban environment
        lack of employment
        marital status- married and never divorced have lowest rate
        family history
Theories: Mass proposed in 1975 that based on biochemical and pharmacological evidence, two types of depression exist: type A and B.
Type A- caused by a disturbance in norepinephrine metabolism.
Type B- caused by a disturbance in serotonin metabolism.

Treatment: for mild to moderate depression: psychotherapy, counselling and drugs are equipotent.
For moderate to severe depression: medications work better.

Until the late 1980's we had available to us:
Tricyclic antidepressants (TCA's)
        amitriptyline
        imipramine
        clomipramine
        trimipramine
        maprotiline
        nortriptyline
        desipramine
Monamine oxidase inhibitors ( reserved for resistant depression)
        phenelzine
        tranylcypromine
Others
        Trazodone
       amoxapine
The TCA's are non selective agents which alter norepinephrine, dopamine and serotonin levels. The side effects most commonly associated with them are anti-cholinergic side effects, sedation, and orthostatic hypotension.
Patients who have responded well to TCA's in a previous episode may use them again.
Circa 1990's A new class of antidepressant drugs is emerging as drugs of first choice. The Selective Serotonin Reuptake Inhibitors (SSRI's)
        Fluoxetine (Prozac)
        Fluvoxamine (Luvox)
        Sertraline (Zoloft)
        Paroxetine (Paxil)

Advantages of new drugs:
        fewer milder side effects
        fewer major side effects
        safe in overdose
        faster to therapeutic dose
        single daily dose- better compliance
Treatment pointers: Choice of drug will depend on history of previous response, side effect profile of drug, symptom relief, and interaction with other drugs taken concurrently.
An SSRI is preferred over a TCA in elderly patients, patients who are at high risk for suicide, and patients with medical conditions that could be adversely affected by TCA's.
  Clinical differences between the SSRI's is very slight.
The SSRI's have a high incidence of nausea, vomiting, CNS disturbances and sexual dysfunction.
Some side effects of anti depressants mimic depression, therefore the clinician needs to differentiate presenting symptoms from drug side effects.
Some SSRI's are more sedating than others. May need to supplement with hypnotics if patient
has difficulty sleeping until depression lifts.
Once acute phase is over, treatment should continue for up to 12cminths to prevent relapse. After 1 episode 60% of patients will relapse, after 2 episodes, 75% will have another.
 

Summary of Pharmacokinetic profiles

Drug	Elimination half life- including metabolites	Active Metabolites	Route of Elimination	Daily Dose (mg)
Fluoxetine	7-15 days	yes	urine, feces	20-80
Fluvoxamine	17-22 hours	no	urine	25-300
Sertraline	26 hours	yes (1/8 as active)	urine, feces	50-200
Paroxetine	12-20 hours	no		10-50

 

Summary of adverse-effect profiles of Paroxetine, Sertraline, Fluvoxamine and Fluoxetine (percentage of patients repoting adverse effect)

effect	Paroxetine ( n = 2,683 )	Adverse Sertraline ( n = 861 )	Fluvoxamine ( n = 24,624 )	Fluoxetine ( n = 1,034 )
Nausea	27.0	26.1	15.7	24.3
Headache	19.0	20.3	4.7	10.4
Sedation	21.0	13.4	6.9	10.1
Insomnia	14.0	16.4	4.5	15.0
Dry mouth	18.0	16.3	4.6	11.2
Constipation	13.0	8.4	2.9	5.4
Diarrhea	11.0	17.7	2.2	12.6
Tremor	10.0	10.7	3.3	10.1
Dizziness	12.0	11.7	3.8	10.0
Weakness or fatigue	15.0	10.6	6.2	10.1
Increased sweating	12.0	8.4	1.7	8.4
Anxiety or agitation	8.0	5.6	1.4	15.3
Vision disturbances	5.0	4.2	--	--
Sexual dysfunction	3.0	17.2	<0.1	--
Vomiting	2.0	3.8	3.2	--
Anorexia	4.0	2.8	2.1	11.7
Taste perversion	2.0	1.2	--	4.9
Urinary disturbances	2.0	1.4	--	0.6

 

Effect on Cytochrome P450 Enzymes

	2D6	3A3/4	2C19	1A2	2C9/10
Representative Substrate	Desipramine Haloperidol (?)	Alprazolam Terfenadine	Diazepam Other Benzodiaz	Theophylline	Phenytoin
Fluoxetine	inhibits metabolism by 40%	mild inhibition	mild inhibition	none	may inhibit (?)
Sertraline	slight inhibition	none metabolized by	slight inhibition	none	none
Paroxetine	inhibits metabolism by >80%	none	none	none	none
Fluvoxamine	none	inhibits	none	inhibits	none

Other new anti-depressants: Moclobemide (Manerix)- this is the first reversible inhibitor of monamine oxidase (RIMA)
        -increases the synaptic concentration of serotonin and norepinephrine
        -reversibility means that the ingestion of tyramine (<40 mg/meal) is unlikely to
        induce a  hypertensive crisis seen with traditional MAOI's
The risk of tyramine reaction is further reduced if the drug is taken immediately after meals. Most common side effects reported: insomnia, dizziness, headaches.
Nefazodone (Serzone)- more similar to Trazodone
        - inhibits reuptake of serotonin (like SSRI's)
        - also is a post synaptic serotonin antagonist
Most common side effects: sedation, dry mouth, nausea, dizziness, constipation, lightheadedness, blurred vision. Avoid Astemizole (Hismanal) and Terfenadine (Seldane) because of potential serious cardiac arrhythmias.
Venlafaxine (Effexor)- serotonin/norepinephrine reuptake inhibitor (SNRI)
        - activity similar to TCA's but without anti-cholinergic side effects or othostatic hypotension.
Side effects are more similar to those of SSRI's: nausea, somnolence, dry mouth, dizziness, nervousness.
Gastro-intestinal adverse effects are reduced if taken with food.
Significant increases in diastolic blood pressure have been reported in 3% of patients receiving doses of less than 100 mg and in 13% of patients receiving doses greater than 300 mg. Therefore regular blood pressure minitoring of patients taking Venlafaxine is recommended.