4. Etiology of Depression
Biogenic Amine Hypothesis
• Depression and mania are due to an alteration in neuronal
and synaptic catecholamine concentration at adrenergic
receptor sites in the brain.
– Depression: deficiency of catecholamine,
especially norepinephrine
– Mania: excess amines
6. Range of emotions
• Euthymia
• Hypomania
• Euphoria
• Mania
• Dysthymia
• Dysphoria
• Depression
7. Clinical features of major depression
One of the following must be present:
– Depressed mood
– Anhedonia (i.e., loss of interest or pleasure)
Plus four or more of the following:
– Decreased or increased appetite
– Unintentional weight loss or gain
– Insomnia or hypersomnia
– Psychomotor agitation or retardation
– Fatigue or loss of energy
– Feelings of worthlessness or excessive or inappropriate
guilt
– Diminished ability to think or concentrate or
indecisiveness
– Recurrent thoughts of death and/or suicidal ideation
– Suicide attempt
12. Clinical manifestations of serotonin syndrome and serotonin
withdrawal syndrome
Classification of
dysfunction
Serotonin syndrome Serotonin
withdrawal
syndrome
Cognitive-
behavorial
dysfunction
Confusion
Hypomania
Agitation
none
Autonomic
nervous system
dysfunction
Diarrhea Diaphoresis
Shivering
Fever
Changes in blood
pressure
Nausea and vomitting
Flu-like symptoms
Dizziness
Light headedness
Chills
Sleep
disturbances
Neuromuscular
dysfunction
Myoclonus
Hyperreflexia
Tremor Seizure
Death
Lethargy
Myalgia sensory
disturbances (e.g.,
paresthesia)
13. Selective 5-HT uptake inhibitors (SSRI)
• 1st
line for depression
• Actions similar in efficacy & time course to TCA
• Acute toxicity is less than that of MAOI or TCA
• Side-effects include nausea, insomnia & sexual
dysfunction.
• dangerous 'serotonin reaction'
– (hyperthermia, muscle rigidity, cardiovascular collapse)
can occur if given with MAOI.
• Long half-lives
15. SSRIs
• Am bec of its stimulatory effect
• Metabolize via cytochrome P450
16. SSRI’s
• Fluoxetine- bulimia
– Most stimulatory
– For depression with negative symptoms
• Paroxetine
– Most sedating
– Depression with anxiety and insomnia
• Sertraline
– Less stimulatory and less sedating
17. Tricyclic antidepressants (TCA)
• TCA are chemically related to phenothiazine
• 2nd
line of choice
• Inhibit reuptake of serotonin and norepinephrine
• Important side-effects:
– sedation (H1-block), postural hypotension (α-adrenoceptor block),
dry mouth, blurred vision, constipation (muscarinic block),
occasionally mania and convulsions.
– Risk of ventricular dysrhythmias through potassium channel block.
19. Cyclic Antidepressants
Mechanism of Action
• Block reuptake of neurotransmitters, causing
accumulation at the nerve endings.
• It is thought that increasing concentrations of
neurotransmitters will correct the abnormally
low levels that lead to depression.
20. Cyclic Antidepressants
Mechanism of Action—Drug Effects
Blockade of norepinephrine:
– antidepressant, tremors, tachycardia, additive
pressor effects with sympathomimetic drugs
Blockade of serotonin:
– antidepressant, nausea, headache, anxiety,
sexual dysfunction
24. TCA
• TCA USER
• HEALTHY
• NONSUICIDAL
• REFRACTORY TO NEWER DRUGS
25. Monoamine oxidase inhibitors
(MAOI)
• Action is long lasting (weeks) due to irreversible inhibition of
MAO A & B.
– Moclobemide has a short duration of action
• 3rd
line of choice
• Main side-effects:
– postural hypotension (sympathetic block)
– atropine-like effects (as with TCA);
– weight gain
– CNS stimulation
– Serotonin syndrome
– liver damage (rare). ISOCARBOXAZID
26. Antidepressants: MAOIs Hypertensive
Crisis and Tyramine
• Ingestion of foods and/or drinks with
the amino acid TYRAMINE leads to
hypertensive crisis, which may lead
to cerebral hemorrhage, stroke,
coma, or death
27. Antidepressants: MAOIs Hypertensive
Crisis and Tyramine
Avoid foods that contain tyramine!
• Aged, mature cheeses (cheddar, blue, Swiss)
• Smoked/pickled or aged meats, fish, poultry (herring,
sausage, corned beef, salami, pepperoni, paté)
• Yeast extracts
• Red wines (Chianti, burgundy, sherry, vermouth)
• Italian broad beans (fava beans)
29. Monoamine oxidase inhibitors
(MAOI)
• Phenelezine,Tranylcypromine,
• Isocarboxazid
– Rarely clinical due to serotonin syndrome
– hypertensive crisis- most common (tyramine-rich foods)
– 3 -4 wks- do not discontinue
– Insomnia effect – not at pm
30. Side effects
• Othostatic hypotension
• Weight gain
• Edema
• Sexual dysfunction
• Hepatocellular damage-isocarboxacid
33. Symptoms of mania
• Grandiose ideations or expansive self-esteem
• Decreased need for sleep
• Pressured speech
• Racing thoughts or flight of ideas
• Distractability
• Psychomotor agitation
• Engaging in dangerous, high-risk activities
34. LITHIUM
• Mechanism of Action
–?
–alters intracellular second messengers:
adenyl cyclase-cyclic AMP system and the G
protein-coupled phosphoinositide systems
(NE and serotonin)
–alters ion channel function
–alters metabolism of GABA
35. LITHIUM
• Adverse effects
–Narrow therapeutic index
–Therapeutic range: 0.5-1.5mEq/L
–Minor S/E: tremors, polyuria,
GI distress,
memory problems, acne,
weight gain
–Long-term S/E: hypothyroidism
–Toxic levels: ataxia, tremors, confusion, coma, sinus
arrest, death
36. LITHIUM
Baseline labs Adverse effects
Thyroid
function
hypothyroidism
BUN/Crea Renal
insufficiency
Electrolytes
(esp.sodium)
Dec. Na
CBC leukocytosis
