Monoamine Hypothesis of Depression (deficiency of NE, 5HT & DA)

Reserpine produces depressive sx

Suicidal depression associated w/ low levels of serotonin metabolites

Tryptophan depletion reinstates depression in former depressed pts.

MAOI & tricyclic antidepressants boost levels of these neurotransmitters

SSRIs increase 5HT

Not enough neurotransmitters? Too many receptors?

Antidepressants boost levels of monoamines

- Monoamine levels increase quickly in response to antidepressants

- Cognitive response takes weeks to appear

Too many receptors?

- Receptors are pathologically up regulated or sensitized

- Once monoamine levels are chronically elevated, receptors desensitize & downregulate

NE, DA, 5HT – all include amino group (NH2)

- All have similar structure

Derived from aromatic amino acids (tyrosine, tryptophan, phenylalanine) by decarboxylase enzymes

Precursors to monoamines

Deaminates (degrades) epinephrine, norepinephrine, 5HT & dopamine

Deaminates tyramine (potent releaser of NE)

Must be inhibited for anti-depressive effect

MAOa selective – Brofaromine (Consonar)

Deaminates dopamine

  Selective inhibition does not produce anti-depressive effect

MAOb selective – Selegiline (Eldepryl)

Most are irreversible

Most are non-selective for MAOa/b

- Relatively selective for A at low doses

- Examples: 

Isoniazid (Laniazid) Anti-TB drug; First antidepressant discovered 

Benmoxin (Neurasil)

Phenelzine (Nardil)

Cheese;

cured meats;

fish;

wine; 

chocolate; 

avocado;

banana 

hypertensive crisis - very high BP; potential organ damage

Serotonin crisis - increased HR; hyperthermia/sweating; dialated pupils; twitching; headache/mental agitation 

Usually appear early then fade as neurotransmitter-receptor sys adjust

Individual differences specific to the pt. & from drug-to-drug

Sexual dysfunction

Weight gain (usually 5HT2C affinity)

Cardiovascular effects

Increased suicidal risks in adolescents

- Not clear that this effect appears in adults

- Black box warning

- Consonar

- MAOI

- MAOa selective

- Deprinol

- Tricyclic 

- first tested for use as antipsychotic

- Elavil

- tricyclic

- inhibitor of 5HT & NE reuptake

- essentially inactive on DA transport

Autonomic effects:

- Anti-cholinergic -- Blurred vision; Dry mouth; Constipation; Urinary retention

- Alpha 1-adrenergic receptor effects –- Orthostatic hypotension; Tachycardia (rapid heart beat): Inhibition of NE uptake (sinus node)& Block of mAch receptors

- Voltage-gated sodium channel -- Overdose can lead to seizures, coma, arrhythmias & heart attack

- Paxil

- SSRI

- Prozac

- SSRI

- Zoloft

- SSRI

- Bupropion (Wellbutrin)

- Amoxapine (Asendin)

- Maprotilinie (Ludiomil)

- Trazodone (Desyrel)

- Welbutrin

- often added to or replaces an SSRI

- does not cause weight gain or sexual dysfunction

- helps w/ smoking cessation