Antidepressants

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Antidepressants - Indications

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Primary indication is Major depressive disorder
Post-partum depression
Anxiety disorders
Bulimia nervosa
Pain
Depression with medical illness
Depression associated with schizophrenia

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General Considerations with the use of Antidepressants

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Dosage
•Start with lowest dose and gradually increase
•Abrupt cessation can lead to withdrawal
Combination of drugs not recommended
Suicide risk
•Study showed increased suicide risk in persons taking antidepressants
•Suicide by overdose may be attempted
- 30% are treatment resistant
Prevention of relapse
•6 mths treatment to prevent relapse
•Increased number of episodes increases the chance for more episodes

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Effects of Antidepressants

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Do not produce euphoria
Have no discernible effects in non-depressed individuals (except MAO-Is)
Have no reinforcing effects (ie: not likely to cause dependence)
In depressed individuals they
•elevate mood
•increase physical activity
•improve appetite and sleep patterns
•reduce morbid preoccupation

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TCA Indications

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Major depression
Anxiety disorders (OCD, phobias)
Nocturnal enuresis
Depression associated with schizophrenia

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Tricyclic Antidepressants

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Amitriptyline (Endep)
Clomipramine (Anafril, Placil)
Dothiepin (Dothep, Prothiaden)
Doxepin (Deptran, Sinequan)
Imipramine (Melipramine)
Nortriptyline (Allegron)
Trimipramine (Surmontil

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TCA Pharmacology

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dirty drugs at therapeutic doses
- SE- seadtion
- anticholinergic effects

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Overdose with TCAs

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CNS
•Excitement, delirium, convulsions, drowsiness, respiratory depression, coma and death
Cardiotoxicity
•Cardiac depression
•Arrhythmias
•Hypotension
TCAs strongly potentiate alcohol effects
•Combination can cause death from respiratory depression

Narrow TI
- 1 weeks supply can be fatal

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MAOI Indications

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Major depression
Major depression when other antidepressants have not worked (Phenelzine)
Atypical depression
Phobic anxiety & panic disorder
Social phobia (Moclobemide)
Anorexia and bulimia nervosa

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Monoamine Oxidase Inhibitors

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Irreversible, non-selective: phenelzine, tranylcypromine
•Bind covalently to MAO-A and MAO-B
Reversible Inhibitor of MAO-A (RIMA): moclobemide
•Binds reversibly and selectively to MAO-A

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MAO MOA

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MAO Pharmacology

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SSRI Indications

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Major depression
Dysthymia
Anxiety disorders (panic disorder, OCD)

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Selective Serotonin Reuptake Inhibitors

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Citalopram (Celapram, Cipramil, Talam, Talohexal)
Escitalopram (Lexapro)
Fluoxetine (Auscap, Fluohexal, Fluoxetine-DP, Fluoxebell, Lovan, Prozac, Zactin)
Fluvoxamine (Faverin, Luvox, Movox)
Paroxetine (Aropax, Oxetine, Paxtine)
Sertraline (Xydep, Zoloft)

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SSRI Relative Potency

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SSRI Pharmacology

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Atypical Antidepressant Indications

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Major depression
Prevention of relapse of major depression
Anxiety disorders (GAD, social phobia)

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Atypical Antidepressants

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Tetracyclic antidepressants (a2-adrenoceptor blockers):
•Mianserin (Lumix)
•Mirtazapine (Avanza, Axit, Mirtazon, Remeron)
NRI:
•Reboxetine (Edronax)
SNRIs:
•Venlafaxine (Efexor), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta)

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Atypical Antidepressants Pharmacology

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Comparison of Side Effects
Side

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Contraindications

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Long Term Effects of Antidepressants

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Over a period of a few weeks…
Down-regulate postsynaptic NA (-adreno-ceptors) and/or 5-HT2 receptors
•Reduction in binding sites
•Reduction in agonist response
Increase activity/sensitivity of post-synaptic 5-HT1 receptors in hippocampus (except MAO-I’s)
Decrease activity/sensitivity of presynaptic a2 adrenoceptors and/or 5-HT1 receptors (inhibitory receptors which control NA and 5-HT release)
•Facilitate monoamine release

Net effect of chronic treatment is an enhancement of monoaminergic function
•optimize monoamine levels and restore optimal receptor sensitivity
Slow adaptive changes correspond to the timecourse of therapeutic effect
•β2 adrenoceptors downregulated
•5-HT2 receptors downregulated
•2 adrenoceptors downregulated

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Comparison of Efficacy

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TCAs used as “gold standard” to measure antidepressant effects against
Newer drugs have reduced side/adverse effects, but not reduced number of “treatment resistant” persons
MAOIs effective in atypical depression
SSRIs very effective in reducing anxiety, agitation, retardation associated with depression.
SSRIs as effective as TCAs in treating moderate depression, but possibly less effective than TCAs in treating severe depression

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A Question of Efficacy?
Kirsch et al (2008) meta-analysis:

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•symptom reduction among depressed patients on placebo ~30%; on antidepressants ~40%
•only 48% of approved antidepressants showed superiority over placebo
•antidepressants only effective in severely depressed (as placebo less effective in this group)