1. Antidepressants
NS204

2. Antidepressant Drug Types
Tricyclic & related drugs
Monoamine oxidase inhibitors
Selective serotonin reuptake inhibitors
Other drugs

3. Depression Somatic Features Psychological Features Anxiety Features
Concentration & attention
Self esteem
Unworthiness
Pessimism
Death wish
Suicidality
Anxiety Features
Anhedonia
Emotional reactivity
Sleep & EMW (~ 2 hrs)
DMV (mornings worse)
Collaterally reported psychomotor retardation
Appetite
Weight
Libido
Self confidence
Guilt
Tension
Worry
Distress

4. What can antidepressants do...?
The older drugs; the tricyclics & related compounds and the MAOIs work best on the somatic or “vital” features of depression
SSRIs and other drugs whose main therapeutic mode of action is on the serotonergic system work best on the anxiety-related elements
There is no compelling evidence that any antidepressant impacts directly on the psychological features of depression
Most antidepressants, including the tricyclics & SSRIs, work by blocking reuptake of neurotransmitters.
Others, including the MAOIs, work by inhibiting the action of enzymes that deactivate neurotransmitters

6. Tricyclic & related drugs
Therapeutic effect has been linked inhibiting the reuptake of NE (primarily) & to a lesser extent, of 5HT
Due to their action on the NE system, their effect is often referred to as ‘energy enhancing’
Therefore they are most effective for moderate to severe depressive episodes where there are pronounced somatic features
Tricyclics & related drugs are also sedative, depending on the degree to which they block H1 receptors – this helps with sleep
The less sedative drugs tend to suit people who are experiencing anhedonia and general social withdrawal
The more sedative drugs, in partciular trazodone (Molipaxin®), tend to suit people who have anxiety features

7. What features does Geraldine have?
“Vital” features
Psychological Features
Concentration & attention
Self esteem
Unworthiness
Pessimism
Death wish
Suicidality
Anxiety Features
Anhedonia
Emotional reactivity
Sleep & EMW (~ 2 hrs)
DMV (mornings worse)
Collaterally reported psychomotor retardation
Appetite
Weight
Libido
Self confidence
Guilt
Tension
Worry
Distress

8. Tricyclic & related antidepressants
Why do about 10 to 20% of patients fail to respond to tricyclic and related antidepressant drugs?
Tricyclic antidepressants don’t really have a direct impact on the psychological features of depression
Inadequate dosage may account for some instances
It could be a question of the wrong drug for the wrong person, and sometimes another tricyclic might work

9. Tricyclic & related antidepressants
Lethal in overdose, especially amitryptiline & dosulepin (Prothiaden®)
Require gradual withdrawal – if stopped suddenly after regular administration for 8 weeks or more, the following may occur:
Gastro-intestinal symptoms (nausea, vomiting, anorexia)
Headache
Giddiness
‘Chills’
Insomnia
Less often, hypomania, panic-anxiety or extreme motor restlessness may occur

10. Main Adverse Effects
Tricyclics are related to the phenothiazines and have similar adverse effects to them, for the most part anticholinergic, but also:
Seizures
Hepatic reactions
Haematological reactions
Cardiotoxicity
Drowsiness (H1)
Urinary retention
Hypotensive effects
Hyponatraemia
Neuroleptic Malignant Syndrome (rarely, highest risk with mainserin, where 1/12 blood count is advised during first 3/12)

11. Tricyclic Adverse Effect Profiles
Amitriptyline
Clomipramine (Anafranil®)
Dosulepin (Prothiaden®)
Doxepin (Sinequan®)
Trimipramine (Surmontil®)
Imipramine (Tofranil®)
Lofepramine (Gamanil®)
Nortriptyline (Allegron®)
Trazodone (Molipaxin®)*
Mianserin*
Sedative (H1) ++ +
Anticholinergic (M) ++
+++ +
* - tricyclic-related compounds

12. Imipramine (Tofranil®) & Amitryptiline
In the liver, imipramine is broken down into desipramine & amitryptiline to nortriptyline
Both of these compounds inhibit NE reuptake
Neither inhibits 5HT reuptake

13. Monoamine Oxidase Inhibitors
Phenelzine (Nardil®)
Tranylcypromine
Isocarboxazid
Moclobemide (Manerix®)

14. Monoamine Oxidase Inhibitors
Have a similar impact on “vital”, somatic features as tricyclics & related compounds
Rather than inhibiting reuptake, they inhibit the enzymes that break down 5HT & NE
They do not have the same histaminergic effects as the tricyclics, and so have a pronounced stimulant effect and are best taken in the morning (particularly tranylcypromine)
Phenelzine & isocarboxazid are the least stimualting & most popular MAOIs

16. Monoamine Oxidase Inhibitors
Usually used as a drug of last resort due to dangers of dietary and drug interactions
Like tricyclics, gradual withdrawal is necessary
Most effective for depression with atypical, hypochondriacal or hysterical features as well as phobic anxiety disorders

17. MAOI dietary & drug interactions
MAOIs potentiate the pressor effects of indirect acting sympathomimetics (found mainly in decongestant preparations) and both should not be used together
MAOIs also potentiate the pressor effect of tyramine, a compound found in certain foods, which should be avoided by people on MAOIs
Avoid:
mature cheese
pickled herring
broad bean pods
meat/yeast extract (Bovril®, Oxo®, Marmite®)
fermented soya bean extract
shrimp paste
caviar

18. MAOI dietary precautions
The person should be advised to eat fresh foods only and to avoid game
Alcohol should also be avoided
The dangers of drug & dietary interaction persist for up to 2 weeks after discontinuation of MAOIs
Throbbing headache may be indicative of tyramine interaction and the person should receive emergency medical attention

19. Other Antidepressants
Triptafen® is a compound preparation of amitriptyline hydrochloride and perphenazine
Motival® is a compound preparation of nortriptyline hydrochloride and fluphenazine
Mirtazapine (Zispin®)
Reboxotine (Edronax®)
Tryptophan (Optimax®)
Duloxetine (Cymbalta®, Yentreve®)
Flupentixol (Fluanxol®)

20. Mirtazapine (Zispin®)
Presynaptic antagonist of alpha2-adrenoceptors
Increases central NE and 5HT transmission through a nonspecific alpha-blockade that causes presynaptic alpha2-receptors to increase NE release
Also a 5HTR-2a antagonist
LSD & other hallucinogenic drugs act at this site
5HTR-2a antagonism has not got a very good antidepressant or anxiolytic effect
Benefits may be linked to fact that 5HTR-2a antagonists can be beneficial for derealisation & dissociative symptoms, part of the effects of LSD & some depression/anxiety presentations
Has sedative effect
Adverse effects include increased appetite & weight gain
Increased risk of orthostatic hypotension & NMS

21. Reboxetine (Edronax®)
SNRI - inhibits NE reuptake (does not affect 5HT reuptake)
Has stimulant effect – best taken am
No anticholinergic effects
Can cause impotence

22. Selective serotonin reuptake inhibitors (SSRIs)
Citalopram (Cipramil®)
Escitalopram (Cipralex®)
Fluoxetine (Prozac®)
Fluvoxamine (Faverin®)
Paroxetine (Seroxat®)
Sertraline (Lustral®)
Duloxetine (Cymbalta®, Yentreve®)*
Venlafaxine (Efexor®)*
* - Also have SNRI effect

23. Selective serotonin reuptake inhibitors (SSRIs)
Inhibit reuptake of 5HT
No more effective in the long term than tricyclics
Fewer antimuscarinic and cardiotoxic effects than tricyclics

24. Discontinuing SSRIs
Adverse effects that can occur if treatment with an SSRI is abruptly withdrawn:
- Gastro-intestinal disturbances
- Headache
- Anxiety
- Dizziness
- Paraesthesia
- Sleep disturbances
- Fatigue
- Flu-like symptoms
- Sweating

25. SSRIs – Facts and Fallacies
Blocking serotonin reuptake is not necessary for antidepressant action
Studies have found that effective blockage of serotonin reuptake by SSRIs and the speed with which they treat depression are not correlated
SSRIs tend not to be effective for severe depression
There is no evidence that depressed people have disordered serotonin systems
(Healy 2009)

26. So how do SSRIs work?
SSRIs have an anxiolytic effect, and are prescribed for some anxiety disorders
Therefore, it has been suggested that this anxiolytic effect plays a key part in their therapeutic usefulness
(Healy 2005)

27. Venlafaxine
It is advisable that people commencing treatment with venlafaxine have an ECG, and also have their blood pressure measured before and periodically during treatment.

28. Venlafaxine
Adverse effects that can occur if treatment with venlafaxine is abruptly withdrawn:
- Gastro-intestinal disturbances
- Headache
- Anxiety
- Dizziness
- Paraesthesia
- Tremor
- Sleep disturbances
- Sweating

29. 5HT Syndrome Similar to NMS, which can also occur
Not just a risk on SSRIs, but on any antidepressants affecting serotonergic system, person experiences:
Muscular jerks & twitches
Tremor
Confusion, agitation, restlessness
Excessive shivering & sweating
Hyperreflexia
Diarrhoea
Not as dangerous as NMS, but fatalities have occurred
Usually resolves with discontinuation of drug