Download Antidepressant Drugs

Antidepressants
NS204
Antidepressant Drug Types
• Tricyclic & related drugs
• Monoamine oxidase inhibitors
• Selective serotonin reuptake inhibitors
• Other drugs
Depression
Somatic Features
Psychological Features
Anxiety Features
Anhedonia
Concentration & attention
Self confidence
Emotional reactivity
Self esteem
Guilt
Sleep & EMW (~ 2 hrs)
Unworthiness
Tension
DMV (mornings worse)
Pessimism
Worry
Collaterally reported
psychomotor retardation
Death wish
Distress
Appetite
Weight
Libido
Suicidality
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
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
What features does Geraldine have?
“Vital” features
Psychological Features
Anxiety Features
Anhedonia
Concentration & attention
Self confidence
Emotional reactivity
Self esteem
Guilt
Sleep & EMW (~ 2 hrs)
Unworthiness
Tension
DMV (mornings worse)
Pessimism
Worry
Collaterally reported
psychomotor retardation
Death wish
Distress
Appetite
Weight
Libido
Suicidality
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
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
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)
Tricyclic Adverse Effect Profiles
Sedative (H1)
Anticholinergic (M)
Amitriptyline
Clomipramine (Anafranil®)
Dosulepin (Prothiaden®)
Doxepin (Sinequan®)
Trimipramine (Surmontil®)
Imipramine (Tofranil®)
++
++
++
++
++
++
++
++
+
++
++
+++
Lofepramine (Gamanil®)
+
+
Nortriptyline (Allegron®)
+
++
Trazodone (Molipaxin®)*
Mianserin*
++
+
+
* - tricyclic-related compounds
++
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
Monoamine Oxidase Inhibitors
•
•
•
•
Phenelzine (Nardil®)
Tranylcypromine
Isocarboxazid
Moclobemide (Manerix®)
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
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
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:
•
•
–
–
–
–
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mature cheese
pickled herring
broad bean pods
meat/yeast extract (Bovril®, Oxo®, Marmite®)
fermented soya bean extract
–
–
shrimp paste
caviar
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
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®)
Mirtazapine
®
(Zispin )
•
Presynaptic antagonist of alpha2-adrenoceptors
•
Increases central NE and 5HT transmission through a nonspecific alphablockade 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
Reboxetine
®
(Edronax )
– SNRI - inhibits NE reuptake (does not
affect 5HT reuptake)
– Has stimulant effect – best taken am
– No anticholinergic effects
– Can cause impotence
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
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
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
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)
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)
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.
Venlafaxine
Adverse effects that can occur if treatment with
venlafaxine is abruptly withdrawn:
- Gastro-intestinal disturbances
- Headache
- Anxiety
- Dizziness
- Paraesthesia
- Tremor
- Sleep disturbances
- Sweating
5HT Syndrome
•
Similar to NMS, which can also occur
•
Not just a risk on SSRIs, but on any antidepressants
affecting serotonergic system, person experiences:
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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