Download Depression Pharmacological Treatments

Depression
Pharmacological Treatments
Dr Rebecca Jacob
Consultant Psychiatrist
Fulbourn Hospital
Cambridge
Depressive disorder:
An increasing cause of disability
worldwide
Rank
1990
2020 (estimated)
1
Lower respiratory infections
Ischaemic heart disease
2
Diarrhoeal diseases
3
Perinatal conditions
Road traffic accidents
4
Unipolar major depression
Cerebrovascular disease
5
Ischaemic heart disease
Chronic obstructive
pulmonary disease
Unipolar major depression
Murray CJ, Lopez AD. Science 1996;274:740–3
Epidemiology of depression
Place
Prevalence (% Pts)
Manchester (UK)1
16.9
Groningen (Neth)1
15.9
Paris (France)1
13.7
Mainz (Germany)1
11.2
• Almost twice as common in women than men2
• Up to 30% of primary care patients have depressive symptoms and
6–10% satisfy criteria for major depressive disorder (MDD)3
1. Adapted from Sartorius N. J Clin Psychiatry 2001 (Suppl 15);8–11;
2. Kessler RC et al. J Affect Disord 1993;29:85–96;
3. Zung W et al. J Fam Pract 1993;37:337–44.
Depression is associated with dysregulation of serotonin (5-HT)
and noradrenaline (NA) in the CNS
Prefrontal
Cortex
Limbic System
5HT and NA role in mental and
physical processes
•
Present in many mental and physical processes:
• Anxiety2
• Pain perception1
• Vasoconstriction1,2
• Urethral sphincter contraction2
• Bladder wall relaxation2
• Gastrointestinal motility2
• Pilomotor contraction2
1. Frazer A. J Clin Psychiatry 2001; 62(Suppl 12): 16–23
2. Stahl SM. Essential Psychopharmacology. 2nd Edition. 2000. Cambridge University Press
A proposed model of symptoms mediated by
5-HT & NA*
*Hypothetical neurobehavioural model using several data
sources based mostly on animal studies
1. Lucki I. Biol Psychiatry 1998; 44: 151–162.
2. Frazer A. J Clin Psychiatry 2001; 62(Suppl 12): 16–23.
3. Jones CL. Prog Brain Res 1991; 88: 381–394.
4. Ressler KJ, Nemeroff CB. Depress Anxiety 2000; 12(Suppl 1): 2–19.
5-HT and Noradrenaline
Case Vignette
• A 33 year old married mother of two children
presents to her GP with low mood, anhedonia,
and diurnal variation in mood.
• How do you proceed to take a history and
manage her symptoms?
Classifying depression
• There are two multi-axial classification systems in
common use
• Diagnostic Statistical Manual (DSM-IV)
• American Psychiatric Association-derived
• Used in the USA (particularly in clinical trials)
• The International Classification of Diseases (ICD-10)
• WHO-derived
• Criteria used in UK and globally (but not in the USA)
Gelder M et al. Shorter Oxford Textbook of Psychiatry. Oxford University Press 2001. Pages 96-100
ICD-10 criteria for depression
The depressive episode must last for at least 2 weeks
• Low mood
• Reduced energy
• Reduced concentration
• Lack of self esteem / self
•
•
confidence
Guilt / worthlessness
Tiredness
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Loss of interest / pleasure
Lack of emotion
Altered sleep
Morning depression
Psychomotor retardation
Loss of appetite / weight
Loss of libido
Gelder M et al. Shorter Oxford Textbook of Psychiatry. Oxford University Press 2001. Pages 271-272
DSM-IV criteria for depression
Five of the following symptoms during the same
2 weeks (must include A or B)
A
B
C
D
E
F
G
H
I
J
Depressed mood present most of day and almost every day
Loss of interest or pleasure in usual activities
Decreased energy or increased fatigability
Loss of confidence or self-esteem
Unreasonable feelings of guilt
Recurrent thoughts of death or suicide
Complaints of diminished ability to think or concentrate
Change in psychomotor activity, with agitation or retardation
Sleep disturbance
Change in appetite
Gelder M et al. Shorter Oxford Textbook of Psychiatry. Oxford University Press 2001. Pages 271-272
NICE symptom classification for
depression
NICE − National Institute for Clinical Excellence.
Adapted from NICE guidelines, Management of depression, Dec 2004.
Treatment options for Depression
Pharmacological
•
Selective Serotonin Reuptake
Inhibitors
•
Noradrenergic and specific
serotonergic antidepressant(NaSSA)
•
Serotonin-Noradrenaline re-uptake
inhibitors
•
Tricyclic antidepressants
•
Monoamine-oxidase inhibitors
•
Combination/ augmentation
therapies.
•
Atypical antipsychotics.
Non-pharmacological
•
Psychotherapy: e.g. CAT, CBT,
Psychodynamic, Interpersonal, Family
Therapies
•
Electroconvulsive therapy
•
Vagus nerve stimulation, Transcranial
magnetic stimulation and deep brain
stimulation remain active avenues of
investigation.
Nemeroff CB.J Psych Res 2006
Depression: Treatment goals
Treatment Goals
Increase
Remission
Rates
Prevent
Relapse
Restore
Physical
Functioning
Restore Social
Functioning
Zajecka JM. J Clin Psychiatry 2003; 64 (suppl 15): 7-12
Treatment phases of depression
• Response2
• Remission3
• Recovery1
• Recurrence1
(≥50% reduction in HAM-D17
(≤7 score on HAM-D17)
(Remission for significant period of time)
(A new episode)
1.Kupfer DJ. J Clin Psychiatry 1991;52 (5, Suppl): 28–34
2.Fawcett J et al J Clin Psych 1997; 58(suppl 6):32–38.
3. Ballenger JC. J Clin Psych 1999; 60(suppl 22):29–34.
Key facts that patients should know
• An episode should be treated for at least six
months AFTER recovery.
• Those with multiple episodes may need
treatment in the longer term.
• Anti-depressants are non-addictive and not
known to cause new side-effects over time.
• Anti-depressants should not be stopped suddenly
due to possible discontinuation syndrome.
Maudsley Prescribing Guidelines 2005-2006
How would you proceed to treat
this patient?
NICE guidelines summary
• Anti-depressants not recommended in mild
depression.
• SSRI first line of therapy.
• Patients must be informed about the withdrawal
effects of anti-depressants.
• For severe or resistant depression, combination
of CBT and anti-depressant recommended
• Patients with two prior episodes and functional
impairment should be treated for at least two
years
Selective Serotonin Reuptake
Inhibitors (SSRI’s)
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Fluoxetine
Sertraline
Paroxetine
Citalopram
Escitalopram
=
=
=
=
=
Prozac
Lustral
Seroxat
Cipramil
Cipralex
Why SSRIs ?
• Safe (safer) in overdose
• Fewer side effects
• Start on a treatment dose
Case Review in OPC
• Patient comes back with increased agitation
with medication, no better – if anything worse
– and is now not really eating and spending
most of the day inside
• What would you advise?
Mirtazapine
Mirtazapine
• Related to mianserin
• NaSSA
• Presynaptic alpha-2 blockade
• Postsynaptic selective HT2 and HT3 blocker
• Also a potent histamine blocker
Mirtazapine
• Sedating
– ? less so at higher doses
• Increased appetite
• ? Blood dyscrasias
• BNF limit of 45mg, some use 60mg
Mirtazapine
Also:
• Relatively cardiac safe
• Not good for diabetes
Case continued…..
• Patient returns again – unable to tolerate
increased appetite with mirtazapine so
stopped it
• What next ?
Options ?
• If problems related to S/E consider
escitalopram
• SNRI
SNRIs – Venlafaxine and Duloxetine
Venlafaxine
• SNRI only at doses of 225mg and above
• Max BNF limit of 375mg
• Some evidence for increased dose
• S/Es of SSRIs
• Sweating, hypertension
• Cardiotoxic
Plot thickens
• Patient more severely depressed and showing
no response to Venlafaxine.
• What do you think you are dealing with by this
stage?
Treatment-resistant/refractory
depression
• Term used in clinical psychiatry to describe
cases of depression that do not respond to
two adequate doses of anti-depressants
prescribed for an adequate period of time.
• Review diagnosis, perpetuating factors
(biological/psychosocial), compliance.
Tricyclic ?
• All have 3-ring structure
• Discovered in 1950s in
search for new
antipsychotic
Tricyclics – how they work
Side effects
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Postural hypotension
Dry mouth
Blurred vision
Urinary retention
Weight gain
Restlessness
Insomnia
MAOIs
• Moclobemide
– RIMA
• Phenelzine
• Tranylcypromine
MAOIs
Diet – avoid tyramine
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Cheeses (except cottage cheese and cream cheese but includes cheese spreads),
watch out for pizza !
Cream that is past its use-by date
Meat and yeast extracts such as Marmite, Vegemite, Promite, Bonox, and Bovril
Meats which have undergone an ageing process such as salami, game, pate, etc.
(although fresh or frozen meats may be eaten)
Caviar and smoked or pickled fish (e.g., pickled herrings)
Stock cubes, packet soups, or commercial soup bases
Soy products such as miso, and fermented soy bean, curd, or paste.
Dehydrated meals (as these may contain stock cubes or similar)
Sauerkraut and broad bean pods
Banana skins, banana chips, or banana flavoured products (banana peel may be
used in the flavouring)
Excessive amounts of caffeine or coffee substitutes (e.g., Ecco)
Protein drinks (e.g., Sustagen)
Home brewed beer
No more than 2 standard drinks per day of red wines, white wines, port, or
manufactured beer
Use only limited quantities of raspberries, raspberry jam, avocado, products made
from unpasteurised milk, and soy sauce
Hypertensive Crisis
• Headache, dizziness, flushing, tachycardia,
photophobia, chest pain
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Treat: EMERGENCY
Phentolamine slow IV infusion
Chlorpromazine can be used
External cooling
Other alternatives
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Lithium
T3
Combination treatments
ECT
TMS, vagus nerve stimulation, deep brain
stimulation.
• Psychosurgery
Summary: Mechanisms of Action
Anti-depressants
SRI
Citalopram
Sertraline
Venlafaxine
Buproprion
Nortriptyline
Mirtazapine
Buspirone
X
X
X
X
NRI
DRI
X
X
X
X
α2
5-HT1a
5-HT 2 antag
5-HT 3 ß block
X
X
ELEMENTS AFFECTING RESPONSE
Effects of specific
treatment*
Amount of
improveme
nt
Non-specific treatment effects
Spontaneous outcome
*In most trials, about 30% more improvements on antidepressant than on placebo
Why can outcomes be ‘poor’ in
depression?
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Under-recognition1
Under-treatment1,2
Poor treatment adherence1
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A total of 50% of patients receiving an initial prescription for
an antidepressant stop treatment in the first month1
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Average drop-out rates are lower in trials of newer
antidepressants compared with older agents (primarily
tricyclic antidepressants)1,3
Poor patient education4
Lack of regular follow-up1
1. Cassano P, Fava M. J Psychosom Res 2002; 53:849–857.
2. Hirschfeld RMA, Keller MB, Panico S, et al. JAMA 1997; 277(4):333–340.
3. Mulrow CD, Williams JW Jr, Chiquette E, et al. Am J Med 2000; 108(1):54–64.
4. ZajeckaJM. J Clin Psychiatry 2003; 64(Suppl 15):7–12.
Questions, comments?
STAR*D
Sequenced Treatment Alternatives
to Relieve Depression
Structure
• Effectiveness not Efficacy Trial
• Equipoise – stratified
– Clinicians and patients decide together which arm
to be randomised within
• Patients & Doctors not blinded (Some
assessments blind)
• No Placebo
Inclusion Criteria
• HAM-D17 14
• Clinician deems antidepressant medication
indicated
• 18-75 years of age
Exclusion Criteria
Psychotic depression
Current anorexia or OCD
History of Bipolar / Psychotic disorder
Currently taking anticonvulsants/ antipsychotics/
mood stabilisers / stimulants
• Intending to be or actually pregnant
• Breastfeeding
• Clear history of intolerance to any medications in
first two levels
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Level 1
Citalopram
Level 2
Level 2a
ADD
Buproprion SR
or Buspirone or Cognitive
Therapy
Level 3
Level 4
SWITCH TO
Mirtazapine or
Nortriptyline
SWITCH TO Buproprion
SR or Sertraline or
Venlafaxine ER or
Cognitive Therapy
Cognitive Therapy THEN
Buproprion SR or
Venlafaxine ER
ADD
Lithium or
Triidothyronine
SWITCH TO
Tranylcypromine or Mirtazapine & Venlafaxine
Flexible & Measurement Based Dosing
20mg for 4 weeks
If QIDS >9 increase dose
QIDS 6-8 increase or continue
QIDS <5 continue
If SEs address and continue or go to next level
40mg for 2 weeks
If…
60mg
Level 1
Citalopram
Level 2
Level 2a
ADD
Buproprion SR
or Buspirone or Cognitive
Therapy
Level 3
Level 4
SWITCH TO
Mirtazapine or
Nortriptyline
SWITCH TO Buproprion
SR or Sertraline or
Venlafaxine ER or
Cognitive Therapy
Cognitive Therapy THEN
Buproprion SR or
Venlafaxine ER
ADD
Lithium or
Triidothyronine
SWITCH TO
Tranylcypromine or Mirtazapine & Venlafaxine
The Armamentarium cont.
• Lithium
• Triidothyronine T3
• Tranylcypromine –MAOI & amine
releaser
Level 1
Responding to Citalopram
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2876 patients with Ham-D ~21
28% Remission
47% Response
9% stopped due to intolerance
4% serious adverse effect
0 suicides
Higher remission rates for well educated, employed,
high income, married, Caucasian females. (i.e. me
and my kind)
• Family history not predictive
150
Exit Doses
96.8
100
120
40
60
80
actual dose
adequate dose
max dose
42.1
30
Milligrams per day
160
0
Mirtazapine
Nortriptyline
Level 3
Augment
T3=Lithium
&T3
&Lithium
45.2 micrograms T3
859.8mg of Li
Lithium levels only assessed in 56.5% median 0.6meq/l
Level 3
Augment
Li or T3
25%
Exits due to intolerance
20%
15%
10%
5%
0%
T3
Li
Lithium caused more exits due to intolerance
Evaluation of the generalizability of recent efficacy trials
of antidepressants for MDD
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86 % of study applicants were ineligible for the trials:
17 % had bipolar disorder,
16 % abused substances,
14 % had mild depression,
13 % had a medical contraindication,
12 % were using other psychotropic that were not
permitted in the trial.
These trials do not address the common clinical
presentations seen in practice.