Transcript ELFT PC teaching - Antidepressant Medicationx

ELFT Training Packages
for Primary Care
- Antidepressant Prescribing
a clinical perspectiveFrank Röhricht
MD FRCPsych
Honorary Professor of Psychiatry
Associate Medical Director
Depression – the syndrome
• “Depression is a change in mood and
behaviour characterised by feelings
of sadness, low self-worth and a loss
of enjoyment in life with less
motivation and energy. Other
common symptoms include sleep and
appetite disruption and a loss of
interest in sexual activity” (Nutt, 2010)
Depression – other
symptoms
• “masked depression”: somatisation
• Alteration in thinking process: Lack of
concentration and attention,
negative/pessimistic thought pattern
• Overlap with anxiety syndromes
(worrying & 'catastrophising thoughts
• Depersonalisation / derealisation
symptoms common in moderate to
severe depression
Depression and physical
health
• Significant co-morbidity with medical
LTCs (CHD, Diabetes, other)
Evidence based treatment?
• Two recently published studies significantly
challenge widely accepted views regarding the
efficacy of antidepressant medications
• Kirsch et al. 2008: “Initial Severity and
Antidepressant Benefits: A Meta-Analysis…” Drug–
placebo differences in antidepressant efficacy…are
relatively small.
• Turner et al. 2008: “Selective Publication of
Antidepressant Trials and Its Influence on Apparent
Efficacy”: publication bias of data from U.S. Food
and Drug (FDA) registration trials results in an
inaccurate characterization of AD efficacy
Kirsch et al. 2008
• “…the overall effect of new generation
antidepressant medications is below recommended
criteria for clinical significance…”
• “…there seems little evidence to support the
prescription of antidepressant medication to any but
the most severely depressed patients, unless
alternative treatments have failed to provide
benefit…”
• …but: similar problems with evidence base for CNT
in meta-analyses on PT (Parker & Fletcher 2007)
Metaanalyses continued
• According to another metaanalysis
from Fournier et al. (JAMA 2010) AD
only effective (significant effect size
of 0.5) at a HAMD score of 25+
• If no response within first four
weeks, change of dose or substance
required
Conclusions:
• AD only recommended for patients whose
depression is of at least moderate severity
• Appr. 20% of these patients will recover with no
treatment at all (within 4-8 weeks)
• Appr. 30% will respond to placebo and about 50%
will respond to AD drug treatment
• For mild or subsyndromal patients side effects
outweigh clinical effects
• AD effect often seen by 2 weeks; if effective
should be taken for 6 months after recovery from
episode
Do the drugs work?
• All antidepressants offer effective
treatment for depression, providing two
conditions are met:
– Adequate dose taken
– Treatment continued for an adequate duration
Do the drugs work?
• Picture complicated by:
– 20% of people will spontaneously recover
within 4-8 weeks
– 30% of people respond to placebo therapy
(50% to antidepressant)
– 25-35% of people will achieve remission with
placebo (50% with antidepressant)
Placebo-response
• More severe depression:
– Less placebo response
• Depression of longer duration:
– Less placebo response
• Elderly, children, adolescents:
– Less response to antidepressants
Classification of AD drugs
• Tricyclics (=TCA’s)
• SSRI’s (selective serotonine reuptake
inhibition / r.i.)
• NARI’s (selective noradrenaline r. i.)
• SNRI’s (serotonine and noradrenaline r.i.)
• MAOI’s (Monoamine oxidase inhibition,
blocking degrading of neurotransmitters)
• Other/atypical (different mode of action,
e.g. presynaptic agonists)
Common features of all AD’s
• They all take weeks to work
• They can all induce mania and
rapid cycling
• They all have withdrawal effects if
stopped suddenly
• The may increase neural growth,
especially in the hippocampus
Common side effects of all ADs
• Can all reduce sodium reduction
(hyponatremia)
• Can all increase risk of bleeding
(depletion of serotonine from
platelets by reuptake inhibition)
• Cave Serotonine syndrome
Tricyclic antidepressants
• Increase of availability of Norepinephrine and
Serotonine in the synaptic cleft, mainly
hippocampus and other limbic areas
• H1 and alpha1 blockage: sedation, hypotension
• ACh muscarinic cholinergic blockage:
tachycardia, hypotension, arrhythmia, dry
mouth, urinary retention, constipation, blurred
vision, confusion
• Established efficacy for moderate to severe
depressive episodes
TCAs - specific
• Doxepin: Good Anxiolytic substance/1025mg tablets
• Trimipramine: stronger sedative; no
interaction with REM sleep pattern, possibly
slightly DA, receptor blockade.
• Amitriptyline: Used in anaesthesia as
adjunctive pain treatment; patients with
range of unspecific somatic symptoms
(particularly pain).
• Clomipramine: mainly acting as SSRI, first
line treatment in OCD
SSRI antidepressants
• Mainly increase of availability of Serotonine (5-HT)
in the synaptic cleft; other mechanism involved
• 5-HT1 important for depression
• 5-HT3 related to gastrointestinal side-effects
• No H1, very minimal alpha 1 and Ach blockade
• Main side effects: abdominal discomfort (mainly
nausea and vomiting, decreased appetite),
agitation (some), headache, sexual dysfunction
(40%), EPS, excessive sweating, anxiety
• Different SSRI’s have different receptor bindings
• Efficacy doubtful in severe depressive episodes
• Cave: Serotonine Syndrome, hyponatraemia
SSRIs - specific
• Citalopram (20-60mg): poor inhibitor of cytochrome
P450 pathways. Possibly few drug interactions.
• Paroxetine (20-50mg): listed for social phobia,
severe withdrawal effects frequently (shortest half
time), more weight gain/sexual dysfct. reported.
• Fluoxetine (20-60mg): longest half-time; can cause
agitation/akathisia, can enhance suicidal risk, potent
inhibitor of CYP1A2.
• Fluoxamine: higher incidence of nausea.
• Sertraline (50-200mg): Nausea less common
SNRI antidepressants
• Strictly speaking only Reboxetine, but also
Nortriptyline and Desipramine with with
high NE/5-HT blocking ratio
• enhanced noradrenergic CNS activity leads
to increase in drive, reduction in
psychomotor retardation
• Cave: delay of AD effect may increase risk
to act on suicidal thoughts
• Nortriptyline (tricyclic): Relatively safe, very
cheap, used for more than 20 years.
SNRI antidepressants
• Strictly speaking only Venlafaxine and
Duloxetine, but also all tricyclic AD
• Increase of availability of Norepinephrine
and Serotonine in the synaptic cleft
• Venlafaxine: safe in OD, but can cause
tachycardia, headaches, abdominal
discomfort and high blood pressure (high
dose); dual action only at higher dose range
Monoamine Oxidase Inhibitors
• Blocking enzyme, reducing breakdown
of monoamines
• Tranylcypromine
• May work when other AD’s do not
• Many interactions with food and drugs
• Can cause hypertensive crisis if
tyramine containing food eaten
• Risk of serotonin syndrome (potentially
lethal) as drug-drug interaction
Atypical antidepressants-1
• Enhance Norepinephrine release /
transmission by effecting (antagonist) the
pre-synaptic alpha-2 adrenergic receptors
• Mirtazepine antagonist of / blocking postsynaptic 5-HT3 receptors, thus lack of
gastrointestinal adverse effects; for
treatment of Akathisia (low dose only); less
likely to cause sexual problems; cave: blood
dyscrasia
• Trazodone: tetracyclic, sedative, safe
(hardly any muscarinic SE, 150-600mg)
Atypical antidepressantsAgomelatine
• Melatonergic agonist (MT1 & MT2 receptors),
5HT2c antagonist, no affinity to other receptors
• Normalising / stabilising circadian rhythm;
increasing NA / DA release in frontal cortex
• Starting dose 25mg at bedtime, up to 50mg
(after two weeks with no improvement)
• SE: monitoring of LFTs due to CI hepatic
impairment, some transient nausea, dizziness;
cave: CYP1A2 inhibitors
• Not recommended by NICE yet, currently third
line: failure of other treatments,
gastrointestinal/sexual/weight gain side effects
Augmentation / other strategies
for treatment-resistant
• “Art beyond science”
• Two or more AD’s combined (e.g. SSRI/SNRI plus
Mirtazepine recommended by NICE)
• Antipsychotic added (usually Quetiapine)
• Lithium, other mood stabilisers; Tri-Iodothyronine;
ECT (severe/life-threatening depression)
• Exercise treatment, St John’s Wort
• Other: Omega-3 fatty acids? Sleep deprivation;
Light therapy; ECT; Vagal Nerve Stimulation
Which antidepressant?
• “Type” of depressive syndrome?
• Severity of illness?
• Previous treatment experiences?
• Contraindication for certain drugs?
• Suicidality?
• Age, gender, ethnicity
• Service users preferences
Depressive syndromes
• Core to all: depressed mood,
anhedonia, reduced affective
modulation
1. Psychomotor agitation, anxiety, insomnia
2. Psychomotor retardation, lack of drive
and initiative = anergia
3. intermediate
4. Psychotic depression
5. “masked” depression
Type 1: Psychomotor agitation,
anxiety, insomnia
• Suicidalty/contraindication for tricyclics:
Trazodone, Mirtazepine
• No Suicidalty/contraindication for tricyclics:
Doxepine, Trimipramine, Amitriptylin
• Advantage: Immediate anxiolytic, sedative
effects due to alpha 1 and H1 blockade,
safing Benzodiazepines
• Monotherapy enhances compliance
• Tricyclics more potent AD drugs in severe
depression
Type 2: Psychomotor retardation,
lack of drive and initiative
• Suicidality: SNRI’s (Venlafaxine) or SSRI’s
(much less effective) or, but only under
close psychiatric monitoring NARI
(Reboxetine) in combination with
tranquilizer
• No suicidality: Reboxetine or Nortriptyline
• Reboxetine safer in elderly patients or in
case of physical comorbidity
Type 3: intermediate,
“depression mainly”
• Consider St. Johns Wort
(900microgram daily) for mild to
moderate syndromes
• Otherwise: SSRI’s