Transcript Overview and update in developments for the treatment of depression Anna Grunze

Overview and update in
developments for the treatment
of depression
Anna Grunze
Consultant
East CMHT,
Northumberland,
Tyne and Wear NHS Foundation Trust
[email protected]
Overview
 Drug treatment of depression
 Suicidality – impact and prevention
 Discussion
2
Drug treatment of depression
• When is it appropriate to use an antidepressant?
• Which antidepressant should you use?
• How long should you treat for?
Drug treatment of depression
• When is it appropriate to use an antidepressant?
The stepped-care model
Focus of the
intervention
STEP 4: Severe and complex1
depression; risk to life; severe selfneglect
STEP 3: Persistent subthreshold depressive
symptoms or mild to moderate depression with
inadequate response to initial interventions;
moderate and severe depression
STEP 2: Persistent subthreshold depressive
symptoms; mild to moderate depression
STEP 1: All known and suspected presentations of
depression
1,2
see slide notes
Nature of the
intervention
Medication, high-intensity psychological
interventions, electroconvulsive therapy,
crisis service, combined treatments,
multiprofessional and inpatient care
Medication, high-intensity psychological
interventions, combined treatments, collaborative
care2, and referral for further assessment and
interventions
Low-intensity psychosocial interventions, psychological
interventions, medication and referral for further
assessment and interventions
Assessment, support, psycho-education, active monitoring
and referral for further assessment and interventions
Categories of evidence for causal
relationships and treatment
Proposed categories of evidence for noncausal relationships
I - Meta-analysis, at least one large good RCT
or replicated smaller RCTs
I - Large representative population samples
II - Small non-replicated RCTs, at least one
controlled study without randomisation or
evidence from at least one quasi-experimental
study
III -Non-representative surveys, case reports
III - Non-experimental descriptive studies
IV - Expert committee reports or opinions
and/or clinical experience of respected
authorities
II - Small, well designed, but not necessarily
representative samples
IV - Expert committee reports or opinions
and/or clinical experience of respected
authorities
Strength of recommendations
A - Directly based on category I evidence
B - Directly based on category II evidence or extrapolated from I
C - Directly based on category III evidence or extrapolated from I or II
D - Directly based on category IV evidence or extrapolated from I, II or III
S - Standard of good practice
Diagnosis of depression: ICD-10 criteria
• Key symptoms (must have at least 2 of these)
– Persistent low mood
– Loss of interest or pleasure
– Fatigue or low energy
• If any of above then ask about:
–
–
–
–
–
–
–
Disturbed sleep
Poor concentration or indecisiveness
Low self confidence
Poor or increased appetite
Suicidal thoughts or acts
Agitation or slowing of movement
Guilt or self blame
4 symptoms = mild
5-6 = moderate
7+ = severe (+/- psychotic
symptoms)
Diagnosis of depression: Grades of severity
• 4 grades of severity used in the guideline:
– Sub-threshold depression (minor depression)
• significant depressive symptoms below the DSM-IV MDD
threshold, including ICD-10 mild depressive episode with only four
symptoms;
– Mild major depression (Mild MDD)
• symptoms barely meet the minimum criteria and mild functional
impairment;
– Moderate MDD
• more than minimum number of symptoms and moderate
functional impairment;
– Severe MDD
• most symptoms are present and marked or greater functional
impairment.
Indications for antidepressants:
Duration and severity of depression guides:
treatment choice (A)
• Antidepressants are a first line treatment for:
– moderate and severe MDD in adults (A),
– Sub-threshold depression that has persisted for 2 years or more (A).
• Antidepressants are an option for short duration mild MDD in
adults (B) especially if:
– there is a history of moderate to severe recurrent depression (D)
– the depression has persisted for more than 2–3 months (D).
• Antidepressants are not a first line treatment for:
– short duration sub-threshold depression in adults (A) but consider if:
• the depression persists for more than 2–3 months (C)
• there is a prior history of moderate to severe recurrent depression
(D)
Drug treatment of depression
• Which antidepressant should you use?
Others:
• Buproprion – UK licence for
smoking
• Buspirone – UK licence for
anxiety
Choosing an antidepressant
Tolerability
Efficacy
Cost,
Preference
Safety
Choosing between antidepressants
Need to tailor choice to circumstance
Difference
in tolerability
Difference
in efficacy
Difference
in cost
Difference
in safety
Choosing between antidepressants
Primary care, mild moderate, ‘uncomplicated’
Difference
in tolerability
Difference
in efficacy
Difference
in cost
Difference
in safety
Choosing between antidepressants
Severe, failed previous treatment, suicidal
Difference
in efficacy
Difference
in tolerability
Difference
in cost
(Difference
in safety)
Severity of Depression and
Response
Per cent response
70
60
50
40
Placebo
Antidepress
30
20
10
0
15
21
27
From Angst (1993)
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Baseline HAM-D
Choice of antidepressant drug
• Match antidepressant to individual patient as far as possible (S)
– see Table 5
• In the absence of special factors:
– choose antidepressants that are better tolerated and safer in overdose (S).
• most evidence for SSRIs
– with other newer antidepressants these are first line choices
• Older TCAs reserved for if first line drug treatment has failed (D)
• MAOIs not first line and should only be initiated by practitioners with
expertise in treating mood disorders (D).
• In more severely ill patients, and where maximising efficacy is of
overriding importance, consider:
– an older TCA, venlafaxine (≥ 150 mg) or escitalopram (20 mg)
Factors to consider in choosing an antidepressant
• patient preference (B),
• associated psychiatric disorder that may specifically respond to
a particular class of antidepressant (e.g. OCD and SRIs) (B),
• previous treatment response to a particular drug (D),
• tolerability and adverse effects of a previously given drug (D),
• likely side effects (e.g. sedation, sexual dysfunction, weight gain)
(C),
• low lethality in overdose if history or likelihood of overdose (D),
• concurrent medical illness or condition that may make the
antidepressant more noxious or less well tolerated (C),
• concurrent medication that may interact (C),
• a family history of differential antidepressant response if
choosing between a TCA and MAOI (C).
Are SNRIs better than SSRIs?
NNT=24
Papakostas, G. I., Thase, M. E., Fava, M., et al (2007) Biological Psychiatry, 62, 1217-1227.
Fatal toxicity of serotonergic and
other antidepressant drugs
FTI= fatal toxicity index expressed as deaths per million
prescriptions.
e
fa
xi
n
Ve
nl
a
e
lin
tra
Se
r
ox
eti
ne
Pa
r
ox
eti
ne
Fl
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pr
am
Ci
tal
o
in
e
M
irt
az
ap
Do
t
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ep
itr
ip
t
in
/D
os
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ep
in
yl
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e
55
50
45
40
35
30
25
20
15
10
5
0
Am
Deaths/million prescriptions (95% CI)
“1993-1999, Single ingestions + alcohol:England,Wales & Scotland”
Buckley N and McManus P, BMJ 2002 325 : 1332-1333
Painful Symptoms Are Highly
Correlated With Depression
50
% Frequency
40
30
Limb pain
Backaches
Joint/articular pain
Gastrointestinal pain
Headaches
Any pain
N=18,980
20
10
0
Normal Mood
Major Depressive Disorder
(MDD)
Ohayon MM, Schatzberg AF. Arch Gen Psychiatry. 2003;60(1):39-47.
Severity of pain and response to SSRI therapy
Odds ratio (OR)
+/- 95% CI
10
OR > 1;
INCREASING
CHANCE OF
NOT
ACHIEVING
RESPONSE
8
6
4
2
0
No pain
Mild
Moderate
Pain severity at baseline
Severe
OR =1;
response
to therapy
N=573
SF-36 scale
Bair MJ et al. Psychomsomatic Med 2004; 66:17–22.
Agomelatine 25-50 mg n = 116; Placebo n = 119
Repeated measures ANOVA
Ketamine i.v. in TRD
•
DB RCT with crossover design
•
18 subjects with MDD being drug free for 2
weeks received a single intravenous infusion of
either ketamine hydrochloride (.5 mg/kg) or
placebo on 2 test days one week apart.
•
Primary outcome measure: 21-item HDRS
•
Subjects receiving ketamine showed significant
improvement in HDRS compared with subjects
receiving placebo within 110 minutes which
remained significant for one week. The effect
size for the drug difference was very large (d =
1.46 [95% confidence interval, 0.91-2.01]) after
24 hours and moderate to large (d = 0.68 [95%
confidence interval, 0.13-1.23]) after 1 week.
AE occurring more commonly with ketamine
were perceptual disturbances, confusion,
elevations in blood pressure, euphoria, dizziness,
and increased libido. In no case did euphoria or
derealization/depersonalization persist beyond
110 minutes
•
* indicates P<.05; †, P<.01; ‡, P<.001.
Zarate et al., 2006
Drug treatment of depression
• How long should you treat for?
Treatment trial duration
• Lack of significant improvement after 2–4 weeks treatment substantially
reduces the probability of eventual sustained response (A).
• After 4 weeks adequate treatment:
– if there is at least some improvement continue treatment with the same
antidepressant for another 2–4 weeks (B),
– if there is no trajectory of improvement undertake a next-step treatment (B);
• in patients who have failed a number of treatments consider longer trials (D)
• After 6–8 weeks adequate treatment:
– if there is moderate or greater improvement continue the same treatment,
– if there is minimal improvement undertake a next-step treatment (B)
• in patients who have failed a number of treatments consider longer trials before
changing treatment (D).
Choice of antidepressant
•
Continuing medication
– Advise use of antidepressants for at least 2 years.
– Maintain level of medication at which acute treatment was effective
(unless there are adverse effects) if:
• the person has had two or more recent episodes of depression
which caused significant functional impairment
• they have other risk factors for relapse
• the consequences of relapse are likely to be severe.
• After 2 years
– Re-evaluate treatment with the person, taking into account age,
comorbidities and other risk factors; thereafter reevaluate as regularly
as needed.
Overview
 Suicidality – impact and prevention
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The extent of suicidality
 Lifetime suicide risk of 6% for affective
disorders (metaanalysis of 27 mortality
studies, Inskip et al, 1998)
 SMRs for suicide: 20.9 (males) and 27.0
(females) for subjects who had ever been
hospitalized for unipolar depression (Ösby et
al., 2001)
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What constitutes “suicidality” ?
• Luckily, completed suicide and suicide attempts are
still a rare event- and thus cannot be captured as a
significant (and unethical) outcome in controlled
trials
• As a consequence, weaker outcomes as “suicidality”
are commonly used, but what is “suicidality”?
– Suicidal ideation
– Suicidal behavior
– …. ?
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Pro AD’s increasing suicide risk
• Increased suicidality (and suicide events) in some
individuals early in AD treatment (Healy and
Whitaker, 2003)
• Meta-analysis of 702 randomized controlled trials
including more than 87,000 depressive and other
psychiatric patients showed a significantly increased
risk of suicide attempts (OR, 2.28), but not of
completed suicides in patients taking SSRIs compared
with placebo (Fergusson et al, 2005)
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Suicide rates vs. SSRI sales, 1980–2000
Ludig & Marcotte, 2005
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Contra AD’s increasing suicide
risk
• Several epidemiological studies show reduction of
suicidality in association with antidepressant
prescription (e.g.,Carlsten et al., 2001; Hall et al.,
2003; Isacsson et al., 1997; Isacsson, 2000;
Ohberg et al., 1998; Rihmer et al., 2000; Ludwig &
Marcotte 2005)
• However, open studies and population-based
studies can easily be subject to several biases and
errors in interpreting results (Möller, 2006)
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Contra AD’s increasing suicide risk
• Following up on FDA warnings, Simon et al.
(Simon et al., 2006) analyzed computerized health
plan records from a total of 82,285 episodes of
antidepressant treatment between 1 January
1992 and 30 June 2003
• Identifying death by suicide and serious suicide
attempts, they found that the risk of suicide
attempts was highest in the months before
starting antidepressant treatment and declined
progressively after starting medication.
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Suicidality risk in RCTs with Antidepressants
Meta-analysis of 372 double blind randomised placebo controlled trials
•
•
•
99231 adults assigned to
antidepressants or placebo
For participants with non-psychiatric
indications, suicidal behaviour and
ideation were extremely rare. For
those with psychiatric indications,
risk was associated with age.
When age was modelled as a
continuous variable, the odds ratio
for suicidal behaviour or ideation
declined at a rate of 2.6% per year of
age (−3.9% to −1.3%, P=0.0001) and
the odds ratio for suicidal behaviour
declined at a rate of 4.6% per year of
age (−7.4% to −1.8%, P=0.001)
Stone et al,2009
Conclusions
• Major depression of at least moderate severity
warrants treatment with ADs
– It is less clear how effective ADs are for milder depression
• Choice between ADs depends on multiple factors
– There are clear differences in side effect profiles
– It is less clear whether there are differences in efficacy
• if there are then these are small and most evident in severely ill
patients
Conclusions (cont)
• Most people who respond start doing so in the first
2-4 weeks
• ADs are potent prophylactic agents
• Clear evidence from epidemiological studies is in
favor of reduced suicide rates with antidepressant
treatment
Thank you !
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