Overview and update in developments for the treatment of depression

1
Overview and update in developments for the
treatment of depression

• Anna Grunze
• Consultant
• East CMHT,
• Northumberland,
• Tyne and Wear NHS Foundation Trust
• Anna.Grunze_at_ntw.nhs.uk

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Overview

• Drug treatment of depression
• Suicidality impact and prevention
• Discussion

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Drug treatment of depression

• When is it appropriate to use an antidepressant?
• Which antidepressant should you use?
• How long should you treat for?

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Drug treatment of depression

• When is it appropriate to use an antidepressant?

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The stepped-care model
Focus of the intervention
Nature of the intervention
STEP 4 Severe and complex1 depression risk to
life severe self-neglect
Medication, high-intensity psychological
interventions, electroconvulsive therapy, crisis
service, combined treatments, multiprofessional
and inpatient care
STEP 3 Persistent subthreshold depressive
symptoms or mild to moderate depression with
inadequate response to initial interventions
moderate and severe depression
Medication, high-intensity psychological
interventions, combined treatments, collaborative
care2, and referral for further assessment and
interventions
STEP 2 Persistent subthreshold depressive
symptoms mild to moderate depression
Low-intensity psychosocial interventions,
psychological interventions, medication and
referral for further assessment and interventions
STEP 1 All known and suspected presentations of
depression
Assessment, support, psycho-education, active
monitoring and referral for further assessment
and interventions
1,2 see slide notes
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WWW.BAP.org.uk
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• Categories of evidence for causal relationships
  and treatment
• I - Meta-analysis, at least one large good RCT or
  replicated smaller RCTs
• II - Small non-replicated RCTs, at least one
  controlled study without randomisation or
  evidence from at least one quasi-experimental
  study
• III - Non-experimental descriptive studies
• IV - Expert committee reports or opinions and/or
  clinical experience of respected authorities

• Proposed categories of evidence for non-causal
  relationships
• I - Large representative population samples
• II - Small, well designed, but not necessarily
  representative samples
• III -Non-representative surveys, case reports
• 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
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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)
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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.

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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 23
  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 23 months
  (C)
• there is a prior history of moderate to severe
  recurrent depression (D)

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Drug treatment of depression

• Which antidepressant should you use?

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• Others
• Buproprion UK licence for smoking
• Buspirone UK licence for anxiety

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Choosing an antidepressant

• Efficacy

• Tolerability

Cost, Preference
Safety
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Choosing between antidepressants
Need to tailor choice to circumstance

• Difference
• in tolerability

• Difference
• in efficacy

Difference in cost
Difference in safety
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Choosing between antidepressants
Primary care, mild moderate, uncomplicated

• Difference
• in tolerability

• Difference
• in efficacy

Difference in cost
Difference in safety
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Choosing between antidepressants
Severe, failed previous treatment, suicidal

• Difference
• in efficacy

• Difference
• in tolerability

Difference in cost
(Difference in safety)
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Severity of Depression and Response
Per cent response
Baseline HAM-D
From Angst (1993)
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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)

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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).

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Are SNRIs better than SSRIs?

• NNT24

Papakostas, G. I., Thase, M. E., Fava, M., et al
(2007) Biological Psychiatry, 62, 1217-1227.
21
Fatal toxicity of serotonergic and other
antidepressant drugs
1993-1999, Single ingestions
alcoholEngland,Wales Scotland
FTI fatal toxicity index expressed as deaths per
million prescriptions.
Buckley N and McManus P, BMJ 2002 325 1332-1333
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Painful Symptoms Are Highly Correlated With
Depression
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Limb pain
N18,980
Backaches
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Joint/articular pain
Gastrointestinal pain
Headaches
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Any pain
Frequency
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10
0
Normal Mood
Major Depressive Disorder (MDD)
Ohayon MM, Schatzberg AF. Arch Gen Psychiatry.
200360(1)39-47.
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Severity of pain and response to SSRI therapy
N573 SF-36 scale
Bair MJ et al. Psychomsomatic Med 2004 661722.
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General aches and pains relief in depressed
patients 60 mg OD study
In a large study (N18,980) 43 of patients with
depression experienced general aches and pains
(GAPs)1
Detke, et al. J Clin Psychiatry 2002 63 308315.
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Agomelatine 25-50 mg n 116 Placebo n
119 Repeated measures ANOVA
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Effect of agomelatine (Valdoxan) on the liver

• Abnormalities of liver function (transaminase
  elevation gt 3 ULN), were commonly reported in
  trials of Valdoxan (1.1 Valdoxan versus 0.7 on
  placebo)
• Elevated transaminase levels usually return to
  normal levels when Valdoxan is discontinued
• Hepatitis (cytolytic) and transaminase elevation
  gt 10 ULN have been rarely reported in trials of
  Valdoxan
• Liver function tests should be performed for all
  doses at initiation of treatment, at around week
  6 (end of acute phase) and around week 12 and 24
  (end of maintenance phase) and thereafter where
  clinically indicated
• Valdoxan is contraindicated in patients
  with hepatic impairment (i.e cirrhosis or active
  liver disease)

Draft SPC
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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

Zarate et al., 2006
indicates Plt.05 , Plt.01 , Plt.001.
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Drug treatment of depression

• How long should you treat for?

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Treatment trial duration

• Lack of significant improvement after 24 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 24 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 68 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).

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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.

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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 ADs 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, 19802000
Ludig Marcotte, 2005
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Contra ADs 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 ADs 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 AntidepressantsMeta
-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, P0.0001) and the odds ratio for
  suicidal behaviour declined at a rate of 4.6 per
  year of age (-7.4 to -1.8, P0.001)

Stone et al,2009
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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

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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

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Thank you !