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Aetiology and treatment of depression in dementia

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Aetiology and treatment of depression in dementia Powered By Docstoc
					Aetiology and treatment of
depression in dementia
Maria Lage Barca – PhD cand.
Norwegian Centre for Ageing and Health
Oslo University Hospital, Ullevål
Trial Lecture – 10th December 2010
Definitions
Depression is a mood disorder that includes
 clinically significant symptoms such as sadness,
 loss of interest, lack of energy, poor self-esteem, guilt,
 impairment of concentration, disturbance of sleep and
 appetite for at least two weeks

Dementia is a brain disorder that includes memory
 impairment and other cognitive symptoms that
 leads to significant impairment in the activities of
 daily living and behavioural or mood symptoms
 that have lasted for at least six months
Depression in the elderly

Depression and dementia are the two most
 prevalent psychiatric disorders in the elderly

Relationship between depression and dementia
• Severe depression      cognitive impairment (Pseudodementia)
• Depression + cognitive impairment (eg. stroke)
• Dementia      depression (Depression in dementia)
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Behavioural and psychological symptoms

   BPSD in a community sample (NPI)




                          Lyketsos et al, 2000
Behavioural and psychological symptoms

BPSD in Norwegian nursing homes (NPI)




Selbæk et al, 2007
Epidemiology - Prevalence
Depression is more prevalent in patients with dementia
 than in those without it
       (Burns 1990, Forsell and Winblad 1998, Rosenvinge and Rosenvinge, 2003)


Prevalence of depression in dementia
    Range 0- 86%
    Major depression: 20- 25 %
    Minor depression/depressive symptoms: 20-30 %
  (Ballard 1996, Lyketsos 1997, 2002, Starkstein 2005, Barca 2010)

Underdiagnosed and undertreated
        (Rovner 1991, Starkstein 2008)
Incidence and Persistence


Incidence of depression: 1.3 – 14% in one year
 (Forsell and Winblad 1991, Ames 1998, Smallbrugge 2006, Barca 2010)

Persistence after one year: 25-63 %
 (Katz 1989, Beekman 1999, Smalbrugge 2006, Barca 2010)
Risk factors of depression in dementia

 Depression earlier in life
  • 18%                  (Agbayewa et al, JAGS 1986)
  • 30%                  (Rovner et al, AJGP 1989)
  • 26% in EOD           (Rosness et al, IJGP 2010)
 Family history of depression (first degree)
 Poor physical health (cardiovascular diseases, stroke)
 Female gender
 Marital Status
 ADL impairment/Dependency?
    Depression vs. Severity of dementia
             Mild                  Moderate            Severe dementia
D
e
p
r
e
s
s
i
o
n

Burns, 1990                                                 Zubencko, 2003
Lyketsos, 2000                                              Starkstein, 2005


No relationship: Ballard 1993, Migliorelli 1995, Cummings 1995, Verkaik 2007
Prognosis


Depression in dementia is associated with negative
  outcomes:
Impairment in quality of life (Gonzalez-Salvador 2000)
Disability in activities of daily living (Forsell and Winblad 1998)
Nursing home placement (Ryden et al 1999, Onder 2007)
Caregiver depression and burden (Clyburn 2000)
Higher morbidity and mortality (Rovner 1991, Katz 1989, Barca 2010)
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Diagnosis of depression – ICD-10
 Core depression symptoms
• Sadness                                          ≥ 2 core symptoms
• Loss of interest
                                                          plus
• Lack of energy
                                                 ≥ 2 additional symptoms
 Additional symptoms
                                                    At least 2 weeks
•   Poor self-esteem
•   Feelings of guilt
•   Suicidal thoughts
•   Diminished ability to think or concentrate
•   Agitation or retardation
•   Sleeping symptoms
•   Appetite symptoms
Diagnosis of depression – DSM-IV
                                                         ≥ 1 core symptom
 Core depression symptoms
• Sadness                                                       plus
• Loss of interest
                                                           ≥ 4 additional
                                                             symptoms
 Additional symptoms
•   Appetite symptoms                                     At least 2 weeks
•   Sleeping symptoms
                                                       Most of the day, nearly
•   Agitation or retardation                                 everyday
•   Fatigue or loss of energy
•   Feelings of worthlessness or innapropriate guilt
•   Diminished ability to think or concentrate
•   Suicidal thoughts
                  Depression in dementia
    Different from that seen in non-demented patients?

                         Lack of motivation
More common ?            Anhedonia
(motivational)           Anxiety
                         Irritability
                         Agitation
overlap with AD
                         Delusions
symptoms?                Hallucinations

Less common ?            Depressed mood
(mood symptoms)          Guilt
                         Hopelessness
                         Suicidality
            Li 2001, Janzing 2002, Olin 2002
Provisional Diagnostic Criteria for depression in
Alzheimer’s Disease (PDC-AD)


• Three or more symptoms of depression must be present for at least 2 weeks
• Two additional symptoms are included: irritability, social withdrawal
• The symptoms must not be present every day, or most of the day

• Alzheimer’s Disease (AD) must be present

                   Olin et al. Am J Geriatr Psychiatry 2002
                   Depression in dementia
    Different from that seen in non-demented patients?




AD patients with depression (n=92) did not differ from
depressed patients (n=47) without dementia

                Chemerinski et al, Am J Psychiatry 2001
Major vs minor depression in dementia
                          RDC Major                RDC Minor
                          depression               depression

Loss of interest          100 %                    50 %
Anxiety                   93.5 %                   61.8 %
Depressed mood            90.3 %                   100 %
Irritability              90.6 %                   64.7 %
Lack of mood reactivity   74.2 %                   47.1 %
Agitation                 71 %                     50.0 %
Retardation               61.3 %                   29.4 %
Lack of energy            45.2 %                   26.5 %

                          Ballard et al. J Affective Disorders 1996
               ‘Sad mood’ in PDC-dAD depression by AD severity




Verkaik, Int J Ger Psychiatry 2009
Engedal et al Int J Ger Psychiatry, Dec 2010
Diagnosis and symptoms - summary

• Phenomenology of depression in dementia is
  still not defined

• Depression in dementia might have some
  differences, such as more irritability and social
  withdrawal

• But sadness seems to still be a core symptom,
  regardless of severity of dementia
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
WHY do patients with dementia have
           depression?
Depression in dementia - Aetiology



• Psychological theory -       ”losses”


• Biological theory - ”Structural,
    neurochemical, genetics”
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Psychological theory


 Depression vs. awarness of deficits
 Loss of occupational function
 Diminished ability to socialize
 Coping strategies
Awarness vs. depression
• Most studies show that there is no relationship between awarness of
  deficits and depression
  (Ballard 1993, Verhey 1993, Cummings 1995, Arkin 2001)


  BUT

• Some studies report relationship between awarness of disease and
  depressive symptoms, minor depression,
  hopelessness and diminished quality of life
  (Harwood 2000 and 2002, Migliorelli 1995, Hurt 2009)
Losses vs. depression


• The experience about losses is probably complex and
  also related to awarness in the disease

• Patients with early onset dementia might experience loss
  of occupational function and this might have a larger
  impact than the diagnosis of depression among older
  patients
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Biological theory

Structural damages
Genetic predisposition

Similarities between depression and dementia
  (result of common underlying processes, or an interaction
  between the two conditions?)
o Hippocampal atrophy
o ”Vascular” theory
o ”Inflammation” theory
Biological theory

Structural damages
Genetic predisposition

Similarities between depression and dementia
  (result of common underlying processes, or an interaction
  between the two conditions?)
o Hippocampal atrophy
o ”Vascular” theory
o ”Inflammation” theory
Loss of cells in locus coeruleus in depressed AD patients compared
to AD patients without depression – Post mortem




                                                    Förstl et al 1992
Cell loss in AD brains and MD (in lifetime)


                                             LC    SN    DR
Zweig et al, 1998                (n=25)      Yes         Yes
Zubencko et al, 1988             (n=14/37)   Yes   Yes
Föstl et al, 1992                (n=14/52)   Yes   No    -
Hoogendijk et al, 1999           (n=12/26)   No    -     -
Hendricksen et al, 2004          (n=7/14)    -     -     No


LC= locus coeruleus (Noradrenergic)

SN= Substantia nigra (Dopamin)

DR= Dorsale raphe (Serotonin)
Lewy bodies
• Lewy bodies in the amygdala increase the risk of
  major depression in dementia
Biological theory

Structural damages
Genetic predisposition

Similarities between depression and dementia
  (result of common underlying processes, or an interaction
  between the two conditions?)
o Hippocampal atrophy
o ”Vascular” theory
o ”Inflammation” theory
Genetic predisposition - dementia

 ApoE ε 4 is a known risk factor for dementia
                (Tanzi 2001, Khachaturian 2004)


• Most studies do not report association with depression in dementia
                (Butters 2003, Cacabelos 1997, Holmes 1997, Hirono 1999)
• Some recent studies report association with depression in dementia
                (Barnes 2006, Fritze 2010)

 One study reported that women carriers of presenilin 1 gene (Chromosome 14)
  unaware of their genetic status had more depressive symptoms
                (Ringman, 2004)
Genetic predisposition – depression


• Polymorphism of the serotonin receptor gene (5HT2A and 5HT2C)
  increases by five times the likelihood of depression in AD
               (Holmes, 2003)

• Alteration on the serotonin transporter gene expression was also
  associated with depression in Parkinson’s disease
               (Mossner, 2001)
Patients with depression in
dementia had loss of
seronotergic function that may
affect the dorsolateral prefrontal
cortex
Biological theory

Structural damages
Genetic predisposition

Similarities between depression and dementia
  (result of common underlying processes, or an interaction
  between the two conditions?)
o Hippocampal atrophy
o ”Vascular” theory
o ”Inflammation” theory
Hippocampus atrophy


                      Typical hippocampus atrophy
                      in Alzheimer’s Disease
Reduced hippocampus volume in
early and late onset depression




     Hickie et al. Br J Psychiatry 2005; 186: 197-202
Biological theory

Structural damages
Genetic predisposition

Similarities between depression and dementia
  (result of common underlying processes, or an interaction
  between the two conditions?)
o Hippocampal atrophy
o ”Vascular” theory
o ”Inflammation” theory
Cardiovascular factors and risk for depression




          Almeida et al. Am J Geriatr Psychiatry 2007; 15: 506-13.
Patients with depression and moderate AD (n=8) had
higher levels of homocysteine compared to those non-
depressed at the same dementia level.
Risk factors for late onset depression



•   Hypertension
•   Diabetes
•   Hyperhomocysteinemia
•   Obesity
•   Smoking
•   Diet (omega 3 fatty acid)
•   Lack of exercise
•   Socioeconomic class
Risk factors for late onset Alzheimer’s Disease
Very well established
• High age
• Genetic polymorphism (ApoE e4)

Established
• Hypertension
• Hypercholesterolemia
• Hyperhomocysteinemia
• Obesity
• Smoking
• Diet (3 omega fatty acid)
• Lack of exercise
• Lack of education/socioeconomic class
• Head injury
Biological theory
Structural damages
Genetic predisposition

Similarities between depression and dementia
  (result of common underlying processes, or an interaction
  between the two conditions?)
o Hippocampal atrophy
o ”Vascular” theory
o ”Inflammation” theory
Late life depression and cytokines

Cytokines are chemical messengers between immune cells and
endothelial cells, playing a key role in mediating immune and
inflammatory responses which can lead to neurochemical (serotonin),
neuroendocrine (cortisol) and behavioural effects (depression)

 The pro-inflammatory cytokines IL-6 (strongest), IL-1 beta, CRP
and TNF alpha are increased in depression (also in LO depression)

 The anti-inflammatory cytokines IL-4; IL-10 and IL-13 are
decreased in depressed patients, (uncertain in LO depression)

        Craddock and Thomas . Essent Psychopharmacol 2006; 7(1): 42-52.
IL-6    (45 AD, 34 MCI patients and 28 Controls)




Bermejo et al. Immunology Letters 2008; 117: 198-202
              TNF-alpha




Bermejo et al. Immunology Letters 2008; 117: 198-202
Inflammation in Depression and dementia/AD

                             Depression     Dementia/AD

Pro-inflammatory cytokines
IL-1                               +               +
IL-6                               +               +
TNF- alpha                         +               +
IFN                                +               +

Anti- inflammatory cytokines
IL-4                               -/?             ?/-
IL-10                              -/?             ?/-

                   Leonard B. Neurochem Res 2007; 32: 1749-56
 Aetiology - summary
Genetic           DEPRESSION
predisposition

                    monoamines



     Vascular                         Inflammatory
     factors                          factors
                  Neurodegeneration

Genetic
predisposition
                                                     Psychological factors
                 DEMENTIA (AD)
Risk factors of depression in dementia

 Depression earlier in life
  • 18%                   (Agbayewa et al, JAGS 1986)
  • 30%                   (Rovner et al, AJGP 1989)
  • 26% in EOD            (Rosness et al, IJGP 2010)
 Family history of depression (first degree)
 Poor physical health (cardiovascular diseases, stroke)
 Female gender
 Marital Status
 ADL impairment/Dependency?
 Severity of dementia?
    Depression vs. Severity of dementia
             Mild                  Moderate            Severe dementia
D
e         Psychological           Genetics               Biological
p         Genetics                                       Genetics
r
e
s
s
i
o
n

Burns, 1990                                                 Zubencko, 2003
Lyketsos, 2000                                              Starkstein, 2005


No relationship: Ballard 1993, Migliorelli 1995, Cummings 1995, Verkaik 2007
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Psychosocial treatment
• Good dementia care

• Cognitive behavioural therapy (CBT)/Cognitive
  rehabilitation

• Adaptation therapy (to decrease the functional impairment)

• Behavioural interventions (Pleasant events, problem
  solving therapy for caregivers)

• Physical activity
Cognitive behavioural therapy (CBT)



• Possibly efficient for patients with depression
  and mild dementia
• Lack of studies
Cognitive rehabilitation


Goal-oriented cognitive rehabilitation for people with
 Early-stage Alzheimer

• Practical aids, strategies to learn new information
• Better than relaxation and no treatment

                       Clare et al, Am J Ger Psychiatry, Oct 2010
Problem adaptation therapy (PATH)

• New 12-week home-delivered intervention for late-life major
  depression with significant cognitive impairment (including
  mild dementia) and disability

• Promote adaptive functioning with tools: calendars, check-
  lists, notepads, timers

             Kiosses et al, Am J Ger Psychiatry, nov 2010
Preliminary results show efficacy


N=30
Behavioural intervention

A 6 months randomised controlled trial, including 72 AD patients
with depression showed that:

’Patient pleasant events’ and ’caregiver problem solving’ was
superior to ’typical care’ and ’patient on waiting list’

                        Teri et al. 1997, 2000, 2003
Physical activity

Cochrane review concluded that there is insufficient
 evidence of efficiency of physical activity on depression

• Only one study of good quality
• Might be that the training programs are not appropriate for
  patients with dementia

                                     Cochrane review by Forbes, 2009
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Biological treatment



• Antidepressants

• Electro-convulsive treatment
RCTs with antidepressants in AD (dementia) patients

Reifler et al 1989                     n=28                     imipramine          = placebo
Nyth et al 1992                        n=98                     citalopram          > placebo
Nyth et al 1994/1994         n=29                    citalopram           > placebo
Fuchs et al, 1993                      n=120                    maprotiline         =placebo
Roth et al 1996                        n=694                    moclobemid          > placebo
Petracca et al 1996                    n=21                     clomipramine        > placebo
Magai et al 2000                       n=31                     sertralin           = placebo
Petracca et al, 2001         n=41                    fluoxetin            = placebo
Lyketsos et al 2003          n=44                    sertralin            > placebo
V. Cunha et al 2007          n=31                    venlafaxin           = placebo
Rosenberg et al 2010         n=131                   sertralin            = placebo

The studies are different by: use of drug, number of patients, outcome measures
        degree of dementia
Most recent RCT


• Included 131 patients diagnosed with the
  Provisional criteria for depression in dementia
• Sertralin equal to placebo

           Rosenberg et al. Am J Ger Psychiatry, Feb 2010
Cochrane Database

 Seven studies were included


 Results and conclusions:
   Weak evidence for effect.
   Significant fewer patients with side-effects in the placebo group.
   Lack of large scale good studies


                                       Bains J et al. Issue 4, 2002
Another meta-analysis
 Five studies were included:

 Results:
   Response: OR 2.32 (1.04 – 5.16), NNT 5
   Remission: OR 2.75 (1.13 – 6.65), NNT 5

   No differences in effect due to choice of drug
   No differences in effects due to severity of dementia

   No differences in drop-outs due to side-effects
   TCA caused decline in cognition

                Thompson et al. Canadian J Psychiatry 2007; 52 (4): 248-255
Expert judgement
Severe depression in AD:                   Mild depression in AD:
    6 RCT’s: 4 of them were effective         3 RCT’s: none of them were
                                                effective



Depression in other dementias:
   No data available




        Lyketsos CG, Olin J. Biol Psychiatry; 2002; 52; 243-252.
Withdrawal of antidepressants
• ”Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly
  patients in nursing homes”.

• Blinded, but not placebo controlled.
   ▫ 70 patients, 35 in each group.

• Withdrew SSRI in patients without a diagnosis (or clinical state) of anxiety and
  depression

• No significant differences between the two groups as measured by MADRS,
  ”Health Index” and ”symptom assessment form” was found.



            Ulfvarson et al. Eur J Clin Pharmacol 2003; 59: 735-740
Withdrawal of antidepressants
An open pilot study

Withdrawal of antidepressants in 11 AD patients in NH for 24 weeks

Cornell score dropped from mean 6.9 at baseline to 3.3 at 24 weeks
follow- up, whereas NPI total score dropped from 29.2 at baseline to
17.3 at follow- up

An DB placebo controlled study is ongoing including 140 patients

        Berg, Selbaek, Engedal. Int J Geriatr Psychiatry 2008; 23(8): 877-9
Electro-convulsive treatment


ECT is seldom used in depression among demented patients and no
evidence based evaluation of its effects. ECT is ”believed” to cause
delirium at a high rate, but is of acceptable safety.

                 Rao, Lyketsos. Int J Geriatr Psychiatry 2000; 15: 729-35.
Expert judgement
 Mild depression: non-pharmacological therapy for both the patient and
  the caregiver

 Severe depression: an antidepressant should be administered
• Bear in mind the lack of evidence
• SSRI are still preferred (sertraline, citalopram, escitalpram)
• Dual action drug might be a good second option (mirtazapine,
  venlafaxine)

 Refractory severe depression: referral to specialist - ECT might be an
  option (especially if dangerousness involved)
                                          Lyketsos and Lee, 2004
Depression in dementia
• Introduction
  ▫ Epidemiology
  ▫ Diagnosis and symptoms
• Aetiology
  ▫ Psychological theory
  ▫ Biological theory
• Treatment
  ▫ Psychosocial treatment
  ▫ Biological treatment
• Conclusion
Conclusion I
• Depression in dementia is highly prevalent and
  persistent

• However, its phenomenology is still not established

• Depression in dementia has a heterogenic aetiology, with
  possible psychosocial, structural and genetic factors

• Non pharmacological strategies should be prioritized for
  mild depression
• Antidepressants might be effective for severe depression
Conclusion II

According to the literature, we should possibly
 start all over again and:

• Understand better its phenomenology
• Define its aetiology
• Start clinical trials that try to target ”the right
  treatment” for ”the right patients”
Thank you for your attention

				
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