Mood and Cognition: Options for Treatment€¦ · Mood and Cognition: Options for Treatment Professor Allan Young Director of the Centre for Affective Disorders Institute of Psychiatry,

1 1

Mood and Cognition:

Options for Treatment

Professor Allan Young

Director of the Centre for Affective Disorders

Institute of Psychiatry, Psychology and

Neuroscience

KCL

Date of Preparation: February 2015 UK/VOR/1501/0066a

2

Disclosures

• Employed by King’s College London; Honorary Consultant

Maudsley and Bethlem Hospitals (NHS)

• Paid lectures and advisory boards for all major pharmaceutical companies with

drugs used in affective and related disorders

• No share holdings in pharmaceutical companies

• Lead Investigator for Embolden Study (AZ), BCI Neuroplasticity Study, and

Aripiprazole Mania Study

• Investigator-initiated studies from AZ, Eli Lilly and Company, Lundbeck, Wyeth

• Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA);

Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK);

Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada);

WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada).

• Associate Director of the NIHR Clinical Research Network; EMCT Cluster Lead

3

Table of contents

The burden of depression

Cognitive symptoms are common

Cognitive symptoms are

debilitating

Cognitive symptoms are not well

treated

4

THE BURDEN OF

DEPRESSION

The burden of depression

5

MDD is among the Top 5 global causes

of DALYs

Murray CJ, Lopez AD. Science 1996;274:740-3

Disease / injury

1990 2020 baseline scenario

Rank Total DALYs (%) Rank Total DALYs (%)

Lower respiratory infections 1 8.2 6 3.1

Diarrheal diseases 2 7.2 9 2.7

Conditions arising during perinatal period 3 6.7 11 2.5

Unipolar major depression 4 3.7 2 5.7

Ischemic heart disease 5 3.4 1 5.9

Cerebrovascular disease 6 2.8 4 4.4

Tuberculosis 7 2.8 7 3.1

Measles 8 2.6 25 1.1

Road traffic accidents 9 2.5 3 5.1

Congenital anomalies 10 2.4 13 2.2

Malaria 11 2.3 24 1.1

Chronic obstructive pulmonary disease 12 2.1 5 4.1

Falls 13 1.9 19 1.5

Iron-deficiency anemia 14 1.8 39 0.5

Protein-energy malnutrition 15 1.5 37 0.6

War 16 1.5 8 3.0

Self-inflicted injuries 17 1.4 14 1.9

Violence 19 1.3 12 2.3

HIV 28 0.8 10 2.6

Trachea / bronchus / lung cancers 33 0.6 15 1.8

MDD, major depressive disorder; DALY, disability-adjusted life-year

6

Depression has more negative effects on health

100

80

60

40

20

0

Mea

n h

ealt

h s

co

re (

0–

100)

90.6

80.3 79.6 79.3 78.9

72.9 67.1

65.8 65.4

58.5

71.8

56.1

In terms of mean health score, depression exerts more of an impact than

asthma, angina, arthritis, or diabetes

Depression adds to the

burden of asthma, angina,

arthritis, or diabetes

Adapted from Moussavi S et al. Lancet 2007;370:851-8

7

Table of contents

The burden of depression

Cognitive symptoms are common

8

Cognitive deficits are common in depression

9

DSM-5 identifies cognitive symptoms as a criterion

item of an MDE

● “Diminished ability to think or concentrate,

nearly every day (either by subjective

account or observed by others)”

1 of the 9 diagnostic criteria for

depression

American Psychiatric Association. DSM-5.

American Psychiatric Publishing, 2013

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition;

MDE, major depressive episode

10

Cognitive dysfunction: common symptoms

in MDD

American Psychiatric Association. DSM-5.

American Psychiatric Publishing, 2013

DSM-5 criterion Additional information

Depressed mood Feeling sad or empty

Anhedonia Markedly diminished interest or pleasure in all or nearly all activities

Significant weight

change

Weight loss and / or increases or decreases in appetite

Sleep problems Insomnia or hypersomnia

Psychomotor problems Psychomotor agitation or retardation

Fatigue Evident as a loss of energy

Feeling worthless or

inappropriately guilty

Excessive feeling of worthlessness or inappropriate guilt, not merely

self-reproach or guilt about being sick

Cognitive problems Diminished ability to think or concentrate, or indecisiveness, either

documented by subjective account or as observed by others

Thoughts of death Recurrent thoughts of death or suicidal ideation; suicidal attempt or plan

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition

11

Many patients with MDD have discernible

cognitive impairments

● Patients with depression performed significantly worse on working memory and

reaction time tests, while patients with schizophrenia were significantly worse on all

tests compared to controls

Neurocognitive test scores in patients with depression (mean HAM-D 22.4),

schizophrenia (mean PANSS 75.6), and control subjects

*p<0.05 depression vs control

HAM-D, Hamilton Depression Rating Scale;

PANSS, Positive and Negative Syndrome Scale Rund BR et al. Acta Psychiatr Scand 2006;113:350-9

Working

memory

0.5

0.0

-0.5

-1.0

-1.5

-2.0

-2.5 Executive

function

Visual

memory

Verbal

memory

Visual info.

processing

Reaction

time

Attention /

vigilance

z-s

core

s

Control (n=50)

Depression (n=45)

Schizophrenia (n=53)

* *

14

Psychomotor speed worsens in MDD

Lee RS et al. J Affect Disord 2012;140:113-24

Study Weight

Std. Mean Difference

IV, Random, 95% CI

Std. Mean Difference

IV, Random, 95% CI

IIonen 2000a

Reischies 2000b

Grant 2001a,b

Neu 2005b

Castaneda 2008a,b

Preiss 2009b

Reppermund 2009b

Kaymak 2010b

van Wingen 2010 (curr)b,c

van Wingen 2010 (prev)b,c

Total (95% CI)

6.4%

12.4%

12.2%

9.3%

12.2%

13.5%

8.8%

7.2%

9.0%

8.9%

100.0%

0.66 [-0.16, 1.49]

0.97 [0.61, 1.32]

0.14 [-0.23, 0.51]

0.97 [0.40, 1.55]

0.04 [-0.33, 0.41]

0.54 [0.26, 0.83]

0.32 [-0.29, 0.93]

1.34 [0.59, 2.08]

0.04 [-0.55, 0.63]

0.05 [-0.55, 0.66]

0.48 [0.21, 0.75]

Controls performing

worse

Patients performing

worse

-2 -1 0 1 2

P=0.0005 aSpatial Span Forwards; bDigit Span Forwards; cDigit Span Backwards

15

Cognitive impairment of functional domains

Std. Mean Difference

IV, Random, 95% CI P value

Cognitive flexibility 0.53 [0.23, 0.83] 0.0007

Attention 0.36 [0.13, 0.59] 0.002

Verbal fluency 0.59 [0.10, 1.07] 0.02

Attentional switching 0.22 [0.00, 0.44] 0.05

Visual 0.53 [-0.05, 1.11] 0.07

Working memory 0.16 [-0.20, 0.51] 0.38

Verbal 0.13 [-0.18, 0.45] 0.4

Lee RS et al. J Affect Disord 2012;140:113-24

16

Age (many studies in

elderly patients)

Age at onset

Educational attainment

Baseline depression severity

MDD subtype

Psychiatric co-morbidity

Symptomatic status

(remission vs non-remission)

Medical co-morbidity

Illness duration

Episode frequency

Treatment

Childhood adversity

Methodological

factors that may

affect the

interpretation of

study outcomes

Limitations of study methodology as they pertain to

cognitive symptoms in MDD

Adapted from: McIntyre RS et al. Depress Anxiety 2013;30:515-27

18

● ‘Hot’ cognition

– Emotional processing; response to negative feedback

– Changes in the ‘hot’ system are more likely to be associated with

antidepressant response

● ‘Cold’ cognition

– Emotion-independent; logical thinking and executive control

(executive, attention, perception, and psychomotor functions)

‘Hot’ and ‘cold’ cognition

Schaefer A et al. Neuroimage 2003;18:938-49

19

DLPFC, dorsolateral prefrontal cortex;

PFC, prefrontal cortex; vmPFC, ventromedial prefrontal cortex

‘Hot’ cognition

Ventromedial prefrontal cortex is

associated with emotion-based

cognition, with associations to emotional

processing areas (eg amygdala)

Connectivity between PFC and

other brain regions

‘Cold’ cognition

Dorsolateral prefrontal cortex is

associated with non-emotional cognition, sensory,

and motor areas (eg basal ganglia and parietal cortex)

‘Hot’ and ‘cold’ cognition have different brain pathways

and connectivity

Wood JN, Grafman J. Nat Rev Neurosci 2003;4:139-47

Image provided by Roger McIntyre

Cingulate Hippocampal

formation

Parietal / occipital

visual-association

areas

Motor structures Dorsolateral

prefrontal cortex

Posterior parietal

heteromodal area

Amygdala

complex Ventromedial

prefrontal

cortex

Inferior temporal

visual association

areas

20

Table of contents

The burden of depression

Cognitive symptoms are common

Cognitive symptoms are

debilitating

21

Cognitive deficits are debilitating

22

Cognitive impairment is associated with

life-functioning disability

Life-function disability

Attention

Working memory

Ideation fluency / executive function

Verbal knowledge

Non-verbal

function

Learning

Motor

Jaeger J et al. Psychiatry Res 2006;145:39-48

23

Prevalence of cognitive symptoms in depressive

episodes and periods of remission

Conradi HJ et al. Psychol Med 2011;41:1165-74

Proportion of time with cognitive symptoms

Proportion of time without

cognitive symptoms

44%

Residual cognitive symptoms in between depressive episodes

Proportion of time with cognitive

symptoms

Proportion of time without

cognitive symptoms

94%

Cognitive symptoms during depressive episodes

24

Functional impairment in the last 30 days in patients who had an MDE in the

past 30 days, past 12 months, >12 months ago, and healthy controls

Cognitive impairment is a common problem

in MDD patients in the short and long term

Groups standardized for age, sex, and ethnicity; all scales were transformed to a scale of 0

(no impairment at any time) to 1.0 (completely impaired for the entire time)

*p<0.05 vs subjects with no history of MDD

CI, confidence interval; WHO-DAS, World Health Organization-Disability Assessment Scale Kessler RC et al. JAMA 2003;289:3095-105

Recency of MDD, mean score (95% CI)

WHO-DAS

domains

Past 30 days

(n=222)

Past 12 months

(n=399)

>12 months ago

(n=889)

No lifetime MDD

(n=4044)

Out of role 0.25 (0.17, 0.33)* 0.06 (0.02, 0.09)* 0.01 (0, 0.02) -0.01 (-0.02, 0)

Self-care 0.10 (0.04, 0.16)* 0.02 (0, 0.04) 0.01 (0, 0.02) 0 (-0.01, 0)

Mobility 0.17 (0.09, 0.25)* 0.02 (0, 0.05) 0.02 (0, 0.04) -0.01 (-0.02, 0)

Cognition 0.29 (0.22, 0.36)* 0.11 (0.07, 0.15)* 0.01 (0, 0.03) -0.01 (-0.002, -0.01)

Productivity 0.21 (0.15, 0.28)* 0.08 (0.04, 0.12)* 0.02 (0, 0.04) -0.01 (-0.02, 0)

Social 0.27 (0.20, 0.33)* 0.06 (0.02, 0.10)* 0.01 (0, 0.02) -0.01 (-0.02, 0)

25

Presence of residual cognitive symptoms during

depressive episodes and periods of remission

Mean proportion of time symptoms are present during

3-year follow-up period (n=267)

Conradi HJ et al. Psychol Med 2011;41:1165-74

1.00

0.80

0.60

0.40

0.20

Mea

n p

rop

ort

ion

of

tim

e D

SM

-IV

sym

pto

m c

luste

r is

pre

se

nt

0.00

Weeks of follow-up

Core symptoms: depressed mood / diminished interest

Cognitive problems

Lack of energy

Sleeping problems

Worthlessness / guilt

Eating problems

Psychomotor problems

Death ideations

DSM-IV, Diagnostic and Statistical Manual of

Mental Disorders, 4th edition

26

Cognitive deficits affect outcomes

Cognitive deficits in MDD are consistent, replicable, and

clinically significant

– Deficits in executive function occur in ~2030% of individuals

– Abnormalities are evident in working memory, attention, and

psychomotor processing speed

Cognitive deficits are a principal mediator of psychosocial

impairment (particularly workforce performance)

Pharmacological, behavioral, and neuromodulatory interventions

hold promise to reduce, reverse, and prevent cognitive deficits

McIntyre RS et al. Depress Anxiety 2013;30:515-27

27

Cognitive symptoms of MDD: impact on patient

Cognitive symptoms negatively affected all aspects of

the patient’s life, especially in the workplace

Work / school life

● Miss / forget deadlines

● Struggle to answer even simple questions

● Struggle to complete even simple tasks

● Loss of ability to focus on conversations and in meetings

● Often miss the point of what is being said to them

● Fear of under-performing

● Lose confidence in their abilities to function, second-guessing their

decisions and instincts at every turn

● Lose the ability to clearly communicate their thoughts and ideas

Social life

● Participation in conversations becomes challenging, causing them to withdraw

from social situations

● Forget important dates, memories, and plans

Family / personal life

● Unable to cope with daily household tasks

● Unable to fulfill their role in the family as spouse and / or parent

● Become frustrated and angry quickly, at times lashing out at others

McIntyre RS et al. Depress Anxiety 2013;30:515-27

28

MSIF, Multidimensional Scale of Independent Functioning

MDD patients 6 months post-hospital discharge1

Cognitive

impairments

were strongly

associated

with impaired

life functioning

at 6 months1-3

1. Jaeger J et al. Psychiatry Res 2006;145:39-48;

2. Greer TL et al. CNS Drugs 2010;24:267-84;

3. McIntyre RS et al. Depress Anxiety 2013;30:515-27

Cognitive symptoms can adversely affect life functioning

independent of improvement in depressive symptoms

12

10

8

6

4

2

0 0 2 3 4 5 6 7

No. part

icip

ants

MSIF score (1=normal functioning; 7=totally disabled)

29

Embarrassment

Mobility

Self-care

Cognition

Social Interaction

Discrimination

MDE

Participation

restriction

Cognition and

embarrassment were

the only determinants

significantly associated

with both MDEs and

work functioning

(participation restriction)

Arrows represent the associations between MDE and activity limitations (a1–a6) and the associations between

activity limitations and participation restrictions (b1–b6)

Mobility

Discrimination

Social

interaction

Self-care

MDE

Buist-Bouwman MA et al. Acta Psychiatr Scand 2008;118:451-8

Survey representative of the adult population in Belgium, France,

Germany, Italy, Netherlands, and Spain (n=21,425)

Cognition

Embarrassment

Cognitive symptoms in MDD mediate psychosocial

impairment in depression

30

Table of contents

The burden of depression

Cognitive symptoms are common

Cognitive symptoms are

debilitating

Cognitive symptoms are not well

treated

31

Cognitive symptoms are not well treated

32

1. Harvey PD. Psychiatry (Edgmont) 2009;6:23-5

Cognitive assessment

● Cognitive symptoms of depression can be assessed subjectively

and objectively by

– Self-report: complaints of cognitive deficits are common

– Clinician rating by interview or behavioral observation

– Wide variety of objective neuropsychological tests

● Subjectively reported symptoms and objectively measured

cognitive deficits are not consistent in MDD1

33

Assessing cognitive function using bedside tests

Common bedside tests to assess cognitive impairment

Not very sensitive for milder cognitive dysfunction seen in depression

Mini-mental state examination Montreal Cognitive Assessment

McIntyre RS et al. Depress. Anxiety 2013;30:515-27

34

Attention and processing speed:

Digit Symbol Substitution Test

● Asks you to match symbols with their corresponding digit as fast as possible

● There is also a speed of processing component, since you have a very small

amount of time to enter the correct symbol

● The score is the number of correct symbols drawn within 90 seconds for

a maximum score of 93

Hasselbalch BJ et al. J Affect Disord 2011;134:20-31

35

● Designed to assess immediate and delayed recall1

1. Lezak MD. Neuropsychological Assessment, 4th Edition, Chapter 11. Oxford University Press.

2. Hasselbalch BJ et al. J Affect Disord 2011;134:20-31

List Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 20-minute

delay

Yacht

Irony

Dummy

Shriek

Reflex

Bandit

Homicide

Hope

Stone

Event

Child

Speech

Moment

Friend

Property

“I am going to read you a list

of words. I want you to listen

carefully and, when I finish,

repeat back as many

words as you can”

Patients with

depression do

more poorly on

this test than

age-matched

comparisons2

Memory: RAVLT

36

Executive function: Trail-Making Test Part B

● The patient draws lines to

connect the circles in an

ascending pattern, but with the

added task of alternating

between the numbers and

letters (ie 1-A-2-B-3-C etc)

● Results are reported as the

number of seconds required to

complete the task; therefore,

higher scores reveal greater

impairment (executive

dysfunction)

Average: 75 seconds

Deficient: >273 seconds

Rule of thumb: most in 3 minutes

8

9

B

H

I

4

3

1 7

C

12 C

2 L

F K

5

J

A

6 E

11

10

D

37

Examples of self-rated cognitive questionnaires

● British Columbia Cognitive Complaints Inventory (BC-CCI)

● Cognitive and Physical Functioning Questionnaire (CPFQ)

● Perceived Deficits Questionnaire (PDQ)

● Medical Outcomes Study Cognitive Functioning

(MOS-Cog) scale

● Cognitive Dysfunction Questionnaire (CDQ)

● Cognitive Failures Questionnaire (CFQ)

● Prospective and Retrospective Memory

Questionnaire (PRMQ)

38

Perceived Deficits Questionnaire (PDQ)

● 20-item self-report assessing self-perceived cognitive difficulties

(5-item version also available)1

● 4 subscales and total score1

– Attention / concentration

– Retrospective memory

– Prospective memory

– Planning / organization

● Originally developed for multiple sclerosis1

● Qualitative testing (focus groups) in depression2

– Items considered understandable, appropriate, and comprehensive

– Preferred PDQ to other cognitive questionnaires

– Minor modifications suggested for PDQ-D

● Validated in an online study of depressed and non-depressed individuals3

1. Sullivan MJ et al. Pain Res Manage 2002;7:120-6;

2. Forsyth B et al. Eur Neuropsychopharmacol 2012;22(Suppl 2):S229-30;

3. Lam RW et al. Unpublished data

PDQ-D, Perceived Deficits Questionnaire – Depression

39

Perceived Deficits Questionnaire – Depression

5-item version (PDQ-D-5)

The following questions describe problems people may have with their memory,

attention, or concentration. Please select the best response based on your

experiences during the past 7 days

During the past 7 days, how often

did you…

Never in the

past

7 days

Rarely

(once or

twice)

Sometimes

(3 to 5 times)

Often

(about once

a day)

Very often

(more than

once a day)

Have trouble getting things

organized? 0 1 2 3 4

Have trouble concentrating on

what you were reading? 0 1 2 3 4

Forget the date unless you looked

it up? 0 1 2 3 4

Forget what you talked about after

a telephone conversation? 0 1 2 3 4

Feel like your mind went totally

blank? 0 1 2 3 4

Add up score in each column:

TOTAL SCORE: _________

40

Current treatments do not address cognitive

dysfunction

There is emerging evidence that, in some patients, the degree of cognitive deficit goes beyond that which can be accounted for by the severity of depressive symptoms

Current treatments (including SSRIs and SNRIs) have a partial or no effect on cognitive dysfunction in patients with MDD

In those with partial or full resolution of depressive symptoms, cognitive impairment may persist

Evidence is accumulating to support the view that, in subgroups of patients, cognitive deficits constitute a dimension of MDD that is independent of, and dissociable from, depressive symptomatology

Airaksinen E et al. Acta Psychiatr Scand 2007;115:458-65;

Behnken A et al. J Affect Disord 2010;122:144-8; Harvey P et al. J Psychiatr Res 2004;38:567-76;

Iverson GL et al. J Affect Disord 2011;132:360-7; Lee RS et al. J Affect Disord 2012;140:113-24;

McClintock SM et al. Neuropsychology 2010;24:9-34;

McDermott LM, Ebmeier KP. J Affect Disord 2009;119:1-8;

Reppermund S et al. Psychol Med 2009;39:603-14;

Naismith SL et al. J Clin Exp Neuropsychol 2003;25:866-77;

Weiland-Fiedler P et al. J Affect Disord 2004;82:253-8

SSRI, selective serotonin reuptake inhibitor;

SNRI, serotonin–noradrenaline reuptake inhibitor

41

Persistent symptoms in STAR*D responders

0

20

40

60

80

100

Mid-nocturnal

insomnia

Concentration /

decision-making

Suicidal ideation Negative self-view

Pa

tie

nts

(%

)

Baseline

Post-citalopram response

1. McClintock SM et al. J Clin Psychopharmacol 2011;31:180-6

Symptoms present in patients with MDD

who responded but did not remit (n=428)1

42

Cognitive dysfunction in depression

Clinically important1

Poor concentration (often described as poor memory) is a core symptom:

“mind going blank” and inability to make decisions

Often patients think they have attention-deficit disorder or, if older, Alzheimer’s disease

Deficits in almost every domain of cognitive functioning2

Processing speed

Attention

Executive function

Working memory

Episodic memory

1. Marazziti D et al. Eur J Pharmacol 2010;626:83-6;

2. Hasselbalch BJ et al. J Affect Disord 2011;134:20-31

43

Summary

• Cognitive deficit is an independent core symptom for the

diagnosis of MDD

• Present treatments have partial or no effect on cognitive

dysfunction in patients with MDD

• Residual cognitive dysfunction may be predictive for a

high risk of relapse and poor outcome for patients with

MDD

• There is the potential to greatly improve treatment to

target cognitive deficits in MDD

44

Take-home messages

● Cognitive dysfunction in MDD is prevalent, persistent, and identified

in symptomatic as well as ‘remitted’ patients

● Cognitive dysfunction can be defined according to domain affected

as well as ‘hot’ vs ‘cold’

● Cognitive dysfunction in MDD may predispose recurrence of illness

● In sub-populations, it is a principal mediator of functional impairment

● Clinicians are encouraged to “THINC” about cognitive impairment in

depression by evaluating patients for subjective complaint as well as

objective measurement