Alex MitchellLeicester (UK)Alex MitchellLeicester (UK)

XXXV SIN - Genova, Italy, 2004XXXV SIN - Genova, Italy, 2004Alex.mitchell@leicspart.nhs.uk

• In Neurology

Markus Reuber (Sheffield) Julian Benito-Leon (Madrid)

• In Psychiatry

RHS Mindham (Leeds) Trevor Friedman (Leicester)Harald Hampel (Munich) Pratibha Nirodi (Harrogate)

• Part I – Key Issues

FeaturesRecognitionAetiology

• Part II – Depression in Specific Conditions

BackgroundEvidence and guidelinesSpecial issues

Depressione

Apathy

Irritability& Anger

Mania &Hypomania

Emotionalism

Dysthymia& Chronic

Depression

Sub-syndromalDepression

Brief ReactiveDepression

Anxiety

Depressione

Apathy

Irritability& Anger

Mania &Hypomania

Emotionalism

Dysthymia& Chronic

Depression

Sub-syndromalDepression

Brief ReactiveDepression

Anxiety

Demenze

Morte

RISK

Depression Parkinson’s Disease Cancer

Motor System Psychomotor Retardation Bradykinesia RetardationReduced Blink Rate Mask-like Facies CachexiaStooped Posture Shuffling Gait Variable

Somatic Reduced Energy Reduced Energy Reduced EnergyFatigue Fatigue FatigueSleep Disturbance Sleep Disturbance Sleep DisturbanceWeight Loss Variable Weight Loss

Psychological Loss of Interest Variable VariablePoor Motivation Poor Motivation? VariableIndecisiveness Indecisiveness Variable

Cognitive Poor Concentration Poor Concentration Poor ConcentrationExecutive Deficits Executive Deficits VariableDepressive Pseudodementia Parkinson’s Dementia Variable

Symptoms in Primary vs Post-Stroke DepressionSymptoms in Primary vs Post-Stroke Depression

Symptom Clusters in 43 patients with PSD & 43 patients with functional depressionLipsey JR et al. (1986) Am. J. Psychiatry 143: 527

Common Neurological PresentationsCommon Neurological Presentations

• Headache• Alzheimer’s disease• Epilepsy• Tremor• Chronic Fatigue• Multiple Sclerosis• Parkinson’s disease• Head Injury• Stroke / Cerebrovascular disease

• After Warlow 2001

Common Neurological PresentationsCommon Neurological Presentations

• Headache• Alzheimer’s disease• Epilepsy• Tremor• Chronic Fatigue• Multiple Sclerosis• Parkinson’s disease• Head Injury• Stroke / Cerebrovascular disease

After Warlow 2001

CNS Disorder Depression (all types)

Cognitive Deficits

Dementia Psychosis

Alcohol 15% 80% 15% 5%

Epilepsy 20% Unknown rare 5%

Alzheimer’s disease 30% 100% 100% 30%

Head Injury 35% 3% Unknown 3%

HIV dementia 25% 40% 25% 6%

Huntington’s Disease 25% 40% Unknown 8%

Multiple Sclerosis 50% 50% 5% 10%

Parkinson’s Disease 50% 80% 30% 20%

Stroke 50% 50% 20% 5%

Subarachnoid Haemorrhage 20% 30% Unknown Unknown

Normal Control 10% 5% 2% 1%

Comorbidity

Hypertension

PostPost--StrokeStrokeDepressionDepression

Risk Factors Precipitants

Cardiovascular Anomaly

Degenerative Change

Trauma

SmokingLipids &Diet

CriticalCriticalAnatomicalAnatomical

LesionLesion

Exercise

Social

Comorbidity

Hypertension

PostPost--StrokeStrokeDepressionDepression

Neuromodulators

Anterior Frontal lobe

Medial Temporal lobe

Basal Ganglia

Risk Factors Precipitants

Cardiovascular Anomaly

FunctionalDisability

Pre-Existing Vulnerability

Final Common Final Common PathwayPathway

Degenerative Change

Trauma

SmokingLipids &Diet

NeurobiologicalMarkers

NeurologicalImpairment Neurophysiology

Neurotransmitters

Neuroendocrinology

Handicap(Quality of Life)

CriticalCriticalAnatomicalAnatomical

LesionLesion

Social Support

Life Events

Coping Style

Exercise

Social

Vicious Circle

Treatment of Post-Stroke DepressionTreatment of Post-Stroke Depression

Special Issues

• Ischaemic vs Haemorrhagic StrokeSSRIs

• Influence on rehabilitationNA vs Serotonin

• Influence on MortalityAntidepressantsOlanzapine and risperidone(Pettenati – XXXV SIN)

Individual Studies

• Placebo ControlledLipsey (1984) n = 34Reding et al (1986) n= 27Andersen et al (1994) n=66Grade et al (1998) n = 21

• Head-to-HeadLauritzen et al (1994) n = 20Dam et al (1996) n =52Robinson et al (2000) n = 56Jorge et al (2003) n=104

Jorge et al (2003) Am J PsychiatryN=104; 9 year follow upNortriptyline, fluoxetine, placebo (RCT

Depression and Prognosis of StrokeDepression and Prognosis of Stroke

626 Patients completed CES-D at one week post strokeDepression, age, medical illness & weakness correlated with functional outcome

J Neuropsychiatr Clin Neurosci 10, 26-33.

In 60 post-stroke rehabilitation patients, fluoxetine improved neurologicaldeficits at 3months compared with placebo and maprotiline

Stroke 27, 1211-1214.

In 91 stroke patients, depressed vs non-depressed were twice as likely todie over the next 10 years.

Am J Psychiatr 150, 124-129.

Treatment of Depression in EpilepsyTreatment of Depression in Epilepsy

Special Issues

• Seizure ThresholdMAOIsLow Dose TCAsSSRIs

ECT !

Individual Studies

• Placebo ControlledFew

• Head-to-HeadEdwards et al (2001) n=133Lamotrigine vs valproate

Edwards KR, Sackellares JC, Vuong A et al 2001 Lamotrigine monotherapy improves depressive symptoms in epilepsy: a double-blind comparison with valproate. Epil & Beh 2:28–36

Treatment of Depression in PDTreatment of Depression in PD

Special Issues

• Movement DisorderEg Paroxetine

PsychosisEg. memantine

Individual Studies

• Placebo ControlledMany!

• Head-to-HeadFew

Depression & Parkinson’s Disease - CorrelatesDepression & Parkinson’s Disease - Correlates

Higher rates of hallucinations, anxiety,cognitive impairment, somatic symptoms

Risk FactorsStage of illnessCognitive ImpairmentStigmaDisability

40% Recovery within one yearNo

Depression60%

MajorDepression

MinorDepression

MajorDepression

60%

NoDepression

10%

MinorDepression

30%Major

Depression10%

MinorDepression

30%

Starkstein et al (1992) JNNP 55, 377-382

Treatment of Head Injury and DepressionTreatment of Head Injury and Depression

Special Issues

• PCS vs Apathy

• Influence on rehabilitationNA vs Serotonin

• Seizures

Individual Studies

• Placebo ControlledMooney & Haas (1993) n= 38Methylphenidate

Wroblewski et al 1996) n=10

Head-to-Head

None

+10Se

verit

y

0

Disorientation & PTADepression & Irritability

Apathy

Post-ConcussionSyndrome

Time (weeks-months after head injury)

+10

Time (weeks-months after head injury)

Seve

rity

0

Post-ConcussionSyndrome Alone

Depression + PCS

Treatment of MS and DepressionTreatment of MS and Depression

Special Issues

• Interferon/Steroids

• Influence on rehabilitation?

• Cognitive Function/QoL

Individual Studies

Placebo ControlledSchiffer & Wineman (1990) n=28desipramine

Mohr et al (2000) n= 32CBT vs usual care

Head-to-Head

None

Treatment of Depression in ADTreatment of Depression in AD

Special Issues

• Stage of Disease

• Influence on prognosis

• Risk of AD in depression!

Individual Studies

Placebo ControlledNyth et al (1992)Volicer et al (1994)Olafsson et al (1992)Reifler et al (1989)Fuchs et al (1993)

Head-to-Head

None

The Natural History of Alzheimer’sThe Natural History of Alzheimer’s

PRE-SYMPTOMATICPRE-CLINICAL

CLINICAL

Pathological Burden

Dia

gnos

is

Dis

ease

Sev

erit

y

Time in YearsT0

T-5 T+10

T-10 T+5

Dea

th

(Bra

in V

olu

me

/ In

trac

ran

ial V

olu

me)

80%

85%

90%

75%

70%

Severe Dementia

Moderate Dementia

Mild Dementia

Mild Cognitive Impairment

23

30

20

12

Dia

gnos

is

Dea

th

No Depression

Depression

Modrego PJ & Ferrández,J. (2004). Depression in Patients With Mild Cognitive Impairment Increases the Risk of Developing Dementia of Alzheimer Type A Prospective Cohort Study . Arch Neurology 61:1290-1293.

Monastero et al (2004) XXXV SIN [Palermo]

Overview of Recommendations - CochraneOverview of Recommendations - Cochrane• The Cochrane Library, Issue 4, 2003 - Therapies for Depression in

Parkinson's Disease (updated 2003)

• The Cochrane Library, Issue 4, 2003 - Psychological treatments for epilepsy (2003 updated)

• The Cochrane Library, Issue 4, 2003 - Pharmacological management for agitation and aggression in people with acquired brain injury

• The Cochrane Library, Issue 4, 2003 - Cognitive behaviour therapy for chronic fatigue syndrome in adults

• The Cochrane Library Issue 2, 2004 - Pharmaceutical interventions for depression & emotionalism after stroke

• Protocol for a Cochrane Review (2003) - Psychological interventions for multiple sclerosis (Expected 2004)

• The Cochrane Library, Issue 4, 2003 - Antidepressants for depression in medical illness (updated 2002)

SNRIs

MilnicpramDuloxetine

NaSSA

Mirtazepine

NARI

ReboxetineAtomoxetine

m SSRIEscitalopram

Head-injury?

Pain?

Cancer?

Dementia?

SNRIs

MilnicpramDuloxetine

NaSSA

Mirtazepine

NARI

ReboxetineAtomoxetine

m SSRIEscitalopram

ExcitingNew Possibilities

• Depression in Physical Illness is CommonUnder-diagnosed

• The mechanisms underlying depressionAre poorly understoodComplex

• The Treatment of DepressionUse a CombinationAvoid TCAs

• The FutureBetter RCTsStudy physical outcomesBetter antidepressants

Global OutcomesPhysical + Somatic SympMortalityParticipation/Concord