Mood Disorders

Prof Allan Young

University of British Columbiaalyoung@interchange.ubc.ca

Lecture Outline

Types of mood disorders

Epidemiology, impact

Risk factors

Presentation and symptoms

Treatment

Neurobiology

Unipolar then Bipolar

Unipolar

Bipolar

“NORMAL” DEPRESSION

– e.g., Grief

Death of a loved one, separation/divorce, financial loss, retirement, leaving home, loss of a pet

Gradually lose capacity to evoke pain, but have fantasies of the loss

Typical functioning should return within 1 year, usually a few weeks or months

“Normal” depression is usually overdiagnosed

Important Aspects of Typology

Polarity: Unipolar vs Bipolar

Severity: hypomania vs mania

major vs minor depression

Subtyping: Melancholia; Psychotic

Course: Chronicity (2 years);

Rapid Cycling

Comorbidity: Schizoaffective; mixed anxiety depression

n.b., generally do not now type by antecedent events except for Post-natal depression; adjustment disorder

Diagnosis in Psychiatry

There are no diagnostic tests for mood disorders only diagnostic interviews

Diagnosis is based on identification of “symptoms” which cluster into “syndromes”

2 main classification systems:

USA DSM (IV): WHO ICD

Classification of Mood Disorders

Bipolar I

Bipolar II

Cyclothymia

Unipolarsingle episode

Unipolar-Hyperthymic

Dysthymia

UnipolarrecurrentUnipolar

Bipolar

Depression is Common

Major Depression (lifetime)-10% of men; 20% of women

Most common mental disorder in primary care

Three times more primary care visits

Higher rates of depressed patients in primary care offices

One-Month Prevalence Rates for Affective Disorders

Ustun & Sartorius, 1993Ustun & Sartorius, 1993

USAUSA5.2%5.2%

LondonLondon7%7%

EdinburghEdinburgh5.9%5.9%

AthensAthens7.4%7.4%

CanberraCanberra4.8%4.8%

WPA/PTD Educational Program on Depressive DisordersWPA/PTD Educational Program on Depressive Disorders

Depression is Significant

Impact on quality of life greater than most chronic medical diseases

Increases morbidity/mortality from co-existing medical conditions

Decreased work productivity

Suicide-7th leading cause of death in US; 70% have mood disorder

Costs over $44 billion yearly (1990)

Digestive disorder (6%)

Musculoskeletal disorders (4%)

Endocrine (4%)

Neuropsychiatricdisorders (28%)

Cancer (11%)Cardiovascular disease (22%)

Sense organ impairment(10%)

Othernon-communicable diseases (7%)

Respiratory disease (8%)

Schizophrenia

Bipolar disorder

Dementia

Substance-use and alcohol-use disorders

Other mental disorders

EpilepsyOther neurological disordersOther neuropsychiatric disorders

Depression

2%

10%

2%

2%

4%

3%

1%2%

3%

Prince et al 2007

Psychiatric Disorders: Underestimated and Disabling Conditions

Contribution (%) by different non-communicable diseases to disability-adjusted life-years worldwide in 2005

October 2009, CZ002663-SERO

Recognition and Treatment Problems

Up to 70% of depression is not recognized or treated

50% of treated patients stop medication within first 3 months

Medication often not used at dosage sufficient to give full remission

Pathway to Psychiatric Care(Goldberg & Huxley, 1980)

Pathway to Psychiatric Care(Goldberg & Huxley, 1980)

ConspicuousConspicuousMorbidityMorbidityLevel 3Level 3

Filter 2Filter 2

PsychiatricPsychiatricPatientsPatientsLevel 4Level 4

Filter 3Filter 3

Morbidity in theMorbidity in theCommunityCommunity

Morbidity in Morbidity in Primary CarePrimary Care

Level 1Level 1

Level 2Level 2

Filter 1Filter 1250250 (per 1000 per year)(per 1000 per year)

230230

140140

1717

Psychiatric Psychiatric In-patientsIn-patientsLevel 5Level 5

Filter 4Filter 4

66

Barriers to Recognition

Somatization-present with physical symptoms

Competing demands

Comorbidity-multiple problems

Stigma

Insurance

Reimbursement

Risk Factors For Mood Disorders

First degree relatives with mood disorders (at least 3 times higher)

Women twice as likely as men

Care taking responsibilities

Current or history of abuse, trauma

Stressful events, loss

DSM-IV Criteria For Major Depression

Four hallmarks, nine symptoms:

– depressed mood

– anhedonia (loss of interest/pleasure)

– four physical symptoms

– three psychological symptoms

For diagnosis-depressed mood or anhedonia & at least 5 of the 9 symptoms

Symptoms most of time for 2 weeks

Depressed Mood

Neither necessary nor sufficient for the diagnosis

Can be misleading

Don’t hang everything on the question “Are you depressed?”

Anhedonia

Loss of interest or pleasure in things that you normally enjoy

May be the most important and useful hallmark

Physical Symptoms

Sleep disturbance

Appetite or weight change

Low energy or fatigue

Psychomotor retardation or agitation

Psychological Symptoms

low self-esteem or guilt

Poor concentration

Suicidal ideation or persistent thoughts of death

Dysthymia

Long term problem with moderate symptoms

Depressed mood most of time for 2 years

Plus 2 other symptoms of depression

High level of chronic impairment

Increased risk for major depression

Bipolar Disorder

Episodes of mania or hypomania along with depressive episodes

Hypomania may be overlooked; patient may hide symptoms or not see as problem

Often misdiagnosed and managed as unipolar depression

Misdiagnosis of Bipolar Patients

Potential risks from antidepressants

– May induce mania or hypomania

– Can cause rapid cycling

Requires mood stabilizer (e.g. lithium or valproic acid) before brief use of antidepressant

Generally need psychiatry consultation or referral

Depression Treatment Psychotherapy

– Alone or as adjunctive therapy

Pharmacotherapy

– Effective for major depression and dysthymia

– Questionable effectiveness in minor depression

Primary care supportive counseling

– Important part of treatment

Evolution of Antidepressants

MAOIs 1950s

TCAs 1950s

Selective Drugs (SSRIs, NARIs, NDRIs) 1970s

SNRIs 1980s

Melatonin Agonists/5-HT Antagonists 2000s

Antidepressants

Tricyclics

MAO Inhibitors-rarely used now except by specialists

SSRIs: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)

Antidepressants

Other new agents (multiple actions)

– bupropion (Wellbutrin)

– mirtazapine (Remeron)

– venlafaxine (Effexor)

Dual action agents: SNRIs

More coming

Drug     Brand     Class     USA, 2007 Prescriptions (in millions)    

Sertraline Zoloft SSRI 29.652

Escitalopram Lexapro SSRI 27.023

Fluoxetine Prozac SSRI 22.266

Bupropion Wellbutrin NDRI 20.184

Paroxetine Paxil SSRI 18.141

Venlafaxine Effexor SNRI 17.200

Citalopram Celexa SSRI 16.246

Trazodone Desyrel SRI 15.473

Amitriptyline Elavil TCA 13.462

Duloxetine Cymbalta SNRI 12.551

Mirtazapine Remeron TeCA 5.129

Nortriptyline Pamelor TCA 3.105

Imipramine Tofranil TCA 1.524

STAR*D Project ResultsSTAR*D Project Results

Level n Remission (%)

QIDS-SR ≤5

Cumulative Remission (%)

1 3,671

2 1,439

3 390

4 123

Warden D, et al. Curr Psychiatry Rep. 2007;9:449–459.

37%

31%14%

13%

37%

56%62%

67%

QIDS-SR = Quick inventory of depressive symptomatology – self report.

First-line Antidepressants with Evidence for Superior Efficacy Against Comparators

Antidepressant Comparator(s)Level of evidence

Duloxetine Paroxetine; pooled SSRIs 2

EscitalopramCitalopram; duloxetine; paroxetine; pooled SSRIs

1

Mirtazapine Trazodone 2

Sertraline Fluoxetine; pooled SSRIs 1

VenlafaxineDuloxetine; fluoxetine; pooled SSRIs

1

Lam RW, et al. J Affect Disord 2009; 117 Suppl 1:S26-S43. Lam RW, et al. J Affect Disord 2009; 117 Suppl 1:S26-S43.

Efficacy and Acceptability of Antidepressants:A Multiple-Treatments Meta-analysis

Trials published between 1991 and 2007 (117 trials), including 25,928 patients

Direct and indirect comparisons of 12 second generation antidepressants

Main outcomes:

Meta-analysis was not funded by industry

Efficacy (response rates)

Acceptability (early termination for any reason)

Cipriani et al. Lancet. 2009; 373(9665):746-58.

Multiple-Treatments Meta-analysis of 12 Second-Generation Antidepressants

FLUOXETINE

Bupropion

Citalopram

Sertraline

Escitalopram

MirtazapineVenlafaxine

Paroxetine

Duloxetine

l

0.8l

0.9l

1.0l

1.1l

1.2l

1.3l

1.4

0.80 –

0.85 –

0.90 –

0.95 –

1.00 –

1.05 –

1.10 –

1.15 –

1.20 –

1.25 –

Efficacy (OR)

Accep

tab

ilit

y (

OR

)

Fluvoxamine

Adapted from Cipriani et al. Lancet. 2009; 373(9665):746-58.

32.932.9%%

6.0%6.0%

29.0%29.0%

1.0%1.0%0%0%

5%5%

10%10%

15%15%

20%20%

25%25%

30%30%

35%35%

TCAsTCAs SSRIsSSRIs

UK-DINLINK*UK-DINLINK*

MacDonald**MacDonald**

Rates of Adequate Dose and Duration

Adequate Dose and Duration: At least 90-120 daysAdequate Dose and Duration: At least 90-120 daysat recommended doses within first six monthsat recommended doses within first six months

*Dunn et. al. *Dunn et. al. J PsychopharmacologyJ Psychopharmacology, 1999., 1999.**MacDonald**MacDonald et. al. et. al. Primary Care Psychiatry, Primary Care Psychiatry, 1997;3(1 Suppl):S7-S101997;3(1 Suppl):S7-S10

Possible Increased Risk of Suicide

FDA Public Health Advisory March, 2004: possible risk of worsening depression and suicidality in patients taking antidepressants

Done in reaction to reports of suicidal ideation and attempts in treatment of major depression in pediatric patients.

Black box warning for children / adolescents September, 2004

Simon et al, 2006 changed our view of things

Suicide risk during antidepressant treatment.

Simon et al AMJPsych, 2006 Jan;163(1):41-7. Population-based data to evaluate the risk of suicide death and serious suicide

attempt in relation to initiation of antidepressant treatment.

METHOD: 65,103 patients with 82,285 episodes of antidepressant treatment between Jan. 1, 1992, and June 30, 2003.

RESULTS: 31 suicide deaths (40 per 100,000 treatment episodes) and 76 serious suicide attempts (93 per 100,000) were identified in the study group.

The risk of suicide attempt was 314 per 100,000 in children and adolescents, compared to 78 per 100,000 in adults. The risk of death by suicide was not significantly higher in the month after starting medication than in subsequent months.

The risk of suicide attempt was highest in the month before starting antidepressant treatment and declined progressively after starting medication.

An increase in risk after starting treatment was seen only for the older drugs.

CONCLUSIONS: The risk of suicide during acute-phase antidepressant treatment is approximately one in 3,000 treatment episodes, and risk of serious suicide attempt is approximately one in 1,000.

Available data do not indicate a significant increase in risk of suicide or serious suicide attempt after starting treatment with newer antidepressant drugs.

Summary of Main Points

Mood disorders very common, have major impact

Important to be able to distinguish specific mood disorder-affects treatment, prognosis, course

Many patients not diagnosed or, if diagnosed, not treated at adequate dosage or long enough

ECTKellner et al, British Journal of Psychiatry (2010) 196: 226-234.

RCT of 230 individuals treated with ECT for depression

Overall remission rate with ECT in the intention-to-treat analysis was 60%.

When ECT is used to treat unipolar major depression that has already failed to remit with vigorous antidepressant treatment, then the remission rate is still about 50%.

The patients in the present study had already been ill for an average of 2.4 years.

Copyright © 2010 The Royal College of Psychiatrists

Kellner, C. H. et al. The British Journal of Psychiatry 2010;196:226-234

Fig. 2 Observed Hamilton Rating Scale for Depression-24 (HRSD-24) total score means.

Copyright © 2010 The Royal College of Psychiatrists

Kellner, C. H. et al. The British Journal of Psychiatry 2010;196:226-234

Fig. 4 95% CI estimates of remission proportions for bitemporal (BT), bifrontal (BF) and right unilateral (RUL) electrode placements.

The Spectrum of Bipolar Disorders

Mania

Hypomania

Depression

NormalMood

Variation

Normal

Goodwin FK, Jamison KR. Manic-Depressive Illness; 1990.

CyclothymicPersonality

CyclothymicDisorder

Bipolar IIDisorder

UnipolarMania

Bipolar IDisorder

SevereDepression

Classification of Mood Disorders

Bipolar I

Bipolar II

Cyclothymia

Unipolarsingle episode

Unipolar-Hyperthymic

Dysthymia

UnipolarrecurrentUnipolar

Bipolar

Bipolar Disorder: Clinical Features

At least 1 episode of mania or hypomania or a mixed episode

Usually associated with episodes of major depression

Cyclic change between mood states

In severe episodes of mania and depression, psychotic symptoms may also be present

Bipolar DisorderManic Depressive Illness

Mania

– Elevated or irritable mood

– Grandiosity

– Decreased need for sleep

– Increased or pressured speech

– Flight of ideas or racing thoughts

– Increased goal directed activity

– Risk taking

– Functional impairment

Depression

– Low mood

– Loss of interest or pleasure

– Change in appetite or weight

– Insomnia or hypersomnia

– Fatigue

– Feelings of worthlessness

– Impaired memory or concentration

– Suicidality

– Clinically significant distress or impairment

SYMPTOMS OF MANIA (3+)– Symptoms last at least 1 week

– Abnormally & persistently elevated/expansive/ irritable mood

– Inflated self-esteem, grandiosity

– Decreased need for sleep

– More talkative than usual

– Flight of ideas

– Distractibility

– Increase in goal-directed activity, or psychomotor agitation

– Excessive involvement in pleasurable activities that have high risk of painful consequences

– Accelerated & pressured speech/disjointed

SYMPTOMS OF HYPOMANIA (3+)– Sustained, elevated, expansive, or irritable

mood, lasting 4 days

– Same symptoms as mania, but less severe

DiagnosesNumber of

Studies Range of Rates

Bipolar I 21 0.0-2.4Bipolar II 11 0.3-3.0Cyclothymia 5 0.5-2.8

Spectrum 11 2.6-7.8-(10.8)

Hypomania 2 2.2-5.7

Summary of Prevalence Rates

Relationship Between Cycle Length and Number of Episodes of Bipolar Disorder

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11

Kraepelin, 1921Zis et al, 1980Angst, 1981Roy-Byrne et al, 1985

Episode

Cyc

le L

engt

h (M

onth

s)

Rate of relapse leading to hospitalisation:Bipolar disorder

Kessing et al. Br J Psych 2004

Rate of relapse leading to hospitalisation (after being discharged for at least 3 days) following first, second, third, fourth and fifth discharges

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Cu

mu

lati

ve s

urv

ival

00 11 22 33 44 55 66 77Time to relapse (years)

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Cu

mu

lati

ve s

urv

ival

00 11 22 33 44 55 66 77Time to relapse (years)

Men Women

Time 1Time 1

Time 2Time 2Time 5Time 5

Time 3Time 3

Time 4Time 4

Time 1Time 1

Time 2Time 2

Time 3Time 3

Time 4Time 4

Time 5Time 5

Early Prospective Findings > 2000 patient-years

Among those who achieve recovery

5% relapse each month.

80% of relapses = Depression

Psychiatric hospitalization = 14.2 /100 pt-yrs

Mortality = 0.11/100 pt-yrs (9 deaths including 2 suicides )

S

T

EP

BB

DD

57%

9%

32%

2%

47%

1%

50%

2%

BP II, Judd et al 2003, n=86, m=13.4 years

Patients are symptomatic for almost half of the time they are ill

No symptoms

DepressiveManic / hypomanic

Mixed / rapid cycling

BP I, Judd et al 2002, n=146, m=12.8 years

45%

13%

36%

6%

BP I, Kupka et al 2004, n=392, m=1 year

BP II, Kupka et al 2004, n=98, m=1 year

53%32%

9%6%

Natural History of Bipolar

Early onset

Lifelong high risk of recurrence

High rates of Depression

Frequent biphasic symptomatology

Low rates of fully sustained recovery

High rates of incomplete remission

Considerable chronicity

Considerable suicide risk

Natural History

The recurrence risk of bipolar I and bipolar II disorders is constant over decades

The suicide risk is 15–20-fold higher than in the general population

The suicide risk persists over decades

Lifetime Comorbidity With BPI Disorder Disorder Prevalence (%) Odds Ratio

Generalised anxiety disorder Social phobia Panic disorder PTSD Any anxiety disorder Alcohol dependence Drug dependence Any substance use disorder Dysthymia Conduct disorder

42.4 47.1 32.9 38.7 93.0 61.2 40.6 71.1 49.7 59.5

14.0* 5.9*

14.0* 8.9*

34.8* 9.8* 8.6* 6.9*

14.9* 10.0*

Dual Diagnosis: High Prevalence of Comorbid Psychiatric Disorders

*p<.05.Kessler RC. In: Tohen M, ed. Comorbidity in Affective Disorders; 1999:1-26.

Long term outcome

In the Zurich study, long-term medication reduced suicides by about 2/3 in both bipolar and unipolar disorders

Unipolar and bipolar patients showed elevated cardiovascular mortality; this mortality was also significantly reduced among treated patients

Bipolar Disorder: Untreated vs TreatedStandardized Mortality Ratios

Neoplasm Cardio-vascular

Cerebro-vascular

Accidents Suicide Other All Causes

UntreatedTreated

29.2*

6.4

1.4*0.6

2.2*1.7 1.6†

1.3 1.62.0 2.0*1.3

2.2*1.3

* p< 0.001 † p< 0.05

Zurich Cohort, n=4061959-1997

Adapted from

Angst, 2000

Phases of treating Bipolar Disorder

Acute episodes continue until symptomatic remission

Acute phase of recovery lasts for a further two months

Continuation phase lasts to month six following recovery

Maintenance phase follows this

Ghaemi, 2004

A. Long-term effective A. Long-term effective antimanic drugsantimanic drugs

A. Long-term effective A. Long-term effective antimanic drugsantimanic drugs

Acute PhaseAcute PhaseAcute PhaseAcute Phase Maintenance PhaseMaintenance PhaseMaintenance PhaseMaintenance Phase

C. PsychoeducationC. Psychoeducation

Treatment

B. Long-term effective B. Long-term effective antidepressant drugsantidepressant drugsB. Long-term effective B. Long-term effective antidepressant drugsantidepressant drugs

A vast array of treatment optionsexist for bipolar disorder

Traditionaltreatments

Lithium

Divalproex

Carbamazepine

QuetiapineOlanzapineRisperidoneZiprasidone AripiprazoleClozapine

Haloperidol

Antipsychotics

Citalopram

Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

Bupropion

Venlafaxine

Nefadozone

Antidepressants

New anticonvulsants

Lamotrigine

Meta-analysis of lithium maintenance- RCTs of prevention of any relapse

Lithium was more effective than placebo in preventing any new episodes of mood disturbance. The average risk of relapse in the placebo group was 60% compared with 40% for lithium. This means that one patient would avoid relapse for every five patients who were treated for a year or 2 with lithium.

Geddes et al, 2004

.010061 1 99.398

Risk ratio (95% CI)

No. of events Control Treat.

0.43 (0.02, 10.21) Bowden 2003 1 / 59 0 / 46

0.19 (0.01, 3.48) Coppen 1971 3 / 37 0 / 28

0.31 (0.01, 7.44) Dorus 1989 1 / 82 0 / 89

0.44 (0.04, 4.69) Glen 1984 2 / 50 1 / 57

0.34 (0.01, 8.14) Greil 1996 1 / 41 0 / 40

0.17 (0.02, 1.37) Greil 1997a 6 / 88 1 / 87

0.22 (0.03, 1.85) Greil 1997b 5 / 58 1 / 52

3.00 (0.15, 61.74) Hardy 1997 0 / 6 1 / 6

0.33 (0.01, 8.10) Lamictal Study 605a 1 / 121 0 / 121

0.47 (0.02, 11.44) Lamictal Study 605aa 1 / 171 0 / 121

0.42 (0.04, 4.48) Prien 1973a 2 / 38 1 / 45

0.43 (0.04, 4.60) Prien 1973aa 2 / 39 1 / 45

0.51 (0.05, 5.59) Prien 1973b 2 / 104 1 / 101

0.35 (0.18, 0.71) Overall (95% CI)

Relative risk – fixed effectDEATHS + DSH Composite outcome

Cipriani A et al,AmJ Psychiatry. 2005 Oct;162(10):1805-19;Baldessarini Rj et al, Bipolar Disord. 2006 Oct;8(5 Pt 2):625-39.

RCT

Suicide risk in bipolar disorder during treatment with lithium and divalproex

Frederick K. Goodwin

Among patients treated for bipolar disorder, risk of suicide attempt and suicide death is lower during treatment with lithium than during treatment with divalproex

HippocampusAmygdala

Cingulate cortex

Neurobiology of Depression

Neurobiology of long term treatment

Moorel et al Lancet 2000

Causal factors in Bipolar Disorder

Genes

• 8-9% of 1st-degree relatives can be expected to have Bipolar Disorder

• MZ = 72-80% DZ = 14%

• Probably multiple genes of small effectBiochemical

• Neurotransmitter levels (norephinephrine, serotonin, dopamine

Psychosocial

• Stressful life events might trigger an episode of either depression or mania

Genes Summary

Genes explain about 60% of the cause of mood disorders

Family members are about 7 times more likely to also have bipolar disorder

Many genes are involved

Common Genes for Bipolar Disorder and Schizophrenia

1 2 3 4 5 6 7 8 9 10 11

12 13 14 15 16 17 18 19 20 21 22 X Y

Bipolar

Schizophrenia

Genes and environment

Gene subset CPathophysiology C

Gene subset APathophysiology A

Gene subset BPathophysiology B

Final Commonpathway

Disease

Environment

Serotonin pathways

Raphe Nucleus

Sleep

Appetite

Sexual activity

Stress response

Anxiety

? Mood

Noradrenaline Pathways

Locus Coeruleus

Sleep

Attention and concentration

Energy

Stress response

? Mood

5-HT/NA Interactions

brake

accelerator

Raphe and LC

Role of 5-HT in mood regulation

Acute tryptophan depletion (ATD)

Little or no effect on mood in healthy subjects (Abbott et al. 1992; Oldman et al. 1994; McAllister-Williams et al. 2003)

Leads to depression in vulnerable groups

Subjects with strong family history (Benkelfat et al. 1994; Klassen et al. 1999)

Euthymic subjects with a history of recurrent depression (Smith et al. 1997; Moreno et al. 1999)

Evidence for a role of 5-HT/NA in depression

Noradrenergic systems

Few consistent findings

Density and affinity of α2-adrenoceptors increased in depressed patients at PM (Meana et al. 1992; Callado et al. 1998)

Serotonergic system

Most consistent findings concern

5-HT1A receptors

Postsynaptic 5-HT1A receptors and depression

Function:

Prolactin and growth hormone responses to intravenous l-tryptophan

Blunted responses in depressed subjects in 5 studies (Power and Cowen, 1992)

State dependent finding (Upadyaya et al. 1991)

Number of receptors:

PET scanning of WAY-100635 binding

10-30% decrease binding sites (Sargent et al. 2000; Drevets et al. 2000)

? Trait marker

Somatodendritic 5-HT1A autoreceptors and depression

Reduced numbers of receptors (Sargent et al. 2000, Drevets et al. 2000)

5-HT1A receptor polymorphism (Albert et al. 2004)

Increased number of receptors in antidepressant naïve patients (Parsey et al. 2005)

? Changes in function

Somatodendritic 5-HT1A receptor function in depression

(McAllister-Williams et al. 2004)

5-HT Neuronal control points

1A

Somatodendritic autoreceptor (5-HT1A)

1D

Terminalautoreceptor (5-HT1D)

5-HTraphecell

post-synapticcell

1A

2A

Postsynaptic 5-HT receptors (e.g. 5-HT1A or 5-HT2A)

Terminal heteroceptor (2)

Postsynaptic NA receptors (1)

1

Decreased Postsynaptic 5-HT1A number and function in depression

? Increased Somatodendritic 5-HT1A and α2-adrenoceptor number or function in depression

Pathogenesis

FoetusFoetus

ChildChild

AdultAdult

Older personOlder person

Illness

Genes

SocialEnvironment

Stress

Psychological

Social

Somatic

Circadian

Stress

GR PVN

GR Pituitary

Adrenals

CRHAVP

ACTH

CORT

GRs MRs

GR/MR

Hippocampus

-ve-ve

-ve

GR/MR mediated-ve feedback

HPA Axis

Cortisol in Depression

Cortisol response on dex / CRH testWatson et al, 2002, 2004.

0

10

20

30

40

50

60

70

80

Co

rtis

ol r

esp

on

se

controlschronic depressed euthymic bipolars Bipolar depressed

CRH

Dexamethasone

pretreatment

HPA axis and depression

HPA axis involved with stress response

50% + of depressives hypercortisolaemic ; 90% have evidence of HPA hyperactivity

Depressed patients also have:

raised CRH levels in CSF

enlarged pituitary glands

enlarged adrenal glands

? Abnormality in depression is impaired feedback

Foetal/infant stress in animals produces long lasting effects on HPA axis responsivity

? Mechanism for social adversity predisposing to depression

What is wrong with the HPA in depression?

Hypercortisolaemia resulting from

CRH hypersecretion (possible AVP involvement)

which may result from corticosteroid receptor down-regulation and thus impaired negative feedback (see Sapolsky et al, 1986)

Is the core abnormality at the corticosteroid receptor level?

The Glucocorticoid Receptor in Mood Disorders

The GR receptor is reduced in frontal and hippocampal regions in unipolar and bipolar brains

Antidepressants, Lithium and ECS increase brain GR receptor number in experimental animals

This effect occurs in vitro and may be independent of effects on monoamines

DEPRESSION

SerotoninSystem

Hypothalo-Pituitary

Adrenal Axis

Corticosterone 5-HT1A receptors

0

10

20

-60 0 60 120 180 240

Time (min)

5-H

T (

fmol

/sam

ple)

sham/fluoxetine

cort/fluoxetine

Cort treatment attenuates ability of SSRI to elevate of forebrain 5-HTGartside, Leitch and Young, Neuropsychopharmacology, 2003.

Local fluoxetine

Systemic fluoxetine

HAMD-21 scores for the metyrapone group (solid circles) and the placebo group (open circles) for days 0, 3, 7, 14, 21, 28, and 35 on the intention-to-treat sample.

Data are presented as mean±SEM.

Jahn, H. et al (2004) Metyrapone as Additive Treatment in Major Depression: A Double-blind and Placebo-Controlled Trial. Archives of General Psychiatry, 61, 1235-1244.

Cortisol Synthesis Inhibition boosts Antidepressant Effects

Conclusions Types of mood disorders: a group of illnesses

Mood Disorders are a leading cause of ill-health world wide

Effective Treatments, both psychological and physical exist

Neurobiology is unknown, however the following are important:

- Genes; probably multiple genes of small effect

- Neurotransmitters; important for MOA of drugs

- HPA axis; potentially provides an integrated of pathophysiology and new treatment

options