Mood Disorders

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Mood Disorders

• Prof Allan Young
• University of British Columbiaalyoung_at_interchange
  .ubc.ca

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Lecture Outline

• Types of mood disorders
• Epidemiology, impact
• Risk factors
• Presentation and symptoms
• Treatment
• Neurobiology
• Unipolar then Bipolar

3

• Unipolar
• Bipolar

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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

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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

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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

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Classification of Mood Disorders
Unipolar single episode
Unipolar recurrent
Unipolar
Dysthymia
Bipolar I
Bipolar II
Bipolar
Cyclothymia
Unipolar- Hyperthymic
8
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

9
One-Month Prevalence Rates for Affective Disorders
Edinburgh5.9
London7
Athens7.4
USA5.2
Canberra4.8
WPA/PTD Educational Program on Depressive
Disorders
Ustun Sartorius, 1993
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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)

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The Burden of Disease Leading causes of
disability worldwide, 1990, in years of
life lived with disability
Murray CJL, Lopez AD. The global burden of
disease. Cambridge, MA Harvard University
Press, 1996
12
Recognition and Treatment Problems

• 30-70 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

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Pathway to Psychiatric Care(Goldberg Huxley,
1980)
230
140
17
14
Barriers to Recognition

• Somatization-present with physical symptoms
• Competing demands
• Comorbidity-multiple problems
• Stigma
• Insurance
• Reimbursement

15
Diagnostic and Monitoring Tools

• Depression diagnostic tools may aid in initial
  diagnosis and tracking response
• PHQ-9 recommended by many organizations
• Important for practices to have some sort of
  system in place for monitoring

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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

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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

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• SYMPTOMS OF DEPRESSION
• Depressed mood most of the day, nearly every day
• Markedly diminished interest/pleasure in
  all/almost all activities
• Significant weight loss/gain when not dieting, or
  decrease/increase in appetite
• Insomnia/hypersomnia
• Psychomotor agitation/retardation
• Fatigue/loss of energy
• Feel worthless or excessive/inappropriate guilt
• Diminished ability to think/concentrate or
  indecisiveness
• Recurrent thoughts of death

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Depressed Mood

• Neither necessary nor sufficient for the
  diagnosis
• Can be misleading
• Dont hang everything on the question Are you
  depressed?

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Anhedonia

• Loss of interest or pleasure in things that you
  normally enjoy
• May be the most important and useful hallmark

21
Physical Symptoms

• Sleep disturbance
• Appetite or weight change
• Low energy or fatigue
• Psychomotor retardation or agitation

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Psychological Symptoms

• low self-esteem or guilt
• Poor concentration
• Suicidal ideation or persistent thoughts of death

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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

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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

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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

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Minor Depression

• Fewer symptoms than major depression
• Shorter duration than chronic depression
• Significant disability
• Best management probably watchful waiting with
  regular follow-up
• Proceed with pharmacologic treatment or
  psychotherapy if symptoms persistent or worsening

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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

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Antidepressants

• Tricyclics
• MAO Inhibitors-rarely used by primary care
  physicians
• SSRIs citalopram (Celexa), escitalopram
  (Lexapro), fluoxetine (Prozac), paroxetine
  (Paxil), sertraline (Zoloft)

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Antidepressants

• Other new agents (multiple actions)
• bupropion (Wellbutrin)
• mirtazapine (Remeron)
• venlafaxine (Effexor)
• Dual action agents SNRIs
• More coming

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Tricyclic Antidepressants

• As effective as newer agents
• Side effects potentially more dangerous
• Cheaper-especially generic forms
• May be good for selected patients
• Start with low dose, titrate q 3-7 days

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Advantages of SSRIs and Other New Agents

• As effective
• Safety better
• Increased patient satisfaction
• Improved adherence to therapy
• Adherence issues especially important in long
  term maintenance therapy

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Suggested Medication Algorithm

• If decision to use medication - usually start
  with SSRI
• If patient elderly or has comorbid panic or
  anxiety-start low, titrate slowly
• Assess after one week then every few weeks
• Titrate dose for total remission

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Rates of Adequate Dose and Duration
Adequate Dose and Duration At least 90-120
days at recommended doses within first six months
32.9
35
29.0
30
25
20
UK-DINLINK
MacDonald
15
10
6.0
5
1.0
0
TCAs
SSRIs
Dunn et. al. J Psychopharmacology,
1999. MacDonald et. al. Primary Care
Psychiatry, 19973(1 Suppl)S7-S10
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Norwegian Study (Malt et al BMJ, 3181180)

• A study of emotional support and counselling
  combined with placebo or antidepressants in GP in
  Norway
• Randomised, double-blind study (n372)
• main outcome measures were 50 reduction in
  MADRS, CGI rating of mild illness and CGI rating
  of much improved

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Norwegian Study -2

• Organised psychotherapy (ie CBT, IPT not
  permitted)
• GPs instructed to convey a sense of hope and
  optimism and to give simple suggestions such as
  increasing physical activity
• In addition patients received Sertraline,
  Mianserin or placebo

36
Norwegian Study-3

• Intention to treat analyses showed
• 47 response to placebo
• 54 response to Mianserin
• 61 response to Sertraline
• Sertraline v Placebo significant, Mianserin not
• Placebo drop out 29 (S16, M14)

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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

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Suicide risk during antidepressant
treatment.Simon et al AMJPsych, 2006
Jan163(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.

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FDA Public Health Advisory

• Points out the need to closely monitor patients
  receiving antidepressants for worsening and
  suicidality especially at beginning of treatment
  and with changes in dosage
• Also need to instruct patients and families to be
  alert for worsening or suicidal thoughts and to
  immediately report such symptoms

46
Severity Tools

• Depression diagnostic tools may be useful for
  tracking response to treatment
• Depression module of PHQ-9 recommended by many
  organizations
• Use before treatment, then each visit

47
Partial or No Response

• At adequate dose, should see response by 4 weeks
• Check for adherence
• Re-evaluate diagnosis
• Adjust dosage if some response or if started low
• Change medication if no response
• Add formal psychotherapy
• Psychiatric consultation

48
Promoting Adherence

• Shared decision making
• Inquire into prior use of antidepressants
• Explain that it may take 2 to 4 weeks for
  therapeutic response, longer for full effect
• Discuss most common side effects
• Advise patients to continue medication even if
  they feel better
• Explain risk of stopping too soon

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Follow Up

• Close follow up by telephone and or visits until
  stable
• Severity tool (PHQ-9) to assess progress
• Titrate dose for total remission
• Maintain effective dose for 6 to 9 months
  (continuation phase)
• Monitor for early signs of recurrence
• Consider maintenance therapy

50
Managing SSRI Side Effects

• Agitation/Insomnia
• Rule out bipolar
• Use adjunctive sedating agent
• Switch to mirtazapine
• Sexual dysfunction
• Switch to bupropion, mirtazapine,
• Add sildenafil in men

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Managing SSRI Side Effects (cont)

• Sedation
• Give medication at bedtime or switch to bupropion
• GI distress
• Give medication after meals
• Antacid, H2 blocker
• Dry mouth-hard candy, liquids

52
Side Effects-Other New Agents

• Bupropion-agitation, headache, lowered seizure
  threshold
• Mirtazapine-sedation, weight gain
• Venlafaxine-GI distress, elevated BP

53
Psychiatric Referral

• Needed when
• bipolar disorder
• suicidality
• questions about diagnosis
• Co-morbid psychiatric conditions
• lack of response to treatment

54
Non-Pharmacologic Interventions by PCP

• Watchful waiting for mild episode
• Physician support and office counseling
• Active listening
• Advice, giving perspective
• Focus on solutions
• Focus on coping strategies (exercise, pleasurable
  activities, and other aspects of self management)

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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

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Summary of Main Points

• Psychotherapy, various medications can be
  effective
• SSRI common first line therapy
• Partnership among physician, patient, family,
  office staff, mental health professionals
  important

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The Spectrum of Bipolar Disorders
Mania
Hypomania
Normal
Depression
SevereDepression
NormalMoodVariation
CyclothymicPersonality
CyclothymicDisorder
Bipolar IIDisorder
UnipolarMania
Bipolar IDisorder
Goodwin FK, Jamison KR. Manic-Depressive Illness
1990.
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Classification of Mood Disorders
Unipolar single episode
Unipolar recurrent
Unipolar
Dysthymia
Bipolar I
Bipolar II
Bipolar
Cyclothymia
Unipolar- Hyperthymic
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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

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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

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• 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

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• SYMPTOMS OF HYPOMANIA (3)
• Sustained, elevated, expansive, or irritable
  mood, lasting 4 days
• Same symptoms as mania, but less severe

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Summary of Prevalence Rates
Number ofStudies
Diagnoses
Range of Rates
Bipolar I
21
0.0-2.4
Bipolar II
11
0.3-3.0
Cyclothymia
5
0.5-2.8
Hypomania
2
2.2-5.7
Spectrum
11
2.6-7.8-(10.8)
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Relationship Between Cycle Length and Number of
Episodes of Bipolar Disorder
Cycle Length (Months)
Episode
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Rate of relapse leading to hospitalisationBipola
r disorder
1.0
1.0
Men
Women
0.8
0.8
0.6
0.6
Cumulative survival
Cumulative survival
Time 1
Time 1
Time 2
0.4
0.4
Time 4
Time 2
Time 5
Time 5
Time 3
0.2
0.2
Time 3
Time 4
0.0
0.0
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
Time to relapse (years)
Time to relapse (years)

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

Kessing et al. Br J Psych 2004
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Bipolar I vs Bipolar II Recurrences
Cumulative Intensity
Time since First Episode (Years)
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Constant risk of relapse over 40yrs
0.4episodes/year
Angst et al. Eur Arch Psychiatry Clin Neurosci.
2003
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Early Prospective Findings gt 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 )

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57 switch or relapse within first 4 years
Tohen et al. Am J Psychiatry. 2003
72
Patients are symptomatic for almost half of the
time they are ill
6
No symptoms
9
Manic / hypomanic
Depressive
Mixed / rapid cycling
53
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BP I, Judd et al 2002, n146, m12.8 years
BP II, Kupka et al 2004, n98, m1 year
BP II, Judd et al 2003, n86, m13.4 years
BP I, Kupka et al 2004, n392, m1 year
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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

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Natural History

• The recurrence risk of bipolar I and bipolar II
  disorders is constant over decades
• The suicide risk is 1520-fold higher than in the
  general population
• The suicide risk persists over decades

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Dual Diagnosis High Prevalence of Comorbid
Psychiatric Disorders
Cookson SADAD2001
plt.05. Kessler RC. In Tohen M, ed. Comorbidity
in Affective Disorders 19991-26.
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Effect of Long-Term Medicationon Suicide Rates
(Zurich data)
of Suicide Rates
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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

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Bipolar Disorder Untreated vs TreatedStandardize
d Mortality Ratios
29.2
Adapted from Angst, 2000
Zurich Cohort, n406 1959-1997
plt 0.001 plt 0.05
Untreated
Treated
6.4
2.2
1.6
2.0
2.2
1.4
1.7
2.0
1.6
1.3
1.3
1.3
0.6
All Causes
Neoplasm
Accidents
Suicide
Cerebro- vascular
Cardio- vascular
Other
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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
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Treatment
A. Long-term effective antimanic drugs
C. Psychoeducation
B. Long-term effective antidepressant drugs
Acute Phase
Maintenance Phase
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A vast array of treatment optionsexist for
bipolar disorder
82
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
83
Meta-analysis of lithium maintenance- RCTs of
prevention of manic relapse

• Lithium was superior to placebo in the prevention
  of manic episodes. The average risk of relapse in
  the placebo group was 24 compared with 14 for
  lithium. This means that one patient would avoid
  relapse for every 10 patients who were treated
  for a year or 2 with lithium.

Geddes et al, 2004
84
Meta-analysis of lithium maintenance- RCTs of
prevention of depressive relapse

• The effect on depressive relapses appeared
  smaller and just failed to reach statistical
  significance. The average risk of relapse in the
  placebo group was 32 compared with 25 for
  lithium. This means that that one patient would
  avoid relapse for 14 patients who were treated
  for a year or 2 with lithium.

Geddes et al, 2004
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Suicide risk in bipolar disorder during treatment
with lithium and divalproex
Among patients treated for bipolar disorder, risk
of suicide attempt and suicide death is lower
during treatment with lithium than during
treatment with divalproex
Frederick K. Goodwin
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Relapse Into Mania or Depression Based on
Symptomatic Rating Scale Criteria
50
OLZ 12 mg/day (n217)
p.055
Li 1103 mg/day (n214)
38.8
40
plt.001
30.0
28.0
30
p.895
of Patients
20
16.1
15.4
14.3
10
0
Bipolar Relapse
Depressive Relapse
Manic Relapse

• Relapse defined by YMRS ?15 and/or HAM-D ?15.
• Tohen M, et al. Am J Psychiatry. In press.

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Neurobiology of Depression
Cingulate cortex
Hippocampus
Amygdala
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During separation distress in guinea pigs, the
most responsive brain areas are the anterior
cingulate (AC), the ventral septal (VS) and
dorsal preoptic areas (dPOA), the bed nucleus of
the stria terminalis (BN), the dorsomedial
thalamus (DMT), and the periaqueductal central
gray area of the brain stem (PAG). In humans
experiencing sadness it is the anterior cingulate
that is most responsive, but other areas that are
also activated include the DMT, PAG, and insula.
The correspondence between the brain regions
activated during human sadness and those
activated during animal separation distress
suggests that human feelings may arise from the
instinctual emotional action systems of ancient
regions of the mammalian brain. OB, olfactory
bulb CC, corpus callosum CB, cerebellum.
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Neurobiology of long term treatment
Moorel et al Lancet 2000
90

• 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 effect
• Biochemical
• Neurotransmitter levels (norephinephrine,
  serotonin, dopamine
• Psychosocial
• Stressful life events might trigger an episode of
  either depression or mania

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The Future of Gene Based Treatment
DNA Based Diagnosis
Novel gene specific targeted medication
Best current medication
Gene therapy
92
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

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Common Genes for Bipolar Disorder and
Schizophrenia
Bipolar
Schizophrenia
94
GRK3 regulates sensitivity to neurotransmitters

• Decreases the sensitivity of neurons to
  neurotransmitters
• Acts as a brake to stress
• Maintains balance in the brain

95
Acute amphetamine treatment models mania

• Acute amphetamine mimics mania in man
• Increased energy
• Rapid thoughts and speech
• Decreased need for sleep
• Euphoria
• Chronic amphetamine and binging mimics psychosis
• Auditory and visual hallucinations
• Paranoid delusions

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GRK3 regulates dopamine

• Dopamine is released by amphetamine
• Dopamine is blocked by antipsychotics
• Amphetamine caused a 14 fold increase in GRK3 in
  the brain

97
GRK3 is a Gene For Bipolar Disorder

• GRK3 is inherited with bipolar disorder
• GRK3 is turned on by amphetamine
• A mutation in GRK3 increases risk to bipolar
  disorder 3 fold
• But this mutation occurs in only 5 of patients

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Genes and environment
Environment
Gene subset A Pathophysiology A
Gene subset B Pathophysiology B
Gene subset C Pathophysiology C
99
Serotonin pathways
Raphe Nucleus
100
Noradrenaline Pathways
Locus Coeruleus
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5-HT/NA Interactions
brake
accelerator
Raphe and LC
102
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)

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

• Noradrenergic systems
• Few consistent findings
• Density and affinity of a2-adrenoceptors
  increased in depressed patients at PM (Meana et
  al. 1992 Callado et al. 1998)
• Serotonergic system
• Most consistent findings concern
• 5-HT1A receptors

104
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

105
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

106
Somatodendritic 5-HT1A receptor function in
depression (McAllister-Williams et al. 2004)
107
5-HT Neuronal control points
? Increased Somatodendritic 5-HT1A and
a2-adrenoceptor number or function in depression
Decreased Postsynaptic 5-HT1A number and function
in depression
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Pathogenesis
109
HPA Axis
Hippocampus
GR PVN
GR/MR
CRH AVP
GR Pituitary
-ve
-ve
ACTH
-ve
Adrenals
GR/MR mediated -ve feedback
CORT
GRs MRs
110
Cortisol in Depression
111
Cortisol response on dex / CRH testWatson et al,
2002, 2004.
Dexamethasone pretreatment
112
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

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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?

114
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

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DEPRESSION
Hypothalo- Pituitary Adrenal Axis
Serotonin System
Corticosterone
5-HT1A receptors
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Cortisol Synthesis Inhibition boosts
Antidepressant Effects
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
meanSEM.
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.
118
CORT effects on 5-HT1A receptors
CORT
Postsynaptic 5-HT1A receptors
Somatodendritic 5-HT1A receptors
?
5-HT1A receptor binding
?
5-HT1A receptor mRNA
5-HT1A electrophysiology
?
5-HT1A behavioural models
119
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