ANXIETY AND DEPRESSION:

SHARED SYMPTOMS,
COMMON TREATMENTS,
SIMILAR CAUSES?
Roger M.Pinder

Secretary ISAD, Treasurer CINP

Editor, Neuropsychiatric Disease and
Treatment
Pharma Consultant, ‘s-Hertogenbosch,
The Netherlands
DECLARATION OF INTEREST
• Until June 2004, I was a full-time employee of
Organon. Since then I have received honoraria
and/or travel support from Organon for chairing
and speaking at symposia.
• I am non-executive Chairman of NeuroCure Ltd
(Dublin).
• I am a consultant to Cypress Bioscience Inc
(San Diego), Daniolabs Ltd (Cambridge, UK),
Nomura Phase4 Ventures (London) and
Organon International Inc (New Jersey, USA).
Anxiety and Depression:
The Facts
Prevalence of mental disorders in
adult Americans 1984-2005
20
18
16
14
Any Anxiety
12
Mood Disorder
10
Social Phobia
8 Panic Disorder
6 Bipolar Disorder
4
2
0
1984 1994 2002 2005

Kessler et al, Arch Gen Psychiat 2005, 62:617-627

 Comorbidity of major
depression with anxiety
disorders in the community
• National Comorbidity Survey: 12 months

• Major depression comorbid with:

– Any anxiety disorder 53.7%

– Panic disorder 9.9%

– Social phobia 31.3%
– Simple phobia 26.2%
– GAD 16.9%
Kessler et al 1994
 Impact of Depression
• 340 million patients worldwide
• Lifetime risk exceeds 17%
• Women have twice the risk of men
• Direct and indirect medical costs in USA in
1990 were $44 billion
Anxiety and Depression:
Shared Symptoms?
Symptoms common to major
depression and anxiety
disorders
Major Anxiety
depression disorder
• Fear
• Panic
• Depressed • Apprehension
mood • Panic attacks
• Anhedonia • Chronic pain • Hypervigilance
• Weight • GI complaints • Agoraphobia
gain/loss • Excessive worry • Compulsive
• Loss of • Agitation rituals
interest • Difficulty
concentrating
• Sleep
disturbances

APA 1994
Keller 1995
Clayton et al 1991
Coplan et al 1990
Consequences of anxiety
symptoms in depression
• More severe illness at baseline
• More psychosocial impairment
• Greater likelihood of chronic illness
• Poorer, slower response to treatment
• Increased use of health care
resources
• Greater likelihood of committing
suicide
Keller et al 1995
Fawcett 1988
 Anxiety as Residual Symptom
of Depression
• Anxiety (both psychological and
somatic) is a common residual
symptom in depression1

• Patients who remain anxious at

the point of remission of the index
episode of MDD have a significantly
shorter time to relapse or recurrence2

e KS, et al. Depress Anxiety. 1996;4(6):312-319.

, Rifat SL. Psychiatry Res. 1997;66(1):23-31.
Anxiety and Depression:
Common Treatments?
Psychotherapy is effective in both
anxiety and depression

• CT
• CBT
• IPT
Antidepressant drugs are effective
in anxiety disorders
• SSRIs (GAD, SAD, PTSD, OCD, Panic
Disorder)
• SNRIs (GAD)
• Mirtazapine (PTSD, Panic Disorder)
• Clomipramine (OCD)
• MAOIs (SAD)
But efficacy in anxiety disorders is
confined to those antidepressants
with a serotonergic component in
their pharmacology
 And anxiolytics are generally not
effective in depressive disorders
• Benzodiazepines (used for insomnia and
anxiety symptoms in depression, but may
worsen response to antidepressants)
• Buspirone (only effective as augmentation
to antidepressants)
Anxiety and Depression:
Similar Causes?
 Brain Structure in Mood and
Anxiety Disorders

• Volumetrics
– Increasing evidence that specific structures
demonstrate cellular loss as a function of
duration of depression and PTSD
– Growing evidence that all antidepressant
treatments and some anticonvulsants may
“regrow the brain” (synaptic plasticity or
neurogenesis)
Hippocampal Volume in Mood
and Anxiety Disorders
• Excessive glucocorticoid exposure
(hypercortisolemia) may result in
hippocampal atrophy in depression and
PTSD; 5-10% loss of volume
• Smaller hippocampal volume in
depression depends upon duration of
episodes; also found in PTSD
• Reduced volume linked to verbal
memory deficits in both disorders
Depression and neurodegeneration
Hippocampal volume and duration of
depressive episode
5800
Hippocampal volume ( mm3)

5300
R2 = 0.36
p = 0.002
4800

4300

3800

3300

2800
0 500 1000 1500 2000 2500 3000 3500 4000
Episode Duration (days)
Sheline et al. J. Neuroscience 1999
 Hippocampal Volume,
Duration of Periods of MDD,
and Age

Hippocampal volume loss was related to the

number of days in MDD and not to age.

Sheline et al. J Neurosci. 1999;19:5034.

 Structural Brain Abnormalities
in Anxiety and Depression
• Sufficient evidence to conclude that brain
structure is abnormal
• Also appears likely that some structural
abnormalities are distinct in depression and
in PTSD
• Progression of illness results in hippocampal
volume loss; effective treatments may modify
brain structure, resulting in growth of new
neurons and new patterns of connectivity
Long-term Health Consequences
of Undertreatment
• Depression and PTSD linked with brain
changes:

– Volume of the hippocampus reduced

– Correlated with number and duration of

previous episodes

• Do brain changes may persist after

resolution of symptoms?
 Consequences of Chronic
Stress
STRESS
Atrophy/ Increased survival
and growth
Glucocorticoids death of
neurons
BDNF

BDNF

Normal survival Glucocorticoids

and growth
5-HT and NE

Antidepressants

Duman et al. 2000

 HPA AXIS AS DIRECT
TARGET FOR
ANTIDEPRESSANT ACTION
• Non-specific antiglucocorticoids such as
steroid synthesis inhibitors
• CRH1 receptor antagonists
• Type II glucocorticoid receptor (GR)
antagonists
• Vasopressin antagonists
 GLUCOCORTICOID
RECEPTOR ANTAGONISTS
• RU 486 (mifepristone) and ORG 34517
are steroidal central GR antagonists
• Both also have antiprogestagenic
activity - mifepristone is abortifacient
• Mifepristone is effective in psychotic
depression and bipolar disorder, ORG
34517 in melancholia
• No studies in PTSD
• No studies on hippocampal volume
ORG 34517, Proof of Principle:
Mean decrease in HAMD-21 at
10 days
14
12
10
8 Paroxetine
Org 34517, 150-300mg
6
Org 34517, 450-600mg
4
2
0
All high DST NS
(n=142) cortisol (n=22)
(n=48)
Hoyberg et al. 2002
 Mifepristone in psychotic
depression: Open label, 7 days,
n=30, % responders
70
60
50
40
30 50mg
20 600mg
1200mg
10
0
HAMD-21 BPRS BPRS
Positive
Symptoms Belanoff et al. 2002
 DOES TREATMENT REVERSE
BRAIN CHANGES IN MOOD AND
ANXIETY DISORDERS?
 We do not know (yet)

• No data available in depression for any

treatment modality including drugs, ECT
and psychotherapy. But:
• Paroxetine (1) and phenytoin (2) increase
hippocampal volume in PTSD and also
improve verbal declarative memory

(1)Vermetten et al, Biol Psychiatry 2003, 54:693-702

(2) Bremner et al, J Psychopharmacol 2005, 19:159-165
 Phenytoin and Brain Volume in
PTSD Patients
% Increase after 300-400mg daily for 3 months
* (n=9); *p<0.05
6

4
Left Brain
Right Brain
3
Left Hippocampus
Right Hippocampus
2

Bremner et al, J Psychopharmacol 2005,19:159-165

 CONCLUSIONS
• Symptoms of anxiety and depressive disorders overlap
to a major extent
• Anxiety and depression commonly occur together
• Anxiety symptoms are frequent in, and a poor prognostic
criteria for, depression
• Treatments for anxiety and depressive disorders are
similar
• Structural brain changes occur in depression and PTSD
• There may be some commonality between depression
and PTSD
• Other anxiety disorders are probably distinct from
depression