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ANXIETY AND DEPRESSION:SHARED SYMPTOMS,

COMMON TREATMENTS,SIMILAR CAUSES?

Roger M.Pinder

Secretary ISAD, Treasurer CINPEditor, Neuropsychiatric Disease and

TreatmentPharma Consultant, ‘s-Hertogenbosch,

The Netherlands



DECLARATION OF INTEREST

• Until June 2004, I was a full-time employee of Organon. Since then I have received honorariaand/or travel support from Organon for chairingand 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) andOrganon International Inc (New Jersey, USA).



Anxiety and Depression:Anxiety and Depression:

The FactsThe Facts



Comorbidity of majorComorbidity of majordepression with anxietydepression with anxiety

disorders in the communitydisorders 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 majorSymptoms common to major

depression and anxietydepression and anxiety

disordersdisordersMajor

depression

Anxiety

disorder

•Depressedmood•Anhedonia•Weight

gain/loss•Loss of

interest

•Hypervigilance•Agoraphobia•Compulsive

rituals

• Fear • Panic

• Apprehension• Panic attacks• Chronic pain• GI complaints• Excessive worry• Agitation• Difficulty

concentrating• Sleep

disturbances

APA 1994Keller 1995

Clayton et al 1991Coplan et al 1990



Consequences of anxietyConsequences of anxiety

symptoms in depressionsymptoms 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 and Depression:Common Treatments?



Antidepressant drugs are effectivein anxiety disorders

• SSRIs (GAD, SAD, PTSD, OCD, PanicDisorder)

• SNRIs (GAD)• Mirtazapine (PTSD, Panic Disorder)

• Clomipramine (OCD)

• MAOIs (SAD)



But efficacy in anxiety disorders isconfined to those antidepressantswith a serotonergic component in

their pharmacology



And anxiolytics are generally noteffective in depressive disorders

• Benzodiazepines (used for insomnia andanxiety 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 andAnxiety Disorders

• Volumetrics

– Increasing evidence that specific structuresdemonstrate 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)

Hi l V l i M d



Hippocampal Volume in Moodand Anxiety Disorders

• Excessive glucocorticoid exposure(hypercortisolemia) may result inhippocampal atrophy in depression andPTSD; 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



H i p

p o c a m p a l v o l u

m e ( m m 3 )

Episode Duration (days)

5800

5300

4800

4300

3800

3300

2800

500 1000 1500 2000 2500 3000 3500 40000

Sheline et al. J. Neuroscience 1999

R 2 = 0.36

p = 0.002

Depression and neurodegenerationHippocampal volume and duration of

depressive episode



Structural Brain Abnormalitiesin 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 hippocampalvolume loss; effective treatments may modify

brain structure, resulting in growth of new

neurons and new patterns of connectivity



Long-term Health Consequencesof Undertreatment

• Depression and PTSD linked with brainchanges:

– 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



Consequences of ChronicStress

STRESS

Glucocorticoids

BDNF

Normal survivaland growth

Atrophy/death of neurons

Antidepressants

BDNF

Increased survivaland growth

5-HT and NE

Glucocorticoids

Duman et al. 2000

HPA AXIS AS DIRECT



HPA AXIS AS DIRECTTARGET FOR

ANTIDEPRESSANT ACTION

• Non-specific antiglucocorticoids such assteroid synthesis inhibitors

• CRH1 receptor antagonists

• Type II glucocorticoid receptor (GR)antagonists

• Vasopressin antagonists

GLUCOCORTICOID



GLUCOCORTICOIDRECEPTOR ANTAGONISTS

• RU 486 (mifepristone) and ORG 34517are steroidal central GR antagonists

• Both also have antiprogestagenic

activity - mifepristone is abortifacient

• Mifepristone is effective in psychoticdepression and bipolar disorder, ORG

34517 in melancholia• No studies in PTSD

• No studies on hippocampal volume

ORG 34517 P f f P i i l



ORG 34517, Proof of Principle:Mean decrease in HAMD-21 at

10 days

0

2

4

6

8

1012

14

All

(n=142)

high

cortisol

(n=48)

DST NS

(n=22)

Paroxetine

Org 34517, 150-300mg

Org 34517, 450-600mg

Hoyberg et al. 2002

Mifepristone in psychotic



Mifepristone in psychoticdepression: Open label, 7 days,

n=30, % responders

0

10

20

30

40

5060

70

HAMD-21 BPRS BPRS

Positive

Symptoms

50mg

600mg

1200mg

Belanoff et al. 2002



DOES TREATMENT REVERSE

BRAIN CHANGES IN MOOD ANDANXIETY DISORDERS?



We do not know (yet)

• No data available in depression for anytreatment modality including drugs, ECT

and psychotherapy. But:

• Paroxetine (1) and phenytoin (2) increasehippocampal 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



Phenytoin and Brain Volume inPTSD Patients

% Increase after 300-400mg daily for 3 months

(n=9); *p<0.05

0

1

2

3

4

5

6

Left Brain

Right Brain

Left Hippocampus

Right Hippocampus

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

*



CONCLUSIONS

• Symptoms of anxiety and depressive disorders overlapto 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 depressionand PTSD

• Other anxiety disorders are probably distinct fromdepression

anxiety and depression, quito 2005

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