Anxiety And Depression, Quito 2005

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 Mood Disorder Social Phobia Panic Disorder Bipolar Disorder

12 10 8 6 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 – Panic disorder – Social phobia – Simple phobia – GAD

53.7% 9.9% 31.3% 26.2% 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 Anxiety disorder

Major depression • Depressed mood • Anhedonia • Weight gain/loss • Loss of interest

• Fear • Panic • Apprehension • Panic attacks • Chronic pain • GI complaints • Excessive worry • Agitation • Difficulty concentrating • Sleep disturbances

• Hypervigilance • Agoraphobia • Compulsive rituals

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 ( mm3)

Hippocampal volume and duration of depressive episode 5800

R2 = 0.36 p = 0.002

5300 4800 4300 3800 3300 2800 0

500

1000

1500

2000

2500

Episode Duration (days)

3000

3500

4000

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 Glucocorticoids

Atrophy/ death of neurons

Increased survival and growth

BDNF

BDNF

Normal survival and growth

Glucocorticoids 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

Paroxetine Org 34517, 150-300mg Org 34517, 450-600mg

8 6 4 2 0 All (n=142)

high cortisol (n=48)

DST NS (n=22) Hoyberg et al. 2002

Mifepristone in psychotic depression: Open label, 7 days, n=30, % responders 70 60 50 40 50mg 600mg 1200mg

30 20 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 5 4 3 2

Left Brain Right Brain Left Hippocampus Right Hippocampus

1 0 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