1. Depression—There are at least two sides to every story.

2. Depression. It’s not only a state of mind. Reference: Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition,Text Revision. Washington, DC; American Psychiatric Association. 2000:345-356,489. The symptoms of depression Emotional Symptoms Include: Sadness Loss of interest or pleasure Overwhelmed Anxiety Diminished ability to think or concentrate, indecisiveness Excessive or inappropriate guilt Physical Symptoms Include: Vague aches and pains Headache Sleep disturbances Fatigue Back pain Significant change in appetite resulting in weight loss or gain

3. Reference: 1.Simon GE, et al. N Engl J Med. 1999;341(18):1329-1335. Depression – the physical presentation In primary care, physical symptoms are often the chief complaint in depressed patients N = 1146 Primary care patients with major depression In a New England Journal of Medicine study, 69% of diagnosed depressed patients reported unexplained physical symptoms as their chief compliant 1

4. Adapted from 1.Silverstein B. Am J Psychiatry. 1999;156(3):480-482. 2.Silverstein B. Am J Psychiatry. 2002;159(6):1051-1052. Aches/pain – a physical symptom of significance Aches/Pain as common as anxiety among depressed patients

5. 76% of compliant depressed patients with lingering symptoms of depression relapsed within 10 months 1 * The importance of emotional and physical symptoms *Psychiatric inpatients and outpatients. Reference: 1.Adapted from: Paykel ES, et al. Psychol Med. 1995;25:1171-1180. 94% of depressed patients who experienced lingering symptoms had mild to moderate physical symptoms 1

6. Serotonin 5HT and Norepinephrine NE in the brain Limbic System Locus Ceruleus (NE Source) Prefrontal Cortex Raphe Nuclei (5-HT source) Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996.

7. There are at least two sides to the neurotransmitter story Sex Appetite Aggression Concentration Interest Motivation Depressed Mood Anxiety Irritability Thought process References: 1.Adapted from: Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications: 2 nd ed. Cambridge University Press 2000. 2.Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43. 3.Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35. 4.Verma S, et al. Int Rev Psychiatry. 2000;12:103-114. Norepinephrine (NE) Both serotonin and norepinephrine mediate a broad spectrum of depressive symptoms Serotonin (5-HT) Vague Aches and pain Functional domains of Serotonin and Norepinephrine 1-4

8. The neurotransmitter pathway story Adapted from References: 1.Stahl SM. J. Clin Psych. 2002;63:203-220. 2.Verma S, et al. Int Rev Psychiatry. 2000;12:103-114. 3.Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43. Dysregulation of Serotonin (5HT) and Norepinephrine (NE) in the brain are strongly associated with depression Dysregulation of 5HT and NE in the spinal cord may explain an increased pain perception among depressed patients 1-3 Imbalances of 5HT and NE may explain the presence of both emotional and physical symptoms of depression. It’s not all in your head Descending Pathway Ascending Pathway Ascending Pathway Descending Pathway

9. Depression: Current treatment outcomes 1 Up to 70% of depressed patients respond (  50% decrease in HAM-D score) to treatment but fail to achieve remission from their emotional and physical symptoms 1* Approximately 30% of depressed patients achieve remission (  7 score on the HAM-D) with treatment 1* References: 1. O’Reardon JR, et al. Psychiatr Ann. 1998;28:633-640. * Antidepressant clinical drug trials.

10. Response and Remission defined Hamilton Depression Rating Scale (HAM-D): 17 Items, Total Score 0 - 52 15 7 Response   50% reduction from baseline HAM-D score Remission: HAM-D Score  7 Depression (Major Depressive Disorder) References: 1. Frank E. Conceptualization and rationale for consensus definition terms in MDD, Arch Gen Psych. 1991; 48:851-855. HAM-D 17 Scores

11. Study in chronic depressed patients *p .05 vs nonresponse. **p .05 vs response. Miller IW, et al. J Clin Psychiatry. 1998;59(11):608-619. Normal (n=482) Remission (n=202) Response (n=122) Nonresponse (n=299) Social Adjustment Scale-SR (Mean ± SD) * ** * 1 2 3 5 Treatment outcome:Effect on work & social functioning Higher Score indicates greater impairment Remitted patients virtually equaled healthy controls on functioning levels at endpoint of 12-week treatment trial (Responders & non-responders did not)

12. Many depressed patients are still depressed. References: 1.Nierenberg AA, et al. J Clin Psychiatry. 1999:60(suppl 22):7-11. 2.O’Reardon JR, et al. Psychiatr Ann. 1998;28:633-640. 3.Lynch ME. J Psychiatry Neurosci. 2001;26(1):30-36. Depressed patients continue to have needs that are not being fully addressed 1 Depressed patients present with emotional and physical symptoms. Approximately 30% of depressed patients achieve remission in clinical trials 2* Up to 70% of patients who respond fail to remit 2* Incomplete relief from symptoms may increase the risk of relapse 2,3 Lingering emotional and physical symptoms may jeopardize achieving remission. *In antidepressant clinical drug trials.