The primary purpose of this protocol is to compare PDE4 levels before and after starting a selective serotonin reuptake inhibitor (SSRI) sertraline, citalopram or escitalopram in unmedicated depressed patients. The secondary purpose is to compare PDE4 levels between unmedicated depressed patients and healthy subjects.

Although direct pharmacological effects of antidepressant should manifest rapidly, before significant symptom relief appears, typically antidepressant treatment needs to be continued for 2 to 4 weeks. This delayed onset of clinical effects indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs). Type 4 PDE (PDE4) is selective to cAMP in the brain. Among components of the cAMP pathway, PDE4 appears to be critical for antidepressant effects because an inhibitor of PDE4, 4-[3-(cyclopenotoxyl)-4-methoxyphenyl]-2-pyrrolidone (rolipram), showed antidepressant effects both in animals and humans, and various forms of antidepressant treatment induced increase in PDE4 in rodents. However, without imaging the cAMP pathway before and after antidepressant treatment in depressives, it is not possible to study adaptive changes in the signal transduction system and its role in the symptom relief.

Recently (R)-[(11)C]rolipram has been successfully used to image PDE4 in animals and humans. We have confirmed that PDE4 levels can be measured reliably by performing (R)-[(11)C]rolipram positron emission tomography (PET) with multiple arterial sampling even in rats. The primary purpose of this protocol is to compare PDE4 levels before and after starting a selective serotonin reuptake inhibitor (SSRI) sertraline, citalopram or escitalopram in unmedicated depressed patients. The secondary purpose is to compare PDE4 levels between unmedicated depressed patients and healthy subjects. Baseline scans of patients will be used for this second comparison. For the first time, these comparisons have become possible with the new PET agent (R)-[(11)C]rolipram. The findings will advance understanding on the role of cAMP signal transduction system in the pathology of depression and the mechanisms of antidepressant effects.

• Healthy Volunteers (n = 20)

Healthy Control Sample (n = 20): Healthy subjects (ages 18-55) will be selected who have not met criteria for any major psychiatric disorder, have no known first-degree relatives with mood disorders, and have a current score on the Hamilton Depression Rating Scale (HDRS; 17 item) (Williams 1988) in the not depressed range (less than or equal to 7). Control subjects will be matched to depressed subjects for age and gender.

MDD Samples (n = 30)

MDD Sample-Currently Depressed (n = 30): Patients (ages 18-55) will be selected with primary MDD currently depressed by DSM-IV criteria for recurrent MDD and current 17-item HDRS score greater than or equal to 18 or Montgomery-Asberg Depression Rating Scale (MADRS) (Noble et al 1991) greater than or equal to 20 indicating the moderately-to-severely depressed symptoms. All subjects must be physically healthy and aged 18 - 55 years.

EXCLUSION CRITERIA:

Subjects will be recruited who are drug-na ve or who have not received psychotropic drugs for at least 2 weeks (6 weeks for fluoxetine) prior to scanning. Effective medications will not be discontinued for the purposes of the study.

Subjects will also be excluded if they have:

1. serious suicidal ideation or behavior
2. psychosis
3. medical conditions or concomitant medications (see Appendix B) that are likely to influence PET measurement or have significant interactions with sertraline, citalopram or escitalopram.
4. a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM-IV criteria)
5. positive urine drug screen
6. current pregnancy (as documented by pregnancy testing prior to scanning)

f. general MRI exclusion criteria

g. major depression that arose following another major medical or psychiatric condition, and h) prior participation in other research protocols within a year such that radiation exposure would exceed the annual guidelines

Additional exclusion criteria applied to patients who will have antidepressant treatment are:

1. previously proved unresponsive to a therapeutic trial of sertraline, citalopram or escitalopram.
2. previously developed allergic reactions to sertraline, citalopram or escitalopram, or discontinued each of these medications due to an adverse effect

Additional exclusion criteria applied to control subjects are:

1. subjects with a current or past history of other axis I psychiatric conditions
2. subjects with first-degree family members with current or past history of mood disorder.

Subjects beyond age 55 are excluded to reduce the biological heterogeneity encompassed by the MDD criteria, and to reduce the variability of PET data.