Inclusion Criteria:

• Subjects will be 144 smokers who have experienced at least one episode of major depressive disorder and 206 smokers who lack a lifetime history of major depressive disorder.
• None will currently meet diagnostic criteria for major depression, nor will they have met criteria in the past 6 months.
• All will be male and female community members between the ages of 18 and 65 who have smoker at least 10 cigarettes a day for the past year.

Exclusion Criteria:

Subjects may not enter the trial if they:

1. have taken monoamine oxidase inhibitors, antidepressants, anti-anxiety agents, lithium, tryptophan or phenothiazines within the past month;
2. are being treated for hypertension with guanethidine, reserpine, thiazide diuretics, beta blockers, or clonidine;
3. are taking Type IC antiarrhythmics (e.g., propafenone and flecanide) or a highly protein-bound drug (e.g., warfarin, digitoxin);
4. have a medically unstable condition or had a major health event in the past 6 months (e.g., myocardial infarct or major surgery);
5. have CBC values more than 10% outside the normal limits, or liver enzymes exceeding 40% of the upper limit of normal;
6. have a history of severe allergies, multiple adverse drug reactions or known allergy to fluoxetine;
7. are actively abusing alcohol or drugs or received inpatient treatment for substance abuse within the past year;
8. are using nicotine replacements;
9. are pregnant, lactating, or of childbearing potential;
10. present current evidence of organic brain disease, definite or subclinical major depressive disorder or serious suicidal risk post-traumatic stress disorder, or premenstrual dysphoric disorder;
11. have a score greater than 14 on the 21-item Hamilton Depression Rating Scale or greater than 15 on the Beck Depression Inventory;
12. have a history of seizures, mania or hypomania, or psychosis. Individuals with bipolar disorder, PTSD, or schizophrenia will be excluded because they might respond adversely to fluoxetine.

Subjects with dysthymic disorder or anxiety disorders will be studied if their current symptoms are not sequelae of an episode of major depression. Excluding such cases would purify the sample by removing mild degrees of dysphoria, but would greatly restrict our ability to generalize any treatment implications to the current population that smokers.