This research study is being done to look at the safety of the medication Mirtazapine (Remeron) in people who have cocaine dependence and depression. Hypotheses I. Cocaine usage will be less in the mirtazapine treatment group (MG) than in the control group (CG). II. A greater increase in Clinician Global Impression (CGI) score will be observed in the MG than in the CG. Secondary Hypotheses: I. A greater decrease in Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) scores will be observed in the MG than in the CG. II. A greater decrease in HIV risk behaviors will be observed in the MG than in the CG. III. A greater improvement in sleep structure will be observed in the MG than in the CG. IV. The proportion of subjects experiencing severe adverse drug reactions that necessitate termination from the study by one of the study clinicians will not differ between the MG and CG. V. Retention will be greater in MG than in CG.

Cocaine dependence is a significant public health problem associated with serious medical, psychiatric, social and economic consequences. It is generally accepted that the euphoria associated with cocaine use is a result of its action on reward pathways via antagonist properties at the dopamine transporter site; cocaine also inhibits reuptake of serotonin and norepinephrine. These actions are thought to underlie cocaine's potent reinforcing properties. With prolonged use, cocaine may deplete these neurotransmitters, affect postsynaptic receptor density, and elicit an overall dysregulation of these neurotransmitter systems. These longer term consequences may account for the post-cocaine depressive symptoms often claimed by cocaine users to contribute to relapse. Treatment for cocaine dependence at the present is primarily psychosocial/behavioral. Currently there is no pharmacological agent approved for treatment of cocaine dependence in conjunction with psychosocial interventions. Several drugs currently approved for other indications are presently under consideration for treatment of cocaine dependence based on their known mechanisms and sites of action. Current approaches include strategies to (1) block the effects of cocaine, (2) substitutes for cocaine, (3) reduce craving or enhance the addict's ability to manage his/her response to craving, and (4) treat underlying conditions (or consequences of cocaine use) that may predispose toward dependence.

Inclusion Criteria:

• Diagnostic Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of cocaine dependence.
• HAM-D score of 12 or above and history of autonomous depression, defined as meeting DSM-IV criteria for major depression or dysthymic disorder during any lifetime period of abstinence of 30 days or longer.
• At least one urine toxicology positive for cocaine benzoylecgonine (BE) over the consecutive two-week baseline screening period during which 6 urine samples have been obtained
• Males and non-pregnant, non-nursing females, 18-64 years of age (inclusive).
• Individuals able to give written informed consent and willing to comply with all study procedures.

Exclusion Criteria:

• Any Axis I diagnosis that, in the opinion of the Principal Investigator, may interfere with the course of the trial.
• Physiological dependence on alcohol or opiates requiring medical detoxification.
• A medical or neurological illness that in the clinical judgment of the investigator would make study compliance difficult or contraindicate the use of mirtazapine.
• Any clinically significant abnormal lab values or liver function tests (LFTs) which are greater than 3 times the normal limit.
• The need or intention to use concurrently with or within four weeks prior to study drug administration, any of the following medications: monoamine oxidase inhibitors and/or sibutramine. In addition, other medications such as alpha2-agonists and medications which affect the enzymes Cytochrome P450 1A2 (CYP1A2), Cytochrome P450 2D6 (CYP2D6), Cytochrome P450 3A4 (CYP3A4) (as inhibitors, substrates, or inducers), and serotonin modulators should be used with caution. The research physician will decide on this issue. A listing of these substances may be found in Appendix I.
• Females of childbearing potential who do NOT agree to use a medically acceptable method of birth control (barrier, intrauterine device (IUD), oral or depot contraceptive medication, or complete abstinence).
• Positive pregnancy test.
• Breastfeeding
• Known drug allergy or sensitivity to mirtazapine.
• Participation in an investigational drug or device study within 1 month of enrollment in the present study.
• Enrollment in an opiate-substitution (i.e., methadone, levo acetyl methadol (LAAM)) treatment program within 45 days of enrolling in the present study.
• Individuals having taken LAAM, methadone or naltrexone within 14 days of enrollment in the present study.
• Individuals who, in the clinical judgment of the Investigator, are actively and acutely suicidal.
• Subjects, who in the opinion of the investigator, have a medical condition that may interfere with study assessments and/or put them at undue risk.
• Subjects, who in the opinion of the investigator, will have difficulty complying with study procedures.