Patient description: The patient is a 47-year-old Asian woman complaining of persistent feelings of sadness. She lost interest in activities she used to enjoy. She states that her mood is mostly depressed for the past 3 weeks. She also lost her appetite , which led to about 5kg weight loss. She complains of loss of energy and feelings of worthlessness nearly every day. She is not using any drugs and she does not smoke. She doesn't drink alcohol. She used to exercise every day for at least 30 min. But she doesn't have enough energy to do so for the past 3 weeks. She also has some digestive issues recently. She is married and has 4 children. She is menopausal. Her husband was recently diagnosed with colon cancer and he is starting his chemotherapy. There is nothing remarkable in her past medical history and her drug history is only positive for Vit D3 1000 units daily. Her family history is negative for any psychologic problems. Her HAM-D score is 20.

Clinical trial eligibility criteria: eligible ages (years): 15.0-30.0,  Bipolar Disorder Major Depression FOR 1. Ages 15 years (inclusive) and able to give voluntary informed consent (parents must also sign consent for subjects under 18) 2. Satisfy for Diagnostic and Statistical Manual 4th edition (DSM-IV-TR) for Bipolar I or II disorder 3. Satisfy for DSM-IV depressive episode-current 4. 17-item Hamilton Depression Rating Scale > 15 but < 25; 5. Young Mania Rating Scale score < 10 6. Satisfy to undergo an MRI scan based on MRI screening questionnaire. 7. Able to be managed as outpatients during the study as ascertained by the following - i. Clinical Global Severity Scale < 5 i.e. moderately ill; ii. No significant suicidal or homicidal ideation or grossly disabled. FOR ALL 1. Ages 15 years and able to give voluntary informed consent (Parental consent must also be obtained for those under 18 years old). 2. Satisfy for DSM-IV-TR Major Depressive Episode using a Structured Interview 3. Never met for mania or hypomania 4. 17-item Hamilton Depression Rating Scale score (HDRS) > 15 and < 25. 5. Young Mania Rating Scale (YMRS) score < 10 6. Satisfy safety to undergo an MRI scan 7. Able to be managed as outpatients during the study as ascertained by the following - i. Clinical Global Severity Scale < 5 i.e. moderately ill; ii. No significant suicidal or homicidal ideation or grossly disabled FOR HIGH RISK UD (HRUD) THE FOR UD: At least one of the following: 1. Family history of bipolar disorder in at least one first degree relative 2. History of any sub-threshold hypomania symptoms 3. History of mood episode related psychotic symptoms FOR LOW RISK UD (HRUD) THE FOR UD: 1. No family history of BD in a first or a second degree relative 2. No past history of any sub-threshold hypomania symptoms 3. No history of psychotic symptoms  FOR AND 1. Meeting DSM-IV for schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, pervasive developmental disorder. 2. History of receiving electroconvulsive therapy in the past 1 year 3. Use of neuroleptics, mood stabilizers or benzodiazepines in the past 2 weeks. 4. Use of antidepressants in the past 2 weeks. 5. If on fluoxetine in the past, then should not have been on this medication for 5 weeks. 6. Acutely suicidal or homicidal or requiring inpatient treatment. 7. Meeting DSM-IV for other substance/alcohol dependence within the past 6 months or abuse in the past 3 months, excluding caffeine or nicotine. The will be evaluated by interview and urinary toxicology screening. The use of caffeine or nicotine will be recorded. 8. Use of alcohol in the past 1 week before the MRI scan. 9. No serious acute or chronic medical or neurological illness, including previously known HIV positive status (due to possible CNS involvement) as assessed by history, physical examination and laboratory examination including EKG, CBC and blood chemistry. 10. Current pregnancy or breast feeding. 11. Metallic implants or other contraindication to MRI. FOR Healthy subjects matched for age, gender and ethnicity will be included 1. Ages 15 years (inclusive) and able to give voluntary informed consent (Parental consent must also be obtained for those under 18 years old) 2. No current or past history of psychiatric illness or substance abuse or dependence. 3. No current or past history of psychiatric illness or substance abuse or dependence in a first degree relative FOR 1. Pregnant or breast feeding. 2. Metallic implants or other contraindication to MRI. 3. Significant family history of psychiatric or neurological illness. 4. Currently taking any prescription or centrally acting medications. 5. Serious acute or chronic medical or neurological illness as assessed by history, physical examination and laboratory examination including CBC and blood chemistry. 6. Use of alcohol in the past 1 week and not being able to avoid alcohol use during the course of the study