Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Double-Blind, Placebo-Controlled, Fixed-Dose, 8-Week Evaluation of the Efficacy and Safety of Lamotrigine in the Treatment of Depression in Patients With Type II Bipolar Disorder
Brief Summary: This study is an 8-week evaluation of an investigational drug for treating depression in bipolar patients. Depressed patients will be given either an investigational drug or placebo and receive psychiatric assessments of their depression at weekly visits. Study drug and all study-related visits are provided at no cost to the patient. The patient agrees to meet with study research staff for roughly 11 clinic visits.


Options:
A: Inclusion Criteria:

1. Bipolar I or II
2. Currently either in remission or subsyndromally ill (Hamilton Depression Scale-17\<14; Clinician Administered Rating Scale for Mania\<12).
3. Age eighteen to sixty.
4. Significant symptoms and/or episodes on at least two occasions in the past three years.
5. Grade six education, able to understand English, and Folstein Minimental Score Exam \> 26 to ensure cognitive ability to participate.
6. On mood-stabilizing medication.

Exclusion Criteria:

1. Substance dependence meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria within the last three months.
2. Acutely highly suicidal or homicidal.
3. Serious other medical condition that would render pharmacotherapy or psychotherapy very difficult such as cancer, severe diabetes, etc.
4. Severe antisocial or borderline personality disorder (personality disorder per se is not exclusionary). Subjects may have other axis I disorders, but bipolar disorder must be the principal disorder requiring treatment.
B: Inclusion

* Patients must provide written and informed consent.
* Diagnosis of Bipolar II Disorder and currently depressed for minimum of the last 8 weeks.

Exclusion

* Patients must not be suicidal.
* Patients must not have a history of non-response to antidepressant treatment.
* Patients must not have a clinical history of substance dependence in the past year or abuse within the 4 weeks prior to study entry.
* Patients must not have had epilepsy or hypothyroidism.
C: Inclusion Criteria:

At Screening Disease to be studied: Has a diagnosis of following disease as defined by DSM-IV-TR criteria.

* Bipolar I Disorder, most recent episode depressed（296.5x）
* Bipolar I Disorder, most recent episode hypomanic（296.40）
* Bipolar I Disorder, most recent episode manic（296.4x） The diagnosis of mood episode will be made with reference to Mini International Neuropsychiatric Interview: M.I.N.I, Japanese Version.

At Screening

The subject who has a diagnose of bipolar I disorder, most recent episode depressed (296.5x) must meet the following criteria:

* Is currently experiencing a major depressive episode or has had a major depressive episode as defined by DSM-IV-TR criteria within 60 days of the screening visit and at least one additional major depressive episode and one manic or hypomanic episode, as defined by DSM-IV-TR criteria, within 3 years of enrolment. A well documented history of a mixed episode that meets DSM-IV-TR criteria may be counted as a previous episode.All subjects must have experienced at least one well-documented manic or mixed episode in the past.
* Has a duration of the most recent/current depressive episode of at least 2 weeks but not longer than 12 months prior to enrolment.
* The subject without current major depressive episode must have a major depressive episode within 60 days of screening and has depressive symptoms at screening or is under treatment for depressive symptoms, which can be confirmed by medical record, etc.
* If the subject is currently experiencing a major depressive episode, the subject must have a minimum total score on the HAM-D (17-item scale) of 18 at the screening. This criterion will not apply to the subject with recent depressive episode.

At Screening

The subject who has a diagnose of bipolar I disorder, most recent episode hypomanic（296.4x） or bipolar I disorder, most recent episode manic（296.5x） must meet the following criteria:

* Has experienced a recent manic or hypomanic episode (current or within 60 days of the Screening Visit) and has had at least one additional manic or hypomanic episode and one depressed episode, as defined by DSM-IV-TR criteria, within three years of enrolment. A well documented history of a mixed episode that meets DSM-IV-TR criteria may be counted as a previous episode. All subjects must have experienced at least one well-documented manic or mixed episode in the past.
* Has a duration of the index manic episode of at least 1 week (unless hospitalised) or hypomanic episode of at least 4 days. In neither case should the index episode be more than 12 months in duration.
* The subject current experiencing hypomania episode or without current episode must have a manic episode which can be confirmed by medical record, etc. The subject without current episode must have a episode within 60 days of screening and has manic or hypomanic symptomatology is under treatment for manic or hypomanic symptoms.
* If the subject's index episode is subject initial manic mood event, subject must have a minimum score of 10 (moderate severity) on the first 11 items of the YMRS at the screening. A threshold YMRS score that indicates significant manic symptoms is not required for patients who previously experienced well-documented DSM-IV-level mania or when the index episode is hypomania or when a subject's index manic or hypomanic episode is documented to have occurred within 60 days of the screening Visit.

At Screening Age: Is at least 20 years of age (at the time of informed consent). At Screening Sex: either sex. Female of child-bearing potential will be eligible for inclusion in this study. However they have to have a negative pregnancy test at the screening visit, agree to further pregnancy testing at the time points determined in study assessments and procedures and practice one of the following methods of contraception from the screening visit until the end of the follow-up examination.

* Abstinence
* Injectable progestogen
* Implants of levonorgestrel
* Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label
* Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
* Double barrier method: condom or occlusive cap (diaphragm or cervical / vault caps) plus spermicidal agent (foam /gel / film / cream / suppository) At Screening In/Out patient: Either At Screening Informed consent: the subject capable of giving written informed consent. At Week 0 of First Phase (titration) If the subject is currently experiencing a major depressive episode, the subject must have a minimum total score at baseline on the HAM-D (17-item scale) of 18 at the start of First Phase. This criterion will not apply to the subject with recent depressive episode.

At Week 0 of First Phase (titration) If the subject's index episode is subject initial manic mood event, subject must have a minimum total score at baseline of 10 (moderate severity) on the first 11 items of the YMRS at the start of First Phase (titration). A threshold YMRS score that indicates significant manic symptoms is not required for patients who previously experienced well-documented DSM-IV-level mania or when the index episode is hypomania or when a subject's index manic or hypomanic episode is documented to have occurred within 60 days of the screening Visit.

At Week 0 of Second Phase (maintenance therapy) Each subject completing 8 to 16 weeks of open-label lamotrigine treatment in the First Phase must meet all of the following inclusion criteria to be eligible for entry into the Second Phase (maintenance therapy, randomization phase).

At Week 0 of Second Phase (maintenance therapy) Has no tolerability problem with lamotrigine at a minimum dosage of 100 mg/day during the final 2 weeks of the First Phase (titration).

At Week 0 of Second Phase (maintenance therapy) Has improved/stabilised during the First Phase (titration) as indicated by a CGI-S score of ≤3 (mildly ill). Once improved, the subject must also demonstrate sustained improvement by achieving a CGI-S score of ≤3 (mildly ill) for at least 4 consecutive weeks of treatment immediately prior to the Second Phase (maintenance therapy) (randomization).

At Week 0 of Second Phase (maintenance therapy) Has demonstrated adequate compliance with the study treatment in the First Phase (titration) (compliance rate: at least 70%).

At Week 0 of Second Phase (maintenance therapy) In/Out patient: Either

Exclusion Criteria:

At Screening Has a DSM-IV-TR diagnosis of rapid cycling and has had more than six mood episodes including depression, mania, hypomania or mixed, in the 12-month period prior to screening. Note: while 4 or more episodes in the past 12 months constitute rapid cycling up to six episodes in the past 12 months are allowed in this protocol.

At Screening Has a DSM-IV-TR diagnosis of bipolar I disorder, most recent episode mixed (296.6x).

At Screening Has a DSM-IV-TR diagnosis of Axis II which would suggest non-responsiveness to pharmacotherapy for bipolar disorder.

At Screening Has a DSM-IV-TR diagnosis of or has received treatment for major depressive disorder, panic disorder, obsessive-compulsive disorder, social phobia, bulimia nervosa, schizophrenia or schizoaffective disorder within 12 months of screening.

At Screening Has a history of substance (including alcohol and drugs) dependence within 12 months of screening or abuse within 1 month of screening according to DSM-IV-TR.

At Screening Patients whose mood episode is due to direct physiological effects of a general medical condition (for example, hypothyroidism, hyperthyroidism) At Screening Has a score of 3 or more on item of the HAM-D related to suicide or is at a high suicidal risk in the judgment of the investigator/sub-investigator.

At Screening Has a history of severe rash or rash due to anti-epileptic drugs. At Screening Patients with severe hepatic/renal/cardiac/pulmonary disorder or hematopoietic disorder. The severity refers to Grade 3 according to the Classification of the Severity of Adverse Experiences (PAB/SD Notification No. 80, dated 29 June 1992).

At Screening Patients have less than 5 years of remission history from clinically significant malignancy (other than e.g. basal cell or squamous cell skin cancer, in-situ carcinoma of cervix or prostate CA in situ).

At Screening Patients with chronic hepatitis typeB and /or typeC which is positive of hepatitis B surface antigen （HBsAg）and/or hepatitis C antibody.

At Screening Has an acute or chronic illness likely to impair drug absorption, distribution, metabolism or excretion or has any unstable physical symptoms likely to require hospitalisation during participation in the study.

At Screening Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study.

At Screening Has a history or current diagnosis of epilepsy. At Screening Has a history of treatment with lamotrigine. At Screening Patients with a history of drug allergy to any ingredient of the test-drug. At Screening Has received an investigational drug within 30 days of screening. At Screening Is morbidly obese (Body Mass Index \[BMI\] \>40) BMI = body weight (kg)/height (m2).

At Screening Patients whom the investigator or sub-investigator considers ineligible for the study.

At Week 0 of First Phase (titration) Has a score of 3 or more on item of the HAM-D related to suicide or is at a high suicidal risk in the judgment of the investigator/sub-investigator and continues .to meet the criteria at the screening visit.

At Week 0 of Second Phase (maintenance therapy) Has signs or symptoms of psychosis. At Week 0 of Second Phase (maintenance therapy) Has a score of 3 or more on item of the HAM-D related to suicide or is at a high suicidal risk in the judgment of the investigator/sub-investigator.

At Week 0 of Second Phase (maintenance therapy) Has had a change in lamotrigine dosage during the final week of the First Phase (titration).

At Week 0 of Second Phase (maintenance therapy) Has a diagnosis of bipolar I disorder, most recent episode of depressed (296.5x) and has experienced manic, hypomanic or mixed symptoms; Has a diagnosis of bipolar I disorder, most recent episode hypomanic (296.40) or most recent episode manic (296.4x) and has experienced depressive symptoms, that require treatment during the First Phase (titration).
D: Inclusion criteria:

1. Age above 18
2. Inclusion is preceded by an affective episode requiring hospitalisation or outpatient drug treatment (index episode) which can be a manic episode (ICD-10 research criteria), a depressive episode of at least moderate degree (ICD-10 research criteria) or a mixed manic state (manic episode with at least additional three ICD-10 depressive symptoms except for difficulties with concentration or thinking, agitation or dyssomnia). The episode can be with or without psychotic symptoms including Schneiderian first-rank symptoms or bizarre delusions as long as the psychotic symptoms do not occur outside the affective episode.
3. No more than 12 months may pass between the onset of the index episode (or admission if that is the case)and date of randomisation (in order to ensure a current risk of relapse as well as reliable psychopathological information).
4. Besides the index episode, at least one previous episode must have occurred within the last five years which meets the criteria mentioned in point number two above. This episode may not necessarily have led to hospitalisation. Two episodes are separated by at least two months without significant symptoms or change in polarity (depression to mania/mixed mania or vice versa).
5. At least one manic episode (or mixed manic episode) within the last 5 years.

Exclusion criteria:

1. Contraindications to the protocol drugs.
2. Severe somatic disease, e.g. epilepsy, which may interfere with study treatment or effect evaluation.
3. Pregnancy (or risk of pregnancy).
4. Subject has prior to randomization received prophylactic treatment with lithium or lamotrigine conducted adequately in the sense of sufficient time and dose and ensuring compliance, and experienced a definite lack of prophylactic effect
5. An ICD-10 diagnosis of abuse within the last year with a subsequent risk of protocol violation. Therefore, subjects with a secondary abuse can often be included in the study.
6. Anticipated protocol violation for other reasons.
7. No written informed consent from the subject can be obtained.
8. The subject has previously been randomised in the study.

Answer: B