The investigators hypothesized that add-on memantine (MM) 5 mg/day may reduce chronic inflammation, and subsequently improve neuro-progression process and cognitive function in middle-to-old aged bipolar II disorder (BP-II) patients. In current proposal, the investigators will conduct a randomized double-blind placebo-controlled study. The investigators will recruit 100-120 patients with BP-II who are older than 40 years old in three years, and allocate them to add-on MM or placebo plus standard valproic acid treatment in a 1: 1 ratio. The investigators will follow up the participants for 12 weeks and measure the severity of mood symptoms, neuropsychological tests and inflammatory markers to evaluate the therapeutic effects of add-on MM.

Emerging evidence showed that chronic inflammation and neuro-progression underlie bipolar disorder (BP). There were several neurobiological similarities between neuro-progression in BP and aging. Patients of BP also had many changes that were associated with early senescence. Meta-analysis showed that the association between dementia and BP were stronger than those with major depressive disorder, too. Therefore, some researchers proposed the theory of bipolar disorder as an illness of accelerated aging. However, BP is frequently under-recognized and misdiagnosed, especially bipolar II disorder (BP-II). Although the lifetime prevalence rate of BP-II ranges around 3-11%, many with BP-II were misdiagnosed as major depressive disorder and did not receive appropriate treatment. Therefore, neuro-progression may be found after decades of disease onset. The neuro-progression process, as accelerated aging process, may occur in the middle age period in BP-II patients, and contribute to the cognitive deficits, which were typically shown in old aged subjects with neurocognitive disorder. However, most of the past studies focused on bipolar I disorder (BP-I), there were few studies to investigate the early neuro-progression process in BP-II. Treatments for the cognitive deficits in middle-to-old aged BP-II patients were also lacked in literature.

Memantine (MM) has neuroprotective effects through the mechanisms of reducing neuroinflammation and increasing neurotrophic factors. The previous study showed that add-on low dose MM with mood stabilizers may attenuate inflammatory status and improve metabolic dysregulation in BP patients. Therefore, the investigators hypothesized that add-on MM 5 mg/day may reduce chronic inflammation, and subsequently improve neuro-progression process and cognitive function in middle-to-old aged BP-II patients. In current proposal, the investigators will conduct a randomized double-blind placebo-controlled study. The investigators will recruit 100-120 patients with BP-II who are older than 40 years old in three years, and allocate them to add-on MM or placebo plus standard valproic acid treatment in a 1: 1 ratio. The investigators will follow up the participants for 12 weeks and measure the severity of mood symptoms, neuropsychological tests and inflammatory markers to evaluate the therapeutic effects of add-on MM. The current proposal will provide the important data in whether add-on MM is able to improve the cognitive deficits due to neuro-progression in BP-II, and to prevent disease progression to a more severe form of neurocognitive disorder.

Inclusion Criteria:

1. Signed informed consent by patient or legal representative.
2. Male or female patient aged ≧40 years.
3. A diagnosis of bipolar II disorder according to Diagnostic and Statistical Manual of Mental Disorders criteria made by a specialist in psychiatry.
4. Patient or a reliable caregiver can be expected to ensure acceptable compliance and visit attendance for the duration of the study.

Exclusion Criteria:

The presence of any of the following will exclude a patient from study enrollment:

1. Women of childbearing potential, not using adequate contraception as per investigator judgment or not willing to comply with contraception for the duration of the study.
2. Females who are pregnant or lactation.
3. Comorbid with substance-related disorders, borderline personality disorder, schizophrenia, mental retardation, dementia or other major psychiatric disorders. But comorbid with anxiety disorder or tobacco use disorder is not an exclusion criteria.
4. Current evidence of an uncontrolled and/or clinically significant medical condition, e.g., cardiac, hepatic and renal failure that would compromise patient safety or preclude study participation.
5. History of allergy or intolerable side effects of valproic acid, memantine, risperidone, fluoxetine, lorazepam.
6. History of receiving electroconvulsive therapy.
7. Levels of total bilirubin, aspartate aminotransferase(AST)、alanine transaminase(ALT) were elevated more than twice of normal range. Levels of Blood urea nitrogen(BUN) and creatinine were elevated more than three times of normal range.
8. Presence of alcohol abuse/dependence or illicit drug abuse/dependence in previous 6 months before beginning of study.