Neuroprotective and neurogenesis agent for treating bipolar II disorder: Add-on memantine to mood stabilizer works

Abstract

Bipolar disorder, characterized by a dysregulation of mood, impulsivity, risky behavior and interpersonal problems, is a recurrent and often becomes chronic psychiatric illness. However, bipolar subtypes are not often recognized in psychiatric settings, especially bipolar II subtype, until Akiskal and Angst made clear definition to bipolar I (BP-I) and bipolar II (BP-II) disorder in 1999. More and more studies, not only on family inheritance, diagnosis, but also on disease process have been reported that BP-I and BP-II are two different disorders with distinct pathological mechanisms. In general, patients with BP-II express less symptoms and have shorter hypomania stages than BP-I. According to a longitudinal research, patients with BP-II have poor recovery than do BP-I patients.

Memantine used to be recognized as a noncompetitive N-methyl-d-aspartate receptor antagonist. However, it was found to have neuroprotective and neurogenesis effect in several neurodegenerative diseases in the past years. We found that memantine could inhibit brain inflammatory response through its action on neuroglial cells and provide neurotrophic effect. The above evidences of benefit on auto-immune system with memantine would support that memantine as add-on therapy to valproate might be more effective than valproate alone on improvement of the neuron degeneration in bipolar disorders. Review articles indicate that not only the mood stabilizers provide with good neuroprotection, but the memantine also have conspicuous anti-autoimmune and neurogenesis effect. Therefore, we propose that drugs with neuroprotective effect and neurotrophic effect may treat neurodegenerative diseases including BP-II. The combination treatment of mood stabilizers memantine may not only augment and improve the remedy for bipolar disorders, but also repair the damaged neurons and neurogenesis through activation of astroglial cell and release of neurotrophic factors.

Introduction

Bipolar disorder (BP) [1] characterized by a dysregulation of mood, impulsivity, risky behavior, and interpersonal problems, is a recurrent and often chronic psychiatric illness [1], [2]. According to the World Health Organization (WHO), BP is the sixth leading cause of disability-adjusted life years worldwide among persons aged 15–44 years [3]. It is associated with functional impairment [4], [5], elevated suicide rates [2], [5], and utilization of mental health systems [6].

The BP is known for recurrent depressive, manic, and mixed episodes, and divided into several categories. The two most common and severe subtypes are bipolar I disorder (BP-I) and bipolar II disorder (BP-II). BP-I is characterized by the occurrence of one or more manic episodes or mixed episodes, accompanied by one or more major depressive episodes, while BP-II requires the presence of one or more major depressive episodes and at least one hypomanic episode. Although some researchers have questioned whether BP-II is simply a milder form of BP-I or is a distinct disorder, more and more researchers have documented that BP-I and BP-II have different etiologies, including genetics, variation, and characteristics during the course of the illness [7], [8]. Long-term follow-ups show that patients with BP-II have a more chronic course, more mood episodes, more major and minor depressive episodes, and shorter inter-episodes, which last longer than those of patients with BP-I [9], [10]. The lifetime prevalence rate of BP-I is about 2.4% [11] while BP-II has been perceived as a common disorder with a prevalence of approximately 3–11% [12], [13].

However, the BP, especially BP-II, is commonly under-recognized, even in psychiatric settings [14], and it may take years before those patients receive a correct diagnosis [15] and appropriate treatment [16]. In our previous study, we found that the misdiagnosis rate of different subtypes of BP is much higher in Taiwan than in Western countries [17]. The current DSM-IV diagnostic criteria for BP-I and BP-II are the same except for different durations of hypomania and manic episodes: for BP-I it is more than 7 days and for BP-II more than 4 days [18]. This may also account for the difficulty in differentiating BP-I and BP-II and for the frequent misdiagnosis of BP-II. Even when correctly diagnosed, fewer than 50% patients are successfully treated [19], and 10–15% may eventually die as a result of suicide. Psychosocial impairments also significantly increase with each increment in the severity of the symptoms of BP-II depression [20].