This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.

Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

This discussion reviews data from two 3-week, double-blind, placebo-controlled pivotal trials of carbamazepine extended release capsules (CBZ ERC; SPD417.301 and SPD417.304); pooled results from these trials; data from a 3-week, double-blind, placebo-controlled trial in lithium non-responders or non-tolerators (SPD417.302); and additional supportive data from a 6-month, open-label, extension trial (SPD417.303). In addition, information on a retrospective chart review of 600 adolescent and adult bipolar patients on CBZ ERC is presented.

In the first large double-blind, placebo-controlled study assessing CBZ ERC in acute mania, manic and mixed bipolar patients from multiple centers were hospitalized and all medications were discontinued. After reaching a stable baseline 2–5 days later, the patients were randomized to CBZ ERC (n=101; 59% with mixed states) or placebo (n=103; 47% with mixed states) for 3 weeks. An aggressive initial titration schedule was implemented, beginning with 200 mg BID and increased by 200 mg/day until good clinical response was achieved or the patient could not tolerate the dosage. Many patients were taking 1,200–1,600 mg/day by the end of week 1. Efficacy was assessed using the Young Mania Rating Scale (YMRS). The Clinical Global Impressions (CGI) scale and the Hamilton Rating Scale for Depression (HAM-D) were also followed.

This discussion focuses on the historical trends of carbamazepine in the treatment of acute mania, acute bipolar depression, and as maintenance treatment for bipolar disorder. Clinical implications of efficacy, safety, tolerability, and drug interactions associated with carbamazepine are discussed as well.

Important progress in bipolar disorders therapeutics began in the 1970s with lithium and the conventional antipsychotics, and continued in the 1980s with carbamazepine, in the 1990s with divalproex, and in the 2000s with lamotrigine and the introduction of the atypical antipsychotics. Electroconvulsive therapy (ECT) has been used throughout these periods and still has a place in bipolar disorder, especially for severe, treatment-resistant, and very acute cases.

Immediate-release carbamazepine was first approved for epilepsy in 1974, followed by approval of carbamazepine extended release capsules (CBZ ERC) for epilepsy in 1997. Reports of carbamazepine use in bipolar disorder began in 1973 in Japan, when Okuma and colleagues reported antimanic efficacy in manic-depressive psychosis. In 1978, Ballenger and Post reported effective use of carbamazepine in bipolar illness. The initiation of CBZ ERC in bipolar disorder trials began in 2001. In 2004, CBZ ERC received Food and Drug Administration approval for the treatment of acute manic and mixed episodes in patients with bipolar disorder (Slide 4).

In 1988, a survey of American psychiatrists reported moderate-to-marked effectiveness for carbamazepine for the following conditions: partial complex seizures (85%), generalized seizures (82%), trigeminal neuralgia (81%), mania prophylaxis (72%), acute bipolar depression (67%), intermittent explosive disorder (65%), acute mania (62%), and schizoaffective disorder (58%). Historically, carbamazepine has been considered superior to lithium for rapid cycling and mixed mania, bipolar II disorder, bipolar disorder not otherwise specified (NOS), and bipolar disorder with mood incongruent delusions or comorbidity. In multiple controlled trials, carbamazepine was as effective as lithium in the treatment of acute mania. Limitations of early controlled carbamazepine trials include lack of parallel placebo groups, small samples (commonly <60 subjects), confounds of concomitant treatments, and low doses used to avoid/attenuate adverse effects.

A 48-year-old woman suffering from treatment-resistant psychogenic stiff neck and severe depression had been treated with a varied regimen of medications, including antidepressants, neuroleptics, and antiepileptics. These treatments did not result in improvement. Therefore, she was treated with a combination of sertraline and risperidone. Depressive symptoms decreased within a few weeks of treatment initiation. The psychogenic stiff neck, which had begun to improve within the first 2 weeks, had disappeared completely after 6 months of treatment with risperidone alone. This case report suggests that risperidone may be effective in some neurological motor disorders comorbid with mood disorders.

The transition from reproductive age to menopause is a major milestone in the female lifecycle. It is a hormonal process with a very clear end result: a menopausal state—though its commencement is gradual and vague. It is unavoidable and perfectly normal. The age of the transition varies widely, a fact that hints at the possibility that the reproductive clock is individualized, ticking at a diversified pace. Therefore, the study of the menopausal transition may actually be a derivative of the study of reproduction because it marks the closing of that chapter in a woman's life.

In a sequential approach, the period of transition is defined as perimenopause, or the menopausal transition, the beginning of the second phase in the life of the adult woman, characterized by a stable, low level of gonadal steroids, as opposed to the cyclic fluctuations during the reproductive phase. This imposed, though anticipated, closing of the reproductive chapter of life is often associated with mixed feelings.

As reviewed by Andrea Riccardo Genazzani, MD, PhD, and colleagues, gonadal steroids exercise a profound effect on many body systems, including the brain, in which they have specific receptors, influencing neurotransmitters and other central nervous system (CNS) mechanisms that are considered to be involved in the regulation of mood, cognition, and behavior. Therefore, it would be anticipated that the menopausal decrease in activity levels of female gonadal hormones, ie, estrogen and progesterone, resulting in substantial changes in mood, cognition, and behavior of menopausal women—but this is not the case. This fact illuminates two issues of social and clinical significance: Menopause, per sé, is a normal healthy situation, and even though it is normal it is characterized by age-related processes that may be slowed down or delayed by gonadal steroids.

The central nervous system is one of the main target tissues for sex steroid hormones, which act on both through genomic mechanisms, modulating synthesis, release, and metabolism of many neuropeptides and neurotransmitters, and through non-genomic mechanisms, influencing electrical excitability, synaptic function, morphological features, and neuron-glia interactions. During the climacteric period, sex steroid deficiency causes many neuroendocrine changes. At the hypothalamic level, estrogen withdrawal gives rise to vasomotor symptoms, to eating behavior disorders, and altered blood pressure control. On the other hand, at the limbic level, the changes in serotoninergic, noradrenergic, and opioidergic tones contribute to the modifications in mood, behavior, and nociception. Hormone replacement therapy (HRT) positively affects climateric depression throughout a direct effect on neural activity and on the modulation of adrenergic and serotoninergic tones and may modulate the decrease in cognitive efficiency observed in climaterium. The identification of the brain as a de novo source of neurosteroids, suggests that the modifications in mood and cognitive performances occurring in postmenopausal women may also be related to a change in the levels of neurosteroids. These findings open new perspectives in the study of the effects of sex steroids on the central nervous system and on the possible use of alternative and/or auxiliary HRT.

Data regarding the increased incidence of psychiatric illness during midlife in women are still conflicting. However, there is a growing consensus that certain groups of women may in fact be at higher risk for mood symptoms and psychiatric disorders during the perimenopausal transition. Mood symptoms during the perimenopause may be related to mood disorders during other periods of hormonal fluctuation throughout a woman's reproductive lifecycle. Elucidating these associations may advance the understanding of mood disorders during the perimenopausal transition. The epidemiology and treatment of perimenopausal mood symptoms compared with the epidemiology and treatment of mood disorders during the late luteal phase of the menstrual cycle, pregnancy, and postpartum. Common risk factors associated with mood disorders during these periods of hormonal changes or instability include poor lifestyle habits, a history of hormonally related mood disorders, stress and negative life events, ethnicity, and comorbidity. Reproductive-related mood disorders also are subject to an improvement in symptoms in response to treatment with selective serotonin reuptake inhibitors. As the morbidity associated with mood disorders during midlife may be quite significant, and as life expectancy continues to increase, recognition, prevention, and treatment of perimenopausal affective illness is becoming increasingly essential.

Perimenopause, the interval of irregular menstrual activity which directly precedes menopause, is characterized by widely fluctuating hormone levels amidst a large-scale decline in circulating estrogen. This phase in a woman's life is typically accompanied by physical discomforts including vasomotor symptoms, such as headaches, insomnia, and hot flushes, as well as genital atrophy. Not surprisingly, studies suggest a significant increase in mood lability for women during this time. While some evidence points toward an exacerbation of bipolar mood symptoms and an increase in schizophrenic psychosis during perimenopause, the majority of research conducted on perimenopausal mental disorders has focused on unipolar depression. Studies vary widely in methodology, definitions of menopausal status, and degrees of depression among subjects; however, the majority of findings indicate an increased susceptibility to depression during the perimenopausal transition. This greater susceptibility may be due to neuroendocrine effects of declining estrogen levels, the subjective experience of somatic symptoms resulting from this hormonal decline, and/or the more frequent occurrence of “exit” or “loss” events for women during this stage of life. At this time, more research is needed to address questions of prevalence, risk, and etiology for depression and other major mental disorders as related to the physiological and psychosocial changes associated with perimenopause.

Alzheimer's disease is a progressive condition characterized by a loss of cognition, altered behavior, and a loss of functional ability, such as bathing, dressing, toileting, and organizing finances. Family and friends provide nearly three quarters of all care for patients with Alzheimer's disease. This informal care results in significant burden to caregivers. Caregiver burden is the set of physical, psychological or emotional, social, and financial problems that family members may experience when caring for impaired older adults. Caregivers of Alzheimer's disease patients report higher rates of physical symptoms, mortality, depression, and fatigue, as well as adverse effects on employment compared with those who are not caregivers for Alzheimer's disease patients. In many cases, the same family members are responsible for both out-of-pocket expenditures and caregiving duties. For this article, a MEDLINE search using the key words “caregiver and Alzheimer's disease” and “cost and Alzheimer's disease” was performed. The purpose of this article is to review the literature on caregiver burden, the components of caregiver burden, effects of caregiving on the health of caregivers, the cost of Alzheimer's disease on the caregiver and society, and the benefits attainable with treatment.

More than 1.7 million American women are expected to reach menopause each year. Recent Canadian statistics show that a 50-year-old woman can now expect to live until her mid-80s, which implies living at least one-third of her life after menopause. The menopausal transition is typically marked by intense hormonal fluctuations, accompanied by vasomotor symptoms (eg, hot flashes, night sweats), sleeps disturbance, and changes in sexual function, as well as increased risk for osteoporosis, cardiovascular disease, and cognitive decline. More importantly, recent studies have demonstrated a significant association between menopausal transition and a higher risk for developing depression. In the post-Women's Health Initiative Study era, physicians and patients are questioning the safety and efficacy of long-term hormone therapy use. This article reviews the current literature on the benefits and risks of using hormone therapy for the treatment of menopause-related mood disturbances and alternate strategies currently available for the management of menopause-related problems, including antidepressants, complementary and alternative medicine, and selective estrogen receptor modulators.