Bipolar disorder as cell membrane dysfunction. Progress toward integrative management.

Abstract

Bipolar disorder (BD) is characterized by periods of abnormally elevated mood (mania) that cycle with abnormally lowered mood (depression). Multiple structural, metabolic, and biochemical abnormalities are evident in the brain's cortex, subcortex, and deeper regions. This disorder is highly genetically conditioned but also highly susceptible to environmental stressors: prenatal or perinatal insults, childhood sexual or physical abuse, challenging life events, substance abuse, and other toxic chemical exposures. Its high morbidity, lost productivity, and suicide risk place a great toll on society. Since World War II, BD has been steadily worsening with earlier age of onset, greater intensity of symptoms, and development of drug resistance. Incidence in children is rising and misdiagnosis is common. Disciplined management of the many risk factors is essential, including cognitive psychotherapy and support from family and community. Lithium has been the foundational treatment, followed by valproate and other mood stabilizers, antidepressants, and anticonvulsants. Several single-nutrient and multinutrient supplements have also proven beneficial. Controlled, double-blind trials show multinutrient combinations of vitamins, minerals, orthomolecules, herbals, and the omega-3 fatty acids EPA and DHA to be effective monotherapy. The molecular action of lithium and valproate converge with nutrients on the level of the cell membrane and its molecular signal transduction systems. This emergent, unified rationale presages effective integrative management of bipolar disorder.

Introduction

Bipolar disorder (BD; manic depressive illness) is a disorder of the brain characterized by extreme changes in mood, enemy, thinking, and behavior. It is one of the earliest identified mental disorders, recognized as early as the time of Hippocrates in 400 BC. (1) Bipolar disorder has left its mark on history--prominent individuals who had symptoms of BD include Winston Churchill. Ernest Hemingway, Abraham Lincoln, Theodore Roosevelt, and Virginia Woolf. (2, 3) It is on the increase, especially among children and adolescents. But despite a considerable existing knowledge base, BD remains one of the most difficult disorders to diagnose, classify, and manage. (4)

Bipolar disorder is a major cause of disability and premature death from suicide, yet it is greatly underdiagnosed, and inappropriate pharmacotherapy often worsens the symptomatology. (5) The existing pharmacotherapies can have devastatingly adverse effects, yet BD management has received surprisingly minimal priority compared with unipolar ("major") depression. This review covers the clinical features of BD and current available therapies. Recent research advances are reviewed and a framework proposed for a more advanced, integrated approach to management.

Diagnosis, Prevalence, Progression

During the time of Hippocrates, this illness was seen as two disorders: mania and melancholia. (1) Its recognition as a single disorder dates to 1921, when the term manic-depressive insanity was coined by Emil Kraepelin, who made significant contributions to classifying the various psychotic disorders. (6) Estimates of the current lifetime prevalence rate of BD vary widely, from 1 percent to as high ns 3.7 percent worldwide for the entire bipolar spectrum. (5,7) Among children and adolescents the incidence has been spiraling upward for the past half century. (8)

Bipolar disorder can manifest at almost any age, but the peak period of onset is adolescence (15-19 years). (9) Later onset suggests a lesser familial genetic contribution. In the United States prevalence appears similar across ethnicities, but misdiagnoses (a general problem with this disorder) are even more frequent in the African American and Hispanic populations. (9)

Bipolar disorder has significant morbidity and mortality: the illness can ravage the patient's employment status and personal relationships, and sexuality and financial management capacities can become distorted. Lifetime risk for suicide is 19 percent, a rate comparable to the mortality rates for some heart diseases and cancers. (9)

Diagnosis and Subtypes

The formal diagnosis of BD is complicated and is somewhat different in the United States than Europe. Following the U.S. Diagnostic and Statistical Manual 4th Edition (DSM-IV), (10) the bipolar disorders involve the presence (or history) of manic episodes, mixed episodes, or hypomanic episodes, usually accompanied by major depressive episodes. The occurrence of mania distinguishes bipolar disorder from other depressive disorders, including major depressive disorder commonly known as clinical depression.

The U.S. DSM-IV recognizes four subcategories of BD: (10)

* Bipolar I disorder--characterized by one or more manic or mixed episodes usually accompanied by major depressive episodes. There can be psychotic features, catatonic features, or postpartum onset. The pattern can be predominantly seasonal or involve rapid cycling. During manic episodes violent behavior is common, such as child or spousal abuse or other antisocial behavior. Some 10-15 percent of these individuals attempt suicide. Bipolar I is highly heritable among first-degree relatives.

* Bipolar II disorder--characterized by one or more major depressive episodes accompanied by at least one hypomanic episode. As with Bipolar I, this disorder is highly heritable and a similar percentage attempt suicide.

* Cyclothymic disorder--characterized by at least two years of numerous periods of hypomanic symptoms that do not meet criteria for a manic episode, and numerous periods of depressive symptoms that do not meet criteria for a major depressive episode. This is a chronic, fluctuating mood disturbance. This disorder often begins in adolescence or early adult life, and has a 15-50 percent risk of subsequent progression to bipolar 1 or II disorder. Often a first-degree family link exists.

* "Bipolar disorder not otherwise specified"--is a catch-all category for cases with bipolar features that do not meet criteria for the three foregoing categories, or for which there is inadequate or contradictory information. For more detail, refer to the DSM-IV.

Criteria for Defining Episodes (10)

The DSM-IV defines a major depressive episode as a minimum two-week period during which there is depressed mood or loss of interest in nearly all activities. Other symptoms must be involved, such as changes in appetite, sleep, or psychomotor activity: decreased energy: feelings of worthlessness or guilt: difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation. The episode must be accompanied by clinically significant distress or impairment in social, occupational, or other important areas of functioning.

A manic episode has a minimum one-week duration in which there is abnormally and persistently elevated, expansive, or irritable mood. Elevated mood is euphoric or excessively high for that individual. Labile alternation between euphoria and irritability is frequently seen. Other symptoms must be present, such as inflated self-esteem or grandiosity, less need for sleep, flight of ideas, distractibility, psychomotor agitation, and self-destructive behavior. Manic episodes are also characterized by "unceasing and indiscriminate" enthusiasm for interpersonal, sexual, or occupational interactions.

A hypomanic episode lasts a maximum of four days, during which time mania is evident. The episode must not be severe enough to cause marked functional impairment or require hospitalization. Symptoms can resemble a manic episode except that delusions, hallucinations, and psychosis cannot be present.

A mixed episode involves at least one week during which the criteria are met for both a manic episode and a major depressive episode nearly every day.

The Bipolar Spectrum

Over the past decade it has become acceptable to view BD as a continuum of symptom severity, ranging from features of relatively mild depression and brief hypomania to debilitating patterns of rapid cycling or frequent mania with psychotic features. Individual patient symptoms can vary in degree of polarity, severity from episode to episode, duration of episodes, and cycling frequency. Many physicians, some very experienced with BD, have trouble distinguishing among the subcategories of BD, and the concept of a bipolar spectrum often has more clinical relevance than bipolar I versus bipolar II. (1)

Conditions Comorbid with Bipolar Disorder

The most frequent comorbid conditions with BD are anxiety-related, (11) such as panic or obsessive-compulsive disorder; (12) substance abuse; so-called disruptive behavior conditions, such as attention deficit disorder and oppositional-defiant disorder; (13) and, among women, post-traumatic stress disorder (PTSD) and eating disorders. (9) Advisedly, patients presenting with any of these other comorbid conditions should be assessed for possible BD.

BD is much more common in multiple sclerosis patients than in the general population. (14) Other significant comorbidities with BD are Asthma (15) and possibly migraine. (16)

Bipolar disorder is linked with schizophrenia (SCZ) through symptomatic, genetic, and pathophysiological similarities. (7) Many neurotransmitter abnormalities seen in SCZ, most notably enhanced sensitivity to dopamine and dopamine agonists, are seen in BD. (1) Also, newer atypical antipsychotics approved for SCZ (olanzapine, risperidone, quetiapine) are proving useful for BD. (1)

BD also has substantial overlap with major depressive disorder (MDD). (10) Just as the pathophysiologies of BD and SCZ do not show marked differences, a 1997 review of studies that directly compared the biological features of unipolar depression with bipolar depression was unable to find consistent differences. (17) Abnormalities of serotoninergic actions are seen in MDD and BD as well as SCZ. (1)

Family studies also suggest linkages between schizophrenia, bipolar disorder, and major depressive disorder. Many families, followed through several generations, demonstrate a prevalence of all three diagnoses. (18) Clinically, many patients show features of two or even all three of these psychiatric illnesses. (19) Mechanistic research suggests shared cell membrane dysfunctions. (18) Proponents of a "continuum" in the major affective disorders suggest a continuum ranging from unipolar to bipolar disorder, through schizoaffective psychosis, all the way to schizophrenia. (1,18)

Rising Incidence among Children and Adolescents

This disorder has probably always afflicted children--in particular the biographies of Beethoven, Newton, and Dickens reveal severe, debilitating, and recurrent mood swings beginning during childhood. (8) In the United States, each generation since World War II has had a higher incidence and earlier age of onset of BD. (8) On average, children with BD experience their first episode of illness 5-10 years earlier than did their parents" generation. (8) Once the illness starts it tends to get worse until treatment is begun.

Children with BD often experience rapid cycling of mood states several times daily. (2) This generally manifests as ongoing, chronic irritability with a few hours of wellness between episodes. (8) The disorder in children is likely more severe than in adults, with many children manic and depressed at the same time and ill for years without intervening periods of wellness. (2)

Adolescents tend to manifest a symptom pattern closer to adult BD. For many, a traumatic event triggers their first episode. Puberty carries increased risk, and in girls the onset of menses may trigger the illness. An estimated 10-15 percent of adolescents with recurrent major depressive episodes develop bipolar I disorder. (8) In this population BD is often misdiagnosed as borderline personality disorder, post-traumatic stress disorder, or schizophrenia.

In the United States an estimated one million or more minors diagnosed with major depression may actually be experiencing early onset BD. (8) The Child and Adolescent Bipolar Foundation estimates a "significant number of children" diagnosed with ADHD actually have BD. (8)

Children and juveniles with BD are at high risk for developing addictions to drugs and alcohol. Those with mania face a heightened risk for trauma exposure (violence, rape, physical or sexual abuse, or other events outside the range of normal human experience). (13) This scenario underscores the harsh reality of childhood BD and the need for improved diagnosis and management.

The Pathophysiology of Bipolar Disorder

The new generation of imaging instrumentation has revolutionized brain research. These macroscopic findings are being integrated with the more traditional microscopic pathological findings to derive clinically relevant understanding of the structural, metabolic, and biochemical abnormalities that encompass bipolar disorder. (20-23)

Structural Abnormalities

The BD brain shows structural abnormalities on a regional basis, (20,22,23) with zones within the cortical, subcortical, limbic, and other regions affected. Best documented is the prefrontal cortex.

Prefrontal Cortex

Within the prefrontal cortex the anterior cingulate cortex areas (ACCA) are known to be centrally involved in mood disorders. The ACCA are thought to be at the functional interface of emotion, cognition, drive, and motor control. (20) Magnetic resonance imaging(MRI) by Drevets and colleagues revealed gray matter volume was reduced 25-40 percent in the ACCA in BD. (20,24)

Drevets' group investigated further, using histological morphometric cell-counting techniques. They found a trend toward reduced numbers of glia "'support" cells but not of neurons. (25) Several subsequent studies established that glial cell numbers were reduced, with caveats that the changes applied specifically to familial but not non-familial BD. (20) Abnormal neuron appearance was evident, but without loss in numbers. Histochemical localization of synaptic and dendritic proteins found reduced amounts for most of them, indicating synaptic and probably also dendrite pathology. In sum, the prefrontal cortex shows "cytoarchitectural" circuit abnormalities specific to BD. (20) Other regions of the prefrontal cortex were implicated in mood disorders on functional and structural grounds. Similar changes were evident as in the ACCA. (20) Glial cell loss was again seen, together with neuronal changes and overall circuit abnormalities.

Hippocampal Formation

The hippocampus has also been implicated in mood disorders. Several MRI studies found significantly smaller hippocampal volumes in BD patients. (20) Histological studies are equivocal on cell changes, but histochemistry suggests subtle synaptic and dendritic abnormalities may be present. (20,26)

Subcortical Regions

In order to test the neurotransmitter imbalance theories of depression and bipolar disorder, cell bodies within the subcortical zones that secrete serotonin and catecholamines were quantified. To date several studies reveal no consistent Changes. (20) Subtle network or circuitry abnormalities cannot yet be ruled out.

Within the deep subcortical white matter lie the most consistent pathologic findings of BD--white matter hyperintensities (WMH). More than 30 MRI or computed tomography (CT) studies have imaged such small areas, where the signal intensity is high relative to the surrounding tissue. (20,22) Most often seen in aging and cerebrovascular disorders, WMH are extremely rare in healthy individuals under the age of 30. Demyelination, glial cell inflammation, or axonal loss linked to brain ischemia and infarction contribute to WMH.

The risk for having WMH was estimated to be 3-7 times higher in BD patients of all ages. (20,22) When present they are generally observed early in the course of illness, although most patients with BD do not have WMH, nor is there any clear …