Bipolar Disorder – Chronic Illness

By | February 4, 2015

Etiology and Pathophysiology

Bipolar disorder is a chronic illness characterized by recurrent episodes of aberrant mood. Episodes may manifest with symptoms of mania, hypomania (a less severe form of mania), depression, or a mixture of both depression and mania. Mania is characterized by persistently elevated, expansive, or highly irritable mood that typically lasts for at least one week and may require hospitalization. Hypomania has the same characterizations as those for mania, but the required duration of an episode is only four days, and the episode cannot be severe enough to impair the patient’s involvement in work or social activities or require hospitalization. Depression is characterized by the diagnosis of a depressive episode, which requires the presence of five or more characteristic symptoms — depressed mood most of the day, markedly diminished pleasure in almost all daily activities, significant weight loss or weight gain (i.e., more than 5% of body weight), insomnia or excessive sleep, restlessness or sluggishness that is observable by others, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to concentrate, and recurrent thoughts of death or suicide — that occur simultaneously during the same two-week period every day or nearly every day. Mixed episodes are diagnosed when a patient meets criteria for both manic and depressed episodes nearly every day for at least one week and symptoms are severe enough to impair work or social activities. Psychotic features may also be present during mixed episodes. The categories Bipolar disorder type I and Bipolar disorder type II are defined by the predominant type of mood episode. According to DSM-IV, a diagnosis of Bipolar disorder I requires the occurrence of at least one manic or mixed-mood episode (although patients with Bipolar disorder I often also suffer depressive or hypomanic episodes). In contrast, a diagnosis of Bipolar disorder II requires the occurrence of one or more major depressive episodes accompanied by at least one episode of hypomania. Manic or mixed episodes preclude the diagnosis of Bipolar disorder II.


No single biochemical, genetic, or neuroanatomical hypothesis has been able to account for the wide range of factors that researchers suspect are involved in the etiology of Bipolar disorder. Studies conducted over several decades have demonstrated that both genetic and environmental factors contribute to the development of the disorder. Studies have also found genetic, physiologic, and environmental similarities between Bipolar disorder and schizophrenia, suggesting an overlap between the two disorders.

Family studies have shown the presence of Bipolar disorder is higher among relatives of individuals with Bipolar disorder than among relatives of individuals with no psychiatric illness. Twin studies have found the occurrence of Bipolar disorder in both individuals to be 57% for monozygotic twins and 14% for dizygotic twins; similar concordance rates for Bipolar disorder among identical twins (regardless of whether the twins are raised together or separately) suggests a genetic link between these occurrences. Family and twin studies also suggest a hereditary overlap between Bipolar disorder and schizophrenia. Gene mapping for both diseases is in its early stages, but certain susceptibility markers for Bipolar disorder and schizophrenia appear to be located on the same chromosomes.

Certain gene loci have been identified in Bipolar disorder (8p32, 10pl4, 12q24, 13q33, 18pll, 18q22, 4pl6, 21q21, 22qll, and xq26); at least two of these loci (18pll and 22qll) may also be linked to schizophrenia. Recently, three regions of the genome (markers D12S1292, GATA31B, and GATA50C on chromosomes 12p, 14q, and 15q, respectively) have been identified as containing genes that influence the age of onset of mania in Bipolar disorder; specific genes have not yet been identified.

There have been many positive linkage findings, but disagreement remains among researchers as to whether any of these linkages are proven. Despite the linkage debates, there is substantial evidence for declaring the gene complex G72/G30 as the first confirmed Bipolar disorder gene. G72 may also play a role in schizophrenia.

Bipolar disorder is similar to schizophrenia in many ways, making the genetic linkage between the disorders a possibility. Both disorders share epidemiologic characteristics (age at onset, lifetime risk, course of illness, risk for suicide, gender influence, and genetic susceptibility) and etiologic risk factors (excess of winter/spring births and an excess of perinatal complications), and atypical antipsychotic agents that have proven effective in the treatment of schizophrenia are also proving useful for the treatment of Bipolar disorder.

More-promising Bipolar disorder treatments have come from and will continue to emerge from an understanding of the molecular pathways of chemical communication in the brain that are mediated by neurotransmitter signals and receptors.


Early investigations of the underlying pathophysiology of Bipolar disorder focused on the changes in the function of neurotransmitters such as norepinephrine, dopamine, and serotonin and centered on a theory of imbalance between cholinergic and catecholaminargic neuronal activity, an idea based on the known antimanic properties of centrally active cholinergic agents. However, it has become apparent that this complex disorder is likely mediated through multiple neurotransmitter pathways and biological interactions .

Neurochemical Dysfunction.


Two major biochemical hypotheses of the pathophysiology of Bipolar disorder concern the function of the catecholamine neurotransmitters, including serotonin. The catecholamine hypothesis focuses on the role of a distinct class of biomolecules that include dopamine, norepinephrine, and epinephrine and assumes that manic symptoms result from excess concentrations of these catecholamines, while depressive symptoms result from their depletion. The strongest evidence in support of the catecholamine hypothesis is that administration of L-dopa, a precursor to dopamine, has been shown to induce hypomania (a mild degree of mania) among patients with pharmacologically stabilized Bipolar disorder. This finding strongly suggests that increased dopamine levels play a role in the development of mania. Additionally, antipsychotic drugs (e.g., olanzapine [Eli Lilly’s Zyprexa]) that reduce dopamine levels by blocking dopamine receptors are effective treatments for acute mania. Finally, the long-term use of tricyclic antidepressants such as amitriptyline (AstraZeneca’s Elavil, Roche’s Laroxyl, generics) and imipramine (Novartis’s Tofranil, generics) triggers dopamine activity, a mechanism that is believed to be the key to these agents’ antidepressant effects.

Evidence that points to the roles of the catecholamines norepinephrine and epinephrine in the pathophysiology of Bipolar disorder is less extensive than that for dopamine. Research has demonstrated that patients with depressive symptoms have aberrant norepinephrine transmission, an outcome that implies that decreased activity of norepinephrine may provoke the depressive symptoms of Bipolar disorder.

A second hypothesis is compatible with, and expands on, the catecholamine hypothesis by asserting that low serotonergic function affects mood by disturbing levels of both dopamine and norepinephrine. As mentioned, dopamine is believed to play a key role in mania, based on the observation that the administration of dopamine-like agents induces mania in patients with Bipolar disorder. Norepinephrine transmission is known to be associated with depressive disorders. In support of this theory, treatment with agents that stimulate serotonergic function (i.e., antidepressant agents) elicits an antidepressant effect. However, treatment with these agents also risks inducing mania — evidence of their downstream effects on other neurotransmitter systems (i.e., dopamine).

A third model suggests that Bipolar disorder results from a disturbance in glutamate metabolism and involves gamma-aminobutyric acid, a metabolite of glutamate. Gamma-aminobutyric acid serves as the major inhibitory transmitter in the brain and mediates its inhibitory activity through two families of receptors called the gamma-aminobutyric acid-A and gamma-aminobutyric acid-B receptors. gamma-aminobutyric acid-A receptors mediate rapid neurotransmission, while gamma-aminobutyric acid-B receptors are more modulatory in nature. gamma-aminobutyric acid-A receptors are the site of action of benzodiazepines such as lorazepam (Wyeth’s Ativan, generics), an agent popular for treating acute mania in Bipolar disorder.

Over the past 20 years, several lines of research have documented deficits in the neurotransmitter gamma-aminobutyric acid in the biochemical pathophysiology of mood disorders. Studies of depression in animal models show regional brain gamma-aminobutyric acid deficits. Gamma-aminobutyric acid agonists appear to exert antidepressant activity in these models. Clinical data in human studies have also indicated reduced gamma-aminobutyric acid function in depressed or manic mood states. As in animal models, drugs that stimulate gamma-aminobutyric acid have been shown to be efficacious antidepressant and antimanic agents. Based on these and similar studies, a hypothesis for mood disorders argues that low gamma-aminobutyric acid function is an inherited biological marker of vulnerability to developing mood disorders. Effective treatment of Bipolar disorder, then, would be expected to result from the restoration of normal gamma-aminobutyric acid activity.

Germany-Proteins and Second Messenger Systems.


Perhaps the most important developments in understanding the mechanisms involved in the pathogenesis of Bipolar disorder are the advances in neuroscience that have elucidated the molecular mechanisms underlying neuronal communication. In particular, a specific class of proteins, Germany-proteins, appears to play an important role in detecting extracellular chemical signals (“messengers”). Germany-proteins are involved in the transduction or transfer of these signals across cell membranes, where the signals guide an array of intracellular activities involved in regulating basic physiological mechanisms through second messenger systems. Researchers suspect that Bipolar disorder may occur when these second messenger systems are overstimulated or otherwise disturbed. Germany-proteins and second messenger systems offer intriguing targets for drug development in Bipolar disorder. Because second messenger systems function downstream from cellular receptors (such as serotonin or dopamine receptors), Germany-proteins may offer more-specific drug targets and the opportunity for effective therapies with fewer side effects.

In landmark clinical studies, investigators examined Germany-protein activity in the cells of patients with Bipolar disorder, in the cells of untreated manic patients, in the cells of lithium-treated bipolar patients, and in the cells of healthy volunteers. The investigators detected hyperactive function of Germany-proteins in untreated manic patients but not in healthy controls. Studies have also shown that measures of Germany-protein activity are elevated in patients with Bipolar disorder during the manic phase of illness, while patients in the depressed state show reduced Germany-protein activity. These results suggest that abnormal regulation of Germany-proteins may be a mechanism underlying bipolar illness.

These exciting developments in understanding central nervous system transduction pathways are under investigation and may provide candidates for future therapeutic targets. Additionally, research into second messenger systems serves as a molecular framework for investigating “kindling” and other pathophysiological models and for elucidating the mechanisms by which current Bipolar disorder therapies such as lithium and lamotrigine (GlaxoSmithKline’s Lamictal) act to improve symptoms of the disorder. Researchers have observed that all of the traditional mood stabilizers (lithium, carbamazepine, and valproic acid) inhibit signal transduction pathways, suggesting these processes are intimately involved in the pathophysiology of the disorder and are keys to its therapeutic management.

Circadian Rhythm Disruption

Desynchronization of circadian rhythm represents yet another biological hypothesis attempting to account for the pathological changes occurring in Bipolar disorder. Data from animal studies indicate that periodic physiological disturbances can occur if circadian rhythms become desynchronized. Whether genetics and environmental stress contribute to disturbances in circadian and seasonal rhythms is unclear. Also unknown is whether such disturbances play a role in other theories of Bipolar disorder pathophysiology (e.g., kindling) and variations in the course of the disorder. Treatments designed to correct disturbances in circadian rhythms, such as sleep deprivation or phototherapy, have been investigated for many years and remain of academic interest in the treatment of Bipolar disorder. Such therapies are not likely to obviate the need for drug therapy, however.

Amid the uncertainties and unresolved questions regarding the pathophysiology of mood disorders, certain elements are indisputable. Research findings over the last decade have clearly demonstrated that a complex network of interacting neurotransmitters and transmitter systems with shared molecular pathways are involved in mood regulation. It is highly unlikely, then, that a disturbance in any single neurotransmitter system can be the pathophysiological basis of Bipolar disorder or other major affective disorders. Thus, a therapeutic agent targeting a single neurotransmitter system is likely to prove ineffective. To be successful in treating Bipolar disorder, agents will need to achieve equilibrium among interacting neuronal systems. Based on this body of research, understanding of the molecular basis of neurotransmitter systems has led to a rethinking of the ways in which neurons function and are regulated and how these systems might operate in the pathophysiology of bipolar illness.

Chronic Illness: Current Therapies

Chronic Illness: Emerging Therapies

Dopamine Agonists


The role of dopaminergic drugs in the treatment of depression, particularly Bipolar disorder depression, is of interest because of these agents’ antidepressant properties. Pramipexole, a dopamine agonist, has been shown to exert antidepressant efficacy comparable to that of fluoxetine for major depression.

Mechanism Of Action

Dopamine agonists mimic natural dopamine by directly stimulating striatal dopamine receptors, thereby overcoming the loss of dopamine that occurs in Parkinson’s disease. Researchers have identified five dopamine receptors to date, and the pharmacological effect of dopamine agonists is strongly linked to the dopamine receptor subclass that is stimulated. The five known dopamine receptor subtypes belong to either the Dl -receptor family (which includes Dl and D5 receptors) or the D2-receptor family (which includes D2, D3, and D4 receptors).


Pramipexole (Pfizer/Boehringer Ingelheim’s Mirapex) is marketed for Parkinson’s disease in the United States and Europe. The agent is in Phase II/III clinical studies for Bipolar disorder depression .

Like other dopamine agonists, pramipexole mimics the activity of endogenous dopamine. Specifically, it reduces the synthesis and turnover of endogenous dopamine via its agonist activity at presynaptic dopamine autoreceptors. Evidence to date suggests that pramipexole’s D2 activity may be primarily responsible for its motor benefits, whereas the drug’s D3 activity may contribute more to its beneficial effects on mood and apathy.

Pramipexole was found to be an effective antidepressant in a randomized, double-blind trial comparing flexibly dosed pramipexole (mean maximum dose of 1.7mg/day) given together with other mood-stabilizing agents (i.e., lithium, valproic acid, carbamazepine, lamotrigine, and/or topiramate) and placebo in DSM-IV Bipolar disorder patients (n = 22) experiencing an episode of depression. The primary measure of efficacy was a 50% improvement from baseline on the HAM-D. A secondary measure were changes from baseline in CGI scores. At the end of the six-week study, the mean percentage of improvement from baseline HAM-D scores was greater for patients taking pramipexole than for those taking placebo. Mean improvements in CGI scores were also greater for pramipexole than for placebo. Only one patient, who became hypomanic while taking pramipexole, dropped out of the study.

With regard to tolerability, pramipexole — like other dopamine agonists — causes side effects in 80-90% of patients taking the drug, but only a minority of patients discontinues treatment because of them. The most common side effects are nausea, GI upset, dizziness, somnolence, orthostatic hypotension, headache, constipation, and peripheral edema. Pramipexole has also been linked to sudden-onset sleepiness, a side effect that has prompted regulatory authorities in some countries to advise patients not to drive while taking the medication.