CENTER ON BEHAVIORAL MEDICINE
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I. Official Definition: DSM IV-TR
A bipolar disorder is a disorder of mood in which the subject manifests extreme presentations at the high agitation (excitement or rage) end of the mood spectrum, and very likely presents as well with expressions of extremely low (depressed) mood. The DSM-IV-TR recognizes four entities of bipolar disorders: bipolar I disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder not otherwise specified; these differ primarily in their severities, frequencies, and the durations of the manic and depressive symptoms manifested. The basis of treatment for a bipolar disorder is the differential diagnosis between the bipolar disorder and other disorders with similar symptoms, and among the four noted subtypes of bipolar disorders. Ongoing research seeks to discriminate between the various mood disorders and to learn the connections between bipolar and additional mood and other disorders with similar symptoms, such that more effective treatments for the bipolar disorders can be established (Bowden, 2002). In this paper, the focus is placed upon Bipolar I Disorder; other bipolar disorders will be referenced but will not receive the detailed treatment given to this mood disorder. (See Appendix A: "Other Bipolar Disorders.")
The identifying characteristic of Bipolar I Disorder (BP-I) is a clinical progression that includes specific mood disturbances, that is, current evidence or a history of (one or more) Manic Episodes or Mixed Episodes, and commonly, one or more Major Depressive Episodes as well.
A Manic Episode (MA-E) is defined as a discrete segment of time during which the person experiences an "abnormally and persistently elevated, expansive, or irritable mood" (American Psychiatric Association, 2000a, p. 357), lasting at least one week, or any length of time if hospitalization is required, and accompanied by at least three additional symptoms from among the following: grandiosity (inflated beliefs about the self), reduced need for sleep (is rested after three hours of sleep); pressured speech; flight of ideas; ability to be distracted easily; increased psychomotor agitation or participation in social, academic, occupational, or sexual goal-directed activities; excessive involvement in pleasurable activities that are highly likely to cause painful consequences (e.g., sexual indiscretions, unlimited monetary spending sprees, senseless investments in business ventures). In the presence of a mood characterized solely by irritability without elevated or expansive characteristics, four rather than three of the above symptoms must be present to establish the criteria for Mania/Manic Episode. The severity of the symptoms of a Manic Episode is high enough that it impairs occupational or social functioning, requires hospitalization, or includes psychotic features (e.g., hallucinations, delusions, thought disorder). In addition, the symptoms cannot meet the requirements for a Mixed Episode (MX-E), in which the person manifests the symptoms for both a Manic Episode and a Major Depressive Episode (e.g., raging behavior suicidal ideation) almost daily for at least one week. Conditions that prohibit a behavioral episode from fulfilling the criteria for a MA-E are present when the symptoms characteristic of a MA-E can be found to result from the direct physiological influence of medication, a drug of abuse, other depression treatments of a somatic nature (e.g., phototherapy or ECT), an encounter with a toxic substance, or the effects of a general medical condition (e.g., brain tumor, multiple sclerosis) (American Psychiatric Association, 2000a; Bowden, 2002).
A Major Depressive Episode (MD-E) is defined as a discrete period, lasting at least two weeks, in which the person experiences either depressed mood or loss of interest or pleasure in almost all activities; children and adolescents may present with an irritable rather than a sad mood. Besides the presence of either or both of these symptoms, MD-E classification requires the manifestation of four additional symptoms from among the following: increased or decreased appetite or weight changes (e.g., significant loss though not dieting, or weight gain); almost daily disturbed sleep, that is the presence of insomnia or hypersomnia; almost daily psychomotor slowing or agitation that is clearly observable to others; feelings of worthlessness; feelings of guilt that are extreme or inappropriate, and possibly delusional; almost daily difficulties with thinking, concentrating, or decision-making that were not present before the period of depression; recurrent thoughts of death (not solely of the fear of death), suicidal ideation, suicidal plans, or actual suicidal attempts. The symptoms must: have been present within one 2-week period, represent an observable change from the behavior manifested by the person prior to this episode, and cause clinically profound distress or impairment in social, occupational or other important functioning. Conditions that prohibit a behavioral episode from fulfilling the criteria for a MD-E are present when the symptoms characteristic of a MD-E can be found to result from the direct physiological influence of medication, a drug of abuse, other depression treatments of a somatic nature (e.g., phototherapy or ECT), an encounter with a toxic substance, or the effects of a general medical condition (e.g., hypothyroidism). In addition, the symptoms cannot meet the criteria for a MX-E, as described above. In the case of Bereavement, a MD-E is indicated when the symptoms continue for longer than two months or represent remarkable functional impairment, obsessional experience of morbid worthlessness, suicidal ideation, psychotic behaviors, or extreme psychomotor retardation.
Conditions that can confound the diagnosis of BP-I include the diagnosis of other syndromes that essentially include the characteristics that rule out a MA-E : Episodes of Substance-Induced Mood Disorder, which can result from the direct effects of a medication, other depression treatments of a somatic nature, a drug of abuse, or encounter with a toxic substance; Mood Disorder Due to a General Medical Condition (e.g., Multiple Sclerosis); Schizoaffective Disorder; Schizophrenia; Schizophreniform Disorder; Delusional Disorder; Psychotic Disorder, NOS (American Psychiatric Association, 2000a; Bowden, 2002). In children particularly, syndromes that must also be ruled out include: Attention deficit Hyperactivity Disorder, Oppositional Defiant Disorder, and medication side effects. For the first of these it is helpful to use elation or grandiosity as a definitive symptom, to avoid misdiagnosing a child with BP-I on the basis of irritability that may have another source (Scheffer, 2002).
Though not so indicated in the official DSM-IV diagnostic features, it has been suggested that the presence of a family history positive for BP-I be included in the qualifications for a BP-I diagnosis, particularly for the potential diagnostic usefulness of this factor with persons who present with subthreshold disease or mixed states (Bowden, 2002).
There are six subclassifications of BP-I, all of which presume at least one episode of mania. The subdistinctions are made according to whether the person is experiencing a first occurrence of mania or a recurrence of the disorder, the latter manifested by a shift in the polarity of the disorder or an interepisode interval of at least two months without manic symptoms. A shift in polarity can occur when: a MD-E evolves into a MA-E or a MX-E; a MA-E or a MX-E evolves into a MD-E. The evolution of each of the following is treated as a single episode rather than as a polarity shift: a HP-E that moves into a MA-E or a MX-E; a MA-E that becomes a MX-E; a MX-E that evolves into a MA-E. If any of these episodes is a first experience of mania, the resulting expression of the disorder is classified: Bipolar I Disorder, Single Manic Episode; if the evolved single episode is a recurrence after the original MA-E, following either a two month period without manic symptoms or a MD-E, the resulting expression of the disorder is classified Bipolar I Disorder, Recurrent, Most Recent Episode, (whatever the resulting outcome): Hypomanic (after an earlier MA-E); Manic; Mixed; Depressed; Unspecified (when criteria for a HM-E, MA-E, MX-E, or MD-E are met except for duration) (American Psychiatric Association, 2000a).
There are various specifiers for BP-I, some of which apply to BP-II and Major Depressive Disorder (MDD) as well. They describe the severity, degree of remission, special motor features, postpartum relationship, chronicity, depth features, atypicality, longitudinal course, seasonal relationship, and cycling course of the disorders (American Psychiatric Association, 2000a). (See: "Appendix B: Specifiers for BP-I, BP-II, and MDD, as Applied to BP-I.")
II. Signs and Symptoms
The official DSM-IV criteria described above delineate many of the signs and symptoms of BP-I. Its definitive feature of at least one MA-E points to its characteristic and predominant pattern of perturbations or elevations of mood, with typical instances of behavioral activation, impulsivity, lack of appropriate inhibition, arousal, and hyperactivity (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
Untreated bipolar disorder may present with more than 10 total episodes of mania and depression over the course of a lifetime. Frequently, the first and second episodes of mania will be separated by as much as five years, however, the tendency is for the period between episodes to narrow. Usually, the duration of episodes and intervening time spans stabilize around the fourth or fifth episode, subject of course to the preeminent variability that marks this disorder (American Psychiatric Association, 2000b).
The psychosocial comorbidity caused by bipolar disorder is considerable: the person's marriage, relationships with children, job, and other life factors are often compromised by the progression of the illness and its prominent symptoms. For example, the rate of divorce for persons with bipolar disorder is nearly two to three times greater than that in the general population, and there is twice the likelihood of occupational deterioration for the bipolar person as for a person in the general population (American Psychiatric Association, 2000b).
Certain phenomenological studies have assessed the prevalence of mood, cognitive, perceptual, and behavioral disturbances of mania. Though they refer to bipolar disorders in general, they are accurate for BP-I persons as a part of that group and so are pertinent to our discussion. Their findings showed the following.
(A) Mood data noted that only a minority of persons with bipolar disorder could be described by a manic state of sustained euphoric mood and grandiose feelings. The experience of most persons who have manic episodes is: irritability (80 %), depressed mood (72 %), mood lability (69 %) equally with euphoria (71 %); the severity of the person's mania and the presence of concurrent psychiatric presentations (such as substance use disorders) has a significant effect on the person's particular mood state. In contrast to persons with bipolar disorder, persons with unipolar depression are more likely to experience emotional blunting than the mood features just described above (Keck, 2001).
(B) Research with the behavioral manifestations of mania showed that the most prevalent signs were pressured/driven speech (98 %), logorrhea (89%), increased psychomotor activity (87%), decrease in the need for sleep (81%), hypersexuality (57%), extreme behaviors (55%). Symptoms that presented less often than these were violence (49%), religiosity (39%), pronounced regression (28%), and catatonic behavior (22%). Though bipolar depression symptoms have commonalities with those of major depressive disorder, evidence has indicated that bipolar depression might be more likely to present with atypical features of hypersomnia, hyperphagia, and leaden paralysis (Keck, 2001).
(C) Common nonpsychotic cognitive disturbances in mania were reported as grandiosity (78%), racing thoughts (71%), and distractibility (68%). Other dangerous symptoms that inhibit or discourage persons from seeking and sustaining appropriate treatment include impaired insight and failure to recognize the signs and symptoms of bipolar disorder. During bipolar depression episodes, common cognitive symptoms include inattention, indecisiveness, and reduced psychomotor activity (Keck, 2001).
(D) Perceptual disturbances, that is psychotic symptoms, are common occurrences during manic episodes. Studies have indicated that at least two thirds of the persons assessed reported that they had had psychotic experiences during a mood episode; another recent study reported that 90% of those studied reported mood-experienced psychoses. There is evidence that during the course of MA-Es or MX-Es, all forms of psychoses (mood-congruent and mood- incongruent delusions, hallucinations, and formal thought disorder) can occur. Evidence estimates that about one-third of persons experience psychoses during bipolar depression (Keck, 2001).
Several remarkable markers of BP-I deserve particular attention because they give us a clearer understanding of the disorder by assisting us to see it from the perspective of its various relationships to particular psychiatric/psychological/social phenomena.
(A) Once manifested, mania shows a high potential for recurrence: At least 90 percent of those who have a single manic episode will develop future episodes (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002).
(B)There is a high rate of suicidality among persons with the bipolar disorders in general: evidence has shown that 29.2 percent of persons with a bipolar disorder attempt to commit suicide (Carlson, 2001); thus this is a specific concern with persons with BP-I, the majority of whom experience predominantly depressive episodes throughout their illness (Bowden, 2003a). Rapid cycling, the tendency to have four (or more) episodes or mania, hypomania (post first MA-E), major depression, or mixed mania and major depression, within one year, indicates a more severe symptomatology in bipolar persons as a whole. About 10-20 percent of bipolar disorder persons are rapid cyclers, and though the majority of these rapid cyclers are BP-II persons, more of those who have BP-I and have this specifier manifest symptoms of psychosis than do others (Lewis, 2003a).
(C) Panic symptoms have long been associated with bipolar disorders, and BP-I in particular. Though research must continue to show a relationship that is significantly correlative, studies with persons who both bipolar disorder and panic symptoms show that comorbidity of these two disorders presents specific challenges for treatment and recovery of such persons. A novel study that researched the prognostic significance of lifetime panic spectrum symptoms on the treatment of persons with bipolar disorder treated and evaluated 66 persons with BP-I, 33 of whom had a history of panic symptoms and 33 of whom did not. Using a pharmacological protocol that included the mood stabilizer, lithium, and an antidepressant if needed, they found that: a lifetime history of panic symptoms was associated with more previous depressive episodes, a greater prevalence of depressive symptoms, and a greater degree of suicidal ideation during the acute phase of treatment; a high level of panic symptoms was positively correlated with a longer time to stabilize in the acute phase of treatment (44 as contrasted with 17 weeks). These results suggested that lifetime panic symptoms pointed to higher levels of depression and suicidal ideation, as well as the need of a longer treatment time to achieve symptom remission in persons with BP-I (Cyranowski, 2002).
(D) Substance abuse, particularly alcoholism, has a history of association with bipolar disorder, particularly BP-I. One study evaluated 267 persons (151 females and 116 males) of whom 209 had BP-I, 44 had BP-II, 9 had BP-NOS, and 5 had Schizoaffective Disorder, to assess gender differences in prevalence, risk, and the clinical correlates of alcoholism comorbidity in bipolar disorder. Evidence showed that the BP-I subgroup had the highest rate of alcoholism of all the bipolar subgroups, though the difference was not significant. In addition, fewer women than men with bipolar disorder had a lifetime history of alcoholism, however, women with bipolar disorder were at a much greater risk for alcoholism compared to women in the general population than were bipolar disordered men as compared to the general population. The clinical characteristics more prevalent in women with comorbid bipolar disorder and a lifetime history of alcoholism than in women with bipolar disorder and without alcoholism, were polysubstance abuse, family history of alcoholism, history of verbal abuse, four or more previous depressive episodes, and social phobia; of these characteristics, the results of further analysis showed a continued significant presence of polysubstance abuse and a presence approaching significance of social phobia. The clinical characteristics more prevalent in men with comorbid bipolar disorder and a lifetime history of alcoholism than in men with bipolar disorder and without alcoholism were family history of alcoholism, family history of drug abuse and /or dependence, family history of bipolar disorder, history of physical abuse, and past suicide attempt; of these results, those that remained significant in a later analysis of the data were family history of alcoholism, while those that approached significance were family history of bipolar disorder and physical abuse (Frye, et al., 2003). The importance of this study to our review of the signs and symptoms of BP-I are the following findings: there is support for the prior work that showed that persons with BP-I have a 60.7% lifetime prevalence for substance abuse or dependence, with alcohol the most commonly abused substance; for patients with alcoholism, excepting only other drug abuse/dependence, mania ranked highest in prevalence of all comorbid axis I diagnoses; men with bipolar disorder have a greater likelihood of a lifetime history of alcoholism than do women, while women with bipolar disorder have a greater risk of developing alcohol addiction as compared to women in the general population than do bipolar men as compared to men in the general population. These and other results of the study described in this article suggest the high comorbidity for bipolar disorder in general, and BP-I in particular, with substance abuse/dependence and alcoholism in particular; they also indicate a direction for further research to discover whether bipolar disorder and alcohol use disorders are: genetically separate but co-occurring with some element of shared risk, genetically separate but overlapping, or phenotypically linked.
(E) Cigarette smoking has been strongly associated with the major affective disorders, particularly major depression, and with alcoholism; it also has a high correlation with suicide. As noted previously, persons with bipolar disorder have a high rate of suicidality, particularly those with BP-I, which suicidal behavior generally occurs while these persons are in the depressive phase of their courses of illness; therefore, by inference, the above references to suicidal persons who are depressed and who smoke bears a relationship to the bipolar population as well.
Chronic nicotine administration precipitates serotonergic depletion in neural areas such as the hippocampal formation and lowers the firing rates of midbrain raphe serotonergic neurons, both of which have been found to precipitate depression. A study of 347 persons (177 males and 170 females), of whom 175 had MDD, 28 had a bipolar disorder in depressed phase, 5 had Dysthymia, 127 had Schizophrenia, and of which total group 184 had at least one prior suicide attempt, explored the psychopathological and biological reasons for the associations between smoking, the major psychiatric disorders, and suicide. Using the results of twin studies that suggested that there is a relationship between lifetime smoking and depression that "resulted 'solely from genes that predispose to both conditions' " (Malone, Waternaux, Haas, Cooper, Li, & Mann, 2003, p. 777), this study examined the possibility of a correlation between smoking and the specific feature of suicidality.
The findings of this study pertinent to our discussion of BP-I signs and symptoms (as well as to its physiological underlying features) are these: smoking was more prevalent among those who had attempted suicide than among those who had not (69% to 44%), and the likelihood of being a suicide attempter was correlated with the amount of smoking in which a person engaged; the level of cerebrospinal fluid (CSF) 5-HIAA (metabolite of serotonin [5-HT]) of depressed persons tested showed that it was negatively correlated with the amount of smoking in which persons engaged. Thus, cigarette smoking has a negative relationship with serotonergic presence and a positive relationship with suicidality. While these relationships do not imply causality, several suggestions have been offered for further exploration: nicotine may produce both biological and behavioral neural effects that heighten the likelihood of suicidality in those who are depressed; reduced serotonergic activity may predispose the person with a psychiatric disorder to both suicidal acts and to smoking; a combination effect could occur in that insufficient serotonin responsivity could increase the probability of habitual smoking (as well as the precipitation of a depressive disorder), and following the initiation of a depressive disorder, smoking could influence a greater decrease in serotonin activity that would increase the risk for suicidality. This study suggests a biological explanation for a relationship between suicidal behavior and smoking (Malone, Waternaux, Haas, Cooper, Li, & Mann, 2003), which can be useful to our discussion of those with BP-I: We can safely assume that we need to be particularly alert to the possible marker of smoking as a potential indicator of a risk factor for suicide in our bipolar clients who engage in tobacco smoking. The treatment hope is that medical enhancement of serotonergic activity may both reduce suicide risk and assist smoking cessation.
(F) Eating disorders, as well as substance abuse disorders, anxiety disorders (mentioned above), and other psychiatric disorders are commonly comorbid with bipolar disorder. Women are at greater risk than men for comorbidity, and the comorbidity factor negatively impacts women's recovery from mania more than men's recovery (Freeman, Arnold, & McElroy, 2002). One complication of treatment in persons with a bipolar disorder and Anorexia Nervosa, for example, is that lithium treatment for mood stabilization may need to be discontinued during the underweight-dehydrated phase(s) of the person's eating disorder to prevent serious damage to the person's physiology by lithium during the time of disturbed metabolism (Powers, 2002).
Thus, the tendencies of bipolar disorder to include manic relapse, suicide, substance abuse (especially alcohol and nicotine), panic symptoms, and eating disorders, can each help us to see a facet of the complex phenomenon that is the disorder itself, and to find new directions for research that will lead to more effective treatments and increased health for our clients with bipolar disorder.
III. Causal Factors: Physiological/Psychological/Sociological
(b) As noted in an earlier paper, the chance of developing a mood disorder is 25% for the child of one parent with bipolar disorder and increases to a 50-75% risk that the child will experience the onset of a mood disorder when both parents have bipolar disorder. In addition, research indicates that bipolar disorder is transmitted more easily than major depressive disorder, indicating that its genetic component is has more potency (Kaplan, Sadock, and Grebb, 1994).
(c) Some evidence also points to the possibility that responsibility for vulnerability to bipolar disorder may reside with a single dominant "bipolar gene" (Carlson, 2001, p. 245), currently hypothesized to be found at one of several chromosomal sites, namely: chromosomes 4, 18, 21, or the X chromosome (Carlson, 2001), though evidence has been reported that would exclude the X chromosome from this study (Barondes, 1998).
(d) The use of a the gene linkage approach, a systematic way of studying the relationships between genes and diseases (here bipolar disorder) has been developed. It seeks to identify the gene that may be involved in a particular disease by locating a gene that is unfamiliar and suspected of involvement in the disease in its universal-to-the-species placement on a specific chromosome. The location is described by means of the physical position of the suspect gene in relation to a marker gene (known gene) on that chromosome; the suspect gene is said to be linked to the marker gene. It is then possible to locate the suspect gene in the cellular material of persons with the disease and in persons with no disease process, such that its structure can be studied to determine the possibility of mutation and genetic responsibility for the disorder (Barondes, 1998).
The process described above was used in a study that sought to discover the chromosomal region(s) that are linked to a gene that may bear some repsonsibility for both psychotic bipolar disorder and Schizophrenia. The research focused on 10 families in which three or more persons had psychotic mood disorder; of the 302 persons in the study, 129 persons had BP-I, 97 persons had BP-II, 69 persons had Recurrent Unipolar Depression, and 7 persons had Schizoaffective Disorder, Manic Type. The findings showed that a genetic overlapping between psychotic bipolar disorder and Schizophrenia does exist, and that there are four overlapping chromosomal regions where genes that share susceptibility for the two disorders might be located; of these, two chromosomal regions, 13q31 and 22q12, were found to be the most significantly linked regions for each of the two disorders. Thus, these results suggest that psychotic bipolar disorder and Schizophrenia may have a common genetic component, and points to a direction for future research to determine the exact location of such genetic expression (Potash, et al., 2003).
(e) The G protein dysregulation and consequent second messenger system dysfunction that have been implicated in responsibility for (up to 10% of cases of) bipolar disorder are believed to result from a genetic polymorphism in the gene for G protein receptor kinase 3 (GRK3). Receptor kinases like GRK3 have been found to have a key role in signal desensitization; thus, it is thought that this polymorphism, P-5, located in the promotor region of the GRK3 gene, could result in increased neural responsivity to dopamine, and thereby cause the extremes in mood that are characteristic of bipolar disorder. Besides its typical function of inducing signal desensitization, GRK3 is at risk for influencing the presentation of bipolar disorder because it has an extensive expression in the brain and because it is vulnerable to the inducement of its expression by amphetamine (dopamine agonist) in animals. One study sequenced the GRK3 gene in several persons with bipolar disorder, identifying six sequence variants in the promotor area; no splice or coding variants were manifested. Families of northern European Caucasian heritage showed significant association between bipolar disorder and the P-5 variant of GRK3. These results suggest a link between the mutant GRK3 gene and bipolar disorder (ReutersHealth Information, 2003). (See below section on signal transduction disruption in second messenger systems.)
(2) Biochemical causes:
(b) In addition to the cornerstone placement of the action of serotonin, norepinephrine, and dopamine in the neurochemical theory of the pathophysiology of mood disorders, some investigators indicate that acetylcholine involvement with the highly interdependent activity of 5-HT, NE; DA, and with the mechanism of intracellular second messenger systems, may influence moods. They continue to investigate as well the roles of the inhibitory neurotransmitter GABA and the excitatory neurotransmitter glutamate in the course of mood disorder, in particular because several agents used to stabilize mood in bipolar disorder (e.g., carbamazepine) with good response modulate the activity of these two neurotransmitters (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
(c) Signal transduction systems within the neuron have also become a focus of attention in the treatment of bipolar disorder. These intracellular networks are mechanisms that are coupled to a membrane-bound receptor and thereby mediate the process in which the neurotransmitter's activation of the receptor affects cellular responses; G proteins, coupled to the receptor from within the cell, stimulate or inhibit second messenger systems and thus transduce the original signal from the neurotransmitter. These second messengers direct the occurrence of phosphorylation, they regulate the removal or addition of various phosphate groups to particular protein targets, e.g., a receptor, an ion channel, such that the proteins are transformed in size or charge and therefore in function as well: This allows for the activation or deactivation of receptors, the opening and closing of ion channels, etc., and thus the moderating of intracellular activities (e.g., neurotransmitter synthesis and gene expression). Bipolar disorder has been associated with potential malfunction in two specific second messenger systems: the cyclic adenosine monophosphate (cAMP) system and the phosphoinositode (PI) system. It is believed that the G proteins may be hyperfunctional in manic persons, causing a miscommunication of the original signal (transduction) to the dysfunction of these two systems and a consequent dysregulation of the effects that these systems produce at the next lower level of cellular communication (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002). (See above section about polymorphism in receptor kinase gene linked to bipolar disorder.)
(d) It has been suggested as well that the pathophysiology of bipolar disorder is influenced by disruptions in the extracellular and intracellular levels of the positively charged calcium ion. Alterations in mood, arousal, and cognition have been related to changes in the levels of extracellular calcium: Clinical manifestations of such changes in calcium levels present as mania, depression, irritability, psychosis, reduced consciousness, delirium, and possibly coma. The intracellular imbalance of calcium also affects second messenger systems whose dysregulation can produce manic behavior. Thus, through their effects on the second messenger systems, calcium ions can direct the synthesis and secretion of neurotransmitters (e.g., 5-HT, NE, DA), the responsivity of neurons, and intraneuronal long-term changes (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
(e) Evidence has shown that excitatory amino acid transporters (EAATs) have been implicated in the bipolar disorders, Major Depressive Disorder, and Schizophrenia. Based on the belief that the abnormalities of psychiatric illnesses resulting from dysregulated glutamatergic neurotransmission (e.g., bipolar disorder mania) are expressed at locations other than at the glutamate receptor, some investigators examined the expression of excitatory amino acid transporters in the striatum. EAAT1 and EAAT 2 are normally expressed in glia, while EAAT3 and EAAT4 normally are expressed in neurons; all of these EAATs have been involved in the presentation of Huntington's Disease, Amyotrophic Lateral Sclerosis, and Schizophrenia. Research with human tissue from mood disordered and schizophrenic subjects showed that persons with bipolar disorder presented with decrease expression of EAAT3 and EAAT 4 transcripts (neuronal), while major depressive disorder persons showed decrease expression of EAAT4, and schizophrenic persons showed decreased expression of EAAT3 transcripts. The investigators reported that these results suggest that alterations in striatal transporter mRNA expression occur solely in neuronal EAATs; this finding adds to the growing body of knowledge that implicates abnormal glutamatergic neurotransmission in the mood disorders and Schizophrenia (McCullumsmith, & Meador-Woodruff, 2002).
(3) Neurological causes:
(b) Studies of hippocampal structure and function in persons with
BP-I sought to determine whether the concentration of a neuronal and
A related study assessed N-acetylaspartate levels in the hippocampal area and the dorsolateral prefrontal cortex to determine possible reductions from normal levels in persons with Schizophreniform Disorder; the research also assessed the relationship between the levels of this substance and working memory deficits. The findings showed that there were selective reductions of N-acetylaspartate ratios in both the hippocampal areas and the dorsolateral prefrontal cortex of the persons with Schizophreniform Disorder tested. A positive correlation was seen in the N-acetylaspartate ratios manifested and the performance of these persons on a test of working memory. These results suggest that, as has been found in studies of persons with Schizophrenia, ratios of N-acetylaspartate are reduced in the hippocampal areas and the dorsolateral prefrontal cortex of persons with Schizophreniform Disorder [, indicating a similar functional deficit in the two disorders]. The results indicate as well that neuronal pathology in the dorsolateral prefrontal cortex is responsible for some of the working memory deficits that are present at the outset of the disorder (Bertolino, et al., 2003). This research, though it does not refer to the bipolar disorders, is included in this discussion as a comparative study, to note the common finding of low concentrations of N-acetylaspartate in the hippocampal areas of persons with Schizophreniform Disorder, Schizophrenia, and BP-I . Along with the results of the study above that sought a gene with shared responsibility for Schizophrenia and BP-I, these comparative results encourage me to wonder about the commonalities yet to be found, and to see directions for future research in alternative treatments.
(c) Research designed to define the neurobiological basis in schizophrenic illness found significant relationships between various genetic, biochemical, and structural abnormalities and suicidal behavior in Schizophrenia. One study found a consistent association between increased neuropeptide Y (Y2) expression in layer IV of the prefrontal cortex and suicidality in Schizophrenia, Major Depressive Disorder, and bipolar disorder. Another study showed a relationship between lower concentrations of CRF in the cerebrospinal fluid and suicidality in the affective disorders and in Schizophrenia. These results suggest that there are neurobiological correlates of suicidality across major psychiatric disorders: Thus, suicidality may be mediated by these genetic and other neurobiological factors whose activity is independent of the genetic (and other) factors involved in the heritability of each separate psychiatric disorder (Tandon & Jibson, 2003).
Research has shown that the role played by such psychosocial stressors seems to change over the course of the illness: Life events that precipitate great stress apparently play a more activating/instrumental role in the early episodes, whereas subsequent episodes seem to occur more spontaneously without clear external precipitating factors. It has been posited that the neurophysiological changes that take place as a result of multiple manic episodes may reduce the neural capacity to sustain a stable euthymic state. Neuronal and neurochemical alterations may be the result of recurrent manic episodes, which alterations raise the probability that the person will experience a more serious course of illness (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
(2) One study reported that the environmental stress experienced by a child with bipolar disorder when he/she senses the strain and problematic effects her/his illness produces on and in the family (system), can have a profoundly negative effect on the child. Though the environment would not be likely to be the sole precipitator of the child's manic episodes, both the sensitivity of children to such stressors and the common knowledge that environmental stressors play a significant role in the initiation and relapse of many disorders/diseases (Scheffer, 2002). As is noted in the example directly above, stress can effect manifestation of mania at other ages as well.
IV. Treatment Approaches: Traditional and Alternative
Because there is a significant risk of self-harm and suicidality to the subject in either the depressive, manic, or mixed episodes of BP-I, the first concern in treatment is to ensure that the person is safe from self-harm. All of the treatment modalities below aim to resolve the painful symptoms quickly to reduce this risk.
Treatment of Mania/Hypomania
(1) Lithium is the usual first-line treatment for BP-I; it is administered most often in the form of lithium carbonate. Its significance as a "first choice" drug rests on its ability to effectively moderate the manic phase of bipolar disorder and to then prophylactically preclude an ensuing depressive episode (Carlson, 2001); lithium has been found to preclude a subsequent episode of mania as well (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002). Lithium's other advantages are: that it neither suppresses normal emotions nor impairs intellectual function (Carlson, 2001). In addition, many point to evidence that indicates that lithium can effectively moderate the potential for suicide in the bipolar person (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002). Its concurrent disadvantages are: a low therapeutic index that requires regular blood testing to monitor the safety of the blood lithium levels, and vigilance in the use of any other medications that could (adversely) enhance lithium's effects; a potential for serious side effects, which effects preclude lithium treatment for persons unable to tolerate them, and which cause many others to become medication non-compliant (Carlson, 2001). Other negative outcomes of lithium pharmacotherapy include the following significant occurrences: inadequate responses in acute mania; while on maintenance, relapse within two years; idiosyncratic development of resistance to the drug after approximately three years of treatment; selective subtypes of bipolar disorder have been found to have varying degrees of resistance to lithium treatment, specifically: mixed episodes, syndromes of rapid cycling, and severe mania with psychosis (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
Despite the fact that its mechanism of action is not entirely clear, lithium has been found to interact with several major neurotransmitters and neuromodulators with the following effects: increase the turnover and reduce the synthesis of DA; heighten the uptake, then reestablish the baseline levels of NE; magnify the neurotransmission capabilities of 5-HT and ACh; increase levels of the inhibitory transmitter GABA, and increase the uptake of the excitatory transmitter, glutamate, with long-term treatment; inhibit the stimulation of adenyl cyclase and the production of inositol; decrease the transport of calcium into the cells (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002). Summarily, lithium exerts an influence on the activities of both the neurotransmitters and the second messenger system, which results in the prevention of extremes of neurosensitivity, and ultimately results in the stabilization of the person's mood (Carlson, 2001; Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
(2) Anticonvulsants: These drugs, prescribed early on to decrease seizures, are gradually coming into their own as significant pharmacotherapeutic alternatives to monotherapeutic lithium treatment; they may be used alone or in conjunction with lithium. Originally used with treatment-resistant presentations of bipolar disorder, extremely acute presentations, or with unmanageable long-term symptoms, they are now being seen as first-line therapeutic agents that often achieve better compliance rates than lithium because of their (generally) better side-effects profile (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002).
(a) Valproate appears to have a very positive presentation: it has been found to be equivalent to lithium in the effectiveness of its treatment of acute mania; its successful treatment of mixed mania and rapid-cycling courses of bipolar has surpassed that of lithium; it has fewer and less serious side effects than lithium, and is therefore more easily tolerated, increasing the probability that it will induce increased medication compliance and decreased need for inpatient treatment. One study indicated concluded that valproate improves manic symptoms by reducing dopaminergic transmission at a presynaptic site of action (Yatham, et al., 2002), while other evidence suggests that the action mechanism of this drug enhances GABA activity and interaction with G proteins in the cAMP second messenger system (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002).
(b) Carbamazepine has the same degree of success in the treatment of acute mania as lithium. It has been effective as well in the treatment of lithium-resistant features of mixed episodes, rapid cycling, and severe mania; whether used independently or together with lithium, it has been successful in the prevention of manic relapses. A disadvantage of this drug is that it has the potential for severe side effects; this characteristic precludes the drug's use on a long-term basis for more than 50% of those for whom it is prescribed. Carbamazepine's function seems to be the modulation of GABA and glutamate: it blocks calcium influx and inhibits the cAMP second messenger system (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002).
Regarding lithium, valproate, and carbamazepine, one study presented evidence that these three mood stabilizing drugs have a similar mode of action: Each appears to affect the metabolism of inositol, which is responsible for message signaling inside the individual neurons. These three drugs deplete the intracellular supply of inositol, which slows down the collapse of growth cones, structures needed for cell growth. The drugs have a particularly significant effect on in the brain because the brain produces its own inositol and signals the eventual release of neurotransmitters. These results suggest that the malfunction that causes the bipolar disorder symptoms assisted by these three drugs may be based in the inositol signaling system (Reuters Health, 2002).
(3) The newer anticonvulsants, lamotrigine, gabapentin, and topiramate, continue to be seen as experimental; they are used in particular for the treatment of refractory symptoms, rapid cycling courses, or in the depressive phase of this disorder.
(a) Lamotrigine seems to function by inhibiting glutamate release. It is apparently well-tolerated, has fewer serious side effects than some other similar drugs, and has a wide range of positive effects. One study credited the drug as equal to lithium in its ability to delay the onset of a mood episode or the need for treatment; particularly effective during the depressive phase of the illness; more effective than lithium at delaying the onset of the depressive phase of the illness. The findings of the study indicated that lithium and lamotrigine possessed pharmacotherapeutic properties that would complement one another in a combined therapy protocol (Barclay, 2002).
(b) Gabapentin finds its usefulness in adjunctiveness to a primary mood stabilizer; it functions to enhance GABA and to inhibit glutamate.
(c) Topiramate is also used as an adjunct to a mood stabilizer; it has the potential for some negative effect on cognitive functioning (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, 2002).
(4) Calcium channel blockers: These drugs work by blocking the influx
calcium into the cell and thus inhibiting the subsequent process of
formation and release.
(5) Atypical antipsychotics: As many as two-thirds of persons with bipolar disorder experience psychoses; during the time between the initiation of a MA-E and the taking effect of a prescribed mood stabilizer, they will receive antipsychotic treatment in this acute phase of mania to decrease agitation, disorganization, and aggression/psychoses. For some persons, continuance of this antipsychotic in addition to the mood stabilizer will be a beneficial form of (combined) therapy. The older antipsychotics, e.g., chlorpromazine, thioridazine, fluphenazine, have given way in most cases to newer antipsychotic medications that have fewer side effects, in particular, extrapyramidal side effects (tardive dyskinesia, etc.). Olanzapine, resperidone, and clozapine are some of these newer drugs.
(a) Clozapine was originally found to be attractive, due to its rapid action on mania and its positive effects on resistant manic/cycling presentations; its tendency to produce agranulocytosis, a dangerous blood disorder, has negatively modified the medical community's initial enthusiasm for this drug, though with frequent blood monitoring, some persons take this drug well.
(b) Olanzapine and resperidone are becoming better known and more used, both as single agents and as adjunctive treatments to lithium for long-term mood stabilization facilitation. Both drugs must be used with care because each can induce mania (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002), and the most usual negative side effect of olanzapine is depression. One study showed that adding olanzapine to the mood stabilizers lithium or valproate increases the time before relapse and extends the time of remission in persons with bipolar disorder (Barclay, 2002). Another study reported that olanzapine seems to be a more effective agent than lithium in the prevention of relapses in bipolar disorder (Lewis, 2003b).
(c) Quetiapine and ziprasidone are apparently useful for the following purposes: quetiapine assists with symptoms of acute mania, rapid cycling, and other resistant presentations; ziprasidone assists with acute mania, though it also has the potential to induce mania (which potential must be considered) (Rivas-Vazquez, Johnson, Rey, Blais, & Rivas-Vazquez, 2002).
Treatment of Bipolar Depression
Because of its ability to evolve into a MA-E or a MX-E, an episode of bipolar depression must be treated with sensitivity to that fact: The use of certain antidepressants to precipitate a manic/hypomanic episode must be considered, and if needed prohibited. The first step in the pharmacological treatment of the depressive phase should be the initiation of a mood stabilizer (e.g., lithium, valproate, or both) in the absence of such treatment, or the enhancement of the mood stabilizing drug that the person is already taking.
The use of the usual unipolar depression antidepressants in the treatment of bipolar depression may be contraindicated in many cases because: some of these drugs can cause a manic episode and/or the onset of a more severe, rapid-cycling course of the disorder; studies have shown no significant benefit to treatment with lithium and an antidepressant over treatment with lithium alone, except in patients with low serum levels of lithium. The judicious use of necessary antidepressant treatment would include bupropion as the first choice of experts, because it does not effect serotonergic activity (which is the general trigger for manic behavior in treatment of bipolar depression), then the SSRIs, particularly paroxetine. It is thought that discontinuation of antidepressants within 3-6 months of remission of the depressive episode is the best prevention against the induction of mania, however, the clinician must balance this decision against the potential for depressive relapse. Many persons require a combination of different medications during the different phases of their bipolar course; one study of pharmacological combination treatment names lithium in conjunction with an anticonvulsant, particularly valproate, as the most effective and safe treatment for bipolar disorder throughout its episodic course (Rivas-Vazquez, Johnson, Rey, Blais, Rivas-Vazquez, et al., 2002). The newer drug, lamotrigine, as noted above, has been found to be effective in the treatment of bipolar depression.
Treatment of Bipolar Disorder
(6) Attention to One's Soul: The Relaxation Response (Can be used in psychotherapy)
Because of the stress factor in bipolar disorder (and in any disorder) the use of the relaxtion response (Benson, 1997, p. 136) is a healthy tool to offer clients as a part of their psychotherapy. It has a calming effect on the body and mind that is the opposite of the fight-or-flight response that, if continuous, can produce the lethal doses of glucocorticoids that cause unlimited damage to our body systems. To achieve the relaxation response, one simply sits quietly and comfortably, focuses on a word or image in the mind, and continues to return to that image or word when distractions come. This practice experienced for about twenty minutes twice per day has extremes of benefits for body and mind (Benson, 1997). (See "Appendix C: Relaxation Response.")
Appendix A: Other Bipolar Disorders
Bipolar II Disorder (BP-II) is diagnosed when the individual presents with an episode of excitement known as a Hypomanic Episode (HM-E). A HM-E includes a period of continually elevated, expansive, or irritable mood that lasts at least four days. For this duration, at least three of the following symptoms must be present (as above in a MA-E): grandiosity (inflated beliefs about the self), reduced need for sleep (is rested after three hours of sleep); pressured speech; flight of ideas; ability to be distracted easily; increased psychomotor agitation or participation in social, academic, occupational, or sexual goal-directed activities; excessive involvement in pleasurable activities that are highly likely to cause painful consequences (e.g., sexual indiscretions, unlimited monetary spending sprees, senseless investments in business ventures). If the mood is solely irritable mood, four of these symptoms must be present. The period of hypomania demonstrates a definite change in functioning that is unlike the person's usual nondepressed (euthymic) mood and is apparent to others, but is not so severe that it: impairs social or occupational functioning, requires hospitalization, or manifests psychotic features. (If a person has been diagnosed with BP-II and developed a MA-E, the diagnosis would then become BP-I; BP-II precludes the presence or history of a MA-E. BP-II diagnosis requires, besides an (HM-E), a history or current evidence of symptoms of a (MD-E). In addition, BP-II is ruled out by the same conditions (noted above) that prohibit BP-I: the diagnosis of: Episodes of Substance-Induced Mood Disorder, which can result from the direct effects of a medication, other depression treatments of a somatic nature, a drug of abuse, or encounter with a toxic substance; Mood Disorder Due to a General Medical Condition (e.g., Multiple Sclerosis or brain tumor); Schizoaffective Disorder; Schizophrenia; Schizophreniform Disorder; Delusional Disorder; Psychotic Disorder, NOS (American Psychiatric Association, 2000a; Bowden, 2002).
Cyclothymic Disorder (CTD) is diagnosed when the individual presents with cyclic elevated and depressive symptoms, the magnitude or duration of which symptoms is less than that required for the diagnosis of either BP-I or BP-II, but which symptoms have presented over least a 2-year span, with symptomatic periods separated by symptom-free intervals of less than two months (American Psychiatric Association, 2000a; Bowden, 2002).
Bipolar Disorder Not Otherwise Specified (BP-NOS) is a category that includes presentations whose symptoms do not meet the criteria for any specific bipolar disorder. Examples of presentations that would receive this diagnosis include these.
(a) BP-II is
because there are periods of hypomania that have not lasted for at
The differential diagnosis between BP-I and BP-II is clarified by the distinctive features of a MA-E or a MX-E, even though the relative degree of symptom severity (milder in BP-II) is somewhat dependent upon a degree of subjectivty in the assessor. However, symptom severity is not the only discriminating feature in the bipolar disorders: genetic, biological, and clinical differentiations underlie the two disorders: evidence shows different genetic linkage patterns with these two bipolar subtypes; studies show that persons diagnosed with BP-II have a greater number of incidences of their disorder than person with BP-I, but that persons with BP-I more often present with psychotic symptoms and have a higher number of hospitalizations (Bowden, 2002). Appendix B: Specifiers for BP-I, BP-II, and MDD, as Applied to BP-I
given for BP-I, according to whether the episode (and therefore the
manifestation of the disorder) meets full criteria as follows.
(b) Specifiers for Partial Remission, Full Remission, Unspecified are
(c) Specifiers that can be used in either a or b above.
Appendix C: The Relaxation
Step 1: Pick a focus word or
that's firmly rooted in your belief system.
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