Bipolar Disorder Uncovered

Stop With Bipolar Disorder

This ebook guide teaches you how to keep your symptoms of bipolar disorder under control and have a manageable, excellent life even with bipolar symptoms. You will be able to stop engaging in destructive behavior, get your emotions under control, and handle stress in the way that you usually envy everyone else doing. It is not fair that you are afflicted with this; bipolar disorder is under-diagnosed and tends to affect your live and lives of those you love in a powerful, often negative way. You can put that behind you now. You no longer have to live that way. This ebook guide teaches you how to tell your negative symptoms to take a hike, and MAKE them do so. You do not have to feel guilt over your disorder. You cannot help it. But now, we can help you control it, and manage your symptoms so you can have the normal life you deserve. Continue reading...

Bipolar Disorder Stop Summary

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Prophylactic Efficacy in Bipolar Disorder

All of the above discussion only relates to acute efficacy. What should one do when the patient is currently depressed If one uses an antidepressant, the next question is what should be done after recovery from the current depression. If the patient responds to an antidepressant, should it be continued or not In other words, do antidepressants prevent new depressive episodes in bipolar disorder The available evidence suggests that, overall, antidepressants do not appear to have long-term preventive benefits in bipolar depression. There have been six double-blind RCTs of prophylaxis of bipolar disorder with antidepressants (Ghaemi et al. 2003). Those studies all compared imipramine with placebo or with lithium. In all cases, imipramine alone or with the addition of lithium were not more effective than lithium alone in the prevention of mood episodes in bipolar disorder. In all cases, there was no added benefit from using imipramine long term. Thus, if one were to conduct a systematic...

Diagnosis Of Bipolar Depression

ALTHOUGH DEPRESSION IS the most common presentation of bipolar disorder, a history of mania or hypomania is required for its diagnosis. Identifying these two behaviors defines the diagnostic problem that bipolar depression represents when faced with a depressed patient, it can be extremely difficult for the clinician to validate the depression as stemming from bipolar disorder.

Treatment Nonresponse

Only note that antidepressant-induced mania is substantially more common in bipolar than in unipolar depression, occurring in about 20 -50 of persons with bipolar disorder versus in less than 1 of persons with unipolar depression (Akiskal et al. 2003 Ghaemi et al. 2004b). New research also suggests that patients with bipolar disorder may be less likely to respond to antidepressants for the acute major depressive episode than those with unipolar depression (Ghaemi et al. 2004b), though other data conflict (Moller and Grunze 2000). Note. Cade's Disease is a term Terrence Ketter, M.D., first suggested to identify classical bipolar disorder, type I (discovered in 1949 by John Cade), which is often highly responsive to lithium (personal communication, July 2001). Abbreviations BPI bipolar disorder type I, BPII bipolar disorder type II, MDD major depressive disorder, MDE major depressive episode.

Depressive Phenomenology

Atypical depressive symptoms seem to be more common in bipolar than in unipolar depression (Agosti and Stewart, 2001 Benazzi 1999, 2001a Ghaemi et al. 2002 Mitchell et al. 2001). In the National Institutes of Mental Health Collaborative Depression Study, a 20-year, prospective cohort study of depressed patients, atypical depressive features were a predictor of bipolar disorder, as opposed to unipolar depression (Akiskal et al. 1995). DSM-IV-TR criteria for atypical features include increased sleep, increased appetite, rejection sensitivity, leaden paralysis, and mood reactivity. The DSM-IV-TR definition of atypical depression is stricter than some clinical definitions, which focus mainly on the sleep and appetite features. An interesting clinical observation is that most bipolar patients have only one of the reversed neurovegetative symptoms that is, many patients experience increased sleep but decreased appetite, or vice versa. If one defines typical depression as decreased sleep and...

Studies of Neurotransmitter Function

Classical transmitter hypotheses in bipolar disorder Regardless of differences in amounts of NE and its metabolites, patients with bipolar disorder appear to have increased reactivity to NE. More so in bipolar than in unipolar depressions, noradrenergic function is more strongly related to mood and psychomotor impairment (Swann et al. 1999), treatment response (Maas et al. 1984), and relationship to stressful events (Swann et al. 1990). Subjects with bipolar disorder have increased sensitivity to subjective effects of stimulants (Anand et al. 2000). Pharmacologically increased NE precipitates mania in subjects with bipolar disorder (Price et al. 1984) and may selectively improve bipolar depression (Osman et al. 1989). Subjects with bipolar disorder have a greater noradrenergic response to orthostasis (Rudorfer et al. 1985) compared with those with unipolar disorder or to controls. A postmortem brain study showed that patients with bipolar disorder had more noradrenergic...

Physiological Studies

Specificity of transmitter-related data in bipolar disorder TABLE 2-3. Some neurophysiological studies in bipolar disorder depression, control Euthymic bipolar disorder, schizophrenia Bipolar vs. unipolar Bipolar vs. nonaffected siblings Schizophrenia, bipolar disorder, control Bipolar disorder, nonaffected and bipolar disorder Prolonged latency in bipolar disorder Prolonged latency in bipolar disorder Abnormalities in arousal or in sensitivity to neurotransmitters may be related to the abnormal regulation of ion distribution (Whybrow and Mendels 1969). Active transport is reduced per sodium pump site in cultured, lymphoblastoid cells from Old Order Amish subjects with bipolar disorder compared with nonaffected relatives or controls (Cherry and Swann 1994). The response of the active transport of sodium to increased sodium influx maintains membrane potential over time in excitable cells, provides the cation gradient that drives uptake processes for neurotransmitters and...

Attention DeficitHyperactivity Disorder

The cardinal symptoms of ADHD (e.g., distractibility, impulsivity, hyperactivity, or emotional lability) are also present in bipolar disorder (Biederman et al. 1996 Carlson 1984). The differential diagnosis is diffi cult because these conditions frequently coexist (Kovacs and Gatsonis 1994). Geller et al. (1995), Wozniak et al. (1995), and West et al. (1995) found rates of 57 -98 of comorbid ADHD in bipolar patients. Butler et al. (1995) found a 22 rate of bipolar disorder in inpatients with ADHD. Attention-deficit disorder (ADD) symptoms often mimic those of dysphoria depression, especially in girls. This may create problems in making the correct diagnosis. However, ADD patients rarely complain of suicidal ideation or thoughts of death and self-harm. Furthermore, a positive family history for bipolar disorder or affective disorder in the family of those patients with ADD should raise a red flag for the treating clinician.

Comorbidity And Suicide

Comorbid psychiatric and substance use disorders are overrepresented in bipolar disorder (Brieger et al. 2003 Kessler et al. 1994, 2005 Regier et al. 1990 Simon et al. 2004 Strakowski et al. 1992). Many of these comor- bidities are associated with a more difficult course of illness and with increased suicidality (Feinman and Dunner 1996 McElroy et al. 2001). In a clinical cohort of bipolar II patients in Spain, those with any comorbid condition fared far worse than those without patients with comorbid conditions, primarily personality disorders and substance use disorders, were more likely to experience suicidal ideation (74 vs. 24 ) and attempt suicide (45 vs. 5 ) (Vieta et al. 2000). Although this sample is likely not representative of the illness as a whole, it does underscore the importance of evaluating comorbid conditions in bipolar disorder. We will examine the impact of several comorbid conditions on suicidality.

Alcohol and Substance Use Disorders

More recent studies of comorbid SUDs or AUDs in bipolar patients have also demonstrated an increase in suicide risk associated with substance and alcohol abuse (Dalton et al. 2003 Hoyer et al. 2004). SUD and AUD comorbidity may be particularly damaging in bipolar disorder and may reveal a unique factor of the disorder. The added suicide risk observed in bipolar patients with comorbid SUDs or AUDs may not be present in unipolar patients (Hoyer et al. 2004). Comparisons of suicide risk associated with comorbid AUDs versus that associated with co-morbid SUDs have not yielded a clear difference. Dalton et al. (2003) demonstrated that drug use may present greater risk than alcohol use, with a twofold increase in suicide risk for bipolar patients with comor-bid substance abuse. However, Tondo et al. (1999) did not find a similar difference. Additionally, they suggested that not all substances are associated with greater suicidality they specify polysubstance abuse, heroin, cocaine, and...

Personality Disorders

In the Stanley Foundation Bipolar Network study of bipolar disorder, Leverich et al. (2003) reported that cluster B personality disorders were associated with a history of suicide attempts in 648 outpatients with bipolar disorder. Prior suicide, in a hierarchical logistic regression, was associated with sexual abuse history, isolation, hospitalizations for depression, and suicidal ideation while depressed, in addition to personality disorders. The strong association that they found with sexual abuse is striking, indicating that it may be that these patients are much more at risk of personality disorders and a more chronic bipolar course (Brodsky et al. 1997).

Genetic Vulnerability

While bipolar disorder and suicidality appear to be heritable, it is unclear whether the vulnerability to suicide is inherited through bipolar disorder or instead through a shared genetic predisposition that is independent of bipolar disorder (or any other shared psychiatric illness, such as unipolar depression or anxiety disorders). The serotonin (5-HT2A) receptor is of particular interest because of the association between serotonin and suicide, but research is sparse and conflicting (likely because of the small sample sizes in recent genetic studies and because suicide is a rare event) (Moffitt et al. 1998 Oquendo et al. 2003). Polymorphisms in the 5-HT2A receptor gene may play a role in the genetic susceptibility to bipolar disorder Bonnier et al. (2002) found a higher-than-expected proportion of bipolar subjects with the A allele for the 5-HT2A receptor gene who had not made a suicide attempt, but others have found no association (Massat et al. 2000 Ni et al. 2002 Tut et al....

Psychopharmacologic Interventions Potential Prophylactic Effects

Given its frequent and historical use in bipolar illness, it is not surprising that lithium has received a great deal of attention in research concerning psychopharmacology and suicide prevention in patients with mood disorders. A variety of meta-analyses, smaller independent studies, and study of lithium and anticonvulsants in two large health insurance databases generally substantiate a cautiously optimistic view of lithium as a prophylactic agent against suicide in bipolar disorder. While research on lithium's protective effects is promising, it is also essential to keep in mind the complications surrounding the research designs as well as the daily clinical problems of treatment noncompliance in the bipolar population. treated patients. After adjustment for a number of demographic factors, including age and psychiatric and medical comorbidity, the risk of suicide death was reported to be 2.7 times greater for patients prescribed divalproex for a diagnosis of bipolar disorder...

Prophylaxis of Episodes

Lamotrigine has been studied in two large, placebo-controlled, long-term (18-months), maintenance trials. These studies were designed to examine patients who had recently been manic (Bowden et al. 2003 Goodwin et al. 2004) and those who had recently been depressed (Calabrese et al. 2003 Goodwin et al. 2004). In both studies, lamotrigine was more effective at preventing or delaying future depressions than mania or hypomania. A combined analysis of 638 patients, who were randomized to one of three groups (lithium, lamotrigine, or placebo), found that both lithium and lamotrigine were superior to placebo at delaying intervention for depression and that lamotrigine was numerically superior to lithium (Goodwin et al. 2004). These studies have led to the approval of lamotrigine by the FDA for maintenance treatment in bipolar disorder.

Bipolar Depression

Valproic acid (usually in the divalproex formulation) is the most widely used mood stabilizer in the treatment of bipolar disorder in the United States. This is due to the documented efficacy of the divalproex formulation in acute mania (Bowden et al. 1994) and effective marketing by Abbott Laboratories. Nevertheless, the utility of valproic acid in bipolar depression is not well characterized. The utility of divalproex in the depressive symptoms of acute mania (Swann et al. 1997) and mixed mania (Calabrese et al. 1992) has been generalized to include efficacy in bipolar depression. Two blinded, controlled studies of valproic acid have been conducted using patients with bipolar depression. In one study, reported by Young et al. (2000), 11 type I and 16 type II bipolar disorder patients were randomly assigned to receive paroxetine or a mood stabilizer in addition to lithium or divalproex. Sixteen patients were randomized to receive two mood stabilizers and 11 received a combination of...

Antidepressants In Bipolar Depression

TREATMENT AND PREVENTION OF bipolar depression is a major problem in the long-term treatment of bipolar illness. While about one-third of patients may experience adequate prophylaxis with lithium or val-proate (El-Mallakh 1994), the majority of patients continue to be symptomatic (Ghaemi 2002). For example, although gender distribution of the bipolar diagnosis is equal, women may experience depression at two or three times the rate in men (Goodwin and Jamison 1990). Additionally, depressive symptoms themselves may be more problematic both type I and type II bipolar disorder patients spend one-third to half of their lives, respectively, experiencing depressive symptoms (Judd et al. 2002, 2003). This depressive morbidity is at least three times as common as manic or hypomanic morbidity (Ghaemi et al. 2000 Post et al. 2003a). Early onset of depression appears to be an especially poor prognostic factor. Among 72 children who have experienced a prepubertal, major depressive episode...

Acute Efficacy in Bipolar I Disorder

In the acute phase, a good amount of evidence suggests that antidepres-sants are more effective than placebo (mostly in the absence of concomitant mood stabilizer) or that certain antidepressants may be more effective than others in RCTs of the acute major depressive episode in bipolar disorder (Amsterdam 1998 Amsterdam et al. 1998 Cohn et al. 1989 Himmelhoch et al. 1982, 1991 Simpson et al. 1991 Thase et al. 1992). Those early studies did not use concomitant mood stabilizers. In the only RCT to assess antidepressant efficacy in lithium-treated patients, imipramine and paroxetine were not overall more effective than placebo when added to lithium for treatment of the acute depressive symptoms in patients with bipolar disorder type I. However, in a secondary analysis of those with low lithium levels (< 0.8), both antidepressants were superior to placebo when added to lithium (Nemeroff et al. 2001).

Novel Treatments In Bipolar Depression

TREATMENT FOR BIPOLAR DISORDER is currently characterized by polypharmacy, even in the best treatment centers (Kupfer et al. 2002) many patients cannot be stabilized without it. In a prospective follow-up of a study by the Stanley Foundation Bipolar Network in which 258 bipolar patients were followed, Post et al. (2003) noted that two-thirds of these patients remained substantially affected by their illness despite treatment, with one-quarter remaining symptomatic for over 9 months. Patients were depressed three times as often as they were manic. These patients were being treated with polypharmacy as reflected by the use of an average of 4.4 psychotropic medications per patient (Post et al. 2003). The tendency for polypharmacy in the treatment of bipolar patients was also reported by Levine et al. (2000), who found that nearly 50 of bipolar patients received three or more psychotropic agents. Demographic characteristics appeared to have a minimal impact on prescription patterns. Such...

Psychological Interventions In Bipolar Depression

THE LAST 5 YEARS HAVE BEEN crucial for the study of psychological treatment as a powerful add-on to medication in the prophylactic treatment of bipolar disorders. After many years of speculation and little evidence, several studies published in outstanding scientific journals showed the efficacy of several psychological approaches in preventing relapses into mania or depression. Training in prodromal identification (Perry et al. 1999), family-focused interventions (Miklowitz et al. 2003), cognitive-behavioral therapy (Lam et al. 2003), and psychoeducation (Colom et al. 2003a, 2003b) reached more than acceptable results in randomized clinical trials. Today, treatment guidelines include psychological interventions as a regular tool for maintaining euthymia (Calabrese et al. 2004 Goodwin et al. 2003). However, when looking at the efficacy of psychotherapy in the acute phases of bipolar illness, we may find a very different scenario (i.e., psychotherapy actually has acute efficacy in...

Cognitivebehavioral Therapy In Bipolar Depression

The efficacy of CBT in the treatment of unipolar depression is unquestionable, both in combination therapy and in monotherapy (Keller et al. 2000 Scott et al. 2000 Ward et al. 2000). However, these results should not be generalized to bipolar depression because the two have subtle but relevant clinical differences. Bipolar depression is often characterized by hypersomnia, inhibition, lethargy, and apathy (mainly behavioral symptoms) whereas unipolar depression is defined by desperation, pessimistic thoughts, and other cognitive signs (Goodwin and Jamison 1990). Although it is true that cognitive symptoms are not absent in bipolar depression, they may be more typical of unipolar depression. Therefore, bipolar depression would better respond to a behavioral therapy focused on activation, whereas a classical, cognitive therapy would be more appropriate for unipolar patients. (For this reason, we will refer to CBT as BCT from this point on because we believe that the behavioral strategies...

Psychotherapy Treatment Of Nuclear Symptoms And Associated Problems

There are several problems often associated with bipolar disorders that may worsen the quality of life of patients and therefore deserve special attention. Patients may run into problems during their adjustment to a diagnosis common reactions to receiving a diagnosis of a severe, chronic illness are denial, anger, ambivalence, and anxiety (Goodwin and Jamison 1990). It is essential for the clinician to respond appropriately in order to to improve illness awareness, treatment compliance, and avoid self-esteem problems (Colom and Vieta 2002a, 2002b). Another problem that should be carefully addressed by therapists is a patient's feeling of loss and grief after the loss of real or abstract objects, such as a job (which is mentioned by 70 of patients and their partners as the most relevant difficulty in the long term Targum et al. 1981 ), job status (which affects more than 30 of patients Harrow et al. 1990 ), economic status, and loss of love relationships and family support. All of...

Future Directions For Practice And Research

UNTIL RELATIVELY RECENTLY, the development of new pharmacological treatments for depression focused so much on unipolar depression that major depression and unipolar seemed almost to be synonymous. Perhaps bipolar depression had taken a back seat because, until recently, all of the agents developed specifically for the treatment of bipolar disorder were introduced as antimanic agents. When depression did occur in a bipolar patient, it was treated with the same antidepressant agents developed for unipolar depression. Now, with the development of new agents (lamotrigine and perhaps also quetiapine) that may be more effective for bipolar than for unipolar depression, interest in bipolar depression has heightened. Another reason for this new emphasis on bipolar depression is recent longitudinal research indicating that depression represents the bulk of the morbidity associated with bipolar disorder. This component of the illness lasts much longer than the manic component, is harder to...

From Clinical Phenomenology To Diagnostic Validity

The first subject that future research must clarify is the diagnostic validity of our current classification scheme. Considering just depression per se, are the bipolar and unipolar forms different Unfortunately the structure of DSM-IV-TR distinguishes bipolar disorder as a separate illness distinct from all other mood disorders (i.e., from the depressive disorders). Thus, the current DSM system obscures the fact that, originally, the bipolar-unipolar distinction was conceived of as a way to distinguish two forms of a recurrent illness. In other words, the DSM structure gives precedence to polarity over cyclicity or recurrence, thereby obscuring the reality that one rather common variant of unipolar illness is as recurrent or cyclic, much like bipolar illness. Kraepelin's original focus on course and recurrence has been lost to the detriment of research and practice. Just as the wastebasket of disorders subsumed under the DSM-IV-TR diagnosis of unipolar major depressive disorder is...

Progress In Neurobiology

The second hypothesis relevant to recurrence is the kindling paradigm. As advanced by Post and his associates (1992), this theory builds on the physiological finding that intermittent, subthreshold electrical or chemical stimuli will produce increasingly strong neuronal depolarization in the limbic system such depolarization can lead to an independent permanent seizure focus, with possible behavioral effects similar to mood disorders. While a direct link between kindling phenomena and clinical recurrence cannot readily be established, the hypothesis does possess the advantage of explaining a number of clinical findings in one theory first, earlier episodes of bipolar disorder tend to be precipitated by environmental stressors, whereas later episodes tend to be triggered less often psychosocially second, the severity of untreated mood episodes tends to worsen over time third, the interval between mood episodes decreases over time and fourth, stressful childhood events may predispose...

Integrating Biological And Psychosocial Aspects Of Mood Disorder

Certainly, an important goal is to integrate psychopharmacological clinical trials with psychotherapeutic aims of treatment and to include combinations of the two treatment modalities as well. This research has valuable practical implications for instance, current data suggest that decisions regarding medication as a component of treatment versus psychotherapy alone (specifically, interpersonal or cognitive-behavioral therapy) should be based more on the nature of the symptoms and especially on whether an illness is recurrent or not, than on speculative etiological bases for the illness. The latter point regarding recurrence is reinforced by Frank et al.'s (1990) landmark study comparing imip-ramine, interpersonal therapy, a combination of the two, and placebo, in which those with three or more episodes responded better to medication or combination treatment than to psychotherapy alone. In other studies of patients with one or two episodes of illness, CBT tended to be as effective as...

Ethics And Public Policy New Questions

There is also a potential negative impact of ethical constraints on the ability to adequately conduct scientific studies. In some placebo-controlled studies of bipolar disorder, more severely ill patients are often excluded by clinicians who are rightfully concerned about the risks of such nontreatment. However, as a consequence, we often see relatively small effect sizes for the difference between drug and placebo in the less severely ill patients who enter those studies. Sometimes these small effect sizes are seized upon by critics as evidence of lack of benefit with psychotropic medications. This kind of rationale has been used with antidepressants, both in children and adults, and with some mood stabilizers, such as the divalproex prophylaxis study. Our profession needs to reach a better consensus about how to achieve ethical protections while at the same time being able to study severely ill patients in randomized clinical trials.

Brain Energy Metabolism In Bipolar Depression

Bipolar disorder as manifested by its opposite poles of depression and mania is characterized by decreased or increased motoric and mental energy expenditure. Does such a unique presentation suggest altered states of brain energy metabolism in this disorder Positron emission tomography (PET) studies report reduced blood flow in depressed mood states, including bipolar depression (Baxter et al. 1985 Drevets et al. 1997 Ketter et al. 2001). PET studies reported lower fluorodeoxyglucose (FDG) uptake in the prefrontal and temporal cortexes and higher uptake in the occipital cortex of depressed patients compared with healthy controls, although in manic states the reverse direction of results was less clear. Single-photon emission computed tomography studies suggested lower cerebral blood flow in the frontal and temporal cortexes of bipolar disorder patients, particularly in the left hemisphere (Strakowski et al. 2000). Kato et al. (1994) reported reduction of brain phosphocreatine in...

Antidepressant Induced Mood Destabilization andor Rapid Cycling

Studies have reported an association. In one report, the cycling terminated when antidepressants were discontinued in about one-third of patients (Wehr et al. 1988). In a retrospective chart review of 109 rapid-cycling bipolar patients, Kukopulos et al. (1983) found that 80 (73.4 ) developed rapid cycling some time after onset of bipolar illness. Specifically, 65 type II and 15 type I individuals developed rapid cycling 11 years after the onset of the bipolar disorder. The number of episodes per year grew from 0.8 to 6.5. In all 80 subjects, onset of rapid cycling was associated with antidepressant treatment that continued through euthymic periods (n 17) or that persisted at least 1 year (n 33), 2 years (n 14), or longer (n 5). The authors pointed out that since 52 of these patients had depressive episodes prior to antidepressant exposure (and were treated with psychotherapy, anxiolytics, electroconvulsive therapy ECT , or not at all), the occurrence of depression, per se, was not the...

Antidepressantassociated Chronic Irritable Dysphoria

In 1987, Akiskal and Mallya introduced the notion of antidepressant-induced, chronic symptoms that include irritability and sleep disturbance in relatives of bipolar patients who have only manifested unipolar depressions. These patients developed a syndrome that consists of 1) unrelenting dysphoria, 2) severe agitation, 3) refractory anxiety, 4) unendurable sexual excitement, 5) intractable insomnia, 6) suicidal obsessions and impulses, and 7) histrionic demeanor (Akiskal and Mallya 1987). More recently, El-Mallakh and Karippot (2005) have described a chronic irritable depressive state that develops after long-term (several years) treatment with antidepressants in both type I and type II patients. This syndrome is specifically manifested by a triad of dyspho-ria, middle insomnia, and irritability, and thus has been labeled antide-pressant-associated chronic irritable dysphoria (ACID). Patients with ACID invariably experience significant social and occupational dysfunction such as...

Specificity Of Bipolar Depression

The biology of bipolar depression encompasses depressive episodes of bipolar disorder and the biology of the underlying illness that gives rise to the depressive episodes. Understanding the biology of bipolar depression should increase the effectiveness of its diagnosis and treatment. In our current nosology, mania or hypomania is required for diagnosis of bipolar disorder (First et al. 1996). Yet, for most patients, depression is the most salient feature of the illness the average patient with bipolar disorder spends three times as much time depressed as manic (Post et al. 2003), and depressive episodes are associated with most of the psychosocial impairment of bipolar disorder and with mortality from suicide (MacQueen et al. 2000). Bipolar disorder usually starts with depression, rather than with mania or hypomania, often resulting in a substantial period of misdiagnosed illness and a course of illness that is worse than when mania is the first episode (Perugi et al. 2000)....

Vagus Nerve Stimulation

Sackeim et al. (2001) conducted an open pilot study of VNS in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to 1) define the response rate, 2) determine the profile of side effects, and 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. VNS treatment lasted 10 weeks. Of 59 completers (one patient improved during the recovery period), the response rate was 30 for the primary 28-item Ham-D measure and 34 for the MADRS. The most common side effect was voice alteration or hoarseness (55 ), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT were four times more likely to respond. None of the 13 patients who had not responded to more than seven...

Genetics

It is an often-underrecognized fact that the primary scientific basis for the distinction between bipolar and unipolar depression, as opposed to the broader concept of manic depressive illness, had to do with genetic studies. Classic research by Perris in the 1960s suggested that patients with bipolar disorder had family members that were diagnosable with bipolar disorder, whereas patients with unipolar depression had family members that were diagnosable with unipolar depression but not bipolar disorder (Perris 1966). This literature on genetic studies has significant clinical relevance if an individual with pure, unipolar, depressive episodes also has a family history of bipolar disorder, it would be in conflict with perhaps the most important scientific basis for the bipolar unipolar distinction. Indeed, depressed patients with a family history of bipolar disorder, who have not experienced spontaneous manic or hypomanic episodes, are at increased risk of antidepressant-induced...

Clinical Specificity

The basic depressive syndrome consists of the inhibition of goal-directed and reward-related activity, experienced as anhedonia and anxious pessimism. Biological models for depression have focused largely on the effects of uncontrollable stressors. These models have moderate pharmacological validity but lack evidence of specificity for bipolar disorder (Machado-Vieira et al. 2004 Nestler et al. 2002). The core depressive or melancholic syndrome appears essentially identical in unipolar and bipolar disorder (Mitchell et al. 1992). On av

Mixed Depressions

The entire gamut of depressive and manic symptoms, alone or combined, can be present during an exacerbation of bipolar disorder. Mixed mania, in which a manic episode is combined with prominent depressive characteristics, has been studied extensively and is recognized in the DSM-IV-TR. There is also a growing body of literature describing mixed depressions, in which a major depressive episode is usually accompanied by two or more symptoms of mania (Benazzi 2003a). Two manic symptoms were found to be diagnostically overinclusive, present in 78.1 of bipolar and 41.5 of unipolar depressions, while three manic symptoms were present in 46.6 of bipolar and 7.6 of unipolar depressions (Benazzi 2001). It may be possible to improve the definition of mixed depression by prioritizing manic symptoms based on their specificity for mania, as McElroy et al. (1992) did for depressive symptoms in their operational definition of mixed mania. Because anxiety and inner tension are ubiquitous in...

Phenomenology

The diagnosis of past manic or hypomanic episodes is where the standard DSM-IV-TR-based approach to bipolar depression begins and ends. This is a necessary but insufficient approach to diagnosing bipolar depression. While the presence of past manic or hypomanic episodes in the depressed patients meets the diagnostic criteria for bipolar depression, the apparent absence of such episodes does not adequately rule out bipolar depression. There are at least two reasons for this First, type I or type II bipolar disorder may still be present in the absence of the patient's report of past manic hypomanic episodes simply because the patient may not be adequately reporting past manic symptoms. Research shows that about half of patients with manic episodes have been shown to lack insight into their manic symptoms (Ghaemi and Rosen-quist 2004 Ghaemi et al. 1995). It is important to interview family members, who are known to report their relatives' mania twice as frequently as the patients...

Structural Imaging

Results of structural magnetic resonance studies have suggested that subjects with bipolar disorder were generally more likely than controls to have white matter hyperintensities, decreased size of the cerebellum, and increased sulcal and third ventricular volumes (Stoll et al. 2000). Other studies have not confirmed any specific relationship between bipolar disorder and hyperintensities (Brown et al. 1992 Sassi et al. 2003). Drevets et al. (1998) reported that subjects with either major depressive disorder or bipolar disorder had reduced prefrontal cortex gray matter volume, apparently independent of mood state or treatment. Reduction in total cortical volume and in volume of the amygdala was reported in adolescent patients with bipolar disorder, suggesting that the reductions were present early in the course of illness and were not secondary degenerative changes (DelBello et al. 2004). Hippocampal volume was reported to be decreased overall in unipolar, but not bipolar, depression...

Functional Imaging

Positron emission tomography and functional magnetic resonance imaging (fMRI) can provide measures related to regional brain activity (Strakowski et al. 2000). PET studies of glucose metabolism have yielded results consistent with reduced activity in the prefrontal cortex, which are consistent with results from nonbipolar depressed subjects (Ketter et al. 2001 Strakowski et al. 2000). There was also increased activity in the cerebellar vermis, possibly a trait-related characteristic in bipolar disorder (Ketter et al. 2001). Mood induction studies in subjects with bipolar disorder (Kruger et al. 2003) found changes in ventral cingulate-corti- cal-limbic activity that were similar to those found in controls, especially with depressive temperaments (Keightley et al. 2003). A study of anhedonia in bipolar and unipolar depressed subjects revealed that, in both, anhedonia was negatively correlated with 2-deoxyglucose uptake in the insula and claustrum and positively correlated with uptake...

In Vivo Spectroscopy

Neurochemistry can be studied in vivo using MRS (Moore and Galloway 2002). Proton MRS showed that subjects with bipolar disorder had abnormal choline metabolism, especially in basal ganglia (Strakowski et al. 2000) and the anterior cingulate cortex (Moore et al. 2000). Studies of inositol metabolism, possibly a site of action for lithium, have produced positive (Stoll et al. 2000) and negative (Moore et al. 2000) results. The finding of reduced N-acetylaspartate levels in dorsolateral, pre-frontal cortex potentially reflects reduced neuronal integrity in that region (Winsberg et al. 2000). Phosphorus MRS suggested the presence of

Conclusions

The picture of bipolar depression that is emerging from these brain imaging studies is one in which affective responses are poorly regulated, possibly resulting from failure of the prefrontal cortex to modulate subcortical and temporal signals (Strakowski et al. 2004, 2005). While some abnormalities are present early in the course of illness (DelBello et al. 2004), others may develop as the illness progresses (Strakowski et al. 2004). Imaging studies reveal a complex interaction of diagnostically nonspecific, affective responses superimposed on characteristics more specific for bipolar disorder. Improved characterization of these structural, functional, and metabolic changes will aid in the development of, and increase the need for, a physiological model for the onset and course of bipolar disorder.

Course of Illness

Because the first episode of bipolar disorder is usually depressive, it is important to identify differences between patients with recurrent depressions who eventually had manic episodes and those who continued without manic episodes. Comparisons between these cohorts of identified unipolar and bipolar patients, as well as comparisons between patients with recurrent depressions who did or did not go on to have manic or hypomanic episodes, showed consistently that bipolar disorder has a more recurrent course (Angst et al. 2003 Kessing and Andersen 1999) with earlier onset (Akiskal et al. 1994 Benazzi 2002, 2004 Kessing 1999) and more frequent episodes (Angst et al. 2003 Goldberg and Harrow 2004 Kessing 1999 Kessing and Andersen 1999 Winokur and Wesner 1987). Similarly, rapid cycling can occur in either illness but is substantially more common in bipolar disorder (Wolpert et al. 1990). These results, combined with the lack of consistent, clinical differences between bipolar and unipolar...

Summary

Despite substantial progress using brain imaging and genetic techniques, our ability to study the biology of bipolar depression is limited by our imperfect ability to describe the phenotype of bipolar disorder. The presence of past mania or hypomania is not sensitive enough, since depression usually precedes mania. This problem can potentially be addressed by the study of endophenotypes, or characteristics like P300 amplitude or response to stimulants that may represent expression of underlying susceptibility genes (Lenox et al. 2002). Bipolar disorder may share characteristics with schizophrenia or with unipolar disorder, while other features may distinguish it from either illness. This would explain the genetic and clinical overlap between bipolar disorder and both schizophrenia and unipolar disorder, as well as the spectrum-like presentation of affective disorders and schizophrenia. There are significant clues with regard to specificity, but few findings that are absolute....

Chromosome

Linkage findings to 4p16, along with findings that suggest psychiatric symptoms are associated with Wolfram's disease (Nanko et al. 1992), have led to the hypothesis that the Wolfram gene (WFS1 wolframin) may be a plausible candidate gene for bipolar disorder. With regard to association studies of this region, Kato et al. (2003) examined the association between mutations and mRNA expression of WFS1 and bipolar disorder in a Japanese sample of 184 unrelated patients with bipolar disorders and 207 unrelated control subjects. The authors found no significant differences in mutations or expression of WFS1 mRNA between the groups, suggesting a lack of importance of this gene in bipolar illness.

Overdiagnosis

Despite the evidence that bipolar misdiagnosis has not decreased in the past decade, some clinicians and researchers express concern about possible overdiagnosis of bipolar disorder. This concern is especially voiced in relation to discussion of broadening the definition of the bipolar spectrum. FIGURE 1-3. How the polarity-based approach to bipolar disorder in DSM-IV-TR can lead to misdiagnosis. In contrast to the extensive literature described above that supports the notion of continued underdiagnosis of bipolar disorder, there is a much more limited body of literature providing empirical evidence of overdiagnosis of bipolar disorder. A MEDLINE search of overdiagno-sis and misdiagnosis for bipolar disorder identifies only three reports of possible overdiagnoses of bipolar disorder, two of which are case reports in letters to the editor. In the only published study (Krasa and Tolbert 1994), of 53 adolescents admitted with a clinical diagnosis of bipolar disorder, 72 met DSM-III-R...

The Bipolar Spectrum

The above discussion of ways to differentiate bipolar from unipolar depression is also relevant to the general concept of a bipolar spectrum. The notion of a bipolar spectrum begins from the fact that many patients do not meet classical definitions of unipolar depression or bipolar disorder type I or II. As shown in Figure 1-1, many patients appear to demonstrate features of bipolarity such as the depressive phenomenology or the illness course mentioned above, and yet the inability to diagnose spontaneous manic or hypomanic episodes precludes the diagnosis of bipolar disorder types I or II. Note. BPI bipolar disorder type I, BPII bipolar disorder type II, D major depression, d subsyndromal depression, M mania, m hypomania, NOS not otherwise specified, RDC Research Diagnostic Criteria. Source. Reprinted from Goodwin FK, Ghaemi SN An introduction and history of affective disorders, in Oxford Textbook of Psychiatry, Vol 1. Gelder MG, Lo-pez-Ibor JJ Jr, Andreasen NC. Oxford, England,...

Chromosome X

Analyses of the NIMH Genetics Initiative pedigrees (waves 1 and 2 153 families) support linkage to the X chromosome on Xp22.1, with a heterogeneity LOD of 2.3 (Mclnnis et al. 1999). More recently, Ekholm et al. (2002) conducted a further examination of the relationship between the X chromosome and bipolar disorder in a sample of Finnish families using a dense marker map. Subjects were 341 individuals from 41 bipolar families. Five diagnostic categories were used, reflecting increasingly broad inclusion criteria. Microsatellite markers were used, and parametric linkage analyses were conducted by using MLINK from the ANALYZE package (Hiekkalinna et al. 2005). Using a dominant model of inheritance, a suggestive maximum two-point LOD score of 2.78 was found at marker DXS1047 under a model including bipolar I and schizoaffective disorders. Previous research from this group has also supported linkage between bipolar disorder and markers on Xq24-q27.1 (Pekkarinen et al. 1995). Zandi et al....

Future Directions

As can be concluded from the present review, numerous regions have at least some support as putative susceptibility loci in bipolar disorder, with 4, 11, 12q, 16, 18, 22q, and Xq arguably showing the most support. Studies have also provided evidence for numerous candidate genes playing a role in bipolar disorder, including the G72 G30 complex, genes involved in the serotonergic and dopaminergic systems, BDNF, and COMT (see Table 3-1). However, while we have attempted to highlight recent significant findings of linkage and association, for many of the positive findings we report there are at least as many negative findings and replication failures. Given that risk for bipolar disorder is probably genetically heterogeneous, some variability in findings is to be expected however, at least some of these findings will likely fail to receive further support in future studies. The question remains of how to conduct research in a way that minimizes misleading results while capturing the...

Epidemiology

Child and adolescent bipolar disorder have been less studied than adult-onset bipolar illness (Sanchez 1999). In adults, the prevalence of bipolar type I disorder is considered to be approximately 1 of the population the rate of the illness in children is a matter of debate. Some studies indicate rates as high as 3.0 -6.5 for the bipolar spectrum (Hirschfeld et al. 2003). study of bipolar disorder in adolescents. The lifetime prevalence of bipolar disorders in this study was approximately 1 , which was similar to that reported in the Epidemiologic Catchment Area Study (Weiss-man et al. 1988). Lewinsohn et al. (1995) studied 1,709 youths. Eighteen bipolar cases were detected (age 14-18 years) and the mean age of onset was 12 3 years. Only two subjects (11 ) met the criteria for bipolar I disorder. More than half of these patients received mental health care, but only one was treated with lithium. The ratio of first-episode depressive patients versus manic patients was 61 to 5 . The...

Clinical Picture

The diagnostic criteria and symptom profile of pediatric bipolar depression are the same as those for adults however, the way the symptoms are expressed varies with the developmental stage of the child (Table 4-1). For example, instead of communicating the sad feelings, children may act out and be irritable towards others, or express multiple somatic complaints, like headaches and stomachaches. Presence of specific symptoms such as psychosis, psychomotor retardation, medication-induced disinhibition hypomania, or a family history of bipolar disorder may indicate that the depressed patient is at risk to develop bipolar disorder (Geller et al. 1994 Strober and Carlson 1982 Strober et al. 1993). Somatic complaints and thoughts of death are common. Adolescent patients may be more likely to present with rapid cycling or mixed episodes. These patients are difficult to treat and are at an increased risk for suicide (Brent Family history of bipolar disorder et al. 1988, 1993 Geller and Luby...

Prepubertal Children

Feelings of sadness or hopelessness than adolescents and adults. In most cases, the most common presentation is sadness. These children may also exhibit mixed symptoms by cycling between depression and ma-nia hypomania several times a day. Egeland et al. (2000) studied the prodromal symptoms most commonly reported by families on initial admission of 58 children who were later diagnosed with bipolar disorder. The most common symptoms were depressed mood (53 ), increased energy (47 ), decreased energy and tiredness (38 ), anger outbursts (38 ), and irritable mood (33 ). Luby and Mrakotsky (2003) studied the association of increased rate of switching to mania in childhood depressive disorder. These patients had an earlier age at onset of an episode of depression as well as a family history of bipolar disorder. From a pool of 174 preschoolers, ages 3.0-5.6 years, 54 of them met modified criteria for major depressive disorder. This study indicated that the group of depressed preschoolers...

Adolescents

The clinical presentation of adolescents is more similar to that of adults than to that of children. McGlashan (1988) and Strober et al. (1995) have reported that adolescents with bipolar disorder may have a more prolonged early course and may be less responsive to treatment when compared with adults. Lewinsohn et al. (1995) reported that 61.1 of adolescents studied with bipolar disorder presented with a major or minor depressive episode. Depression should be considered when a previously well-functioning child performs poorly academically and in other school functions, withdraws from friends or society, or commits delinquent acts. Atypical clinical presentation is common in adolescents with bipolar disorder (McElroy et al. 1992). Substance abuse is commonly seen with depressive disorders in adolescents (Rao et al. 1995). Strober et al. (1993) studied 60 hospitalized, depressed adolescents (ages 13-16 years) and found that at the 3- to 4-year follow-up, 20 of these patients had...

Schizophrenia

Some of the negative symptoms seen in schizophrenia are also seen in depression. Children with clinical presentation of bipolar disorder and psychotic mood disorders are often misdiagnosed as having schizophrenia (Ferro et al. 1994) however, their symptoms may be distinguishable by the associated mood-incongruent hallucinations and paranoia seen in patients with schizophrenia. Furthermore, patients with schizophrenia have an insidious onset and are less likely to have episodic pattern of mood changes and lack family history of bipolar disorder.

Psychotherapy

Psychosocial interventions are critical in the management of pediatric bipolar depression, although there is no proven, superior psychothera-peutic method. Pavuluri et al. (2004b) suggested the integration of cognitive-behavioral therapy and interpersonal therapy to help patients and families deal with their negative cognitions. A manual-driven, adjunc-tive, multiple-family, group treatment for adolescents (ages 8-12 years) with bipolar depression was attempted by Fristad et al. (2002). The results and impact of this treatment on the adolescents are still pending. Although lacking in documented scientific merit as a proven treatment for bipolar disorder, cognitive-behavioral therapy has shown promise especially for adolescents with bipolar depression (see Chapter 10, Psychological Interventions in Bipolar Depression).

Pharmacotherapy

There is a paucity of studies involving children with diagnoses of bipolar disorders. As of now no standardized, scientific research data exist for the treatment of pediatric bipolar depression. Several agents have been clinically tried with limited success in controlling this complex illness. There is a great need for clinical trials examining the safety and efficacy of psychotropic medications in the treatment of bipolar depression in children. The U.S. Food and Drug Administration has approved lithium for treatment of bipolar disorder in individuals age 12 years or older adult studies indicate significant effect size for lithium (Schou 1968 Strober et al. 1990). Only a few studies have examined the efficacy of lithium in children from both the prepubertal and adolescent population. Available data indicate lithium is both safe and effective in youths and can be prescribed in a manner similar to that for the adult population (Strober et al. 1995 Weller et al. 1986). El-Mallakh et al....

Phase of Illness

The frequency and duration of depressive symptoms and episodes is one factor in the high incidence of suicide and suicide attempts in bipolar disorder. In a study of 31 suicides of people with bipolar disorder, nearly 80 occurred during an episode of depression, 11 while in a mixed state, and 9 while the person was recovering from a episode of psychotic mania (Isometsa et al. 1994). We can therefore conclude that depression, whether during a major depressive or mixed episode, is associated with suicide. Dilsaver et al. (1994) reported that whereas suicidal ideation was rare in pure mania (occurring in 1 of 49 subjects studied), 55 of the patients with mixed mania had suicidal ideation, and that this difference was significant (P 0.0001). Additional observations support the notion that it is depression that puts patients with bipolar disorder at risk of suicide. Those with a course of illness characterized predominantly by mania or mania with mild depression were found by Angst et al....

Rapid Cycling

The DSM-IV-TR defines rapid cycling as four discrete episodes of mania or depression occurring within 1 year. However, the actual appearance of rapid cycling in bipolar disorder can be quite varied, and research surrounding rapid cycling (including research focusing on suicidality) remains inconsistent. While the prevalence of rapid cycling in bipolar disorder is unclear and may be difficult to diagnose, it appears that its identification is necessary for effective suicide prevention. In a sample of 603 bipolar individuals, MacKinnon et al. (2003) found patients with rapid cycling to be significantly more likely than non-rapid cyclers to have attempted suicide (42 vs. 27 respectively). Coryell et al. (2003) also found rapid-cycling bipolar disorder to be associated with more serious suicide attempts, although it was not associated with a greater number of completed suicides. Thus, there appears to be a significant additional burden on the patient as a result of the rapid cycling that...

Psychosis

It does not appear that psychosis raises the risk of suicide in bipolar illness. Angst and Preisig (1995) found in their Zurich cohort that the presence of schizophrenic symptoms did not have a differential impact on suicide rates. Grunebaum et al. (2001) reported that the presence of delusions in 429 subjects with schizophrenia, unipolar depression, and bipolar disorder did not correlate with whether they had suicidal ideation or had made a suicide attempt. Tsai et al. (2002) reported that in a cohort of Chinese patients, mood-congruent psychotic symptoms at the onset of illness were in fact associated with reduced risk of having made a suicide attempt.

Anxiety Disorders

Comorbid anxiety and anxiety disorders appear to be associated with increased suicidal behavior in bipolar disorder. Simon et al. (2004) found that a history of an anxiety disorder was an independent risk factor for a more severe and debilitative course of bipolar illness, and brought on higher risk of attempting suicide (odds ratio 2.45, 95 CI 1.4-4.2). Anxiety disorders were highly prevalent in this study, with a lifetime history of an anxiety disorder in 51.2 of the sample. A current anxiety disorder was present in 30.5 of subjects. Henry et al. (2003) did not find such an association in a smaller sample of 318 subjects with bipolar disorder. Only 24 of this sample had a lifetime anxiety disorder, and there was no increase in suicide attempts in the subjects with a history of an anxiety disorder. This sample may not have had enough statistical power to find such a difference, and their negative finding may represent a type II error (i.e., failing to find a difference when one...

Eating Disorders

Eating disorders, while not as common of a comorbidity in bipolar disorder as substance use or anxiety disorders, is overrepresented in bipolar disorder (Krishnan 2005). In an inpatient sample there was an association between bipolar illness and eating disorders and 32 of the patients had a history of suicide attempts and self-injurious behavior (Stein et al. 2004). While rates of suicides and suicide attempts is high in patients with eating disorders, there is not enough data currently available to know whether the presence of an eating disorder in patients with bipolar disorder increases the suicide risk compared with patients without eating disorders (Corcos et al. 2002).

Medical Comorbidity

Low cholesterol levels may be linked to suicide and aggression, but there is conflicting data in the literature on bipolar disorder regarding the cholesterol level of suicide attempters (Zureik et al. 1996). Bocchetta et al. (2001) observed that men with affective disorder treated with lithium and with fasting cholesterol in the lowest quartile were more likely to have a history of suicide attempts or a first-degree relative who had committed suicide than subjects whose cholesterol was in the highest quartile. Tsai et al. (2002), however, reported no association between fasting cholesterol and completed suicides in a Chinese cohort compared with living controls.

Suicide Prediction

There are characteristics that are overrepresented in bipolar patients with suicidality (Table 5-1) hopelessness, aggressivity, severity of depressed mood, and suicidal ideation have been repeatedly found to be associated with suicidality (Ahrens and Linden 1996 Beck et al. 1993 Brown et al. 2000 Minkoff et al. 1973 Oquendo and Mann 200l). These symptoms are neither specific to bipolar disorder, nor easily accounted for by any component of the clinical presentation of the patient with bipolar disorder. A complex matrix of mood disorder, family history and genetics, comorbidity (especially anxiety and substance use, including nicotine), medical history (including head injury), and social and economic factors may contribute to the presence and severity of these symptoms. While not all are amenable to clinical intervention, many are, and awareness by the clinician and the social network of the bipolar patient may contribute to reducing risk and increasing the probability of suicide...

Adjunctive

The combination of valproic acid with an antipsychotic appears to be more effective than divalproex alone. Tohen et al. (2002) reported the addition of olanzapine or placebo to lithium or valproic acid in the treatment of 344 patients with type I bipolar disorder who were experiencing a manic or mixed manic episode. In a subanalysis of 85 patients who had a Ham-D score of 20 or more, the improvement in depressive symptoms was significantly greater in those treated with a combination than those treated with monotherapy (Baker et al. 2004). However, as noted above, efficacy in dysphoria associated with mania does not mean efficacy in bipolar depression.

Topiramate

Topiramate is an anticonvulsant with several interesting properties (Yen et al. 2000) it is associated with weight loss, may be an effective anti-obesity agent (Bray et al. 2003 Wilding et al. 2004), and may actually increase insulin sensitivity (Wilkes et al. 2005a, 2005b), possibly making it useful in the management of weight gain and obesity, which frequently accompany bipolar disorder (McElroy et al. 2004). Furthermore, topiramate may be effective in reducing binge-eating behavior (McElroy et al. 2003), bulimia (Hedges et al. 2003 Hoopes et al. 2003), and alcohol consumption (Johnson et al. 2003). For these reasons, topi-ramate is a frequently used drug in bipolar patients. However, initial reports that topiramate is an effective mood stabilizer have not been borne out by more extensive double-blind, placebo-controlled studies. Unfortunately, many of these reports remain unpublished and therefore cannot be critically reviewed. Two studies have been performed with topiramate in...

Gabapentin

Sokolski et al. (1999) and Young et al. (1999) both reported a significant decrease in symptoms of hypomania and depression in mildly ill type I or type II bipolar disorder patients. Again, anxiety symptoms were not specifically measured, but may have accounted for most of the improvement.

Omega3 Fatty Acids

In a cross-national comparison, Noaghiul and Hibbeln (2003) found a correlational relationship between greater seafood consumption and lower prevalence rates of bipolar disorders. However, research into the use of PUFAs in the treatment of bipolar disorder has lagged behind research regarding PUFAs as treatment for unipolar depression. To date, a number of open and controlled studies has been performed to examine whether omega-3 fatty acids are also useful in bipolar depression and exhibit mood-stabilizing properties in bipolar disorder. Chiu et al. (2003) have found significantly reduced arachidonic acid (20 4n-6) and docosahexaenoic acid (22 6n-3) compositions in bipolar patients as compared with normal controls. There were no differences in total The first and best-known published study of omega-3 prophylaxis in bipolar disorders was reported by Stoll et al. (1999). These authors found that omega-3 fatty acids were well tolerated by patients, they improved the short-term course of...

Mfoinositol

The PI cycle has been suggested as playing a pivotal role in bipolar disorders. Berridge et al. (1989) found that inositol depletion may be the key for lithium's effect in bipolar affective disorder. Williams et al. (2002) showed that all three mood stabilizers (lithium, valproic acid, and carbamazepine) inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects are reversible by inositol, thus implicating inositol depletion in the action of mood stabilizing agents. These data suggest that inositol depletion, like lithium, would be therapeutic in bipolar disorder. On the other hand, the encouraging results of inositol treatment in major depression suggest that inositol treatment might be therapeutic in bipolar depression.

Clinical Course

Pears to be a particularly vulnerable period for suicide. Hoyer et al. (2004) examined the characteristics of all first hospitalizations for affective disorder in Denmark between 1973 and 1993, finding that 3,141 of 53,466 patients committed suicide (6 ), and that the suicide risk was highest on the day following discharge and the day following admission. The risk declined over time, remaining high for 6 months following discharge. Interestingly, the risk associated with time after discharge declined with increasing duration of illness, supporting the notion that suicide risk is highest early in the course of affective illnesses, including in bipolar disorder. Fagiolini et al. (2004) reported that in a cohort of 175 patients with bipolar disorder, suicide attempts tended to occur at a relatively young age and in the early part of the patients' illnesses. A history of suicide was also associated with a greater number of prior episodes, higher depression scores at entry, and higher body...

Ketogenic Diet

Ketogenic Diet and Bipolar Disorder El-Mallakh and Paskitti (2001) suggested that the KD may be an effective mode of treatment for bipolar disorder. They hypothesized that the acidosis associated with the KD reduces intracellular sodium and intra-cellular free calcium, both of which are elevated in ill bipolar patients. However, Yaroslavsky et al. (2002) reported no beneficial effect of the KD in a case study of a bipolar woman. These authors applied a KD consisting of fats, carbohydrates, and protein in a 4 1 ratio (fats and carbohydrates to protein) to induce production of ketoacids in a slim, 49-year-old, physically healthy woman with severe, resistant, rapid-cycling bipolar disorder. The patient had early-onset bipolar disorder that deteriorated into continuous cycling episodes of manic-depressive illness without euthymic intervals. The patient was nonresponsive to lithium, carbamazapine, and valproic acid (individually or in combination) and the patient, her family, and the...

Misdiagnosis

Numerous clinical studies now confirm that about 40 of persons with bipolar disorder are initially misdiagnosed with unipolar depression (Ghaemi et al. 2001). In some cases, the problem is not so much misdi-agnosis as it is the natural history of the illness if depressive episodes precede manic episodes, then the current nosology, correctly applied, would lead to misdiagnosis. This is sometimes called pseudounipolar depression. However, about 90 of patients with bipolar disorder will have a manic episode by the time they experience three major depressive episodes (Goodwin and Jamison 1990), so at some point clinicians would have the opportunity to observe and diagnose manic episodes. Besides the clinical studies mentioned above, surveys of patients with bipolar disorder support a 50 or higher rate of misdiagnosis (Hirschfeld et al. 2003b Lish et al. 1994). Both a survey and clinical studies indicate that it takes about a decade from the time patients seek help from mental health...

Dopamine Agonists

Goldberg et al. (2004) conducted a randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. In this study, 22 depressed outpatients with DSM-IV-TR, nonpsychotic bipolar disorder were randomly assigned to receive placebo or a flexible dose of pramipexole added to existing mood stabilizers for 6 weeks. More patients given pramipexole (10 of 12) than patients given placebo (6 of 10) completed the study. Sixty-six percent patients taking pramipexole and only 20 taking placebo had an improvement of at least 50 in their Ham-D scores the mean percentage of improvement from baseline was greater for patients taking pramipexole than for those taking placebo (48 vs. 21 ). One patient developed hypomania while taking pramipexole.

Mental Disorders and Psychiatric Treatment

Most suicides are associated with a relatively small number of mental disorders or conditions. Patients with affective disorders (depression and bipolar disorder) and schizophrenia are at higher risk for suicide (Rossau & Mortensen, 1997 Roy, 1989). Thought disorders such as a paranoid delusional system or auditory hallucinations that tell a person to kill himself or herself or a loved one, especially when combined with depressed mood, put the sufferer at high risk (Resnik, 1980). Individuals with psychotic depressive reactions are at especially high risk for suicide.

Focus On Issues Use Of Punishment In Treatment

There are behaviorally deficient and psychotic people who, for a variety of reasons, engage in self-destructive behavior. This behavior may escalate to the point at which the person is hitting, scratching, biting, or gouging himself or herself most of the day. In some cases, self-destructive acts are so frequent and intense that the person is hospitalized. Occasionally physical injury is irreversible, as when a child bangs his or her head on a wall until brain damage occurs. Although positive reinforcement programs have been used to alleviate severe behavior problems, these contingencies are not always successful. Because of this, behavior therapists have resorted to punishment as a way of reducing self-destructive behavior.

Target Validation And Functional Genomics

Under the reported recessive model, showed no evidence for a linkage between chromosome lq and schizophrenia a finding that could not be ascribed to ethnicity, statistical approach, or population size. Another group (116) using two prefrontal cortex tissue from two separate schizophrenic populations showed an up-regulation of apolipoprotein LI gene expression that was not seen in tissue from patients with bipolar disorder or depression. The genes related to apolipoprotein LI gene expression are clustered on the chromosome locus 22ql2, providing another target for the functional genomic approach to target discovery and validation. Yet another locus at chromosome 3q has been reported (117).

Case Study 4 Candidate Gene Selection Building Biological Rationale Around Genes Recommended Tools Hgb Ensembl

In our hypothetical study we are looking for a gene with a possible role in bipolar depression, therefore to prioritize our candidate genes, we might first review the literature to search for a link between the candidate genes in the region and this disease pathway. The aetiology of bipolar disorder, like many complex diseases is poorly understood, this makes it difficult to establish a clear biological rationale for any gene in this disorder. Where biological rationale is found it could range from convincing support, such as upregulation of the gene or a related gene or pathway component in a disease model or in a similar phenotype to the most basic support, such as being expressed in a tissue affected by the disease. of over-interpreting tenuous links between genes. This could be a particular problem in the case of poorly understood diseases, where unknown pathways would largely fail to register as a form of rationale. This issue is an argument to support a truly investigative...

Methods for Locating Genes

Linkage, the oldest of these methods, has been used in genetic studies for many years. Some of the very early psychiatric studies applied this technique to finding gene locations for mental illness by using knowledge of Mendelian patterns of transmission. For example, George Winokur, who was chairman of the department of psychiatry at Iowa for many years and an eminent investigator of bipolar disorder, made the observation that manic-depressive illness and red-green color blindness co-occurred in some families. He also noted that father-to-son transmission rarely occurred in bipolar disorder. This led him to propose that bipolar illness might be linked to the X chromosome. Although this observation has not been consistendy replicated, perhaps because the gene is one of small effect in a polygenic multifactorial disorder, it may point to one of the genes involved in bipolar illness. Candidate gene studies start from the opposite direction. They begin with the theory that a particular...

Human Correlational Studies

Relatives of alcoholics Drug abuse Bipolar disorder Relatives of bipolar disorder Pathological gamblers tion of paranoid schizophrenia (sensation seeking is actually low in more withdrawn individuals with schizophrenia), these are disorders characterized by impulsive and sensation-seeking behaviors in their active stages. Mania is a caricature of sensation seeking in its active stage, but even when patients with bipolar disorder are not having a manic episode, they score high on the SSS. Relatives of persons with alcoholism and sons of individuals with bipolar disorder also have low levels of MAO, even though they do not yet have the disorders this suggests that MAO is a latent biological trait common to all of them.

How Are Mood Disorders Treated

Mood stabilizers are primarily used to treat bipolar disorder. As the name suggests, they abort the activity of the emotional roller coaster and even out the mood swings so that the emotional temperature fluctuates mildly around the zero point. Because bipolar disorder is a very debilitating illness, mood stabilizers are a godsend to people who previously used to swing between mania and depression. Because being high can be subjectively fun for a person with mania, people with this condition sometimes dislike mood stabilizers because they get rid of the highs. Usually, however, people with mania eventually develop insight about the destructive effects of manic episodes. For example, the gifted poet Robert Lowell, who suffered from severe bipolar illness, spoke gratefiilly about the benefits of taking lithium after it became available in the early 1970s. One of his friends described Lowell's remarkable improvement on lithium

The NCI60 Cell Line and GNF Gene Expression Atlas Ratios

As the NCI60 data focuses on tumour-derived cell lines, it is not well suited for the determination of expression in normal tissues, although obviously this data would be very valuable for studies of cancer genetics. However, the GNF data track presents some very valuable information for complex disease genetics, including a breakdown of gene expression across different regions of the brain. This data is very valuable for candidate prioritization, as certain regions of the brain may have a more significant role in bipolar depression than others. For example, functional neuroimaging studies of bipolar patients have identified the thalamus as a key component of the main neuroanatomic circuitries which are altered in psychiatric illnesses, such as bipolar disorder (Soares and Mann, 1997). This information indicates that expression in the thalamus could help to prioritize candidate genes for analysis.

Physical Examination Of Mood Disorder

What has the patient's mood been like How intense has it been Has it been labile or fairly unchanging How long has it lasted Is it appropriate to the patient's circumstances In case of depression, have there also been episodes of an elevated mood, suggesting a bipolar disorder For depressive and bipolar disorders, see Table 16-1, Disorders of Mood, p. 599.

TABLE 161 Disorders of Mood

Mood disorders may be either depressive or bipolar. A bipolar disorder includes manic or hypomanic features as well as depressive ones. Four types of episodes, described below, are combined in different ways in diagnosis of mood disorders. A major depressive disorder includes only one or more major depressive episodes. A bipolar I disorder includes one or more manic or mixed episodes, usually accompanied by major depressive episodes. A bipolar II disorder includes one or more major depressive episodes accompanied by at least one hypomanic episode.

Children at Risk for Depression

With no history of psychiatric disorder. Finally, in a study conducted recently in our laboratory, we induced a negative mood state in children of parents with bipolar disorder and children of never-disordered parents, and then administered an emotion Stroop task and a self-referent encoding task to the children (Gotlib, Traill, Montoya, Joormann, & Chang, 2005). In contrast to the control offspring, we found the children of bipolar parents to exhibit an attentional bias for social-threat and irritable-manic words on the emotion Stroop task, and better recall of negative words that they had endorsed on the self-referent encoding task.

Behavior or Psychomotor Activity

Excessive body movements may be associated with anxiety, drug reactions, or the manic phase of bipolar disorder. Reduced movements may represent organic brain dysfunction, catatonic schizophrenia, or drug-induced stupor. Depression can manifest either via agitation or psychomotor retardation. Sometimes, paranoid clients constantly scan their visual field in an effort to be on guard against external threat. Repeated motor movements (such as dusting off shoes) may signal the presence of obsessive-compulsive disorder. Similarly, repeated picking of imagined lint or dirt off clothing or skin is sometimes associated with delirium or toxic reactions to drugs medications.

Background

The differential diagnosis of depression includes many other psychiatric and medical disorders. The psychiatric disorders include dysthymic disorder, bereavement, and bipolar disorder. Numerous medical conditions can cause depressive symptoms. Common among these are hypothyroidism and anemia. The role of pharmacologic agents and substance use. abuse, or dependence also should be investigated, as these can cause significant mood changes. This is especially true of alcohol, sedatives, narcotics, and cocaine.

The Hillgard Family

Because of the central dynamic of this case, that is, Mr. Hillgard's egocentricity combined with his futile and damaging ways to retain control, the fallout is easy to comprehend. There truly was one major risk factor, namely, Mr. Hillgard's extremely destructive behavior, and because of the control he exerted over this family, Mrs. Hillgard and the children found no escape. But despite numerous attempts, Mr. Hillgard refused to engage in psychological treatment. He had no doubt that his pain was caused by the accident and that was that. His overdeveloped sense of masculinity and subsequent emasculation were the principal contributors to his children's problems and eventually to his own suicide.

Abstract

Cannabis has been used for medical purposes for centuries. With the discovery of cannabinoid receptors, there has been an explosion of research on both natural and synthetic cannabinoids. This chapter reviews both animal and human research demonstrating the potential role of cannabinoids in motivational processes and their associated disorders (hunger, appetite, pain), psychological disorders (anxiety, depression, bipolar disorder, schizophrenia, alcohol dependence) and central nervous system disorders (vomiting and nausea, spasticity, dystonia, brain damage, epilepsy). The most likely applications for can-nabinoid agonists are for the treatment of loss of appetite, pain, anxiety, vomiting, nausea and epilepsy. The most likely applications for cannabinoid antagonists may be for anxiety, schizophrenia, spasticity, and dystonia. It is difficult to formulate an hypothesis concerning the potential treatment of depression, bipolar disorder and alcohol dependence since very little work has...

Physical Findings

Bipolar Disorder (Manic-Depression) sufficient for the diagnosis of bipolar disorder. All patients diagnosed with depression should be questioned about mania, as the treatments are different. Bipolar disorder is typically treated with mood stabilizers, which include valproate, carbamazepine. and lithium. The use of antidepressant agents in bipolar disorder may precipitate acute manic behaviors. A. Bipolar disorder

Conclusion

This review has suggested that cannabinoids may be useful in the treatment of many disorders. The most likely applications for cannabinoid agonists are for the treatment of loss of appetite, pain, anxiety, vomiting, nausea and epilepsy. The most likely applications for cannabinoid antagonists may be for anxiety, schizophrenia, spasticity, and dystonia. It is difficult to formulate an hypothesis concerning the potential treatment of depression, bipolar disorder and alcohol dependence since very little work has been done with these disorders at this point of time.

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