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PubMed1999

Genetics of bipolar disorder.

Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed.

Bipolar Disorder↗

PubMed2006

Long-term use of atypical antipsychotics in bipolar disorder.

Bipolar disorder is a chronic disease that may require lifetime treatment. The maintenance therapy of bipolar disorder can be challenging for the treating clinician. Currently, according to the American Psychiatric Association (APA) guidelines, lithium, valproic acid, lamotrigine, carbamazepine, oxcarbazepine, and the antipsychotics are recommended for the maintenance treatment of bipolar disorder. The antipsychotics are recommended to be continued only if the clinician decides that they are necessary for the control of persistent psychosis or for prophylaxis against recurrence. Although the APA guidelines provide sufficient evidence for the use of these mood stabilizers, newer drugs such as the atypical antipsychotics are being investigated for use in the maintenance phase of treatment of bipolar disorder.

Antipsychotic Agents↗

PubMed2003

Unmet clinical needs in bipolar disorder.

Bipolar disorder is a complex, chronic condition associated with considerable morbidity and mortality, including a high rate of suicide. Currently available treatment options for bipolar disorder fail to adequately address many of the important needs of bipolar patients. Long-term maintenance therapy with lithium has been shown to prevent further episodes of mania and depression and to decrease the likelihood of suicide. However, many patients stop lithium treatment after only a few weeks, because of either untoward side effects or other factors, such as the belief that they no longer require medication. Even when lithium is taken regularly and at adequate doses, many patients continue to exhibit severe functional disability and also fail to achieve remission. Bipolar depression is also poorly understood and difficult to treat. A number of adjunctive medications are used in combination with lithium, but residual symptoms and recurring episodes of mania and depression remain common. Recently, atypical antipsychotics, such as olanzapine, risperidone, and quetiapine, have been evaluated for the treatment of bipolar disorder. Although considerable research is still needed, preliminary findings suggest that some of these agents may act as mood stabilizers, improving the acute symptoms of mania without inducing depression or rapid cycling. The role of atypical antipsychotics in maintenance therapy for bipolar disorder is currently being evaluated in a number of large clinical trials.

Anticonvulsants↗

PubMed2005

Efficacy of atypical antipsychotics in bipolar disorder.

Bipolar disorder is a severe and recurrent disorder. Atypical antipsychotics have emerged as both an alternative and adjunct to conventional mood stabilisers. The manic phase of the illness is the best studied, and it appears that a class effect with regards to efficacy is present in both monotherapy and augmentation studies. Evidence for efficacy of atypical antipsychotics in depression is emerging. At this stage controlled data are available for both olanzapine and quetiapine. Maintenance data demonstrating efficacy are available for olanzapine. Atypical antipsychotics have utility in treating acute agitation and aggression in manic episodes of bipolar disorder. Subgroup analyses from trials treating manic phase bipolar disorder, and an open-label study of rapid cycling, have suggested that atypical antipsychotics may be useful for the treatment of mixed states and rapid cycling. Several studies have suggested that atypical antipsychotics may be useful in treatment-refractory episodes of bipolar disorder. The current available data suggest greater efficacy of the atypical antipsychotics in mania than in depression, although the data are fairly clear that induction of depression is not an issue with the atypical antipsychotics. A number of trials are underway that will hopefully address many of the questions still pending.

Adolescent↗

PubMed2006

Brain network dysfunction in bipolar disorder.

Bipolar disorder is a common psychiatric condition with significant associated morbidity and mortality. Despite its significance, the neurophysiology and neuropathology of this illness is incompletely understood. Recent advances in neuroimaging techniques have helped to begin clarifying these areas. Specifically, bipolar disorder appears to arise from abnormalities within discrete brain networks (eg, the anterior limbic network). The expression of the symptoms of bipolar disorder does not appear to result from single, localized brain lesions, but rather are emergent properties of dysfunction of these brain networks. As neuroimaging techniques continue to improve, the underlying neural basis of bipolar disorder will be clarified.

Affect↗

PubMed1999

Treatment of aggression in patients with bipolar disorder.

Bipolar disorder is generally viewed as a disturbance of mood. However, prominent aspects of behavior that occur during depressive and manic states of bipolar disorder, including psychosis, aggression, and anxiety, are not specific to mood syndromes and occur across many psychiatric states. Severe hyperarousal--beyond that usually associated with classic manic or depressive episodes--could result in a variety of behavioral or symptomatic disturbances including aggression, impulsivity, and anxiety. Since aggression is a well-recognized aspect of mood syndromes, the management of aggression is likely to be an important component of managing bipolar disorder.

Aggression↗

PubMed2005

[Clinical masks of bipolar disorders].

Bipolar disorders usually present as alternating episodes of melancholy and mania. However, other clinical situations appear in a masked form before being spotted. The principal one is hypomania that declares itself as an attenuated form of a manic episode. Its principal signs are an increase in energy, hyperactivity and disinhibition. In other cases, bipolar disorders express themselves as impulsive behaviours. More rarely, the mask of a bipolar illness is translated into behaviours such as intermittent alcohol abuse. The consummation of alcohol is sudden and paroxysmal. It is a type of dipsomania. Finally, bipolar disorders can express themselves as difficulty in impulse control. The two most frequent examples are impulse buying and pathological gambling.

Alcoholism↗

PubMed2005

Working memory and inhibitory control among manic and euthymic patients with bipolar disorder.

Bipolar disorder (BPD) is a severe psychiatric illness that is characterized by episodes of extreme mood states. The affective components of bipolar disorder have been studied extensively, but only recently have investigators begun to systematically examine its cognitive concomitants. Although executive dysfunction has been reported in this population, especially while patients are manic, the tasks administered in many previous studies have made it difficult to determine the specific executive abilities that were compromised. The present study examined 15 patients with bipolar disorder who were manic, 18 who were euthymic, and 18 healthy participants. Tests were selected to evaluate two specific aspects of executive functioning in these participants. The Object Alternation Task was given as a measure of inhibitory control, and the Delayed Response Task was included as a measure of spatial delayed working memory. All groups performed similarly on the Delayed Response Task. On the Object Alternation Task, however, the manic and euthymic patients committed significantly more perseverative errors than healthy participants. These results indicated that patients in the present sample had relatively normal working memory abilities, but had a deficit in behavioral self-regulation, which was evident across mood states.

Adolescent↗

PubMed2003

Issues in the treatment of bipolar disorder.

Bipolar disorder is a chronic, recurring illness that requires long-term prophylactic treatment. However, treatment is often complicated by misdiagnosis and inappropriate medication selection. A number of therapies are available for the treatment of bipolar disorder and the ultimate therapeutic choice depends on the individual patient's current symptoms, disease history, and comorbid illnesses. However, research is needed to improve the overall prognosis for patients with bipolar depression, particularly because approximately 20% of patients commit suicide. Mania is the most dramatic expression of bipolar disorder and may overshadow the impact of the depressive phase of the illness. Compared with mania, episodes of bipolar depression are more frequent, of longer duration, and are associated with higher rates of morbidity and mortality. Therefore, successful treatment and prevention of bipolar depression remains an essential treatment goal.

Antidepressive Agents↗

PubMed2001

Bipolar disorder.

Bipolar disorder (manic-depressive illness) is a common, recurrent, and severe psychiatric disorder that affects 1% to 3% of the US population. The illness is characterized by episodes of mania, depression, or mixed states (simultaneously occurring manic and depressive symptoms). Bipolar disorder frequently goes unrecognized and untreated for many years without clinical vigilance. New screening tools have been developed to assist physicians in making the diagnosis. Fortunately, several medications are now available to treat the acute mood episodes of bipolar disorder and to prevent further episodes with maintenance treatment.

Anticonvulsants↗

PubMed2000

Functional impairment and cognition in bipolar disorder.

Bipolar disorder is a common, chronic and severe mental disorder, affecting approximately 2% of the adult population. Bipolar disorder causes substantial psychosocial morbidity that frequently affects the patient's marriage, children, occupation, and other aspects of the patient's life. Few studies have examined the functional impairment in patients with affective illness. Earlier outcome studies of mania reported favorable long-term outcomes. However, modern outcome studies have found that a majority of bipolar patients evidence high rates of functional impairment. These low reports of functional recovery rates are particularly surprising. The basis for such limited functional recovery is not entirely clear. Factors associated with functional dysfunction include presence of inter-episode symptoms, neuroleptic treatment, lower social economic class, and lower premorbid function. Cognitive dysfunction, a symptom domain of schizophrenia, has been identified as an important measure of outcome in the treatment of schizophrenia. Recently, there has been some suggestion that there may be impaired neuropsychological performance in euthymic patients with recurring mood disorders. Whether impaired neuropsychological performance in associated with the functional impairment in bipolar patients who have achieved syndromal recovery is an intriguing question. The literature on functional impairment and cognition in bipolar disorder is reviewed.

Adult↗

PubMed2004

The importance of subsyndromal symptoms in bipolar disorder.

Bipolar disorder continues to be characterized by poor clinical and functional outcomes in many patients. Poor outcomes may be related to subsyndromal symptoms, defined as symptoms that fail to meet the full diagnostic criteria for a mood episode. Several recent studies indicate that subsyndromal symptoms in bipolar disorder are strongly associated with deficits in both social and occupational functioning. Furthermore, subsyndromal symptoms appear to increase the risk of relapse. Combined, these factors emphasize the importance of aggressive treatment strategies at the onset of subsyndromal symptoms. In addition, the use of subsyndromal symptoms to broaden the diagnostic criteria for bipolar disorder is receiving increased attention. This article reviews and discusses these important issues.

Bipolar Disorder↗

PubMed2006

Emerging drugs for bipolar disorder.

Bipolar disorder is a relatively common condition characterised by recurrent episodes of mania and depression, and associated with high levels of morbidity and mortality. Although there have been substantial advances in the pharmacotherapeutics of this condition over the last 10-15 years, the benefits have been predominantly in terms of tolerability and safety, with no new treatments being demonstrated to be more effective than lithium--the prototype mood stabiliser. This article reviews current and emerging medications for bipolar disorder. Most of the emerging treatments in pharmaceutical industry developmental programmes are new or modified anticonvulsants or atypical antipsychotics. A number of possible future directions and challenges for the field are discussed. The treatment of bipolar disorder is unlikely to advance substantially until the causative pathogenetic molecular processes are elucidated.

Bipolar Disorder↗

PubMed2005

Long-term treatment in bipolar disorder.

Bipolar disorder is a lifelong illness with a course that is usually chronic or recurrent. Severity of complications is generally proportionate to the number of episodes, especially depression. In addition to potentially preventing episodes, effective treatment reduces mortality. This article reviews long-term treatment strategies for bipolar disorder, focusing on depressive episodes, and discusses treatment studies, including problems in design. Treatment effectiveness, including reduction of suicide risk, is enhanced if patients and physicians collaboratively recognize and treat prodromal symptoms, preventing the emergence of episodes. Strategies for treatment differ as one progresses from obtaining syndromal recovery in the acute episode, to functional recovery during continuation treatment, to stability during maintenance treatment. Successful long-term treatment of bipolar disorder requires integrated pharmacologic and nonpharmacologic treatments combined with a therapeutic alliance that facilitates a proactive, preventive approach to the illness.

Acute Disease↗

PubMed2004

Living with bipolar disorder.

Bipolar disorder is a chronic, episodic disease characterized by intermittent episodes of depressive and manic symptoms. It causes significant and long-lasting distress, functional impairment and morbidity, and is associated with a high risk of mortality. Quality of life and disease burden, particularly in terms of lifestyle and general functioning, are gaining increasing recognition as valid therapeutic targets for intervention. Quality of life among patients with bipolar disorders is significantly impaired both during and between acute episodes. Somatic and mood symptoms, stigmatization, comorbid conditions, associated cognitive deficits and the burden of treatment all can combine to severely undermine patient quality of life and functioning at all levels. The tolerability of treatment is an important consideration when choosing a therapeutic option as patient satisfaction with, and adherence to, treatment can influence health outcomes and quality of life. Early intervention with the appropriate treatment can alter the course of bipolar disorder and improve the long-term experience of patients in their management of the disease.

Antidepressive Agents↗

PubMed2004

[Anticonvulsants and antipsychotics in the treatment of bipolar disorder].

Bipolar disorder is a complex medical condition, and up to the date there is no single treatment with proven efficacy in the control of all aspects of the illness. The available literature on the use of anticonvulsants (valproate, carbamazepine, oxcarbazepine, lamotrigine, gabapentin, topiramate, clonazepam) and atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) for acute and prophylactic treatment of bipolar disorder was reviewed. There is a large amount of evidence that lithium is efficacious in the prophylaxis of episodes and better for acute mania than for depressive episodes. Other data show that carbamazepine and valproate are effective in acute manic episodes. Lamotrigine has been shown to reduce cycling and effective in depressive episodes. Based on the available data, olanzapine was found to be the most appropriate atypical antipsychotic agent for the treatment of manic bipolar patients, although there are also studies suggesting the efficacy of risperidone, aripiprazole and clozapine. The preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar disorder are still very limited. There is no consistent information supporting the prophylactic use of newer antipsychotics.

Acute Disease↗

PubMed2003

Rationale for using lithium in combination with other mood stabilizers in the management of bipolar disorder.

Bipolar disorder is a complex illness, and no single agent has been proven in randomized, placebo-controlled trials to effectively prevent and/or control all aspects of the illness-acute mania, rapid cycling, and breakthrough depression. However, for the most important issue, prophylaxis of episodes, lithium has more evidence of efficacy than any other agent. Like lithium, typical antipsychotics, carbamazepine, divalproex, and the atypical antipsychotic olanzapine are effective in the treatment of mania. Carbamazepine, divalproex, and olanzapine seem effective in preventing manic episodes but, like lithium, are less effective in preventing depression. Few trials have been conducted in the more difficult-to-treat characteristics of bipolar disorder, specifically, rapid cycling and break-through depression. For patients with rapid cycling, carbamazepine or divalproex therapy may improve symptoms, but only lamotrigine has been shown to reduce cycling, mostly in the bipolar II group, in a randomized, placebo-controlled study. For the treatment of depressive episodes, lithium and olanzapine have shown modest efficacy in controlled trials, and among the mood stabilizers, lamotrigine has the most robust effect. Because manic symptoms may respond best to one agent and depressive symptoms to another, combination therapy may be the optimal treatment for many patients with bipolar disorder. For example, lithium augmentation may improve overall response rates to treatment with carbamazepine or divalproex, and the lithium-lamotrigine combination should provide effective prevention of both mania and depression. Also, each mood stabilizer may be given at lower doses when given in combination, resulting in a reduced side effect burden and improved compliance.

Anticonvulsants↗

PubMed2003

When do antidepressants worsen the course of bipolar disorder?

Bipolar disorder may be more prevalent than previously believed. Because a substantial number of patients with bipolar disorder present with an index depressive episode, it is likely that many are misdiagnosed with unipolar major depression. Even if a correct diagnosis is made, depressive symptoms in bipolar disorder are notoriously difficult to treat. Patients are often treated with antidepressants, which, if used improperly, are known to induce mania and provoke rapid cycling. This article explores diagnostic conundrums in bipolar depression and their possible solutions, based on current research evidence. It also elucidates current evidence regarding the risks and benefits associated with antidepressant use and evaluates alternative treatment regimens for the depressed bipolar population, including the use of traditional mood stabilizers such as lithium, novel anticonvulsants such as lamotrigine, and atypical antipsychotics.

Journal Article↗