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This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.
Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.
Various terms have been used to describe mania when it is accompanied by depressive symptoms. In this article, we attempt to define and discuss 3 of these terms: dysphoric mania, mixed state, and mania with mixed features specifier. We conclude that whatever term is used, it is important to be aware that mania is more often unpleasant than pleasant, and that the unpleasantness is not limited to depression.
We performed a qualitative review of treatment studies of binge eating disorder (BED), focusing on randomized clinical trials (RCTs). Limited effectiveness has been demonstrated for self-help strategies, and substantial effectiveness has been shown for cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). CBT and IPT may each be more effective than behavior weight loss therapy (BWLT) for reducing binge eating over the long term. The stimulant pro-drug lisdexamfetamine dimesylate (LDX) is the only drug approved by the FDA for the treatment of BED in adults based on 2 pivotal RCTs. Topiramate also decreases binge eating behavior, but its use is limited by its adverse event profile. Antidepressants may be modestly effective over the short term for reducing binge eating behavior and comorbid depressive symptoms, but are not associated with clinically significant weight loss. A RCT presented in abstract form suggests that intranasal naloxone may decrease time spent binge eating. There is no RCT of obesity surgery in BED, but many patients with BED seek and receive such surgery. While some studies suggest patients with BED and obesity do just as well as patients with obesity alone, other studies suggest that patients with BED have more post-operative complications, less weight loss, and more weight regain. This evidence suggests that patients with BED would benefit from receiving highly individualized treatment.
Clinicians are fairly comfortable with the management of acute mania because of the abundance of research studies available. However, there are several important aspects of bipolar disorder that the field has been far less successful with, including management of acute and preventive treatment of bipolar depression, comorbid illnesses, and break-through depression in the context of long-term treatment. There is tremendous complexity in the various symptoms and behavioral dimensions associated with bipolar depression. To facilitate understanding of bipolar depression, this article focuses on treating and managing the bipolar outpatient at risk for a depressive relapse. The discussion poses several challenges associated with bipolar depression and addresses the morbidity of depressive states as well as acute and long-term management of this disorder. The best practices for the varying clinical states of bipolar depressive disorder will be demonstrated through two case examples of patients struggling with disturbances common in bipolar patients.
One of the most challenging clinical topics in psychiatry is the diagnosis and treatment of bipolar depression. The term mood stabilizer is frequently employed in the treatment of the hospitalized bipolar patient, although clinicians do not universally agree on a consensus definition of this term. Most clinicians would agree that a mood stabilizer refers to a medication that is effective for the acute treatment of manic, mixed, hypomanic, or depressive episodes. Many experts agree that such treatment should offer efficacy against mania, should not worsen depression, and preferably should treat depression as well. In addition, the acute effectiveness in stabilization should not be at the expense of inducing alternate mood symptoms or switching the patient into the alternate phase of illness. From a maintenance standpoint, a mood stabilizer should also prevent against future relapse or recurrence of manic, mixed, hypomanic, or depressive symptoms or episodes (Slide 1).
In addition to use of mood stabilizers, there are other issues surrounding treatment of the hospitalized patient with bipolar depression, including the commonly comorbid issue of substance abuse. Hazardous drinking may more commonly occur in bipolar depression or depressive phase of illness, representing a more complex clinical picture. To facilitate understanding of this complex disorder and its appropriate treatment, this discussion centers around the case of a major depressive episode in a patient with a past history of of mania (ie, bipolar I depression or bipolar depression).
Bipolar disorder is a prevalent psychiatric disorder with a high rate of misdiagnosis and evidence of degenerative progression. Research indicates that the interval between bipolar episodes decreases steadily until the patient settles into a relatively frequent course of mania and depression. Various imaging techniques have been used in the understanding of the brain pathology underlying bipolar disorder through identification of patterns consistent with disruption of the normal brain activity in bipolar patients. These techniques have demonstrated evidence of abnormalities in the structure and function of the prefrontal cortex. In addition, the cerebellar vermis, which serves as an error-detection function to modulate the iterative network, appears to shrink with recurrent episodes. Functional imaging demonstrates that the anterior limbic network is overactivated and overresponsive in patients with bipolar disorder. In many patients, those deficits are often compensated for by activation of other brain areas. Ultimately, when the compensation fails, expression of bipolar symptoms arise. Using magnetic resonance spectroscopy, simple models can be constructed based on the hypothesis that mitochondrial function may be impaired in bipolar disorder. There is also increasing evidence that psychotropic medications can affect specific brain regions that are thought to be involved in the pathogenesis of psychiatric disorders. Glutamate levels appear to be elevated in untreated patients with bipolar disorder, which may cause glutamatergic neurotoxicity and negative therapeutic implications. Further advances in brain imaging may contribute to the improvement of available therapies and the understanding which treatments will be most suitable for specific patients.
The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness.
To describe the rationale and methods of the SFBN.
The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.
The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilisers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.
Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.
The Stanley Foundation Bipolar Network (SFBN) evaluates treatments, course and clinical and neurobiological markers of response in bipolar illness.
To give a preliminary summary of emerging findings in these areas.
Studies with established and potentially antimanic, antidepressant and mood-stabilising agents range from open case series to double-blind randomised clinical trials, and use the same core assessment methodology, thereby optimising the comparability of the outcomes. The National Institute of Mental Health Life Chart Method is the core instrument for retrospective and prospective longitudinal illness description.
The first groups of patients enrolled show a considerable degree of past and present symptomatology, psychiatric comorbidity and functional impairment. There are associations of both genetic and early environmental factors with more severe courses of illness. Open case series with add-on olanzapine, lamotrigine, gabapentin or topiramate show a differential spectrum of effectiveness in refractory patients.
The SFBN provides important new data for the understanding and treatment of bipolar disorder.
We examined relationships among positive, negative, and depressive symptoms in schizophrenia and major depression with psychosis.
Patients with schizophrenia (n = 17) and major depression and psychotic features (n = 25), with no prior psychopharmacologic treatment were assessed on scales measuring positive psychotic, negative, and depressive symptoms.
Analyses revealed that depressive symptoms positively correlated with anhedonia/asociality and avolition/apathy in both patient groups. Positive psychotic symptoms significantly correlated with depressive symptoms in the schizophrenic group.
Several specific symptoms used in defining both depressive and negative syndrome constructs appear to be shared. The relationship between positive symptoms and depression in schizophrenia and not psychotic depression suggests the severity of depression may be involved in this relationship.
Neuroleptic malignant syndrome, a dangerous complication of neuroleptic treatment, was first reported in the French literature in the 1960’s. Although long assumed to be rare, the syndrome has beat widely reported recently, particularly in the United States. Does this surge of reports reflect a true increase in the frequency of the syndrome, or merely increased scientific interest in the disorder? A review of available epidemiologic data favors the latter possibility: the syndrome probably continues to affect about 1% of neuroleptic-treated patients, a figure little different from the original French estimate more titan 20 years ago.
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