In patients whose bipolar depression is unresponsive to monotherapy, consider the combination of lithium with lamotrigine.[3] Alternatively, consider short-term augmentation of antidepressant agents with a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), bupropion, and monoamine oxidase inhibitor (MAOI); patients using this treatment strategy must be closely monitored for triggering of manic symptoms.[3]

As in severe mania or severe mixed episodes, consider adding clozapine for augmentation, and closely monitor the patient for metabolic or other adverse effects.[3] Because of the known complications involved with clozapine, it is recommended that a psychiatric consultation be initiated.

The VA/DoD found insufficient evidence for or against the use of augmentation with aripiprazole, olanzapine, risperidone, haloperidol, oxcarbazepine, topiramate, ziprasidone, valproate, or carbamazepine in bipolar depression.[3] However, the VA/DoD advised against the use of gabapentin and tricyclic antidepressant agents (TCAs) for monotherapy or augmentation in patients with acute bipolar depression, except in cases in which there was[3] : (1) a previous good response during depression without a switch to mania or (2) a history of treatment of refractory depression.

Dosing or medication adjustments

Switch to another effective treatment for patient intolerance to side effects. For patients that switch into mania or hypomania or enter a mixed manic state, follow the recommendations discussed above in Mania/hypomania or mixed episodes.

Reevaluate patients every 1-2 weeks for a minimum of 6 weeks. As noted earlier, the therapeutic range of lithium is a serum trough concentration between 0.6-1.2 mEq/L; for valproate, 50-125 mcg/mL; and for carbamazepine, 4-12 mcg/mL.[3] If the patient’s serum concentrations of their medication fall below the therapeutic range, adjust the drug’s dose to the maximum range. For medications without known therapeutic plasma concentrations, increase the dose until symptomatic improvement, patient intolerance, or the manufacturer’s maximum dose limits have been reached.[3]

In patients with a partial treatment response (no response 2-4 weeks after initiation of an adequate medication dose), consider augmenting the medication with additional agents as discussed under Combination therapy,discontinuing the current drug (tapered withdrawal with monitoring for antidepressant syndrome and mood destabilization) and switching to another effective agent, or electroconvulsive therapy (ECT) if multiple trials of switching medications/augmentation strategies have been unsuccessful.[3]

Other considerations
A study by Bauer et al suggested that lithium may also have a neuroprotective role.[83] However, this agent is also associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment. Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.[84]

Atypical antipsychotics are increasingly being used for the treatment of both acute mania and mood stabilization. The broad range of antidepressants and ECT are used for an acute depressive episode (ie, major depression). However, ECT may also be considered for patients with severe mania or treatment-resistant mania, those who prefer ECT, and pregnant women with severe mania.[3] Ansari and Osser developed a very useful algorithm for the Harvard South Shore Program to treat a bipolar patient in a depressed phase through “an organized, sequential, and evidence-supported approach.”[85] Finally, another set of medications is chosen for the maintenance and preventive phases of treatment.

Diazgranados and colleagues reported that for patients with treatment-resistant bipolar depression, impressive and swift antidepressant effects occurred when a single intravenous (IV) dose of the N -methyl-D -aspartate (NMDA) antagonist ketamine was administered.[86] Increasingly, the role of glutamate in mood disorders is being researched, and experimental evidence shows that the NMDA receptor antagonist ketamine may be helpful in short-term treatment of depression, even in the context of bipolar disorder. However, it is important to note that the benefit of such treatment disappeared after 4 days.

Although antidepressant medications are most often prescribed for patients with bipolar disorder who are experiencing an acute depression, a study found that antidepressants were not statistically superior to placebo or other current standard treatment for bipolar depression.[87]

Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.[88] These medications not only serve to stabilize the patient’s mood, as the name implies, they can also dampen extremes of mania or depression. Kessing et al found that, in general, lithium was superior to valproate.[89]

Atypical antipsychotics (including ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, and asenapine) are also now frequently used to stabilize acute mania—or even to treat bipolar depression in some cases.

In the treatment of depression associated with bipolar disorder type II, Swartz and associates reported that 95% of relevant trials were published later than 2005.[90] They noted compelling evidence for the efficacy of quetiapine and preliminary support for the efficacy of lithium, antidepressants, and pramipexole. However, mixed support was noted for lamotrigine.[90]

Maintenance
The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented,[91] as is the use of long-acting antipsychotics to help with the maintenance phase. The APA’s 2005 guideline watch for the treatment of patients with bipolar disorder considered both lamotrigine and lithium to have substantial utility in the maintenance treatment of patients with bipolar disorder.[52]

Popovic et al suggested the use of a Polarity Index to guide the choice of maintenance therapy in bipolar patients.[92] Based on results from randomized, placebo-controlled trials, the investigators indicated that this index may provide a measure of the relative preventive antimanic versus antidepressive efficacy of drugs that are used to treat bipolar disorder.[92] They defined a Polarity Index value greater than 1.0 as having a relative greater antimanic prophylactic efficacy, whereas a value less than 1.0 would have a relative greater antidepressive efficacy. The following are this study’s polarity indices results for maintenance drugs in bipolar disorder[92] :

Risperidone: 12.09
Aripiprazole: 4.38
Ziprasidone: 3.91
Olanzapine: 2.98
Lithium: 1.39
Quetiapine: 1.14
Lamotrigine: 0.40
Note that Popovic et al indicated the respective polarity indices for valproate and oxcarbazepine were potentially unreliable owing to the failure of their maintenance trials.[92]

There have been concerns that ziprasidone may have adverse effects on body weight, fasting lipids, and fasting glucose. When Pappadopulos et al looked at a comprehensive set of analyses of metabolic alternations in patients on this medication, they found no significant differences between the ziprasidone and placebo groups in levels of fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the controlled studies.[93]

According to a multiple treatments meta-analysis of treatments for acute mania, the most efficacious treatments are haloperidol, risperidone, and olanzapine, significantly outperforming primary mood stabilizers and other antipsychotic medications.[94] In several randomized, double-blind, controlled studies, olanzapine monotherapy was significantly more effective in treating manic or mixed episodes than haloperidol[95] or divalproex monotherapy.[96] The adjunctive use of olanzapine with divalproex or lithium,[97] or of risperidone with divalproex or lithium, was also significantly more effective than divalproex or lithium alone.[98, 99]

As outlined in the APA’s 2002 clinical practice guideline,[100] benzodiazepines have sedative effects, which may make them useful adjunctive medications until antimanic medications take effect. Additionally, the guideline stated that manic symptoms may be treated with chlorpromazine, which was deemed superior to placebo in a randomized trial and was deemed comparable to lithium (for controlling manic and psychotic symptoms) in acute treatment comparison trials.

Children and adolescents who have bipolar disorder are particularly challenging to treat, and their discussion is beyond the scope of this article (see the Medscape Reference article Pediatric Bipolar Affective Disorder). However, Hamrin and Iennaco developed guidelines and recommendations for medications and management approaches after an extensive literature review using research findings on medication effectiveness in this population.[101]

There is evidence that risperidone may be the best first-line treatment for childhood mania, as shown in a randomized controlled trial with patients aged 6 to 15 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) diagnosis of BPI (manic or mixed phase).[102] Specifically, risperidone was significantly more effective than lithium or divalproex sodium for the initial treatment of childhood mania; however, use of risperidone had the potential for serious metabolic side effects.[102]

Caution in polyantipsychotic therapy in bipolar disorder
In August 2010, the FDA announced that lamotrigine carries a risk of aseptic meningitis.[103]

In a study that sought to evaluate the safety and tolerability of second-generation antipsychotic (SGA) polytherapy compared with monotherapy in patients with bipolar disorder receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), Brooks et al concluded that although polytherapy was fairly common in bipolar disorder, it was also associated with increased side effects (eg, dry mouth, sexual dysfunction, and constipation) and increased health service use (almost threefold) but not with improved clinical status or function.[104] Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.[104]

Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is useful in a number of instances in patients with bipolar affective disorder, or manic-depressive illness (MDI), such as the following[3] :

When rapid, definitive medical/psychiatric treatment is needed
When the risks of ECT are less than that of other treatments
When the bipolar disorder is refractory to an adequate trial with other treatment strategies
When the patient prefers this treatment modality
Often, the severity of the patient’s symptoms, the lack of response to medications, or the presence of contraindications to certain medications necessitates the use of ECT. This treatment modality has proven to be highly effective in the treatment of acute mania.

The 2010 Department of Veterans Affairs/Department of Defense (VA/DoD) clinical practice guideline for management of bipolar disorder indicates ECT is the primary therapy in bipolar disorder patients that present with psychotic symptoms, catatonia, severe suicidality, food refusal leading to nutritional compromise, or who have a history of previous positive response to ECT.[3] Indeed, in a review of 50 years’ experience with ECT for acute manic episodes, data from early literature revealed that 313 of 400 patients with acute mania who received ECT showed significant clinical improvement.[105]

Dietary and Activity Measures
Unless the patient with bipolar affective disorder, or manic-depressive illness (MDI), is on monoamine oxidase inhibitors (MAOIs), no special diet is required. Patients should be advised not to make significant changes in their salt intake, because increased salt intake may lead to reduced serum lithium levels and reduced efficacy, and reduced intake may lead to increased levels and toxicity.

Although a meta-analysis by Starris et al found strong evidence that bipolar depressive symptoms may be improved by adjunctive use of omega-3, omega-3 does not improve bipolar mania.[106]

Patients in the depressed phase are encouraged to exercise. These individuals should try to develop a regular daily schedule of major activities, especially times of going to bed and waking up. Propose a regular exercise schedule for all patients, especially those with bipolar disorder. Both the exercise and the regular schedule are keys to surviving this illness. However, increases in exercise level, with increased perspiration, can lead to increased serum lithium levels and lithium toxicity.

Complications
The main complications of bipolar affective disorder, or manic-depressive illness (MDI), are suicide, homicide, and addictions.

Previously or currently suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk for suicide. The risk of self-destructive behavior and death is lifelong. Hong et al’s study demonstrated a genetic link between bipolar disorder and suicidal behavior, especially in white individuals.[107] According to a more recent study, men with bipolar disorder are at higher risk for suicide.[108]

The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study, a 2-year prospective, observational study, suggested the following characteristics found in patients with bipolar disorder who are suicidal may help identify subjects at risk for suicidal behavior[109]:

Female sex
A history of alcohol abuse
A history of substance abuse
Young age at first treatment for a mood episode
Longer disease duration
Greater depressive symptom severity (5-item Hamilton Depression Rating Scale [HAMD-5] total score)
Current benzodiazepine use
Higher overall symptom severity (Clinical Global Impression-Bipolar Disorder [CGI-BP]: mania and overall score)
Poor compliance.

Quality of life (QOL) has been an important way to look at the effects of mental illness. Bipolar disorder type I (BPI) results in diminished quality of life as measured by health utility and QOL and utility-based health-related quality of life. The QOL losses in patients with BPI were less than those in persons with schizophrenia. The patients with depression sustained the greatest loss in QOL.[111]

In a study by Fiedorowicz et al, hypomania symptoms were frequently associated with progression to bipolar disorder, even when symptoms were low intensity; however, most patients did not have hypomania symptoms at baseline.[112] The study concluded that monitoring for progression to bipolar disorder is necessary in patients with long-term major depressive disorder.

Some of the most challenging situations involve children and adolescents with severe emotional lability. Often, psychiatrists have applied the bipolar diagnosis to this group. Leibenluft reviewed this situation and concluded that children have increasingly been diagnosed with bipolar disorder.[113] In some cases, the criteria were clearly met, whereas other cases were less clear.

Severe mood dysregulation is a syndrome formulated to describe the symptoms of children who do not clearly meet the criteria for bipolar disorder. Leibenluft’s findings revealed that nonepisodic irritability in youths is common and is associated with an elevated risk for anxiety and unipolar depressive disorders (not bipolar disorders) in adulthood. In fact, data suggest that children and adolescents with severe mood dysregulation have lower familiar rates of bipolar disorder than children and adolescents with bipolar disorder.

Prevention and Long-Term Monitoring
Prevention is the key to the long-term treatment of bipolar affective disorders, , or manic-depressive illness (MDI), as follows:

First, use medications such as lithium serve as mood stabilizers
Second, psychoeducation is instituted for the patient and the patient’s family; it is critical that the patient and the patient’s family understand and recognize the importance of medication compliance and the early signs of mania and depression
Regardless of the pharmacologic regimen chosen in individual patients with acute bipolar mania, hypomania, or mixed episodes, and those with bipolar depression, reevaluate for treatment response every 1-2 weeks for a minimum of 6 weeks.[3] Continue to monitor these individuals for the following situations[3] :

Depressive symptoms (or changes in), suicidal/homicide ideation
Neurovegetative symptoms
New-onset/change in psychotic symptoms or manic/hypomanic symptoms
Illicit substance use
Medication side effects and compliance
Medical stability
Significant psychosocial changes
Reevaluate all patients for treatment response at 4-8 weeks, after each change in treatment, and periodically until full remission is achieved.[3] Full remission is defined in patients with mania as the absence of significant mania symptoms for 2 months; in patients with mixed episode, it is the absence of significant mania or depression symptoms for 2 months; and in those with bipolar depression, it is the absence of significant depressive symptoms for 2 months.

Treat adult patients who have had an acute manic episode for a minimum of 6 months after the initial episode is controlled; encourage these individuals—as well as those who have had more than 1 manic episode or with 1 manic and 1 depressive episode, or 3 or more depressive episodes—to continue on lifelong prophylactic pharmacotherapy.[3] Following full remission of the depressive episode, consider withdrawing antidepressant treatment after 4-6 months. Discontinuation should consist of a gradual taper over a minimum 2-4–week period, unless medically contraindicated.[3]

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