With the number of approved agents for the treatment of mania and depression nearly tripling, appropriate management of bipolar disorder has become increasingly complex over the last decade. Until relatively recently, the mainstay treatment of bipolar disorder included lithium, divalproex, and, to a lesser extent, carbamazepine. However, with the approval of all of the atypical antipsychotics, as well as the approval of the novel antiepileptic agent lamotrigine as a maintenance therapy, our armamentarium for managing bipolar disorder has increased significantly.
The prevalence of the disease, treatment outcomes, and key side effects of lamotrigine and the atypical antipsychotics, olanzapine and quetiapine, were featured topics at this year's APA meeting. In addition, 2 novel approaches to treatment for bipolar depression -- repetitive transcranial magnetic stimulation and vagus nerve stimulation -- were discussed, as well as the importance of psychoeducation as a component of a comprehensive treatment plan for bipolar disorder.
Lamotrigine received approval from the US Food and Drug Administration (FDA) for the maintenance treatment of bipolar I disorder in 2003, but appears to have better efficacy for prevention of relapse into depression than for the treatment of mania. Several large, randomized, placebo-controlled trials have supported the use of lamotrigine in the treatment of bipolar disorder.[2-7] A recent open-label study of lamotrigine suggests that it improves clinical severity in patients with bipolar disorder either as a monotherapy or in combination with valproate, with similar results. In this same open-label trial, self-reported quality of life enjoyment and cognitive function scores improved over 12 weeks when lamotrigine was added to ongoing bipolar therapy. However, the data supporting the use of lamotrigine for treatment of bipolar depression are mixed: Some studies showed that the agent produced significant improvement over placebo, but in at least 1 study, no significant improvement for bipolar I disorder was shown, and in another, improvement for bipolar I disorder, but not bipolar II, was observed.
One of the most severe and troubling potential side effects associated with the use of lamotrigine is a rash, which, in severe cases, can lead to toxic epidermal necrolysis or Stevens-Johnson syndrome. Dr. Joseph R. Calabrese, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, described the appropriate clinical management of lamotrigine-associated rash in his presentation at the APA meeting. Although the percentage of patients experiencing a benign rash in lamotrigine studies was roughly equivalent in the active treatment placebo groups, there was a higher rate of dropout because of the side effect (6.3% dropout rate in the lamotrigine 200-mg group and 4.7% in the 50-mg group vs 3% dropout rate in the placebo group). To reduce the potential for rash, Dr. Calabrese suggests gradual uptitration of the dosing, starting with 25 mg for the first 2 weeks, 50 mg for Weeks 3 and 4, and increasing to 100 mg and 200 mg in Weeks 5 and 6. Drug interactions are particularly important to consider; in particular, the dose of lamotrigine should be halved when used in conjunction with divalproex and doubled when used with carbamazepine.
It is crucial to determine whether lamotrigine-associated rash is benign or serious. Benign rashes do not require drug discontinuation, whereas patients with serious rashes require immediate discontinuation of the drug and potential treatment; and lamotrigine should be discontinued permanently.
Dr. Calabrese suggested that rashes that occur within 5 days of initiating treatment are probably not drug-related, and the rash should usually resolve within 10 to 14 days. The body and immune system typically take several days to mount a true hypersensitivity reaction, making the likelihood of a Stevens-Johnson type complication within the first day or two of initiating treatment unlikely. These benign rashes are spotty, nonconfluent, nontender, and are not associated with any significant laboratory abnormalities. Upon diagnosis of benign rash, dose escalation should be temporarily halted or the medication discontinued while the rash is monitored. Furthermore, patients must be advised to contact their provider if symptoms worsen or new symptoms emerge. Antihistamines or a topical steroid can be prescribed for management of pruritis. Once the rash resolves, lamotrigine treatment can be resumed, but at a lower starting dose of 5 mg to 12.5 mg/day, and with a slower titration schedule.
If onset of rash occurs more than 5 days after lamotrigine therapy has begun, it is more likely drug-related. Patients should be warned that in the event of a delayed onset of rash, lamotrigine should be discontinued and they should contact their provider. Severe rashes are confluent and widespread, purpuric and tender, and are prominent in the neck and upper trunk areas. Any involvement of the eyes, lips, or mouth should be considered a sign of a severe rash. These more severe rashes are often accompanied by fever, malaise, anorexia, pharyngitis, and lymphadenopathy and may be associated with abnormalities in a complete blood cell count, liver function tests, blood urea nitrogen, creatinine, or a urine analysis.[12,13] After lamotrigine is stopped, patients should be monitored for other organ involvement (hepatic, renal, hematologic), and patients may require hospitalization if the rash or organ involvement is particularly severe or life-threatening. Dr. Calabrese stressed that patients who have experienced a severe rash with lamotrigine should not be rechallenged with the drug.
Olanzapine was the first of the atypical antipsychotics to be approved for the treatment of bipolar disorder. It has demonstrated efficacy in the management of bipolar mania,[14-16] depression, and maintenance treatment. Olanzapine/fluoxetine combination treatment has shown a higher response rate for bipolar I depression than olanzapine monotherapy, with a larger separation from placebo observable at 1 week (P < .001). In fact, the olanzapine/fluoxetine combination is the only treatment currently available with an FDA indication for bipolar depression. Generally, treatment with the combination has a similar side-effect profile to that of olanzapine monotherapy, particularly weight gain, which presents a barrier to its use.
Weight gain with olanzapine is 60-65 times more prevalent with active drug than with placebo (18.7% with olanzapine monotherapy 5-20 mg; 19.5% with olanzapine 6/12 mg + fluoxetine 25/50 mg combination treatment; 0.3% with placebo). Although weight gain is an issue with several of the atypical antipsychotics, it is more significant for olanzapine than for quetiapine, which only increases the risk of weight gain 3-4 times that of placebo.[2,17,19] Clinicians need to monitor this side effect in all patients and counsel them carefully about the risks associated with increased body mass index and waist circumference. The American Psychiatric Association/American Diabetes Association Consensus Statement on Diabetes Care suggests monitoring patient weight at baseline, once a month for 3 months, and then quarterly. A fasting blood sugar should be taken at baseline, 3 months, and annually, and a fasting lipid profile should be taken at baseline, 3 months, and every 5 years afterwards. Thus, despite the proven efficacy of olanzapine, the weight gain, lipid changes, and/or overt diabetes that some individuals experience after starting this medication can be a significant obstacle to its use.
Quetiapine received FDA approval for the treatment of bipolar mania in 2004, and recent data strongly support its use for the treatment of bipolar depression as well. In fact, Dr. Calabrese believes the efficacy data for quetiapine is probably the strongest for any bipolar depression treatment currently available. Bolder I and Bolder II (BipOLar DEpRession) are 8-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled studies for quetiapine monotherapy in the treatment of bipolar depression. Data from Bolder I, published last year, have indicated a robust effect of quetiapine monotherapy in the treatment of bipolar depression as measured by decreases in the Montgomery Asberg Depression Rating Scale (MADRS). Data from Bolder II show strikingly similar results and further support a role for quetiapine as a first-line treatment for depression in bipolar patients.
Dr. Terence Ketter, Professor, Department of Psychiatry and Behavioral Science, Stanford School of Medicine, and colleagues evaluated the impact of quetiapine monotherapy on the rate of improvement of different symptoms of bipolar depression and bipolar mania, focusing on individual MADRS items. In an attempt to better understand the mechanisms underlying the general symptoms, this information could eventually lead to treatments tailored to an individual patient's needs. For example, with quetiapine, there is a particularly dramatic and rapid improvement in sleep quality that seems to account for the bulk of total MADRS improvement; a bipolar patient with prominent sleep disturbances may therefore derive particular benefit from this agent.
Dr. Robert Hirschfeld, Professor and Chair of the Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, presented some interesting pooled data from the Bolder I and II studies which evaluated the specificity of the effect of quetiapine on bipolar depression symptoms. Treatment responses to quetiapine in individuals with high vs low baseline anxiety were compared to determine whether the agent's effect differed in subsets of patients. Improvement in total MADRS score was equivalent in the high- and low-anxiety groups, and similar results were found for subgroups of patients with and without lassitude and somnolence/sedation. These data are consistent with an antidepressant effect for quetiapine independent of any effects on anxiety or other symptoms.
For quetiapine, sedation or somnolence is the most common adverse event, leading to treatment dropout in approximately 8% of cases. Recent data collected in the Bolder I and II studies indicate that a high proportion of patients experience sedative effects from quetiapine, most within the first week of treatment (62.6% with 300 mg/day; 60.3% with 600 mg/day; 16.7% with placebo). Although approximately 50% of patients experience this side effect, only 10% find it intolerable. Dr. Calabrese recommends that providers explain to patients that tolerance may develop over several weeks, thereby diminishing the sedative effects of the drug. In addition, as described above, this side effect may actually be used clinically for specific patient populations, such as in the treatment of patients with anxiety or agitation. Indeed, in patients reporting insomnia as one of their prominent symptoms, the sedative effects may prove quite beneficial.
Repetitive Transcranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation paradigm that uses a strong and rapidly alternating magnetic field to stimulate brain tissue via a coil placed on the scalp. While stimulating the brain in a manner theoretically similar to that used in electroconvulsive therapy (ECT), rTMS stimulates a focal region of cortex, thereby avoiding the cognitive side effects that are often associated with ECT. It is important to note that rTMS does not produce a seizure. A few pilot studies have evaluated the efficacy of rTMS for bipolar depression, one showing positive results and another indicating a trend toward improvement in the treatment group.
The current data supporting rTMS in depression, which has been better studied than bipolar depression, do not conclusively support its widespread use. The most recent meta-analysis of published rTMS trials did not support long-term efficacy, but in an earlier meta-analysis combining data from 23 trials primarily involving the treatment of major depression, the effect of rTMS was statistically significant. However, due to the heterogeneous effect of the trials, and with only a few studies showing substantial clinical response or remission, this statistical significance may not necessarily translate into a clinically relevant effect.
Whether methodologic issues (eg, length of treatment, stimulus frequency and intensity, coil placement) or the lack of actual seizure induction (eg, magnetic seizure therapy) are crucial to a more robust efficacy of this type of modality remains to be solved. A large, randomized, double-blind clinical trial with a larger sample size must be performed before the efficacy of rTMS in bipolar depression can be determined.
Vagus Nerve Stimulation
Vagus nerve stimulation (VNS), approved in 2005 for the management of treatment-resistant depression, uses mild electronic pulses to intermittently stimulate the left vagus nerve. A recent study evaluating VNS + treatment as usual (TAU) to a similar group of treatment-resistant patients who received only TAU indicated similar efficacy for the subset of bipolar depressed patients and the unipolar depressed patients.
A small pilot study (n = 10) suggests that VNS may also be a possible treatment for patients with rapid cycling bipolar disorder who have a MADRS score decrease from baseline of 37% after 1 year. Current FDA approval for VNS recommends its use in depressed patients who have failed adequate response to 4 or more antidepressant treatments. As bipolar depression is often more resistant to pharmacologic intervention, VNS may be a useful treatment modality for bipolar depression.
However, one must still be cautious, as the clinical data to guide us in the use of VNS are still very limited. Short-term data show no difference between masked active stimulation and sham stimulation over a 10-week period. A 1-year study comparing TAU to TAU + VNS in patients with treatment-refractory depression did show a significant decrease in Hamilton Rating Scale for Depression (HAM-D) scores. However, even though this effect was significant, there was only a 3-point difference in HAM-D scores. More data are needed in this area so that the risks and benefits of this relatively costly and expensive procedure can be understood before its widespread adoption.
Psychoeducation for Bipolar Disorder
Psychotherapy in bipolar disorder has shown benefit as an adjunctive treatment to improve the efficacy of pharmacotherapy. Cognitive therapy has proven particularly useful for relapse prevention in euthymic patients, but until fairly recently, no systematic clinical trial had been employed to provide evidence for improved recurrence and hospitalization rates.
The Importance of Psychoeducation
Psychoeducation involves more than just providing disease information to patients; it includes a much richer combination of tools to improve functional outcomes for patients and their families. In a randomized controlled trial involving group psychoeducation for euthymic bipolar patients with a Young Mania Rating Scale score < 6 and HDRS score < 8 for at least 6 months, 21 sessions were included in the psychoeducation paradigm on topics ranging from understanding the disease and its treatment to developing tools for stress management and problem solving. The effect observed in this trial is particularly impressive because the control group received not only pharmacologic treatment, but also a nonstructured group intervention. The groups were both exposed to a group treatment environment, but 1 group received structured psychoeducation while the other received nonstructured group intervention. In the 2-year follow-up, there were significant differences between the groups (P < .003) with regard to time to recurrence and in manic, depressive, and mixed relapse rates during and after psychoeducation. Perhaps most compelling were the differences in hospitalization rates between the groups, indicating that in the long run, psychoeducation can save money for the patient and the healthcare system at large.
Psychoeducation can have an impact on treatment efficacy, most simply via enhancement of compliance and improving the regularity of daily life and sleep habits. It is possible that more complicated mechanisms are involved, such as neurogenesis and neuroplasticity. In support of enhanced treatment compliance, a recent study found more stable lithium levels during psychoeducation.
It should be noted that, like all treatments, psychoeducation has potential adverse effects, including dependence, excessive self-check of mood and behavior, and placing too much value on self-care.
As more treatments for bipolar disorder become available, we are better able to tailor our strategies to individual patient care. The above summaries of APA presentations outline some of the major benefits and problems associated with several of the newer drugs and nonpharmacologic treatments available. One must also consider the cost/benefit analyses for individual patients, as many of these newer treatments are significantly more expensive than traditional therapies. However, these new medications furnish clinicians with more options when designing treatment strategies. The evidence supporting rTMS and VNS for the treatment of bipolar depression is still limited, and these options should be limited to smaller subsets of treatment-resistant patients.