Choosing first and second agents
As outlined in the Table, there are only weak clinical indicators of an increased likelihood of response to a major mood stabilizer (lithium, valproate(Drug information on valproate), carbamazepine(Drug information on carbamazepine), or lamotrigine(Drug information on lamotrigine)). Nonetheless, several of these may be useful, including a positive family history in first-degree relatives of response to lithium(Drug information on lithium) for bipolar disorder or response to lamotrigine for anxiety disorder, and a negative family history of affective disorders in those responding to carbamazepine.
Comorbidities are particularly pertinent, often problematic, and require specific adjunctive pharmacological treatments. About 40% of patients with bipolar disorder present with a comorbid anxiety disorder.15 One of the correlates of lithium nonresponse or inadequate response is the presence of an anxiety disorder, leading to the necessity of using an adjunctive agent if lithium is in the core regimen. In the realm of anxiety disorder treatments, it is noteworthy to emphasize that 2 agents that are not effective in the treatment of acute mania, and therefore not considered mood stabilizers, ie, gabapentin(Drug information on gabapentin) and topiramate(Drug information on topiramate), may nonetheless be useful in targeting specific anxiety disorder comorbidities.7 For example, gabapentin is effective in the treatment of panic disorder and social phobia and, in the absence of data to suggest otherwise, one may infer that this drug would also be effective when these anxiety disorders are comorbid with bipolar illness. Whether this is actually the case ultimately deserves specific clinical trials in patients with bipolar disorder, but in their absence, the physician needs to decide whether to use such agents as adjunctive therapy on an individual basis.
A number of studies indicate that patients with bipolar disorder and comorbid anxiety disorders have a poorer outcome and more difficult course of illness than those without anxiety comorbidity.16 However, in those patients with a complicated course of illness such as that manifested by ultrarapid or ultradian cycling, the traditional use of antidepressant agents for a variety of anxiety disorders may be problematic. In these instances, there is much data to support the addition of another mood stabilizer with evidence of anxiolytic properties such as valproate, lamotrigine, or carbamazepine or an atypical antipsychotic such as quetiapine(Drug information on quetiapine) (which has been shown to have marked anxiolytic effects as monotherapy in bipolar depression, in addition to its antidepressant and sedative effects).17 The addition of a mood stabilizer or an atypical antipsychotic may further target mood stability and may provide antianxiety effects better than the addition of an antidepressant, which may be mood-destabilizing. Again, the principle of attempting to yield a "2-for-1" benefit of an adjunctive agent is highly desirable compared with a "1-for-1" agent or a "0-for-1" agent, such as in the hypothetical antidepressant example noted above (where the positive anxiolytic effects are canceled out by the mood-destabilizing effects, yielding no additive benefit).
Many of the same caveats are appropriate for considering agents that may be used for substance-abuse comorbidities in patients with bipolar illness when they have only been tested in the primary syndrome. The study by Johnson and colleagues18 suggests that topiramate has marked efficacy in reducing intake of and craving for alcohol(Drug information on alcohol) in those with primary alcoholism. However, since topiramate has been widely used as an adjunct in multiple clinical trials in patients with bipolar illness with some success, the potential utility of this agent instead of one such as acamprosate(Drug information on acamprosate) or disulfiram(Drug information on disulfiram), which have not been widely studied or used in patients with bipolar illness, would appear greater.
In some instances, there may be direct discrepancies between the estimate of the efficacy of a given agent in the primary syndrome, based on controlled clinical trials, and the potential or theoretical value of that agent in patients with bipolar disorder. A good example of this may be baclofen(Drug information on baclofen): preliminary data indicate that it is more effective than placebo in reducing cocaine abuse19; however, this agent might be considered relatively contraindicated in those with bipolar disorder because it has been reported to exacerbate depression in a small series of affectively ill patients studied in a double-blind, on-off-on design.20
In addition to the possible consideration of topiramate because of its positive effects compared with placebo in a controlled study of cocaine abuse, one might also consider a clinical trial of modafinil(Drug information on modafinil) in light of the report of its efficacy in a controlled trial in primary cocaine users.21 Emerging evidence also shows that modafinil may have positive effects on residual depression, fatigue, attention, and energy symptoms in inadequately treated patients with bipolar disorder who are depressed.22
Minor augmenting agents
Some data support the use of triiodo- thyronine (T3) augmentation in those patients with more difficult-to-stabilize bipolar disorder. There is considerable evidence for the efficacy of T3 augmentation, particularly in unipolar depression, and potentially positive effects in patients with bipolar disorder have been seen as well (Frye et al, unpublished data, 2000). Moreover, Kocsis and colleagues23 reported that T3 augmentation of lithium improved subtle aspects of cognition. It is pertinent to remember that T3 augmentation has been found to be useful independent of abnormalities in the thyroid axis. The use of low doses (25 to 37.5 µg in the morning) with the short half-life of T3 and usually a benign adverse-effects profile should be distinguished from the supraphysiological doses of T4 recommended by Bauer and Whybrow24 and Bauer and colleagues25 for treatment-refractory depression and rapid cycling.
In these instances, one might expect minor increases in tachycardia, nighttime sweating, etc, where one is attempting to push the patient toward a free thyroxin index of 150% of normal, often that achieved with 200 to 400 µg daily. However, because of the long half-life of T4, titration should proceed extremely slowly. Because of questions about acute and long-term tolerability, this strategy should be reserved for later in the sequence of clinical trials as opposed to T3 augmentation, which is often benign and useful early in augmentation strategies.
On the basis of multiple rationales, augmentation with folate (1 mg in women and 2 mg in men) can be considered a useful early strategy in those with difficult-to-treat depressive components of bipolar illness. Controlled clinical trials, albeit small, indicate that folate was more effective than placebo in potentiating the antidepressant effects of serotonin-selective antidepressants in patients with unipolar depression26 and augmenting the effects of lithium prophylaxis in patients with bipolar disorder.27 Moreover, it reduces levels of homocysteine, which have been associated with a greater degree of cognitive impairment and are a risk factor for cardiovascular disease. Valproate increases homocysteine levels so that regular use of folate with this agent would appear indicated. Folate supplementation in women of childbearing age is also worthy of consideration in relation to the possibility of unwanted pregnancy during treatment with valproate, carbamazepine, or lithium, which have been associated with the potential for severe congenital malformations.
Topiramate and zonisamide(Drug information on zonisamide) have both been shown to decrease the number and amount of binges in eating disorders.28,29 In addition, in those with nonbinge eating disorders, both have been associated with the potentially positive side effect of weight loss in numerous studies in both patients with seizure disorders and those with affective illness. Thus, use of these agents in conjunction with a drug that is prone to cause weight gain or as an adjunctive weight-loss drug in those who have already gained weight may be considered. Because some patients taking topiramate may have cognitive impairment and word-finding difficulties, even with low doses, zonisamide may be a useful alternative. Although no controlled trials are available, open clinical observations suggest the potential usefulness of zonisamide against affective symptomatology, particularly mania.30
Although the results of a recent study of 6 g of eicosapentaenoic acid (EPA) versus placebo were negative,31 a number of studies of 1 to 2 g of omega-3 fatty acids or higher doses of the combination have shown positive results in controlled clinical trials in unipolar and bipolar depression.32 There is some ambiguity about efficacy, but the high tolerability and safety of this compound make it worthy of consideration, particularly in youths, where the risk-benefit ratio is paramount.
In this article I have not dealt with the crucial variable of augmenting with cognitive-behavioral and psychoeducational approaches, but it should be understood that these are an absolute necessity for the long-term optimal treatment of almost all patients with bipolar illness. Adequate psychoeducation is likely to facilitate the goal of achieving and maintaining remission with the fewest adverse effects, independent of the number of agents required.