The pharmacological treatment of bipolar disorder

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LONG-TERM PROPHYLAXIS

The primary aim of long-term treatment is the prevention of recurrent episodes (either mania or depression) (see also Chapter 11). According to current guidelines, any patient who has had at least two episodes in 5 years is likely to benefit from prophylactic treatment (American Psychiatric Association, 1994). Despite problems with tolerability, lithium still remains the 'gold standard' against which other treatments are measured. The effectiveness of long-term treatment with lithium to prevent recurrences in bipolar disorder is supported

Cochrane risk difference plot (random effects)

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DL pooled risk difference = 0.28847 (95% CI = 0.156013 to 0.420926)

Cochrane risk difference plot (random effects)

Vorbach 1994 (imipramine)

Bergmann 1993 (amitriptyline)

Wheatly 1997 (amitriptyline)

Philipp 1999 (imipramine)

Woelk2000 (imipramine)

JAMA 2002 (sertraline)

Vorbach 1994 (imipramine)

Bergmann 1993 (amitriptyline)

Wheatly 1997 (amitriptyline)

Philipp 1999 (imipramine)

Woelk2000 (imipramine)

JAMA 2002 (sertraline)

DL pooled risk difference = 0.031472 (95% CI = -0.024581 to 0.087525)

Figure 7.1b Comparison of St John's wort with comparator drug—proportion of patients improved after St John's wort minus those improved after comparator (risk difference). Data previous to 1997 cited from (Linde et al., 1996). Computation and graphics were done with StatsDirect, Version 1.9.15, May 2002

DL pooled risk difference = 0.031472 (95% CI = -0.024581 to 0.087525)

Figure 7.1b Comparison of St John's wort with comparator drug—proportion of patients improved after St John's wort minus those improved after comparator (risk difference). Data previous to 1997 cited from (Linde et al., 1996). Computation and graphics were done with StatsDirect, Version 1.9.15, May 2002

by at least nine controlled, double-blind studies (Baldessarini et al., 1996; Burgess et al., 2001; Price & Heninger, 1994; Tondo et al., 2001). To date, lithium remains the firstline choice for maintenance treatment in patients with a 'classical' course of illness (Maj, 2000).

Some subtypes of what has become known as the 'bipolar spectrum' may not respond as well to lithium. These include patients with 'mixed mania', that is, depression during mania. (Swann et al., 1997), and 'rapid cycling' (Dunner & Fieve, 1974). Emerging evidence would seem to suggest a role for anticonvulsants in these patients. For example, carbamazepine, compared with lithium or placebo, is effective in the long-term treatment of bipolar disorder, with an overall response rate of 63% in 14 controlled or partially controlled studies. (Dunn et al., 1998). Although it does not have worldwide approval as yet, carbamazepine does seem to be more effective in the treatment of bipolar spectrum than classical bipolar disorder. (Berky etal., 1998; Greiletal., 1998). Similarly, sodium valproate has demonstrated efficacy in rapid-cycling bipolar disorder (Calabrese et al., 1993), and controlled studies on the prophylactic benefits of valproate are beginning to emerge. (Bowden et al., 2000).

There have been promising reports on the efficacy of the newer anticonvulsants, such as lamotrigine, gabapentin and topiramate (De Leon, 2001) (Calabrese et al., 2002). Until evidence from controlled studies is available, it remains prudent to reserve these drugs for refractory cases.

Alternative treatment strategies, or potential augmentative agents, include a number of other compounds which may have some clinical utility, but for which the evidence remains weak. These include calcium channel antagonists such as verapamil, nifedipine and ni-modipine (Dubovsky, 1993); thyroid hormones. (Bauer et al., 1998; Baumgartner et al., 1994); the antipsychotic clozapine. (Hummel et al., 2002); and some of the 'novel' antipsychotics, including risperidone and olanzapine (Yatham, 2002). With long-term treatment, it is essential that patients are well informed about the risks and implications of stopping medication. Substantial evidence exists that abrupt discontinuation of lithium is associated with an increased risk of relapse (Baldessarini et al., 1999). The risk, particularly of mania, may be minimised by gradually reducing the lithium dose (Faedda et al., 1993). Although comparable studies are not available for the anticonvulsants, a similarly cautious approach would seem advisable.

MANAGEMENT OF ACUTE MANIA

Early research supported the use of lithium in the treatment of acute mania. More recently, the superiority of lithium to other treatments, such as valproate, has been questioned (Bowden et al., 1994). Nonetheless, the efficacy of lithium is without doubt. In an early review of 10 uncontrolled trials of 413 patients with bipolar disorder, 81% displayed reduced manic symptoms during acute lithium treatment (Goodwin & Ebert, 1973). The overall response rate to lithium in four placebo-controlled studies of 116 patients with acute mania was 78% (Goodwin etal., 1969;Maggs, 1963; Schouetal., 1954; Stokes etal., 1971). These studies also demonstrated that up to 2 weeks of treatment with lithium may be necessary to reach maximal effectiveness for manic patients. Due to this delayed effect, particularly in instances of severe mania or psychotic symptoms, with associated acute behavioural disturbance, additional use of an antipsychotic or a benzodiazepine is usually required. Antipsychotics, such as haloperidol and chlorpromazine, have been shown to be useful in the rapid control of severely agitated or psychotic patients with bipolar disorder (Gelenberg & Hopkins, 1996). Despite their widespread use, the high frequency of extrapyramidal side effects has led to caution, particularly in the long term, due to the risk of tardive dyski-nesia. There is also evidence that antipsychotic medication, far from helping patients with depressive episodes, may in fact worsen symptoms (Kane, 1999). For these reasons, the use of 'novel' antipsychotics has been advocated, and positive evidence is accumulating to support the treating of acute mania with risperidone, olanzapine or clozapine (Yatham, 2002).

Another approach to reduce the need for antipsychotics is the adjunctive use of benzodiazepines. Clonazepam and lorazepam are the most widely studied compounds, either alone or in combination with lithium. The interpretation of many of these studies is confounded by small sample sizes, short durations of treatment, use of antipsychotics and difficulties in distinguishing possible antimanic effects from nonspecific sedative effects (Bradwejn et al., 1990; Edwards et al., 1991). However, taken together, these studies suggest that benzodiazepines are effective, in place of or in conjunction with a neuroleptic, to sedate the acutely agitated manic patient while waiting for the effects of other primary mood-stabilizing agents to become evident. The fact that lorazepam is well absorbed after intramuscular injection (unlike other benzodiazepines) has made it particularly useful for some very agitated patients (Chouinard et al., 1993).

Carbamazepine has been widely used in the treatment of acute mania where its sedative effects may be advantageous (Post et al., 1998). The results of 19 controlled trials, since 1978, support the efficacy of carbamazepine, or its derivative oxcarbazepine, in the treatment of acute mania, either alone or in combination with lithium or antipsychotics (McElroy & Keck, 2000).

Valproate has also been shown to be effective in the treatment of acute mania. A review of 16 uncontrolled studies (McElroy et al., 1992) reported an overall response rate of 63% in 663 patients. The only placebo-controlled parallel-group study of valproate versus lithium for acute mania published to date (Bowden et al., 1994) showed a significant improvement in 49% of patients receiving lithium, 48% of those receiving valproate and 25% of those receiving placebo. Valproate is well tolerated and has very few drug interactions, making it more suitable for combined treatment regimens (Freeman & Stolle, 1998).

Of the newer anticonvulsants, a review of the recent literature suggests that there is no current evidence to recommend the use of gabapentin in bipolar disorder (mania or hypomania). The strongest evidence is for lamotrigine, but in depressive episodes, not mania or hypomania. Topiramate has shown some promise in both depressed and manic bipolar patients, with the added benefit of promoting weight loss (Calabrese et al., 2002; De Leon, 2001). Overall, however, the evidence is still very limited.

It is worthwhile mentioning that electroconvulsive therapy (ECT) has been shown to be one of the best treatment options in acute mania (Mukherjee et al., 1994). Current practice, influenced as it is by political as well as clinical issues, reserves ECT for clinical situations where pharmacological treatments may not be possible, such as pregnancy or severe cardiac disease, or when the patient's illness is refractory to drug treatments (American Psychiatric Association, 1994).

MANAGEMENT OF DEPRESSIVE EPISODES

The pharmacological treatment of depressive episodes in bipolar disorder represents a particular challenge. Although almost all of the antidepressants used in the treatment of unipolar depression are effective in the treatment of bipolar depression, the response rates are lower, and there is the risk of precipitating a manic episode or inducing or accelerating rapid cycling (Compton & Nemeroff, 2000; Sachs et al., 2000). The first steps in managing depression in a bipolar patient should involve the initiation of a 'mood stabiliser', if patients are 'drug-free'. If patients are taking prophylaxis, this must be optimised, serum levels checked, and any associated problems, such as hypothyroidism, excluded or treated. If depressive symptoms persist, a decision needs to be taken whether to add an antidepressant or an additional mood stabiliser (Sachs et al., 2000).

Although evidence is scarce, recent studies have suggested that the selective serotonin reuptake inhibitors (SSRIs) may be better tolerated, work more quickly, and have a lower associated risk of inducing mania or rapid cycling than the tricyclic antidepressants (Bauer et al., 1999; Nemeroff et al., 2000). Similarly, although controlled clinical trials comparing standard clinical treatments for depression in patients with bipolar disorder are lacking, it is a widely accepted clinical practice to add a second mood stabilizer to the treatment regimens of patients with bipolar disorder. A recent study compared the addition of an antidepressant with that of a second mood stabilizer in depressed patients who were receiving lithium carbonate or valproate. Both groups showed significant improvement in depressive symptoms during the 6-week trial, the antidepressant group tolerating the combination better (Young et al., 2000).

As mentioned previously, monotherapy with lamotrigine appears to have utility, particularly in the treatment of refractory bipolar depression, but further confirmation of this is awaited (Calabrese et al., 1999). Other suggested strategies include the use of adjunctive thyroxin (Bauer et al., 1998) and the novel use of inositol (Chengappa et al., 2000). Again, the use of ECT, in severe depression, or where urgent treatment is necessary, should not be overlooked (American Psychiatric Association, 1994).

SUICIDE PREVENTION

Since patients with bipolar disorder represent a group at high risk of suicide, it is reasonable to ask whether the above treatment strategies reduce the occurrence of suicidal acts. Retrospective and prospective studies do suggest that long-term lithium therapy reduces the risk of suicide, and may even reduce the known associated risk of cardiovascular disease (Schou, 2000; Tondo et al., 1997). At present, there are still few data available on the antisuicidal effects of the anticonvulsants in bipolar disorder (Goodwin, 1999). Prospective studies looking at the issue of outcome in bipolar disorder suggest that lithium may be significantly superior to carbamazepine in this regard (Greil et al., 1997).

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