Paul E. Keck Jr., M.D.
Susan L. McElroy, M.D.
In this chapter, we review strategies for treating bipolar disorder, drawing primarily on data from randomized controlled trials. Where such data are lacking, strategies based on data from open trials, naturalistic studies, and expert consensus guidelines are included. The treatment of bipolar disorder in children and adolescents is covered elsewhere in this book (see Chapter 55 in this volume, “Treatment of Child and Adolescent Disorders,” by Wagner and Pliszka).
Manic and mixed episodes are medical emergencies and frequently require treatment in a hospital to ensure the safety of patients and those around them. The primary goal of treatment of manic and mixed episodes is rapid symptom reduction, followed by full remission of symptoms and restoration of psychosocial and vocational functioning (Hirschfeld et al. 2002).
Pharmacotherapy is the cornerstone of treatment of acute manic and mixed episodes and of bipolar disorder in general. We review medications that have shown efficacy in the treatment of acute manic and mixed episodes. Although these agents typically produce rates of response (defined as ≥50% reduction in manic symptoms from baseline to endpoint) of approximately 50% in short-term (3- to 4-week) trials, relatively few patients (<25%) actually achieve remission of symptoms within these time intervals while receiving monotherapy with any of these agents. Thus, use of combination therapy is common in clinical practice to improve response and remission rates (Suppes et al. 2005).
Lithium has been a mainstay of treatment for acute mania for more than 50 years, with superior efficacy compared with placebo (reviewed in Goodwin and Jamison 2007) and equivalent efficacy compared with divalproex (Bowden et al. 1994), carbamazepine (Lerer et al. 1987; Small et al. 1991), risperidone (Segal et al. 1998), olanzapine (Berk et al. 1999), quetiapine (Bowden et al. 2005), aripiprazole (Keck et al. 2003a), and typical antipsychotics (Garfinkel et al. 1980; Johnson et al. 1971; Platman 1970; Prien et al. 1972; Shopsin et al. 1975; Spring et al. 1970; Takahashi et al. 1975). Lithium produced improvement in psychotic as well as manic symptoms in these trials.
Lithium response for acute mania can be maximized by titrating to plasma concentrations at the upper end of the therapeutic range (1.0–1.4 mmol/L) as tolerated (Stokes et al. 1976). In randomized controlled trials, significant clinical improvement usually was reported within 7–14 days among responders (Keck and McElroy 2001). Common side effects associated with acute treatment with lithium include nausea, vomiting, tremor, somnolence, weight gain, and cognitive slowing. Lithium also may interfere with thyroid function and exacerbate renal disease; thus, monitoring of thyroid and renal function tests is an important part of lithium administration.
Divalproex and related formulations of valproic acid had superior efficacy compared with placebo (Bowden et al. 1994, 2006; Brennan et al. 1984; Emrich et al. 1981; Pope et al. 1991) and equivalent efficacy compared with lithium (Bowden et al. 1994; Freeman et al. 1992), haloperidol (McElroy et al. 1996), and olanzapine (Zajecka et al. 2002) in randomized controlled treatment trials of acute bipolar manic or mixed episodes. Olanzapine was superior to divalproex as measured by mean reduction of manic symptoms and proportion of patients in remission at study completion in a second head-to-head comparison trial (Tohen et al. 2002a). Müller-Oerlinghausen et al. (2000) found that valproate augmentation of typical antipsychotics led to significantly lower mean antipsychotic dosages and higher response rates compared with placebo added to typical antipsychotics in patients with acute mania.
Acute antimanic response is correlated with divalproex plasma concentrations between 50 and 125 mg/L, with some evidence of greater response at the upper end of the therapeutic range (Allen et al. 2006; Zajecka et al. 2002). Some patients may require plasma concentrations greater than 125 mg/L, but side effects become progressively more prevalent above this level. Divalproex administered at a therapeutic starting dosage of 20–30 mg/kg/day has shown good tolerability in inpatients, and some evidence indicates a more rapid response than with gradual titration from a lower (e.g., 750 mg/day) starting dosage (Hirschfeld et al. 1999; Keck et al. 1993).
Divalproex is generally well tolerated during treatment of acute manic or mixed episodes. Common side effects include somnolence, nausea, vomiting, tremor, weight gain, and cognitive slowing. Enteric-coated and extended-release formulations (the latter requiring a 20% dosage increase to yield plasma concentrations equivalent to those with immediate-release formulations) have improved tolerability compared with valproic acid formulations. Rare serious adverse events include pancreatitis, thrombocytopenia, significant hepatic transaminase elevation, hyperammonemic encephalopathy in patients with urea cycle disorders, and hepatic failure.
An extended-release formulation of carbamazepine was superior to placebo in two large randomized, placebo-controlled multicenter trials (Weisler et al. 2004b, 2005). These findings replicated earlier results from a placebo-controlled crossover trial (Ballenger and Post 1978). Common side effects of carbamazepine include diplopia, blurred vision, ataxia, somnolence, fatigue, and nausea. Less common side effects include rash, mild leukopenia and thrombocytopenia, and hyponatremia. Rare serious adverse events include agranulocytosis, aplastic anemia, hepatic failure, pancreatitis, and exfoliative dermatitis.
In the only large randomized, placebo-controlled multicenter trial of oxcarbazepine in acute mania to date, a 7-week study in children and adolescents, oxcarbazepine was not superior to placebo in reduction of manic symptoms (Wagner et al. 2006). Thus, the use of oxcarbazepine in acute bipolar mania is not supported by evidence from clinical studies but rather is based on the drug’s putative similarities to carbamazepine in mechanism of action and improved tolerability.
Chlorpromazine (Klein 1967) and haloperidol (McIntyre et al. 2005) were superior to placebo in randomized controlled trials. Typical antipsychotics bear the burden of neurological and neuroendocrinological side effects and may carry an increased risk of postmanic depressive episodes (Kukopulos et al. 1980).
The atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, and cariprazine have all shown efficacy in the treatment of acute bipolar mania in at least two randomized, placebo-controlled trials.
Olanzapine was found to be superior to placebo (Tohen et al. 1999, 2000), superior or equal in efficacy to divalproex (Tohen et al. 2002a; Zajecka et al. 2002), and comparable in efficacy to lithium (Berk et al. 1999; Niufan et al. 2008), risperidone (Perlis et al. 2006), and haloperidol (Tohen et al. 2003a) in mean reduction of manic and mixed symptoms in 3- to 4-week monotherapy trials. Adjunctive treatment with olanzapine was superior to placebo in patients whose symptoms were inadequately responsive to lithium or divalproex monotherapy (Tohen et al. 2002b). In short-term studies, the most common side effects associated with olanzapine were somnolence, constipation, dry mouth, increased appetite, weight gain, and orthostatic hypotension.
Risperidone was superior to placebo (Hirschfeld et al. 2004; Khanna et al. 2005) and comparable to olanzapine (Perlis et al. 2006), haloperidol (Smulevich et al. 2005), and lithium (Segal et al. 1998) in mean reduction of manic and mixed symptoms as monotherapy in 3- to 4-week trials. Risperidone was superior to placebo as an adjunctive therapy with lithium or divalproex in one placebo-controlled trial (Sachs et al. 2002), but not in a second placebo-controlled trial in combination with lithium, divalproex, or carbamazepine (Yatham et al. 2003). The rate of extrapyramidal side effects (EPS) associated with risperidone was low when the drug was administered at average dosages up to 4 mg/day (Hirschfeld et al. 2004; Sachs et al. 2002; Yatham et al. 2003), but not when administered at average dosages of 6 mg/day or greater (Khanna et al. 2005; Segal et al. 1998). In short-term trials, other commonly occurring side effects included prolactin elevation, akathisia, somnolence, dyspepsia, and nausea.
Quetiapine was superior to placebo as monotherapy in two 12-week studies in adult patients (Bowden et al. 2005; McIntyre et al. 2005) and was comparable to lithium in a 4-week study in adult patients (Li et al. 2008). Similarly, quetiapine was superior to placebo as adjunctive treatment with lithium or divalproex (Sachs et al. 2004; Yatham et al. 2004). The mean modal dosage of quetiapine associated with antimanic efficacy in most studies was approximately 600 mg/day (Vieta et al. 2005b). Quetiapine was also superior to placebo in the reduction of hypomanic or mild manic symptoms among outpatients in an 8-week trial (McElroy et al. 2010a). The most common side effects from quetiapine in monotherapy trials were headache, dry mouth, constipation, weight gain, somnolence, and dizziness.
Ziprasidone was superior to placebo (mean dosage=120–130 mg/day) in two 3-week monotherapy trials in adult patients (Keck et al. 2003b; Potkin et al. 2005) and comparable to haloperidol in a 12-week trial (Ramey et al. 2003). Ziprasidone was not superior to placebo as an adjunctive treatment with lithium in a study designed to prove superior onset of action by 2 weeks of treatment (Weisler et al. 2004a). Ziprasidone-related side effects in monotherapy trials included headache, somnolence, EPS, akathisia, and dizziness.
Aripiprazole had significantly greater efficacy in the reduction of manic symptoms compared with placebo in three 3-week trials (Keck et al. 2003a, 2007; Sachs et al. 2006) and equivalent efficacy compared with haloperidol (Vieta et al. 2005a) and lithium (Keck et al. 2009) in adequately powered 12-week comparison trials. Aripiprazole was initiated at 15 or 30 mg/day. Common side effects associated with aripiprazole in the placebo-controlled trials were headache, nausea, vomiting, constipation, insomnia, and akathisia.
Asenapine was superior to placebo in mean reduction of manic symptoms in two 3-week trials (McIntyre et al. 2009, 2010). Common side effects attributed to asenapine were EPS and mild weight gain.
Cariprazine, a dopamine D3 and D2 receptor partial agonist, was superior to placebo in reduction of manic symptoms in three randomized controlled trials (Calabrese et al. 2015; Durgam et al. 2015; Sachs et al. 2015). The most common side effects associated with cariprazine (occurring in ≥10% of subjects and at twice the rate with placebo) were akathisia, EPS, tremor, dyspepsia, and vomiting.
In the studies of atypical antipsychotics reviewed in this section, no significant differences in response were seen between patients with and patients without psychotic features or between patients with manic episodes and patients with mixed episodes among all agents, with the exception of trials of quetiapine, many of which excluded patients with mixed episodes. The prototypical atypical agent clozapine was reported to have substantial efficacy in several large case series of patients with treatment-refractory mania (Calabrese et al. 1996; Green et al. 2000) but has not been studied in placebo-controlled trials in mania.
Electroconvulsive therapy (ECT) is an important treatment option for manic patients with severe, psychotic, or catatonic symptoms. ECT was superior in efficacy both to lithium (Small et al. 1988) and to the combination of lithium and haloperidol (Mukherjee et al. 1994) in prospective comparison studies. In addition, ECT in combination with chlorpromazine was superior to sham ECT and chlorpromazine (Sikdar et al. 1994). Although these were small studies, their findings are consistent with those of other naturalistic studies of ECT in the treatment of acute mania (Black et al. 1987; Thomas and Reddy 1982). There is a risk of neurotoxicity in patients receiving ECT while also receiving lithium; thus, lithium should be discontinued when ECT is administered (Hirschfeld et al. 2002).
In two short-term monotherapy pilot trials (Yildiz et al. 2008; Zarate et al. 2007) and one adjunctive therapy trial (Amrollahi et al. 2011), the protein kinase C inhibitor tamoxifen was superior to placebo in reduction of manic symptoms.
Placebo-controlled trials of the extended-release formulation of the atypical antipsychotic paliperidone in acute mania have thus far yielded mixed findings (Berwaerts et al. 2011, 2012b; Vieta et al. 2010).
The goal of treatment of bipolar depression is full remission of symptoms (Hirschfeld et al. 2002). This straightforward goal is complicated by the limited efficacy of many mood stabilizers in bipolar depression (Zornberg and Pope 1993), often requiring the adjunctive use of unimodal antidepressants with the attendant risk of cycle acceleration or switching.
Eight of nine placebo-controlled trials conducted in the 1960s and 1970s in patients with bipolar I and II disorders found lithium superior to placebo in acute bipolar depression (reviewed in Zornberg and Pope 1993). In an analysis of five studies in which it was possible to distinguish “unequivocal” lithium responders from patients who had partial but incomplete improvement in depression, Zornberg and Pope (1993) reported that 36% had an unequivocal response, compared with 79% who had partial but incomplete benefit.
Quetiapine (300 mg/day and 600 mg/day) was superior to placebo in reduction of depressive symptoms in four large 8-week multicenter trials involving outpatients with bipolar I and II depression (Calabrese et al. 2005a; McElroy et al. 2010b; Thase et al. 2006; Young et al. 2010). No significant difference in efficacy was found between the two quetiapine dosage groups. However, the rate of side effects was lower in the 300 mg/day groups compared with the 600 mg/day groups. Switch rates were low across all treatment groups and were not significantly different among the quetiapine and placebo groups.
Olanzapine and the combination of olanzapine and fluoxetine (OFC) were superior to placebo in reducing depressive symptoms in an 8-week trial of 833 patients with bipolar I depression (Tohen et al. 2003c). However, the OFC was superior not only to placebo throughout the trial but also to olanzapine for weeks 4 through 8. No significant differences in switch rates (6%–7%) were found among the three groups. Brown et al. (2006) compared OFC with lamotrigine (titrated to 200 mg/day) in a 7-week comparison trial in outpatients with bipolar I depression. Patients receiving OFC had greater reductions in depressive symptoms compared with patients receiving lamotrigine, although the lamotrigine group may have had a greater response with a longer trial, given the need for gradual lamotrigine titration. Switch rates were not significantly different between the two groups.
Findings from two placebo-controlled trials indicate that lurasidone is efficacious in the treatment of bipolar I depressive episodes (reviewed by Franklin et al. 2015). Notably, the onset of therapeutic effect occurred within the first 2–3 weeks of treatment among responders. Safety data from these trials also suggest that lurasidone is significantly less likely than other atypical agents to produce metabolic side effects.
In an initial large 7-week randomized, placebo-controlled trial, lamotrigine (at 50 mg/day and 200 mg/day) was superior to placebo in patients with bipolar I depression (Calabrese et al. 1999). Switch rates (3%–8%) were not significantly different among the three groups. A second large placebo-controlled, parallel-group, flexible-dose trial involving patients with bipolar I and II depression did not find a significant advantage for lamotrigine over placebo (Bowden 2001). In a double-blind crossover trial, Frye et al. (2000) found lamotrigine superior to placebo in improving depression in patients with treatment-refractory rapid-cycling bipolar I or II disorder. Lamotrigine was superior to placebo when added to lithium treatment in an 8-week trial in patients with breakthrough depressive episodes (van der Loos et al. 2009). Common side effects of lamotrigine in these studies included headache, nausea, infection, and xerostomia. The risk of serious rash from lamotrigine can be reduced by carefully adhering to recommended titration schedules (GlaxoSmithKline 2016), but patients should be warned of the risk of rash and of the need to report any such symptoms immediately.
In two small controlled trials in patients with treatment-refractory bipolar depression, response to carbamazepine was superior to that seen with placebo (Post et al. 1986) or lithium (Small 1990). The results of these initial intriguing findings have not been followed by large placebo-controlled, parallel-group studies.
Two small randomized, placebo-controlled trials of divalproex in the treatment of acute bipolar depression yielded opposite findings. Sachs and Collins (2001) did not find divalproex to be superior to placebo in one pilot trial, whereas Davis et al. (2005) found divalproex superior to placebo in reduction of depressive and anxiety symptoms in a later pilot study.
Because of the meager evidence base, current recommendations regarding the use of antidepressants in conjunction with mood stabilizers for acute bipolar I depression tend toward the conservative (i.e., avoid antidepressants if possible). However, some general impressions can be gleaned from the available clinical trials. First, switch rates associated with newer antidepressants in short-term trials, in general, appear to be lower than those associated with tricyclic antidepressants (TCAs) in older studies (Thase and Sachs 2000). Second, among all of the antidepressants studied, the most substantial evidence for efficacy rests with the monoamine oxidase inhibitor (MAOI) tranylcypromine (Himmelhoch et al. 1991), but safety concerns often eliminate this agent from first-line therapy choices (Hirschfeld et al. 2002). Bupropion (Sachs et al. 1994) and selective serotonin reuptake inhibitors (SSRIs) (Nemeroff et al. 2001) are common first-line agents administered in conjunction with mood stabilizers.
ECT had significantly greater efficacy than MAOIs, TCAs, or placebo in several randomized controlled trials in patients with bipolar depression (reviewed in Zornberg and Pope 1993). ECT may be particularly indicated for patients with severe, psychotic, or catatonic symptoms.
Very few randomized controlled trials of any form of psychotherapy for patients with acute bipolar depression have been conducted. Cognitive-behavioral and interpersonal therapy have demonstrated efficacy in the treatment of unipolar major depression, but these modalities have been examined only in very small preliminary studies in patients with bipolar depression, thus far without conclusive findings (Cole et al. 2002; Zaretsky et al. 1999).
Two preliminary placebo-controlled trials found the dopamine D2 and D3 receptor agonist pramipexole superior to placebo in the adjunctive treatment of depression in patients with bipolar I or bipolar II disorder (Goldberg et al. 2004; Zarate et al. 2004). Switch rates with pramipexole did not differ significantly from those with placebo.
In a 1-week placebo-controlled trial, Watson et al. (2012) examined the efficacy of mifepristone in improvement in spatial working memory in 60 patients with bipolar depression. They found that mifepristone (600 mg/day) treatment was associated with sustained improvement in spatial working memory as an independent variable apart from improvement in depressive symptoms.
Bipolar disorder is a recurrent lifelong illness in more than 90% of the patients who experience a manic episode (Goodwin and Jamison 2007). Because of the high risk of recurrence and morbidity associated with mood episodes and interepisode symptoms, maintenance treatment is usually recommended after a single manic episode (Hirschfeld et al. 2002). The goals of maintenance treatment include prevention of syndromal relapse and subsyndromal symptoms, optimization of functioning, and prevention of suicide.
Lithium is the most extensively studied medication in the maintenance treatment of bipolar disorder. Data from randomized, placebo-controlled trials conducted in the 1960s and 1970s indicated that lithium protected against relapse, with a fourfold lower risk compared with placebo at 6-month and 1-year follow-up (Keck et al. 2000). Lithium was superior to placebo in preventing relapse into mania in two randomized controlled parallel-group trials lasting 18 months (Bowden et al. 2003; Calabrese et al. 2003).
The optimal maintenance lithium serum concentration is an important consideration in successful maintenance treatment. Maintenance lithium serum concentrations usually are lower than those required to produce acute antimanic efficacy. However, studies by Gelenberg et al. (1989) and Keller et al. (1992) found a serum level–response relationship, with levels of 0.4–0.6 mEq/L being associated with 2.6 times the relapse rate and a significantly greater likelihood of experiencing subsyndromal symptoms compared with levels of 0.8 mEq/L or higher. There was also a serum level–side effect relationship, with patients at higher levels experiencing significantly higher rates of side effects, often leading to discontinuation. Perlis et al. (2002), in yet another reanalysis of the Gelenberg et al. (1989) data, reported that an abrupt drop in serum lithium levels, whether due to random reassignment or to nonadherence, was the most powerful predictor of relapse. The optimal lithium level for many patients will be the level that balances relapse prevention and suppression of subsyndromal symptoms against minimization of bothersome day-to-day side effects.
Two large 18-month placebo-controlled maintenance trials comparing lamotrigine (200–400 mg/day) with lithium (0.8–1.1 mEq/L) found lamotrigine, but not lithium, superior to placebo in preventing depressive episodes (Bowden et al. 2003; Calabrese et al. 2003). In contrast, lithium, but not lamotrigine, was superior to placebo in preventing manic episodes. Of the nearly 1,200 patients who received lamotrigine in these trials, 9% developed a benign rash (morbilliform or exanthematous eruptions), compared with 8% of the 1,056 patients receiving placebo. When patients who received lamotrigine during the open-label run-in phase of the studies were included in the analysis, the total incidence of rash was 13%, with two cases of serious rash requiring hospitalization (Calabrese 2002).
Calabrese et al. (2000) conducted a 6-month placebo-controlled relapse prevention study of lamotrigine (mean dosage=288 mg/day) in 182 patients with rapid-cycling bipolar I or II disorder. There was no significant difference between the lamotrigine and the placebo treatment groups in time to need for additional medications for recurrent mood symptoms.
The only randomized, placebo-controlled maintenance study of divalproex in bipolar I disorder found no significant difference in time to development of any mood episode among patients receiving divalproex, lithium, or placebo (Bowden et al. 2000). A number of unforeseen methodological limitations in this trial complicated interpretation of its results. Among patients who received divalproex for treatment of the index manic episode in an open treatment period prior to randomization, divalproex was superior to placebo on rates of early termination due to any mood episode (29% vs. 50%) during the subsequent year. Divalproex was also compared with olanzapine in a 47-week blinded maintenance trial (Tohen et al. 2003b). Calabrese et al. (2005b) compared divalproex with lithium in a 20-month study of patients with rapid-cycling bipolar disorder and found comparable relapse rates in both treatment groups.
There are no data regarding the optimal maintenance valproic acid concentration in bipolar disorder. Current practice usually consists of titrating to therapeutic serum concentrations (50–125 μg/mL) and, as with lithium, balancing relapse and subsyndromal symptom prevention against minimization of side effects (Hirschfeld et al. 2002). Treatment with valproate appears to pose an increased risk of polycystic ovarian syndrome (PCOS), although the relationship between PCOS and weight gain as a possible mechanism is unclear (Hirschfeld et al. 2002).
Although a number of studies have examined the efficacy of carbamazepine in the maintenance treatment of bipolar disorder, most of these studies yielded results that were difficult to reliably interpret on methodological grounds (Dardennes et al. 1995).
Olanzapine was comparable to divalproex in a 47-week comparison trial (Tohen et al. 2003b) and to lithium in a 1-year comparison trial (Tohen et al. 2005). Olanzapine received an indication for maintenance treatment in bipolar disorder based on superiority over placebo in prevention of manic and depressive episodes over 48 weeks (Tohen et al. 2006). The combination of olanzapine and lithium or divalproex was superior to placebo and lithium or divalproex in relapse prevention over 18 months in patients who had initially responded to the active combination acutely (Tohen et al. 2002b) and then were re-randomized (Tohen et al. 2004). However, patients in the combination therapy group had twice the weight gain of patients in the monotherapy group.
Aripiprazole was superior to placebo in preventing manic relapse over a 6-month follow-up period in patients with bipolar disorder who were initially stabilized on aripiprazole monotherapy for an acute manic or mixed episode (Keck et al. 2006, 2007). By contrast, no significant difference between aripiprazole and placebo was found for rates of depressive relapse. However, the overall low rate of depressive relapse in this trial may have been due to the inclusion of patients whose index episodes were manic or mixed rather than depressive.
Two 104-week adjunctive placebo-controlled trials found quetiapine in combination with lithium or divalproex to be superior to placebo with lithium or divalproex in prolonging time to recurrence of a mood episode (Suppes et al. 2009; Vieta et al. 2008). The quetiapine combination groups also had lower proportions of patients experiencing a mood event.
In a 6-month maintenance trial, ziprasidone was superior to placebo in combination with lithium or divalproex in prolonging time to intervention for a mood episode and in proportion of patients requiring an intervention during the length of the trial (Bowden et al. 2010).
In two randomized controlled trials, risperidone (long-acting injectable formulation) was found to be superior to placebo in prevention of relapse, both as monotherapy and as adjunctive therapy (Quiroz et al. 2010; Vieta et al. 2012).
Evidence from one placebo-controlled trial suggests that paliperidone extended release may be efficacious as a maintenance treatment in patients with bipolar disorder (Berwaerts et al. 2012a).
The use of ECT in the maintenance treatment of bipolar disorder has never been studied systematically in a randomized controlled trial. However, several naturalistic studies suggest that maintenance ECT may be a useful treatment alternative for patients whose symptoms are inadequately responsive to pharmacotherapy (Schwarz et al. 1995; Vanelle et al. 1994).
Most patients with bipolar disorder experience a common cluster of psychological problems stemming directly from the illness. A number of specific psychosocial interventions as adjuncts to mood stabilizer therapy have been shown to improve the long-term outcome of bipolar disorder (reviewed in Rizvi and Zaretsky 2007). The best-studied interventions include educational, interpersonal, family, and cognitive-behavioral therapies. Randomized controlled trials conducted over 1- to 2-year follow-up periods support the efficacy of cognitive-behavioral therapy (Lam et al. 2005), family-focused and related forms of therapy (Clarkin et al. 1990, 1998; Miklowitz et al. 2003; Rea et al. 2003), interpersonal and social rhythm therapies (Frank et al. 2005), and group psychoeducation (Colom et al. 2003) in reducing or delaying mood episode recurrence, increasing treatment adherence, and improving functioning. Family-focused, interpersonal, and social rhythm therapies were all associated with delaying time to depressive episode relapse compared with brief treatment (Miklowitz et al. 2007).
There have been substantial advances in the pharmacological treatment of bipolar disorder in the past two decades. A number of medications have demonstrated efficacy in the treatment of acute mania in placebo-controlled trials, either as monotherapy or as an adjunct to mood stabilizers. In addition, available data indicate that combination therapy with an antipsychotic and a mood stabilizer is more rapidly effective, with better overall response rates in acute mania, than either mood stabilizers or antipsychotics alone.
The treatment of bipolar depression remains one of the least-studied aspects of the illness. The “mood stabilizer first” strategy and the combined use of mood stabilizers and antidepressants in moderate to severe bipolar depression are common approaches.
Most patients with bipolar disorder require treatment with more than one medication during the course of their illness. The efficacy of combination strategies is only now receiving close scrutiny. Recent studies suggest that for some patients, the use of combinations of antidepressants and mood stabilizers as maintenance treatment may be important to prevent depressive relapse.
The role and efficacy of different types of psychotherapy at different phases of illness management in bipolar disorder are now becoming clearly established. These components of treatment are important in educating patients and families, improving insight and treatment adherence, enhancing coping skills, and dealing with the sequelae of mood symptoms and episodes—and, it is hoped, improving functioning and outcome. Treatment advances in bipolar disorder are finally occurring rapidly. Bringing these treatments to patients with bipolar disorder is both the challenge and the reward of helping people manage this illness.
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