Prophylaxis of Bipolar disorder

A review of the available treatments

Bipolar disorder
 

Characterised by alteration between states Can be subdivided into 3 categories



A manic episode with or without a previous major depressive episode constitutes bipolar I disorder Depression interspersed with episodes of hypomania constitutes bipolar II disorder Hypomania cycling with less severe periods of depressive symptoms for at least 2 years is termed cyclothymia

Epidemiology and risk factors

 

About 1.6% of the US population has bipolar disease The lifetime risk in most countries is reported as 1% to 1.5%, and is probably around 2% when bipolar II symptomatology is included There is strong evidence for an inherited predisposition to bipolar disorder in most patients


Nearly two thirds have a positive family history of affective illness

First occurrences are more likely before age 30, and recurrences are the rule


Adolescence through the early 20s is the peak age of onset: about 25% of first episodes occur before age 20

Kessler RC, et al. Arch Gen Psychiatry 51:8-19, 1994; Weissman MM, et al. JAMA 276:293-299, 1996; Berretini WH, et al. Proc Natl Acad Sci U S A 91:5918-5921, 1994.

Prognosis


Patients with bipolar I disorder are symptomatically ill nearly half the time and have a high probability of relapse Bipolar II disorder is more chronic, more depressive, and associated with more neuroticism and emotional instability between episodes than bipolar I Impaired psychosocial functioning and a high risk for suicide are common to all types of bipolar disorder.

Keller MB. J Clin Psychiatry. 2004;65 Suppl 15:10-4

Course of illness
Men Women

Kessing LV et al. Br J Psychiatry. 2004 Nov;185:372-7

Challenges


Bipolar disorder is characterized by frequent recurrence incomplete interepisode recovery, and poor interepisode functioning Challenges associated with the management of bipolar disorder


Not simply the treatment of acute episodes of mania and depression but also prevention of syndromal recurrence and assurance of full interepisode recovery both symptomatic and functional

Frank E et al. Am J Psychiatry 2006;163 (6): 981-985

Treatment Strategies


Must address both acute symptoms and longterm needs of patients The goal of therapy is to induce and sustain a remission


If that is not possible, a regimen that at least results in fewer, briefer, and milder episodes is desirable To decrease mortality, to reduce the rate of relapse and to shorten illness duration

The aims of long-term treatment



Sachs GS. J Clin Psychopharmacol 16(suppl 1):S32-S47, 1996.

Polypharmacotherapy


Increasingly popular in the treatment of all phases of bipolar disorder and is now considered the norm


In the period 1990 1995, 43.8% of patients with refractory bipolar disorder or unipolar depression were discharged on 3 medications compared to only 3.3% in 1974 1979 Individuals with bipolar disorder now receive on average > 4 different medications annually, with polypharmacy started early in the patient s illness

Goodwin G et al. European Psychiatry 2005;20: 365 371

When to consider prophylaxis?



The use of long-term prophylactic medication can be considered in patients who have had even a single episode of mania


Patients meeting criteria for bipolar I disorder

In bipolar disorder, functional impairment associated with an episode of illness often persists substantially beyond symptomatic recovery Observational data suggest that prevention of early relapse could be associated with a more benign course of illness

Taylor MJ et al. CNS Drugs 2006; 20 (4): 303-310

Relapse prevention


All the guidelines* place lithium (Li) and valproate (VPA) at the top of the list of options for long-term treatment Trend to increasingly recognize atypical antipsychotics, particularly olanzapine, as an additional alternative Increasing prominence of lamotrigine for prevention of depressive relapses

*British Association of Psychopharmacology (BAP); American Psychiatric Association (APA); Canadian Network for Mood and Anxiety Treatments (CANMAT); Texas Implementation of Medication Algorithms (TIMA) McAllister-Williams RH. J Psychopharmacol. 2006 Mar;20(2 Suppl):12-6

Reviewing treatments for prophylaxis of bipolar disorder

Lithium


Early reports (from the 1960s and 1970s) demonstrated Li to be superior to placebo in preventing affective episodes in placebo-controlled maintenance studies in which patients were monitored for up to 1 year


Relapse rates for patients taking Li averaged 37% compared with 79% for those on placebo Li had a better prophylactic effect on manic rather than depressive episodes

Another study showed that more than 50% of patients relapsed within 6 months of Li discontinuation

Prien RF, et al. Arch J Psychiatry 41:1096-1104, 1984; Suppes T, Arch Gen Psychiatry 48:1082-1088, 1991

Lithium


A recent meta-analysis was able to include data from five randomised trials invinvolving 1237 participants, of whom 770 had received lithium or placebo


Use of lithium reduces the risk of both depressive and manic re-lapse (relative risks 0.72 and 0.62, respectively) The effect appeared numerically, if not statistically, most robust for avoiding further mania

Geddes JR et al. Am J Psychiatry 2004; 161 (2): 217-22

Lithium


Naturalistic studies for longer follow-up periods suggest that a substantial number of patients do not respond adequately to Li maintenance Rates for those who remained episodefree for a period ranging from 18 months to 5 years were 33%, 36%, and 37% in certain studies

Keck PE, et al. J Clin Psychopharmacol 16(suppl 1):15S-23S, 1996; Prien RF, et al. Psychopharmacol Bull 26:409-427, 1990; Maj M et al. Arch Gen Psychiatry 48:772, 1991

Lithium


15 year outcome with Li



91 patients with BD commenced on prophylactic lithium treatment during hospitalization and were followed until death or censoring occurred during up to 15.3 years of observation


27 patients died (six from suicide) during the observation period, which was an excess mortality compared to the general population Fifty percent of the patients were admitted for more than one month per 20 months of observation and admitted more than once for each four years of observation Only 19 (21%) patients were not admitted to hospital during the observation period In addition to lithium prophylaxis given for variable lengths of time, the majority of the 36 (40%) patients, from whom treatment data were available, received various other drug treatments during follow-up.

Licht RW, et al. Bipolar Disord. 2008 Feb;10(1):79-86

Lithium


Neuroprotective or neurotoxic


970 papers in medline were retrieved for this search

  

Eighty-nine papers supported the neuroprotective effect A total of 116 papers supported the neurotoxic effect Nine papers supported no hypothesis

Possibility of a neurotoxic effect in real-life clinical practice even in closely monitored patients with 'therapeutic' lithium plasma levels

Fountoulakis KN et al. Int J Neuropsychopharmacol. 2008 Mar;11(2):269-87

Lithium


Predictors of response


Family history of bipolar disorder and a previous episode sequence of manic-depressive illnesseuthymia were associated with a favorable response to Lithium Patients with rapid cycling, mixed mania, episode sequence of depression-mania-euthymia, multiple prior episodes, comorbid substance or alcohol abuse or dependence, and familial negative affective styles were less likely to respond to Lithium maintenance

Bowden CL. J Clin Psychiatry 56(suppl 3):S25-S30, 1995; Keck PE, et al. J Clin Psychopharmacol 16(suppl 1):15S-23S, 1996

Lithium


Advantages


It is a safe, efficacious, inexpensive mood stabilizer that revolutionized the treatment of bipolar disorder Until recently, it was considered the initial treatment of choice for first episodes of manicdepressive illness because it has high efficacy in euphoric manic states While it is highly efficacious in patients with euphoric mania, it is not equally useful for all categories of bipolar disorder

Lithium


Disadvantages


Published and anecdotal reports indicate that 30% to 50% (or up to 80%, depending on subtype) of patients do not respond to Li People with severe mania, psychosis, and especially mixed states (ie, depressive mania) respond relatively poorly Li is more effective in preventing biphasic episodes that begin with a mania and switch to a depression followed by an interval of wellness (M-D-I) than those that begin with a depression and switch to mania and then to an interval of wellness (D-M-I) A history of substance abuse (including alcoholism), neurologic insult, or developmental disorders predicts a poor response, perhaps indirectly through the association of these factors with mixed-states disorder

Bowden CL. J Clin Psychiatry 56(suppl 3):S25-S30, 1995; Suppes T, Arch Gen Psychiatry 48:1082-1088, 1991;

Keck PE, et al. J Clin Psychopharmacol 16(suppl 1):15S-23S, 1996

Lithium


Disadvantages


Li's narrow therapeutic range is well recognized

 

Effective use requires careful dose titration and mandatory serum monitoring with dosage adjustments as needed Subsyndromal affective symptoms are more likely to occur with low levels (0.4 to 0.6mEq/L) and usually will be followed by a full-blown episode

Li also has a narrow therapeutic-to-toxic index

Another practical disadvantage of Li is the time lag before it takes effect in the treatment of acute mania


A beneficial response is not typically observed until after 7 to 14 days of therapy.

Dunner DL, et al. Arch Gen Psychiatry 30:229-233, 1974; Gelenberg AJ, et al. N Engl J Med 321:1489-1493, 1989.

Valproic acid (VPA)



VPA, a branched-chain fatty acid, has been available commercially in the US since 1978 as an antiepileptic


A congener of VPA, valproate sodium, was introduced into clinical use a few years later Because VPA and sodium valproate can commonly cause GI intolerance, a sustained-release formulation of the prodrug, divalproex sodium, which comprises a 1:1 ratio of VPA and valproate sodium, was later introduced into clinical use Although VPA, valproate sodium, and divalproex sodium are 3 distinct compounds, the systemically absorbed and active component of each is VPA

McElroy SL, et al. J Clin Psychopharmacol 12(suppl 1):S42-S52, 1992.

Valproic acid (VPA)



Controlled and uncontrolled studies have demonstrated that VPA has therapeutic efficacy comparable to that of Li in acute mania VPA can be considered a therapy of choice in some patients with bipolar disorder, including those unable to tolerate Li and others for whom Li was not effective, such as those with rapid cycling and mixed states VPA's faster onset of action (2 to 5 days with oral loading vs 7 to 14 days for Li) is a clinical advantage

McElroy SL, et al. J Clin Psychopharmacol 12(suppl 1):S42-S52, 1992.

Valproic acid (VPA)



Two randomised trials involving 623 participants



Valproate with lithium or placebo



Patients receiving valproate were less likely than those receiving placebo to withdraw from the study because of relapse (relative risk 0.63), and on this secondary measure there was no statistically significant difference between the valproate and lithium groups

Valproate with olanzapine continuation after the treatment of mania



Rates of relapse did not differ significantly between the two treatment groups

Bowden CL, et al. Arch Gen Psychiatry 2000; 57 (5):481-9; Tohen M, et al. Am J Psychiatry 2003; 160 (7): 1263-71

Valproic acid (VPA)



A study compared divalproex to lithium in the longterm management of patients with recently stabilized rapid-cycling bipolar disorder 20-month, double-blind, parallel- group comparison was carried out in recently hypomanic/manic patients who had experienced a persistent bimodal response to combined treatment with lithium and divalproex Sixty patients were randomly assigned to lithium or divalproex monotherapy in a balanced design after stratification for illness type (bipolarI versus bipolar II disorder)

Calabrese JR, et al. Am J Psychiatry. 2005 Nov;162(11):2152-61

Valproic acid (VPA)



The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively


The rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/ mania relapse

There were no significant differences in time to relapse The proportion discontinuing prematurely because of side effects was 16% for lithium and 4% for divalproex.

Calabrese JR, et al. Am J Psychiatry. 2005 Nov;162(11):2152-61

Valproic acid (VPA)



Predictors of response to treatment



Unlike Li, divalproex is effective in patients with pure and mixed mania, rapid cycling, and comorbid substance abuse

Valproic acid (VPA)



Advantages


A growing body of well-conducted clinical research indicates that VPA is well-tolerated and effective, especially for shortterm (2- to 4-week) treatment of acute mania


VPA's antimanic or mood-stabilizing effects may be augmented by concomitant use of Li, neuroleptics, CBZ, or thyroid hormone VPA can also reduce the frequency and intensity of recurrent episodes of both mania and depression over extended periods


Its short onset of action (2 to 5 days), particularly when a loading-dose strategy is used, is an advantage in the management of acutely manic patients

Especially benefit patients with rapid cycling, mixed (dysphoric) states, neurologic abnormalities (eg, EEG abnormalities, mental retardation), or histories of head trauma

McElroy SL, et al. J Clin Psychopharmacol 12(suppl 1):S42-S52, 1992.

Valproic acid (VPA)



Advantages


Multiple dosage formulations are available



Allows for appropriate dosage titration and individualization of therapy

Regardless of the dosage formulation used, VPA, in contrast to Li and CBZ, has less of an adverse effect on cognition and mental functioning

McElroy SL, et al. J Clin Psychopharmacol 12(suppl 1):S42-S52, 1992.

Valproic acid (VPA)



Disadvantages


VPA tends to inhibit the hepatic metabolism of some other compounds



This can be disadvantageous for patients requiring polypharmacy with hepatically metabolized drugs However, symptomatic liver dysfunction is rare and occurs almost exclusively in persons aged 2 years or younger

Hepatotoxicity is a concern with use of VPA



Potentially important drug interactions can occur with coadministration of VPA and carbamazepine (CBZ)

Dreifuss FE, et al. Neurology 37:379-385, 1987; Ketter TA, et al. J Clin Psychopharmacol 12:276-281, 1992.

Carbamazepine(CBZ)


It is an anticonvulsant with antimanic and possibly antidepressant properties that can be used in patients with bipolar disorder Although well-controlled study data are lacking, there is evidence that the drug is effective in the management of acute mania, particularly in patients who have responded inadequately or are unresponsive to Li CBZ may have a slightly shorter onset of action than Li

Bowden CL, et al. Practical Clinical Guidelines for the Management of Bipolar Disorder: Monograph on Treatment. Deerfield, Ill., Discovery International, 1992.

Carbamazepine(CBZ)


Controlled studies comparing CBZ with placebo indicate that CBZ is superior to placebo in the treatment of bipolar disorder after 1 year In studies comparing the drug with Li, a majority of patients taking either drug required adjunctive treatment for breakthrough manic or depressive episodes Although CBZ was effective in the reduction of affective episodes and the prolongation of euthymic periods, the effect was incomplete for most patients Rapid cycling, mixed mania, and a negative family history of mood disorder were associated with response to CBZ

Keck PE, et al. J Clin Psychopharmacol 16(suppl 1):15S-23S, 1996; Post RM, et al. Psychiatry Res 21:71-83, 1987

Carbamazepine(CBZ)


Advantages and disadvantages



It is effective as monotherapy in difficult-to-treat, acutely manic patients (eg, those with documented nonresponse or intolerance to Li) Also useful as adjunctive therapy when used concomitantly with Li, VPA, neuroleptics, and thyroid hormones Disadvantages of CBZ include its ability to autoinduce and heteroinduce drug metabolism, which complicates its own routine clinical use


Subtherapeutic blood levels may result from its half-life being cut in half (from 20 to 30 hours to 10 to 15 hours) anywhere between 3 weeks and 6 months into the treatment course

Joyce PR. Int Clin Psychopharmacol 3:123-129, 1988.

Lamotrigine


Two 18-month studies have been reported in which 638 participants were randomised to lamotrigine, lithium or placebo


Lamotrigine and lithium were found to be superior to placebo in delaying the time to treatment for a new mood episode (median survival 86 days vs 184 days [lithium] and 197 days [lamotrigine]) The effects of lamotrigine appeared superior in the prevention of depressive relapse, while lithium was superior for preventing mania

Goodwin GM, et al. J Clin Psychiatry 2004; 65 (3): 432-41

Olanzapine


A trial compared the efficacy of olanzapine and lithium for the prevention of mood episode relapse/recurrence Patients meeting symptomatic remission criteria were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5 20 mg/ day (N=217), or lithium (target blood level: 0.6 1.2 meq/liter) (N=214)

Tohen M, et al. Am J Psychiatry. 2005 Jul;162(7):1281-90

Olanzapine

Olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium cotreatment
Tohen M, et al. Am J Psychiatry. 2005 Jul;162(7):1281-90

Olanzapine


A placebo-controlled, double-blind study investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolarI disorder Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder at two consecutive weekly visits following 6-12 weeks of open-label acute treatment with 5-20 mg/day of olanzapine were randomly assigned to double-blind maintenance treatment with olanzapine (N=225) or placebo (N=136) for up to 48 weeks

Tohen M, et al. Am J Psychiatry. 2006 Feb;163(2):247-56

Olanzapine

Tohen M, et al. Am J Psychiatry. 2006 Feb;163(2):247-56

Olanzapine


During olanzapine treatment, the most common emergent event was weight gain


During the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4) In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2)

Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode

Tohen M, et al. Am J Psychiatry. 2006 Feb;163(2):247-56

Aripiprazole


A 26-week, double-blind, placebo-controlled relapse prevention study of aripiprazole was designed a priori with a prospective, 74-week, double-blind, placebo-controlled extension phase Efficacy and tolerability of aripiprazole for relapse prevention in bipolar I disorder was, therefore, evaluated for 100 weeks


Patients with DSM-IV bipolar I disorder, recent manic or mixed episode, received open-label aripiprazole 15 or 30 mg/day (started at 30 mg/day) for 6 to 18 weeks Patients achieving stabilization entered the double-blind phase, at which point they were randomly assigned to double-blind treatment with aripiprazole or placebo for 26 weeks Patients who completed the 26-week stabilization continued in a double-blind fashion with aripiprazole or placebo for an additional 74 weeks and were monitored for relapse, efficacy, and tolerability

Keck PE Jr, et al. J Clin Psychiatry. 2007 Oct;68(10):1480-91

Aripiprazole


161 patients met the stabilization criteria and were randomly assigned to aripiprazole (N = 78) or placebo (N = 83)
 

Over a 100-week treatment period, aripiprazole monotherapy was effective for relapse prevention in patients who were initially stabilized on aripiprazole for 6 consecutive weeks, and it maintained a good safety and tolerability profile

At 100 weeks, time to relapse was significantly longer with aripiprazole Aripiprazole was superior to placebo in delaying time to manic relapse (p = .005) Mean weight change from baseline to 100 weeks (last observation carried forward) was +0.4 +/- 0.8 kg with aripiprazole and -1.9 +/- 0.8 kg with placebo

Keck PE Jr, et al. J Clin Psychiatry. 2007 Oct;68(10):1480-91

Combination therapy

Goodwin G et al. European Psychiatry 2005;20: 365 371

Drug Combinations - recommendations

Selecting combinations


Anti-epileptics, novel antipsychotics, and lithium have complementary mechanisms of action in the treatment of bipolar disorder Compared to antipsychotics, anti-epileptics have different mechanisms of action; these include blocking calcium channels, modulating potassium channels, increasing GABAergic and serotonergic function or altering glutamate function


Thus, depending on the target receptor, antiepileptics have varying degrees of antidepressant/antimanic properties

Always preferable to use treatments that have previously been studied in combination, although this is not always possible

Combination therapy in acute mania

Muller-Oerlinghausen B,et al. J Clin Psychopharmacol 2000;20:195 203.

Combination therapy in acute mania



3-week, multicenter, double-blind, randomized, placebo-controlled study



Risperidone in combination with a moodstabilizer (divalproate or lithium) was found to be more effective than placebo in the treatment of acute mania In the same study, treatment with risperidone and carbamazepine was not shown to be more effective than placebo

Yatham LN, et al. Br J Psychiatry 2003;182:141 7.

Conclusion


Treatment for bipolar disorder consists of 2 goals

 

Managing urgent situations Transitioning patients into maintenance therapy

Long-term management of bipolar disorder is a crucial component of treatment because the recurrence of the illness negatively affects patients' daily lives and increases their risks for poor health and suicide An ideal maintenance treatment for bipolar disorder is relatively simple to take, prevents recurrence of both manic and depressive episodes, and is well-tolerated over the long term.

Conclusion


Although many different types of medications are used for maintenance therapy of bipolar disorder, none can be considered ideal for a majority of people with bipolar disorder, and each specific form of therapy has different strengths and limitations Clinicians need to be aware of unique efficacy and side effect factors when choosing long-term therapy and consider treatment components, goals, and individual patient characteristics, which are essential to the successful long-term management of bipolar disorder