Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update A detailed review was published in 2004 on the sus propiedades terapéuticas en las diferentes fases de los therapeutic properties of the medications used in the trastornos bipolares llevando a proponer un cambio en treatment of bipolar disorders (Tamayo, JM et al. Actas Esp su clasificación genérica como “estabilizadores del estado Psiquiatr 2004;32(Supl. 1):3-17). At the time it could be de ánimo” a una nueva incluyendo: antimaníacos, esta- concluded that although mood stabilizers (euthymics) share bilizadores parciales del ánimo y eutimizantes. some action mechanisms, they are also significantly different from each other with respect to their therapeutic properties Desde entonces, han sido publicados varios estudios in the various phases of bipolar disorders. This led to a doble-ciego aleatorizados y meta-análisis, explorando la proposed change in their generic classification as “mood eficacia y tolerabilidad de estos medicamentos. Esta re- stabilizers” to a new classification that includes: antimanic visión actualizada pretende evaluar, a la luz de la nueva medications, partial mood stabilizers, and euthymics.
evidencia, la validez de la propuesta de clasificación pu-blicada en ese entonces.
Since then, several randomized, double-blind studies and meta-analyses that explore the effectiveness and Palabras claves:
tolerability of these medications have been published. This Eutimizantes, Trastorno Bipolar, Antimaníacos, Estabilizadores del ánimo updated review aims to assess the validity of the proposed classification in the light of new evidence.

Key words:
Euthymiants, Bipolar Disorder, Antimanics, Mood stabilizers
Bipolar disorders (BDs) share the presence of depressive Actas Esp Psiquiatr 2011;39(5):312-30 symptoms and a high risk of recurrence and chronification with unipolar depressive disorders and, in the case of Bipolar Disorder II (BD II), a greater prevalence in women. However, Diferencias terapéuticas de los medicamentos
the presence of manic or hypomanic episodes distinguishes para el tratamiento de los trastornos
one condition from the other.1, 2 BDs can be subdivided into bipolares: siete años después
different types depending on the episodes that the patient has presented throughout life. Bipolar Disorder I (BD I) differs from other BDs in that at least one manic or mixed En el 2004 fue publicada una revisión detallada so- episode has occurred. BD II is characterized by one or more bre las características terapéuticas de los medicamentos depressive episodes with at least one hypomanic episode utilizados en el tratamiento de los trastornos bipolares with a minimum duration of 4 days. The cyclothymic disorder [Tamayo JM et al. Actas Esp Psiquiatr 2004;32(Suppl. is characterized by a chronic recurrent pattern of oscillation 1):3-17]. En aquél momento se podía concluir que si bien between hypomanic and depressive symptoms of less severity los eutimizantes compartían algunos mecanismos de ac- than observed in BD I or II, although 15% to 50% of these ción, eran a la vez sustancialmente diferentes respecto a patients will progress to BD I or especially to BD II.3 An international cross-sectional study (11 countries) conducted in more than 61,000 adults living in the community using DSM-IV criteria and the CIDI (Composite Tel.: (574) 352-5749.
E-mail: [email protected] International Diagnostic Interview) scale of the WHO showed Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update that the prevalences in the community were 0.6% BD I, 0.4% (34.2%).4 The most common nonpsychiatric comorbidities BD II, 1.4% sub-threshold BD and 2.4% for the bipolar include cardiovascular diseases and obesity.13, 14 spectrum in general. The prevalence of the bipolar spectrum varies significantly between countries, ranging from 0.1% in With regard to treatment, fewer than half of India to 4.4% in the United States (USA), suggesting that international patients with BDs receive mental health cultural factors could greatly influence the detection of the treatment. In low income countries, only 25.2% of patients disorder. However, for the authors the rates of prevalence, report a contact with the mental health system at some time severity, impact and comorbidities of BDs are “remarkably in their lives.4 As for studies that evaluate the effectiveness similar” at the international level. This study made it possible and safety of medicinal products for the treatment of BDs, to confirm that symptom severity and suicidal behavior the majority usually include only patients with BD I. Few increased from sub-threshold BD to BD I, but that the double-blind, randomized studies have focused exclusively functional alterations are similar in all the BD subtypes and on patients with BD II or other subtypes of bipolarity. As has depend to a great extent on the presence of depressive been mentioned, there are substantial differences in the course and prognosis of different bipolar subtypes. An independent evaluation of the pharmacologic effect of The differences between the different subtypes of euthymics in each subtype is necessary. On the other hand, bipolar disorders are substantial and go beyond the evaluations of therapeutic pharmacologic effect in bipolar symptomatology and severity of the affective episodes. patients in special situations, such as comorbidity, gender, For example, the study of the National Institute of Mental RC, mixed episodes or high rates of suicide are usually scant Health Collaborative Depression of the United States and the available evidence often cannot be extrapolated. A showed that the percentage of weeks in which subjects still greater problem is suggested by a sub-analysis of data with BD I and II experienced depression was 31% and from an international multicenter study of patients with BD 52%, respectively, in a 15-year follow-up. In contrast, the I.15 The authors found that demographic and cultural weeks of hypomanic, manic or mixed episodes reported diversity can contribute to variations in the study results. was 10% and 1.6%, respectively.5, 6 In comparison with The dosage, disease severity and response to placebo vary pure manic episodes, mixed manic episodes occurred substantially among countries like India, Russia and the more often in female patients, had a greater frequency of U.S.A. Other authors conclude that international multicenter episodes in the previous 12 months, more suicide attempts, studies are usually accompanied by factors that complicate a greater rapid cycling rate (RC), less social activities and the interpretation of the data related to differences in the more occupational impairment. During 24 months of nature and severity of BD, cultural conceptions of BD, follow-up, the group with mixed episodes had a diagnostic criteria, the measurement of severity and adverse significantly lower recovery rate than patients with pure manic episodes (36% versus 46%, p = 0.006).7 Although only 10% to 15% of patients present four or more episodes a year, patients who develop an RC pattern THERAPY OF BIPOLAR DISORDERS
present a very high risk of suicide attempts and attain only partial remissions or exhibit a marked tendency to The treatment of BDs can reduce the associated change polarity.8 In addition, women seem to have a morbidity and mortality, diminish the frequency, severity greater risk of RC.9, 10 Finally, patients with a predominantly and psychosocial consequences of the affective episodes, depressive polarity tend to present an onset of disease in and improve psychosocial functioning in periods of euthymia the depressive phase, an earlier age of onset, longer (normal mood). Nevertheless, it is calculated that only one disease duration, more suicide attempts and more delayed third of the persons with BD receive treatment. Management BD diagnosis than patients with predominantly manic includes pharmacologic intervention (for the control of the acute episode and the maintenance phase), the development of daily activity patterns and individual and group With respect to comorbidity, 65% of patients with BDs psychotherapy.17, 18 The objectives of intervention vary with exhibit one or more Axis I comorbidity diagnoses in the the disease phase and prevailing mood. In the acute phase, course of life, whereas more than 40% of patients have 2 or treatment is designed to stabilize the mood of the present more diagnoses and 25% have 3 or more.12 Among the most episode in order to achieve remission (defined as a complete common Axis I comorbidities in patients with BD are return to the basic level of functioning and the virtual substance abuse/dependence disorders (40-60%) and anxiety absence of symptoms), guarantee the safety of the patient disorders (50%). The international mental health study and those around them, prevent cycling from one episode to showed that up to three fourths of patients with BD exhibit another and prevent suicidal behavior. In the maintenance at least one other psychiatric condition in comorbid form, phase, the aim of treatment is to optimize protection against panic attacks being the most frequent comorbidity (present recurrence and reduce the frequency of depressive, mixed, in almost 50% of patients), followed by alcohol abuse manic or hypomanic episodes. At the same time, attention Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update must be given to improving the patient’s functioning and episodes when used in monotherapy, but lack double- reducing subsyndromic symptoms and the adverse effects of blind, randomized, placebo-controlled studies that treatment, to treating comorbidities and cognitive problems, demonstrate their effectiveness in the control of increasing knowledge of the patient and family members depressive symptoms or BD prophylaxis.
about the disease and improving compliance with 2. Partial mood stabilizers: mood stabilizing agents with demonstrated effectiveness in the control of manic episodes and/or the prevention of manic recurrences, At present it is thought that most first-line treatments but not in the control of the depressive episodes or the for the acute manic episode produce an appreciable clinical prevention of recurrences. Or those that, in inverse effect within no more than 10 to 14 days. When selecting form, are effective in the control of depressive episodes the primary treatment, the general rule is to use what was and/or in the prevention of depressive recurrences, but successful in the treatment of the index episode. Although not in the control of manic episodes or in the prevention treatment guides recommend monotherapy as a first-line strategy,19 multiple drug treatments are often used without 3. Euthymics: agents used as monotherapy that in double- the support of evidence or, sometimes, without clear or blind, randomized, placebo-controlled studies have adequate optimization of the monotherapy.20-22 For example, been demonstrated to be effective in the control of Perlis et al.23 mention that it is likely that differences in the mixed and depressive manic episodes; and that have effectiveness of the acute treatment of mania between also been demonstrated to be effective in the monotherapy with second-generation antipsychotics (SGAs) prophylactic management of patients with BD for both and the addition of another medication are small, if any can the prevention of both manic and depressive episodes.
be found. A recent meta-analysis reports that more than 50% of patients with a manic episode respond properly to This classification, like others, does not include concepts monotherapy with lithium, anticonvulsants or SGAs.24 like ‘bipolar antidepressants,’ medications that would only be effective in the bipolar acute depressive phase. The use of However, the literature suggests that some patients do monotherapy with antidepressants in bipolar patients in the not respond to acute treatment with monotherapy, especially depressive phase is not justified but contraindicated in if they have a bipolar depressive episode.22, 24 These patients usually need combination therapy and the best strategy is to begin with the better studied medications and then to try Finally, it should be highlighted that effectiveness in less tested agents if these drugs are ineffective or not double-blind, randomized studies is usually measured on the tolerated. If the symptoms cannot be controlled within the basis of the change in the total score of different scales recommended time for observing an appreciable clinical validated for this purpose. However, other aspects that go effect, the first step must be to optimize the dose of the beyond the changes in mood states that are also part of the current medication to ensure that the blood levels are within syndromic picture of bipolar patients, such as cognitive therapeutic range. It is also important to identify problems alterations or compromised functionality, are rarely of noncompliance with the medication, a frequent cause of considered as measures of primary effectiveness and, relapses. If the symptoms continue, other options include therefore, information on the impact of pharmacologic adding or switching to another medication, again treatments on those points is usually scarce.
emphasizing the optimal dose and compliance with the therapeutic regimen. It is recommended that each pharmacotherapeutic regimen be evaluated for at least 2 DRUG THERAPY OF THE MANIC EPISODES
weeks before concluding that the patient is unlikely to respond (generally defined as a reduction in the symptoms Patients with BDI who present acute manic or mixed targeted by therapy of less than 30%). In patients with episodes usually require a rapid and aggressive intervention severe or treatment-refractory disease, electroconvulsive for the control of agitation, affective symptoms and, in some therapy (ECT) and experimental or novel treatments can be cases, psychotic symptoms. Different studies have considered. In addition, there is some evidence, as yet limited, demonstrated that antipsychotics usually act more rapidly in that coadjuvant psychosocial interventions can help to the control of agitation, excitation, grandiosity, hostility and increase the response to pharmacologic treatment.25 psychotic disorganization than lithium or anticonvulsants.27, 28 Despite this, the use of conventional antipsychotics as Seven years ago an evidence-based definition was antimanics must be evaluated in relation to the risk of adverse proposed that allowed the classification of these medications effects. Patients with bipolar disorder have higher rates of according to their effectiveness in different phases of BD26: incidence of extrapyramidal symptoms (EPS) than observed in patients with schizophrenia,29, 30 they have high rates of 1. Antimanic agents: The antimanic agents that have been tardive dyskinesia31 and they have been associated to a demonstrated to be effective in the control of manic greater risk of depressive episodes and rapid cycling.32, 33 Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update MDR
Risk Ratio
Risk Ratio
Study or Subroup
Events Total Events Total Weight M-H, Random, 95% CI
M-H, Random, 95% CI
Bowden, 1994
Total (95%CI) I2 = 40%
336 100.0%
1.62 [1.23, 2.13]
Bowden, 1994
Total (95%CI) I2 = 0%
438 100.0%
1.39 [1.16, 1.65]
Wagner, 2006
Total (95%CI) I2 = 0%
218 100.0%
2.02 [1.56, 2.62]
McIntyre, 2005
Total (95%CI) I2 = 64%
481 100.0%
1.63 [1.25, 2.12]
Keck, 2003a
Total (95%CI) I2 = 44%
573 100.0%
1.49 [1.22, 1.83]
Tohen, 1999
Total (95%CI) I2 = 27%
284 100.0%
1.63 [1.28, 2.08]
Bowden, 2005
Total (95%CI) I2 = 68%
197 100.0%
1.52 [0.97, 2.37]
Hirschfeld, 2004
Total (95%CI) I2 = 33%
418 100.0%
1.77 [1.44, 2.17]
Keck, 2003b
Total (95%CI) I2 = 0%
219 100.0%
1.58 [1.25, 2.00]
Total (95%CI)
1824 3798
697 2299 100.0%
1.61 [1.49, 1.75]
Heterogeneity: Tau2 = 0.01; Chi2 = 28.23, df = 21 (P = 0.013); I2 = 26%; Test for overall effect: Z = 11.29 ( P < 0.00001)Response is defined as a reduction of ≥50% with respect to baseline points in the measure of primary efficacy after 7 to 10 weeks of treatment. M-H, Mantel–Haenszel (ref. 24) Favours placebo Favours MDR
Figure 1 Random relative risk (RR) and 95% confidence intervals (CI) for response rates in monotherapy (MDR) vs. placebo in the treatment of acute mania episodes.
Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update Recent studies suggest that the use of injectable SGAs in Despite the available evidence, combined therapy monotherapy form permit the control of acute manic continues to be the universally accepted method of episodes that is at least similar to that observed with treatment for manic patients not refractory to monotherapy, conventional antipsychotics but with a lower incidence of the same as 7 years ago.20, 22 In patients who do not respond to monotherapy, a meta-analysis suggests that combined therapy (a SGA plus lithium or an anticonvulsant) can offer With respect to the management of the manic/acute a slightly higher response rate, although with diminished mixed episode in the patient who does not require parenteral tolerability.53 However, Cipriani et al.54 have questioned the management, some expert consensus recommendations and utility of this meta-analysis because the sample sizes and treatment guides suggest that the treatment of choice is heterogeneity of the studies lead to a biased result that monotherapy with a mood stabilizing agent like lithium, favors combined therapy. In addition, in all the studies on carbamazepine or valproic acid, followed by combined which this meta-analysis is based, the monotherapy that therapy with a mood stabilizer plus a SGA.19, 38, 39 However, was ineffective for the control of the manic episode is used two recent meta-analyses show that SGA monotherapy is as the comparator of the combined therapy. On the other equally effective in the treatment of acute episodes of hand, it should be taken into account that drug interactions, mania.24, 40 One of these meta-analyses24 included data from lower tolerability, decreased compliance and greater costs 31 randomized controlled studies and found that can jeopardize the hypothetical benefits of combined monotherapy with lithium, valproic acid or SGA (n = 3798) is associated to a greater probability of response (defined as a reduction of at least 50% on the scale of primary effectiveness, usually the Young Mania Rating Scale, or DRUG THERAPY OF THE MIXED EPISODES
YMRS) [RR = 161 (95% CI, 1.49-1.75)], although with a greater risk of interruption due to AEs [1.57 (95% CI, 1.22- The same as 7 years ago, few studies have evaluated the 2.03)] than patients treated with placebo (n = 2299). impact of pharmacologic treatments or electro-convulsive Additional comparisons demonstrated that the patients therapy (ECT) in the acute phase and maintenance of patients treated with mood stabilizers (lithium, oxcarbazepine or with mixed episodes. Most of these publications are post hoc valproate; n = 1112) had a greater probability of response analysis of double-blind studies or open-label studies. [1.57 (95% CI, 1.36-1.81)] with a greater risk of interruption Considering these limitations, it could be said that the due to AEs [2.07 (95% CI, 1.46-2.93)] than patients treated presence of mixed affective episodes or a pattern of rapid with placebo (n = 975). Likewise, patients treated with SGA cycling continues to be a risk factor for poor response to (n = 2107) had a greater probability of response [1.59 lithium. Valproate in patients with mixed manic episodes, (95% CI, 1.44-1.75)] with a greater risk of interruption due administered as monotherapy or associated to other to AEs [1.36 (IC 95%, 1.03-1.79)] than patients treated with antimanics, has been shown to have a broader spectrum of effectiveness than carbamazepine or lithium. Recent studies suggest that the SGAs (especially olanzapine and aripiprazole) Other later meta-analyses and double-blind studies can be as effective as valproate in this type of patients.55, 56 have also confirmed the effectiveness of lithium,40 In some cases, ECT is necessary for the control of this type of anticonvulsants40, 41 and SGA40, 42-46 in the control of manic episodes. One of them reported negative results for valproate versus placebo (n = 225).41 DRUG THERAPY OF THE DEPRESSIVE EPISODES
With respect to the treatment of children and adolescents with bipolar disorder, lithium was until a few Neither evidence-based guides17, 19 nor a recently years ago the only treatment approved by the FDA for the published meta-analysis58 recommend antidepressant treatment of children over 12 years. However, the level of monotherapy for the management of bipolar depressive evidence on the management of acute manic episodes with episodes, but approximately 50% of patients are treated this drug and anticonvulsants in adolescents is based on few initially with an antidepressant, more than twice as many randomized studies and47 several randomized, double-blind, as those who receive anticonvulsants as the first option.59 placebo-controlled studies have suggested recently the The guides also suggest that clinicians interrupt effectiveness of several SGAs in acute manic episodes in antidepressant treatment during the manic episodes and children and adolescents: aripiprazole,48, 49 olanzapine50 and recommend considering the use of other medications that risperidone.51 A recent comparative analysis based on 9 have been demonstrated to be effective in patients with double-blind studies concluded that SGAs exhibit more bipolar depression. Despite these recommendations, more effectiveness than lithium and anticonvulsants in the than 15% of patients continue to receive antidepressant treatment of manic episodes, although with greater rate of treatment during manic episodes.60 The possibility that adverse events like weight gain and drowsiness.52 antidepressants might cause a change of polarity in the Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update MDR
Risk Ratio
Risk Ratio
Study or Subroup
Events Total Events Total Weight M-H, Random, 95% CI
M-H, Random, 95% CI
lamotrigine 200
Total (95%CI) I2 = 0%
317 100.0%
1.17 [0.97, 1.41]
Total (95%CI) I2 = 0%
376 100.0%
1.05 [0.89, 1.24]
Total (95%CI) I2 = 51%
299 100.0%
1.34 [1.02, 1.76]
quetiapine 300/600
Total (95%CI) I2 = 74%
222 100.0%
1.58 [1.10, 2.26]
Total (95%CI)
709 1419
469 1214 100.0%
1.26 [1.10, 1.44]
Heterogeneity: Tau2 = 0.02; Chi2 = 17.32; df = 8 (P = 0.03); I2 = 54 %; Test for overall effect: Z = 3.37 (P = 0.0008) Response is defined as a reduction of ≥50% with respect to baseline points in the measure of primary efficacy after 3 to 6 weeks of treatment. ER-CBZ, extended release carbamazepine; M-H, Mantel–Haenszel (ref. 24) Favours placebo Favours MDR
Figure 2 Random relative risk (RR) and 95% confidence intervals (CI) for response rates in monotherapy (MDR) vs. placebo in the treatment of bipolar depression episodes.
manic episodes is a common concern.17 Nonetheless, most RC. As in the case of research on the change of mood studies do not suggest an increased risk of change of polarity, the body of proof in relation to RC is small. Even polarity with antidepressants (3.8% vs. 4.7% for placebo), so, shortening of the cycle duration has been served with although the rate of change of polarity with tricyclic TCAs66 but not with SSRIs67. Finally, a recent publication of antidepressants (TCAs) seems to be greater than with a study of 144 patients with BD I with 9.5 years of follow- selective serotonin reuptake inhibitors (SSRIs) or up concluded that almost 40% of the patients treated with monoamine oxidase inhibitors (MAOIs).61 Venlafaxine can antidepressants presented at least one mixed manic episode also lead to a greater rate of change to mania or hypomania and that the appearance of this type of episodes was than other antidepressants like the SSRIs and bupropion.62 associated to a larger number of suicide attempts A meta-analysis has confirmed that the conversion to (p < 0.001), a greater rate of treatment-induced emergent manic episodes was observed exclusively with TCAs manias (p = 0.010) and more time with the disease [RR = 1.93 (95% CI, 1.13-3.30)],63 whereas another meta- (p = 0.022). The authors found that the presence of mixed analysis has confirmed that the concomitant use of mania was associated significantly with the use of dual euthymics reduces the risk of conversion to mania compared antidepressants (p = 0.041) but not with TCAs or SSRIs.68 A to the use of antidepressants in monotherapy.64 Moreover, previous post hoc analysis based on a double-blind study for Licht et al.,65 using the criteria of Bradford-Hill, the controlled with the combination of fluoxetine and conversion rates seen with antidepressants in association olanzapine in patients with bipolar depression showed that with euthymics in patients with BD must be attributed to the frequency of mixed depression in the 8 weeks of the natural history of the disease and not to the use of treatment was comparable to the frequency observed in those medications. For these authors, many states of patients treated with olanzapine monotherapy or placebo, treatment-induced emergent mania (TEM) attributed to and that the response rates with olanzapine + fluoxetine in antidepressants may be due to a shortening of the such patients were comparable to those of patients without depressive episode without a direct effect of the concomitant manic symptoms and higher than those of antidepressant on the conversion. They conclude: patients with mixed depression treated with placebo.69“antidepressants do not prevent mania.” Another serious problem reported in the literature is that antidepressants Cruz and Vieta70 claim that the effectiveness and safety could reduce the duration of the bipolar cycle and induce of antidepressants in bipolar depression are still a matter of Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update debate and that meta-analyses of the topic58, 61 include data of three randomized controlled studies concludes that studies of poor quality and varied effect sizes that can patients with BD I treated with lamotrigine (≥ 200 mg/day) (n = 327) have a similar opportunity for response and remission as patients treated with placebo (n = 317). Some studies even suggest that selective serotonin Similar results were observed when patients with BD I and reuptake inhibitors (SSRI) or dual serotonin and noradrenalin patients with BD II were taken into account and when all reuptake inhibitors (SNRI) are effective as monotherapy in the the doses of lamotrigine studied were considered.24 Another control of acute depressive phases in patients with BD II.71-73 meta-analysis of 5 studies with lamotrigine, all of them With regard to BDI, two studies have demonstrated that the negative, confirms that the effectiveness of lamotrigine is combination of fluoxetine with olanzapine is more effective marginal with respect to placebo [RR = 1.14 (95% CI, 1.00- than olanzapine alone in the treatment of patients with type 1.30)].84 A third meta-analysis shows that only in patients I bipolar depression, but the effect of monotherapy with with marked severity (score of more than 24 on the fluoxetine was not evaluated.74, 75 In combination with other Hamilton depression scale) is a significant difference euthymics, the available evidence does not seem to support appreciated versus placebo in favor of lamotrigine the use of antidepressants in type I bipolar depression.76 [RR = 1.21 (95% CI, 1.06-1.41)].85 With respect to SGAs, Even McElroy et al.77 found that quetiapine, unlike paroxetine, patients treated with aripiprazole (n = 373) had a similar is significantly more effective than placebo in patients with opportunity for response and remission as the patients bipolar depression I or II. In general, the risk of a change of treated with placebo (n = 376) in two controlled double- polarity, RC or tachyphylaxis in bipolar patients treated with blind studies.86 The only two monotherapies that have antidepressant monotherapy form would seem to exhibited statistically significant response rates compared contraindicate its use.10, 78, 79 It should be noted, however, that to placebo in two meta-analyses were olanzapine [RR = 1.34 a recent meta-analysis failed to observe differences between (95% CI, 1.02-1.76) and 1.28 (95%CI, 1.05-1.57)] and the use of antidepressants in monotherapy or associated to quetiapine [RR = 1.58 (95% CI, 1.10-2.26) and 1.37 (95% CI, euthymics and a hypothetical increase in the risk of long-term recurrences (10 years).64 Another review also could not confirm a greater risk of RC or suicide with the use of antidepressants In the case of refractoriness there is little evidence of in BD and the author concludes that most of the evidence has differences in the magnitude and rate of response with been obtained from small studies with several methodological electroconvulsive therapy (ECT) in patients with bipolar biases, leading to an over-interpretation of the risks of using depression are compared to patients with unipolar depressive disorder. Some small studies, however, show that patients with bipolar depression seemed to have On the other hand, in depressive episodes it is essential more rapid clinical improvement, requiring fewer to reduce or discontinue conventional antipsychotics if they treatments then unipolar patients.88-90 With respect to RC, are administered concomitantly with other euthymics, these patients exhibit clearly lower response rates to because this single measure can lead to diminished depressive lithium, anticonvulsants or antipsychotics and may require combinations of two or three medications.91 As mentioned previously, although it is debated whether As far as the use of monotherapies in patients with antidepressant use in patients with BDs is useful, the first bipolar depression, a meta-analysis included 9 randomized, reports refer mainly to TCAs, which have been associated controlled studies. The general relative risk (RR) with regard with a high risk of RC. Nevertheless, more recent and to response in patients with bipolar depression treated substantive evidence indicates that, in the worst of cases, with monotherapy (n = 1419) was 1.26 (95% CI, 1.11-1.44), the risk of changing polarity and perhaps also of RC and but with a risk 1.77 (95% CI, 1.38-2.26) times greater of the appearance of suicidal tendencies has been interruption of the therapy as a result of AEs compared to overestimated and is applicable to new antidepressants.80 patients treated with placebo (n = 1214).24 As for With regard to lamotrigine, a double-blind, placebo- anticonvulsants, two meta-analyses that included 4 controlled study that showed that lamotrigine was double-blind studies with small sample sizes suggest superior to placebo in patients with BD I and RC after 26 greater antidepressant response rates for patients treated weeks of treatment (p = 0.037) did not demonstrate a with valproate versus placebo [RR = 2.00 (95% CI, 1.13- significant difference (p = 0.427) when these patients 3.53) and RR = 2.10 (95% CI, 1.10-4.03)].82, 83 A small study were analyzed independently.92 In patients with impaired in ambulatory patients with bipolar depression (67% with thyroid function, L-thyroxine (0.025-0.5 mg/day) or RC) showed that 38.5% of patients with BD I showed a liothyronine has been demonstrated to be effective in response in comparison with 10.7% of the placebo group association with anticonvulsants or lithium.93, 94 ECT, (p = 0.017).41 On the other hand, in contrast with general together with certain psychopharmaceuticals, can also be perception and the recommendations of some guides considered a valid option for the treatment of RC patients supported by experts,39 a meta-analysis that includes the Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update PROPHYLACTIC PHARMACOTHERAPY OF BIPOLAR
natural history study in the United States (NIMH Depression DISORDERS
Collaborative Study) show that patients diagnosed of BD II and patients diagnosed of BD I invest a considerable part of The primary goal of maintenance treatment of BDs is to their days experiencing depressive or hypomanic prevent recurrences. The long-term treatment must be subsyndromic affective symptoms (16.2% and 14.1%, considered seriously after the stabilization of the first respectively), or symptoms consistent with minor depression, episode because the prevention of recurrence in the first dysthymia or hypomania (27% and 20.1%, respectively).101 stages of disease can lead to a more benign general course. Consequently, patients with BD II have a somewhat smaller Several studies have found that discontinuing maintenance percentage of asymptomatic days than patients with BD I treatment with lithium or other medications produces high (44.2% vs. 53.4%).5, 6 The recent results of the STEP-BD study recurrence rates compared to continuing treatment, the risk identify residual manic symptoms as significant predictors of recurrence being especially high in the first year after of the time to manic or depressive recurrence. The presence interruption.96 The Systematic Treatment Enhancement of residual manic symptoms in the phase of recovery and the Program for Bipolar Disorder (STEP-BD) study found that proportion of elevated mood days in the previous year is patients with problems of substance abuse have an increased associated significantly with a shorter time to the recurrence risk of recurrence of the manic symptoms, whereas patients of the manic, hypomanic or mixed episode. With each with an existing anxiety disorder or eating disorder in the additional hypomanic or manic symptom, the risk of course of life have a greater risk of recurrence of depressive symptoms.97 Another natural history study of 154 patients with BDs, with an 18-month follow-up, shows that proper If the patient responds to acute treatment with and uninterrupted maintenance was greater in patients who monotherapy, that medication generally must be continued did not present a new affective episode, did not require in the maintenance phase as monotherapy. In the case of hospital management, did not have a pattern of RC or did persistence or reappearance of affective symptoms, the not have some concomitant personality disorder.98 present standard of practice is to continue treatment with the index medication and add a second medication to try to There is considerable debate about the optimal duration achieve the desired response. If the second medication is not of maintenance treatment, especially after a depressive effective, a third medication can be added or used to replace episode. As BD is currently recognized as a chronic, recurrent one of the two prior medications, and this process is repeated and disabling disease, several authors recommend long-term until remission or at least an acceptable response is achieved. maintenance, including after the first episode.99 No consensus opinion exists about how long the patient should continue with these complex regimens and, for that The lack of compliance with prescribed treatment is a reason, it is not surprising that an increasing number of serious obstacle for the effective prevention of recurrence. A persons with BDs are being treated with up to 3, 4 and 5 study in patients who received long-term treatment with medications approved for the condition.101-104 Effective lithium or anticonvulsants found that almost 50% of the maintenance therapy is especially crucial for the prevention participants (n = 98) were considered noncompliant with of depressive episodes, due to the risk of suicide. Although it the drug regimen at some time during the 2 previous years, is likely that all the effective maintenance therapies reduce and that almost one third of patients missed 30% or more of the risk of suicide by diminishing the probability of their medications in the previous month.100 The lack of recurrences, only lithium is backed by empirical evidence compliance may be due to multiple factors, including age showing that it can reduce the risk of suicidal behavior and (more frequent in young people), substance abuse, the side effects of medications, unwillingness to forego the good moods, and generally negative feelings about taking the Some evidence-based guides, such as those of the medication and having a chronic mental disease.21 In an Canadian Network for Mood and Anxiety Treatments effort to increase compliance with treatment, clinicians (CANMAT) and the International Society for Bipolar must maintain a supportive relation with patients and ask Disorders (ISBD), suggest that lithium, divalproate, about patients’ compliance with and expectations of olanzapine, quetiapine and depot risperidone can be treatment. Patients and their families must be encouraged effective in the prevention of manic or depressive episodes to consult the doctor if drug-related problems occur.100 in bipolar patients. Lamotrigine in the prevention of depressive episodes and aripiprazole in the prevention of Despite the use of evidence-based pharmacologic manic episodes are also considered as first-line treatments.39 treatments, affective recurrence is observed in at least half of A recent review of 15 studies designed to evaluate the the persons who have BDs with intervals of up to 2 years.100 In prophylactic effect of euthymics in patients with BD addition to complete syndromic recurrence, patients concluded that aripiprazole, olanzapine, quetiapine, depot diagnosed with BDs often experience subsyndromic levels of risperidone and lithium are effective in the prevention of affective symptoms. For example, the data of a long-term manic recurrences as they present the necessary number to Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update Table 1 Adverse events most commonly observed with medications used in the treatment of BDs
Adverse event
Therapeutic options
fl uid retention, increased diet and exercise, non- appetite, hypothyroidism thiazide diuretics neural tube defects, folic prevent administration dose reduction (titration) quetiapine (?), olanzapine (?) topiramate as second option, aripiprazole necrosis and idiosyncratic suspend immediately Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update Table 1 Continuation
Adverse event
Therapeutic options
spontaneous normalization lithium in the case of increased appetite (various diet, exercise, metformin, galactorrhea, gynecomas-tia, osteoporosis (rispe- PL = plasma levels; AP = antipsychotics; CBZ = carbamazepine; BZD = benzodiazepine* versus 2% to 4% in controls; ** versus 0.2/100ml in controls. (adapted from ref. 26) treat (NNT) to observe benefits with respect to placebo, placebo for a period of 12 to 24 months indicated that less than 10. Similarly, lamotrigine, quetiapine and lithium lithium reduces the risk of recurrences in only 42% (95% CI, presented significant NNTs in the prevention of depressive 30% - 52%).110 Poor prophylactic response to lithium is particularly common in patients with mixed affective episodes, rapid cycling, patients with continuous transition As for the general prophylactic value (prevention of from depressive to manic episodes without an intermediate both manic and depressive episodes) of the euthymics, as of period of euthymia (normal mood), negative familial history 1990 twelve placebo-controlled studies that evaluated the of BD, more than 3 affective episodes, concomitant use of prophylactic value of lithium had been published. When the substances of abuse, BD secondary to general medical combined rate of recurrences of these studies was estimated, conditions, or presentation or exacerbation of other it was found that recurrences were present in 80% of the pathologies like acne, psoriasis, cognitive dysfunction, renal patients who received placebo and in 35% of the patients or thyroid insufficiency.26, 109, 111 On the other hand, the risk who received lithium.107 Three meta-analyses confirm that of general recurrence (either manic or depressive) depends lithium is effective in the general prevention of affective significantly on how lithium is discontinued. A joint analysis recurrences in patients with BD I in comparison with placebo of the available studies indicates that, in comparison with [HR = 0.68 (95% CI, 0.53-0.86), RR = 0.65 (95% CI, 0.50- the gradual suspension of lithium, rapid cessation (i.e., in 0.84)]108, 109 and OR = 0.29 (95% CI, 0.09-0.93).108-110 fewer than 14 days) is associated with a significant reduction Nevertheless, one of these meta-analyses that included 9 in the time to recurrence of mania (5 times) or depression randomized studies (n = 825) that compared lithium to (2.8 times), as well as suicide attempts (2 times). In addition, Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update Table 2 Highest risk pharmacologic interactions observed with medications used in the treatment of BDs
Therapeutic options
metabolic induction of increase OxCBZ doseOxCBZ metabolic induction of increase dose of other medications metabolic induction or increase or reduce dose (avoid QTc inhibition metabolic inhibition or increase or reduce dose (avoid QTc (risperidone, paliperidone, aripiprazole) metabolic induction or increase dose, especially in female NSAIDs = nonsteroid anti-infl ammatory drugs; ACEIs = angiotensin-converting enzyme inhibitors; TCAs = Tricyclic antidepressants; OxCBZ = Oxcarbamaze-pine; CBZ = carbamazepine; LTG = lamotrigine (adapted from ref. 26) the risk of recurrence after a rapid interruption was greater patients per treatment arm demonstrated that lithium (0.4-1 in patients with BD II than in patients with BD I.112 mmol/L) is superior to valproate (750-1250 mg/day) in the prevention of recurrences, generally after 24 weeks of The possible reduction of the prophylactic effect with treatment [HR = 0.71 (95% CI, 0.51-1.00)],114 and the time to time (although different from placebo) is not only observed recurrence is significantly longer (14.7 months vs. 6.2 with lithium. Although several studies document the months, respectively).115 In any case, the low doses of effectiveness of divalproate in acute patients and in patients valproate and the accepted lower limit for lithium plasma with mixed mania or rapid cycling, more double-blind concentrations could have influenced the results. A sub- studies are required to evaluate their long-term effectiveness. analysis of a maintenance study suggests that concentrations A Cochrane review, not updated, found that the time to of at least 6 mmol/L are necessary in the case of lithium to occurrence of an affective episode does not differ between observe an adequate prophylactic effect with the cation.116 divalproate and lithium. No significant differences were observed in the number of patients who left the study due With regard to other euthymics, a meta-analysis also to recurrence.113 Nevertheless, a prospective, international, demonstrated effectiveness in the general prevention of multicenter, natural history study (BALANCE) with 110 affective recurrences in patients with BD I, compared to Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update placebo, for olanzapine [RR = 0.58 (95% CI, 0.49-0.69)], inferior to olanzapine.117 This was confirmed by another lamotrigine [RR = 0.84 (95% CI, 0.71-0.99)] and valproate meta-analysis in which olanzapine was superior to lithium [RR = 0.63 (95% CI, 0.44-0.90)].108 Another meta-analysis or valproate in the prevention of manic episodes [RR = 0.37 also demonstrated that the general prophylactic effect (95% CI, 0.24-0.57)].122 A double-blind, controlled study versus placebo is also superior for valproate, lamotrigine, does not show any differences in the prophylactic olanzapine and aripiprazole.117 Similarly, another meta- effectiveness of lamotrigine or lithium for manic episodes analysis demonstrated that olanzapine as monotherapy is superior to placebo in the prevention of recurrences of any type [RR = 0.58 (95% CI, 0.49-0.69).118 With respect to A double-blind, placebo-controlled study has aripiprazole, however, a recent systematic review to demonstrated that the use of sustained-release injectable identify placebo-controlled, double-blind studies of the risperidone is effective in the prevention of recurrences in prophylactic effect of this SGA in patients with BDs advises patients with an index episode of mania (p < .001).120 This of limitations in the interpretation of some studies. The has been confirmed in the natural history of the disorder in authors find that the duration of treatment and low rate Spain in an open-label study with 14 bipolar patients who of completers (2.1% of 567 patients at 72 weeks) of the exhibited multiple recurrences due to poor therapeutic only study found are insufficient to support the prophylactic compliance.124 Finally, a comparative study not controlled effectiveness of aripiprazole.119 Finally, a placebo- with placebo suggests that asenapine, in magnitude similar controlled, double-blind study demonstrated the general to olanzapine, could be effective in the prevention of prophylactic effectiveness of long-acting injectable affective recurrences in patients with an index episode of risperidone (p < 0.001).120 Other meta-analyses have compared several euthymics With respect to depressive recurrences, the duration of with each other in the general prophylaxis of BDs. One of antidepressant therapy after a bipolar depressive episode is them demonstrated that lithium is superior to still matter of debate, although nobody doubts the carbamazepine [OR = 0.48 (95% CI, 0.27-0.84)] and has a importance of maintaining long-term use of the euthymic prophylactic effect equivalent to lamotrigine, valproate or mood stabilizer. In the meta-analysis by Beynon et al.,117 and olanzapine (although lithium has a lower hospitalization the authors conclude that only valproate and imipramine rate than olanzapine [OR = 1.78 (95% CI, 1.08-2.93)]).117 are superior to placebo in the prevention of depressive Another study that compared carbamazepine and lithium recurrences in patients with BDs. Lamotrigine has been showed that both euthymics can be equally effective in the found to be superior to placebo in reducing additional prevention of recurrences in general in patients with BD.121 interventions to prevent depressive episodes. However, the Another meta-analysis concluded that olanzapine is as addition of imipramine to the prophylactic therapy with effective as lithium or valproate in the prevention of any lithium does not diminish the risk of future depressive affective episode.122 Finally, a double-blind controlled episodes and, as shown in a previous study,126 the risk of study demonstrated the general prophylactic effectiveness manic episodes may be duplicated. A meta-analysis of lamotrigine and lithium without any significant confirms that lithium does not exhibit significant differences between the two compounds [RR = 0.92 effectiveness in the prevention of depressive recurrences [RR = 0.84 (95% CI, 0.65-1.10)].108 With regard to other euthymics, the same meta-analysis only finds effectiveness With respect to the control of manic/mixed recurrences, in the prevention of depressive recurrences for valproate in a recent meta-analysis concludes that only olanzapine and comparison with placebo [RR = 0.40 (95% CI, 0.20-0.82)].108 aripiprazole are superior to placebo and that lithium is Meta-analysis with olanzapine in monotherapy also does superior to placebo in the prevention of re-hospitalization not demonstrate the superiority of this SGA over placebo for mania or additional interventions for the control of in the prevention of depressive recurrences [RR = 0.78 those episodes.117 Another meta-analysis, nevertheless, (95% CI, 0.58-1.04)].118 A double-blind, placebo-controlled found that lithium is more effective than placebo [RR = 0.63 study demonstrated that long-acting injectable risperidone (95% CI, 0.44-0.91)] and similar to olanzapine [RR = 0.37 is not superior to placebo in the prevention of depressive (95% CI, 0.24-0.57)] in the prevention of manic recurrences recurrences in patients with BD with an index episode of (108). An additional meta-analysis confirmed that olanzapine in monotherapy is superior to placebo in the prevention of manic recurrences.118 A placebo-controlled, double-blind With respect to meta-analyses that compare several study demonstrated the general prophylactic effectiveness euthymics, none of the studies has demonstrated the of long-acting injectable risperidone for manic episodes.120 superiority of any medication over the others in the prevention of depressive recurrences.117, 122 A double-blind With respect to meta-analyses that compare several controlled study also failed to demonstrate the prophylactic euthymics to each other, one of them found that lithium is effectiveness of lamotrigine with respect to lithium in Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update depression [RR = 0.69 (95% CI, 0.41-1.22)].123 Likewise, an as an antidepressant can be considered. Evidence from several yet unpublished maintenance study127 suggests that studies suggests that if the patient exhibited an adequate continued treatment with extended release (XR) quetiapine response during the acute depressive phase, combination in comparison with placebo and lithium increases the time treatment can continue with positive results and no to recurrence of any phase in patients with an episode index additional risks for patients. Several studies coincide in reporting that those patients who interrupted the antidepressant after achieving remission of a bipolar As has been mentioned, for patients who present a depressive episode presented a depressive recurrence within recurrence during their monotherapy treatment, combined a significantly shorter time than those that continued to therapy can offer a better alternative, but the larger take the antidepressant. In addition, these studies confirmed number of AEs demands that each treatment be that the use of antidepressants associated with euthymics individualized.128 Olanzapine plus lithium or valproate in was not accompanied by a greater risk of manic recurrences symptomatic remission,129 lamotrigine plus lithium,130 and in the long term.75, 136-139 However, more research is required quetiapine plus lithium or valproate131, 132 are backed by to establish a definitive conclusion.
some evidence supporting their use in the maintenance phase of patients with BD I with a previous manic episode. It must be considered, however, that in the case of COMMON ADVERSE EVENTS OF MEDICATIONS
associations with lithium or valproate in these studies USED IN THE TREATMENT OF BIPOLAR DISORDER
only patients who had a history of poor response to lithium or valproate in the mania phase were included, Due to the variety of effective therapeutic options which introduces a bias in the monotherapy comparator existing, clinicians can make a selection of medications on the group. Moreover, the BALANCE naturalistic study brings basis of their long-term tolerability and not only on the basis into question the effectiveness of combined therapy with of their effectiveness. The presence of adverse events (AE) is lithium in comparison with monotherapy with this cation one of the first reasons for discontinuing therapy and for poor in the prophylactic phase of treatment of BDs.114 In a treatment compliance in patients with BD.140 The rates of meta-analysis the authors conclude that despite the discontinuation for AEs are usually higher with active extended use of combined therapy in the maintenance medications like lithium, valproate and olanzapine than with phase of BDs, no adequate evidence exists to support this placebo according to a meta-analysis on the prophylactic practice as the front-line treatment.117 A European effect of euthymics. Lamotrigine had the same tolerability as naturalistic study with 1076 bipolar patients concluded placebo.108 In another meta-analysis comparing SGA with that patients treated with olanzapine monotherapy (29%) traditional mood stabilizers, weight gain was the only AE had fewer recurrences than patients in combined therapy more common with SGAs.52 A meta-analysis with olanzapine with olanzapine plus traditional mood stabilizers (71%) showed that the rate of withdrawals motivated by AEs with (p = 0.01). In addition, patients treated with combined this SGA is no greater than the rate observed with placebo in therapy had a greater risk of adverse events like tremor bipolar patients receiving long-term treatment [RR = 0.59 (OR 2.37, 95% CI 1.44–3.89) and polyuria (OR 3.08, 95% CI (95% CI, 0.21-1.67)].122 The generalized use of SGAs in patients 1.45–6.54), although there was more weight gain with with BD has motivated physicians to consider the risks that monotherapy.133 Another meta-analysis found that these medications represent. In a meta-analysis the risks of patients with BD treated with various SGAs experienced withdrawal for different AEs were compared in patients with more dry mouth (number needed to harm, or NNH = 4), bipolar disease versus patients with schizophrenia. In acute tremor (NNH = 6), sedation (NNH = 8), sexual dysfunction mania, no SGA was accompanied by more withdrawals due to (NNH = 8) and constipation (NNH = 11) than patients AEs than in schizophrenia, but in bipolar depression both olanzapine (NNH = 24) and quetiapine (NNH = 7) led to more withdrawals due to AEs than in schizophrenia.141 Table 1 offers Few studies have evaluated the preventive effect and an updated summary of the most common adverse events safety of long-term combined maintenance therapy with with medications for the control and prevention of BDs, while antidepressants. Antidepressants in monotherapy are not Table 2 presents the pharmacologic interactions with the recommended for the maintenance of patients with BDs highest risk (adapted from ref. 26).
who recovered from a depressive episode.135 Some authors maintain that when antidepressants are combined with lithium, anticonvulsants or SGAs, no additional benefit is CONCLUSIONS
evident in comparison with monotherapy.76 Nevertheless, in the case of a bipolar depressive episode that is considered Seven years ago, a review proposed a new definition of refractory to treatment with euthymic monotherapy, or in the medications used in the treatment of BDs based on the case of a depressive episode that occurs during randomized, placebo-controlled, double-blind studies.26 maintenance therapy in the form of relapse or recurrence, New studies published since then have confirmed the Therapeutic and Pharmacologic Differences between Medications Used in the Treatment of Bipolar Disorders: Seven-Year Update utility of that classification and show that antimanic into account the higher cost, diminished likelihood of agents (medications that have been demonstrated to be compliance and greater rates of AEs.
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