PCN Frontier Review
Guideline for treatment of bipolar disorder by the Japanese Society of Mood Disorders, 2012
- Details on the Committee for Treatment Guidelines of Mood Disorders are found at the end of the article, under Acknowledgments.
Correspondence: Shigenobu Kanba, MD, PhD, Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Email: firstname.lastname@example.org
The Japanese Society of Mood Disorders established a committee for treatment guidelines of mood disorders, which created the first edition of a treatment guideline for bipolar disorders on 10 March 2011. The committee has now created a second edition, which we report here. In creating this treatment guideline, the first step was to have several bipolar disorder specialists review well-conducted studies and meta-analyses. Based on this evidence, and with a consensus among the specialists, treatment procedures that were considered optimal were compiled and the strength of recommendation for each treatment method was determined. The first draft, prepared in this manner, was further revised through a process of critical investigation by all committee members to produce the final edition.
THE JAPANESE SOCIETY of Mood Disorders established a committee for treatment guidelines of mood disorders (Soichiro Nomura, chairman), which created the first edition of a treatment guideline for bipolar disorders on 10 March 2011. The committee has now created a second edition, which we report here.
Physicians who treat mood disorders should search guidelines, refer to information about new drugs and new clinical studies, and come to an understanding for the best treatment procedure for each case. However, it is anticipated that such efforts may be beyond the control of clinicians who are extremely busy. Therefore, the Japanese Society of Mood Disorders decided to create guidelines, hoping to help physicians who treat cases of mood disorder.
In creating this treatment guideline for bipolar disorders, the first step was to have several bipolar disorder specialists review well-conducted studies and meta-analyses. Based on this evidence, and with a consensus among the specialists, treatment procedures that were considered optimal were compiled and the strength of recommendation for each treatment method was determined. The first draft, prepared in this manner, was further revised through a process of critical investigation by all committee members to produce the final edition.
In making use of the guidelines, some precautions are necessary, as described below:
- This guideline for bipolar disorders assumes that those who consult it will be psychiatrists with clinical experience. The reasons are that bipolar disorders: (i) rapidly advance to more severe episodes; (ii) are resistant to antidepressants in the depressive episode; (iii) demonstrate a high suicide rate; (iv) cause severe disability; and (v) have a long disease duration. Thus, we recommend that specialists treat these disorders.
- There are various biases in the clinical studies and meta-analyses upon which these guidelines depend. For example, the patients who participate in studies do not always represent patients who visit clinicians. How the protocol is designed causes differences in the results of drug comparisons. Generally, many protocols and clinical studies investigate short-term effects or side-effects, whereas actual treatments may require longer periods. On the other hand, with meta-analyses, there may be publication bias and distorted results due to analyses that combine different qualities, subjects, and methods. Therefore, when referring to the guidelines, clinicians should be aware that the results of any clinical study have limitations.
- The guidelines should not restrict the physician's discretion for treatment. Patient symptoms vary individually, and the patient's personality and social environment before the disease differs. To determine the best treatment, the physician in charge must examine each patient carefully. The physician should then consider clinical information, including the guidelines and the patient's (and family's) desires, in a comprehensive manner before deciding on treatment.
- It is a misapprehension to consider only treatments according to the guidelines are sufficient. Mood disorders are not homogenous and simple and thus cannot be managed by perfunctory treatment. The disorders consist of biological, psychological and social factors. It is good clinical practice to consider how to intervene for each factor and to proceed while adding discreet correction to the evaluation and treatment. For example, whereas the master of a vessel checks a marine chart, the physician sees a guideline. Depending on the weather, the master must change the ship's course using discrimination at that moment, which can be accomplished first through careful observation and experience, and only secondarily by the evidence summarized on a chart.
- As described above, because a guideline can be prepared based only on evidence, descriptions of psychosocial therapies that are not easily used for comparative studies will naturally be a small part. However, this does not underestimate the importance of psychosocial treatment. If a patient is in anguish over psychological stress or maladaptation to an environmental circumstance, clinicians frequently observe that such situations lead to the onset or recurrence of bipolar disorders. In the other direction, having a bipolar disorder exacerbates psychosocial problems, which in turn worsen the symptoms, resulting in a vicious cycle. Although they may lack sufficient evidence of validity, it must be noted that psychosocial therapies are important treatments equivalent to drug therapies. Treatment bases include the establishment of collaborative relationships between patients and physicians, empathy for the anguish of patients and families as well as support for them, and recommendations for the patient's symptoms and problems at each encounter. This treatment guideline will be useful for physicians who treat their patients with such attitudes and perspectives.
A constant problem in creating a treatment guideline in Japan is the question of whether health insurance will cover certain drugs. In Japan, where clinical trials tend to be delayed, there may not have been clinical studies for the disorders that have been approved as indications for a specific drug in other countries. This guideline summarizes the latest and best treatment methods based on medical evidence, and is not restricted based on any limits on indications allowed by health insurance coverage; it also does not consider economic aspects. When use of a certain drug is not covered by health insurance, the case is described as off-label use.
Finally, the Japanese Society of Mood Disorders has posted this guideline on its home webpage. When it is determined that reconsideration of the guidelines is necessary due to newly reported important studies, it will be updated. Even so, given the rapid progress of medical science, it should be assumed that the guideline recommendations might not be current. Thus, the contents of the guideline that will be updated at different times cannot be guaranteed to be accurate and complete. Moreover, in using the recommended drugs, all indications, contraindications, usage/dose and side-effects must be reviewed and confirmed from the documents attached to these medical products. Caution must be always exercised regarding emergency safety information.
Home page of Japanese Society of Mood Disorders: http://www.secretariat.ne.jp/jsmd/
1. Manic Episode (Table 1)
Table 1. Treatment guidelines for manic episodes
|● Most recommended treatment|
|When the manic condition is intermediate or severe:|
|Lithium and atypical antipsychotic drugs (olanzapine, aripiprazole, quetiapine, risperidone) in combination |
|In mild manic conditions:|
|● Next recommended treatment|
|Atypical antipsychotic drugs (olanzapine, aripiprazole, quetiapine, risperidone)|
|Combination of valproic acid and atypical antipsychotic drug|
|● Other recommended treatment|
|Combination of two or more mood stabilizers|
|Mood stabilizers and typical antipsychotic drugs (chlorpromazine, sultopride, haloperidol, levomepromazine, timiperone, zotepine) in combination|
|● Treatments that are not recommended|
Manic episodes in bipolar disorders are often exacerbated so rapidly such that treatment cannot catch up with the condition. Moreover, a patient's actions during manic episodes may greatly affect the patient's social life and quality of life, so that urgent management may be needed. Accordingly, the patient often cannot be managed with outpatient treatment and hospitalization in the psychiatric ward is often required. Mood stabilizers, such as lithium, have been considered the first-line of treatment for manic episodes. However, these drugs do not provide an immediate effect and thus antipsychotic drugs with strong sedative effects are usually combined with mood stabilizers at the beginning. After 3–4 weeks of observation with combined therapies, at a time when the patient has become relatively stable, antipsychotic drugs can be reduced and/or stopped and subsequently mood stabilizers alone are administered to maintain the patient's condition.
Previously, when antipsychotic drugs were combined with mood stabilizers, antipsychotic drugs, such as haloperidol or levomepromazine, were used frequently and often caused problematic extrapyramidal symptoms and/or excessive sedation. In the last decade, atypical antipsychotic drugs, such as risperidone, olanzapine, aripiprazole, and quetiapine, have appeared and increasingly been combined with mood stabilizers in place of the typical antipsychotic drugs. Their use has reduced the problems of extrapyramidal symptoms and excessive sedation.
Another change is an expectation that atypical antipsychotic drugs themselves may have the effects similar to mood-stabilizers. Accordingly, the effects of atypical antipsychotic drugs alone on manic episodes have been increasingly reported. In various guidelines published around the world, the first-line treatment of manic episodes is single administration of atypical antipsychotic drugs as well as mood stabilizers.[1, 2] When 68 randomized, controlled, comparative trials (RCT) were meta-analyzed with indices of degree of improvement and dropout rate 3 weeks after initiation of the drug, it was reported that atypical antipsychotic drugs are more effective than mood stabilizers. Although the meta-analysis re-confirmed the immediate effectiveness of atypical antipsychotic drugs, courses longer than 3 weeks were not analyzed; therefore, the issue of whether the effects lead to mood stability was not clarified.
Taking into consideration that the final treatment objectives for bipolar disorders are long-term prevention of recurrence of the manic conditions as well as its remission, treatment drugs for manic episodes should be chosen after examining the risk and benefit of the drugs for recurrence prevention.
In this guideline, based on recent RCT and meta-analyses, drug therapies for manic episodes are investigated.
- There are various opinions about the definition of mood stabilizers and consistent agreement has not yet been achieved about the drugs to be included among mood stabilizers. In this guideline, following widespread custom, lithium, lamotrigine, valproic acid, and carbamazepine are included as mood stabilizers.
- Atypical antipsychotic drugs are also called second-generation antipsychotic drugs and cause extrapyramidal symptoms less frequently. Just as there are some first-generation antipsychotic drugs that cause fewer extrapyramidal symptoms, there are some second-generation antipsychotic drugs that can cause extrapyramidal symptoms. Thus, a clear boundary cannot be drawn between the groups. In this guideline, atypical antipsychotic drugs are not defined clearly; rather, we follow the idiomatic usages.
2. Evidence for each drug
I. Mood stabilizers
In 1949, Cade in Australia discovered the anti-manic action of lithium. Since then, lithium maintained its position as the first option for manic treatment for approximately 60 years. Many were suspicious of this claim for lithium for a period of time because there were methodological problems in initial studies. However, lithium has been used as an active control drug in investigation of the anti-manic effects of atypical antipsychotic drugs and these results have been integrated. Recent meta-analyses have reconfirmed that lithium has significantly greater anti-manic effects than placebo.[6, 7] As stated previously, however, lithium has no immediate effect and takes 10 days to exert its clinical effect, which is comparable to olanzapine. Thus, for manic patients presenting with severe excitability and an irascible condition, an atypical antipsychotic drug needs to be combined with lithium.
In addition, patients with manic psychosis who respond poorly to lithium are defined as follows: (i) the number of past recurrences exceeds 10; (ii) mixed state, or notable agitation and/or dysphoric mood; and (iii) mood-incongruent psychotic features. However, patients with mania who have favorable responses to lithium are the so-called typical manic patients, presenting with euphoria or elation.
Fine tremors of the hand and fingers (27%), excessive urination (30–35%), thyroid hypofunction (5–35%), memory disturbance (28%), weight gain (19%), sedation (12%), and digestive symptoms (10%) were the various side-effects. Bradycardia, sinus node dysfunction syndrome, or renal dysfunction are rare but may occur. Thus, caution must be exercised for these side-effects as well as for its teratogenic action. Among the teratogenic actions specific for lithium is Ebstein's anomaly. Administration to pregnant women is contraindicated.
Lithium's therapeutic concentrations and intoxicating concentrations are very close together. In the case of a manic episode, it is necessary to maintain a high concentration, approximately 1.0 mEq (mM)/L. Measurement of the blood concentration is more frequent at the beginning of administration or when the dose is increased, and should be conducted approximately once a week. The blood lithium concentration should be measured before taking the drug in the morning (at its lowest value or trough value). As a rule, non-steroidal anti-inflammatory drugs (NSAIDs) should not be combined with lithium, because lithium excretion from the kidneys is inhibited, increasing its concentration and the risk of lithium intoxication.
Valproic acid was originally administered as an antiepileptic drug. However, it was categorized as a mood stabilizer by P. A. Lambert. Meta-analyses have confirmed that valproic acid exerts significantly greater anti-manic effects than placebo.[6, 7] In contrast to lithium, valproic acid exerts anti-manic effects in manic patients with a higher number of the recurrences. It may be very effective for patients with strong frustration, mixed conditions, or rapid cycling.
Nausea (7–34%), excessive sedation (7–16%), thrombopenia (27%), leukopenia, and headache (10%) are the common side-effects reported. Other side-effects requiring caution include polycystic follicular syndrome, hyperammonemia, pancreatitis, and drug eruption. Teratogenic action is relatively high. Because valproic acid inhibits drug-metabolizing enzymes, the concentration of drugs combined with it may be increased.
Compared to lithium, the therapeutic and toxic concentrations of valproic acid are not as close. However, to avoid toxicity and reach the therapeutic concentration, it is desirable that the blood concentration of valproic acid is measured in the morning (at the lowest value or trough value). The therapeutic concentrations for manic episodes are reported to be 70 μg/mL or higher, which exerts greater anti-manic effects than lower doses or placebo. In certain cases, a concentration exceeding 100 μg/mL may be needed. Caution should be exercised, however, to avoid exceeding 120 μg/mL.
Although carbamazepine was developed as an antiepileptic drug, Hanaoka, Takezaki, and Okuma established its status as a mood stabilizer. Meta-analyses have confirmed that carbamazepine exerts significantly higher anti-manic effects than placebo.[6, 7]
The side-effects include dizziness (44%), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (5–40%), somnolence (32%), nausea (29%), vomiting (18%), and drug eruption (13%). Hepatic dysfunction, thrombopenia, and leukopenia may occur. Rarely, critical drug eruptions accompanied by systemic symptoms (Stevens–Johnson syndrome) may occur. Because carbamazepine induces drug metabolic enzymes, the concentrations of drugs combined with it may be decreased.
Compared to lithium, the effective and toxic concentrations are not as close. However, when necessary, the blood concentration in the morning (at the lowest value or trough value) is measured. Because the therapeutic blood concentration when used as an antiepileptic drug is 5–10 μg/mL, this concentration is adopted when carbamazepine is used as a mood stabilizer. The therapeutic blood concentration for use as a mood stabilizer has not been investigated in a precise way.
II. Atypical anti-psychotic drugs
Olanzapine has been confirmed to exert significantly greater anti-manic effects than placebo.[6, 7, 14] Because olanzapine causes increased appetite, increased bodyweight, lipid abnormalities, increased blood sugar level, and worsened diabetes, administration is contraindicated for patients with diabetes.
Aripiprazole has been confirmed to exert significantly greater anti-manic effects than placebo.[6, 7, 15] Aripiprazole is unlikely to cause extrapyramidal symptoms and hyperprolactinemia, but frequently causes akathisia.
Quetiapine (off-label use)
Quetiapine has been confirmed to exert significantly greater anti-manic effects than placebo.[6, 7] Quetiapine is unlikely to cause extrapyramidal symptoms and hyperprolactinemia. Because it increases appetite, bodyweight, lipid abnormalities, and blood sugar levels, as well as worsens diabetes, administration is contraindicated for diabetes patients.
Risperidone (off-label use)
Risperidone has been confirmed to exert significantly greater anti-manic effects than placebo.[6, 7] Risperidone causes extrapyramidal symptoms and hyperprolactinemia at a relatively high rate.
III. Typical anti-psychotic drugs
Chlorpromazine, sultopride, haloperidol, levomepromazine, timiperone (only the injection is covered by health insurance) and zotepine (off-label use) show anti-manic effects and have been used for a long time. However, because of risks of extrapyramidal symptoms, excessive sedation, and depression, these drugs should be selected carefully. (Although some specialists say that zotepine belongs with the atypical anti-psychotic drugs, in this paper it is classified as a typical anti-psychotic drug.)
IV. Combined use of mood stabilizers and anti-psychotic drugs
When an anti-psychotic drug, such as olanzapine, quetiapine, or risperidone, is combined with a mood stabilizer, such as lithium, valproic acid, or carbamazepine, meta-analyses results reveal that the combined use with anti-psychotic drugs exerted significantly greater anti-manic effects than the combined use with placebos.[17, 18]
V. Other drugs
Verapamil and topiramate, which gained attention temporarily for anti-manic effects (both are off-label use), as well as lamotrigine, which is on application for an expanded indication to include bipolar disorders, have not demonstrated greater anti-manic effects than placebo.
In addition, electroconvulsive therapy can be considered in drug-resistant cases as an alternative therapy.
To deepen consciousness of the disease and establish adherence to treatment, it is important to begin the psychosocial treatments referenced in the section on maintenance therapies when manic episodes are alleviated to some extent.
Although benzodiazepines may be used adjunctively and temporarily for manic excitation and agitation, the drug should be administered carefully because disinhibition may occur. Special caution is necessary for manic patients with increased impulsivity and aggressiveness and for those with comorbid alcohol dependency.
Regarding drug treatment for manic episodes, lithium has been used for the longest period and has been well studied for its therapeutic effects and side-effects. Because lithium has a risk for toxicity, and particularly because toxicity is likely to be induced by dehydration, the drug cannot be easily used for severe manic episodes. However, because a drug that prevents recurrence should be started during mania (and given that lithium is the least expensive among the effective drugs for mania), lithium should be considered the first-line treatment. In the case that lithium is ineffective, valproic acid should be considered next. However, when the reaction to each drug can be anticipated from characteristics of past clinical courses or clinical characteristics suggestive of drug response, this order needs to be optimized and the decision should be made on a case-by-case basis. Administration of a single atypical anti-psychotic drug (olanzapine, aripiprazole, quetiapine, risperidone) is also an option.
In cases where management by administration of a single mood stabilizer is possible, monotherapy is an option. However, when an urgent sedative effect is needed, combination with atypical anti-psychotic drugs becomes necessary. No clear indication regarding which atypical anti-psychotic drug should be selected is currently available and the selection should be made according to the profile of side-effects.
2. Major Depressive Episode (Table 2)
Table 2. Treatment guidelines for major depression episodes
|● Recommended treatment|
|● Other recommended treatment|
|Combination of lithium and lamotrigine |
|● Not recommended treatment|
|Use of tricyclic antidepressants|
|Single treatment with antidepressants|
Depressive episodes of bipolar disorders (bipolar depression) have the following problems: (i) the episodes are likely to be under-diagnosed; (ii) there are many refractory cases; (iii) the risk of suicide is high; and (iv) the risk of manic switch is present.
For the treatment of acute bipolar depression, reports with extensive data, such as RCT, had previously been insufficient. However, beginning in 2005, reports with improved data, including large RCT, have been presented continuously. As a result, the content of available treatment guidelines in Japan and other countries have become outdated. Therefore, we have developed a new guideline for the treatment of acute bipolar depression, based on the results from reports, such as RCT and meta-analyses.
The final objective of treatment for bipolar disorders is long-term prevention of recurrence as well as remission from the depressive state. Therefore, it is necessary to select medications for the depressive state with a view to long-term maintenance of the remission.
At present, bipolar disorders are classified into types I and II in the DSM-IV-TR. However, there were only a few clinical trials specialized for each of them. In creating this guideline, we did not classify the disorders into bipolar types I and II. Similarly, rapid cyclers were not distinguished.
2. Evidence for each drug
Evidence related to drugs that are available for the treatment of bipolar depression is introduced based mainly on the results of large placebo-controlled RCT and meta-analyses. In addition, the use of antidepressants is explained in the following paragraphs.
Quetiapine (off-label use)
Quetiapine at 300 mg/day or 600 mg/day was reported to be more effective as a treatment for acute bipolar depression than placebo. There are two reports of placebo-controlled RCT (n = 509, 542).[20, 21] According to these reports, the effects of 300 mg/day and 600 mg/day were not significantly different. According to a recent large placebo-controlled RCT, quetiapine at 300 mg/day or 600 mg/day was effective as a treatment for acute bipolar depression, compared to lithium at 600–1800 mg/day or placebo.
Lithium (off-label use)
In the 1970s, there were reports in nine RCT or crossover studies stating that lithium was effective as a treatment for acute bipolar depression compared to placebo, although the sample sizes were small (n = ∼40). Moreover, the effectiveness of lithium is reported in the meta-analyses. However, it may take 6–8 weeks before the efficacy of lithium appears. To exceed a level of 0.8 mEq/L of the plasma concentration 12 h after the previous administration, it may be required to increase the dose.
However, according to results of a recent large placebo-controlled RCT, 600–1800 mg/day of lithium was not significantly different from placebo in its effects for bipolar depression.
Olanzapine at 5–20 mg/day was effective as a treatment for acute bipolar depression compared to placebo (n = 833). Moreover, according to this report, the combination of olanzapine with fluoxetine, an antidepressant (termed OFC) and olanzapine monotherapy were both more effective than placebo, although the treatment with OFC was more effective. (Note: OFC has not been approved for use in Japan).
Lamotrigine (off-label use)
For lamotrigine at 200 mg/day, there is a report stating that lamotrigine was effective as a treatment for acute bipolar depression (n = 195). On the other hand, there is a report on treatment for acute bipolar depression stating that no significant difference from placebo was found in four of five placebo-controlled RCT (n = 195–259, 50–400 mg/day for 7–10 weeks). However, there is a post-hoc analysis from the same data showing that lamotrigine was effective for intermediate to severe bipolar depression cases scoring 25 or higher on the Hamilton Rating Scale for Depression (HRSD) compared with placebo, although no significant difference with placebo was found in mild to intermediate bipolar depression cases scoring 24 or less on HRSD before treatment. The results of a recent meta-analysis also suggest the efficacy of lamotrigine.
Lamotrigine may cause critical skin disorders, such as mucocutaneous ocular syndrome (Stevens–Johnson syndrome) or toxic epidermal necrolysis (Lyell syndrome); therefore, caution is required. These critical skin disorders were observed at a high rate in patients in whom the starting dose was higher than the recommended dose, the dose was increased rapidly, or valproic acid was given in combination. Thus, in using lamotrigine, it is recommended to start with a small dose and increase it gradually.
Carbamazepine (off-label use)
There is only one small RCT showing the efficacy of carbamazepine for bipolar depression.
Valproic acid (off-label use)
There are only small reports showing the efficacy of valproic acid for bipolar depression. According to the results of recent meta-analyses, valproic acid was reported ineffective for bipolar depression in one report and effective in another report.
Aripiprazole (off-label use)
As a treatment drug for bipolar depression, aripiprazole monotherapy is ineffective according to two placebo-controlled RCT (n = 374, 375). An 8-week treatment with aripiprazole at 5–30 mg/day did not demonstrate significantly higher efficacy than placebo.
Other drugs (off-label use)
There have been reports stating that ascorbic acid (vitamin C), ethylenediaminetetraacetic acid + ascorbic acid, pramipexole (RCT), and zonisamide (case series) are effective, and reports stating that the additional administration of modafinil, topiramate, pramipexole, N-acetylcysteine (RCT), gabapentin, bromocriptine, and levothyroxine (T4) (case series) are effective, although these are the results of small studies.
3. Controversy on the use of antidepressants
For evidence of the effects of antidepressants, there have been reports stating that fluoxetine, paroxetine, imipramine and tranylcypromine are more effective than placebo.
However, in using antidepressants as a treatment for acute bipolar depression, the risk of manic switch or rapid cycling must always be taken into consideration. The risk of manic switch is 2–3% for selective serotonin reuptake inhibitors (SSRI) in meta-analyses, and no significant difference was found compared with placebo. For tricyclic antidepressants, although the values are different among various reports, there is one report of an 11.2% manic switch rate, suggesting that the risk of manic switch is higher compared to SSRI. Although there are few data regarding serotonin noradrenaline reuptake inhibitors (SNRI) causing a manic switch, it is possible that the risk is higher than that for SSRI. Given the risk of manic switch, an antidepressant alone (in particular, tricyclic antidepressants) is not recommended for treating bipolar depression.
For bipolar II disorder, small studies have reported that fluoxetine and venlafaxine (not approved in Japan) are effective, with low risk of a switch into hypomania[32, 33] and thus may be effective. However, no similar report has been presented on other antidepressants. Therefore, when an antidepressant is considered an option for bipolar II depression, it should be done very carefully.
4. Combination therapy with mood stabilizers and antidepressants
In clinical circumstances, bipolar depression has been frequently treated with a combination of a mood stabilizer, such as lithium or valproic acid, and an antidepressant, such as an SSRI. However, for the efficacy of the combination therapy using mood stabilizers and antidepressants, there have been no reports with a high evidence level.
According to the results of a large RCT (the STEP-BD study), combination therapy with a mood stabilizer and an antidepressant (paroxetine or bupropion) was not superior to treatment with a mood stabilizer alone, although the risk of a manic switch requiring emergency treatment did not differ. According to the results of a recent meta-analysis, combination therapy with a mood stabilizer and an antidepressant was not significantly better than mood stabilizer monotherapy.
5. Combination therapy with two mood stabilizers
Clinically, bipolar depression has frequently been treated using a combination of two mood stabilizers. However, there are no reports with a high evidence level in support of the efficacy of combination therapy with mood stabilizers as treatment for acute bipolar depression, except for a report of a placebo-controlled RCT showing that lithium (0.6–1.2 mEq/L) and lamotrigine (200 mg/day) was more effective than lithium and placebo (n = 124).
6. Electroconvulsive therapy
There have been few RCT reporting the effects of electroconvulsive therapy for bipolar depression. According to a comparative study with unipolar depression (major depressive disorders), the antidepressant effects of electroconvulsive therapy were not significantly different between unipolar and bipolar depression and the onset of effects was significantly earlier in bipolar depression.
Based on the above evidence, the recommended medications for the treatment of bipolar depression have been selected, including quetiapine (300 mg/day), lithium (after reaching a level exceeding 0.8 mEq/L for at least 8 weeks), olanzapine (5–20 mg/day), and lamotrigine (200 mg/day, for cases scoring 25 or higher on HRSD). However, at present, drugs other than olanzapine are off-label use. For combination therapy with mood stabilizers, the combination of lithium and lamotrigine can be recommended. Electroconvulsive therapy is also recommended. Data on treatment with carbamazepine or valproic acid monotherapy are insufficient, so these are not recommended. The use of antidepressants (particularly tricyclic antidepressants) is controversial, but it is not currently recommended as a treatment option considering the current data.
In addition, psychoeducation for the patients, family-focused therapy, supportive psychotherapy, cognitive therapy, or interpersonal therapy are also important therapies and should not be disregarded, although evidence about their efficacy is insufficient.
3. Maintenance Therapy (Table 3)
Table 3. Treatment guidelines for Maintenance treatment
|A. Drug therapy|
|● Most recommended treatment|
|● Next recommended treatment|
|Combination of lithium or valproic acid and quetiapine|
|Combination of lithium and lamotrigine|
|Combination of lithium and aripiprazole|
|Combination of lithium and valproic acid|
|● Other recommended treatment|
|Risperidone depot injection (for patients with poor adherence even after sufficient psychoeducation)|
|Combination among mood stabilizers or combination of mood stabilizers and atypical anti-psychotic drugs |
|● Treatments that are not recommended|
|Use of antidepressants (in particular, tricyclic antidepressants)|
|Treatment with antidepressants alone|
|B. Psychosocial treatment (Combination with drug therapy in all cases)|
|● Recommended treatment|
|Interpersonal–social rhythm therapy|
|● Other recommended treatment|
|Cognitive behavioral therapy|
|● Treatments that are not recommended|
|Treatment with psychosocial treatment alone without drug therapy|
In bipolar disorders, although episodes of mania and depression may remit, recurrences cause subsequent psychosocial complications. Thus, maintenance therapy (recurrence prevention therapy) is important.
In a study of 4-year outcomes in 75 in-patients with manic psychosis, 72% of the patients had recurrences. Because recurrence occurred in 72% for this limited observation period, the lifetime non-recurrence rate is considered to be low for bipolar disorders.
Based on analyses of the recurrence risk and the burden of treatment risks, patients and physicians should decide on the timing of maintenance therapy. Although it is difficult to set a constant standard, the start of maintenance therapy should be considered in the following situations: (i) a severe episode of manic psychosis has occurred even once; (ii) manic episodes have occurred twice or more; (iii) severe depressive conditions have been repeated; and (iv) a family history is present.
Although one basis of maintenance therapy for bipolar disorders is drug therapy, psychoeducation is important for long-term maintenance of drug therapy as well.
Many clinical studies have been conducted for bipolar I disorder or bipolar disorders that partially include bipolar II disorder, and clear evidence for bipolar II disorder is often not present. Thus, evidence regarding bipolar disorders is explained first, followed by individual discussions of bipolar II disorder, rapid cyclers, and pregnancy/delivery issues.
In addition, many clinical studies on maintenance therapy are conducted for 1 or 2 years, using the outcome measure of ‘recurrence of either type of episode’ among others. Because long-term preventive therapy is usually provided for bipolar disorder, it is valuable to consider studies on mortality; for example, the total death rate (including suicide) in persons taking lithium is low.
2. Evidence for each drug
In large-scale clinical studies that have been conducted measuring recurrence of a mood episode in bipolar disorders, drugs that have demonstrated efficacy as single agents in maintenance therapy include lithium, lamotrigine, olanzapine, aripiprazole, and quetiapine.
Among these, lithium, lamotrigine, olanzapine, and quetiapine demonstrate preventive effects on both manic and depressive episodes. On the other hand, aripiprazole has shown preventive effects on the recurrence of manic episodes only.
In addition, where the dropout rate is an outcome measure, valproic acid and carbamazepine tended to be effective in small-scale clinical studies.
Lithium (off-label use)
The efficacy of lithium in maintenance therapy has been recognized in many clinical studies.[6, 43, 44] Because the number of cases and the quality of the studies are insufficient compared to more recent clinical studies, in meta-analyses where clinical studies are selected by quality, the efficacy of lithium is likely to be evaluated as low. However, the quality of clinical studies changes with the times, and it is necessary to take into consideration that clinical studies that re-confirm the efficacy of lithium are not being conducted.
Although many clinical studies have demonstrated the efficacy of lithium in maintenance therapy, the efficacy has decreased with time. In place of the research diagnostic criteria or Feighner criteria, employing DSM diagnostic standards have expanded the range of subjects for clinical studies, which may be related to reduced lithium effectiveness. Moreover, in recent clinical studies, patients who showed a positive response to a new drug in the acute episode are selected and then randomized to investigate the efficacy of maintenance therapy in many cases. Therefore, results need to be interpreted with caution because patients who are non-lithium responsive may be selected.
However, RCT that were optimized to demonstrate the effects of new drugs and used lithium as a control drug showed a significantly longer period until recurrence with lithium compared to placebo[39, 45, 46] and valproic acid.
In addition, independent of the preventive effects, lithium has suicide-preventive effects. Although lithium has a narrow safe range, such that toxicity is easily induced, lithium decreases death rates by all causes and even taking the risk of the toxicity of high-dose lithium into consideration, the appropriate use of lithium has a favorable influence on mortality.
In two studies of patients with bipolar I disorder where the preventive effects of lithium, lamotrigine, and placebo were compared, the period to recurrence was significantly longer with lamotrigine than with placebo.[45, 46] Although the recurrence-preventive effects were observed for both mania and depression, the effects were more notable for depressive episodes.
In placebo-controlled clinical studies in Japan, the period to study discontinuation due to the recurrence of mood episodes was significantly longer in the groups administered lamotrigine.
In studies where placebo or lamotrigine was added for patients who were receiving lithium treatment for depressive conditions, the period to recurrence of depression was significantly longer in the groups with lamotrigine, indicating the efficacy of combination lithium and lamotrigine therapy.
Caution must be exercised to minimize the occurrence of critical skin disorders, such as Stevens–Johnson syndrome or toxic epidermal necrolysis (Lyell syndrome). These skin disorders were found at a high rate in cases where the administration initiation dose was higher than the recommended dose, cases of rapidly increased dose, and cases of combined treatment with valproic acid. In using lamotrigine, a small starting dose and gradual increase of the dose are recommended.
Valproic acid (off-label use)
In an RCT of valproic acid with lithium as a control drug for patients with bipolar I disorder, efficacy was not observed for the time to recurrence of any mood episode, which was the outcome measure. The dropout rate for valproic acid was significantly lower than that for placebo, which suggests the preventive effects of valproic acid.
In contrast, in a study where the preventive effects of lithium, valproic acid, and combined therapy with lithium and valproic acid were compared (the BALANCE study) in bipolar I disorder, the recurrence risk was significantly lower in the lithium and combination groups compared with the valproic acid group. No significant difference was found between the combination group and the lithium group.
Carbamazepine (off-label use)
Carbamazepine tended to be more effective for recurrence prevention than placebo, but the result was not significant. Although its maintenance effect was comparable to lithium, the dropout rate was higher with carbamazepine.
Olanzapine (off-label use)
In two RCTs where the effects of olanzapine in maintenance therapy were compared with placebo, olanzapine prevented recurrences of all episodes.[41, 54] The preventive effects for manic episodes were higher than for lithium and the preventive effects for episodes of depression were not different from lithium.
Quetiapine (off-label use)
In an RCT where quetiapine was compared with lithium and placebo, the period to recurrences of all episodes was significantly longer in the quetiapine group than the placebo group.
In studies where quetiapine was added to lithium or valproic acid, the addition of quetiapine significantly decreased the recurrence rate.[55, 56]
Risperidone (off-label use)
Although it was a small number of cases, in a study on maintenance therapy where a depot injection form of risperidone was added to the current treatment, the recurrence rate was significantly lower with depot risperidone compared with the control group.
Aripiprazole (off-label use)
In a 26-week study of aripiprazole with a placebo control, preventive effects were found. In the other RCT where aripiprazole or placebo was added to patients who showed no reaction to lithium or valproic acid alone, preventive effects were found. In post-hoc analyses, preventive effects were found when combined with lithium, but not with valproic acid. In an RCT of 24 weeks of maintenance therapy where aripiprazole or placebo was added to valproic acid, no significant difference was observed between the groups for the period to recurrence. In an RCT of 52 weeks of maintenance therapy where aripiprazole or placebo was added to lamotrigine, the aripiprazole group tended to have a longer period to the recurrence of manic psychosis or mixed episodes but the difference was not significant (P = 0.058).
Others (off-label use)
For other new drugs or supplements, there is no drug demonstrating robust efficacy as maintenance therapy.
Because there are no data that long-term administration of benzodiazepines positively impacts the long-term course of bipolar disorders and because therapeutic dose dependency is also present, these drugs should not be used without thought. They may be used for treating anxiety disorders temporarily.
If insomnia occurs due to stress or other factors during maintenance therapy and the risk of the recurrence is a concern due to the sleep disorder, a benzodiazepine sleep-inducer may be used temporarily but these drugs should not be used for a long period.
3. Guidelines for lithium treatment
Serum lithium concentrations should be measured. In addition to the time of treatment initiation, the concentration is measured during maintenance therapy at least two to four times a year. Additionally, measurements should be conducted at dose increases, recurrences, at the start of combination treatment with a drug where an interaction is suspected, during complicated physical disease, for suspected incompliance of taking the drug, upon the appearance of side-effects, or for suspected intoxication.
For blood concentrations, a trough level (the lowest level) is desirable for the measurement. The concentration may be measured before taking the morning dose in many cases. In particular, levels from blood that was collected at times when the concentration is unstable immediately after taking the drugs should not be used.
The therapeutic concentration is 0.4–1.0 mEq/L as a standard. Although the better efficacy is observed with higher levels (0.8–1.0 mEq/L) than that with lower levels (0.4–0.6 mEq/L), the side-effects are stronger. When prevention is possible with a low dose, it is preferable. In cases where a low dose is insufficient, a higher dose should be considered.
Because rapid discontinuation of lithium increases the risk of recurrence, when discontinuing lithium therapy, the dose should be decreased slowly over a period of 2–4 weeks or longer.
Side-effects of lithium treatment, including reduced renal concentration ability, hypothyroidism, hyperparathyroidism, and increased bodyweight, may occur. Glomerular filtration rate, thyroid-stimulating hormone, and blood calcium concentrations are useful for screening.
4. Psychosocial treatment
Although the main treatment for bipolar disorders is drug therapy, for the acceptance of drug therapy, it is essential for patients to obtain knowledge of the disease and to nurture accepting attitudes of the disease. In this regard, it is important to conduct psychoeducation. To prevent recurrence, it is particularly effective to instruct patients to visit a physician when initial signs of recurrence are noticed.
Among psychosocial treatments, those that were shown to be effective for preventing the recurrence of bipolar disorders are (group) psychoeducation,[65, 66] interpersonal–social rhythm therapy, family-focused therapy, and cognitive behavioral therapy.[69, 70] In addition, there is a report that meta-analyses reveal no maintenance effects of cognitive behavioral therapy.
However, the efficacy of psychoanalysis and client-centered therapy (counseling) has not been proven.
5. Bipolar II disorder
In the case of bipolar II disorder, the clinical judgment of maintenance treatment is difficult in comparison with bipolar I disorder, and thus case-by-case decisions should be made. In cases with frequent severe depressive conditions and family history of bipolar I disorder, maintenance treatment may be considered.
Although the diagnostic criteria for bipolar II disorder have not been changed since DSM-IV in 1994, the range of the patients diagnosed with bipolar II disorder in clinical settings may have expanded. Therefore, it is unknown whether the data from previous clinical studies can be applied to current patient populations. There have only been a few clinical studies specializing in bipolar II disorder and the evidence to date is insufficient. Efficacy is suggested for lithium, lamotrigine, and carbamazepine. Although studies recommending treatment with SSRI alone exist, there are opinions expressing concern about manic switch or condition worsening.
For psychosocial treatments, it is reported that psychoeducation and interpersonal–social rhythm therapy are effective for bipolar II disorder, with no clear evidence related to differences with bipolar I disorder.
6. Rapid cyclers
A comparison between lithium and valproic acid showed no difference in effects.
In a placebo-controlled RCT of lamotrigine, there was no difference of time to additional pharmacotherapy, whereas the dropout rate was low. This suggested a possibility of effectiveness.
An RCT suggested that quetiapine was effective for rapid cyclers compared to valproic acid. In post-hoc analyses of clinical studies on quetiapine in maintenance therapy, the quetiapine group of rapid cycling patients with bipolar I disorder showed a significantly longer period to recurrence than the placebo group.
Because tricyclic antidepressants are known to induce rapid cycling, it is necessary to discontinue these drugs. Other drugs that may induce rapid cycling include L-dopa, other dopamine agonists, and estrogen.
Hypothyroidism (decrease of serum T4 or free T4 level) is a reported risk factor for rapid cycling, and thus the administration of thyroid hormone may be effective for refractory rapid cyclers.
There is evidence that taking lithium and valproic acid during the first 3 months of pregnancy increases malformation risks. Thus, in principle, contraception is needed when patients are taking these drugs. Carbamazepine, lamotrigine, and atypical antipsychotic drugs have not been established as safe in pregnancy.
In cases where the patient desires to become pregnant or deliver, it is necessary to discuss the risks and benefits of several options with patients and their spouses: continuing the same dose, changing the dose, completely discontinuing the drugs, and temporarily discontinuing but resuming the drugs.
Note: This guideline is intended to be a reference for the treatment of bipolar disorders. Actual clinical practice should be conducted based on the discretion of the individual physician. In clinical practice, many factors influence clinical decision-making. Thus, it is not appropriate to state that certain clinical practices are outside the medical standards when the treatment is not conducted according to this guideline.
Committee for Treatment Guidelines of Mood Disorders: Tsuyoshi Akiyama,1 Toshiaki Furukawa,2 Ryota Hashimoto,3 Teruhiko Higuchi,4 Shigenobu Kanba,5 Tadafumi Kato,6 Toshihide Kuroki,7 Kuniaki Maekubo,8 Masaru Mimura,9 Hitoshi Miyaoka,10 Nobutaka Motohashi,11 Kazuyuki Nakagome,4 Soichiro Nomura (Chairman),12 Tetsuro Ohmori,13 Norio Ozaki,14 Nobuhiro Sugiyama,15 Takeshi Terao,16 Koichiro Watanabe,17 Yoshifumi Watanabe,18 Kazuo Yamada,19 and Shigeto Yamawaki.20
Writing assistance provided by: Yasuo Araki,16 Kentaro Kohno,16 Shinjiro Goto,16 Tomofumi Miura,5 and Keisuke Motomura.5
Department of Psychiatry, NTT Medical Center Tokyo, Tokyo
Department of Health Promotion & Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka
National Center of Neurology and Psychiatry, Tokyo
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka
RIKEN Brain Science Institute, Saitama
Hizen Psychiatric Center, Saga
Maekubo Clinic, Osaka
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo
Department of Psychiatry, Kitasato University School of Medicine, Kanagawa
Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi
Department of Psychiatry, National Defense Medical College, Saitama
Department of Psychiatry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya
Department of Psychiatry, Shinshu University School of Medicine, Nagano
Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita
Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi
Department of Psychiatry, Tokyo Women's Medical University, Medical Center East, Tokyo
Department of Psychiatry and Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima
The conflicts of interests among the authors (Japan Medical Association Guideline 2012) are as follows: Tadafumi Kato, none; Shigenobu Kanba lectures (Astellas, Asahi Kasei, Mitsubishi Tanabe, GlaxoSmithKline, and Mochida), scholarships (Shionogi and GlaxoSmithKline) and research funded by Ono Pharmaceutical; Takashi Terao, lectures (GlaxoSmithKline, Otsuka Pharmaceutical, Pfizer, Eli Lilly Japan, and Meiji Seika Pharma); and Kazuo Yamada, lectures (GlaxoSmithKline).